Comprehensive pharmacy review- Notes

1. Drug Product Development Introduction Active pharmaceutical ingredient (API): component that produces pharmacological activity (drug substance). May be produced by chemical synthesis, from natural product, enzymatic reaction, recombinant DNA, fermentation, etc. New chemical entity (NCE): drug substance with unknown clinical, toxicological, physical, chemical properties. According to the FDA, NCE is an unapproved API. Drug product: finished dosage form containing API and excipients. Generic drug products: after patent expiration of brand drug. Therapeutically equivalent to the brand and has the same drug amount in the same dosage form. Must be bioequivalent (same rate and extent of absorption)  same clinical results. May differ from brand in excipients (tablets only unless safety studies are done) or physical appearance. Abbreviated New Drug Application (ANDA): submitted to the FDA for approval of generic drugs. Preclinical safety and efficacy studies are not required. Human bioequivalence is needed (on healthy human volunteers). Chemistry, manufacturing and controls for generics are similar to the brand. Specialty drug products: existing products developed for new delivery system or new therapeutic indication. Safety and efficacy studies are not required. Example nitroglycerin transdermal patch after sublignual tablets.

New drug approval Preclinical (animal safety / pharma)  IND  Phase I (healthy human safety)  Phase II (↓# patients)  Phase III (↑# patients)  NDA  FDA green light for marketing Phase IV (scale up)  Phase V (continuous improvements). Preclinical stage: animal pharmacology and toxicology to determine safety and efficacy. Formulation is not final. Phase I: Submit an Investigational New Drug (IND)  clinical studies on healthy volunteers to determine toxicity and tolerance. For oral drugs  simple hard gelatin capsule. Phase II: small number of patients under close supervision. Dose-response studies to determine optimum dosage for treatment. Determine the therapeutic index (toxic dose/effective dose). Develop final drug formulation (bioequivalent to that used in initial clinical studies). Start chronic toxicity studies for 2 years in 2 species. Phase III: large-scale multicenter clinical studies with final dosage form (from phase II) to determine safety and efficacy in patients. Watch for new, rare, toxic or side effects. NDA submission: FDA satisfaction with safety and efficacy for marketing. Phase IV: scale-up in preparation for marketing. Only minor modifications on the formulation are allowed. Phase V: continuous drug product improvements after marketing.

Product development New chemical entities Preformulation: Physical and chemical characterization of the drug and dosage form during preclinical phase. Includes general properties (particle size / shape, polymorphism, crystalline structure, density, surface area, hygroscopicity), solubility (dissolution, pH-solubility profile, various solvents), chemical properties (surface energy, pH stability profile, pKa, temperature stability, excipient interactions), stability analytical methods. Formulation development: continuing process. Injections: final formulation is developed in preclinical phase, stability in solution is critical, few excipients allowed, no bioavailability for IV. Topicals / local: final formulation developed in phase I, study release in in vitro diffusion cell models, local irritation and systemic absorption are the issues. Topicals / systemic: drug delivery through skin / mucosa / rectum, final formulation in phase III.

Oral drugs: final formulation in phase II. Final product considerations: size, shape, color, taste, skin feel, viscosity, physical appearance, production equipment / site.

Product line extensions: Dosage forms with change in physical form or strength but not use or indication. Usually occurs during Phases III, IV, V. Regulatory approval: based on stability, analytical / manufacturing controls, bioequivalence studies, clinical trials Solid products: Different strength in a tablet or capsule form  only bioequivalence required (simplest case). Easier if in vitro dissolution / in vivo bioavailability correlation exists. Modified release: clinical trials required. If new indication  new NDA and new efficacy studies. Liquid products: If an extension of a liquid  same as above for solids If an extension of a solid  if big difference in extent / rate of absorption  new clinical trials.

Preapproval inspections Manufacturing facility is inspected prior to NDA / ANDA approval or after a major reported change to NDA / ANDA. Includes: general cGMP inspection, reviews documentation, verifies traceability of information to documentation, consults the chemistry / manfucaturing / control (CMC) section of NDA / ANDA, make a final recommendation.

Scale-up and post-approval changes (SUPAC) Guidelines to  # of manufacutring changes that require preapproval by the FDA. Examples: minor formulation changes, change site of manufacture, batch size  or , change manufacturing process / equipment. 1. Very minor changes not requiring approval are reported in an annual report. Examples: compliance with guidance, label description, deletion of colorant, expiration date extension, ∆ container / closure type (not size), analytical method 2. Changes being effected supplement: minor changes but require some validation, documentation. A supplement but no pre-approval is required. Examples: new specs, label changes on clinical info, different cGMP manufacturing facility but same process. 3. Preapproval supplement: major changes require specific preapproval. Examples: adding or deleting an ingredient, relaxing specs, deleting a spec or method, method of manufacture, in-process controls. Therapeutic and Bio-equivalence: must be shown for any change. Minor change  comparable dissolution profiles. Major change  in vivo bioequivalence study.

GMPs Minimum requirements for manufacturing, processing, packing, or holding drugs. Include criteria for personnel, facilities, processes to ensure final product has the correct identity, strength, quality, purity. Quality Control (QC): department responsible for establishing process and product specifications. The QC dept test the product and verifies specs are met. This includes acceptance / rejection of incoming raw materials, packaging components, water, drug products, environmental conditions. Quality Assurance (QA): a department that determines that the systems and facilities are adequate and that written procedures are followed.

2. Pharmaceutical Calculations and Statistics Fundamentals of measurement and calculation Inverse proportion: the inverse of the ‘scissors’ method is used in case of dilutions. Example: 100 ml of 10% solution is diluted to 200 ml, what is the final concentration? Inverse ‘scissors’  200/10 = 100/x  5%. Aliquot: used when the sensitivity of the measurement device is not great enough for the required measurement. Example: balance sensitivity is 6 mg, accuracy is +/-5%  minimum weighable quantity is: 5/100=6/x = 120 mg. If you need to weigh 10 mg drug  add a diluent to get a final concentration of 120 mg drug in the diluted mixture (120x120 = 1440 mg)  then weigh 120 mg of the diluted mixture. Systems of measure: Apothecaries’ system of fluid measure, Apothecaries’ system for measuring weight, Avoirdupois system for measuring weight (pound, ounce, grain=65 mg), metric system.

Children doses First choice: body weight or mass and mg/kg dosing. Fried’s rule for infants: (age in month / 150) x adult dose Clark’s rule: (weight in lb / 150) x adult dose Child’s dosage based on body surface area: (BSA in m2 / 1.73) x adult dose

Percentage, ratio strength, concentrations Percentage w/v, Percentage v/v, Percentage w/w, Ratio strength Be careful 3 g drug in 27 g water is 10% solution (3/30) BUT 3 g drug in 30 g water is 9% (3/33). Molarity: number of moles of solute dissolved in 1 liter of solution Molality: number of moles of solute dissolved in 1 kg of solution. Advantage over molarity: using weight avoids problems with volume expansion or contraction upon the addition of solutes. Normality: is the number of equivalent weights of solute per liter of solution. Equivalent weight = atomic weight or molecular weight / valence. Preferred way of expressing concentration of acids, bases and electrolytes. One equivalent is the quantity that supplies or donates one mole of H+ or OH-. One equivalent of acid reacts with one equivalent of base. Mole fraction: ratio of number of moles of one component to the total moles of a mixture or solution.

Dilution and concentration Constant amount of drug  volume is inversely proportional to concentration. Quantity1 x concentration1 = quantity2 x concentration2. Allegation medial: method for calculating average concentration of a mixture of two or more substances. Allegation alternate: method for calculating number of parts (relative amounts) of two or more components of known concentration to be mixed when final concentration is known. IMPORTANT. See example is page 16. Dilution of alcohols: alcohol + water  volume contraction. Use w/w instead of v/v for accuracy. Percentage strength: of concentrated acids is expressed in w/w. For diluted acid  w/v. To determine the volume of concentrated acid for dilution, use specific gravity.

Electrolyte solutions Divalent: calcium, ferrous, magnesium, sulfate. Trivalent: aluminum, ferric, citrate. All others are monovalent.

Milliequivalents (mEq) Definition: amount in mg equivalent to a solute equal to 0.001 of its gram equivalent weight. Unit used to express concentration of electrolytes

Milliosmoles (mOsmol) Osmotic pressure is directly proportional to the total number of particles in solution. Unit for measuring osmotic concentration: mOsmol.

For non-electrolytes: 1 millimole = 1 mOsmol (1 molecule = 1 particle) For electrolytes: number of particles depends on degree of dissociation. Example: completely dissociated KCl  1 millimole = 2 mOsmol (2 particles, K and Cl for each molecule). Example: completely dissociated CaCl2  1 millimole = 3 mOsmol ↑ solute concentration  ↑ interaction between dissolved particles  ↓ actual osmolar concentration compared to ideal osmolar concentration.

Isotonic solutions Isosmotic: solution with the same osmotic pressure. Isotonic: solution with the same osmotic pressure as body fluids. Hypotonic: solution with ↓ osmotic pressure than body fluid (opposite is hypertonic) Preparation of isotonic solutions Colligative properties (e.g. freezing point depression) are representative of the number of particles in solution. Dissolve 1 g MWt of non-electrolyte in 1 L of water  depression of freezing point by -1.86 C. For electrolytes: freezing point depression = -1.86 x number of species produces upon dissociation. Freezing point depression of body fluids = -0.52 C. Take dissociation of weak electrolytes into account. In weak solutions, every 2 ions produce 1.8 ions, every 3 ions produce 2.6 ions (about 10% loss). NaCl equivalents Definition: the amount of NaCl that is equivalent to the amount of particular drug in question. Isotonic fluid: 0.9% NaCl. Example: NaCl equivalent for KCl to 0.78  1 gram KCl = 0.78 g of NaCl. Calculating amount of NaCl required to adjust isotonicity: calculate the total amount of NaCl required (volume x 0.9%)  calculate the NaCl equivalent of all substances in the solution  calculate and add the difference as NaCl or another material (as NaCl equivalent).

Statistics Frequency distribution: classify individual observations into categories corresponding to fixed numeric intervals (interval frequencies)  plot number of observations in each category versus category descriptor. Normal distribution: bell-shaped (Gaussian) curve. Estimates of population mean: the population mean is the best estimate of the true value. Sample mean: arithmetic average. Accuracy: degree to which measured value agrees with true value. Error (bias): difference between measured value and true value. Median: midmost value of a data distribution (average of two midmost values if even number of observations). Normal distribution  median = mean. Median is less affected by outliers or skewed distribution. Mode: most frequently occurring value in a distribution, it is useful for non-normal distributions especially bimodal distributions. Estimates of variability: infinite # of observations  population variance. Finite # of observations  sample variance. Range: useful to describe variability only in very small number of observations. Standard deviation: square root of variance. Precision (reproducibility): degree to which replicate measurements made exactly the same way agree with each other (expressed as relative standard deviation). Standard deviation of the mean (standard error): estimate of variability or error in the mean obtained from N observations. SE = SD/(sq. root of N). Used to establish confidence intervals.

3. Pharmaceutical Principles and Drug Dosage Forms I. Intermolecular forces of attraction Atoms vary in electronegativity, so, electron sharing between atoms will be unequal. So, the molecule behaves like a dipole over a covalent bond. Dipole moment (mu) = distance of charge separation X charge Nonpolar molecules: perfect symmetry and dipole moment = zero. Example: carbon tetrachloride.

When the negative pole of a dipole approach the positive pole of another  molecular attraction called “dipole-dipole interaction”. If similar poles approach  molecular repulsion (intermolecular repulsive forces)

Types of intermolecular forces of attraction Van der Waals forces (liquids) Induced dipole induced dipole (London dispersion force): when a transient dipole in a nonpolar molecule induces another transient dipole in another molecule. Force = 0.5-1 Kcal/mole Dipole-induced dipole (Debye induction force): A transient dipole is induced by a permanent dipole. Force = 2 Kcal/mole Permanent dipole (Keesom orientation force): 4 Kcal/mole Hydrogen bonds Hydrogen ions are small and have a large electrostatic field, so it approaches highly electronegative atoms (O, F, Cl, N, S) and interact electrostatically to form a hydrogen bond. Force = 5 Kcal/mole. Ion-ion, ion-dipole, ion-induced dipole Force of positive-negative ion interaction in the solid state = 150 Kcal/mole. Covalent and ionic forces are much stronger than van der Waals forces.

States of matter Gases Molecules move in straight path at high speed until they randomly collide with another molecule, creating pressure. Intermolecular forces ~ zero. Ideal gas law: Pressure (P) x Volume (V) = number of moles (n) X Molar Gas Constant (R) X Temperature (T) Gases in pharmacy: anesthetics (nitrous oxide, halothane), compressed oxygen, liquefiable aerosol propellants (nitrogen, CO2, hydrocarbons, halohydrocarbons), ethylene oxide for sterilization of heat labile objects. Volatile liquids (ether, halothane, methoxyfurane) are used as anesthetics. Amyl nitrite (volatile liquid) is inhaled as a vasodilator in acute angina. Sublimation: a solid is heated directly to the gaseous or vapor state (or vice versa, also called deposition) without passing through the liquid state. Examples: camphor, iodine. Liquids Van der Waals intermolecular forces are sufficient to impose some ordering. Hydrogen bonding  cohesion in liquids. Surface and interfacial tension Molecules at the surface of the liquid experience a net inward pull from the interior and they tend to contract. This makes liquids assume a spherical shape as it is the volume with minimum surface and least free energy. Surface free energy / surface tension: the work required to  the surface area A of the liquid by 1 unit area. Example: SFE for water = 72 mN/m. Interfacial tension: at the surface of two immiscible liquids. Viscosity Viscosity = shear stress / shear rate Non-Newtonian viscosity: exhibit shear dependent or time dependent (apparent) viscosity. Shear dependent viscosity: Shear thickening (dilatancy) as in suspensions of small deflocculated particles with high solid content. Shear thinning (pseudoplastic): as in polymer solutions. Plastic (Bingham body): as in flocculated particles in concentrated suspensions that have yield value. Time dependent viscosity: yield value of plastic systems may be time dependent. Thixotropic systems are shear thinning but they do not recover viscosity after shear is removed, i.e., structural recovery is slow

compared to structural breakdown. It occurs in heterogenous systems with three dimensional structural network (gel-sol transformation). Negative (anti)thixotropy: viscosity  with  shear up to an equilibrium (sol-gel transformation). Solids High intermolecular forces. Crystalline solids: fixed molecular order, distinct melting point, anisotropic (properties are nto the same in all directions). Amorphous solids: randomly arranged molecules, nondistinct melting point, isotropic (properties are the same in all direction). Polymorphs: substance has more than one crystalline form. Different molecular arrangments / crystalline lattice structure, melting point, solubility, dissolution rate, density, stability. Polymorphs are common in steroids, theobroma oil, cocoa butter. Latent heat of fusion: heat absorbed when 1 g of solid melts.

III. Physicochemical behavior Homogenous systems Solution: homogenous system in which a solute is molecularly dispersed or dissolved in a solvent. Nonelectrolytes: substances that do not form ions in solution, e.g., estradiol, glycerin, urea, sucrose. Solution doesn’t conduct electricity. Electrolytes: form ions in solutions. Solution conducts electricity. Can be strong (completely ionized in water; HCl, NaCl) or weak (partially ionized; aspirin, atropine).

Colligative properties: Depend on the total number of ionic and nonionic solute molecules in solution. They are dependent on ionization but independent of other chemical properties of the solute. Vapor pressure depression: (Raoult’s law): partial vapor pressure is equal to the product of the mole fraction of the component in solution and the vapor pressure of the pure component. Boiling point elevation and freezing / melting point depression Osmotic pressure: Osmosis is the process by which solvent molecules pass through semipermeable membrane from dilute solution to concentrated solution. That is because solvent molecules have lower chemical potential in concentrated solution. Osmotic pressure is the pressure that must be applied to solution to prevent the flow of pure solvent. It is defined by the van’t Hoff equation.

Electrolyte solutions and ionic equilibria +

Arrhenius dissociation theory: an acid is a substance that liberates H (donates protons) in water, a base liberates OH (accpets protons). Lowry Bronsted theory: applies to both aqueous and + nonaqueous systems. In water, a free proton combines with water forming hydronium ion (H3O ). A strong acid in water can behave as a weak acid in a different solvent. Lewis theory: defines acid as a molecule or ion that accepts an electron pair from another atom. A base donates an electron pair to be shared with another atom. pH is the negative logarithm of molar H+ concentration. As pH , H+ concentration  exponentially. Ionization: is the complete separation fo the ions in a crystal lattice when the salt is dissolved. Dissociation: is the separation of ions in solution when the ions are associated by interionic interactions. For weak electrolytes, dissociation is reversible. According to the law of mass action,  concentration of dissociation products results in  dissociation. pKa is the dissociation constant of a weak acid. pKb is used for weak bases. Acids and bases that can accept or donate more than one proton will have more than one dissociation constant. Henderson-Hasselbalch equation: describes the relationship between ionized and nonionized species of a weak electrolyte (base is UP). pH = pKa when [dissociated species] = [nondissociated species], i.e., 50% ionization. Solubility of a weak electrolyte varies as a function of pH. Solubility of a weak acid  with  pH. Opposite is true for weak bases.

Buffer: a mixture of salt with acid or base that resists changes in pH when small quantities of acid or salt are added. Buffer is a combination of weak acid and its conjugate base (salt) (more common), or a weak base and its conjugate acid (salt). Buffer capacity: is the number of gram equivalents in an acid or base that changes the pH of 1 liter buffer by 1 unit. Maximum buffer capacity occurs when pH = pKa. Higher concentration of buffer constituents  buffer capacity due to the  acid or base reserve.

Heterogenous (disperse) systems: Suspension: two phas system that is composed of solid material dispersed in a liquid. Particle size is > 0.5 mm. Emulsion: heterogeneous system that consists of one immiscible liquid dispersed in another as droplets. Droplets diameter > 0.1 micron. Emulsions are inherently unstable because the droplet tend to coalesce. An emulsifying agent is used to prevent coalescence. In ideal (not real) dispersion, the dispersed particles are uniform in size and do not interact. Stokes’s law defines Sedimentation rate. The rate  with  particle size and the difference in density between particles and medium. The rate  with  medium viscosity. High particulate (dispersed phase) concentration leads to  particle collision and  aggregation, coalsecnce, instability. Avoidance of particle-particle interactions: if particles have similar electrical charge (e.g. from the surfactant). Zeta potential (magnitude of the charge) is the difference in electrical potential between the particle charged surface and dispesion medium. When zeta potential is high ( attractive forces, which results in deflocculation and stability. Coalescence of droplets in O/W emulsions is  by electrostatic repulsion of similarly charged particles. Creaming: is the reversible separation of a layer of emulsified particles. Mixing or shaking may be sufficient to reconstitute the emulsion. Phase inversion: from o/w to w/o emulsion or vice versa.

IV Chemical kinetics and drug stability Degradation rate depends on concentration, temperature, pH, solvents, additives, light, radiation, catalysts (polyvalent cations), surfactants, buffers, complexing agents. Order of reaction: the way in which the concentration affects rate. Zero order: rate is independent of concentration, e.g., 5 mg/hr, i.e., straight line concentration vs. time. First order: rate depends on the first power of concentration, e.g., 5% / hr. Concentration  exponentially with time. Straight line log concentration vs. time. t1/2 = 0.693/k, t90% = 0.104/k. Half life is concentration independent. Temperature:  T   reaction rate (Arrenius equation). Solvent: may change pKa, surface tension, viscosity, reaction rate, etc. Additional reaction pathways may be created (e.g. aspirin in ethanol). pH: H+ catalysis occurs at  pH, OH- catalysis occurs to  pH. Rate constant at intermediate pH range is usually lower than at  or  pH. pH of optimum stability (point of inflection) is measured. Aromatic esters (benzocaine, procaine, tetracaine)  t1/2 is presence of caffeine due to complex formation.

Modes of pharmaceutical degradation: Hydrolysis: most common. Occurs for esters, amides, lactams. H+ and OH- are the most common catalysts. Esters easily hydrolize and should be avoided in liquids. Oxidation: by oxygen in the air or in solvent. Oxidizable compounds should be packed in an inert atmosphere (nitrogen or CO2). Oxidation involves free radical mechanism and chain reaction. Free radicals take electrons from other compounds. Antioxidants react with free radicals by providing electrons. Antioxidants include: ascorbic acid, tocopherols, sodium bisulfite, sodium sulfite, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate. Photolysis: degradation in sunlight or room light. Molecules may absorb the proper wavelenght of light (usually 50% of total weight. Content uniformity: USP standards apply if drug 20 um  do not reach bronchioles. Particles 2-6 um  reach alveolar ducts. Particles 1-2 um  retained in the alveoli. Particles < 0.6 um  exhaled, not deposited. Transdermal (percutaneous): suitable for small lipid soluble molecules (clonidine, nitroglycerin, fentanyl, scopolamine, testosterone, estradiol). Local activity: topical antibiotics, anti-infectives, antifungals, loacal anesthetics. Minimum systemic absorption.

Biopharmaceutical principles Physicochemical properties Drug dissolution: bioavailability rate limiting step for drugs with limited solubility. Diffusion is described by Noyes Whitney equation (similar to Fick’s law). Drug solubility in a saturated solution is a static equilibrium property. Dissolution rate is a dynamic property with a rate. Particle size / surface area: inversely related.  surface area   dissolution rate. For some hydrophobic drugs,  particle size  aggregation to  surface free energy. To prevent aggregate formation, small particles are molecularly dispersed in PEG, PVP (povidone), dextrose. Examples: Griseofluvin molecular dissolution in water soluble carrier (PEG 400)   bioavailability. Partition coefficient: ratio of solubility at equilibrium in nonaqueous solvent (n-octanol) to that in aqueous solvent (water). Hydrophilic drugs ( water solubility)  dissolution. Ionization: ionized form is more polar and more water soluble. Based on Henerson-Hasselbalch equation. Salt formation: type of salt affects dissolution, bioavailability, duration of action, stability, irritation, toxicity. Soluble salt may be  stable than nonionized form (e.g. sodium aspirin vs. aspirin). Effervescent forms: contains acid drug and sodium bicarobnate, tartaric acid, citric acid. Water is added prior to use. Excess sodium bicarbonate forms an alkaline solution in which the drug dissolves. CO2 is formed by the decomposition of carbonic acid. For weak acids, potassium and sodium salts are more soluble than polyvalent cation salts. For weak bases, common water soluble salts include hydrochloride, sulfate, citrate, gluconate. Polymorphism: ability to exist in > 1 crystalline form. Polymorphs have different physical properties. Amorphous non-crystalline forms have  dissolution. Chirality: drug exists as optically active stereoisomers or enantiomers  different PK / PD. Most chiral drugs are used as racemic mixtures. Example: ibuprofen has R and S enantiomers, only S is active. Hydrates: drug may exist in hydrated, solvated form and anhydrous form. Anhydrous ampicillin dissolves faster than hydrated ampicillin. Complex formation: Chelates are complexes involving a ring-like structure and a metal. Natural chelates: hemoglobin, cyanocobalamin, insulin). Tetracycline forms a chelate with polyvalent metal ions   water solubility   absorption. Many drugs adsorb strongly on charcoal or clay (kaolin, bentonite) by forming complexes. Theophylline + ethylene diamine   water soluble complex (aminophylline). Many drugs are complexed with cyclodextrins to  solubility. Large drug complexes (drug-protein) do not cross cell membranes easily  free drug must first dissociate for absorption or glomerular filtration.

Delivery system formulation Complex formulation  bioavailability issues. For oral solid dosage forms, dissolution is the rate limiting step. For CR or SR, release from the delivery system is the rate limiting step.

Solutions: are homogeneous mixtures of solutes dispersed molecularly in a dissolving medium. Aqueous solution is the most bioavailable and consistent form (no dissolution). Oral solutions are used as reference preparations for solid oral forms. Elixir (drug dissolved in hydroalcoholic solution) has  bioavailability. Alcohol  solubility. However, drug may ppt when elixir is diluted in the GI with food, but absorption is still rapid because of  surface area. A viscous drug solution (syrup) may  mixing, dilution and GI gastric emptying. Suspensions: bioavailability from suspension is similar to solutions due to  surface area. Suspending agents: hydrophilic colloids (celluloses, acacia, xantham gum).  viscosity may have issues as syrups above. Capsules: Hard gelatin caps are simple (contain powders) and preferred new drugs early clinical trials. Soft gelatin caps contain nonaqueous solution, suspension or powder. It may have  bioavailability if water miscible vehicle is used (e.g. lanoxicaps), and vice versa. Aging and storage may affect gelatin shell moisture content and bioavailability. Compressed tablets:  ratio of excipients : drug   possiblity of excipients affecting bioavailability. Lubricants are usually hydrophobic, water-insoluble   drug surface wetting   dissolution and bioavailability. Surfactants  dissolution and bioavailability. Modified release dosage forms: products that alter the rate or timing of drug release. More stringent quality control is used. Dose dumping, abrupt drug release, is a problem. Allows  in dosing frequency. They provide more flat consistent plasma concentration that avoids toxicity and lack of efficacy. A loading dose may be used. Delayed release control the timing of release, e.g. enteric coating. Transdermals: have occlusive backing film to prevent TEWL to  hydration and permeation. Concentration gradient is maintained by a drug reservoir. Targeted drug delivery: place the drug at or near the receptor (e.g. specific cell such as tumor, organ, tissue). Systems include macromolecular drug carriers (proteins), liposomes, nanoparticles, monoclonal antibodies. Inserts and implants: drug is impregnated into a biodegradable material and released slowly. Inserted into vaginal, buccal cavity, skin. Example: l-norgestrol implant is inserted in the upper arm for 5-year contraception.

6. Basic Pharmacokinetics Introduction Rates and orders of reactions Reaction rate: velocity of the reaction Reaction order: way in which the drug (reactant) affects the rate Zero order reaction: drug concentration changes with time at a constant rate. Rate constant = Ko (concentration / time; mg/ml/hr). Linear correlation of concentration vs. time with slope=Ko and intercept = Co. First order reaction: change of concentration with time is the product of the rate constant and concentration of the remaining drug. Drug concentration decreases by a fixed percent in each time unit. Linear correlation of log concentration with time. Rate constant )K) = 1/hour. Half life t1/2=0.693/k.

Models and compartments Model: mathematical description to express quantitative relations in a biological system. Compartment: group of tissues with similar blood flow and drug affinity.

Drug distribution Drugs distribute quickly to tissues with ↑ blood flow Drug cross capillaries by passive diffusion and hydrostatic pressure. Drugs easily cross the capillaries of the kidney glomerulus. Brain capillaries are surrounded by glial cells forming a thick lipid membrane (BBB)  ↓ diffusion of polar and ionic hydrophilic drugs. Tissue accumulation due to drug/tissue physicochemical or affinity. Lipid soluble drug  accumulate in adipose (fat) tissue

Tetracycline  accumulate in bone (calcium Complexation). Plasma protein binding: results in a big complex  can’t cross membranes. Albumin: major plasma protein for drug binding. Alpha1-glycoprotein: binds basic drugs (e.g. propranolol) in the plasma. ↑ bound drugs (e.g. phenytoin) can be displaced by other ↑ bound drug  ↑ free unbound drug  in effect / toxicity.

One-compartment model Intravenous bolus injection Very rapid drug entry. Rate of absorption is negligible. Entire body is one compartment  all tissue equilibrate rapidly. Drug elimination: first order kinetics. Elimination rate constant = renal excretion rate constant + metabolism (biotransformation) rate constant Some controlled release oral drugs have zero absorption rate constant. Apparent volume of distribution (Vd): hypothetical volume of body fluid in which drug is dissolved. Vd is needed to estimate amount of drug in the body (Db) relative to concentration in plasma (Cp). Cp = Db / Vd More drug distribution into tissues  ↓ Cp  ↑ Vd

Single oral dose Rapid absorption then elimination, both with first order kinetics. Time to reach max concentration (tmax) depends only on absorption and elimination rate constants but not on Vd or Db. AUC: calculated using trapezoidal rule by integrating the plasma drug concentration over time. AUC depends on Do, Vd, elimination K but not absorption K. Lag time: at the beginning of systemic drug absorption, e.g. due to delay in gastric emptying.

Intravenous infusion Absorption: zero order. Elimination: first order (when infusion stops) Steady state concentration (Css): target plateau drug concentration where fraction of drug absorbed = fraction of drug eliminated. Loading dose (DL): initial IV bolus dose to produce Css as rapidly as possible. Start IV infusion at the same time. DL: amount of drug that, when dissolved in the apparent Vd, produces the desired Dss. Reaching 07% of Css without DL takes ~ t1/2. Time to reach Css depends on the drug elimination half life. IV infusion: ideal for drugs with narrow therapeutic window (controls Cp).

Intermittent intravenous infusion Drug is infused for short periods to prevent accumulation and toxicity. Used for aminoglycosides (e.g. gentamicin).

Multiple doses Drug is given intermittently in multiple-dose regimen for continuous or prolonged therapeutic activity to treat chronic disease. Give new dose before previous dose completely eliminated  Cp accumulation  ↑ to Css. ∞ At steady state: Cp fluctuations between a max and a min (C min-max). Superposition principle: assumes that previous drug doses have no effect on subsequent doses  total Cp = cumulative residual Cp from each previous dose. Dosing rate = dose size (Do) / dose interval (e.g. X mg/hr). ∞ Same dosing rate  same average Css but may be different (C min-max). Some AB  multiple rapid IV bolus injections. Oral immediate release drug products (multiple doses)  rapid absorption, slow elimination. Maintenance dose (DM): after loading dose to maintain Cp at Css. If DM dosing interaval = elimination t1/2  DL = 2 x DM

Multi-compartment models Drug distributes into different tissue groups at different rates. Tissues with ↑ blood flow equilibrate rapidly with the drug. Two-compartment model (IV bolus): First, rapid distribution into highly perfused tissue (central compartment)  rapid decline in Cp (distribution phase). Both are first-order processes. Then, slow distribution into peripheral tissues (tissue compartment)  slow decline in Cp after equilibration (elimination phase). Vd = Vd at steady state + central + tissue compartment volumes. Two-compartment model (oral): two-compartment ONLY if absorption is rapid but distribution is slow. Models with additional compartments: example of a third compartment: deep tissue space. If frequent interval dosing  third compartment accumulation. Elimination rate constant: two constants; one for elimination from central compartment, the other for elimination after complete distribution.

Nonlinear pharmacokinetics Also known as capacity-limited, dose-dependent, or saturation PK. Result from the saturation of an enzyme of carrier-mediated system. Do not follow first-order kinetics as the dose ↑. AUC or drug excreted in urine are not proportional to dose Elimination t1/2 may ↑ at ↑ doses. Michaelis-Menten equation: describe velocity of enzyme reactions in nonlinear PK. It described rate of change of Cp after IV bolus. If Cp is ↑  the equation is a zero-order rate of elimination. If Cp is ↓↓  first-order. Note that first-order PK = linear PK

Clearance Total body clearance (ClT) ClT = drug elimination rate / Cp = K x Vd ClT and Vd are independent variables. T1/2 is a dependent variable. A constant volume of the Vd is cleared from the body per unit time. First order PK: ClT = renal clearance + non-renal (hepatic) clearance ↓ ClT  ↑ t1/2. ↑ Vd  ↑ t1/2

Renal drug excretion Major route of elimination for: polar drugs, water-soluble drugs, drugs with ↓ MWt ( 1  filtration + active tubular secretion.

Hepatic clearance Volume of drug-containing plasma cleared by the liver per unit time. Measurement of hepatic clearance (ClH) Main mechanism for non-renal clearance. Measured indirectly (difference between total and renal clearance). ClH = hepatic blood flow x extraction ratio. Extraction ratio: drug fraction irreversibly removed by an organ or tissue as the drug-containing plasma perfuses the tissue. Blood flow, intrinsic clearance, protein binding All these factors affect hepatic clearance. Blood flow: to the liver is ~ 1.5 L/min. After oral GI absorption  to mesenteric vessels  to hepatic portal vein  through the liver  to hepatic vein  to systemic circulation. Intrinsic clearance: ability of the liver to remove the drug independent of blood flow due to inherent ability of the biotransformation enzymes (oxidases) to metabolize the drug as it enters the liver. This is affected by enzyme inducers (Phenobarbital, tobacco) and inhibitors (cimetidine, lead). Protein binding: bound drugs are not easily cleared by the liver or kidney. Only free drug crosses the membrane into the tissue and is available to metabolizing enzymes. Biliary drug excretion Active transport (secretion) process. Separate systems for weak acids and weak bases. Excretes ↑ MWt drugs (>500) or polar drugs (digoxin, reserpine, glucuronide conjugates). Drugs may be recycled by enterohepatic circulation. GI absorption  mesenteric vessels  hepatic portal veins  liver  secrete to the bile  store in gallbladder  empty into the GI through the bile duct (recirculation). First pass effect (pre-systemic elimination) Portion of oral drugs may be eliminated before systemic absorption due to rapid drug biotransformation by liver enzymes. Measure absolute bioavailability (F). If F < 1  some drug was eliminated before systemic absorption. Common for drug with high liver extraction ratio. If ↑ first-pass effect  ↑ dose (e.g. propranolol, penicillin), different route (e.g. nitroglycerin, insulin), or modified dosage form (e.g. mesalamine).

Non-compartment models Some PK parameters can be estimated with non-compartment methods using comparison of the AUCs. Mean residence time (MRT): average time for the drug molecules to reside in the body. Called Mean Transit Time or Sojourn Time. It depends on the route of administration. Assumes elimination from the central compartment. MRT = total residence time of all drug molecules in the body / total number of drug molecules. Mean absorption time (MAT): difference between MRT and MRTIV and an extravascular route. Clearance: volume of plasma cleared of the drug per unit time. Steady-state volume of distribution (Vss): amount of drug in the body at steady sate and the average steady-state drug concentration.

Clinical pharmacokinetics The application of PK principles to the rational design of an individualized dosage regimen. Objectives: maintenance of an optimum drug concentration at the receptor site to produce effect for the desired period, and minimization of SE.

Toxicokinetics Application of PK principles to the design, conduct, and interpretation of drug sate evaluation studies. Used to validate dose-related exposures in animals in preclinical drug development to predict human toxicity.

Clinical toxicology: study of SE of drugs and poisons. PK in intoxicated patient (↑↑ dose) may be very different from a patient taking therapeutic doses.

Population pharmacokinetics Study of sources and correlation of variability in drug concentration in the target patient population. Includes PK and non-PK parameters such as age, gender, weight, creatinine clearance, concomitant disease.

7. Bioavailability and bioequivalence Definitions Bioavailability: measurement of the rate and extent to which the active moiety becomes available at the site of action. It is also the rate and extent of active drug that is systemically absorbed. Bioequivalent drug products: a generic drug product is considered bioequivalent to the reference brand drug product if both products are pharmaceutical equivalents and have statistically the same bioavailability for the same dose, in the same chemical form, similar dosage form, by same route of administration, under same experimental conditions. Generics: requires abbreviated NDA for FDA approval after patent expiration. Must be a therapeutic equivalent but may differ in shape, scoring, packaging, excipients, expiration dates, labeling. Pharmaceutical equivalents: drug product that contain the same active drug, same salt, ester or chemical form, same dosage form, identical in strength and route of administration. May differ in release mechanism, shape, scoring, packaging, excipients. Reference drug product: usually the currently marketed brand name with full NDA and patent protection. Therapeutic equivalent drug products: are pharmaceutical equivalents that can be expected to have the same clinical effect and safety profile under same conditions. Pharmaceutical alternatives: are drug products that contain the same therapeutic moiety but are different salts, ester or complexes or are different strength or dosage forms (tablet vs cap, instant release vs SR).

Bioavailability and bioequivalence Acute pharmacologic effect Examples: change in heart rate, blood pressure, ECG, clotting time, Forced Expiratory Volume (FEV1). Alternative to plasma concentration when that is not possible or inappropriate. Measure effect vs. time. Onset time: time from drug administration till achieving the minimum effective concentration (MEC) at the receptor site as evidenced by pharmacological response. Intensity: proportional to the # of receptors occupied by the drug up to a maximum pharmacological effect, which may occur before, at or after peak drug absorption. Duration of action: time for which the drug concentration remains above MEC. Therapeutic window: concentration between the MEC and minimum toxic concentration (MTC). As concentration ↑  other receptor interactions lead to SE. In vitro test (e.g. dissolution) can be used instead if statistical correlation to in vivo data has been established. Example: dermato-PK for topical drugs for local effect.

Plasma drug concentration Most common method for measuring systemic bioavailability. Time for peak plasma concentration (Tmax): relates the rate constant for drug absorption and elimination. Absorption depends on the dosage form and formula, while elimination is only drug dependent. Peak plasma concentration (Cmax): Cmax at Tmax relates to the intensity of pharmacological response. Ideally Cmax should be within the therapeutic window. AUC vs time: relates the amount or extent of systemic drug absorption. AUC is calculated using the trapezoidal rule, expressed as mg.hr/ml

Urinary drug excretion Accurate method if the active moiety is excreted unchanged in ↑ quantities in urine. Cumulative amount of active drug excreted in urine is related to extent of systemic drug absorption. Rate of drug excretion is related to rate of systemic absorption. Time for complete excretion relates to the total time for complete systemic absorption and excretion.

Relative and absolute bioavailability Relative bioavailability: systemic availability of the drug from a dosage form as compared to reference standard given by the same route. It is a ratio of the AUCs (maximum is 1 or 100%). Very important for generic bioequivalence studies. Absolute bioavailability (F): fraction of drug that is systemically absorbed. It’s the ratio of AUC for oral dosage form / AUC for IV. A parenteral IV drug solution has F = 1.

Bioequivalence for solid dosage forms Design of bioequivalence studies Guidance provided by Division of Bioequivalence, Office of Generic Drugs, FDA. All studies are done with healthy subjects. Fasting study: blood samples are taken at zero time, and appropriate intervals to obtain adequate description of concentration vs. time profile. Food intervention study: required if bioavailability is known to be affected by food. Give products immediately after a standard high fat content breakfast. Multiple dose steady-state study: required for extended release products in addition to single-dose fasting and food intervention study. Measure three consecutive days of trough concentrations (Cmin) to ascertain steady state. Last morning dose is given after overnight fast, continue fasting for 2 hours. Take blood samples. In vitro bioequivalence waiver: a comparative in vitro dissolution may be used instead for some immediate release oral dosage forms. No bioequivalence study is required for certain solution products (oral, parenteral, ophthalmic).

PK data evaluation Single dose studies: calculate AUC to last quantifiable concentration, AUC to infinity, Tmax, Cmax, elimination rate constant (K), elimination half life (t1/2). Multiple dos studies: steady state AUC, AUC to last quantifiable concentration, Tmax, Cmax, Cmin, % fluctuation (Cmax-Cmin / Cmin).

Statistical data evaluation Drug considered bioequivalent if difference from reference is < -20% or +25%. ANOVA is done on log transformed AUC and Cmax data. The 90% confidence interavals of the means of AUC and Cmax should be 80-125% of the reference product.

Drug production selection Generic drug substitution It’s dispensing generic drug in place the prescribed product. The substituted drug has to be a therapeutic equivalent. Prescribability: current basis for FDA approval of therapeutic equivalent generic product. It’s measurement of average bioequivalence where test and reference population means are statistically the same. Switchability: assures that the substituted product produces the same response in the individual patient. It’s the measurement of the individual bioequivalence including intra-subject variability and subject-byformulation effects.

Therapeutic substitution The process of dispensing a therapeutic alternative. For example: dispensing amoxicillin for ampicillin. The substituted drug is usually in the same therapeutic class (e.g. calcium channel blockers) and is expected to have a similar clinical profile.

Formulary issues A formulary is a list of drugs. Positive formulary: lists all drugs that may be substituted. Negative formulary: lists drugs which can’t be substituted. Restrictive formulary: lists only drugs that may be reimbursed without justification by the prescriber. States provide guidance for drug product selection through formulary. FDA annually publishes Approved Drug Products with Therapeutic Equivalence Evaluations (the “Orange Book”). It is also published in the USP/DI Volume III. Orange Book Codes: A Rated: drug products that are considered therapeutically equivalent. B Rated: drug products that are not considered therapeutically equivalent. AB Rated: products meeting bioequivalence requirements.

8. Organic Chemistry and Biochemistry Organic chemistry Functional groups affect hydrophilicity, lipophilicity, reactivity, shelf life, stability, biotransformation, metabolism.

Alkanes Also called paraffins, saturated hydrocarbons. General formula: R-CH2-CH3. Lipid soluble. Common reactions: halogenation, combustion. Chemically inert to air, heat, light, acids, bases. Stable in vivo.

Alkenes Also called olefins, unsaturated hydrocarbons. General formula: R-CH=CH2. Lipid soluble. Common reactions: addition of hydrogen or halogen, hydration (to form glycols), oxidation (to form peroxides). Volatile alkenes and peroxides may explode in presence of O2 and spark Stable in vivo. Hydration, peroxidation, reduction may occur.

Aromatic hydrocarbons Based on benzene. Exhibit multicenter bonding. Lipid soluble. Common reactions: halogenation, alkylation, nitration, sulfonation. Chemically stable. In vivo: hydroxylation, diol formation.

Alkyl halides Halogenated hydrocarbons. General formula: R-CH2-X. Lipid soluble. ↑ degree of halogenation  ↑ Solubility. Common reactions: dehyro-halogenation, nucleophilic substitution. Stable on the shelf. Not readily metabolized in vivo.

Alcohols Contains OH group. May be primary (R-CH2-OH), secondary (R1/R2-CH-OH), or tertiary (R1/R2/R3-COH). Alcohols are lipid soluble. Low molecular weight alcohols are water soluble. ↑ hydrocarbon chain length  ↓ water solubility.

Common reactions: oxidation, esterification. Oxidation: primary alcohol  aldehyde  acid. Secondary alcohol  ketone. Tertiary alcohol  not oxidized. Stable on shelf. In vivo: oxidation, sulfation, glucuronidation.

Phenols Aromatic compounds containing OH groups directly connected to aromatic ring. Monophenols  one OH. Catechols  two OH. Phenol (carbolic acid): water soluble. ↑ ring substitution  ↓ water solubility. Most phenols are lipid soluble. Common reactions: with strong bases to form phenoxide ion, esterification with acids, oxidation to form colored quinones. On the shelf: oxidation with air or ferric ions. In vivo: sulfation, glucuronidation, aromatic hydroxylation, o-methylation.

Ethers General formula: R-O-R. Lipid soluble. Partially water soluble. ↑ hydrocarbon chain  ↓ water solubility. Common reaction: oxidation to form peroxides (may explode). In vivo: o-dealkylation. Stability ↑ with size of alkyl group.

Aldehydes General formula: R-CHO (contains a carbonyl group C=O). Lipid soluble. Low molecular weight aldehytes are also water soluble. Common reactions: oxidation (to acids, in vivo and in vitro) and acetal formation.

Ketones General formula: R-CO-R (contains a carbonyl group C=O). Lipid soluble. Low molecular weight ketones are also water soluble. Nonreactive and very stable on the shelf. In vivo: some oxidation or reduction.

Amines Contain an amino group (-NH2). Primary (R-NH2), secondary (R1/R2-NH), tertiary (R1/R2/R3-N), quaternary (R1/R2/R3/R4-N+ X-). Lipid soluble. Low molecular weight amines  water solubility. ↑ branching  ↓ water solubility (primary amines and most soluble). Quaternary amines (ionic) and amine salts are water soluble. Common reactions: oxidation (air oxidation on shelf), salt formation with acids. Aromatic amines are ↓ basic  ↓ reactive with acids. In vivo: glucuronidatin, sulfation, methylation. 1ry oxidative deaminatin. 12y/2ry  acetylation. 2ry/3ry  dealkylation.

Carboxylic acids General formula: R-COOH (Carboxyl group –COOH). Lipid soluble. Low molecular weight acid and Na/K salts  water soluble. Common reactions: salt formation with bases, esterification, decarboxylation. Very stable on shelf. In vivo: conjugation (with glucuronic acid, glycine, glutamine), beta oxidation.

Esters General formula (R-COOR). Lipid soluble. Low molecular weight esters are slightly water soluble. Common reaction: hydrolysis to form carboxylic acid and alcohol (in vivo by esterases / in vitro).

Amides General formula: R-CONH2 or R-CONR1/R2 (lactam form). Lipid soluble. Low molecular weight amides are slightly water soluble. No common reactions. Very stable on shelf. In vivo: enzymatic hydrolysis by amidases in the liver.

Biochemistry Amino acid and proteins Monomeric units of protein (peptide bonds). Formula: NH2-CH-R/-COOH. Proteins are made of 20 AA, differ in R side chain (alpha (C)). Protein hydrolysis to AAs by acids, bases, enzymes. + AA ionize (depending on pH) to zwitterions structure (NH3 -CH-COO /R)  ↓ water solubility, ↑ melting point. Levels of protein structure: primary, secondary (alpha/beta), 3ry, 4ry.

Carbohydrates Polyhydroxy aldehydes or ketones Monosaccharides: simple single unit sugars, e.g., glucose, fructose. Oligosaccharides: short chains of monosaccharides joined covalently, e.g. sucrose (has to convert into glucose, fructose before GI absorption), maltose (hydrolyzed by maltase into 2x glucose), lactose (milk sugar, has to convert into galactose, glucose before GI absorption). Polysaccharides: long chains of monosaccharides, e.g., cellulose, glycogen.

Pyrimidines and purines Bases  bond with ribose  nucleosides  bond with phosphoric acid  nucleotides  building blocks of nucleic acid. Exhibit tautomerism (isomerism): can be keto or enol. Pyrimidines bases: cytosine, uracil, thymine. Purine bases: adenine, guanine DNA bases: thymine, cytosine, adenine, guanine RNA bases: uracil, cytosine, adenine, guanine.

Biopolymers Enzymes Linked amino acid chains (proteins)  catalysts for biological reactions. They reactions’ ↓ activation energy but do not change reaction equilibrium point, are used up or changed in the reaction. May require cofactors or coenzymes. Cofactor: inorganic (metal ion) or nonprotein organic molecule. Prosthetic group: cofactor firmly bound to apoenzyme (protein portion of a complex enzyme). Coenzymes: organic cofactor that is not firmly bound but actively involved in catalysis. Holoenzyme: complete catalytically active enzyme system. Lyases: removes functional group (deaminase, decarboxylase). Ligases: bind two molecules (e.g. DNA ligase  2 nucleotides). Isomerases: change DL, cistrans, vice versa. Polysaccharides Also called glycans. Long chain polymers of carbohydrates. Homopolysaccharides: Contains one type of monomeric units. Starch  plant’s reserve food, two glucose polymers (linear water soluble amylose, and branched water insoluble amylopectin), enzymatic hydrolysis  maltose (glucose disaccharide). Glycogen  branched D-glucose chain, polysaccharide storage in animal cells (liver, muscles). Cellulose  water soluble, in plant cell wall, linear D-glucose chain, can’t be digested (hydrolyzed) by humans.

Heteropolysaccharides: contains two or more monomeric units. Heparin  acid mucopolysaccharide with sulfate derivatives, contains glucosamine, in lung tissue, used to prevent clotting. Hyaluronic acid  in bacterial cell wall, virteous humor, synovial fluid, contains glucosamine. Nucleic acids Linear polymers of nucleotides  pyrimidine and purine bases linked to ribose or deoxyribose sugars (nucleosides) and bound to phosphate groups. Phosphodiester bonds: join successive DNA / RNA nucleotides. DNA: compared to RNA it lacks an OH group and contains T rather than U. (DT, RU). DNA: two complementary alpha helical strands coiled to form double helix. Hydrogen bonding between specific base pairs hold the strands together. Hydrophobic bases are on the inside of the helix. Hydrophilic deoxyribose phosphate on the outside. Backbone: alternating phosphate and pentose units with a purine or pyrimidine attached to each. Strong acids associated with cellular cations and basic proteins (histones, protamines). rRNA (ribosomal): in ribosomes. mRNA (messenger): the template for protein synthesis  specifies the polypeptide amino acid sequence. tRNA (transfer): carries activated amino acids to ribosomes for incorporation to the growing polypeptide chain.

Biochemical metabolism Factors affecting metabolism: substrate concentration, enzymes, allosteric (regulatory) enzymes, hormones, compartmentation. Catabolism: degradation reactions that release energy for useful work (e.g. mechanical, osmotic, biosynthetic). Anabolism: biosynthetic (build-up) reactions that consumer energy to form new biochemical compounds (metabolites). Amphibolic pathways: may be used for anabolic or catabolic purposes. Example: Krebs cycle, it breaks down metabolites to release 90% of the organism’s energy, but it also uses metabolites for form compounds such as AA.

Bioenergetics Substrate level phosphorylation: forms one unit of ATP per unit of metabolite, no oxygen required. Oxidative phosphorylation: forms 2 or more ATP per unit of metabolite. Uses oxidoreductase enzymes (e.g. dehydrogenases) using cofactors NAD (nicotinamide A dinucleotide) or FAD (flavin). Energy released from the reaction is used to form ATP in the mitochondria.

Carbohydrate metabolism Catabolism: releases energy from carbohydrates. Glycogenolysis: breakdown of glycogen into glucose phosphate in the liver, skeletal muscles  controlled by glucagon and epinephrine. Glycolysis: breakdown of sugar phosphates (e.g. glucose, fructose, glycerol) into pyruvate (aerobically) or lactate (anaerobically) to produce energy (ATP) Anabolism: consumes energy to build complex from simple molecules Glycogenesis: formation of glycogen in the liver and muscles from glucose in diet  controlled by insulin. Gluconeogenesis: formation of glucose from noncarbohydrate sources (e.g. lactate, pyruvate).

Krebs cycle Location: in the mitochondria. Absent in RBCs (no mitochondria) Catabolism: converts pyruvate (glycolysis), acetyl CoA (fatty acid degradation) and amino acids  into CO2 and water with release of energy. Oxygen dependent (aerobic). Anabolism: forms amino acids (aspartate, glutamate) and heme ring from metabolites. Electron transport: accept electrons and hydrogen from oxidation of Krebs cycle metabolites and couples the energy released to make ATP.

Lipid metabolism Catabolism Triglycerides stores in fat cells (adipocytes) are hydrolyzed by hormone-sensitive lipases into three fatty acids and glycerol Fatty acids: broken down by beta oxidation to acetyl CoA  to Krebs cycle  breaks down to CO2, water and energy release. Ketogenesis: very rapid break down of fatty acids leading to formation of ketone bodies (as in DM). Glycerol: enters glycolysis  oxidized to pyruvate  to Krebs cycle  CO2 and water. Steroids: may be converted to bile acids, vitamin D, hormones. Anabolism Fatty acids: formed in the cytoplasm. Unsaturation occurs I the mitochondria or endoplasmic reticulum. Essential fatty acids: linoleic acid (can not be synthesized, diet is only sources). Terpenes: derived from acetyl CoA. Include: cholesterol, steroids, fat soluble vitamins (ADEK), bile acids. Sphingolipids: forms a ceramide backbone with fatty acids. Joins with other compounds to form cerebrosides, sphingomyelin Phosphatidyl compounds: i.e. phosphatidyl choline (lecithin), ethanolamine.

Nitrogen metabolism Catabolism Amino acids: amino group is removed by transaminase. Carbon skeleton is broken down to acetyl CoA or citric acid derivatives  oxidized to CO2 and water for energy. Glycogenic amino acids form glucose as needed by guconeogenesis. Purines: 90% is salvaged, 10% degrade to uric acid using xanthine oxidase. Pyrimidines: breaks down to B-alanine, ammonia, CO2 Anabolism Amino acids: from citric acid cycle intermediates. Essential AA: TIM (threonine, isoleucine, methionine), HALL (histidine, arginine, lysine, leucine), PVT (phenylalanine, valine, tryptophan)  PVT TIM HALL Purines / Pyrimidines: from aspartate, carbamoyl phosphate, CO2, other AA.

Nitrogen excretion Excess nitrogen is toxic  must be eliminated, mainly as urea. Urea synthesis: in the liver using the Krebs-Henseleit pathway. Amino acid  AA transferases (transaminases) + pyridoxine (vitamin B6) as coenzyme  Ammonia  + glutamate  glutamine  + CO2  carbamoyl phosphate  urea cycle  urea. Uric acid synthesis: most purines are salvages. Remaining purines are excreted as uric acid.

9.

Microbiology

Taxonomy and nomenclature Taxonomy Classification or ordering into groups based on degree of relatedness. Bacteria are named using the Linnaean or binomial system (genus species = homo sapiens = human)

Morphology Cultural morphology Based on size, shape and texture or colonies grown inj axenic (pure) cultures Each colony originates from a Colony Forming Unit (CFU) consisting of a single cell or group of adherent cells

Microscopic morphology Based on size, shape and arrangement of bacterial cells

Stains Bacteria are small and transparent  must be stained to be examined by light microscopy Simple Single dye colors the cells (e.g. gentian violet, safranin) Gram Gram-positive = purple Gram-negative = pink Acid-fast Stains only cells that have an outer layer of a waxy lipid (acid-fast) not those lacking that layer (non acidfast) Spore Heat is used to facilitate the dye entering the spore Capsule Two dyes stain the cell and backgrounds allowing the visualization of the unstained capsular material

Bacterial cell shape and arrangement Cocci (spherical) -Chains (streptococci) -Clusters (staphylocci)

-Pairs / diplococci (streptococcus pneumoniae) -Packets

Bacilli Cylindrical rod-shaped (pseudomonads, Escherichia) Coccobacilli (combination of small rods or flattened cocci) Spirochetes (helical like a corkscrew) Fusobacteria (tapered ends and slightly curved) Filamentous (organisms are branching) Vibrios (comma shaped) Pleomorphic (exist in varied forms)

Other parameters Presence or spores, capsules or slime layers Mobility or type of flagella Monotrichous = single flagella at either pole Amphitrichous = flagellum at both poles Lophotrichous = flagella at either or both poles Peritrichous = flagella distributed evenly all around

Structure of the prokaryotic cell Overview Small and simple in design Less complex inside, more complex outside Lack a true nucleus, nuclear membrane or intracytoplasmic membraneous organelles (e.g., endoplasmic reticulum) Cytoplasm is immobile (no endo or exocytosis) Multiply asexually by binary fission (no mitosis) Protein synthesis mediated by 70s not 80s ribosomes Genetic materialsingle supercoiled circular strand of DNA (nucleoid)

External structures Capsule and slime layer Flagella Pili (fimbriae)

Cell wall periplasmic space and cytoplasmic membrane Internal structures

Microbial physiology Metabolism and energy production Genetics

10. Immunology 11. Biotechnology 12. Principles of PD / Med Chemistry Effects of drugs Drug action is the results of interaction between drug molecules and cellular components (receptors)  modulate ongoing cellular processes  alteration of function. Drug receptor: any macromolecular component Physiological receptors: receptors for endogenous ligands. Example: adrenergic receptors for catecholamines. Agonist: drugs that resemble the effects of endogenous molecules. Example: bethanechol stimulates cholinergic receptors. Pharmacologic antagonists: drugs that lack intrinsic activity and produce effects by ↓ action of endogenous molecules at receptors. Competitive: propranolol competes with catecholamines at beta receptors. Noncompetitive: MAO irreversible inhibitor tranylcypromine. Partial antagonist: inhibits endogenous ligand from binding to the receptor but has some intrinsic activity. Example: nalorphine on opiate receptors. Physiological antagonism: drug acts independently at different receptor to produce opposing action. Example: epinephrine and acetylcholine. Neutralizing antagonism: two drugs bind to each other to form inactive compound. Example: digoxinbinding antibody sequesters digoxin.

Mechanisms of drug action Cell surface receptors: can be proteins, glycoproteins or nucleic acids. Can be located at the cell surface, cytoplasm, or inside the nucleus. Receptor binding is very specific. Interactions: van der Waals, ionic, hydrogen, covalent  influence duration and reversibility of drug action. Interaction depends on chemical structure of drug and receptor. Signal transduction by cell-surface receptors: drug receptor binding triggers signal through second messenger or effector in the cycoplasm. Example: isoproterenol binds beta receptor (coupled to adenylate cyclase via stimulatory G protein) ↑ cAMP. Second messengers may cause change in protein synthesis. Signaling mediated by intracellular receptors: drugs bind to soluble DNA-binding protein cytoplasmic receptors  regulate gene transcription. Examples: thyroid hormone, steroid hormones, vitamin D, retinoids. Target cell desensitization / hypersensitization: cellular protective mechanisms exist to maintain homeostasis and prevent overstimulation / understimulation of target cells. Down regulation: occur due to continuous prolonged drug exposure  ↓ receptor #. Desensitization: is the result of down regulation. Effect of subsequent drug exposure is ↓. Example: chronic albuterol use  down regulation of beta receptors  tolerance. Heterogenous desensitization: nonspecific desensitization by altering components of the signaling pathway. Hyperactivity/hypersensitivity: due to long term exposure to antagonists followed by abrupt cessation  new receptor synthesis  upregulation. Pharmacologic effects not mediated by receptors: Colligative drug effects lack requirement for specific structures. Examples: volatile general anesthetics are lipophilic  interact with cell membrane lipid bilayer  ↓ excitability. Cathartics (mg sulfate, sorbitol)  ↑ osmolarity of intestinal fluids. Antimetabolites: structural analogs of endogenous compounds  incorporated into cellular components, examples: methotrexate, 5-fluorouracil, cytarabine. Antacids: such as Al hydroxide, Ca carbonate, Mg hydroxide act by ionic interaction to ↓ gastric acidity

Concentration-effect relationship ↑ dose  ↑ concentration at site of action  ↑ effect  up to a ceiling. Quantal dose-response curve: # of patients exhibiting a defined response by specific drug dose. Bell shaped. Graded dose-response curve: magnitude of drug effect vs. drug dose. Efficacy is measured by the maximum effect. Potency compared different molar doses of different drugs needed to produce the same effect. Log dose-response curve: drug effect vs. log dose. Used to compare efficacy and potency of different drugs with same mechanism of action (same slope). Efficacy; determined by the height of the curve (Emax). Potency: compared using ED50 (dose producing 50% of Emax). Competitive antagonist: parallel shift to the right, same Emax is achieve but at ↑ dose. Noncompetitive antagonist: nonparallel shift to the right, lower Emax (action cannot overcome if more agonist is present).

Enhancement of drug effect Addition: two different drugs with same effect  cumulative effect. Example: trimethoprim and sulfamethoxazole inhibit two different steps in folic acid synthesis  ↓↓ bacterial growth. Synergism: two different drug with same effect  effect is ↑ than cumulative sum. Example: penicillin and gentamicin against pseudomonas. Potentiation: one drug with no effect alone will ↑ effect of another active drug. Example: carbidopa (inactive dopa analog) ↓ degradation of levodopa.

Selectivity of drug action Therapeutic index: TD50/ED50 (median toxic dose / median effective dose). Margin of safety: minimum toxic dose for 0.1% of population (TD0.1) / minimum effective dose for 99.9% of population (ED99.9). More practical

Drug sources and major classes Natural products Alkaloids (x-ine): plant-derived nitrogen containing compounds. Alkaline. Examples: morphine (opium poppy), atropine (belladonna), colchicine (autumn crocus, neutral). Peptides / polypeptides: polymers of amino acids. From humans or animals. Smaller than proteins. No oral activity, short half life. Example: somatostatin, glucagon. Steroids: from humans or animal. Estradiol, testosterone, hydrocortisone. Hormones: chemicals formed in one organ and carried in the blood to another. Mostly steroids or proteins. Made synthetically, by recombinant DNA (insulin) or from animals (thyroid, conjugated estrogens). Glycosides: sugar moiety bound to non-sugar (aglycone) moiety by glycosidic bond. From plant (digitoxin) or microbial (streptomycin, doxorubicin). Vitamins: Water soluble: B1 (thiamine), B2 (riboflavin), B3 (niacin), B6 (pyridoxine), B12 (cyanocobalamin), C (ascorbic acid), folic acid, pantothenic acid, H (biotic). Lipid soluble: A (retinol), D (ergocalciferol), E (alpha-tocopherol), K (phytonadione). Polysaccharides: polymers of sugar from animals or humans (heparin). Antibiotics: penicillin, tetracycline, doxorubicin.

Synthetic products Drugs synthesized from organic compounds. May have chemical structure resembling active natural products (hydroxymorphone  morphine, ampicillin  penicillin). Peptidomimetics: molecules with no peptide bonds, molecular weight < 700, activity similar to original peptide (e.g. losartan).

Drug action and physiochemical properties Drugs must enter and be transported by body fluids. Drugs must pass membrane barriers, escape ↑ distribution to site of loss, penetrate to active site, be removed from active site, metabolized to a form easily excreted. Drug polarity: relative measure of lipid and water solubility. Measured in Partition Coefficient: ratio of solubility in organic solvent to solubility in aqueous solvent (log value). Water solubility: depends on ionic character and hydrogen ion bonding. Nitrogen and oxygen containing functional groups  ↑ water solubility. Required for GI dissolution, parenteral solutions, ophthalmic solutions, good urine concentration. Lipid solubility: ↑ by nonionizable hydrocarbon chains and ring systems. Required for penetrating GI lipid barrier, penetrating BBB, IM depot injectables. Ionization constant (Ka): indicates the relative strength of acids and bases. Expressed in negative log (pKa). Strong acids: HCl, H2SO4, HNO3 (nitric), HClO4 (perchloric), HBr, HIO3 (iodic). Strong bases: NaOH, KOH, MgOH2, CaOH2, BaOH2, quaternary ammonium hydroxides. Weak acids: organic acids containing carboxylic (-COOH), phenolic (Ar-OH), sulfonic (-SO2H), sulfonamide (-SO2NH-R), imide (-CO-NH-CO-), beta carbonyl (-CO-CHR-CO-) groups. Weak bases: organic bases containing amino groups (1ry –NH2, 2ry -NHR, 3ry –NR2) and saturated heterocyclic nitrogen. Aromatic or unsaturated heterocyclic nitrogen are very weak bases  do not form salts. Le Chatelier’s priniciple governs ionization (weak acid at ↓ pH  ↓ ionization  cross lipid membranes). Rule of nines: |pH-pKa|=1  90:10 (1 nine), |pH-pKa|=2  99:1 (2 nines). Salts: virtually all salts are strong electrolytes. Inorganic salts: made by combining drugs with inorganic acids or bases (HCl, NaOH). Salt form has ↑ water solubility  ↑ dissolution. Organic salts: made by combining acidic and basic organic molecules  ↑ lipid solubility  depot injections (e.g. penicillin procaine). Amphoteric salts: contain acidic and basic functional groups  form internal salts or zwitterions  solubility problems. Neutralization reaction: e.g., occur when an acidic solution of an organic salt is mixed with a basic solution. The nonionized organic acid or base will ppt  IV drug incompatibility. Drugs whose cation ends with –onium or –inium and anoic is Cl, Br, I, nitrate, sulfate (e.g. benzalkonium chloride, cetylpyridinium chloride) are quaternary ammonium salts  neural solution in water.

Structure and pharmacologic activity Drug structure specificity Structurally non-specific drugs: drug interaction with cell membrane depends more on the drug’s physical properties than on its chemical structure. Interaction usually depends on cell membrane’s lipid nature and drug’s lipid attraction. Examples: general anesthetics, some hypnotics, some bactericidal agents. Structurally specific drugs: pharmacologic activity depends on drug binding to specific endogenous receptors.

Drug receptor binding Receptor site theories: Lock-key theory: over-simplification that assumes a complete complementary relationship between drug and receptor. Induced fit theory: also assumes a complete complementary relationship between drug and receptor but provides for mutual conformational changes between drug and receptor, it can explain phenomenon of allosteric inhibition. Occupational theory of response: further postulates that intensity of pharmacologic response is proportional to number of occupied receptors. Receptor site binding: ability of a drug to bind to specific receptor is mostly determined by its chemical structure not physical properties. Chemical reactivity influences its bonding ability and exactness of fit to the receptor. Drug interaction is similar to fitting a jigsaw puzzle pieces, only drugs of similar shape and chemical structure can bind and producer response. Usually only a portion of the drug molecule is involved in receptor binding. Pharmacophore: functional group that is critical for receptor interaction. Drugs with similar pharmacophores may have similar qualitative but not quantitative activity. Agonist: good receptor fit  ↑ affinity  ↑ response. Antagonist: drug with some binding but no pharmacophore  no response but it blocks other drugs from binding.

Stereochemistry Types of stereoisomers: optical, geometric, conformational. Optical isomers: contains at least one chiral (asymmetric) carbon (four different substitutes). Enantiomers: optical isomers that are mirror image of each other, identical physical and chemical properties, potentially different potency, receptor fit, activity, metabolism, etc. One enantiomer rotate the plane of polarized light clockwise (dextro, D, +), the other counter clockwise (Leve, L, -). Example: dextrorphanol  narcotic analgesic and antitussive, levorphanl  only antitussive. Racemic mixture: equal mixgture of D and L enantiomers, optically inactive. Diastereomers: stereoisomers which are neither mirror image, nor superimposable. Drug must have a minimum of 2 chiral centers. Different physicochemical properties (solubility, volatility, melting point). Epimers: special type of diastereomers, compounds are identical in all aspects except stereochemistry around one chiral center. Epimerization is important for drug degradation and inactivation. Geometric (cis-trans) isomers: occurs due to restricted rotation around a chemical bond (double bond, rigid ring system). Cis-trans are not mirror images, have different physicochemical and pharmacologic properties, because functional groups can be separated by different distances  not equal fit to receptors. If functional groups are pharmacophores  different biologic activity. Example: cis-diethylstilbestrol has 7% estrogenic activity of trans-diethylstilbestrol. Conformational isomers (rotamers, conformers): non-superimposable molecule orientations due to atoms rotation around single bonds. Common for most drugs, allows drugs to bind to multiple receptors. Example: Ach 2-forms: transmuscarinic, gauche  nicotinic Bioisosteres: molecules containing groups that are spatially and electronically equivalent, same physicochemical properties. Isosteric replacement of functional groups  alter metabolism  ∆ potency, SE, activity, duration of action (e.g. procainamide, an amide, has longer duration of action than procaine, an ester). Isosteric analogs: may act as antagonists (e.g. alloxanthine is a xanthine oxidase inhibitor, compared to its isostere, xanthine, the enzyme substrate).

Mechanisms of drug action Interaction with receptors Agonists: have both affinity and intrinsic activity with the receptor.

Partial agonists: interact with same receptors but with similar affinity but lower intrinsic activity  ↓ response. Pharmacologic antagonists: bind to the same receptor as the agonist but with no intrinsic activity. Can be reversible, irreversible, competitive, noncompetitive (like enzyme inhibitors). Chemical antagonists: two compounds react  inactivation of both. Example: heparin (acidic polysaccharide) with protamine (basic protein), chelating agents as metal poisoning antidotes (EDTA for calcium / lead, penicillamine for copper, dimercaprol for mercury / gold / arsenic). Functional / physical antagonists: produce antagonistic physiologic actions by binding at separate receptors. Example: acetylcholine, NEp.

Interaction with enzymes Activation Due to ↑ enzyme protein synthesis. Examples: barbiturates, antiepileptics (phenytoin), rifampin, antihistamines, griseofulvin, oral contraceptives. Mechanism: by allosteric binding or coezymes such as vitamins (esp vitamin B complex), cofactors (Na, , Mg, Ca, Zn, Fe). Inhibition Due to interaction with the apoenzyme, coenzyme or enzyme. Reversible inhibition: results from non-covalent interaction. Equilibrium exists between bound and free drug. Irreversible inhibition: results from covalent stable interaction. Competitive inhibition: occurs when there is a mutually exclusive binding of the substrate and inhibitor. Noncompetitive inhibition: occurs when the drug binds to an allosteric site on the enzyme.

Interaction with DNA/RNA Inhibition of nucleotide biosynthesis: caused by folate, purine, pyrimidine antimetabolites. Folic acid analogs: e.g. methotrexate, trimetrexate, ↓ dihydrofolate reductase  ↓ purine, thymidylate. Purine analogs: e.g. 6-mercaptopurine, thioguanine, act as antagonists in the purine bases synthesis. Pyrimidine analog: e.g. 5-fluorouracil, ↓ thymidine synthase. Inhibition of RNA/DNA biosynthesis: due to interference with nucleic acid synthesis. Use mainly as antineoplastic agents (Cancer chapter).

Inhibition of protein synthesis Tetracyclines: ↓ tRNA binding to ribosomes and block release of completed peptides from ribosomes. Erythromycin, chloramphenicol: bind to ribosomes, ↓ peptidyl transferase, ↓ formation of peptide bond, ↓ peptide chain formation Aminoglycosides: binding to ribosomes  formation of abnormal protein, ↓ addition of AAs to peptide chain, misreading of mRNA tempelate  incorporation of incorrect AAs in peptide chain.

Interaction with cell membranes Digitalis glycosides: ↓ cell membrane Na-K pump  ↓ K influx, ↓ Na outflow. Quinidine: prolong polarized and depolarized states of membrane potential in myocardial membranes. Local anesthetics: interfere with membrane permeability to Na-K  block impulse conduction in nerve cell membranes. Polyene antifungals: e.g. nystatin, amphotericin B, alter membrane permeability. Antibiotics: e.g. polymyxin B, colistin, alter membrane permeability Acetylcholine: ↑ membrane permeability to cations. Proton pump inhibitors: ↓ H+/K+ pump in parietal cell membranes  ↓ efflux of protons to the stomach.

Nonspecific action Form monomolecular layer over entire areas of cells. Large dose is given. Examples: volatile general anesthetic gases (ether, nitrous oxide), some depressants (ethanol, chloral hydrate), antiseptics (phenol, rubbing alcohol).

13. Autonomic and Central Nervous Systems Receptor summary tables Inhibitory receptors Types: M2, Alpha-2, D2, GABA, Opioid (mu, delta, kappa) Action: ↓ cAMP, ↑ K conductance, ↓ Ca conductance, ↑ Cl conductance (GABA) Mechanism Ganglion blocker ↓ neurotransmitter synthesis ↓ neurotransmitter release ↑ neurotransmitter release ↓ neurotransmitter storage ↓ neurotransmitter metabolism

Organ / tissue Heart Arterioles Eye Lung Urinary bladder Intestine

Uterus Fat (adipose) tissue Glands

Receptor B1 M Alpha-1 Beta-2 Alpha-1 M Beta-2 M Alpha-1 M Alphabeta Apha-1 M Alpha-1 Beta-2 Beta-3 M

Excitatory receptors Types: M1, Nicotinic, Alpha1, Beta-1, D1, Glutamate, H1-2. Action: ↑ cAMP, ↓ K conductance, ↑ Ca (cation) conductance, ↑ IP3/DAG

Adrenergic

Cholinergic Hexamethonium, mecamylamine Bretylium, guanethidine Botulinum toxin Amphetamine, tyramine Reserpine Cocaine, desipramine Not a major mechanism Pargyline (MAOAI), selegiline Neostigmine, physostigmine (MAOBI), tolcapone (COMTI) Action ↑ conduction velocity, ↑ contraction rate /force ↓ conduction velocity, ↓ contraction rate /force Constricts cerebra, cutaneous, visceral arterioles Dilates skeletal muscle arterioles Iris contracts  mydriasis Sphincter / ciliary contraction  miosis Relaxes bronchial / tracheal muscles Contraction, ↑ secretions Contracts sphincter muscles Relax sphincters, contracts smooth muscles. ↓ peristalsis Contracts sphincter ↑ motility (perisalsis), relax sphincters, ↑ secretions Contraction Relaxation Adipolysis, mobilize fatty acids ↑ secretions (eye, sweat, saliva, nasal)

Adrenergic agonists Direct-acting agonists: Examples: Ep, NEp, terbutaline, dobutamine, naphazoline. Alpha agonist: phenhylephrine. Beta agonist: isoproterenol Catecholamine (Ep, NEp) synthesis: Tyrosinse  tyrosine hydroxylase  DOPA  dopa decaroxylase  dopamine  dopamine hydroxylase  NEp  Ep. Catecholamine deactivation: methylation by catechol O-methyltransferase (COMT) and oxidative deamination by monoamine oxidase (MAO). Indirect acting agonists (sympathomimetics): Chemically related to catecholamines. Act by ↑ neurotransmitter release. Examples: amphetamine, tyramine, ephedrine. Post-junctional alpha-1: Location: iris, arteries, veins, hair follicle muscles, heart, GI sphincters. Agonist effect: vasoconstriction, smooth muscle contraction. Examples: phenylephrine. Pre-junctional alpha-2: Effect: ↓ neurotransmitter release, lipolysis, platelet aggregation. Examples: clonidine, methylnorepinephrine. Beta-1: Location: heart. Effect: ↑ force / rate of contraction. Examples: dobutamine. Beta-2: Location: bronchial / vascular smooth muscles. Effect: smooth muscle dilatation / relaxation. Examples: albuterol, terbutaline. Beta-3: Location: fat cells. Effect: lipolysis (for obesity).

Epinephrine: medullary hormone, stimulate all receptors (alpha1-2, beta1-2). Use: treat bronchospasm, hypersensitivity / anaphylactic reactions, ↑ duration effect of local anesthetics (SC), restore cardiac activity in cardiac arrest, glaucoma (topically, vasoconstriction  ↓ aqueous humor production). Norepinephrine: adrenergic neurotransmitter, stimulate alpha1-2, beta-1 (weak beta-2). Phenylephrine: alpha-1 agonist. Use: pressor in hypotensive emergency, ↑ duration effect of local anesthetics, nasal decongestion Alpha-1 agonists for nasal decongestion: phenylephrine, oxymetazoline, xylometazoline, phenylpropanolamine Alpha-2 agonists (clonidine, methyldopa, guanfacine, guanabenz): for ↑ BP. Clonidine is used to ↓ intraocular pressure during surgery. Isoproterenol: beta1-2 agonist, bronchodilator, cardiac stimulant in cardiac shock / arrest. Dobutamine: beta-1 agonist, improve heart function in CHF emergency. Beta-2 agonists (albuterol, terbutaline, metaproterenol): systemic or local bronchodilators for asthma. General SE: arrhythmias, pulmonary hypertension, edema, cerebral hemorrhage, rebound nasal congestion, anxiety.

Adrenergic antagonists Alpha blockers: include ergotamine, prazosin (alpha-1), phenoxybenzamine (nonselecive, irreversible), tolazoline. Beta blockers: similar structure to beta agonists. Examples: metoprolol (beta-1), propranolol (nonselective). Prazosin (x-azosin): vasodilation  for hypertension and BPH symptoms. SE: first dose syncope, de BP, dizziness, drowsiness, palpitation, fluid retention, priapism (continuous penis erection). Phenoxybenzamine / phentolamine: nonselective alpha blockers, treat vasospasm, acute hypertensive emergency (e.g. pheochromocytoma, MAOI, sympathomimetics). SE: ↓ BP, tachycardia, ↓ ejaculation, miosis, nasal congesion. Tolazoline: for neonatal pulmonary hypertension. Labetolol: alpha-1 and beta1-2 blocker, for hypertension. Propranolol: nonselective beta blocker, for prophylaxis of angina pectoris, ventricular arrhythmias, migraine, for hypertension, ↓ heart rate in anxiety and hyperthyroidism. SE: bradycardia, CHF, bronchoconstriction, ↑ triglycerides, ↓ HDL, depression. Sudden d/c is cadiotoxic. B1 blockers (acetbutolol, metoprolol, atenolol): for hypetension, arrhythmia, angina. For glaucoma: eye drops of timolol (B1-2 blocker) and betaxolol (B1 blocker).

Cholinegic agonists Nicotinic receptors: Location: at postganglionic neuroeffector sites. Muscarinic receptors: Location: at all autonomic ganglia and at the neuromuscular junction of somatic nervous system. Acetylcholine: endogenous neurotransmitter, very short half life (v. rapid hydrolysis by AChE), ester of acetic acid and choline, very potent. Direct acting agonists: structurally similar to acetylcholine but more resistant to AChE  longer duration. Examples: methacholine, bethanecol. Use: non-obstructive urinary retention (bethanechol), glaucoma (pilocarpine, miosis). Indirect acting agonists: most are AChE inhibitors. Reversible inhibitors: most are carbamates (carbamic acid esters), e.g. physostigmine, neostigmine, pyridostigmine. Irreversible inhibitors: organophosphate esters, insecticides, nerve gas, e.g. isoflurophate, echothiophate. Use: glaucoma (miosis), myasthenia gravis, hypercholinergic crisis (neuromuscular junction depolarization blockade), anticholinergic toxicity. General SE: bronchospasm, abdominal cramps, ↓ BP, syncope, ↓ heart rate, salivation, sweating, lacrimation, miosis, flushing, tremors, diarrhea.

Cholinegic antagonists Quaternary nitrogen: doesn’t pass BBB, e.g. ipratropium, glycopyrrolate, propantheline. Tertiary nitrogen: pass BBB, e.g. benztropine, dicyclomine, pirenzepine, tropicamide. Uses: ↓ gland / bronchial secretion before anesthesia (atropine, glycopyrrolate), induce sedation / ↓ motion sickness (scopolamine), ↓ vagal stimulation of the heart (atropine), produce mydriasis / cycloplegia (homatropine), ↓ GI spasms (propantheline), asthma (ipratropium), Parkinson’s / extrapyramidal disorders (benztropine, trihexyphenidyl), cholinergic toxicity (atropine).

Ganglionic blockers: e.g. mecamylamine, trimethaphan, for hypertensive crisis. SE: mydriasis, ↑ intraocular pressure, blurred vision, dry mouth, constipation, urinary retention, fever, nervousness, drowsiness, dizziness, tachycardia.

Neuromuscular blockers Nondepolarizing (competitive) drugs Examples (x-curine, x-curonium, x-curium): curare alkaloids (tubocurarine, metocurine, contain a tertiary amine), and synthetic analogs (atracurium, doxacurium, mivacurium, pancuronium, vecuronium, pipercuronium). Mechanism: compete with ACh for nicotinic receptors at the NMJ  ↓ end-palate potential  depolarization potential not reached. Action is overcome by ↑ dose cholinesterase inhibitor. Uses: SE: respiratory paralysis, histamine release, bronchospasm, tachycardia

Depolarizing (noncompetitive) drugs Examples: succinyl choline (pseudo-cholinesterase metabolism  short action), galantamine. Contain quaternary nitrogen. Mechanism: desensitize nicotinic receptors at NMJ. React with nicotinic receptors  long (2 min) depolarization of excitable membrane  ↓ receptor sensitivity  unresponsive. Similar effect to excess ACh. Uses: SE: respiratory paralysis, painful muscle fasciculation, Muscarinic response (bradycardia, ↑ secretion, cardiac arrest).

General anesthetics Effect: depress CNS and induce reversible state of analgesia, amnesia, unconsciousness, ↓ sensory / autonomic reflexes, skeletal muscle relaxation, loss of all sensation. Ideal drug: rapid smooth induction and rapid recovery. General SE: respiratory / CNS / CV depression. Halothane  ↑ sensitivity to catecholamines.

Volatile (inhalation) anesthetics: Examples: simple lipophilic molecules, nitrous oxide (N2O, inorganic), halothane (halogenated HC), ethers (x-flurane, methoxyflurane, isoflurane, desflurane, sevoflurane). Mechanism: absorbed and excreted through the lungs. May be supplemented with analgesics (↓ anesthetic dose), skeletal muscle relaxants, antimuscarinics (↓ bronichial secretions during surgery). Halothane  ↑ heart sensitivity to catecholamines, arrhythmia.

Nonvolatile (IV) anesthetics Water soluble: Ultra-short acting barbiturates (thiopental), ketamine, BZD (diazepam, midazolam), morphine, fentanyl, droperidol. Imidazole: propylene glycol solution. Propofol: emulsion. Use: induce drowsiness and relaxation before inhalational general anesthesia.

Local anesthetics Most are structurally similar to cocaine. Ester drugs: rapid hydrolysis by plasma esterases  short action. Examples: cocaine, procaine, chloroprocaine, benzocaine, tetracaine. Amide drugs: longer acting, liver metabolism. Examples: lidocaine, dibucaine, mepivacaine, bupivacaine, etidoacione, prilocaine. (VELD) Mechanism: block Na channels in nerve membrane  reversible block of nerve impulse conduction, reversible loss of sensation, no loss of consciousness. At tissue pH  lipophilic, uncharged, 2ry or 3ry amine form  diffuse through connective tissue and cell membrane  enter nerve cells  convert to ionized charged ammonium cation active form  block generation of action potential  remain trapped in cell (ionized  can’t cross cell membrane).

Epinephrine: mix with local anesthetic  vasoconstriction  ↓ blood flow  ↓ systemic absorption  longer local effect, no systemic toxicity. Use: regional nerve block for pain relief, anesthesia for minor operations, topical anesthesia (dyclonine and pramoxine as throat lozenges and hemorrhoids cream), anesthesia for lower limb / pelvic / obstetric surgery when injected in the epidural. SE: systemic absorption  seizures, CNS / respiratory / myocardial depression.

Antipsychotics Typical (classical) drugs: phenothiazines, thioxanthines (x-othixene, thiothixene, chlorprothixene), butyrophenones (haloperidol). Atypical (newer) drugs: clozapine, risperidone, pimozide, loxapine, molindone, quetapione, sertindole, remoxipride. Advantages: more effective for negative symptoms, ↓ extrapyramidal SE. Phenothiazines (x-omazine, x-perazine): chlorpromazine, triflupromazine, prochlorperazine, trifluoperazine, fluphenazine, thioridazine. Fluphenazine esters (decanoate, enanthate)  very lipophilic  very long acting. Mechanism: block dopamine receptors in the brain (extrapyramidal SE). Other possible effects: H1, alpha1, muscarinic. Atypical drugs: also serotonin antagonism. SE: Central: drowsiness, extrapyramidal (akathesia, dystonia, akinesia, tardive dyskinesia), poikilothermy, ↑ appetite, weight gain, ↑ release of hormones. Peripheral: postural hypotension, reflex tachycardia, impaired ejaculation, dry mouth, blurred vision, liver toxicity.

Antidepresseants / antimanics MAO-I: phenelzine, isocarboxazid (↓ potent), tanylcypromine (↑ potent). Mechanism: block oxidative deamination of brain biogenic amines (NEp, serotonin). Effect takes 3 weeks. Use: depression, phobic anxiety, narcolepsy, ↑ SE  ↓ use. SE: CNS (stimulation, tremor, agitation, mania, insomnia), ↓ BP, anticholinergic SE (constipation, dry mouth, urinary retention). DI: tyramine foods, sympathomimetic drugs (hypertensive crises), TCA: secondary or tertiary amines, x-ipramine, x-triptyline, x-pin (doxepin, amoxapine, dibenzoxazepine). Mechanism: ↓ CNS re-reuptake of biogenic amines (Nep, serotonin). Also block beta, serotonin receptors, ↓ reuptake. Use: depression, enuresis (bedwetting), obsessive-compulsion, anxiety. SE: CNS (drowsiness, confusion), ↓ BP, tachycardia, anticholinergic SE, bone marrow depression, mania. Atypical antidepressants: bupropion, trazadone, mefazadone, SSRI, venlafaxine. Mechanism: ↓ CNS re-reuptake of biogenic amines. SE: similar to TCA + blurred vision, tinnitus, sex dysfunction. Antimanics (mood stabilizers): lithium carbonate, valproic acid, carbamazepine. Mechanism: lithium ∆ transmembrane Na exchange, ∆ neurotransmitter release, ↓ inositol metabolism. Use: manic depression / bipolar disease. SE: lithium causes ↑ urination, fine hand tremor (↓ with time).

Anxiolytics / sedative-hypnotics Examples: BZD (diazepam, alprozlam, flurazepam, halazepam, oxazepam, prazepam, lorazepam, chlordiazepoxide, clorazepate), buspirone, zolpidem. Old drugs: barbiturates, hydroxyzine  no longer used due to ↑ risk of tolerance, dependence, withdrawal reactions, and ↑ SE (↑ CNS depression). Diazepam: not basic enough to form water soluble salt with acid  dissolve in propylene glycol for IV, may ppt if mixed with water. Barbiturates: derivatives of barbituric acid. Long / branched / unsaturated side chain  ↑ lipid solubility  ↑ metabolism, ↓ onset, ↓ duration of action, ↑ potency. Phenobarbital (barbiturates)  strong enzyme inducer. Weak acids, in overdose  alkalinize the urine  ↑ excretion. BZD: Mechanism: GABA-ergic, ↑ chloride channel opening  ↑ chloride conduction  ↑ membrane hyperpolarization. Also CNS depression (hypnotic, anesthetic, anticonvulsant, muscle relaxant, ↑ alcohol depression). Use: anxiety, insomnia, pre-anesthesia, during acute alcohol withdrawal. SE: CNS depression, ataxia, confusion, abuse / dependence. Buspirone (x-pirone): Mechanism: bind to central dopamine, serotonin receptors. No CNS depression (hypnosis, anti-convulsion, alcohol interaction, no abuse, no rebound anxiety). Use: anxiolytic (effect takes a week). SE: headache, dizziness. Zolpidem (Ambien): Mechanism: strong sedation but ↓ anxiolytic effect (for insomnia). Use: insomnia. No abuse, rebound insomnia, or respiratory depression.

Barbiturate: Mechanism: similar to BZD. Use: Ultra-short acting barbiturates (thiopental): induce anesthesia. Long acting barbiturates (phenobarb): antiepileptics. SE: hypnosis, drowsiness, nystagmus, bradycardia, ↓ BP, anemia, liver toxicity, respiratory depression. DI: enzyme induction Chloral hydrate: aldehyde prodrug. Use: induce sleep, pre-anesthesia. SE: toxic active cumulative metabolite, CNS depression, ↑ alcohol effect, leukopenia. DI: enzyme induction

Antiepileptics Older agents: long-acting barbiturates (phenobarb, mephobarb, metharbital, primidone), phenytoin (hydantoin), succinimides (ethosuximide, phensuximide), valproic acid, trimethadione, dimethadione. Newer agents: carbamazepine, BZD (diazepam, clonazepam, clorazepate), gabapentin (GABA analog), lamotrigine, felbamate. Pharmacology: ↓ or prevent excessive discharge and ↓ spread of excitation from CNS seizure center. Phenytoin: ↑ Na efflux Barbiturates, BZD, valproic acid: ↑ GABA-ergic inhibitory neuronal function. Tonic-clonic (grand mal)  carbamazepine, pheytoin, phenobarb. Uses: Status epilepticus  diazepam, phenytoin, phenobarb Absence (petit mal)  clonazepam, phenobarb, valpric acid Myoclonic  clonazepam Partial  gabapentin, lamotrigine, flebamate Pscyhomotor  carbamazepine, phenytoin, phenobarb General SE: CNS (drowsiness, confusion, diplobia, nystagmus), blood toxicity, allergy, Stevens-Johnson, birth defects (no safe drugs here). Phenytoin: gingival hyperplasia, arrhythmias. IV barbiturates / BZD SE: CV collapse, respiratory depression

14. Autacoids Autacoids are local autopharmacological agents or local hormones. May also function as neurotransmitters (e.g. histamine, serotonin). Also include leukotrienes (discussed later).

Histamine Chemistry: bioamine derived from dietary histidine. H1-antagonists: diphenhydramine, dimenhydrinate, doxylamine, clemastine, meclizine, cyclizine, hydroxyzine, cyproheptadine, promethazine, chlorpheniramine, brompheniramine, tripelennamine, pyrilamine. New H1 antagonists (loratadine, desloratadine, fexofenadine, cetirizine, astemazole, acrivastine) are less sedating due to their inability to cross BBB. H2-antagonists: ranitidine, cimetidine, famotidine, nizatidine. Pharmacology: H1-receptors: allergic and anaphylactic responses (bronchoconstriction, vasodilation, spasmodic GI smooth muscle contraction, ↑ capillary permeability, itching, pain). H2-receptors: ↑ secretion of gastric acid, pepsin, intrinsic factor. Indications: exogenous histamine may be used for diagnosing gastric acid function (not very safe). H1-blockers: ↓ allergy symptoms (seasonal rhinitis, conjunctivitis), common cold (rhinovirus) infection, urticaria. Agents with ↑ anticholinergic effect (meclizine, cyclizine, dimenhydrinate, diphenhydramine): motion sickness and vertigo nausea and vomiting. Promethazine: antiemetic. Hydoxyzine: mild anxiolytic. H2-blockers: gastric hypersecrtion (ulcers, Zollinger-Ellison, GERD). SE: H1-blockers: CNS (sedation, depression, fatigue, except in new agents), GI upset, anticholinergic (dry mouth, constipation). Non-sedating H1-blockers: arrhythmia, especially with hepatic enzyme inhibitors, grapefruit. H2-blockers: CNS (dizziness, confusion), liver / kidney damage, liver enzyme inhibition (cimetidine), androgenic effects (cimetidine).

Serotonin Chemistry: serotonin is 5-HT (5-hydroxytryptamine). Bioamine synthesized from tryptophan. Serotonin agonists (triptans): idole derivatives of serotonin. Also cisapride, benzamide, ergot alkaloids (ergonovine, dihydroergotamine, bromocriptine, methylsergide, partial agonists / antagonists). Serotonin antagonists: ondasetron, granisetron.

Pharmacology: Serotonin: vasoconstriction, platelet aggregation, nausea / vomiting, anxiety, depression, appetite, ↑ acetylcholine release. Serotonin agonists: Cisapride: releases Ach (treat GERD, off market). Serotonin antagonists: prevents nausea / vomiting. Indications: Agonists: drugs use the serotonin system to affect the CNS and modulate behavior (dexfenfluramine as anorexiant, buspirone as anxiolytic, SSRI for depression). Triptans and ergots are used for migraines. Ergots are used to postpartum hemorrhage (vasoconstriction uterine contraction). Bromocriptine is used to prevent post partum breast enlargement. Antagonists: prevents nausea and vomiting due to cancer chemotherapy. SE: Agonists: dizziness, tight chest, coronary vasoconstriction (CI in angina, ↑BP). Cisapride: arrhythmia, diarrhea. Ergots: cold / ischemic extremities, GI upset. Antagonists: headache, dizziness, constipation.

Prostaglandins Chemistry: derivatives of prostanoic acid (ringed structure). Membrance phospholipids  phospholipase A2  arachidonic acid  COX enzyme  PG. COX I: protects gastric mucosa (PG), homeostasis (thromboxane synthesis). COX II: expressed only in response to inflammation or injury. PG classification subscripts relates to the number and position of double bonds in the aliphatic chains. Pharmacology: Endogenous: release in response to insults (chemical, bacterial, mechanical). Cause pain and edema. Physiologic responses: PGI: vasodilation, ↓ platelet aggregation, ↑ gastric release of bicarbonate and mucus (protect epithelium). PGE: ↓ platelet aggregation, ↓ gastric acid secretion, broncho-relaxation. PGD/PGF: bronchoconstriction. Indications: PGE1 analogs: misoprostol to prevent NSAID induced GI ulcers, alprostadil for impotence due to erectile dysfunction. PGE2 analogs: dinoprostone is abortifacient, for cervical ripening in pregnancy. PGF2alpha analogs: latanoprost topically to ↓ intraocular pressure in glaucoma, carboprost is abortifacient (not available in US). PGI analog: epoprostenol treats pulmonary hypertension. SE for PGE: CNS (irritability, fever, seizures, headache), cardiovascular (hypotention, arrhythmia, flushing), respiratory depression, hematologic (anemia, thrombocytopenia), diarrhea, abortion.

16. Endocrinology Pituitary hormones Posterior pituitary hormones Oxytocin: octapeptide. Action: stimulate uterine contraction, induce labor. Use: promote delivery, control postpartum bleeding. SE: uterine spasm / rupture, fetal effects (bradycardia, jaundice), water intoxication / coma. Vasopressin: octapeptide. Action: vasopressor and anti-diuretic. hormone (ADH) activity. It ↑ reabsorption of water at distal renal tubules. Use: neurogenic diabetes insipidus, postoperative abdominal distention. SE: GI cramps, vomiting, tremor, sweating, bronchoconstriction.

Anterior pituitary hormones Protein molecules: available therapeutically, include: corticotropin, thyrotropin, thyrotropin-releasing hormone, growth hormone Corticotropin: also known as Adrenocorticotropic hormone (ACTH). Single chain 39-AA polypeptide. Action: stimulate adrenal cortex to secrete adrenocorticosteroids. Use: diagnosis of adrenal insufficiency. Growth Hormone: also known as Somatotropin, 191-AA chain. Action: stimulate protein, carbohydrate and lipid metabolism to ↑ cell, tissue, organ growth. Use: for children with growth failure due to ↓ endogenous growth hormone secretion. SE: antibody formation. Thyrotropin: also known as Thyroid Stimulating Hormone (TSH). It’s a glycoprotein. Thyrotropin-Releasing Hormone: tripeptide. Pituitary gonadotropins: not available therapeutically, include: Follicle-Stimulating Hormone (FSH), Luetinizing Hormone (LH), Prolactin (Luteotropic Hormone, LH), menotropin (human Menopausal gonadotropin, hMG).

Menotropin: produce ovarian follicular growth and induce ovulation by FSH and LH-like actions. Use: induce ovulation and pregnancy in anovulatory infertile women, ↑ spermatogenesis in men. SE: gynecomastia in men, hypersensitivity, thromboembolism, ovary enlargement.

Gonadal hormones Estrogen Estrogen receptors: in the nucleus in the vagina, uterus, mammary glands, anterior pituitary, hypothalamus  alter mRNA. Uses: oral contraceptives (with progestins), menopause symptoms, acne, osteoporosis, prostate cancer. SE: edema / fluid retention, weight gain, ↑ triglycerides, hypertension, thromboembolism, MI, stroke, GI upset, endometrial cancer. Estradiol: principal estrogenic hormone, in equilibrium with estrone. Estradiol esters are used as IM injections in oil for depot action (valerate, cypionate). The esters hydrolyze slowly in muscle tissue before absorption (prodrugs). Synthetic estrogens: resist first pass metabolism  ↑ oral efficacy. Examples: ethinyl estradiol, 3methyl ether mestranol (contraceptives), quinestrol (ERT). Non-steroidal synthetic estrogens: e.g. diethylstilbestrol. Estrogen antagonists: e.g. clomiphene, tamoxifen citrate, toremifene citrate. Uses: clomiphene  induce ovulation, tamoxifen  breast cancer. Aromatase inhibitors: anastrozole, letrozole (non-steroidal)  ↓ conversion of androgens to estrogens. Use: advanced breast cancer. Selective estrogen receptor modulators (SERM): raloxifene  ↓ bone resorption, ↓ bone turnover. Estrogen effect on bone and lipids but estrogen antagonist effect on uterus and breast. Use: prevention of osteoporosis.

Progestins Progesterone: C-21 natural steroidal progestin. Synthetic progestins: 17alpha-hydroxyprogesterones, 17alpha-ethinylandrogens. ↑ lipid solubility, ↓ first pass metabolism, ↑ oral effect Mechanism: similar to estrogens (intracellular receptors  ∆ mRNA). Uses: oral contraceptives (alone or with estrogens), uterine bleeding, dysmenorrhea, endometriosis. SE: irregular period, breakthrough bleading, amenorrhea, weight gain, edema. 17alpha-hydroxyprogesterones: e.g. medroxyprogesterone acetate, megestrol acetate 17alpha-ethinylandrogens: e.g. norethindrone, norgestrel, androgens with progesterone activity. Used as oral contraceptives.

Androgens / anabolic steroids Testosterone: C-19 steroid natural androgen / anabolic agent. Androgens: testosterone 17-enanthate (ester with long IM action), fluoxymesterone (oral). Anabolics: oxandrolone, dromostanolone. Mechanism: testosterone  5alpha-reductase (in cytoplasm)  dihydrotestosterone  bind to androgen receptor in nucleus  ∆ mRNA Uses: androgen replacement, breast cancer, endometriosis, female hypopituitarism (with estrogens), treating –ve nitrogen balance, anemia. SE: fluid retention, ↑ LDL, ↓ HDL, female masculinity, ↓ female fertility. Anti-androgens: flutamide, bicalutamide, nilutamide (all non-steroids)  competitive androgen inhibition by receptor binding. Use: prostate cancer (with luteinizing hormone releasing hormone). 5alpha-reducatse inhibitors: finasteride  ↓ conversion of testosterone to dihydrotestosterone. Use: BPH, androgenic alopecia.

Adrenocorticosteroids Synthesis: in the adrenal cortex. All steroids have fused reduced 17-carbon-atom ring. Most natural steroids have some mineralo- and gluco- effect. All require cytoplasmic receptors to transfer to the nuclei of target tissue cells.

Uses: replacement therapy (adrenal insufficiency), last resort for severe disabling arthritis, severe allergic reactions, ulcerative colitis, kidney disease, cerebral edema, topical anti-inflammatory. SE: peptic ulcer, GI bleeding, ↑ intraocular / intracranial pressure, headache, muscle weakness, skin atrophy, edema, weight gain, excitation, irritability, hypertension, hyperglycemia, osteoporosis, flushing, hirsutism, cushingoid moon face / buffalo hump, ↓ immunity, ↑ infections. Mineralocorticoids: ↑ Na retention, ↑ K excretion. Glucocorticoids: anti-inflammatory, protein-catabolic, immunosuppressant. Cortisone / hydrocortisone: natural glucocorticoids. Synthetic and semi-synthetic glucocorticoids try to ↓ mineralocorticoid activity. Examples: prednisone, prednisolone, triamcinolone, betamethasone, dexamethasone. Aldosterone: natural mineralocoritoid. Synthetics: fludrocortisone acetate, desoxycoriticosterone acetate.

Antianemic agents Iron Iron preparations: ferrous salts are better absorbed from GI than ferric salts. Examples: ferrous sulfate, ferrous gluconate, ferrous fumarate. Iron dextran (IV) = colloidal complex of ferric hydroxide and low molecular weight dextrans. Iron (ferrous salts): easy GI absorption  stored in bone marrow, liver, spleen as ferritin and hemosiderin  incorporate into hemoglobin  iron reversibly binds molecular oxygen. Iron (ferrous salts): iron deficiency anemia (hypochromic, microcytic RBCs  poor oxygen transport). Cyanbocobalamin (Vit B12): nucleotide-like macro-molecule. Includes cyanide and cobalt. Iron (ferrous salts): GI distress, constipation, diarrhea, heartburn

Vitamin B12 (cyanocobalamin) Vit B12: easy GI absorption in the presence of intrinsic (Castle’s) factor (glycoprotein produced by gastric parietal cells). Deficiency causes megaloblastic anemia and demyelination of nerve cells  irreversible CNS damage. Important for cell growth. Vit B12: megaloblastic anemia due to vit B12 deficiency (hyperchromic, macrocytic, immature RBCs). Vit B12: no common SE

Folic acid Folic acid: structure includes PABA, glutamic acid. Folic acid: easy GI absorption, stored intracellularly. Precursor for several coenzymes (derivatives of tetrahydrofolic acid). Deficiency causes megaloblastic anemia but not neurologic damage. Folic acid: megaloblastic anemia due to folic acid deficiency. Folic acid: rare allergy if taken parenterally.

Thyroid hormones / inhibitors (52) Synthesis of thyroid hormones Concentration of iodide in thyroid gland  iodination of tyrosine residues on thyrogobulin (glycoprotein)  proteolysis of thyroglobulin into T4 (thyroxine, levothyroxine), and T3 (triiodothyronine, liothyronine). T4 is less potent but has longer duration than T3. T4 converts to T3 by peripheral deiodination. Control: involves hypothalamic-pituitary-thyroid feedback. TRH is secreted by hypothalamus  ↑ release of TSH (thyrotropin) by the anterior pituitary  ↑ production of T4/T3 in thyroid.

Thyroid preparations Action: mimic the activity of endogenous thyroid hormones  regulate growth and development, calorigenic and metabolic activity, positive inotropic / chronotropic effects (sensitize beta receptors). Use: hypothyroidism (e.g. Myxedema), Myxedema coma, cretinism, simple goiter, endemic goiter. SE: rare, palpitations, nervousness, insomnia, weight loss. Sodium salts of T4/T3. T4 can be given alone (converts to T3).

Liotrix: 4:1 mixture of levothyroxine sodium to liothyronine sodium, no advantages over levothyroxine only. Thyroid USP: from dried defatted thyroid gland of domestic animals. Standardized based on iodine content. Thyroglobulin: purified extract of frozen porcine or bovine thyroid gland, contains T4 and T3. Thyrotropin (TSH): purified and lyophilized hormone from bovine anterior pituitary. Use: detection and treatment of thyroid cancer. SE: anaphylaxis, urticaria, gland swelling, tachycardia, arrhythmia, GI upset.

Thyroid inhibitors Use: treat hyperthyroidism (e.g. Grave’s disease, toxic adenoma). Ionic inhibitors: such as thiocyanate (SCN-) and perchlorate (ClO4-), inorganic monovalent anions  ↓ concentration of iodide by the thyroid. Use: rarely use as drugs, but metabolism of foods (e.g. cabbage) and drugs (e.g. nitroprusside) can produce excess SCN-. ↑ concentration iodides: such as Lugol’s solution, iodides ↓ their own transport, ↓ synthesis of mediators, ↓ hormone release. Use: before thyroid surgery to make gland firmed and ↓ its size. SE: Iodism (↑ salivation, skin rashes, eyelid swelling, sore gum/teeth/larynx/pharynx). 131 Radioactive iodine ( I) sodium: trapped by thyroid gland  incorporated into tyrosine / thyroid hormone. Radioactive beta particles  local destruction of thyroid cells. SE: delayed hypothyroidism. 131 Thiourylenes: ↓ thyroid synthesis. Examples: propylthiouracil, methimazole. Use: with I to control mild hyperthyroidism. SE: urticaria, dermatitis, blood toxicity, joint pain / stiffness.

17. Drug Metabolism and Interactions Drug metabolism Definition: drug metabolism (or biotransformation) is the biochemical changes drugs an foreign chemicals (xenobiotics) undergo in the body leading to formation of metabolites. Inactive metabolites: examples: hydrolysis of procaine to p-aminobenzoic acid, oxidation of 6mercaptopurine to 6-mercapturic acid. Metabolites with similar activity: examples: codeine is demethylated to morphine (↑ activity), acetohexamide is reduced to l-hydroxyhexamide (↑ activity), imipramine demethylated to desipramine (same activity). Metabolites with altered activity: retinoic acid (vitamin A) is isomerized to anti-cancer agent isoretinoic acid, antidepressant iproniazid is dealkylated to anti-TB isoniazid. Bioactivated metabolites (prodrugs): enalapril hydrolyzed to enalaprilat, suldinac is reduce to the active sulfide, levodopa is decarboxylated to dopamine.

Biotransformation pathways Phase I reactions Polar functional groups are introduced to the molecule, or unmasked by oxidation, reduction, hydrolysis. Oxidation: Most common reaction. Mostly in the liver. Catalyzed by cytochrome P450. Cytochrome P450: oxidases, bound to smooth endoplasmic reticulum, require NADH, exist in multiple isoforms (CYP11Ax, CYP17By, etc)  large # of substrates. Involved in metabolism or bile acids, steroids, xenobiotics / drugs. Oxidized drug  ↑ polarity / water solubility  ↓ tubular reabsorption  ↑ urine excretion. Reduction Same goal as oxidation (↑ polarity by reductases). GI bacterial flora  azo and nitro reduction reactions. Enzymatic hydrolysis Addition of water across a bond  ↑ polar metabolites.

Esterase: present in the plasma and tissues, nonspecific, hydrolyzes esters to alcohol and acid, responsible for activation of many prodrugs. Example: procaine. Amidase: hydrolyze amides into amines and acid (deamidation) in the liver. Example: procainamide.

Phase II reactions Functional groups of the original drug or a phase I metabolite are masked by a conjugation reaction  ↑↑ polar metabolites  ↑ excretion, no crossing of cell membranes (pharmacologically inactive, no toxicity). Conjugation reactions: combine parent drug (or metabolite) with certain natural endogenous constituents (glucuronic acid, glutamine, glycine, sulfate, glutathione). Requires high energy molecule and an enzyme. High energy molecule: consist of coenzyme bound to endogenous substrate, parent drug, or metabolite. Enzyme: called transferases, found in the liver and catalyze the reaction. Glucuronidation: most common conjugation pathway due to large supply of glucuronic acid (high energy form reacts using glucuronyl transferase). Common with OH group (form ethers) and COOh group (form esters). Reaction adds 3-OH groups and 1-COOH group  ↑↑ hydrophilicity. Glucuronides with ↑ MWt  bile excretion  to intestines  intestinal beta-glucuronidase hydrolyze the conjugate  reabsorption. Sulfate conjugation: using sulfo-transferase. Amino acid conjugation: reaction of glycine or glutamine with aliphatic or aromatic acids to form amides using N-acyltransferase. Glutathione conjugation: very critical for preventing toxicity from harmful electrophilic agents (halides, epoxides). Glutathione (tripeptide) + electrophile + glutathione S-transferase  mercapturic acid. Methylation: of oxygen- nitrogen- or sulfer-containing drugs  less polar but inactive metabolites. Example: COMT methylates catecholamines such as epinephrine. Acetylation:  less polar metabolites with N-acetyl-transferase. Metabolites (e.g. of sulfonamides) may accumulate in the kidney  crystalluria / tissue damage.

Factors influencing metabolism Species differences Qualitative differences: occur mainly in Phase II reactions. Determines the actual metabolic pathway. It can result from a genetic deficiency of a particular enzyme or difference in a particular endogenous substrate. Quantitative differences: occur mainly in phase I reactions. Due to difference in the enzyme level, presence of species specific isozymes, amount of endogenous inhibitor or inducer, extent of competing reactions.

Physiologic / disease state Due to pathologic factors that alter liver function. Congestive heart failure: ↓ output ↓ hepatic blood flow  ↓ metabolism ∆ albumin production  fraction of bound drug.

Genetic variations Acetylation rate: depends on the amount of N-acetyl-transferase, which depends on genetic factors. Fast acetylators  ↑ hepatotoxicity from isoniazid. Slow acetylators  ↑ other isoniazid SE. PM Phenotype: ↓ metabolism of B-blockers, antiarrhythmics, opioids, antidepressants.

Drug dosage ↑ dose  may saturated metabolic enzymes. As the saturation approaches 100%  change from first to zero-order metabolism. When metabolic pathway is saturated > possible alternative pathways. Example: therapeutic APAP doses  glucuronic / sulfate conjugation, toxic doses  conjugation is saturated  N-hydroxylation  liver toxicity

Nutritional status Conjugation agent levels (sulfate, glutathione) is dependent on nutrition

↓ protein diet  ↓ glycine, ↓ oxidative drug metabolism capacity. Diet ↓ in essential fatty acids (linoleic acid)  ↓ synthesis of certain enzymes  ↓ metabolism of hexobarbital. Diet ↓ in minerals (Ca, Mg, Zn)  ↓ metabolism. ↓ Fe  ↑ metabolism. Diet ↓ in vitamins (A, B, C, E): ↓ C  ↓ oxidation. ↓ E  ↓ dealkylation, hydroxylation.

Age Metabolic enzyme systems are not fully developed at birth  ↓ doses in infants / children to avoid SE, especially for glucuronide conjugation. Older children  liver develops faster than ↑ in body weight  ↓ efficacy. Elderly  ↓ metabolizing enzymes  ↓ elimination  ↑ Cp  ↑ SE

Gender Due to ∆ androgen, estrogen, adrenocorticoid activity  ∆ CYP450 isozymes. Example: oxidative metabolism is faster in men.

Administration route Oral: first-pass effect  ↑ oral dose IV: by pass first-pass effect  ↓↓ dose compared to oral dose. Sublingual / rectal: also bypass first-pass effect. Variable absorption from rectal administration.

Chemical structure Presence of certain functional groups influences drug’s metabolic pathway (route, extent, degree of metabolism).

Circadian rhythm Nocturnal Cp of theophylline, diazepam are ↓ than diurnal Cp.

Extra-hepatic metabolism Plasma: contains esterases (hydrolyze esters). Simple esters (procaine, succinyl choline) are rapidly hydrolyzed in the blood. Esterases can also activate prodrugs. Intestinal mucosa: microsomal oxidation, conjugation (glucuronide, sulfate)  first pass effect of lipid soluble drugs during absorption. Intestinal bacterial flora: secrete metabolizing enzymes. Ulcerative colitis  ↑ flora. Diarrhea, antibiotics  ↓ flora. Flora secrete beta glucuronidase  hydrolyze polar glururonide conjugates of bile  reabsorption of free nonpolar bile acids  eneterohepatic circulation. Flora convert vitamin K to active form, and cyclamate (sweetener) to cyclohexylamine (carcinogen). Flora produce azoreductase  converts sulfasalazine to 5-aminosalicylic acid (anti-inflammatory) and sulfapyridine (antibacterial). Stomach acidity: degradation of penicillin G, carbenicillin, erythromycin, tetracycline, peptides / proteins (insulin). Nasal mucosa: ↑ CYP450 activity and metabolism on nasal decongestants, anesthetics, nicotine, cocaine. Lung: first pass metabolism of IV, IM, transdermal, SC drugs but to ↓ degree than the liver. Also, second pass metabolism for drugs leaving the liver. Placenta: if drug is lipid soluble enough to get to circulation  pass through the placenta too. Placenta is not a physical or metabolic barrier to xenobiotics. Very little metabolism occurs. Smoking induce certain enzymes in pregnant women  ↑ carcinogens from polycyclic HC. Fetus: depends on fetal age, ↓↓ glucuronic acid conjugation. Chloramphenical  ↓ glucuronidation  gray baby syndrome. ↓ bilirubin glucuronide  neonatal hyperbilirubinemia.

Strategies to manage metabolism Pharmaceutical Sublingual tablets: deliver drugs directly to systemic circulation, bypassing hepatic first pass metabolism. Example: nitroglycerin. Transdermal products: continuous drug supply for long period of time. Example: nitroglycerin. IM depots: continuous drug supply for long period of time. Example: highly lipid soluble esters of esradiol (benzoate) and testosterone (enanthate)  slow absorption and activation by hydrolysis. Enteric coated tablets: protect acid sensitive drugs. Examples: omeprazole, erythromycin, methenamine. Nasal administration: for lung delivery of peptides (e.g. calcitonin salmon) which has no oral bioavailability. Lung contains protease inhibitors  peptide stability.

Pharmacologic Levodopa (L-dopa): amino acid precursor of dopamine (for Parkinson’s). Unlike dopamine, it can penetrate BBB and reach CNS to be decarboxylated to dopamine. Carbidopa: DOPA decarboxylase inhibitor that does not cross BBB  ↓ peripheral activation and SE. Beta-lactam AB: use clavulanic acid (a beta-lactamase inhibitor). Ifosfamide: alkylating agent  in vivo metabolic activation  nitrogen mustard. Acrolein is a byproduct of metabolic activation  react with nucleophiles on renal proteins  hemorrhagic cystitis. Combine ifosfamide. with mesna (neutralizes acrolein in the kidney).

Chemical Testosterone: not orally active due to rapid oxidation of 17-OH group. Methyl-testosterone: 17alphamethyl group  ↓ potent but no rapid first pass metabolic deactivation  used orally. Same for estradiol analogs. Tolbutamide: oxidation of para-methyl group  rapid deactivation. Chlorpropamide: non-metabolizable para-chloro group  long t1/2. Isoproterenol: potent beta agonist for asthma. Rapid metabolism by COMT (catechol)  poor oral activity. Metaproterenol: not metabolized by COMT  orally active, long t1/2. Octreotide: synthetic octa-peptide  ↓ severe diarrhea in tumors, SC. It mimics action of somatostatin (14-AA peptide, short t1/2, only IV infusion) but resistant to hydrolysis, proteolysis.

Prodrugs Require in vivo biotransformation (phase I) to produce activity The following are potential advantages for prodrugs:

↑ water solubility Useful for ophthalmic and parenteral formulations Example: sodium succinate esters, sodium phosphate esters to make water-soluble steroid prodrugs

↑ lipid solubility ↑ duration of action: estradiol lipid-soluble esters (benzoate, valerate, cypionate)  prolonged activity (IM of esters in oil). ↑ oral absorption: by converting carboxylic acid groups to esters  converted back to active acids by plasma esterases. Example: lipophilic orally absorbed enalapril  very potent orally inactive enalaprilat. ↑ topical absorption: of steroids by masking hydroxyl groups as esters or acetonides  ↓ polar  ↑ dermal permeability. Examples: triamcinolone acetonide, betamethosone valerate, diflorasone diacetete. ↑ palatability: sulfisoxazole acetyl (ester, ↓ water solubility, ok taste for children)  sulfisoxazole (bitter)

↓ GI irritation NSAIDs  ulceration by direct irritant effect of acidic molecules and ↓ of gastro-protective PG. Sulindac, nabumetone  prodrugs with ↓ GI effect

Site specificity Methyldopa: structurally similar to L-dopa  transported to CNS  metabolized to active alphamethyldopamine  central alpha-2 agonist Omeprazole: activated at acidic pH < 1  inhibition of H+/K+ATPase. Formaldehyde: effective urinary tract antiseptic. Orally  ↑ toxicity. Methenamine  non-toxic prodrug  hydrolyzes to formaldehyde and ammonium ions in acidic urine (pH 1000 tablets). Inventory record maintenance: keep inventory separate at the registered location for 2 years. Keep CII inventory separate. Must be readily retrievable. Submission to DEA is not required. Perpetual inventories: not required. New or changes in schedules: inventory required for that drug only.

Obtaining controlled substances CII: DEA Order Form 222 is required. Forms are issued by DEA, serially numbered with the certificate of registration inforamtion. Triplicate copies each. List info for drugs and supplier (one supplier per form). Form is invalid for purchasing 60 days of signature. Only used by previously authorized and deisgnated individuals. Send copy 1 and 2 to supplier, retain copy 3. Maintain for 2 years. A purchaser / supplier may cancel part or all of the order by notifying the other party in writing. CIII-V: no form is required but records need to be maintained (2 years).

Storage of controlled substances One of two ways: in a securely locked well constructed cabinet OR dispersed throughout the stock of other drugs to prevent theft. Report theft or significant loss immediately to DEA using Form 106.

Disposal of controlled substances DEA Form 41 must be submitted and pre-authorized. Always keep records. Options for disposal: transfer to a registered person or entity (use Form 222 for CII), delivery to or destroy in the presence of DEA agent or office. Regular disposal of controlled substances: DEA may authorize disposal without pior approval. Always keep records.

Disposal (dispensing) pursuant to a valid Rx Authorized prescribers Only by a practioner who is licensed by the state (not federally). Usually: physicians, dentists, vets, podiatrists (DEA starts with A or B). Other professionals may be licensed but with restrictions (DEA starts with M). Authentication of DEA number (7 digits): (1 + 3 + 5) + 2x(2 + 4+ 6)  double digit  the right digit has to match digit 7. Purpose for prescribing Must be in good faith only for legitimate medical reasons during the normal course of pratice (medical history and physical exam performed). A vet can not prescribe for humans. It does not have to be within

specialty if physician is a specialist. Can not prescibe controlled drugs for the sole purpose of detoxification of maintenance of addiction (only if within a treatment program). Prescribing CII must be written unless it is an emergency  oral drugs only, no alternative, written Rx is not possible, only necessary quantity, prescriber must be known to the pharmacist  written Rx must be provided within 7 days of oral Rx (mail or in person), otherwise notify DEA. CIII-V can be oral or fax. Faxed Rx: ok for CIII-V. For CII  ok to prepare the Rx but no released to the patient without written Rx  exceptions include injectable home health, hospice, and LTC Rx (no written Rx required) . Dispensing a Rx Time validity: 6 months for CIII-IV and no time limit for CII and CV (although questionable after 6 months). No limitation on quantity either. Apply good faith principles. All information on the Rx must be complete (including S/N). Label: must have pharmacy name / address, S/N, date of original filling, patient name, prescriber name, drug info, directions, Cautionary Auxilliary Sticker. Separate record files: CII, CIII-V, other Rx all separate, OR Combine all C with CIII-V or combine CIII-V with non control as long as C is stamped in red on CIII-V. Refills: no refills for CII. For CIII-IV  up to 5 refills in 6 months. No limit for C-V (use good faith). Maintain either physical or computerized records (certain characteristics). Partial dispensing: allowed for CIII-IV within 6 months. For CII: allowed only if not enough stock(within 72 hr), or terminally ill patient / LTC (within 60 days). Transfer of refills (CIII-V): allowed only once. Write ‘Void’ or ‘Transfer’ on Rx.

Dispensing without a prescription Only if not a prescription drug. Only pharmacist can dispense only limited quantities (wihtin 48 hr period) with records kept (2 years), in good faith. Purchaser must be 18 years and present an ID (if not familiar).

Security considerations Seals / seals: seals required for all packages and containers. Labels must clearly designate the schedule (II-V). Felony convictions: no registrant may employ felons conviced with a narcotic offense.

DEA inspections Inspected are conducted only in a reasonable manner and during business hours, only after registrant notification or court warrant. Specifics of the inspection scope must be provided.

Violation under the act Penalties depend on type of schedule, nature of violation, and knowledge and intent of the violator, first or recurrent offense. Pharmacist must be proven to be negligent not only an inadvertent mistake. May include civil penalty or imprisonment.

Federal Food, Drug and Cosmetic Act Passed following the sale of sulfanilamide elixir with deadly diethylene glycol (car antifreeze) in 1937. Act requires the use of NDA to prove to the FDA that the drug is safe and effective. Drug: articles intended for use in diagnosis, cure, mitigation, treatment or prevention of disease in man or animals. Also, articles other than food intended to affect the structure or function of the body. Also, articles in the USP.

Legend (Rx) drugs Includes the following types of drugs: Habit-forming drugs: such as narcotics or hypnotics. Safety: drugs that are not safe except under supervision of a licensed practioner. IND: files on a NCE. Allows the conduct of research to prove safety and efficacy (exemption from the Act). Include phases 1-3.

Phase 1: use on healthy humans to determien metabolism, pharmacology, mechanism, SE. Phase 2: well-controlled closely monitored studies on small # of patients to evaluate efficacy for a certain indication and also SE and risks. Phase 3: expanded clinical trials on patients to confirm safety and efficacy and risk/benefit relationship NDA: acceptable proof of safety and efficacy to the FDA  approved for use in certain indications. Treatment INDs (treatment protocols): allows a practioner to use an investigational drug as treatmetn in serious and life-threatening disease when no alternatives are available.

OTC medications FDA determined drug is safe for self-administration. Usually, drugs are not habit forming,  toxicity / SE. Must have adequate clear directions and must comply with FDA monograph (to avoid misbranding). A legend (Rx) drug may be converted by the FDA to OTC.

Generic / Proprietary drugs Generic name is the chemical name, common name or official name in the compendium. ANDA: submitted for drugs that have already been proven safe and effective. The brand / generic must have the same active, dosage form, strength, route, indications, conditions of use. Only bioavailability and bioequivalence have to be shown. Approved bioequivalent drugs are listed in the orange book.

Established names for drugs Established name: Commissioner of the FDA has the authority to designate names. Name has to be simple and useful. The FDA recongizes the US Adopted Names Council (USAN) in deriving names for NCE. Otherwise, use the name in the official compendium title. Otherwise, common or usual name is used.

Drug recall Voluntary manufacturer recall: may be completely voluntary or after several attempts by the FDA to receive court ordered recalls. Drug recall classification: assigned by the FDA. Class I: potential for serious SE and death. Class II: potential for temporary or reversible SE or when serious SE are unlikely. Class III: not likely to cause serious SE Recall procedure: strategy should consider the depth of the recall, need for public warning. First layer of notification (to wholesalers) is done by the company. Public notification is made by the FDA in the weekly FDA Enforcement Report.

Misbranding and adulteration Adulteration: change or variation from official formulary or manufacturer’s standards. Drug contains filthy, putrid, decomposed substance. Drug was prepared, packed, held under unsanitary conditions where it might have been contaminated. Container has poisonous substance. Drug contains unsafe color. Drug strength, quality or purity is different from claimed compendium standard. Drug contains another substance that  its quality or strength. OTC that is not properly packaged (tamper-proof) or labeled. Ophthalmic product that is not sterile. cGMP: a drug is adultrated if not manufactured in conformity with cGMP. Misbranding: a drug is sold or dispensed with a violative label. False or misleading label. Imitation or name used of another drug. Insulin or antibiotic that is not batch certified. Drug dispensed in non-child proof container. Label without proper info (drug info, precautions, pharmacy info, Rx#, date, names of patient / prescriber, directions, etc), oral contraceptive / estrogen / progesterone / IUD without patient insert, package, Rx drug without Rx, ophthalmic preparation that is not sterile. Violations under the Act: exemption in certain cases of good faith (violative product receive by the pharmacy in good faith), receipt of drug with a signed written guaranty from the wholesaler. Seizures: of adultrated / misbranded product after a court hearing or without a hearing if there is propable cause of danger to public health. Investigations and inspections: done by the US Secretary of Health and Human Services. Investigations must be authorized, within reasonable limits, time, manner and scope.

Package inserts Manufacturer’s insert: full disclosure is required by the manufacturer. Enclosed with every commercial container. Contains essential informative and accurate scientific information for safe and effective drug use. It can’t be promotional in tone, false or misleading. Patient package insert: due to certain SE with certain products, patient inserts must be dispensed, including refills. That includes the following: Oral contraceptives, IUDs, Estrogen products, Porgestational products, Isoproterenol inhalation products, Miscellaneous (e.g. Isotretinoin  serious fetal harm if pregnant). For isoproterenol, label with “Do not exceed prescribed dose. Contact physician if difficult persists”.

Prescription drug samples Currently, sample distribution is very restricted. All sale, purchase, trade of samples are banned. Sample records are maintained by the manufacturer for 3 years. Pharmacies can not accept samples. Importation after exporting is illegal.

Medical devices Safety and effectiveness are required. Class I: reasonable assurance of safety and quality Class II: no reasonable assurance of safety and quality, but has sufficient info to establish controls to ensure safety and quality Class III: no reasonable assurance of safety and quality (generally, they can not be marketed). Medical device tracking: required if failure may lead to serious SE. Tracking allows recalls. Manufacturer’s reports: manufacturer, hospitals, pharmacies, etc are required to report to the FDA potential link to death or adverse SE. Misbranding and adulteration: same as drugs

Poison Prevention Packaging Act The Act (1970) require child-resistant containers for all drugs (difficult for children under age of 5 to open easily within short period of time). Enforced by the Consumer Product Safety Comission. Requests for non-child resistant container: request can be made by the prescriber in a specific prescription, but a blanket request can’t be made. Patient can request that for one or all Rx (does not have to be in writing). Reuse of child-resistant containers: generally prohibited. Allowed for glass containers when a new child resistant cap is used. Manufacturer’s packaging: no child-resistant container if the product will be repackaged by the pharmacist, but is required if product will be dispensed directly to the patient. Exemptions for easy access: OTC non-child-resistant packaged can be sold as long as child-resistant alternative is offered. Label “For Households Withouth Children” or “Package Not Child Resistant”. Hospitals and institutions: the Act applies to houshold substances (“any substance produced or distributed for sale for consumption or use by individuals in the household”). Act does not apply if drug is given by hosptial personnel and not directly dispensed to the patient. Miscellaneous special packaging: such as furniture polish containing petroleum distillates, drain pipe cleaners, turpentine, pain solvents, lighter fluid.

Exceptions Sublingual nitroglycerin and sublingual / chewable isosorbide dinitrate at low doses. Erythromycin ethylsuccinate granules for oral suspension ( doses). Oral contracpetives / conjugated estrogen / norethindrone acetate in memory-aid (mnemonic) packages ( dose). Medroxyprogesterone acetate tablets. Anhydrous cholestyramine powder. Colestipol powder ( dose) Potassium supplements (effervescent tablets, liquid, powder) ( dose). Sodium fluoride (tablet / liquid,  dose). Betamethasone tablets in dispenser packages ( dose).

Prednisone or methylprednisolone tablets ( dose) Pancrelipase tablet, capsule, powder ( dose) Mebendazole tablets ( dose)

Anti-Tampering Act Act passed in 1984 due to death from OTC capsules containing cyanide. Applies to consumer products (food, drug, device, cosmetic, other articles). OTC tamper-resistant packaging: required from some products (contact lens, ophthalmic solutions). Contain a visible indicator of breach or tampering. Product / tamper-resistant technology design must be distinct to avoid easy duplication by commonly available processes. OTC tamper-resistant labeling: clearly alert consumers to specific tamper-resistant feature on the package. Medical devices and cosmetics: required for certain products Violations: include tampering, false communication or conspiracy for either.

Mailing Prescription Medications All drugs, including narcotics, can be mailed by the physician or pharmacist. Place drugs in a plain outer container or securely wrap in plain paper. Make no outside markings that indicate nature of content. Exception: do not mail flammable liquids or alcoholic beverages.

Omnibus Budget Reconciliation Act (OBRA) The US Constitution states that the federal government has no authority to regulate the practice of pharmacy (done by the states). Federal government can indirectly affect practice by attaching conditions of participation and reimbursement for federally funded programs. Medicaid: Rx are paid jointly by federal and state governments. Federal reimbursement require the pharmacist to get a patient and medication history, conduct DUR, offer counseling to the patient. Manufacturer’s best price: for manufacturer’s to participate in Medicaid, they must offer “best price” (lowest price for the purchaser).

Narcotic Treatment Programs Methadone can be used as part of a total narcotic addition treatment program. Regulations were established by the FDA and DEA. It is used for maintenance or detoxification. Facility has to be approved by the FDA, DEA and state authority. Detoxification treatment: dispensing a narcotic drug in  doses to  withdrawal physiologic or psychologic symptoms. Maximum period: 6 months. Maintenance treatment: dispensing a narcotic drug at stable dosage levels to treat heroin or morphinelike dependence. Requirments for patient admittance: has been physiologically dependent on a narcotic for one year and still is. Patient participation must be voluntary. Patient has to sign “Conset to Methadone Treatment” after being infomred properly. Take home methadone: only to patients, judged by the physician, are responsible in handling narcotic drugs. Patient must come to the clinic for observation at least 6 days a week, then gradually  observations to once a week. Dispense methadone as any CII drug.

24. Reviewing and dispensing prescriptions Definitions Prescriptions: orders for medications, non-drug products, and services. Practitioners may prescribe medications only in their field of practice. Information in the Rx: patient name and address, date, name and dosage form of the product, product strength, quantity (directly or indirectly), directions to the pharmacist (preparation, labeling), directions for the patient (quantity, schedule, duration, avoid “as directed”), refill information (“as needed” means one year), prescriber information (signature, DEA if controlled). Medical orders: orders for medications intended for use by patients in an institutional setting.

Information in medication order: patient information, date and time, name and dosage form, product strength, route of administration, signature, directions to the pharmacist, instructions for administration.

Understanding the Rx Understanding the order: all info must be understood and consistent, including disease condition, reason for treatment, type of units used. Evaluating appropriateness: follow up if incomplete info was provided. Evaluate allergies, route of administration, drug-drug / food / disease interactions, safety for intended use, proper quantity and dosage, incompatibilities, legitimate prescriber. Discovering inappropriate Rx: Drug Utilization Review: review medication profiles to ensure appropriateness. Therapeutic intervention: calling the prescriber to discuss concerns regarding the Rx. Following the intervention, the Rx may be dispensed as written, with changes or not at all.

Processing the Rx Involves use of technicians and automation, save pharmacist’s time for patient counseling and education. Record Rx number, original date of filling, product and quantity dispensed, pharmacist’s initials. Product selection: involves generic substitution, formulary / therapeutic substitution policies. Product preparation steps: obtain proper medication amount, reconstitute if necessary, extemporaneous compounding, assembly of delivery unit, selection of proper package or container. Labeling: contains name and address of pharmacy, patient’s name, original date of filling, Rx number, directions for use, product name and manufacturer, product strength, quantity dispensed, prescriber name, expiration date, pharmacist initials. Unit-dose packages: contain one dose or unit of medication, label identifies drug name, strength, lot#, expiration date. Auxiliary labels: to ensure proper medication use, storage, federal transfer of narcotics, etc. Record-keeping: include patient profile system that includes demographic information (allergies, DOB, disease, weight, occupation, OTC use) and record of all medications.

Dispensing medication and counseling Counseling patients: evaluate patient’s understanding, supply additional information, proper use, storage, appearance, name, route of administration, duration of use, reason for the Rx, SE (frequency, severity, actions to manage and minimize), OTC or food interactions. Counseling health professionals: especially in institutional setting where the professional administers the drug. Other information: cost, drug-drug or nutrition interactions, physical incompatibilities, interference with lab tests,

Patient monitoring Pharmaceutical care plan: to ↑ frequency and benefits of desired outcomes. Includes: assessment (review medical conditions and symptoms), plan (decision on appropriate therapy), monitoring (review outcome goals and endpoints). Drug-related problems: unnecessary therapy, wrong drug, wrong dose, SE, poor compliance, need for additional therapy.

25. Sterile Products and Parenterals Introduction Sterile products: parenterals, irrigating solutions, ophthalmics Aseptic technique: preparation procedures to maintain sterility Pyrogens: metabolic byproducts of live and dead microorganisms that cause fever upon injection. Tonicity: related to osmotic pressure. Hypotonic solution: ↓ osmotic pressure than blood or 0.9% NaCl. Cause cells to expand  hemolysis, pain. Isotonic: exert same osmotic pressure as blood or 0.9% NaCl. Hypertonic: must be administered through a large vein to avoid phlebitis and ensure rapid dilution. Clean rooms: areas constructed and maintained to ↓ probability of environmental contamination of sterile products. They have the following:

High-efficiency particulate air (HEPA) filters: used to clean the air entering the room. Remove all particulates < 0.3 mm with efficiency ~ 100%. HEPA filtered rooms are Federal Class 10,000, i.e., they contain 0.3 mm passes through HEPA filter. Anemometer is used to measure air flow velocity and a particle counter is used to count particles.

Sterilization methods and equipment Thermal: using either moist or dry heat. Moist heat (autoclave): most reliable and widely used. Microorganisms are destroyed by cellular protein coagulation. Minimum 121 C for 15 minutes. Dry heat: minimum 160 C for 120 minutes. More potential damage to product due to ↑ temperature. Chemical (gas): used for surfaces and porous materials (e.g. surgical dressings). Ethylene oxide is used with gas and moisture. Residual gas must be dissipated before product use. Radioactive: for industrial sterilization of products in sealed packages that can not be heated (e.g. surgical equipment, ophthalmic ointments). Use either electromagnetic or particulate radiation. May accelerate drug decomposition. Mechanical (filtration): removes but does not destroy and clarifies solutions by eliminating particulates. Depth filter: consists of fritted glass or unglazed porcelain. Membrane (screen) filter: with thickness of 1-200 mm. A mesh of millions of microcapillary pores filter the solution by physical sieving. Pores make up 75% of surface  ↑ flow rate than depth filters. Particulate filters (0.5-5 mm): remove particles or glass, rubber, plastic, etc. Used to ↓ risk of phlebitis by removing undissolved particles of reconstituted powders, cannot be used for blood, emulsions, suspensions, colloids. Microbial filters ( 100ml. Packaging materials: Glass: clarity for easy inspection, ↓ interaction with content. Plastic polymers: durability, easy storage / disposal, ↓ weight, ↑ safety, e.g., PVC and polyolefin.

Routes of administration Subcutaneous: usually in the arm or thigh. Example: insulin.

Intramuscular: e.g. mid-deltoid, gluteus medicus, < 5ml. Used for prolonged or delayed absorption (e.g. methylprednisolone). Intravenous: most important and common, immediate therapeutic response, no recall of inadvertent overdose, e.g., antibiotics, cardiac drugs. Intradermal: only very limited volume, e.g., skin tests and vaccines. Intra-arterial: deliver ↑ drug concentration into target side with little dilution by circulation, e.g., diagnostic radiopaque materials and antineoplastics. Hypodermoclysis: injection of large volumes of solution into SC tissue to provide continuous abundant drug supply, e.g., antibiotics for children. Intraspinal: e.g. local anesthetics during surgery (lidocaine, bupivacaine). Intra-articular: injection into joint space, e.g., corticosteroids (hydrocortisone, methylprednisone) for arthritis. Intrathecal: injection into the spinal fluid, e.g., antibiotics, cancer chemotherapy.

Parenteral preparations IV admixtures: one or more sterile drug product added to an IV fluid.

IV fluids Used in preparation of parenteral products (vehicles for IV admixtures). Dextrose (d-glucose): 5% dextrose in water (D5W). Used for reconstitution, as hydrating solution. Higher concentration dextrose (e.g. D10W) provide source of carbohydrates in parenteral nutrition. pH of D5W is 3.5-6.5  instability of acid-labile drugs. Concentration > 15%  give through central vein. Use cautiously in DM. Sodium chloride: usually as 0.9% solution  isotonic (normal saline). NaCl 0.45% is half-normal saline. Used for admixtures, fluid and electrolyte replacement. Bacteriostatic NaCl for injection (0.9%): for multiple reconstitutions (bacteriostatic  benzyl alcohol, propylparaben, methylparaben). Water: for reconstitution and dilution of NaCl, dextrose. Use Sterile or Bacteriostatic Water for Injection. Ringer’s solution: used post-surgically for fluid and electrolyte replacement. Lactated Ringer’s (Hartmann’s solution): contains sodium lactate, NaCl, KCl, CaCl2, may be combined with D5W. Ringer’s injection: does not contain sodium lactate, may be combined with D5W.

IV electrolytes Cations: Sodium: main extracellular cation, important for interstitial osmotic pressure, tissue hydration, acid-base balance, nerve-impulse transmission, muscle contraction. Examples: Na chloride, acetate, phosphate. Potassium: main intracellular cation, important for muscle (esp cardiac) contraction, neuromuscular excitability, protein synthesis, carbohydrate metabolism. Examples: potassium chloride, phosphate, acetate. Calcium: important for nerve impulse transmission, muscle contraction, cardiac function, bone formation, cell membrane permeability. Examples: calcium chloride, gluconate, gluceptate. Magnesium: important for enzyme activities, muscle excitability, neuromuscular transmission. Example: magnesium sulfate. Anions: Chloride: main extracellular anion. With sodium, it controls interstitial osmotic pressure, blood pH. Examples: sodium, potassium, calcium chloride. Phosphate: main intracellular anion. Important for enzyme activities, controlling calcium levels, buffer to prevent changes in acid-base balance. Examples: sodium, potassium phosphate. Acetate: bicarbonate precursor  used as alkali to preserve plasma pH. Examples: sodium, potassium acetate.

Parenteral antibiotics Route: direct IV, short term IV infusion, IM, intrathecal. Use: serious infections requiring ↑ concentration, GI is inaccessible.

Parenteral antineoplastics May be toxic and hazardous during prep, administration. Safe handling: use vertical laminar flow hood, syringes and IV tubing with Luer-Lok fittings, closed-front cuffed surgical gowns, double layered gloves, negative pressure technique, final dosage adjustment with care, special care priming IV sets, prime before adding the drug, special disposal, wash hands, monitor health of personnel. Patient problems: Infusion phlebitis: vein inflammation, pain, swelling, heat sensation, site redness, avoid by drug dilution and filtration. Extravasation: infiltration of the drug into SC tissues surround the vein. Response: local hydrocortisone or anti-inflammatory, antidote with cold compress, warm compress to ↑ blood flow and wash vesicant away from damage tissue.

Parenteral biotechnology products Examples: monoclonal antibodies, vaccines, colony-stimulating factors. Uses: cancer chemotherapy, HIV, hepatitis B, infections, transplant rejection, rheumatoid arthritis, inflammatory bowel, respiratory diseases. Characteristics: protein and peptide biotechnology drugs: short t1/2, special storage (freezing, refrigeration), avoid vigorous shaking not to destroy protein molecules. Route: direct IV, IV infusion, IM, SC. Require reconstitution.

Irrigating solutions Manufactured by the same standards for IV products but not intended for injection. Labeling differenced specified in USP, i.e., different acceptable particulate matter levels, volume, container design. Topical administration: packaged in pour bottles into desired. For irrigating wounds, moistening dressings, cleaning surgical instruments. Infusion: e.g., perfuse tissues to maintain integrity of surgical field, remove blood, clear field of view as in urologic surgeries. Add Neosporin G.U. irrigant, an antibiotic, to ↓ risk of infection. Dialysis (dialysates): e.g., in renal failure, poisoning, electrolyte disturbances. They remove waste matter, serum electrolytes, toxic products. Peritoneal dialysis: hypertonic dialysate (dextrose, electrolytes) is infused in the peritoneal cavity via surgically implanted catheter  remove toxins by osmosis and diffusion  finally drain. Antibiotics, heparin may be added. Hemodialysis: patient’s blood is transfused through a dialyzing membrane that removes toxins.

Needles and syringes Hypodermic needles Stainless steel or aluminum. Gauge: the outside diameter of the shaft. Large number (27) small diameter (13). SC: 24-25. IM: 1922. Compounding: 18-20. Bevels: slanting edges cut into needle tips to facilitate insertion. Regular bevel: most common, for SC, IM. Short bevel: used onlyfor shallow penetration (IV). Intradermal bevel: most beveled. Lenghts: from ¼ to 6 inches, depending on desired penetration. IV: 1¼ - 2½ inch. Compounding parenterals: 1½. Intradermal / SC: ¼. Intra-cardiac: 3½.

Syringes Glass or plastic barrel and tight-fitting plunger, small opening to accommodate needle. Luer syringe: oldest, universal attachment for all needle sizes. Syringe volumes: 0.3 – 60 ml. Insulin syringes have unit graduations (100 units/ml) rather than volume graduations. Calibrations: may be metric or English, vary depending on size. Syringe tips: Luer-Lok: threaded to ensure needle fit tightly, for antineoplastic drugs. Luer-Slip: unthreaded so needle does not lock into place, may be dislodged. Eccentric: set off center to allow needle to remain to injection site and minimize venous irritation. Catheter: used for wound irrigation and enteral feedings and not for injections.

Intravenous drug delivery Injections sites Peripheral vein injection: preferred for non-irritating drugs, isotonic solutions, short term IV therapy. Use dorsal forearm for venipuncture. Central vein injection: preferred for hypertonic solutions, long-term IV therapy. Use thoracic cavity vein, e.g., subcalvian.

Intermittent infusion Continuous drip infusion: slow infusion to maintain therapeutic level ro provide fluid and electrolyte replacement. Rate: ml/hr or drops/min. Use for drugs with narrow therapeutic index, e.g., heparin, aminophylline. Intermittent infusion: infusion at specific intervals (4hr), for antibiotics. Direct bolus injection: rapidly deliver small volume of undiluted drug. Use for immediate effect as in emergency. Additive set infusion: using volume control device, for intermittent delivery of small amounts. Piggyback method: used when drug cannot be mixed with primary solution, a supplemental secondary solution is infused through the primary system, avoids a second puncture or further dilution. Admixtures: also called manufacturer’s piggyback, a vehicle is added to the drug, example: Add-Vantage system. Intermittent infusion injection devices: also called scalp-vein, heparin-lock, butterfly infusion set. Permit intermittent delivery without multiple punctures or prolonged venous access. Use dilute heparin or normal saline to prevent clotting in the cannula.

Pumps and controllers Pumps Piston-cylinder mechanism: a syringe like apparatus Linear peristaltic mechanism: external pressure to expel fluid out of the pumping chamber. Volumetric pump: for intermittent infusion (e.g. antibiotics), continuous infusion, parenteral nutrition, etc. Syringe pump: used for intermittent or continuous infusion of drug in concentrated form (e.g. antibiotics, opiates). Mobile infusion pump: small infusion devices for ambulatory and home patients. For chemotherapy and opiates. Implantable pump: surgically planted under skin to provide continuous drug release, usually an opiate. The pump reservoir is refilled by injecting drug into pump diaphragm. Patient-controlled analgesia (PCA) pump: used for intermittent or on demand delivery of narcotics. Benefits: ↑ cost, ↑ training, ↑ accurate flow rate, detect infiltration, occlusion and air, save nurse time. Controllers Use no pumping pressure. Use gravity and control infusion rate by electronic counting of drops. Compared to pumps: ↓ complex, ↓ expensive, reasonable accuracy, used for uncomplicated infusion but not arterial or small vein infusion.

IV incompatibilities Types of incompatibilities Physical: mixing causes visible change in appearance. Example: evolution of CO2 when sodium bicarbonate and HCl are mixed. It can be a visible color change or pptn (e.g. phosphate and calcium). Chemical: chemical degradation causing toxicity or loss of activity. Complexation: such as calcium and tetracycline  inactive tetracycline complex. Oxidation: when a drug loses electrons  color change, inactivity. Reduction: when a drug gains electrons. Photolysis: chemical decomposition by light  hydrolysis or oxidation  color change. Therapeutic: e.g. bacteriostatic (tetracycline) then bactericidal (penicillin G)  ↓ activity of penicillin G. Factors affecting compatibility pH: ∆ in pH  ↑ incompatibility. Acid + base = salt  may ppt.

Temperature: ↑ temp  ↑ degradation. Use fridge or freezer. Degree of dilution: ↑ dilution  ↓ ion interaction  ↓ incompatibility. Length of time in solution: ↑ time  ↑ chance of incompatibility Order or mixing: do not add incompatible drugs in sequence (e.g. calcium, phosphate), mix well. Preventing incompatibilities Administer solutions quickly after mixing, mix each drug well after addition, ↓ number of mixed drugs, consult references.

Hazards of parenteral drug therapy Physical Phlebitis: usually a minor problem, minimize by proper IV insertion technique, dilution of irritating drugs, ↓ infusion rate. Extravasation: caused by vesicant drugs Irritation: ↓ by varying injection site and applying moisturizer Pain: common with peripheral infusion of concentration drugs, ↓ by diluting the drug or switching to central vein. Air embolism: can be fatal Infection: critical in central IV lines, can be local or systemic (septicemia). Allergic reaction: due to hypersensitivity to IV solution, additive Central catheter misplacement: may cause air embolism or pneumothorax, verify proper placement radiologically Hypothermia: due to shock or cardiac arrest, may be due to cold IV solution, injection solution at room temp only. Neurotoxicity: serious problem in intrathecal / intraspinal injection of drugs containing preservatives (avoid preservatives) Mechanical Pump/controller failure: may cause fluid overload, incorrect dose, or runaway infusion. IV tubing: can become kinked, split, cracked, produce particles Glass containers: may break  injury Rubber vial closures: may interact with drug solution Particulate matter Therapeutic Drug instability: may lead to therapeutic ineffectiveness Incompatibility: may cause toxicity or ↓ effectiveness Labeling errors: may cause using incorrect drug or dosage Drug overdose: may be caused by runaway IV infusion, pump / controller failure, nursing / pharmacy errors. Preservative toxicity: can be serious, esp in children. Example: benzyl alcohol in premature infants  gasping syndrome (fatal acidotic toxic state).

Quality Control / Quality Assurance Quality control: day-to-day assessment of all operations including analytical testing of raw materials and finished product. Quality assurance: oversight function, involves the auditing of QC procedures and systems. Sterility testing: USP standard calls for 10-test samples from large batches, minimum of 2 samples from small batches. Test conducting using membrane sterilization method  membrane is cultured for microbial growth. Pyrogen testing: qualitative fever response in rabbits or in vitro limulus lysate testing. Clarity testing: to check for particulate matter. Swirl and look it against light source and dark background. QA programs: include training, monitoring the manufacturing process, QC check, documentation. Process validation: a mechanism for ensuring processes consistently result in sterile products of acceptable quality. Includes written procedures, evaluation of aseptic technique by process simulation.

Process stimulation testing: duplicate sterile product production except that a growth media is used instead of drug product. Incubate final product: no growth  successful aseptic technique. Documentation: of training procedures, QC results, laminar flow hood certification, production records, etc.

35. Drug use in special patient populations Pediatrics PK consideration PK parameters change as children mature from birth to adolescence. Gastrointestinal absorption: Gastric pH: neonates are achlohydric (pH >4) but pH ↑ quickly in the first few weeks of life  ↑ absorption of basic drugs and ↓ absorption of acidic drugs, ↑ absorption of drugs destroyed by acidic pH (penicillins). Gastric emptying: long and highly variable in neonates and preemies, normal by age 6 months (t1/2 65 min). Drugs absorbed in the intestine: ↓ emptying rate  ↓ absorption, ↓ peak concentration. Formula has ↑ caloric density  2x as fast gastric emptying in breast fed infants. Underlying disease state: may ∆ gastric emptying rate, total surface area, absorption of lipids Bile acid production: ↓ in preemies (1/2) than adults  ↓ fat and drug absorption (e.g. Vitamin D). Pancreatic enzyme function: affects absorption of lipid soluble drugs. Neonates have ↓ lipases  ↓ absorption of chloramphenicol oral suspension. Percutaneous absorption Skin hydration  ↑ in neonates and preemies. SC thickness  normal in newborns, ↓ in preemies. TEWL  ↑ in neonates. Intramuscular absorption Affected by absorption surface area, blood flow, injection site, muscle activity. Preemies  ↓ muscle mass, ↓ muscle contractility  erratic IM absorption. IM absorption is normal in infants and children but is discouraged due to pain. Distribution Protein binding: acidic drugs bind to albumin. Basic drugs bind to alpha1-acid glycoprotein. Both proteins are ↓ in neonates  ↑ free drug. Normal levels at 1 year old of age. Size of body compartments: Extracellular fluid volume is 40% in neonates, 20% at age one. Polar compounds (e.g. aminoglycosides) distribute into extracullar fluids  loading dose is requires in neonates to rapidly achieve therapeutic concentrations. Body fat is ↓↓ in preemies, higher in newborns and reaches a peak at one year. A ↓ body fat  ↓ Vd for lipophilic drugs (diazepam). Endogenous substances: neonates may have ↑ free fatty acid and unconjugated bilirubin  bind to plasma proteins and ↓ degree of drug protein binding (↑ unbound drug). Bilirubin competes with certain drugs for albumin binding sites. If displaced  potential drug induced kernicterus. Metabolism Mostly occur in the liver. Some occur in the intestine, lung, skin. Liver metabolism is affected by enzyme inducers (Phenobarbital, phenytoin, carbamazepine, rafampin) and enzyme inhibitors (cimetidine, erythromycin). Phase I reactions: non-synthetic reactions (oxidation, reduction, hydrolysis, hydroxylation) that usually result in inactive or ↓ activity metabolites. Most important enzymes are cytochrome P-450 monoxygenase system (50% of adult level at birth). Phase II reactions: synthetic conjugation reactions (with glycine, glucuronide, sulfate) that result in polar water soluble inactive compounds for renal and bile elimination. Enzymes systems are ↓ at birth and ↑ with age. Glucuronide conjugation  chloramphenical, sulfate conjugation  acetaminophen, sulfonamides  acetylation,

Elimination Kidney is the major route of elimination for water soluble drugs and metabolites. Processes involved: glomerular filtration, tubular secretion, tubular reabsorption. Filtration and secretion ↑ eilimination, reabsorption ↓ elimination. All processes are ↓ in neonates. Renal blood flow (important for glomerular filtration) is ↓ in neonates. Only unbound drugs undergo glomerular filtration.

Problems in drug monitoring Therapeutic monitoring depends on correlation between serum concentration and therapeutic effect. The relationships are established for adults and may not work for infants. Side effects: Most common with antibiotics (vancomycin, penicillins, cephalosporins), anticonvulsants, narcotics, antiemetics, contrast agents. Examples: red-man syndrome with vancoymcin, syndrome of inappropriate antidiuretic hormone (SIADH) with carbamazepine. Dosing consideration: Body surface area = square root of (height x weight / 3600). Dose intervals: may be longer for neonates and shorter for older children.

Pregnancy Fetal development Withdraw all unnecessary medications 3-6 months before plans for conception. Blastogenesis: first 2-3 weeks after fertilization. Germ formation occurs. Embryonic cells are undifferentiated. Organogenesis: 2-8 weeks. Most critical period of development as organs start to develop. Drug exposure may cause major congenital malformations. Fetal period: 9 weeks to birth. At 9 weeks, the embryo is called a fetus. Maturation and growth occurs. Low risk of major congenital malformations.

Placental transfer of drugs Functions of placenta: nutrition, respiration, metabolism, excretion, endocrine activity to maintain fetal and maternal well being. In order for a drug to cause teratogenic or pharmacological effect, it has to pass from the maternal circulation to the fetal circulation through the placenta. Placenta is not a protective barrier: most substances pass the placenta by passive diffusion due to concentration gradient. Placenta acts similar to any other lipid membrane. Factors affecting drug transfer: Molecular weight: ↓ (< 500 dalton)  cross easily, large (heparin)  does not cross. pH: weakly acidic and weakly basic drugs cross easily. Lipid solubility: ↑  cross easily. Most oral drugs are designed for optimal lipid membrane transfer. Drug absorption: during pregnancy  ↓ gastric tone and motility  delayed gastric emptying  ↓ absorption. Drug distribution: during pregnancy  ↑ Vd with gestational age, ↑ fat content, ↑ total body fluid. Plasma protein binding: only free unbound drugs cross placenta. Albumin and alpha1-acid glycroprotein are ↓ during pregnancy  ↓ free drugs. Placenta membrane becomes thinner with gestational age. Blood flow ∆ with meals, exercise, drugs and may ∆ placental crossing. Embyotoxic drugs: may terminate or shortens pregnancy, especially in early pregnancy. Examples: ACE inhibitors, hormones, antidepressants. st Teratogenic drugs: risk of teratogenesis is highest during the 1 trimester  physical malformations, mental abnormalities. Teratogenic effect depend on the time during gestation when the drug is taken, and organs developing at this point. FDA Classification: Category A (safety documented in humans), Category B (safety documented in animals, or safe in humans but damaging in animals), Category C (human safety unknown, may be damaging in animals), Category D (damaging in humans, only use in life-threatening situations), Category X (highly damaging in humans and may be animals, absolute contraindication). Examples: vitamin A derivatives (isotretinoin), ACE inhibitors, warfarin (use heparin instead), estrogens, androgens, thyroids (methimazole, carbimazole, propylthiouracil), cortisone, ethanol (Fetal Alcohol Syndrome, FAS), antibiotics (tetracycline (teeth), metronidazole, quinolone), anticonvulsants (phenytoin, valproic acid, sodium valproate, trimethadione), lithium (Ebstein’s anomaly), antineoplastics (methotrexate, cyclophosphamide, chlorambucil, busulfan), finasteride (avoid handling of tablets and semen of male users). Fetotoxic drugs: more likely during fetal period (9 weeks to birth). CNS depression (barbiturates, tranquilizers, antidepressants, narcotics), Neonatal bleeding (NSAIDs, anticoagulants, use Tylenol

instead), Drug withdrawal (habitual maternal use of barbiturates, narcotics, benzodiazepines, alcohol), Reduced birth weight (cigarette smokers, alcoholics, drug abusers), constriction of ductus arteriosus rd (NSAIDs in 3 trimester may cause pulmonary hypertension).

Drug excretion in breast milk Transfer from plasma to breast milk: affected by factors influencing human membrane transfer. This is, like other membranes, a semipermeable lipid barrier. Unionized drugs may pass by passive diffusion. Low molecular weight molecules pass through small pores. Larger molecules must dissolve first in the lipid membrane. Drug’s physicochemical properties: human milk is more acidic than plasma. Acidic drugs are unionized  diffuse into milk and back. Basic drugs become ionized in milk  trapped in milk. Plasma protein bound drugs can’t pass into milk. ↑ lipid solubility  ↑ passage to milk. Drugs affecting hormonal influence: primary hormone is prolactin. Bromocriptine  ↓ prolactin  suppress lactation if desired. Other drugs to ↓ prolactin: L-dopa, ergot alkaloids. Drugs to ↑ prolactin: metoclopramide, sulpiride. Minimizing infant’s drug exposure: choose drugs with no active metabolites, short t1/2, no milk accumulation. Adjust route of administration, dosing schedule to ↓ infant’s exposure. Drugs that enter breast milk: narcotics, barbiturates, BZD, alcohol, antidepressants, antipsychotics, metoclopramide, anticholinergics (dicyclomine).

Geriatrics People >65 years use 33-50% of all prescriptions. 75% of elderly are Rx users. 20% of elderly experience SE. Incidence of SE is 2-3x higher in elderly. SE may be overlooked in elderly because they are similar to disease symptoms. Causes of ↑ SE in elderly: polypharmacy, multiple diseases, more severe diseases, ↓ drug elimination, ↑ sensitivity to drug effects. One third of elderly use => 6 drugs. Polypharmacy  ↑ drug interactions, ↑ drug-disease interactions. ↑ noncompliance in elderly especially with females, ↓ socioeconomic status, living alone, polypharmacy, multiple disease, complicated regimens. Disease  ↑ noncompliance. Example: macular degeneration, cataract, hearing loss, arthritis, Alzheimer. Clinical trials during drug development may not test drugs on the elderly (↑ SE). ↑ osteoporosis  ↑ fractures due to falls because of drugs causing dizziness, drowsiness, syncope, hypotension, blurred vision. Avoid long acting BZD, use lorazepam, oxazepam (no active metabolites, phase I metabolism).

Pharmacokinetics ↓ liver metabolism (phase I)  ↑ drug accumulation Absorption: can be affected by delayed gastric emptying, ↑ gastric pH, ↓ GI motility. Usually, the rate but not the extent of absorption is affected. Distribution: ↑ body fat / lean muscle mass ratio  ↑ Vd of fat soluble drugs (diazepam, propranolol). ↓ total body water  ↓ Vd of water soluble drugs (acetaminophen). ↓ serum albumin  ↓ protein binding  ↑ free drug (warfarin, phenytoin). Kidney excretion: very important. ↓ glomerular filtration, ↓ tubular secretion rate. 50% ↓ in renal function by age 70 in normal patients. Serum creatinine is not a good measure of renal function as creatinine also ↓ with age. ↓ dose of renally eliminated drugs to avoid SE and toxicity. Examples: digoxin, procainamide, H2 antagonists, lithium, aminoglycosides. Liver metabolism: ↓ phase I (but not phase II) metabolism and ↓ blood flow  ↑ t1/2, ↑ SE of BZD, some analgesics.

Pharmacodynamics Altered response to certain drugs. ↓ response to beta blockers, ↑ response to analgesics, BZD, warfarin. Generally, start low and titrate slow. ↑ sensitivity to anticholinergic SE  avoid if possible.

36. Clinical laboratory tests General principles Monitor therapeutic / SE: e.g. serum uric acid after allopurinol, or liver function after isoniazid. Estimate proper dose: serum creatinine or creatinine clearance before giving renally excreted drug Decide on alternative / additional therapy: WBC count after AB Drug-caused test misinterpretation: false positive urine glucose test after cephalosporin. Normal test values: usually mean +/- 2 SD. Standardization: using international system of units (SI). Basic SI unit is the mole (more physiologically meaningful as reaction occurs at molecular level). Lab error: due to specimens (spoiled, incomplete, wrong sampling time), bad reagents, inaccurate procedure, technical errors. Basic battery of tests: with routine physical and hospital admission include ECG, chest x-ray, electrolytes, urinalysis, hemogram. Types of test: quantitative (normal range), qualitative (-ve / +ve), semi-quantitiatve (1+, 2+, e.g. urine glucose).

Hematological tests RBCs RBC count: number of RBCs per cubic mm of blood, an estimate of the blood Hb content. Normal: 4.5 million/mm3 (higher in men). Hematocrit or packed cell volume (PCV): measures percentage (fraction) by volume of packed RBCs in whole blood after centrifugation. Hct is usually 3x the Hb value. Normal: 45% (higher in men). Low Hct  anemia, over hydration, blood loss. High Hct  polycythemia, dehydration. Hemoglobin test: measures grams of Hb in 100 ml (1dl) of whole blood, an estimate of the oxygen carrying capacity of RBCs. It depends on the number of RBCs and amount of Hb in each RBC. Normal: 15 g/dl (higher in men). Low Hb  anemia. RBC (Wintrobe) indices: info on the size, Hb concent, Hb weight of RBCs. Used to categorize anemias. Poikilocytosis: ∆ in RBC shape as in sickle-cell anemia. Anisocytosis: ∆ in RBC size as in folic acid and iron deficiency anemia. Mean corpuscular volume (MCV): ratio of Hct to RBC count. Measures average RBC size (anisocytosis). Normal: 90. Low MCV  microcytic anemia (iron deficiency). High MCV  macrocytic anemia (folic acid or vitamin B12 deficiency). Mean cell Hb (MCH): measures amount of Hb in average RBC. Normal: 30. Mean cell Hb concentration (MCHC): measures average Hb concentration in average RBC. Normal: 35. Low MCHC  hypochroma (pale RBCs) as in iron deficiency. RBC distribution width (RDW): normal RBCs are equal in size  bell-shape normal histogram distribution  high RDW in anemia (iron, folic acid, vitamin B12 deficiency). RDW is never below normal. Reticulocyte count: measures immature RBCs (reticulocytes), which contain nuclear material (reticulum), Normal: 1% of all RBCs. It measures bone marrow production of mature RBCs. High reticulocyte count  hemolytic anemia, acute blood loss, response to treatment of factor deficiency anemia. Low reticulocyte count  drug-induced aplastic anemia. Erythrocyte sedimentation rate (ESR): measures rate of RBC sedimentation of whole uncoagulated blood. It reflects plasma composition. Normal: 10 mm/hr (higher in females). High ESR  acute or chronic infection, tissue necrosis, infarction, malignancy. Use to follow disease course, differentiate diagnosis (angina  normal ESR, MI  ↑ ESR).

WBCS WBC count: number of WBCs in whole blood. Normal: 7000 / mm3. High WBC count (leukocytosis)  due to infection (esp. bacterial), leukemia, tissue necrosis. Low WBC count (leukocytopenia)  due to bone marrow depression due to cancer, lymphoma or antineoplastic drugs. WBC differential: evaluates the distribution and morphology of WBC cell types including granulocytes (neutrophils, basophils, eosinophils), and non-granulocytes (lymphocytes, monocytes).

Neutrophils: may be mature or immature. Chemotaxis: congregation of neutrophils at site of tissue damage of foreign body invasion  first line defense  phagocytosis and degradation of invaders. Neutrophilic leukocytosis (↑#, ↑ fraction of immature cells)  systemic bacterial infection (e.g. pneumonia), viral infection, fungi, stress (physical, emotional, blood loss), inflammatory disease (rheumatism), drug hypersensitivity, tissue necrosis, leukemia, certain drugs (Ep, lithium). Neutropenia (↓#, < 1000/mm3)  overwhelming infection as bone marrow is unable to keep up with demand, viral infections, chemotherapy drug reactions. Basophils: called mast cells in the tissues. Basophilia (↑#)  leukemia. Eosinophils: associated with immune reactions. Eosinophilia (↑#)  acute allergic reaction (asthma, hay fever, allergy), parasitic infections. Lymphocytes: critical for immunologic activity, produce antibodies. Types: T and B. Lymphocytosis (↑#)  viral infection. Lymphocytopenia (↓#)  severe debilitating disease, immunodeficiency, AIDS. Atypical lymphocytes  in infectious mononucleosis. Monocytes: phagocytic cells. Monocytosis (↑#)  TB, bacterial endocarditis, during recovery of acute infections.

Platelets (thrombocytes) Smallest in size. Involved in clotting. Normal: 225,000 / mm3. Thrombocytopenia: ↓ platelets due to disease or drugs. Moderate: < 100,000. Severe: < 50,000.

Serum enzyme tests Creatinine kinase (CK) Location: heart, skeletal muscle, brain tissue Use: aid diagnosis of acute MI (necrosis) or skeletal muscle damage. Isoenzymes of CK: CK-MM in skeletal muscle (major), CK-MB in heart, CK-BB in brain  used to identify source of damage. ↑ CK-MB  heart necrosis Interference: exercise, fall, IM injection.

Lactate dehydrogenase (LDH) LDH converts lactate to pyruvate and vice versa. Found in all cells. Isoenzymes: 1 and 2 (heart), 3 (lungs), 4 and 5 (liver, skeletal muscles). Use: aid diagnosis of MI, liver / lung disease.

Alkaline pohsphatase (ALP) Location: produced mainly in the liver and bones Use: serum ALP is sensitive (↑) to biliary obstruction as in bile duct stone. Serum ALP ↑ due to ↑ osteoblastic activity (e.g. Paget’s disease, hyperparathyroidism, osteomalacia).

Asparatate aminotransferase (AST) Formerly known as serum glutamic-oxaloacetic transaminase (SGOT) Location: mainly in the heart and liver. Use: ↑ AST in acute hepatitis, cirrhosis, fatty liver, passive liver congestion (as in CHF).

Alanine aminotransferase (ALT) Formerly known as serum glutamic-pyruvic transaminase (SGPT) Location: mainly in the liver Use: more specific but less sensitive than AST for liver damage. ALT ↑ only in severe liver damage.

Cardiac troponins Use: identify MI injury, prognosis of unstable angina. More specific than CK-MB. Troponin T  in cardiac and skeletal muscles. Tropnonin I  only in cardiac muscle. Normal: Troponin T  < 0.1 ng/ml, Toponin I  < 1.5 ng/ml.

Liver function tests Liver enzymes Certain enzymes (LDH, ALP, AST, ALT) ↑ with liver dysfunction. They indicate only liver damage but not ability to function

Serum bilirubin Bilirubin is a breakdown product of hemoglobin, main bile pigment. Indirect bilirubin (unconjugated): bilirubin released from Hb breakdown, bound to albumin, water insoluble, not filtered by glomerulus. Direct bilirubin (conjugated): Unconjugated bilirubin travel to the liver  separate from albumin  conjugate  actively secret to the bile  filtered by the glomerulus. Normal values: Total bilirubin  0.5 mg/dl. Direct bilirubin  0.1 mg/dl. ↑ bilirubin  tissue deposition  jaundice. Causes: hemolysis, biliary obstruction, liver cell necrosis. Hemolysis: ↑ total but not direct bilirubin. Normal urine. Biliary obstruction: may be intra-hepatic (e.g. due to chlorpromazine), or extra-hepatic (biliary stone)  ↑ total and direct bilirubin. Bilirubin present in urine  dark color. Liver cell necrosis: due to viral hepatitis  ↑ total and direct bilirubin. Bilirubin present in urine  dark color.

Serum proteins Normal total serum protein level: 7 g/dL. Transport agents. Albumin: made in the liver (liver disease  ↓albumin ) Globulin: ↓ albumin  compensatory ↑ in globulin.

Urinalysis Appearance Normal urine: clear, pale yellow to deep gold color. Red urine: presence of blood or phenolphthalein (laxative) Brownish-yellow urine: presence of conjugated bilirubin.

pH Normal urine: slightly acidic (pH = 6) Alkaline pH: due to acetazolamide use (bicaronaturia), or due to leaving urine sample at room temperature.

Specific gravity Normal urine: 1.015 ↑ specific gravity: DM, glucose in urine, nephrosis (protein in urin) ↓ specific gravity: due to diabetes insipidus (↓ urine concentration).

Protein Normal: 65 mg/24 hr. Glomerular membrane prevents most blood protein from entering urine Albuminurea: abnormal glomerular permeability. Proteinuria: due to kidney disease, bladder infection, fever

Glucose Normal renal threshold for glucose: blood glucose of 180 mg/dl. Glycosuria: due to DM.

Ketones Usually absent in urine. Excreted when body has used available glucose stores and began to metabolize fat due to uncontrolled DM, or due to ↓↓ carbohydrate diet  Ketonuria. Ketone bodies: betahydroxybutyric acid (major), acetoacetic acid, acetone.

Microscopy Hematuria: presence of RBCs may indicate trauma, tumor, systemic bleeding. Squamous cells indicated vaginal contamination due to menstruation in women. Casts: protein conglomerations may be due to renal disease. Crystals: pH-dependent, uric acid crystals in acidic urine, phosphate crystals in alkaline urine. Bacteria: usually absent in urine (sterile), if present may be due to UTI or urethral contamination.

Renal function tests Renal function ↓ with age. Use results to adjust drug dosage if needed. ↓ renal function  ↓ urea / creatinine excretion  ↑ their blood levels. Azotemia/uremia: ↑ retention of nitrogenous waste (BUN / creatinine) in blood. Renal azotemia: due to renal disease, e.g. glomerculonephritis. Prerenal azotemia: due to dehydration, ↑ protein intake, hemorrhagic shock. Postrenal azotemia: tumors or stones in the uterers, urethra, prostate. Clearance: volume of plasma from which a measured amount of substance is eliminated (cleared) into urine per unit time. Use to measure glomerular function

BUN (blood urea nitrogen) Urea: end product of protein metabolism, produced in the liver. Urea is filtered at the glomerulus, then 40% is reabsorbed at the tubules  urea clearance is 60% of true GFR Normal BUN: 13 mg/dl. ↓ BUN: due to liver disease ↑ BUN: due to renal disease, ↑ renal blood flow, ↑ protein intake.

Serum creatinine Creatinine: metabolic breakdown product of muscle creatine phosphate Normal level: 1 mg/dl, but varies based on the muscle mass Creatinine excretion: by glomerular filtration and tubular secretion. ↑ serum creatinine  renal insufficiency. 50% ↓ in GFR  doubling of serum creatinine.

Creatinine clearance Rate at which creatinine is removed from blood by the kidney. Normal value: 100 ml/min (100 ml of blood cleared of creatinine / min). Creatinine clearance parallels GFR, more sensitive than BUN. Creatinine clearance = (urine creatinine concentration x urine rate) / serum creatinine. Cockroft and Gault equation: used to estimate Clcr based on body weight, age, gender, and serum Cr when urine information is N/A.

Electrolytes Sodium Major extracellular cation. Cellular osmosis and water balance: controlled by sodium, potassium, chloride and water. Normal level: 140 mEq/L. Concentration is a ratio of Na to water. ∆ Na  ∆ water balance not electrolyte balance. Na control: by antidiuretic hormone (ADH) and aldosterone. Hypothalamus  release ADH from pituitary gland  ↑ renal reabsorption of sodium.

↓ blood Na,↑ blood K, angiontesin II  aldosterone (mineralocorticoid) release from adrenal cortex  ↑ Na reabsorption in exchange for K urine secretion. Hyponatremia: due to ↑ Na loss (kidney disease), ↓ Na intake, overhydration (non-saline fluid replacement, ↑ water intake), ↓ mineralocorticoid (↓ Na reabsorption), SIADH. Hypernatremia: due to ↓ Na excretion, ↑ Na intake (hypertonic IV), dehydration (loss of free water as in diabetes insipidus), ↑ mineralocorticoid, ↑ Na drug (Na bicarbonate, ticarcillin).

Potassium Most common intracellular cation. Normal level: 140 mEq/L intracellular, 4.5 mEq/L in blood (10% extracellular  can not use that measure). Role: electrical conduction in heart and skeletal muscles, water balance, acid-base balance. K regulation: by kidneys, aldosterone, blood pH, insulin, K intake. ↑ blood pH  ↓ blood potassium / ↓ blood sodium Hypokalemia: most K is lost through kidneys, due to vomiting, diarrhea, laxative abuse, diuretics (mannitol, thiazides, loop), ↑ mineralocorticoids, glucosuria, ↓ K intake, metabolic alkalosis / insulin / glucose (all move K intacellularly). Signs: fatigue, dizziness, ECG, pain, confusion Hyperkalemia: due to ↓ kidney elimination, ↑ K intake, cellular breakdown (tissue damage, hemolysis, burns, infections), metabolic acidosis, potassium sparing diuretics, ACE inhibitors.

Chloride Major extracellular anion  critical for acid-base balance. Not important clinically. Only confirms Na levels. Normal: 100 mEq/L Cl retention usually happens with Na and water retention. Anion gap = sodium – (chloride + bicarbonate) Hypochloremia: due to fasting, diarrhea, vomiting, diuretics. Hyperchloremia: usually due to metabolic acidosis, or dehydration, ↑ Cl intake, renal failure.

Bicarbonate / CO2 HCO3-/CO2 is the most important buffering system to maintain pH (acid base balance). Normal level: 25 mEq/L. Bicarbonate binds to hydrogen to form carbonic acid which can convert to CO2 and water. Hypobicarbonatemia: due to metabolic acidosis, renal failure, hyperventilation, diarrhea, carbonic anhydrase inhibitors, drug toxicity (salicylate, methanol, ethylene glycol). Hyperbicarbonatemia: due to metabolic alkalosis, hypoventilation, ↑ bicarbonate intake, diuretics.

Minerals Calcium Role: bone integrity, nerve impulse transmission, muscle contraction, pancreatic insulin release, gastric hydrogen ion release, blood coagulation. Normal level: 10 mg/dl. Ca reservoir in bones (44% calcium) maintains plasma level. 40% of calcium is bound to plasma proteins (albumin) Only free unbound ionic calcium is important physiologically  depends on amount of serum protein (albumin) Hypocalcemia: due to ↓ parathyroid hormone or ↓ vitamin D. Can be caused by loop diuretics. Hypercalcemia: due to malignancy or metastasis, hyperparathyroidism, Paget’s disease, thiazide diuretics, ↑ Ca intake, ↑ vitamin D.

Phosphate PO4 is a major intracellular anion  source of phosphate for ATP and phospholipids synthesis. Normal level: 4 mg/dl. Ca and PO4 are affected by same factors  consider together Hypophosphatemia: due to ↓ vitamin D, hyperparathyroidism, malnutrition / anabolism, aluminum antacids, Ca acetate, alcoholism Hyperphosphatemia: renal insufficiency, ↑ vitamin D, ↑↓ parathyroid

Magnesium Second most abundant intracellular and extracellular cation. Role: activates enzymes for carbohydrate / fat / electrolyte metabolism, protein synthesis, nerve conduction, muscle contraction. Normal level: 2 mEq/L. Hypomagnesemia: more common, due to ↓ GI absorption, ↑ GI fluid loss, ↑ renal loss. Signs: weakness, tremor, ↑ reflexes, arrhythmia. Hypermagnesemia: due to ↑ Mg intake with renal insufficiency, Addison’s disease. Signs: bradycardia, flushing, sweating, ↓ Ca. Summary table Indicator RBC Count

Normal 4.5 million/mm3

Hematocrit (packed cell volume) Hemoglobin Poikilocytosis Anisocytosis Mean corpuscular volume

45% (~3xHb)

Mean cell Hb concentration RBC distribution width Reticulocyte count

Erythrocyte sedimentation rate

WBC Count

15 g/dl ∆ RBC shape ∆ RBC size 90: average RBC size, (Hct / RBC count) 35: average Hb / RBC Normal distribution 1% immature RBCs (reticulocytes) 10 mm/hr

7000 / mm3

Neutrophils

Lymphocytes

Eosinophils

Lactate dehydrogenase (LDH) Alkaline pohsphatase (ALP)

Asparatate aminotransferase (AST) (also celld SGOT) Alanine aminotransferase (ALT) (also called SGPT)

anemia, blood loss, overhydration anemia

iron deficiency anemia hypochroma (pale RBCs), ↓ iron anemia

anemia (iron, folic acid, vitamin B12 deficiency) hemolytic anemia, acute blood loss

drug-induced aplastic anemia

↑ in females, acute or chronic infection, rheumatoid arthritis, tissue necrosis, MI, malignancy Leukocytosis  infection (esp. bacterial), leukemia, tissue necrosis Neutrophilic leukocytosis  bacteria (pneumonia), viral, fungi, stress, rheumatism, drug hypersensitivity, tissue necrosis, leukemia Lymphocytosis  viral infection

225,000 / mm3

Creatinine kinase (CK) Cardiac troponins

Low

Leukocytopenia  bone marrow depression due to cancer, lymphoma, antineoplastic drugs Neutropenia ( 200 mg/dl, LDL > 130 mg/dl, HDL < 35 mg/dl), hypertension, smoking, diabetes, obesity, family history, sedentary life style, chronic stress type A personality, ↑ age, male gender, oral contraceptives, gout. Factors that ↑ O2 demand: exercise, smoking, cold temp.

Etiology 1. ↓ blood flow: atherosclerosis with or without coronary thrombosis is the most common cause. Coronary arteries are progressively narrowed by smooth muscle cell proliferation and accumulation of lipid deposits (plaque). Coronary artery spasm is a sustained contraction that can occur spontaneously or induced by irritation (catheter, hemorrhage), cold exposure, ergot drugs. The spasm can cause Prinzmetal angina or MI. Traumatic injury such as impact of steering wheel on the chest. Embolic events can also occur abruptly. 2. ↓ blood oxygenation: blood oxygen carrying capacity ↓ in anemia. 3. ↑ oxygen demand: can occur with exertion or emotional stress (sympathetic stimulation). Systole: two phases (contraction and ejection). Contractile (inotropic) state affects oxygen requirement. ↑ ejection time  ↑ oxygen demand.

Angina Pectoris Episodic reversible oxygen insufficiency. May be caused oxygen imbalance (tachycardia, anemia, hyperthyroidism, hypotension, arterial hypoxemia). . Patient complaints: squeezing pressure, sharp pain, burning, aching, bursting, indigestion-like discomfort, radiating pain to the arms / legs / neck / shoulders / back. Physical examination: usually not revealing, especially between attacks. Note history, risk factors, description of attacks, precipitation patterns, intensity, duration, relieving factors. Treat risk factors: Hypertension should be controlled. Obesity should be ↓ through diet and exercise. Smoking should be stopped, but watch for anxiety. Quitting results in 50% ↓ in morality. Transdermal nicotine patches helps quitting over 10 weeks using decreasing doses of nicotine. Nicotine gum and bupropion can also be used. Also, clonidine. Types Stable (classic / exertion) angina: most common form, usually due to a fixed obstruction in a coronary artery. Triggered by exertion, emotional stress or heavy meal and relieved by rest or nitroglycerin. The pain builds a peak radiating to the jaw, neck, shoulder, arms and then subsides. Prinzmetal’s angina (vasospastic or variant angina): due to coronary artery spasm (↓ blood flow). Initially occurs at rest, pain may disrupt sleep. Calcium channel blockers are preferred over beta blockers. Nitroglycerin may not help. Unstable angina: due to significant coronary artery vasospasm and platelet aggregation. Characteristics: may occur at rest, ↓ response to nitroglycerin, pattern change / ↑ severity. Progressive unstable angina may signal imminent MI. Immediate hospitalization required. Nocturnal angina (angina decubitus): occurs in the recumbent position and is not related to rest or exertion. Occurs due to ↑ ventricular volume (↑ demand). Relieved by diuretics (↓ left ventricular volume). Nitrates may improve nocturnal dyspnea. Diagnostic tests ECG: normal in 60% of patients. May show ↑ Q-wave, T-wave inversion, ↓ ST segment. Stress / exercise ECG: helps diagnose patients with normal ECG. ↓ ST-segment. 201 99m Stress perfusion imaging: with thallium or technetium sestamibi. Expensive. Pharmacologic stress test: when coronary artery disease is suspected but patient can’t exercise. Use IV dipyridamole, adenosine (↓ AV conduction), dobumatime to induce cardiac ischemia in ECG. Coronary arteriography / cardiac catheterization: very specific, sensitive, invasive, expensive, risky (2% mortality rate). Antihyperlipidemics Bile acid sequestrants: Cholestyramine chloride is a basic anion-exchange resin. Colestipol HCl is a copolymer. Mechanism: insoluble, nonabsorbable, hydrophilic, anion-exchange resins bind bile acids in the intestine  ↑ bile acid synthesis from cholesterol  cholesterol depletion. SE: bad taste (before

meals), GI upset, constipation, bloating, dyspepsia, ↓ other drugs’ absorption (e.g. digoxin, may use in toxicity), fat soluble vitamine (ADEK) deficiency. Statins: lovastatin, atrovastatin, simvastatin, pravastatin, fluvastatin, cerivastatin. Preferred in the evening. Mechanism: ↓ HMG-CoA reductase (converts HMG-CoA to mevalonate; precursor for cholesterol)  ↓ cholesterol synthesis. SE: liver toxicity, monitor creatine kinase (CK) in case of skeletal muscle complaints (myopathy, rhabdomyolysis), headache, rash. CI: fibrates / cyclosporins  ↑ risk of liver damage. Fibric acid derivatives: gemfibrozil, clofibrate, fenofibrate (micronized prodrug). Mechanism: ↓ synthesis / ↑ catabolism of triglycerides / cholesterol. SE: GI upset, ↑ liver function (monitor combined use for statins). Niacin (nicotinic acid): SE: flushing / itching (tolerance in 2 weeks, may be ↓ with aspirin), ↑ liver function, GI upset. Other drugs: probucol, eicosapentaenoic acid (EPA), docashexanoic acid (DHA). Probucol SE: arrhythmia, syncope. Nitrates Chemistry: Nitrites (amyl nitrite)  organic esters of nitrous acid, Amyl nitrite: very volatile, flammable liquid, by inhalation for CN poisoning. Nitrates (nitroglycerin, isosorbide)  organic esters of nitric acid. Nitroglycerin: very volatile, flammable, special storage, dispense in original glass container, protect from body heat, special IV plastic tubes to avoid absorption and loss of effect, extensive first pass effect (use transdermal or sublingual). Dosage form: Nitroglycerin: sublingual / buccal tabs, topical ointment, transdermal, IV. Isosorbide mono / dinitrate: tablets. Mechanism: fast acting, form free radical nitric oxide (NO, endothelium-derived relaxing factor, EDRF)  activates guanylyl cyclase  ↑ cGMP  dephosphorylation of myosin light chain  muscle relaxation, venous dilation (↓ vascular resistance)  peripheral blood pooling  ↓ venous return  ↓ preload (left ventricular volume) ↓ respiratory symptoms (shortness of breath, nocturnal dyspnea). Also ↓ arterial pressure  ↓ afterload  ↓ oxygen demand. Also some ↓ in afterload. Use: use sublinigual (up to 3 tabs in 15 minutes), transmucosal (buccal tabs / spary) or IV nitroglycerin for acute attacks of angina pectoris. Sublingual tabs / oral tablets / transdermals can be used prophylactically before known stress (eating, sex). IV nitroglycerin is used for emergency unstable angina. SE: may ↓ BP  reflex tachycardia / postural hypotension, headache (transient, temporary, prevented by Tylenol 15-30 beforehand), dizziness, methemoglobinemia Nitrate tolerance: loss of efficacy, avoid by requiring 12hr nitrate free periods. Otherwise, higher doses may be required. Beta blockers Mechanism: ↓ sympathetic heart stimulation (B1)  ↓ heart rate and contractility (-ve inotropic / chronotropic)  ↓ oxygen demand at rest / exertion, ↓ arterial blood pressure. Use: with nitrates to ↓ frequency and severity of exertional angina. May narrow coronary artery  combine with calcium blocker, avoid in Prinzmetal’s angina. Use propranolol. SE: bronchoconstriction, mask hypoglycemia (tachycardia), cardiac compensation (fatigue, shortness of breath, edema, dyspnea). Withdrawal syndrome and angina / MI if suddenly d/c. Calcium channel blockers Mechanism: prevent / reverse coronary spasm by ↓ calcium influx into smooth / cardiac muscle  ↑ blood flow / oxygen supply. Also ↓ dilate arterioles and ↓ heart contractility  ↓ total peripheral resistance  ↓ oxygen demand / afterload. nd Use: 2 choice to nitrates and beta blockers in stable angina (may combine). Critical in Prinzmetal’s angina / angina at rest. Diltiazem / verapamil / bepridil: watch for heart block / cardiac compensation due to –ve inotropic effect. Careful with other –ve inotropic drugs (beta blockers, anti-arrhythmics). Verapamil constipation  straining and ↑ oxygen demand. Nifedipine: peripheral vasodilation, limited –ve inotropic effect. SE: hypotension, tachycardia (combine with beta blocker), dizziness, edema.

Other drugs: Maximal therapy: nitrate, CCB, beta blocker combination. Morphine: in unstable angina when nitroglycerin fails. Aspirin: use indefinitely in stable and unstable angina. Heparin/enoxaparin/dalteparin: with aspirin in unstable angina.

Myocardial infarction Severe prolonged deprivation of oxygen to part of the heart  irreversible necrosis. Usually due to occlusive thrombus near a ruptured atherosclerotic plaque. May lead to ventricular fibrillation (most disorganized arrhythmia)  cardiac arrest and death (sudden death syndrome). Mortality rate: 30%. Signs and symptoms: Persistent severe chest pain or pressure (crushing, squeezing, elephant heavy). Pains beings in the chest and may radiate to the left arm, neck, leg, etc. Onset of pain is not associated with exertion. Unlike in angina, pain persists > 30 minutes and is not relieved by nitroglycerin. MI may be silent (no pain). Other symptoms: anxiety, impending doom, sweating, GI upset. Complications Lethal (ventricular) arrhythmia: arrhythmias resistant to lidocaine may respond to procainamide and bretylium. CHF: left ventricular failure  pulmonary congestion  diuretics. Digoxin ↑ contractility, compensate for heart damage. Cardiogenic shock: due to ↓ cardiac output. Occurs when area of infarction > 40% and compensatory mechanisms are ineffective. Vasopressors (alpha stimulants to ↑ BP) and inotropes may be used. Use vasodilators (nitropursside) to ↓ preload and afterload. Intra-aortic balloon pump may be used. Diagnostic tests Because MI is life threatening emergency, diagnosis is presumed and treatment is initiated based on complaints and immediate 12-lead ECG. Serial 12-lead ECG: abnormalities may be absent in the first few hours. ST elevation. Ventricular premature beats and ventricular arrhythmia are the most common arrhythmia. Cardiac enzymes: creatine kinase (MB-CK) is elevated within hours, peaks at 24 h and back to normal at 72 h. Cardiac troponin I and T (cTnI, cTnT) patterns are similar to MB-CK but more sensitive. 99m Lactase dehydrogenase (LDH) use is not longer common. Cardiac imaging include tc pyrophosphate scintigraphy, myocardial perfusion, radionucleotide ventriculography, coronary angiography. Treatment: Nitrates: may ↓ chest pain  ↓ anxiety and ↓ catecholamine release (↓ coronary spasm  less ↑ in oxygen demand). Morphine: causes venous pooling and ↓ preload, cardiac workload, oxygen consumption (IV). Drug of choice to ↓ MI pain and anxiety. SE: orthostatic hypotension, respiratory depression, constipation (use docusate). Vagomimetic effect  bradyarrhythmia (if excessive  reverse using atropine). Oxygen: Three liters/min via nasal cannula for chest pain, hypoxia and ischemia Warfarin: for treatment of acute MI to ↓ mortality, prevent recurrence, ↓ complications (stroke). Target INR: 2.5-3.5. Antiplatelet agents: abciximab, eptifibatide, tirofiban  ↓ platelet glycoprotein receptors. Beta blockers: propranolol, metoprolol, atenolol. Given in early acute MI to ↓ oxygen demand, cardiac workload, ischemia, infarction  ↓ post MI mortality. ACE inhibitors: after MI to ↑ exercise capacity, ↓ mortality in case of CHF, ↓ ventricular remodeling. Antihyperlipidemics: ↓ cholesterol  ↓ MI mortality. Calcium channel blockers: avoid in acute MI or in left ventricular malfunction. ↓ incidence of reinfarction. Dipyridamole: relax smooth muscles, ↓ coronary vascular resistance (↑blood flow). Also, anti-platelet action. Used for angina pectoris prophylaxis. SE: ↓ BP, headache, dizziness. Others: intra-aortic balloon, coronary angiography, PTCA.

Thrombolytic agents Atherosclerotic plaques are made of lipids and fibrous proteins. Lesion rupture triggers release of serotonins, thromboxane A2 and adenosine diphosphate alteplase  platelet aggregation  clot. The resulting fibrin traps RBCs, platelets, plasma proteins to form thrombus. Clot dissolution is caused by conversion of plasminogen to plasmin mediated by plasmingoen activators. Use as early as possible ( 200 or diastolic > 140  ↑↑ quick organ damage. Reduction of BP must be gradual (15 mmHg over first hour) to avoid compromising organ perfusion (esp. cerebral) Drugs: vasodilatos (nitroprusside, hydralazine, diazoxide, nicardipine, nitroglycerin), enalaprilat, adrenergic inhibitors (labetolol, esmolol, phentolamine (alpha blocker)), fenoldopam (dopamine D1 agonist, vasodilator), trimethaphan (ganglionic blocker)

40. Congestive Heart Failure Introduction Definition: condition due the inability of the ventricle to deliver adequate quantities of blood to the metabolizing tissues during normal activity or at rest. It’s called ‘Congestive’ because of the edema caused by fluid backup due to poor pump function. Etiology: common in the elderly. CHF is not an independent diagnosis as it is superimposed on an underlying cause (usually coronary artery disease). Low-output failure: metabolic demands are normal but heart is unable to deliver be enough blood output. This is the most common type. High-output failure: due to ↑ metabolic demands (hyperthyroidism, anemia). Treatment goals: remove underlying cause (drugs, anemia, hyperthyroid); relieve symptoms / ↑ pump function (↓ metabolic demand, ↓ fluid volume excess, digitalis, inotropes, cardiac transplant).

Pathophysiology CHF  compensatory mechanisms to normalize cardiac output (stroke volume x heart rate)  ∆ left ventricle geometry  ventricular dilation, hypertrophy, ↑ cardiac wall thickness (cardiac remodeling).

Compensation Sympathetic response: ↓ cardiac output  sympathetic activation  ↑ Ep, NEp  ↑ heart rate, ↑ blood flow to vital organs (brain, heart). Hormonal stimulation: sympathetic blood flow redistribution  ↓ renal perfusion  ↓ glomerular filtration rate  sodium / water retention, activation of renin-angioensin-aldosterone system  more sodium retention, volume expansion. Concentric cardiac hypertrophy: ventricular remodeling. Frank-Starling mechanism: ↑ blood volume  ↑ cardiac chamber stretch to accommodate excess fluid (distention)  ↑ contractile force to expel fluid to the arteries.

Decompensation Over time, compensatory mechanisms become exhausted and ineffective  viscous cycle of compensation  compensation become self-defeating. Afterload: tension in ventricular muscles during contraction, amount of force needed for the ventricle to overcome pressure in the artery, also called ‘intravascular systolic pressure’. Preload: force exerted on the ventricular muscle at the end of diastole that determines degree of muscle stretch, also called ‘ventricular end diastolic pressure’. As fluid volume ↑  ↑ demand on exhausted pump  fluid backup  symptoms of CHF.

Clinical evaluation Symptoms are due to blood backing up behind the failing ventricle. Symptoms are first related to the failing side, then to both sides. Left-sided CHF Blood can’t be pumped from the left ventricle to the peripheral circulation  left ventricle can’t accept blood from left atrium and lung  blood back up in pulmonary alveoli  pulmonary edema. Symptoms: dyspnea, less effort to trigger exertional dyspnea, wheezing cough, exertional fatigue, nocturia. Paroxysmal (sudden) nocturnal dyspnea and orthopnea result from volume pooling in the recumbent position  relieved by propping with pillow or sitting upright. Physical findings: Crackles indicate air movement through fluid-filled passages, tachycardia (early compensatory mechanism). Diagnostic tests: cardiomegaly (heart enlargement), left ventricular hypertrophy, pulmonary congestion. Right-sided CHF Blood can’t be pumped from the right ventricle to the lung  right ventricle can’t accept blood from right atrium and circulation  blood back up in whole body  systemic edema.

Symptoms: tightness and swelling (fingers, skin), nausea, vomiting, abdominal pain on exertion due to liver enlargement. Physical findings: vein distention due to ↑ venous pressure, tender enlarged liver, bilateral leg edema. Diagnostic tests: ↑ liver enzymes (ALT) due to liver congestion.

Therapy Bed rest Advantages: ↓ metabolic needs, ↓ heart workload, ↓ heart rate and dyspnea, ↑ diuresis  ↓ fluid volume. Disadvantages: venous stasis  thromboembolism, ↓ risk by using anti-embolism stockings, leg exercises.

Dietary controls Small frequent meals with ↓ calories  ↓ metabolic demand ↓ sodium (3g/d) to ↓ volume. Education patient about sodium containing products (antacids, NSAIDs, sodium bicarbonate, baking soda, water softeners).

Drug-related actions ↑ ejection fraction can be achieved by: 1. Directly ↑ heart contractility using inotropic agents: dopamine, dobutamine, milrinone, amrinone. 2. ↓ resistance to ejection by relaxing peripheral blood vessels: vasodilators such as hydralazine, nitroprusside, nitrates 3. Affecting cardiac remodeling: ACE inhibitors, beta blockers, vasodilators (nitrates). Addressing the underlying problem is more important than symptoms.

Digitalis glycosides (Digoxin) Source: Plant steroidal glycosides. Digoxin: from Digitalis lanata; Digitoxin: from Digitalis pupurea; Ouabain: from Strophanthus gratus. Chemistry: Sugar (glycone portion) + steroidal nucleus (aglycone/genin portion) bonded with glycoside (ether) linkage. ↑ hydroxyl groups ↑ polarity ↓ protein binding / liver biotransformation / renal reabsorption ↓ duration of action. Ouabin v. short duration only IV. + + + + Mechanism: Inhibit Na /K ATPase  ↑ intracellular Na , ↓ intracellular K , ↑ calcium entry  +ve inotropic effect, ↑ CO, ↑ renal blood flow (perfusion)  deactivate RAAS  ↑ diuresis, ↓ edema, prolongs PR interval in EKG. Also: ↑ vagal tone in SA node -ve chronotropic effect, ↓ CNS sympathetic flow, systemic vasoconstriction. Use: CHF, left ventricular systolic dysfunction, rapid atrial fibrillations / flutter, paroxysmal atrial tachycardia. (CI in ventricular fibrillation / flutter). Dosage forms: tablet, capsule, injection, elixir. Dosing: Rapid digitalization: IV in acute need, steady state in 1 day. Slow digitalization: orally, steady state in 1 week. Serum levels: first ↑ sharply and then ↓ sharply as drug enters the heart. Measure after 5 hr of dosing (steady state). Target: 1 ng/ml. Potassium: antagonize digitalis effect. ↓ potassium  ↑ digitalis toxicity. DI with potassium altering drugs (diuretics, ACE inhibitors). Magnesium: inversely related to digitalis effect (↓ Mg  ↑ toxicity) (similar to potassium). Calcium: ↑ digitalis inotropic effect. ↑ calcium  arrhythmia. Metabolism: in the kidneys. Serum creatinine affects elimination. Toxicity: common due to narrow therapeutic index. Can be fatal. ↑ toxicity with quinidine, verapamil, amiodarone. Early: GI (anorexia, diarrhea, nausea, vomiting), CNS (headache, confusion, delirium, muscle weakness, fatigue, visual disturbance). Later: ventricular fibrillation / flutter, AV block, atrial tachycardia, premature ventricular contraction. Treatment of toxicity: d/c digitalis and any potassium depleting drug, give potassium IV if hypokalemic, treat arrhythmia with lidocaine IV, cholestyramine to prevent absorption (binds digitalis), purified digoxin-specific Fab fragment antibodies.

Inotropic drugs (IV emergency use) Dopamine: ↓ dose: ↑ kidney blood flow, ↑ urine output. Moderate dose: ↑ cardiac output. ↑ dose: ↑ peripheral resistance, ↑ pulmonary pressure, tachycardia. Very short t1/2. Dobutamine: similar chemical/pharmacological alternative to dopamine. Amrinone / milrinone  bipyridine derivatives. Mechanism: inhibit phosphodiesterate (PDE) isozyme in heart cells  ↑ cAMP  vasodilation, ↑ cardiac contractility. SE: thrombocytopenia, hypotension, headache. Amrinone: nonglycoside, non-sympathomimetic inotrope. Unstable in dextrose  use saline for IV (sodium may also be a problem in CHF). Milrinone: renally excreted.

Diuretics Used for all CHF patients with fluid retention / edema. Monitor fluid loss and ↓ in edema by following body weight Thiazides: effective, commonly used. Disadv: weak, hypokalemia. Loop: v. effective, orally / IV for acute pulmonary edema. Hypokalemia. Potassium sparing: weak, balance the hypokalemia. Aldosterone antagonists: e.g. spironolactone.

ACE inhibitors For long term, not acute, management of CHF. First line agents. Mechanism: ↓ enzyme for converting angiotensin I to angiotensin II (potent vasoconstrictor)  ↓ total peripheral resistance  ↓ afterload. ↓ angiotensin II also  ↓ aldosterone release  ↓ sodium / water retension  ↓ venous return and ↓ preload.

Vasodilators Mechanism: ↓ afterload (artery dilation) / ↓ preload (venous dilation)  ↓ pulmonary congestion, ↑ cardiac output. Nitroprusside: IV, dilates both veins and arteries. Prazosin: alpha-1 blocker, dilates both veins and arteries. Hydralazine: dilates arteries. Nitrates: dilates veins. Higher dose for CHF than for angina.

Beta blockers For long term, not acute, management of CHF. Only carvedilol (Beta-1-2-Alpha-1 blocker) is approved for CHF. Actions of norepinephrine: peripheral vasoconstriction, sodium retention by the kidney, cardiac hypertrophy, arrhythmia, hypokalemia, cell death (apoptosis) due to ↑ stress.

Calcium channel blockers No evidence of benefit in CHF symptoms. Do not use. Verapamil is particularly contraindicated because of the significant –ve inotropic effect. Nifidipines are less dangerous (no heart effect)

41. Thromboembolic Disease Introduction Defintion: venous thromboembolic disease (VTED) occurs when elements of the Virchow’s triad (vascular injury, venous stasis, hypercoaglate state ( protein C / S, antirhombin III)) are present resulting in deep venous thrombosis (DVT) and pulmonary embolism (PE). Incidence: total is 500K, symptomatic is 250K. Risk factors: patient specific (age>40, obesity, varicose veins, immobility, pregnancy,  dose estrogen, hypercoagulate state, lupus anticoagulant), illness / surgery (pelvic / hip / lower limb trauma or surgery or cancer, MI, heart failure, inflammatory bowel, sepsis, kidney disease, polycythemia).

Prevention: nonpharmacologic ( venous stasis with external pneumatic compression or graduate compression stockings), pharmacologic (anticoagulant drugs or heparins).

Oral anticoagulants – warfarin Indications Prevention of: VTED (1ry, 2ry), systemic arterial embolism in prosthetic heart valve or atrial fibrillation, acute MI in peripheral arterial disease, stroke and death in acute MI, venous thrombosis, pulmonary embolism, coronary occlusion in acute MI.

Mechanism Chemistry: Coumarin derivatives (warfarin, dicumarol) are water insoluble weak acids. Chemically related to vitamin K. ↑ protein bound. ↑ liver metabolism. ↓ therapeutic index. Therefore, ↑↑ drug interactions. Mechanism: antagonists of vitamin K. ↓ reductase responsible for interconversion of vitamin K and its epoxide  liver production of defective () vitamin K-dependent coagulant proteins or clotting factors (2 (prothrombin), 7, 9, 10). Does not work in vivo.

PK Warfarin is a racemic mixtuer of equal R/S forms Rapid absorption  Cmax in 90 minutes.  inter-individual variability in dose response. Used mostly orally, but also IV. Pregnancy X. Effect and depletion of clotting factors occurs after 3 day. Meanwhile, use UFH or LMWH if needed (5 day overlap). Effect also take time to wear off after d/c. Dose: 2.5-10 mg. Duration: 3-12 months.

Monitoring Initial daily monitoring of prothrombin time (PT) and international normalized ratio (INR). Then  frequency of monitoring gradually to every 4 weeks. PT results are highly dependent of type of reagent. INR = patient PT / mean lab control PT. Target: 2-3 (risk  2.5-3.5). ISI: International Sensitivity Index, a measure of thromboplastin responsiveness to  in clotting factors.  ISI   responsive reagent  PT ~ INR Warfarin is sensitive to metabolic enhancers / inhibitors, vitamin K. Antibiotics  ↓ GI bacterial flora  ↓ vitramin K  ↑ warfarin toxicity. SE: hemorrhage / bleeding (treat with vitamin K, i.e. phytonadione IM/SC), skin necrosis (due to ↓ protein C), urticaria, purpura, alopecia.

Unfractionated heparin Chemistry: large very acidic muco-polysaccharide molecule Indications: IV/SC with warfarin for proven VTED. Prevents / treats DVT, PE. Works in vivo to prevent clotting of blood samples. Avoid IM ( hematoma). Mechanism: inhibition / inactivation of thrombin (factor IIa, converts fibrinogen to fibrin clot), activated factor Xa (converts prothrombin II to thrombin IIa), by antithrombin (AT) III. PK: plasma proteins other than AT III compete for heparin binding. Short t1/2. Large molecule  can’t cross placenta  safer in pregnancy. Clearance: combination of saturable and non-saturable first-order kinetic models. Involve rapid followed by gradual elimination.  inter- and intra- individual variability (due to ∆ plasma proteins and clearance). Administration: start with a 70 units/kg loading dose for fast response, then continuous dose (1000 unit/hr or weight-based) SE: hemorrhage, thrombocytopenia (common), urticaria. Antidote: protamine sulfate (ver basic protein). Monitoring: measure activated partial thromboplastin time (aPTT) (patient aPTT / mean lab control aPTT)  target: 1.5-2.5, but is dependent on the reagent. Heparin assay may also be used for monitoring.

Low molecular weight heparin Examples (x-parin): enoxaparin (Lovenox), dalteparin, ardeparin Chemistry: fragments of standard heparin produced by controlled chemical or enzymatic depolymerization of heparin. Minimum 18 saccharide units. Very acidic  anions at physiologic pH  ↓ absorption from GI. Given only parenterally as sodium salts. Heparin: mean MWt 15K. LMWH: mean MWt 5K. Indications: prevention and treatment of venous thromboembolism (venous thrombosis, VTED, unstable angina pectoris, MI, surgery). Mechanism: very similar to heparin with more effect on Xa than on IIa. PK:  binding to heparin-binding proteins than heparin   bioavailability at  doses and more predictable effect / uniform absorption.  binding to endothelial cells   plasma t1/2 and doseindependent renal clearance. ↓ SE than heparin. aPTTT can NOT be used to monitor effect. No approbriate assay available. Danaparoid: low MWt heparinoid. It’s a glycosaminoglycan from porcine mucosa. Similar mechanism / uses. CI: bleeding and pork product sensitivity.

Lepirudin Chemistry: recombinant DNA (almost identical to hirudin). Mechanism: ↓ thrombin (factor IIa) thrombogenic activity (antithrombin). Use: anticoagulant in case of heparin-induced thrombocytopenia. SE: cerebral bleeding, allergic/ skin reactions.

Antiplatelet agents Aspirin: Mechanism: ↓ dose  permanent inhibition of COX  ↓ thromboxane A2. Use: ↓ mortality post-MI, prevent MI reinfarction. Ticlopidine / clopidrogel: Mechanism: interfere with ADP-induced platelet-fibrinogen binding  ↓ glycoprotein GPIIb/IIIa receptor. Use: ↓ MI, stroke risk. SE: ↑↑, diarrhea, rash, GI upset, neutropenia. Fab fragments (Abciximab): Mechanism: monoclonal antibodies against GPIIb/IIIa receptor  ↓ platelet interaction. Use: coronary angioplasty, atheroctomy. SE: bleeding, thrombocytopenia, antibody formation, arrhythmia. Eptifibatide / Tirofiban: Mechanism: same as Abciximab. Use: acute coronary syndrome, coronary angioplasty. Glycoprotein IIb/IIIa receptor antagonists  ↓ fibrinogen, adhesion ligands. SE: bleeding, fever, headache. Dipyridamole: Mechanism: ↓ RBC adenosine, ↓ phosphodiesterase ( ↑ cAMP), ↓ thromboxane A2. Use: for thromboembolism prophylaxis after valve replacement. SE: nausea, GI upset, headache, rash, dizziness. Also relax smooth muscles, ↓ coronary vascular resistance (↑blood flow). Anagrelide: Mechanism: ↓ platelet production. Use: ↓ platelet count in thrombocythemia. SE: CHF, MI, heart block, arrhythmia. Cilostazol: Mechanism: PDE III inhibitors  ↑ cAMP  vasodilation. SE: CHF.

Thrombolytic agents General Mechanism: ↑ conversion of plasminogen to plasmin (serine protease), which hydrolyzes fibrin and dissolves clots. General SE: bleeding (GI / GU / intracranial / catheter site), and allergic reactions (skin rash, bronchospasm, edema, urticaria). Alteplase / reteplase (t-PA): recombinant DNA-derived tissue plasminogen activators (t-PA) consisting of amino acids. Called ‘Clot Selective’ because it acts on fibrin-bound plasminogen. SE: acute MI, acute pulmonary embolism. No allergy issues (human-derived) Streptokinase: protein derived from cultures of Group C beta-hemolytic streptococci ( hypersensitivity). ↓ fibrinogen and factors 5 & 8. Acts on bound & free plasminogen (not selective). Use: acute MI, DVT, arterial thrombosis. Anistreplase: also called ‘Anisolyated Plasminogen Streptokinase Activator Complex, APSAC’. Prodrug, activated in vivo by deacylation. Use: acute MI, coronary arterial thromobi. SE: arrhythmia, ↓ BP Urokinase: two-chain serine protease from cultured human kidney cells. Mechanism: enzymatically active (plasminogen  plasmin). Use: coronary arterial thrombi, pulmonary embolism.

42. Infectious Diseases 43. Seizure Disorders 44. Parkinson’s disease Disease state and pathology Slowly progressive degenerative neurologic disease. Incidence: over 50 years of age (mostly 60’s)= 0.1%. Pathogenesis: Depigmentation of substantia nigra. Loss of dopaminergic input to the basal ganglia (extrapyramidal system) which is responsible for initiating, modulating, sequencing motor activity  motor disability. Parkinson’s is due to imbalance between dopamine (inhibitory neurotransmitter, ) and acetylcholine (excitatory neurotransmitter, ). Diagnosis: depends on clinical findings, tests to rule out secondary cause, PET scan to visualize dopamine uptake in substantia nigra and basal ganglia.

Etiology Primary (idiopathic): called classic Parkinson’s or paralysis agitans. Most common. Incurable disease. Can be due to absorption of highly potent neurotoxins (CO, manganese solvent, MPTP) or exposure to cell toxic hydrogen peroxide and free radicals; both products of dopamine catabolism. Secondary: small percentage, usually curable. Drugs: dopamine antagonists / antipsychotics (phenothiazines (chlorpromazine, perphenazine), haloperidol, reserpine). Toxins: CO, heavy metals (manganese, mercury, MPTP). Infections: syphilis, encephalitis. Others: Wilson’s disease, arteriosclerosis. Pseudo-Parkinson’s: due ↑ dose of older (traditional) antipsychotic agents, more in the elderly

Signs and symptoms Tremor: initial complaint. Most evident at rest (resting tremor) and with  frequency movement. Pillrolling tremor: involve thumb and forefinger. Action tremor: with activity. Limb rigidity: ratchet-like movement when limb is moved passively Akinesia (difficult) / bradykinesia (slow): including masked-face (fixed expression) with  spontaneous emotional responses. Postural difficulty: walking with stooped, flexed posture,  arm swing in rhythm with the legs. Mental status: depression (50%), dementia (25%), psychosis. 2ry disease effects: cardiovascular (orthostatic hypotension, arrhythmia), GI (constipation,  salivation),  urinary frequency, impotence, hallucinations. Unified Parkinson’s Disease Rating Scale (UPDRS): used to monitor disease progress and evaluate drug efficacy. Includes: mental status, behavior, mood, daily activities (speech, swallowing, walking, etc), clinicians motor evaluation (speech, mobility, tremor, etc).

Treatment: Non-drug: Exercise / physical therapy: very beneficial for mobility and mood. Nutrition: to  risk of poor nutrition, weight loss,  muscle mass.  fiber and fluid intake to prevent constipation.  calcium to preserve bone structure.  antioxidants (e.g. vitamin E) to  oxidative stress. Psychological rehabilitation: support for patient, family. May need to treat depression, dementia. Drugs: TCA (anticholinergic, dopaminergic, for depression). Beta blocker (propranolol,  lipid solubility), BZD, primidone for action tremor. Diphenhydramine: antihistamine with anticholinergic effect for mild tremor (CNS SE, avoid in elderly). Principles of therapy: if drug fails  use another class, except bromocriptine and pergolide (try both in sequence). Build dose gradually up. Never d/c drug suddenly. Late disease disabilities: Levodopa  motor fluctuation, dyskinesia,  response  control by changing dose and timing. Non-levodopa: urinary urgency  oxybutynin, constipation  fiber / PEG,  salivation  antihistamines / anticholinergics,  sweating  beta blocker / anticholinergic, orthostatic

hypotension  desmopressin, pain  amitriptyline, depression / dysphagia  liquid levodopa, daytime sleepiness  selegiline. Definitions: Dyskinesias: reversible jerky movements. On-off effect: oscillations in response and sudden changes in mobility from no symptoms to full symptoms within minutes. End-dose (wearing-off) effect: may improve by shortening the dosing interval. Drug holiday: temporary d/c of levodopa to reverse down-regulation of dopamine receptors and regain efficacy.

Individual drugs Anticholinergic agents Examples: benztropine, trihexyphenidyl (both structurally related to atropine), biperidene, procyclidine, orphenadrine. Use: mild symptoms, esp. tremors (not bradykinesia / pos. imbalance). Mechanism: block action of acetylcholine in basal ganglia. SE: dry mouth,  sweating (  heat tolerance), urinary retention, constipation (use stool softener), delayed gastric emptying,  intraocular tension, GI upset, dizziness, agitation, hallucinations, hypotension. CI: obstructed GI or GU, glaucoma, cardiac disease. Avoid drugs with anticholinergic activity (antihistamines, antidepressants, phenothiazines),  digoxin level. Avoid combo with haloperidol ( tardive dyskinesia severeity, schizophrenia,  haloperidol level).

Dopamine precursor (Levodopa/carbidopa) Most effective.  effect /  SE in 4 years. Dopamine can’t cross BBB (not used). Mechanism: Levodopa: converted by dopa decarboxylase to dopamine   dopamine in CNS (crosses BBB). Carbidopa: levodopa analog that does not cross BBB   peripheral decarboxylation of levodopa   peripheral SE,  CNS bioavailability,  dose needed by 75%. SE: due to peripheral conversion to dopamine (GI upset, arrhythmia, postural hypotension). Others: hallucinations, psychosis, blood dyscriasis, GI upset, insomnia CI: glaucoma, may activate malignant melanoma. Pyridoxine (vit B6)  ↑ peripheral decaroxylation  ↓ effect. MAOI hypertension. TCA / Food  absorption. Metoclopramide:  levodopa level. General dopamine agonist SE: ↓ BP, syncope, arrhythmia, insomnia, hallucinations, psychosis.

Direct acting dopamine agonists Ergot alkaloids (ergolines): bromocriptine, pergolide. Others: pramipexole, ropinirole. All mimic dopamine effect (direct agonist). Bromocriptine SE: first-dose cardiovascular collapse (postrual hypotension, fainting, tachycardia, dysrhythmias, dizziness), hallucinations, pulmonary toxicity, GI upset. V. long t1/2.  response variability. Pergolide Mechanism: semisynthetic ergosine derivative. 1000x more potent than bromocriptine.  prolactin,  LH,  growth hormone. SE: dysrhythmias, ↓ BP, hallucinations, insomnia, GI upset CI: 90% protein bound (cautious with other protein bound drugs), antipscychotics  contradictory effects. Non-ergot dopamine agonists Examples: pramipexole, ropinirole Mechanism: bind to dopamine D2/D3 receptors. Also, antioxidant/O2 free radical scavenger, moderate antidepressant. Start  dose and  gradually to titrate best balance of efficacy / SE. Also d/c gradually.  levodopa dose if used together. SE:  compared to non-selective agonists (motor fluctuations, dyskinesia). Orthostatic hypotension, syncope, bradycardia, hallucinations, GI upset,

CI: liver metabolism. pramipexole: cimetidine  clearance. Ropinirole: smoking  metabolism, ciprofloxacin  metabolism.

Indirect acting dopamine agonists MAO-I: Selegiline Mechanism: MAO-B selective inhibitor   catecholamine (dopamine) breakdown in the brain (MAO-A is in the GI, MAO-B is in the brain). Used when levodopa wears off. Only MAO-A metabolizes tyramine (exogenous amine in beer, wine, cheese, smoked meat)  hypertensive crisis if inhibited. SE: hypertensive crisis (possibly with tyramine but ↓ risk),  levodopa SE, dizziness, hallucinations, insomnia, orthostatic hypotension, syncope, arrhythmia, GI upset/bleeding. CI: meperidine, other opioids. Catechol-O-methyltransferase (COMT) inhibitors Examples (x-capone): tolcapone Mechanism: Selective reversible inhibitor of COMT; main enzyme for peripheral and central metabolism of catecholamines including levodopa to O-methyldopa (doubles levodopa t1/2). It can be combined with selective MAO-B inhibitor (selegiline). SE: liver toxicity (jaundice, lethargy, fatigue, appetite loss, clay colored feces, monitor ALS/AST), orthostatic hypotension, hallucinations, diarrhea,  levodopa SE, rhabdomyolysis. Amantadine Mechanism: antiviral agent used to prevent influenza. It  dopamine pre-synaptic reuptake,  dopamine synthesis and release. Some anticholinergic effect ( tremor, ridigity, bradykinesia). Fast acting drug (effect within few weeks). Drug tolerance occurs (d/c for a few weeks or use only when needed). SE: anticholinergic SE, hallucinations, dizziness, seizures, CHF, reversible skin rash (livedo reticularis), blood effect, insomnia, ∆ speech. CI:  effect of anticholinergics, HCTZ/triamterene   excretion   blood level.

Surgical treatment Require needle insertion in the brain  possible hemorrhage. Deep brain stimulation: implant  frequency electrode into target site and connect lead to SC pace maker  functional inhibition of target regions in the brain. Globus pallidus internus pallidotomy: surgical resection of parts of the globus pallidus. Retal nigral transplantation: implantation of embryonic dopaminergic cells to replace degenerated neuronal cells.

45. Schizophrenia Pathophysiology Genetic studies: 10x  in risk with family history. 50% chance in both of monozygotic twins. Neurophysiologic theories: mainly due to  dopamine. Serotonin and glutamate may play a role. Dopamine may  in some brain areas. Psychosocial theories: may be triggers but not causes. Stress,  interpersonal skills, bad family communications, socioeconomic factors. Population prevalence: 1%.

Diagnosis Using Diagnostic and Statistical Manual (DSM) of Mental Disorders. Diagnosis by exclusion after ruling out medical and mental causes of psychosis. Symptoms: delusions, hallucinations, disorganized speech / behavior, negative symptoms (6 months + 1 month active symptoms causing social or occupational dysfunction). Types: paranoid (delusions of grandeur or persecution), catatonic (psychomotor disturbances), disorganized (incoherent responses), residual (history but no acute psychosis), undifferentiated.

No known cure. Objective is to relieve symptoms and restore function. Treatment: pharmacotherapy, psychotherapy.

Antipsychotics Agent selection: based on patient history and drug safety. Atypical antipsychotics in new diagnosis or first episode (safer drugs). Antipsychotics are more effective for  positive symptoms. Maximum effect: 6-8 weeks. One episode  d/c gradually after 6 months. Multiple episodes: indefinite treatment.

Typical antipsychotics Examples: phenothiazines (chlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine, trifluperazine), haloperidol, loxapine, molindone. Mechanism: block dopamine (D2) activity. Cause hyperprolactinemia. Potency:  potency   extrapyramidal symptoms.  potency  sedation, anti-cholinergic, cardiovascular SE. Efficacy: as good as the typical drugs for the positive but not the negative symptoms. Generally, more SE than the typical drugs. Extra-pyramidal SE Acute dystonias: sudden muscle spasms (neck, jaw, back, eyes). Common in the first 2 days. Treatment: IV/IM anticholinergic (diphenhydramine, benztropine). Akathisia: motor restlessness, inner tension and agitation, urge to move (pacing). Common in the first weeks or months. Treatment; anticholinergic, beta blocker, BZD. Pseudoparkinsonism: parkinsonism induce by dopmine blockade. Common in the first weeks or months. Treatment: anticholinergic or switch to atyptical drug. Tardive dyskinesia (TD): latent extrapyramidal effect (after months / years). Abnormal movement (face, tongue, shoulders, hipds, extremities, fingers, toes, etc). Movements are fixed (dystonic) and rhythmic. It’s due to prolonged dopamine blockade  dopamine receptor up-regulation   sensitivity to stimulation. Treatment: may be irreversible, d/c therapy, when  dose symptoms may first worsen due to dopmaine blockade and still up-regulated receptors,  dose may initially mask symptoms but will remerge later. Best approach is prevention (monitor). Neuroleptic malignant syndrome (NMS) Uncommon but sudden onset, serious and may be fatal. Symptoms: extrapyramidal effects, hyperthermia, tachycardia,  BP, incontinence. Management: d/c drug, bromocriptine or dantrolene (muscle relaxant), supportive therapy.

Atypical antipsychotics Examples: risperidone, olanzapine, clozapine, quetiapine. Block serotonin more than dopamione-2 receptors. Less extrapyramidal SE than typicals. No hyper-prolactinemia. Treat negative symptoms better than typicals. Clozapine: only drug with no EPS/TD. Only effective drug for refractory patients. However, use as last resort due to agranulocytosis (monitor CBC weekly). It has  anticholinergic SE.

Other condiserations SE by recptor type: histamine H1  sedation; serotonin 5-HT  weight gain; dopamine D2  EPS / hyperprolactinemia; muscarinic  anticholinergic / cognitive / tachycardia; alpha-1  orthostatic hypotension / reflex tachycardia. Rapid tranquilization: for acute psychosis with agitation and aggression. Use injectable typical drug (IM haloperidol). Noncompliant patient: use long acting IM drugs every 3 weeks; either haloperidol decanoate or fluphenazine decanoate. Convert existing oral dose to its injectable equivalent. Switching drugs: cross taper and titrate ( old,  new). Adjunctive therapy: if 3 agent tried unsuccesfully  use clozapine or augmentative therapy (BZD anixiolytics or modd stabilizers such as lithium, valproic acid or carbamazepine).

46. Mood Disorders Mood range: depressiondysthymia (dysphoria)euthymiaeuphoria (hypomania)mania Dysphoria (dysthemia): mood depression below normal range but above depression. Euphoria (hypomania): mood elevations above normal range but below mania extreme. Euthymia: the range of normal fluctuation in mood Mood disorders: sustained elevation or depression in mood that impairs ability to function in the society. Risk of suicide:x10-20.

Major Depression Incidence: more in women (2x men). 15-20% chance in woman’s lifetime. Etiology: Biogenic amine theory: due to depletion of serotonin and norepinephrine. Dysregulation theory: cyclic nature of depression is due to impaired balance of neutrotransmitters not absolute ↓ or ↑. Familial history plays a role. Clinical depression: ↓ mood,anhedonia, appetite ↑ ↓ , weight ↑ ↓, sleep ↑ ↓, psychomotor ↑ ↓, fatigue, worthlessness, guild, ↓ thinking / concentration, suicidal Diagnosis: using Diagnostic and Statistical Manual (DSM) IV criteria. Patient must have persistent symptoms for 2 weeks.

Treatment: Psychotherapy, pharmacotherapy, and electroconvulsive therapy. Pharmacotherapy with antiderpssants is 50-60% effective. It has three phases: acute (6 wk, resolve symptoms), continuation (6-9 months, prevents relapse) and maintenance (3 or > years, prevents recurrence). Drug selection: all drugs are equally effective with different mechanisms and SE. Select drug with SE profile that complements the disease process. For example, depression with psychomotor agitation  sedative antidepressant, depression with psychomotor retardation  activating antidepressant. Therapy initiation: start with half of the lowest dose to minimize SE  ↑ to target range in 1-2 weeks, then titrate based on response. GRADUAL. Lag time exists between therapy initiation and clinical response due to changes in postsynaptic receptor sensitivity. Resolution of anxiety and insomnia in 1-2 week. Full effect in 4-6 weeks. Serotonin syndrome: tremor, seizure, hyperreflexia, hypomania, agitation, fever, diarrhea, confusion. May occur when two serotonin enhancing drugs are used concomitantly or close to each other (e.g. MAOI, SSRI). Serotonin withdrawal syndrome: lethargy, myalgia, chills, dizziness, flu-like symptoms Tricyclic Amines (TCA) Examples: amitriptyline, nortriptyline, protriptyline, imipramine, trimipramine, desipramine, doexpin Serum concentrations are established for some drugs. Mechanism: blocks serotonin and norepinephrine reuptake. Also bind to cholinergic, histaminergic, alpha-adrenergic receptors (SE). SE: anticholinergic (blurred vision, dry mouth, constipation, urinary retention), alpha blockade (orthostatic hypotension), antihistamine (sedation, take at bedtime), ↓ seizure threshold, ECG changes, lethal if overdoes. Not first choice for depression. Other uses: neuropathic pain, insomnia. Monoamine oxidase inhibitors (MAOI) Examples: phenelzine, tranylcypromine, isocarboxazid. Mechanism: ↓ monoamine oxidase  block break down of biogenic amines  ↑ serotonin and norepinephrine in the brain Not first choice for depression. Only for depression with agitation, hypersomnia, anxiety. ↑ SE: orthostatic hypotension, weight gain, edema, sexual dysfunction. Isocarboxazid  liver damage. May result in accumulation of sympathomimetic amines  hypertensive crisis  CI with decongestants, foods with tyramines (aged cheese, wine). MAO: 2 wk washout period before start or when D/C.

Bupropion (Wellbuterin) Mechanism: ↓ reuptake of epinephrine, serotonin, dopamine. SE: stimulation similar to SSRI  give in the morning, ↑ seizure esp with eating disorders. Selective Serotonin Reuptake Inhibitors (SSRI) Examples: fluoxetine, norfluoxetine, sertraline, paroxetine, citalopram, demethylsertraline, fluvoxamine (for OCD). Mechanism: selectively block serotonin reuptake  ↑ level ↓ SE: stimulation and insomnia (give in the morning), GI, sexual dysfunction, (weight gain?). Abrupt D/C  serotonin withdrawal syndrome (except fluoxetine)  D/C gradually. Metabolized by cytochrome P-450  drug interactions. Fluoxetine: norfluoxetine has long t1/2 5 wk washout period after D/C. Venlafaxine (Effexor) Mechanism: ↓ reuptake of epinephrine, serotonin, dopamine (similar to bupropion). CI: MAOI. Dose gradually. SE: nausea, GI (take with food), sustained hypertension (monitor BP). Trazadone Low dose is commonly used for insomnia with stimulating antidepressants. Mechanism: ↑ serotonin. ↑ SE: sedation, hypotension, GI Nefazodone Structure is similar to trazadone. Mechanism: ↑ serotonin. SE (↓ than trazadone): sedation, hypotension, GI, dry mouth. Interaction: ↑ protein binding  interact with warfarin, phenytoin. Cytochrome P-450 inhibitor  ↑ drugs metabolized by P-450. Mirtazapine Mechanism: ↓ presynaptic alpha-2 receptors  ↑ norepinephrine and 5-HT central concentration. Specific affinity to 5-HT1 receptors  ↓ SE compared to SSI (no insomnia, agitation, sexual dysfunction). Blocks H1  sedation, and 5-HT2c  ↑ appetite. SE: sedation (take at bedtime), weight gain, dry mouth.

Bipolar disorder Incidence: 1% of the population. More common in female teens or early 20’s. Etiology: Family history in 90% (genetics). Due to imbalance and fluctuation in neurotransmitter levels. ↑ norepinephrine  manic episode, ↓ norepinephrine  depression. ↓ GABA (gamma-aminobutyric acid, inhibitory neurotransmitter)  mania, due to unopposed excitatory neurotransmitters (norepinephrine, dopamine). ↓ calcium in CSF  mania. ↑ calcium in CSF  depression. G protein: involved in signal transduction and activation of other neurotransmitters. Hyperactive G protein  mood instability. Glutamate binding to G proteins linked to NMDA is involved. Psychosocial and physical stressors trigger early episodes. Diagnosis: using DSM-IV and history of mania and depression. Mania: elevated, expansive or irritable mood for 1 week. Grandiose ideations, expansive self-esteem, ↓ sleep, racing thoughts, distraction, psychomotor agitation, dangerous activities. Mixed episode (mood incongruent): mania and depression symptoms. Bipolar I: manic or mixed episode. Bipolar II: depressive and hypomanic episode. Cyclothymia: depressive and manic symptoms for 2 years. Rapid cycling: four depressive, manic, hypmanic or mixed episodes in 12 months Clinical course: untreated episodes last days to months. Interval between episodes: 1-2 years. Episode sequence is unpredictable. Early onset  bad prognosis.

Treatment Acute, maintenance and continuation phases (like depression). Antipsychotics, antidepressants, and mood stabilizers may be used. Antipsychotics: short term therapy during acute mania to ↓ psychosis and agitation. Antidepressants: use for depression with suicidal tendency. Use cautiously to avoid triggering mania. Lithium First line therapy (except for mixed episodes or rapid cycling). Monovalent cation like Na and K. Citrate salt  liquid, carbonate salt  tablet. Food may delay absorption. Take with food to avoid rapid rise in serum concentration and SE. Highly distributed but takes 3 days  delayed response. Eliminated through the kidneys with no metabolism. nd Mechanism: unknown. ↓ norepinephrine / serotonin, ↑ membrane stabilization, ↑ cAMP / cGMP (2 messengers). Dose: narrow therapeutic index. Can be used to acute mania (↑ and ↓ dose gradually, quick action for mania but slow for deperssion) or preventative maintenance (mania, depression). Require Cp monitoring. If high dose  psychosis, psychomotor agitation  give BZD or antipsychotics. SE: ↑↑↑. Monitor Cp. Categorized into early, long term, and toxicity. Polydipsia, polyuria, nocturia, dry mouth, weight gain, ↓ libido, tremors, CNS. Toxicity: use emesis, gastric lavage, hemo- or peritoneal dialysis but not charcoal. st CI: renal failure, pregnancy 1 trimester. Interactions: drugs that ↑ serotonin  serotonin syndrome. With BZD, antipsychotics  ↑ neurotoxicity. Valproic Acid (VA) Indications: anticonvulsant that works as a mood stabilizer. Can be used in acute episodes or as a mood stabilizer. Forms: elixir  sodium valproate, capsules  VPA, enteric coated tabs  divalproex, injections  sodium valproate sodium SE: ↑↑. Monitor Cp. Blood (agranulocytosis, thrombocytopenia), weight gain, liver / pancreas damage, GI upset (↓ in divalproex). CI: sensitive to enzyme inhibitors and inducers. CBZ Indications: anticonvulsant that works as a mood stabilizer. Use in bipolar if lithium fails. nd Mechanism: modulate NEp and cAMP (G protein-linked 2 messenger system). SE: CNS: drowsiness, dizziness, blurred vision, diplobia, nystagmus, confusion, headache. Dose related: blood dyscrasias, ↑ dose gradually to avoid SE, GI upset (take with food). Non dose related: skin SE. Metabolic enzyme inducer (drug interactions, monitor Cp). Complete monitoring (blood count, live function, BUN, electrolytes, TSH). New Mood stabilizers (anticonvulsants) (gabapentin, lamotrigine) Indications: both mood elevation during epilepsy. Not approved, though, for mood stabilization (no systematic data). Lamotrigine: structure is similar to phenytoin and CBZ. Mechanism: block sodium-mediated release of glutamate and aspartate, may also block GABA and Ach release. SE: dizziness, blurred vision / diplobia, GI upset, rash / photosensitivity. Gabapentin: structure is similar to GABA (but no effect on GABA). Mechanism: unknown. ↑ dose gradually. Short t1/2  frequent administration. SE: somnolence, dizziness, nystagmus, fatigue.

Other topics Use of dual mood stabilizers Combination of lithium and CBZ or VPA. Watch for leukocytosis / leukopenia. Do not combine CBZ and VPA (↑↑ blood dyscrasias). May also combine one of the three (older drugs) with one of the two newer drugs (above).

Mood stabilizers in pregnancy nd rd Older drugs (lithium, VPA, CBZ) may cause birth defects. If necessary, use lithium only in 2 and 3 trimester. If necessary, give folic acid with VPA to ↓ risk.

47. Asthma and COPD Asthma Definition Reversible chronic airway inflammation. It involves obstruction, ↑ airway responsiveness, episodic asthma symptoms. Pathologic changes are not permanent. Classification: mild intermittent, and persistent (mild, moderate, severe) Incidence: 15 million Americans (one third children). 50% of children outgrow asthma by mid-teens, may return to asthma later in life.

Etiology Allergens (pollen, dust mite, animal dander, mold, food), occupational exposures (chemicals, flour, wood, textile dust), viral respiratory infections, exercise, emotions (anxiety, laughter, stress, crying), irritant exposure (odors, chemicals, irritants), environmental exposure (weather change, cold air, smoke, sulfer dioxide), drugs (hypersensitivity, aspirin, NSAID, cholinergics (bethanechol), anti-adrenergics (B blockers)). Allergic rhinitis is twice as common in asthmatics.

Pathology / pathophysiology Postmortem examination: smooth muscle hypertrophy, airway plugs (inflammatory cells, debris, proteins, mucus), vessel vasodilatation, inflammatory cellular infiltrate, collagen deposition. Major contributing processes Inflammatory cells: such as mast cells, eosinophils, activated T cells, macrophages, epithelial cells  secrete mediators. Airway obstruction: due to bronchoconstriction, airway wall edema, mucus plug formation, airway remodeling, smooth muscle hypertrophy, hyperplasia. Obstruction  ↓ ventilation  ventilation / perfusion (V/Q) imbalance  hypoxemia and ↓ partial pressure of arterial oxygen (PaO2). Hyper-responsiveness: ↑ response to stimuli due to ↑ inflammatory mediators and infiltration by inflammatory cells. Airway inflammation: contributes to hyper-responsiveness, obstruction, respiratory symptoms, ↓ mucociliary function, ↑ airway permeability to allergens / irritants. Autonomic neutral control: ↑ cholinergic sensitivity ↑ parasympathetic tone, reflex bronchoconstriction. Airway remodeling: due to persistent inflammation in poorly controlled asthma  collagen deposition and fibrosis  permanent airway abnormalities. Sequencing of events in asthma Triggering: exposure to trigger (allergen, aspirin, virus, etc)  antigen binds to IgE  attach to activated mast cells. Early response: begins in < 30 min and resolves in < 2hr, blocked by beta agonist or cromolyns. Late response: begins 6 hr after trigger, persistent airway obstruction, inflammation, hyperresponsiveness, occurs in 50% of cases, may last several days, blocked by corticosteroids or cromolyns. Signaling: inflammatory cells (mast cells, lymphocytes, eosinophils, macrophages, epithelial cells) release chemical signals (cytokines, chemokines, eicosanoids, leukotrienes)  attract more inflammatory cells. Migration: influx of inflammatory cells (eosinophils, lymphocytes, monocytes, granulocytes); ↑ adhesion molecules  attract cells to the airways. Cell activation: required before cells can release inflammatory mediators. Eosinophils activation  ↑ inflammatory mediators  smooth muscle constriction, initiate chemotaxis. Leukotrienes 

bronchoconstriction, ↑ mucus, ↑ vascular permeability, ↑ responsiveness. Other mediators recruit more inflammatory cells to the airways in the late asthmatic response. Tissue stimulation and damage: due to release of inflammatory mediators from activated cells. Epithelial damage  ↑ airway responsiveness  may cause remodeling.

Clinical evaluation Physical findings Acute exacerbations: occur suddenly or gradually, usually at night or early morning. Shortness of breath, tachypnea, tachycardia, wheezing at end of exhalation, chest tightness, cough. Chronic poorly controlled severe asthma: chronic hyper-inflation, barrel chest. Signs of respiratory distress: cyanosis (↓ PaO2 / ↑ PaCO2), use of accessory muscles, inability to speak in sentences, ↓ mental status, PEFR < 50% of normal. Potentially fatal asthma: history of sudden severe exacerbations, poor self-perception of asthma, history of intubation or ICU admission, visits to ER or hospitalization for asthma, frequent beta agonist use (>2 canisters / month). Diagnostic tests Pulmonary function tests: determine degree of obstruction, may be normal between exacerbations. Forced expiratory volume in 1 second (FEV1): ↓ during exacerbation. Air trapping and lung hyperventilation  ↑ residual volume (RV), ↑ total lung capacity (TLC). Peak expiratory flow rate (PEFR): correlates with FEV1, used to monitor therapy, triggers, need for emergency care. Measure PEFR in early morning before medications, and may be again midday. Diurnal variation > 20% in PEFR indicate ↑ responsiveness, and poor control. Blood analysis: ↑ WBC count during acute exacerbation, eosinophilia, leukocytosis (due to WBC demargination due to corticosteroids). Sputum analysis: may reveal eosinophils, clumps of epithelial cells, bacterial if infected, mucous in small airways. Pulse oximetry: noninvasive measure of degree of hypoxemia during acute exacerbation. It measures oxygen saturation in arterial blood (SaO2) and pulse. Arterial blood gas: help gauge the severity of exacerbations. Early stages  hyper-ventilation  ↓ PaCO2  fatigue of respiratory muscles. Respiratory acidosis: poor prognostic sign  respiratory fatigue  ↓ respiratory rate  ↑ PaCO2. ECG: may show sinus tachycardia, especially in the elderly. Chest radiograph: may show pneumonia, hyperinflation. Allergy skin and radioallergosorbent test: identify possible allergic triggers.

Complications Status asthmaticus: severe asthma exacerbation that fails to respond to therapy  life threatening. Symptoms: ↓ consciousness, cyanosis, ↑ PaCO2, PEFR < 100 L/min or FEV1 < 1 liter. Treatment: oxygen, inhaled beta agonist, anticholinergic, IV steroids. If respiratory acidosis  tracheal intubation, mechanical ventilation. Pneumothorax: acute exacerbation with air accumulation in the pleural space. Symptoms: chest pain, dyspnea, cough, anxiety, lung collapse. Treatment: oxygen, pleural air aspiration, analgesics. Atelectasis: airway obstruction  ↓ gas exchange during respiration  collapsed lung. Symptoms: worsening dyspnea and anxiety, hyperventilation, ↓ breath sounds, cyanosis. Treatment: postural drainage, chest percussion, coughing / breathing exercise, bronchodilators, bronchoscopy to remove secretions.

Therapy principles Acute exacerbations At home: depends on EFV or PEFR. If < 50% of personal best  aggressive treatment. Limit inhaled albuterol to 3 treatments of 3 buffs by MDI at 20 min intervals or one nebulizer treatment. If response is poor  use oral corticosteroid, go to ER if needed. In the hospital: inhaled albuterol, mechanical oxygen ventilation (up to 90% saturation), anticholinergic, oral or IV corticosteroids, intubation.

Persistent asthma Step-down approach: aggressive. Start treatment one step above assessed severity for rapid control, review every 3 months. Then, do gradual step-wise reduction in treatment. Step-up approach: start treatment at the same step as assessed severity, and adjust upward as needed. Always, control environment to avoid triggers. If daily or ↑ use of inhaled albuterol  consider long-term therapy (e.g. anti-inflammatory). A rescue course of systemic corticosteroids may be used. Exercise-induced bronchospasm (EIB) Warm-up period helps prevent EIB. Prevent EIB by using short acting beta agonist (albuterol) 15 min before exercise, long acting beta agonist (salmeterol) 45 min before exercise, or cromolyn sodium 1 hr before exercise. Keep albuterol handy. Chronic asthma (NIH guidelines) Severe persistent: ↑ dose inhaled steroid + ↓ dose oral steroid + long acting bronchodilator (inhaled or oral salmeterol, SR theophylline). Moderate persistent: inhaled steroid + long acting bronchodilator for nigh time symptoms (inhaled or oral salmeterol, SR theophylline) (drop oral steroid). Mild persistent: only one of the following: ↓ dose inhaled steroid, inhaled cromolyn, SR theophylline, leukotriene modifier. Mild intermittent: no daily medications. Albuterol for attacks.

Therapeutic agents Beta agonists Short acting: albuterol (R- and S- isomers), levalbuterol (only active R-enantiomer), metaproterenol, pirbuterol, for acute exacerbation and EIB prophylaxis. Long acting: salmeterol, formoterol for asthma maintenance, EIB prophylaxis, nocturnal symptoms, ↑ ↑ albuterol use, COPD. Mechanism: stimulate beta 2 receptors  ↑ adenyl cyclase  ↑ cAMP  bronchodilation, ↑ mucociliary clearance, ↓ inflammatory cell mediator release. SE: tremors (due to B2 activation in skeletal muscles), gluconeogenesis (↑ glucose), activation of Na K ATPase, cardiac stimulation (due to partial B1 stimulation: palpitation, tachycardia), nervousness, headache. Administration: inhalation ↓ systemic SE (preferred over oral). Always use salmeterol with inhaled steroid, except for EIB prophylaxis. May combine long and short acting. Tachyphylaxis: occurs due to regular use. It’s due to down-regulation due to moving of beta receptors from cell surface to inside the cell. Effect may be reversed with steroids. Paradoxical bronchoconstriction: due to cold-Freon effect or use of adjuvants. ↑ bronchial hyperactivity: due to irritants such as methacholine and histamine. May be due to albuterol’s S-isomer. Drug interactions: hypertensive crisis with MAO inhibitors, TCA and methyldopa. Beta blockers (e.g. propranolol)  bronchospasm. Combined with sympathomimetics  ↑ heart effect, vasoconstriction (prevent by alpha blockers, phenolamine). Corticosteroids Mechanism: Bind to glucocorticoid receptors in the cell cytoplasm  alter gene transcription  ↓ inflammatory response, ↓ airway hyper-responsiveness, ↓ mucus. Use: in case of allergic component. Added only when anticholinergic / beta agonist combo is ineffective. Systemic steroids: used for rapid response during acute exacerbations (few hours). IV steroids: hydrocortisone and methylprednisone. Alternative to oral steroids to prevent respiratory arrest in hospitals. Switch to oral steroids after stabilization. Oral steroids: prednisone, prednisolone. Used in emergencies if possible when there is no risk of respiratory arrest. Used in burst doses for a week. Dose tapering may be required. Inhaled steroids: fluticasone, flunisolide, triamcinolone, beclomethasone, budesonide. Used for chronic treatment, not for acute exacerbations. Less SE and less efficacy. ↑ steroid penetration into bronchial tree by giving bronchodilator several minutes prior.

Systemic steroids SE: hyperglycemia, ↑ BP, CHF, peptic ulcer, immunosuppression, chronic infections, osteoporosis, glaucoma, depression, psychosis, cataract, skin changes. If long term, minimize SE by giving morning dose or alternate day dosing. Inhaled steroids SE: fungal infection, voice hoarseness, dry mouth. May ↓ children growth velocity, but uncontrolled asthma also retards growth. Systemic SE with large doses. Gargle and wash mouth after use to ↓ fungal infections, systemic absorption. Interactions: enzyme inducers (rifampin, barbiturates, hydantoins)  ↑ steroid metabolism. Oral contraceptives, estrogens, enzyme inhibitors  ↓ steroid clearance. ↑↑ hypokalemia with thiazide and loop diuretics, amphoterecin  ↑ digitalis toxicity. Cyclosporine  ↑ steroid concentration. Leukotriene modifiers Leukotrienes: derivatives of fatty acids formed by lipoxygenase. No ring structure. Covalently linked to 23 amino acids. Slow reacting substances of anaphylaxis. ↑ eosinophil and neutrophil migration, ↑ leukocyte adhesion, ↑ neutrophil and monocyte aggregation, ↑ capillary permeability, ↑ smooth muscle contraction, ↑ mucous secretion, bronchoconstriction, . Effect: anti-inflammatory and bronchodilation  ↓ steroid dose. Leukotriene receptor antagonists (x-lukast) Examples: zafirlukast, montelukast Mechanism: prevent interaction of leukotrienes with receptors by ↓ cysteinyl leukotriene-1  block effect of histamine in asthma and allergy reactions. Take zafirlukast on empty stomach (max absorption). SE: ↓↓, can be used in children. GI upset, dizziness. Churg-Strauss syndrome: eosinophilic vasculitis angiitus when steroids are d/c or ↓. DI: enzyme inhibitor, ↑ effect of warfarin / theophylline. Lipoxygenase inhibitor (Zileuton) Mechanism: blocks 5-lipoxygenase  ↓ leukotrienes synthesis from arachidonic acid. SE: liver dysfunction and ↑ ALT (monitor, esp in alcoholics). Others (mild): headache, GI upset, myalgia. DI: ↑ effect of warfarin, theophylline, propranolol. Mast cell stabilizers (Cromolyn, nedocromil Na) Effects: Nonsteroidal anti-inflammatory. Less effective than steroids. Used only for asthma maintenance, EIB prevention. Mechanism: ↓ mast cell degranulation, ↓ inflammatory cells. SE: ↓↓, used in children. Wheezing, coughing, nasal congestion, throat irritation / dryness. Methyl xanthines (theophylline) Use: alternative to B-agonists and steroids in acute attacks and to long acting B-agonist in persistent asthma. Combine with inhaled steroids  control night or early morning symptoms. Effects: ↓ mucus, ↑ mucociliary transport, ↑ respiration, anti-inflammatory, ↑ renal diuresis. Mechanism: ↓ phosphodiesterase  ↑ cAMP, antagonize adenosine receptors. Less bronchodilation than B-agonists. Oral (SR): ↑ compliance. ↓ fat tissue distribution, calculate dose based on lean body weight. Gradually titrate dose upward. IV: rare. Start with loading dose, then maintenance infusion. Theophylline anhydrous  oral solids, theophylline monohydrate  oral solutions. Aminophylline  IV. SE: palpitations, restlessness, nervousness, insomnia, seizures, GI upset, diarrhea, dizziness. Do not use in pregnancy. Therapeutic drug monitoring: monitor SE, serum level, other drugs use. Clearance is age and condition specific. Interactions: multiple drug and other interactions. ↑ clearance (↓ level) with smoking, ↑ protein. ↓ clearance (↑ level) with age (↑↑ or ↓↓) , fats and carbohydrates, CHF. CI: peptic ulcer or uncontrolled seizure. Anticholinergics Postganglionic muscarinic block  bronchodilation.

Use: more effective in COPD than in asthma. Ipratropium sodium: quaternary ammonium compound. Used with or as an alternative to beta agonist in acute attacks. Slow onset and long duration compared to beta agonists  give regularly. SE: ↑ intraocular pressure if touches the eye, ↓ anticholinergic. Atropine aerosols, glycopyrrolate (quaternary ammonium compound): rarely used due to ↑ SE and ↓ efficacy. Used in nebulizers Other drugs Antihistamines: if patient has allergic rhinitis. Prevent release of histamine mediated response that influence asthma. Antibiotics: used to treat infections (change in volume, color, viscosity of sputum). Sputum cultures are useless because COPD are chronically seeded. Chronic antibiotic preventative used can be considered in case of frequent exacerbations. M. pneumoniae or Legionella pneumophilia  macrolide . C. nd rd pneumoniae  oral doxycycline. Pneumonia in the hospital  2 or 3 generation cephalosporin or beta-lactam with b-lactamase inhibitor. Magnesium sulfate (IV): cause little bronchodilation, ↑ respiratory muscle strength in hypomagnesemic patients. Immunotherapy: may ↑ lung function, ↓ symptoms. Non-pharmacologic Humidified O2: ↓ flow rate helps reverse hypoxemia (use if PaO2 < 55 mmHg), esp. at night/during exercise. Goal: SaO2 > 90%. Heliox: helium / oxygen mixture that is less dense than air  ↑ ventilation during acute attack. IV fluids: and electrolytes are given if volume is depleted. Environmental control: avoid allergens and triggers. Use allergen-resistant mattresses / pillow encasements, ↑ filtration vacuum cleaners, avoid ferry pets, carpets and draperies. Vaccines: used to prevent infections that may trigger asthma (e.g. influenza and polyvalent pneumococcals). Drug delivery options MDIs: accurate with good technique and a spacer. A facemask may be needed for children. Wait 1 min between buffs. Spacers and holding chambers: ↓ drug deposition in the upper airway, ↓ oral absorption, ↓ local / systemic SE. Spacers are important for ↑ dose steroids or if hand-lung coordination is poor. Nebulizers: require ↓ patient coordination. Disadvantages: cost, time consuming, ↑ size, inconsistent drug delivery. Used in ↑ dose beta agonists, anticholinergics, cromolyn in children. Dry powder inhalers: more common, avoid the use of Freon propellants, easier to use. First load the dose, and then inhale rapidly. No spacers. Keep away from moisture.

COPD Chronic bronchitis Definition: excessive mucus production by the tracheo-bronchial tree  edema and bronchial inflammation  airway obstruction. Pathophysiology: respiratory tissue inflammation  vasodilation, congestion, mucosal edema  ↑ mucus. Neutrophils infiltration. Cilia impairment. Cartilage atrophy. Airways become blocked by thick, tenacious mucus secretions  sputum rich productive cough. Normally sterile airways become colonized by Strept pneumoniae, H influenza, Mycoplasma. Recurrent viral / bacterial infections  ↓ body defenses, ↑ mucus accumulation, ↓ ciliary activity. Airway degeneration  ↓ gas exchange  exertional dyspnea. Hypoximia, ↑ PaCO2 (hypercapnia). Physical findings: chronic productive cough after age 45 (first in winter, worse in the morning). Progressive exertional dyspnea, obesity, wheezing, prolonged expiration, right ventricular failure, cyanosis (called “blue bloater”) Diagnostic tests: hypoxemia  ↑ erythropoiesis  polycythemia (↑ RBCs). ↑ WBC due to infections. Sputum: thick, colored (if infected), ↑ neutrophils, microorganisms. Arterial blood gas: ↓ PaO2 (hypoxemia), ↑ PaCO2 (hypercapnia). ↓ FEV1. Right ventricular hypertrophy and cor pulmonale in ECG.

Emphysema Definition: permanent alveolar enlargement and destruction of the alveolar walls, ↓ alveolar surface area. Pathophysiology: Inflammation, ↑ mucus secretion  alveoli air trapping.  tissue damage  ↓ space into which normal lung tissue expands.. Alveoli merge  ↑ space for air trapping. Alveolar wall destruction  small airways collapse. Hypercapnia and respiratory acidosis are uncommon because of compensatory ↑ in respiratory rate. Physical findings: cough is chronic but less productive than in chronic bronchitis, starts at age 55. Exertional dyspnea is progressive, constant, more severe than in bronchitis. Other findings: weight loss, tachypnea, prolonged expiration, ↓ breath sounds. Patient usually maintain good oxygenation through tachypnea  “pink buffer”. Diagnostic tests: small chance of ↓ AAT in blood or infections in sputum. ↓ PaO2 and ↑ PaCO2 in arterial blood gas, ↓ FEV1.

Etiology Smoking: causes pulmonary hyperactivity and persistent airway obstruction. Alpha-1 antitrypsin (AAT) is a serine protease inhibitor  ↓ neutrophil elastase. ↑ risk of COPD when smoking is combined with genetic ATT deficiency. Others: exposure to irritants (sulfur dioxide, polluted air, noxious gases, dusts), family history, social, economic factors.

Complications Pulmonary hypertension: lung congestion  ↓ pulmonary vascular bed space  pulmonary hypertension  cor pulmonale (right ventricular hypertrophy)  right heart failure. Acute respiratory failure: advanced emphysema  brain respiratory center damage  ↓ cerebral oxygenation  ↑ PaCO2  hypoxia, respiratory acidosis  respiratory failure. Infection: chronic bronchitis  trapping of excessive air, mucus, bacteria and ↓ coughing and deep breathing  infection. Polycythemia: ↑ in RBCs  hypercoagulate state, embolism, stroke.

Therapy Anticholinergics: First line treatment for COPD. Beta blockers, corticosteroids, theophylline, O2, etc (see above) Mucolytics: such as acetylcysteine  ↑ sputum clearance, ↓ mucus plugs. May cause bronchospasm. Expectorants: such as guaifenesin. Avoid potassium iodide. Chest physiotherapy: loosens secretions, re-expand lungs, ↑ efficacy of respiratory muscle. More important in outpatient. Physical rehabilitation: ↑ exercise tolerance and ↑ diaphragm and abdominal muscle tone. Smoking cessation: and avoidance of irritants. Use drugs with behavior intervention for maximum success. Surgery: lung volume reduction therapy

48. Rheumatoid Arthritis Introduction Definition: chronic, systemic, autoimmune, inflammation of the synovial joint. More common in women (2-3:1). 2% of the population.

Classification: Four of the following criteria have to be met 1. Morning stiffness for 1 hour before improvement 2. Three joints have fluid or soft tissue swelling 3. One joint in the hand joints must be swollen. 4. Symmetric arthritis: involvement on both sides of the body.

5. Subcutaneous (rheumatoid) nodules 6. ↑ serum rheumatoid factor 7. Radiological erosion or decalcification of bones May also include extra-articular organ manifestations (GI, infections, etc)

Etiology Human leukocyte antigen (HLA-DR4) + environmental factor  inappropriate immune response  chronic inflammation Tumor necrosis factor (TNF) ↑ in RA and Crohn’s disease. Infections may ppt RA in predisposed patients, e.g., polyarthritis with lyme disease

Pathogenesis Vasodilation, edema, sensation of heat, loss of function, ↑ production of thick boggy synovial fluid, effusion accumulation. Pannus: exuberant synovial thickening due to inward overgrowth of enlarged synovium across the surface of articular cartilage  cartilage degradation, bone loss, x-rayed marginal erosions, bone rubbing, pain.

Clinical course Variable and unpredictable, polycyclic course (intermittent remissions) or progressive course (relentless rapidly advancing destructive deforming inflammation  permanent join deformities  progressive functional decline, ↓ range of motion, work disability, loss of 4-10 years of life expectancy. Early symptoms: aching, joint pain, fatigue, then hand and feet synovitis (swelling, warmth, tenderness). Morning stiffness: maximal pain and stiffness on awakening (30 min)

Diagnosis and clinical evaluation Mainly clinical joint evaluation with lab and x-ray results. Rheumatoid nodules: firm, round, rubbery masses in the SC of joints prone to pressure (e.g. elbows). X-ray: soft tissue swelling, osteoporosis, erosions. Laboratory findings: ↑ Rheumatoid factors (antibodies) especially IgG and IgM, ↑ erythrocyte sedimentation rate due to inflammation, microcytic anemia, antinuclear antibody test. Monitoring parameters: morning stiffness duration, number of affected joints, severity of pain, range of motion, deformity and circumference of joints, time to walk 50 feet, depression, weight loss, sedimentation rate.

Therapy Mechanical therapy A balanced daily program of rest and exercise (↑ muscle strength and joint motion). Use lightweight splints during night (or even day) to align joints. Avoid complete immobilization. Consider joint replacement.

Symptomatic pharmacological therapy Aspirin First line agent, first as analgesic and then ↑ dose for inflammation. Dose: 4-5 g daily. SE: bleeding and ↓ platelet function (7 days after d/c), tinnitus in ↑ doses, GI (↓ by enteric coating or taking with food) Nonacetylated salicylates Examples: salsalate, choline salicylate  safer for aspirin sensitive patients. ↓ anti-inflammatory effect, ↓ respiratory SE, ↓ effect on platelets.

Other NSAID Examples: naproxen, ibuprofen, sulindac, piroxicam. May be better tolerated than aspirin. Try for 2 weeks before change. Chemistry: x-en  propionic acids, others  acetic acids. Avoid in asthmatics  may trigger bronchospasm. ↑ bleeding time /↓ platelet function (effect reverse quickly if d/c) GI upset, ulceration, hemorrhage (↓ platelets). ↓ GI ulcers by using misoprostol (Cytotec, ↑ SE: diarrhea) or H2-antagonists. Ibuprofen, naproxen  ↓ GI SE  available OTC. Piroxicam  ↑ GI SE, CI in elderly. ↓ renal blood flow  renal failure (esp with diuretics or CHF). Temporary CNS effects (headache, drowsiness, confusion, anxiety, etc) esp. with indomethacin. Avoid in the elderly. Meclofenamate: diarrhea COX-2 inhibitors Rofecoxib, celecoxib, valdecoxib. Anti-inflammatory, analgesic, antipyretic with ↓↓ GI SE.

Second line agents Known as Slow Acting Anti-rheumatic Drugs (SAARD) or Disease Modifying Anti-Rheumatic Drugs (DMARD). They modulate immune response to ↓ progression of erosion. All slow are acting (min 3 months for effect), except methotrexate. Used w/ NSAID. All have ↑↑ SE. Methotrexate (Rheumatrex) First line for severe RA. Immunosuppressive folic acid antagonist and antineoplastic. Give a weekly dose, oral or IM. Aspirin ↓ methotrexate secretion  ↑ toxicity SE: GI, bone marrow suppression, hepatitis, ↑ infection. Give folic acid supplements. CI in creatinine < 40. Pregnancy X. Azathioprine (Imuran) Purine analogue immunosuppressive antimetabolite. Converts to 6-mercaptopurine  ↓ purine synthesis  cytotoxicity to dividing cells   lymphocyte proliferation. SE: GI, hepatitis, bone marrow depression. Also for leukemia. 2 Antidote: Leucovorin Ca (tetrahydrofolic acid derivative) Gold compounds IM: gold sodium thiomalate, aurothioglucose. SE: proteinuria. Oral: auranofin. SE: metallic taste, diarrhea, GI, stomatitis General SE: blood toxicity, rash. Gradual build up of dose. Try for a min of 6 months Penicillamine (Depen) ↓ immune response. Taken on empty stomach to ↑ absorption. Dosing: do low-go slow. ↑ SE: rash, fever, proteinuria, hematologic, autoimmune diseases. Other drugs Hydroxychloroquine (Plaquenil): antimalarial for mild RA. ↓ SE: Retinal toxicity (retinopathy) due to drug deposition in the cones  monitor for vision acuity. GI upset. Sulfasalazine (Azulfidine): very effective in slowing progress of joint damage. SE: GI, rash, rare blood dyscrasias, hepatitis Cyclophosphamide (Cytoxan): Toxic antineoplastic prodrug. SE: ↑↑, hemorrhagic cystitis (treat with mesna), bone marrow depression, sterility, alopecia. Etanercept / Infliximab: TNF-alpha inhibitor  ↓ TNF (cytokine) binding to inflammatory cell surface. Biological Response Modifier. Given SC. SE: respiratory infections, autoantibody formation. NO effect of kidney function. Leflunomide: immuno-modulator. Mechanism: ↓ dihydroorotate dehydrogenase (critical for pyrimidine synthesis). SE: rash, diarrhea, alopecia, rash, anemia. Pregnancy X.

Mycophenolate mofetil: immuno-suppressant. SE: diarrhea, GI, hematologic. Used to prevent cardiact and renal allograft rejection. Other drugs: chlorambucil, cyclosporine, minocycline. Corticosteroids Prednisone. Last resort. They do not alter the course of RA. Used for acute flare ups, before action of slow acting drugs kicks in, systemic RA symptoms, or in case of intolerance to other drugs. Can be used as intra-articular injection if symptoms are localized. SE: GI bleeding, slow wound healing, hyperglycemia, hypertension, osteoporosis.

Topical therapy Capsaicin: for symptomatic treatment. It’s the pungent ingredient of hot pepper. Mechanism: depletes and prevents accumulation of substance P, a chemical mediator in pain transmission from the periphery to CNS (sensory nerve fibers). It produces a sensation of warmth. Use: joint pain, arthritis tenderness, neuralgia, psoriasis. SE: erythema (reflex vasodilation), histamine release. Counter-irritants: methyl salicylate, menthol, allyl isothiocyanate, produce a mild inflammatory reaction. Effect may be actually due to the massage during application not the drug itself.

Combination second line therapy Step-down bridge approach: combo of antimalarial, oral gold, parenteral gold and methotrexate. Remove medications and taper dosage after 3 months to the antimalarial alone. Saw-tooth strategy: use second line agent early and serially substitutes with other agents before previous agents lose efficacy. Graduated-step paradigm: combo therapy only for patients at active disease. Escalate treatment as needed.

49. Hyperuricemia and Gout Introduction Hyperuricemia: ↑ serum uric acid > 7 mg/dl. Gout: recurrent acute attacks of urate crystal-induced arthritis. It may include tophi-deposits of monosodium urate. Incidence: 1% of the population, almost all men. ↑ risk with alcoholism, obesity. Uric acid synthesis: purine  xanthine oxidaze  urice acid (adenine and guanine are purine bases). One gram in the body. No biological function. 66% daily turnover. Uric acid elimination: 66% through the kidneys, 33% through the GI. At urine pH (acidic, 4-5)  poorly soluble free uric acid. At physiologic pH (7.4)  uric acid as monosodium urate salt. Asymptomatic hyperuricemia: ↑ serum uric acid but no symptoms of arthritis. May be harmless. Drug treatment may be unnecessary. May develop gout later. Maintain good urine output to prevent stone formation, ↓ purine foods, monitor.

Etiology Primary: due to defect in purine metabolism or uric acid excretion. It is due to uric acid ↑ production or ↓ renal clearance or both. Under-excretors (90%): excrete < 600 mg/day on a purine restricted diet. Secondary: renal failure (↓ excretion), hematologic diseases (↑ nucleic acid breakdown to uric acid). Drug induced gout: Ethanol  ↑ production and ↓ secretion. Aspirin and salicylates  ↓ uric acid tubular secretion (↓ excretion). Diuretics (except spironolactone)volume depletion / ↓ tubular secretion. Cyclosporine, pyrazinamide, levodopa  ↓ urate renal clearance. Ethambutol, nicotinic acid  compete for urate secretion  ↓ excretion Cytotoxic drugs  ↑ nucleic acid turnover.

Pathophysiology Gouty arthritis develop when monosodium urate crystals deposit in the join synovium  inflammatory response  gout attack  join swelling, redness, warmth, tenderness  tophi (urate deposits)  joint deformity, disability, renal impairment. Renal complications: Acute tubular obstruction: due to uric acid pptn in the ureters and collecting tubes. Urolithiasis: uric acid stones due to low urine pH. Chronic urate nephropathy: urate deposits in the renal interstitium.

Acute gouty arthritis Painful arthritic attacks of sudden onset. Triggers: trauma, cold exposure. Initial attack is abrupt and usually occur at night or early morning  very hot swollen, tender joints. Podagra: attack in the metatorso-phalangeal joint. Attacks last 1-2 weeks (longer as the disease progresses). May include fever, chills, malaise. Diagnosis: Urate needle-shaped crystals in synovial fluid (-ve birefringence). Serum ↑ urate, ↑ erythrocyte sedimentation rate, ↑ leukocytes. Dramatic therapeutic response to colchicine. Acute attack pattern with remission periods.

Therapy Immobilize affected joints. Start anti-inflammatory drugs immediately. Start urate-lowering drugs after attack is over. Colchicine: drug of choice for ↓ pain and inflammation and ending the attack. Mechanism: antimitotic, ↓ chemotaxis of leukocyte to inflamed area, ↓ phagocytosis and ↓ urate deposition. Orally or IV (never IM or SC due to irritation). ↑ SE: diarrhea, GI, bone marrow depression, irritation if given IM. NSAIDs: if first choice is colchicine is not tolerated or not started immediately. Examples: indomethacin, naproxen, sulindac. SE: GI, CNS headache and drowsiness / dizziness. Take with food. Aspirin ↓ dose  ↓ uric acid secretion, ↑ dose  ↑ uric acid secretion. Corticosteroids: Methylprednisolone acetate given intra-articular with diagnostic / therapeutic aspiration. Prednisone (oral), Triamcinolone acetonide (IM) or methylprednisolone (IV).

Intercritical gout Symptom free period between attacks. Non-drug urate lowering: ↓ high-purine diet (meats, legumes), ↓ obesity, ↓ alcohol. Limited effect. Prophylaxis: ↓ dose colchicine or NSAID. Urate lowering therapy ( 20%. Coffee: peptides in regular and decaf coffee  ↑ gastrin release  ↑ gastric juice flow. A direct coffeeulcer link is not proven. Associated disorders: ↑ incidence with hyper-parathyroidism, emphysema, rheumatoid arthritis, alcohol cirrhosis. Advanced age: pylorus degradation  ↑ bile reflux into the stomach  ↑ ulcers. Corticosteroids: NO link between corticosteroids and ulcers. Psychological factors: minor factor, contrary to the opposite belief.

Pathophysiology Ulcers occur due to imbalance between factors protecting gastric mucosa and factors causing mucosal corrosion. Protective factors: thick mucosal mucus is a barrier between luminal acid and epithelial cells. This barrier ↓ inward movement of hydrogen ions and allow neutralization by bicarbonate ions in fluids secreted by the stomach and duodenum. Alkaline and neutral pancreatic biliary juices buffer acid entering duodenum from the stomach. Corrosive factors: gastric mucosa is unable to resist corrosion by irritants such as HCl and pepsin. Mucosal barrier may not be intact. Physiologic factors: Duodenal ulcer: ↑ gastric emptying rate, ↑ post-prandial acid secretion, ↑ serum pepsinogen I, ↑ pepsin secretion, ↑ # of acid producing parietal cells. Gastric ulcer: ↓ gastric emptying rate, ↓ mucosal resistance, ↑ serum gastrin, ↓ mucosal PG.

GERD: reflux occur via transient lower esophageal sphincter relaxation (TLESR). People with GERD  ↑ TLESR frequency. Dyspepsia: caused by PUD, GERD, gastric cancer, biliary tract disease.

Clinical presentation Only 50% of patients experience classic ulcer symptoms. Pain: heartburn, aching, burning, cramping. May be due to chemical stimulation or spasm. Duodenal ulcer pain: more localized and often peaks between 12-2 AM. Gastric ulcer pain: less localized. Food: may ↓ duodenal ulcer pain but ↑ gastric ulcer and GERD pain. So, duodenal ulcer patients may gain weight and gastric ulcer patients may lose weight. Pain occurs 1.5-3 hr after meals in duodenal but only 1 hr after meals in gastric ulcer. Disease course: usually chronic with remissions and exacerbations. Relapse may be more common in spring and autumn. Test for and eradicate H pylori and use maintenance drugs to ↓ recurrence.

Clinical evaluation Blood test  hypochromic anemia. Stool test  occult blood in chronic ulcers. Gastric secretion tests  hyper-HCl secretion in duodenal ulcers, normal or subnormal HCl secretion in gastric ulcer. Upper GI barium x-ray: reveals ulcer crater. Upper GI endoscopy: most conclusive test. Biopsy: may be necessary to detect malignancy. H pylori status: using non-invasive (serology or breath test, false negative breath test with PPI, antibiotics or bismuth compounds) or invasive (histological bacterial visualization or urease activity test) tests.

Complications Hemorrhage Clinical picture: fresh blood vomit, bloody / tarry stool, coma, hypovolemic shock (heart rate > 110, systolic BP < 100). Management: ensure airway, breathing, circulation. IV crystalloids or colloids (e.g. hetastarch), monitor / correct electrolytes, gastric lavage, vasoconstrictors, antacids, H2 antagonists, PPI, vasopressin (GI muscle and blood vessel contraction).

Perforation Sudden acute upper abdominal pain, rebound tenderness, and finally, peritonitis and shock. Symptoms may ↓ with time (dangerously misleading). Emergency surgery is needed.

Obstruction Occurs due to inflammatory edema, spasm or scarring. Clinical picture: postprandial vomiting / bloating, appetite / weight loss, abdominal distension. Management: continuous gastric suction, monitor fluids and electrolyte status, perform saline load test to measure degree of obstruction. Liquids feeding and daily aspirations may be needed.

Post-surgical complications Dumping syndrome: rapid gastric emptying in 10% of patients after partial gastrectomy. Clinical picture: weakness, dizziness, anxiety, tachycardia, flushing, sweating, abdominal cramps, nausea, vomiting, diarrhea. Occur between 15 and 120 minutes after the meal. Management: eat six small meals, ↑ protein and fat and ↓ carb. Ingest fluids 1 hr before or after a meal but not with it. Give anticholinergics to delay gastric emptying. Other complications: reflux gastritis, stomal ulceration, diarrhea, malabsorption, early satiety, iron deficiency anemia.

Refractory ulcers Dyspeptic symptoms after 8 wk therapy. Perform gastroscopy and biopsy to exclude: Crohn’s disease, TB, lymphoma, carcinoma. Treatment: only PPI offer maximum acid ↓. Eradicate H pylori. D/C NSAID. Perform surgery if all fails.

Maintenance regimens 70% of ulcers recur in a year (90% in 2 years) after healing and therapy d/c. Use long-term maintenance therapy in: concomitant disease, 4 relapses / year, many risk factors (old, male, NSAID, alcohol, smoking, family history, history of complications). H pyloric eradication ↓ need for continuous therapy.

Therapy Antacids As effective as H2 antagonists. Examples: magnesium, aluminum and calcium salts. Antacids are not widely used for PUD. Continue therapy for only 7 weeks. Typically given 2 hours after meals at bedtime. Effect lasts for 3-4 hours. Mechanism: Neutralize gastric acid  ↑ gastric pH  ↓ pepsin activity and ↑ mucosal barrier  heat and treat ulcer pain. Non-systemic antacids: such as magnesium or aluminum are preferred over systemic antacids (e.g. sodium bicarbonate) to avoid alkalosis. Liquid antacid: ↑ buffering capacity than tablets but not as convenient. Antacid mixtures: such as aluminum hydroxide and magnesium hydroxide ↓ each drug dose and ↑ effect. Side effects are negated (aluminum  constipation, magnesium  diarrhea). Calcium carbonate: not preferred ( acid rebound, delayed pain relief and ulcer healing, constipation, hypercalcemia). It may produce milk-alkali syndrome esp with milk (hypercalcemia, alkalosis, kidney damage). Acid neutralizing capacity (ANC): number of mEq of a 1 N solution of HCl that can be brought to a pH of 3.5 (99% neutralization) in 15 minutes. For duodenal ulcers, 50 mEq/hr or 125 mEq/day of antacid is needed for neutralization. Precautions: Use calcium and magnesium carefully in renal disease (e.g. elderly). Sodium bicarbonate is CI in hypertension, CHF, renal disease, edema. Use aluminum carefully in patients with dehydration, GI obstruction. Calcium carbonate + alkali (sodium carbonate) + milk = milk-alkali Long term aluminum hydroxide use  hypo-phosphatemia, osteomalacia. Aluminum hydroxide is used to treat hyperphosphatemia. Interactions: Generally, take other drugs 30-60 min before antacids. Avoid antacids (polyvalent cations) with tetracycline (↓ absorption), cipro. May destroy enteric coating leading to premature release in the stomach. Interfere with absorption of: ranitidine, cimetidine, iron, digoxin, phenothiazines, anticholinergics. ↓ effect of sucralfate.

H2 receptor antagonists Preferred in mild-moderate GERD due to lack of effect on GI motility. Mechanism: competitively ↓ action of histamine at parietal cell H2 receptors  ↓ volume and H+ concentration of gastric acid. General SE: nausea, dizziness, renal damage (adjust). Absorption is ↓ with antacids (give 1 hr before antacids). All available oral or IV. Cimetidine: first drug, ↓ gastric acid by 50%. SE: liver damage, hematologic (thrombocytopenia, agranulocytosis, aplastic anemia), weak androgenic (gynecomastia), confusion. Cytochrome P-450 inhibitor  ↓ metabolism of phenytoin, theophylline, Phenobarbital, lidocaine, warfarin, imipramine, diazepam, propranolol, procainamide. Ranitidine: more potent drug, ↓ gastric acid by 70%. Used with bismuth citrate and clarithromycin to eradicate H pylori. Famotidine: most potent, ↓ gastric acid by 94% for 10 hr. Nizatidine: newest drug, similar to ranitidine. Oral. DI: ↓ absorption of drugs requiring acidic pH (e.g. ketoconazole).

Sucralfate Non-absorbable disaccharide containing sucrose and aluminum.

Mechanism: adheres to the base of ulcer crater forming a mucosal protectant barrier against acids and bile salts (esp. in duodenal ulcers). Acidic pH is required for polymerization. SE: constipation. Give 1 hr before meals and at bedtime for 6 weeks. Interactions: antacids ↓ sucralfate mucosal binding, give 45 min apart. Surcralfate ↓ absorption of digoxin, iron, phenytoin, cimetidine, tetracyclines, ciprofloxacin.

GI anticholinergics Examples: atropine, propantheline. No proven value in ulcer healing Mechanism: ↓ basal and stimulated gastric acid and pepsin secretion. Most effective at night in large doses with antacids  delay gastric emptying. Or, take 30 min before food (↓ acid by 40%) SE: dry mouth, blurred vision, urinary retention, constipation, tachycardia CI: gastric ulcer (they prolong gastric emptying), narrow angle glaucoma.

Prostaglandins (misoprostol) Mechanism: PG E1 analgoue  ↑ mucus  protect gastric mucosa against NSAID damage, ↑ bicarbonate, ↓ acid. NSAID  ↓ prostaglandins  ↓ bicarbonate and mucus secretion  damage. Use: QID prevention of NSAID induced gastric ulcer in ↑ risk patients. SE: diarrhea, GI pain (take with food). CI: abortifacient, pregnancy category X.

Proton pump inhibitors Examples (x-prazole): omeprazole, lansoprazole, esmoprazole, rabeprazole, pantoprazole. Omperazole sulfenamide is the active form. Mechanism: forms a stable disulfide bond with sulfhydryl group near potassium binding site on luminal + + side of gastric proton pump H K ATPase  pump shuts down. Very rapid ulcer healing and symptom control compared to other drugs (e.g. H 2 blockers). 90% acid reduction for 24 hr with no achlorhydria. Omeprazole is better than ranitidine or misoprostol for preventing or healing NSAID ulcers. Omperazole can be used in infants. SE: headache, diarrhea, GI pain / upset, flatulence. Take before food. Interactions: ↓ absorption of drugs requiring acid pH (ketoconazole, ampicillin, iron). Omeprazle may ↓ or ↑ cytochrome P-450 metabolism.

Bismuth compounds Examples: bismuth subsalicylate (Pepto-Bismol), ranitidine bismuth citrate (RBC), colloidal bismuth subcitrate (not FDA approved). Mechanism: bismuth prevents adhesion of H pylori to gastric mucosa, ↓ H pylori growth, ↓ release of proteolytic enzymes. Use: most effective in combination with PPI or antibiotics. SE: CNS/neutrotoxicity, dark stool / tongue, headache, diarrhea, rash, salicylism in ↑ doses (tinnitus, hyperpyrexia, confusion, tachycardia). Antibiotics for H pylori: metronidazole, tetracycline, clarithromycin, amoxicillin, bismuth subsalicylate, omperazole / lansoprazole. Optimum regimen: bismuth subsalicylate QID + metronidazole QID + tetracycline QID + omperazole QD = 2 wk  90% eradication.

Prokinetic agents Example: metoclopramide, erythromycin, cisapride (d/c due to ↑ incidence of arrhythmia / torsades). Mechanism: ↑ ACh release  ↑ gastric emptying (no effect on acid secretion). SE: diarrhea, GI upset, headache. Interactions: antifungals (ketoconazole, itraconazole, fluconazole, miconazole)  ↓↓ cisapride metabolism  severe arrhythmia. Rapid gastric emptying can affect absorption of narrow therapeutic drugs. CI: arrhythmia, CHF, ischemic heart, renal failure, respiratory failure.

Diet / social modification Milk may ↑ gastric acid (used to be recommended, no more). Milk leaves the stomach quickly  no extended buffering. Small frequent meals may ↑ ulcer pain by causing acid rebound (used to be recommended, no more) Strict dietary limitations are now considered unnecessary. Avoid certain foods: caffeinated drinks, alcohol, smoking, NSAIDs.

Surgery Used in complicated, incapacitating ulcer unresponsive to therapy. Vagotomy: severs a branch of the vagus nerve  ↓ HCl secretion. Antrectomy: removes the antrum  ↓ some acid secreting mucosa. Others: gastrectomy, funoplication.

51. Diabetes Introduction Definition 1. Dysfunction in metabolism of fat, carbohydrate, protein, insulin 2. Dysfunction of blood vessels and nerves function and structure 2-10% of US population (half undiagnosed)

Classification General common symptoms: polydipsia, polyuria, dry skin, polyphagia, fatigue, frequent skin / vaginal infections, visual disturbances. 1. Type 1 (Insulin-Dependent, Juvenile-Onset, Ketosis-Prone) Insulin production/secretion is destroyed. Usually in children and adults 30. 80% are also obese. Not prone to ketosis except during stress (infection, surgery, trauma). Etiology: a. Genetics: 90% concordance between monozygotic twins. 15% chance in offspring of diabetics. b. ↓ beta cell:  ↓ insulin. c. Insulin site defect  insulin-resistant tissue (insensitivity) Clinical presentation: develops gradually. Evidence of damage to retina, kidneys, peripheral vasculature. 3. Gestational (pregnancy) Glucose intolerance detected during (late) pregnancy (3% of pregnants). Test tolerance 6 wk postpartum. Usually returns to normal. 4. Other types (Secondary Diabetes) Due to disease of pancreas, genetics, endocrinopathies (Cushing’s), drugs (thiazides, loops, corticostroids,  hyperglycemia) 5. Diabetes insipidus: Cause: pituitary disease with ↓ production of antidiuretic hormone (ADH)  kidney can’t conserve water, lithium (↓ sodium reabsorption). Symptoms: polyuria (20 L / d), severe thirst, polydipsia, watch for dehydration. Treatment: anti-diuretic hormone (vasopressin) analogs  desmopressin (oral), lypressin (nasal), maintain fluids / electrolytes. (Desmopressin is also used in Hemophilia A and von Willebrand’s disease).

Pathophysiology Normal glucose regulation Insulin:

Structure: endocrine hormone secreted by beta-cells of pancreas. It is a 51-amino acid chain with two polypeptide chains and two inter-chain disulfide bonds. It is derived from proinsulin (86 amino acids). Proinsulin can be used to determine the purity fo insulin products. Mechanism: glucose  ATP closes potassium channels  membrane depolarization  calcium influx  fusion of insulin granules  insulin release. Insulin and glucose  activate N/K ATPase force potassium into the cells  hypokalemia.  Glucose effects: ↑ glucose transport across cell membranes, ↑ glucose storage as glycogen in muscles / liver (glycogenesis), ↓ glucose formation from glycogen in muscles / liver (glycogenolysis), ↓ glucose formation from amino acids (gluconeogenesis)  ↓ breakdown of fatty acids to ketone bodies (lipolysis) (insulin prevents ketoacidosis  absent in type II DM), ↑ adipose (fat) tissue formation from triglycerides and fatty acids.  ↑ incorporation of amino acids into proteins Counter-regulatory hormones: glucagon (from pancreas alpha-cells), epinephrine, norepinephrine, growth hormone, cortisol.  Glycogen: carbohydrate consisting of branched chains of glucose units. Principal form of carbohydrate storage, mainly in the liver and muscles. Breaks down easily to glucose when needed.

Abnormal glucose regulation General Insulin insufficiency, resistance  hyperglycemia. Liver: ↑ glycogenolysis, ↑ neoglucogenesis, ↓ glycogenesis. Muscle (peripheral tissue): ↓ glucose uptake  cells use protein as energy source  protein breakdown  ↑ carbohydrates / glucose  ↑ hyperglycemia. Renal glucose threshold: 180 mg/dl. ↑ BG concentration  exceeds kidney’s glucose reabsorptive capacity  glucose excreted into urine (glucosuria)  osmotic diuresis  dehydration, electrolyte abnormalities  coma, death. Diabetic Ketoacidosis (DK) (Type 1) No insulin to break glucose  triglycerides breakdown (lipolysis)  free fatty acids and glycerol. ↑ glycerol  ↑ liver glucose production  ↑ hyperglycemia. Free fatty acids  acidosis  breakdown in the liver  ketone bodies  kidney excretion  ketonuria  exceeds kidney excretion limit  ketonemia  coma, death. A ketone body: acetoacetate  converted in the liver to acetone  excreted + -3 through the lungs  acetone fruity breath. ↑ anion gap (Na – (Cl + HCO )) Ketone bodies urine detection: add sodium nitroprusside and ammonia  purple color. May also occur in severe vomiting or starvation. Initially, the body compensates for acidosis by ∆ breathing patterns (Kussmaul: rapid deep breathing) and by blood buffering systems (bicarbonates, proteins). If Type 2 DM  Hyperglycemic hyperosmolar nonketotic syndrome (HHNK), presence of even ↓ insulin prevents fat breakdown, ketonemia, ketoacidosis (Ketosis-resistant).

Laboratory findings Diagnostic criteria: 1. Random BG > 200 mg/dl with classic DM symptoms (polydipsia, polyuria, polyphagia, weight loss). 2. Fasting BG > 125 mg/dl. 3. 2-hour BG > 200 mg/dl during an oral glucose tolerance test (OGTT) using 75 g anhydrous glucose in water. DM predisposition: Impaired fasting glucose (IFG): fasting BG 110-125 mg/dl. Impaired glucose tolerance (IGT): 2-hr OGTT BG 140-200 mg/dl. Gestational diabetes: testing is done at 26 weeks in all women (unless ↓ risk: normal weight, no family history, and 140  glucose tolerance: 100 g, 3 hr. Goals of management: euglycemia with no symptoms, prevent acute complications, prevent vascular and neuropathic disease, prevent / treat risk factors (↑ BP, ↑ blood lipids), normal life expectancy and quality of life.

Patient education and self care ↓ Modifiable risk factors: smoking, ↑ BP, ↑ blood lipids, BMI > 27. Identify BG patterns: effect of diet, exercise, medications on BG. Foot care: ↑ lower-extremity complications due to neuropathy, peripheral vascular disease, trauma, infections. Inspect shoes and feet skin color and integrity daily. Clean feet daily and dry well. Do not use hand to sense water temperature if neuropathic (sensation loss). Trim nails. Moisturize dry skin but NOT between the toes. Wear well fitting shoes and cotton socks. Avoid walking barefooted. Do not self-treat skin foot conditions. Skin care: dry skin is common due to diuresis and dehydration or anhidrosis (autonomic ↓ in perspiration,)  use aqueous non-alcoholic moisturizers. ↑ skin infections due to ↑ BG and ↓ circulation. Always use sunscreen (sun burn  ↑ BG). Avoid skin trauma. Keep skin clean and regularly inspect for abrasions, swelling, pain. Dental care: DM accelerates periodontal disease. Should effectively brush and floss, and have an annual exam. Eye care: DM is the leading cause of visual impairment and blindness. Should have annual dilated eye exam.

Assessment of glycemic control Self monitoring of blood glucose (SMBG): allows assessment of response to factors affecting BG (diet, drugs, stress, etc). Gives immediate feedback to adjust diet, exercise, insulin, etc. Urine glucose testing: only retrospective information (not recommended). Urine ketone monitoring: more important during illness, infection, trauma (even for type 2), type 1 patients with BG consistently >250 mg/dl, pregnant diabetics, patients on a diet to lose weight. Hemoglobin A1c test (glycol-hemoglobin, glycosylated hemoglobin): long term BG monitoring, reflects average BG over 7-16 weeks. Stable for 120 days (RBC lifespan). Perform 1-2x / year. Hemoglobin A1c < 7% is targeted (normal = 6% (130 mg/dl), if >8%  additional intervention). BG ~ A1c x 20-30. Glycosylated fructosamine test: measures BG control over 3 weeks. Useful for short-term follow-ups (e.g. pregnancy).

Acute changes in glycemic control Hyperglycemia Mild to moderate hyperglycemia BG 200-250 mg/dl. Rapid onset (hr). No metabolic abnormalities. Acute: due to illness, emotional distress, or ↑ dietary calories. Rebound (Somogyi effect): rebound hyperglycemia following severe/prolonged hypoglycemia, e.g. overnight insulin reaction). May be ↑ BG pattern in early morning due to counter-regulatory hormones. Moderate to servere hyperglycemia BG > 250 mg//dl. Few days duration with acidosis or ketosis (Diabetic Ketoacidosis, DKA). Common in children with undiagnosed Type 1 DM. Precipitating factors: stress, infection, ↑ alcohol consumption, improper insulin therapy, dietary noncompliance. Physical findings: Kussmaul’s respirations, acetone breath odor, dehydration, dry skin, ↓ consciousness (confusion, coma), abdominal pain. Can be deadly. Therapy: insulin IV infusion (Regular), fluid / electrolyte replacement. Severe hyperglycemia BG > 500 mg/dl. ↑ serum osmolarity. Duration: days/weeks. Mostly in Type 2 DM. Higher mortality rate than DKA. Precipitating factors: conditions that ↑ insulin requirement and predispose to dehydration (burns, GI bleeding, CNS injury, MI), use of glucogenic drugs (steroids, glucagon, thiazide diuretics), high glucose products (peritoneal dialysis, enteral nutrition).

Physical findings: ↑↑ dehydration, ↑ serum osmolarity (> 280 mOs), no ketosis / acidosis (hyperglycemic hyperosmolar nonketotic syndrome, HHNK), polyuria, polydipsia, hypotension, tachycardia, palpitations, rapid respiration, nausea, vomiting, abdominal discomfort, ↓ CNS function (confusion, coma, seizures, myoclonic jerking). Therapy: insulin, fluid / electrolyte replacement.

Hypoglycemia Mild hypoglycemia symptoms: adrenergic (tachycardia, palpitations, shakiness), cholinergic (sweating), mild CNS glucopenia (↓ concentration, dizziness, hunger). Moderate hypoglycemia: ↑ CNS effect  confusion, motor impairment, no unconsciousness. Severe hypoglycemia: coma, seizure, motor impairment. Pseudo- hypoglycemia: hypoglycemic symptoms perceived (mostly adrenergic) but BG is normal. Hypoglycemia unawareness: no or little symptoms but BG is low. Sweating or neurologic impairment is noticed. Precipitating factors: excess insulin or oral hypoglycermic, delayed or ↓ food, ↑ exercise, alcohol, drug interaction ↓ BG, ↓ progesterone in menstruation, new insulin bottle with full potency, gastroparesis (delayed stomach emptying), change in insulin injection site (↑ absorption if SC near exercising muscle). Treatment of hypoglycemia: if conscious  10-15 g fast acting simple oral carbohydrate (milk, juice, regular soda), 3 g glucose tablet or hard candy, honey, glucose gel. Repeat in 10-15 min if BG is not back to normal. If unconscious  IV glucose (10-15% dextrose) or glucagons injection (1 mg IM, SC, or IV).

Long-term complications Macrovascular Atherosclerosis: coronary, cerebrovascular, peripheral Peripheral vascular disease: pain, chronic “cold feet”, insufficient circulation to heal distal lesions  gangrene Hypertension: with diabetes  ↑↑ cardiovascular disease, stroke, transient ischemic events. Causes acceleration of retinopathy, nephropathy, atherosclerosis. Hyperinsulinemia / insulin resistance  diabetic hypertension. Coronary artery disease: autonomic neuropathy  Silent myocardial infarction (atypical, no chest pain). Management: daily ↓ dose aspirin, ACE inhibitor (for ↑ BP), cardio selective beta blocker (for cardiac disease).

Eye (retionopathy) Consequence of microvascular changes, leading cause of new blindness. Treatment: laser photocoagulation. Nonproliferative (background) retinophathy: retinal microaneurysms, blot hemorrhages, retinal edema, hard exudates, macula edema Preproliferative retinopathy: ↑ abnormality of tiny vessels, retinal ischemia, white patches of oxygenstarved retina (soft or cotton-wool spots). Proliferative retinopathy: lack of oxygen  weak vessel grow or proliferate (neovascularization) from retinal surface to vitreous cavity. Fragile vessels may bleed into vitreous cavity  hemorrhage  obscured vision  scar tissue and new vessels grow  vitreous pull on the retina  retinal detachment.

Nephropathy Most common cause of End Stage Renal Disease (ESRD) ↑ microalbuminuria, positive dipstick (clinical) albuminuria, proteinuria / ↑ BP, ↓ glomerular filtration, ↑ creatinine. ACE inhibitors helpful, ↓ protein intake, treat UTI. For ESRD  fluid / electrolyte restriction, dialysis.

Neuropathy Peripheral neuropathy: esp. in sensiomotor nervous system. Symptoms first in distal lower extremities then upper extremities (Stocking-glove distribution). Signs: impaired perception of pain / temperature  numbness / tingling, impaired balance, ↓ proprioception (perception of body parts movement), motor nerve damage  muscle weakness / atrophy. Autonomic neuropathy: genitourinary  neurogenic bladder, sexual dysfunction. GI  gastroparesis, nocturnal diarrhea, fecal incontinence, chronic constipation. Cardiovascular  orthostatic hypotension, cardiac denervation.

Foot, skin and mucous membranes Due vascular changes and peripheral neuropathy  alter nerves that control blood flow and skin hydration Infection by staph, beta-hemolytic strept, fungus  cutaneous infection (furunculosis, carbuncles), Candida (genital, upper thighs, under breast), cellulites, lower-extremity vascular ulcers Atrophic round painless lesions, diabetic dermopathy (red-brown popular spots) esp. in lower extremities. Necrobiosis lipoidica diabeticorum (ulcerative necrotic lesion) Peripheral neuropathy  loss of protective sensation, inability to detect minor trauma  ulcers Infection, injury, neuropathy, vascular disease  gangrene Sensory exam of feet (protective sensation)  10 g monofilament Protective footwear (deep sole shoes, molded shoes, orthotics)

Significant interactions affecting glycemic control Hyperglycemia (direct glucogenic effect): corticosteroids, furosemide, thiazides, sunburns, nicotinic acid, phenytoin, pentamidine, protease inhibitors, sympathomimetics, isoniazid, sulfinpyrazone, theophylline toxicity. Hypoglycemia: MAO-I, fluoxetine, salicylates (↑ dose), alcohol, fenfluramine, pentamidine Prolonged hypoglycemia / masking hypoglycemic symptoms: B1 beta blockers (e.g. propranolol)

Therapy Medical nutrition therapy (MNT) Carbohydrate counting: 50% of total calories. DM therapy may include pre-meal short acting bolus insulin (lispro, regular, semilente). Otherwise, maintain consistent CHO intake. Fat: limitations on type and amount. Critical for weight loss and treating hyperlipidemia. Target: < 30% of calorie intake and < 300 mg/day cholesterol. Protein: important in end stage renal disease and may delay dialysis. Fiber: bran, beans, fruits, vegetables may help BG and lipids. Alter diet based on stress, illness, exercise, etc. Spaced meal intervals help match hypoglycemic therapy effect.

Physical activity Careful exercise ↑ cell glucose uptake  ↓ BG Careful if patient has severe retinopathy. Patients with cardiovascular disease or over 45  cardiovascular evaluation and stress test. Aerobic activity: e.g. swimming, walking, running, preferred due to positive effect on BG (↓), cardiovascular, BP, lipids, circulation, weight loss. Anaerobic activity: e.g. weight lifting, should be avoided. Potential negative cardiovascular, BP, retinopathy effects.

Insulin and insulin analogues For type 1 DM and only uncontrolled type 2. Mechanism / structure: see above Factors ↑ insulin requirement: infections, weight gain, puberty, inactivity, hyperthyroidism, Cushing’s disease

Factors ↓ insulin requirement: renal failure, weight loss, ↑ exercise, nutrient malabsorption, hypopituitarism, adrenal insufficiency. Concentration: U-100 or U-500 for insulin resistance. Source: human, bovine, porcine, synthetic (Lispro insulin, Humalog), or a mixture. Human insulins are made by enzymatic conversion of terminal amino acid of porcine insulin (Novolin, semisynthetic), or by recombinant DNA (Humulin). Human insulin  ↓ antigenicity. Short-acting: Lispro  synthetic, shortest onset and duration. Regular  soluble insulin with neutral pH, only clear insulin (IV), only insulin that can be mixed freely. Semilente (prompt insulin zinc suspension)  finely divided amorphous prep, use acetate buffer, mix only with other lente, similar duration to Regular, Aspart insulin analogues. Intermediate-acting: NPH (isophane insulin suspension)  similar to protamine zinc but with no excess protamine. Lente (insulin zinc suspension)  mixture of 70% ultralente crystals and 30% semilente powder. Long-acting: Protamine zinc  use phosphate buffer. Ultralente (extended release zinc suspension)  large crystalline. Glargine insulin analogue (very long acting). Pre-mixed insulin: 50/50 Regular/NPH, 70/30 Regular/NPH, 75/25 Lispro/Protamine Lispro  regular as pre-meal bolus and NPH intermediate for later control of hyperglycemia. Other mixtures can be prepared extemporaneously for tailored ratios. DM Type 1 example: pre-breakfast is 2/3 of total daily dose (TDD) 1:2 short : intermediate. Bedtime is 1/3 of TDD 1:2 like pre-breakfast. Or give pre-supper rapid/short and then bedtime intermediate. DM type 2 example: bedtime only or 2-3 daily injections. Subcutaneous: for routine administration. Absorption of regular insulin is fastest from abdomen > arm > buttock > thigh. Monitor variations in absorption. Randomly rotate injection site to avoid lipohypertropy. If ↑ variations  avoid random rotation of injection site. Exercise, hot showers, baths, massages  ↑ blood flow to injection site. Abdomen is least likely to have ↑ absorption  preferred site for preexercise insulin. Continuous Intravenous (insulin drip): provide Regular insulin for acute hyperglycemia, ketoacidosis, HHNK, or during surgery. Continuous SC infusion (insulin pump): short acting insulin is infused continuously during the day to deliver ↓ doses (basal insulin). Bolus dose (determined by algorithms) is delivered by the patient before each meal. Offers tighter glycemic control. Used for diabetics with ↑ BG fluctuations, irregular work schedules, lifestyles, or meals. Require frequent SMBG (BG self-monitoring) and training. SE: hypoglycemia (tachycardia, sweating, hunger, convulsions and insulin shock), hypersensitivity, injection site local irritation.

Insulin secretagogues Drugs (all acidic): Sulfonyrlureas: First gen: chlorpropamide, tolbutamide, acetohexamide, tolazamide, more lipid-soluble, more potent. Second gen: glyburide, glipizide, glimperide. Also repaglinide. Mechanism: block ATP-sensitive potassium channels  ↑ insulin pancreatic release (primary), and also as sensitizers with time (secondary). Use: Type 2 (useless in type 1, require functioning beta cells). Chlorpropamide: longest duration of action. CI in liver and kidney disease. ↑ SE severity and frequency, disulfiram-reaction (also with tolbutamide). Use insulin instead during stressful conditions (↑ risk of hyperglycemia due to ↑ counter-regulatory hormones release). SE: severe / prolonged hypoglycemia (esp. in the elderly, w/ glipizide / glyburide), GI upset, sulfa sensitivity, sun sensitivity, headache, rash, tachycardia, hematologic problems, cholestatic jaundice. CI: allergy to sulfa drugs, pregnancy, lactation. Altered protein binding of sulfonylureas: alcohol, salicylates, NSAID’s, methyldopa, chloramphenicol, MAO-I, clofibrate, probenecid. Therapy failure: due to ↓number of functioning beta cells. Primary: failure to control BG within 4 weeks. Secondary: initial control of BG, but fails to maintain control, due to progression of DM. Repaglinide: less hypoglycemia.

Insulin sensitizers Drugs: biguanides (metformin, basic drug), thiazolidinediones (rosiglitazone, pioglitazone).

Mechanism: anti-hyperglycermic not hypoglycemic. ↑ sensitivity to insulin,  (metformin  work on liver, ↓ hepatic glucose production, gluconeogenesis), (glitazones  ↑ sensitivity / ↓ insulin resistance in muscle and adipose tissue). Thiazolidinediones bind to PPARs. Use: significant insulin resistance. Biguanides SE: fatal lactic acidosis, metallic taste, GI upset, ↓ vitamin B12, no hypoglycemia. May be fatal if at ↑ risk of lactic acidosis (liver / kidney disease, hypoperfusion, hypoxia, radiography). Phenformin was d/c. Glitazones SE: liver toxicity / failure (monitor), weight gain, edema, GI upset, no hypoglycemia. Troglitazone was d/c due to liver toxicity. CI: liver disease. May resume ovulation in premenopausal women. Highly protein bound (99%).

Alpha-glucosidase inhibitors Drugs: acarbose (polysaccharide), miglitol (basic monosaccharide) Mechanism: inhibit intestinal enzyme alpha-glucosidase  ↓ absorption of complex carbohydrates (starch, dextrins, disaccharides). Use only glucose or lactose for correcting hypoglycermia if it occurs. Use: significant post-prandial hyperglycemia. Minimal effect on pre-prandial or fasting BG. Good combination with insulin secretagogues. Take with first bite of meal. SE: GI (diarrhea, abdominal pain, flatulence) due to undigested carbohydrates in the lower GI, no hypoglycemia. CI: GI conditions (inflammatory bowel, colonic ulcer, obstructive bowel, intestinal gas), liver cirrhosis (monitor liver function), pregnancy.

52. Thyroid Disease Physiology Thyroid hormone regulation / function Thyrotropicn-releasing hormone (TRH): secreted by the hypothalamus, triggers the release of TSH through negative feedback mechanism. Thyroid stimulating hormone (TSH): released by the anterior pituitary gland, controls thyroid hormone secretion and transport. Thyroid gland produces thyroxine (T4), triiodothyronine (T3) (both for growth, development, metabolic rate), and calcitonin (↓ blood calcium). Thyroid hormone is transported in the circulation by thyroxine-binding globulin (TBG), and albumin. Protein binding protects hormone from premature metabolism, excretion, and prolongs its t1/2. Metabolism: T4T3 conversion in pituitary gland, liver, kidneys. Degradation: by deiodination  feces / urine excretion. Function: Activate mRNA and ↑ protein synthesis or catabolism (↑ dose). ↑ growth, development, ↑ basic metabolic rate, ↑ blood flow, ↑ cardiac output, ↑ heart rate, fine muscle tremor, fatigue wakefulness, ↑ lipid mobilization and degradation, ↑ bone remodeling (rate of resorption > rate of formation).

Biosynthesis Dietary iodine: critical for thyroid hormone synthesis, reduced to inorganic iodide then exracted from plasma by the thyroid by iodide trapping (iodide pump). Organification: oxidation of iodide by peroxidase. Synthesis starts with iodide-tyrosine binding  modoiodo then dioiodo-tyrosine.

Thyroid function studies Serum total thyroxine (TT4): Most direct reflection of thyroid function by indicating hormone availability in tissues. Total (free and bound) T4 is determined by radio-immunoassay (sensitive, rapid). TBG ↑ during pregnancy  misleading results (bound T4).

↑ TT4  hyperthyroidism, and vice versa Serum total triiodothyronine (TT3): Measures total (free and bound) T3. TT3 rise before TT4, useful for early detection. ↑↑ in hyperthyroidism (more than T4), responsible for symptoms. Pregnancy  ↑ TT3. Resin triiodothyronine (RT3U): Evaluates the binding capacity of TBG. Clarifies whether abnormal T4 is due to thyroid disorder or abnormal protein binding. If abnormal thyroid in the blood  RT3U changes in same direction (↑ in hyperthyroid). If abnormal protein binding  RT3U changes in opposite direction (↓ in hyperthyroid). Serum thyrotropin (TSH) assay: Serum TSH assay: most sensitive test for hypothyroid, but nor reliable in hyperthyroid (TSH is suppressed). Sensitive TSH assay: uses monoclonal antibodies known as immuno-radiometric or immunometric (IMA) method (vs. the older radio-immunoassay). ↑ sensitivity, ↑ cost, more commonly used to control over treatment of replacement therapy. Free thyroxine (T4) index (FTI): Not a separate test but rather an estimation of free T4 level by a calculation involving serum T4 and RT3U. ↑ FTI  hyperthyroid or ↓ TBG. Strategies for testing Most common and ↓ expensive: TT4, RT3U, FTI. Thyroid disease screening for healthy population is not cost effective. Screen only target population (elderly, chronic disease hospitalization, Use FTI and Sensitive TSH for disease diagnosis.

Hypothyroidism Classification Primary hypothyroidism: due to gland destruction or dysfunction caused by disease or therapy (radiation, surgery). Secondary hypothyroidism: due to ↓ TSH secretion (pituitary disorder). Thyroid gland is normal but not enough TSH stimulation. Tertiary hypothyroidism: ↓ TRH (hypothalamus) to stimulate pituitary

Causes Hashimoto’s thyroiditis: chronic autoimmune thyroiditis. Treatment of hyperthyroidism: e.g. radioactive iodine, subtotal thyroidectoym, antithyroid drugs. Goiter: enlargement of the thyroid gland. Endemic goiter: due to inadequate dietary iodine (malnutrition). Sporadic goiter: due to foods or drugs containing progoitrin (inactive  hydrolysis  active goitrin)  ↓ oxidation of iodine to iodide. Goitrogenic drugs: propylthiouracil (PTU), iodides, cobalt, lithium, phenylbutazone. Other causes: thyroiditis, thyroid cancer. Surgical excision

Signs and symptoms Vague early symptoms: lethargy, fatigue, sensitivity to cold, weight gain, constipation. Later: features of Myxedema such as dry flaky inelastic sin, coarse hair, puffy face / hands / feet, eyelid droop, slow speech / thought, ↓ libido, coma (if not controlled). Myxedema coma Life threatening condition in old patient with undiagnosed hypothyroidism Precipitating factors: alcohol, sedative / narcotic use, antithyroid overdose, d/c thyroid replacement, infection, cold exposure, radiation, surgery.

Symptoms: coma, hypothermia, ↓ respiratory rate  failure, hypometabolism  fluid / electrolyte retention  fluid retention, hyponatremia, ↓ heart rate / contractility, ↓ heart output. Treatment: rapid restoration of T3 and T4 to normal levels. IV bolus levothyroxine, oral liothyronine, then oral levothyroxine.

Drugs Desiccated thyroid preparations: not commonly used anymore. Different preparations are not bioequivalent (varying amounts of actives depending on source (bovine, ovine, porcine). Fixed ratio (liotrix) preparations: standard ratio of T4/T3. T3 is, however, unnecessary (T4 converts to T3)  cause SE tremor, headache, palpitations, diarrhea. Levothyroxine: agent of choice, predictable results, no T3. Individual variable response to different preparations  care if to switch. Use ↓ dose for elderly or chronically ill patients. Results start after 2 wk, full response after 4-5 months (TSH levels ↓ to normal levels).

Precautions Careful in the elderly and in case of cardiac disease. Start with ↓ doses. Watch for cardiac complications (palpitations, arrhythmia, angina). Monitor thyroid levels (T4, RT3U, FTI, sensitive TSH). Long term levothyroxine therapy can cause thyrotoxicosis. Accelerated bone loss due to over treatment  nontraumatic fracture. CI: cholestyramine (bile acid sequestrant)  ↓ thyroxine bioavailability. Separate drug by 6 hours.

Hyperthyroidism / thyrotoxicosis Grave’s disease (diffuse toxic goiter) Most common form. Occurs usually in young women. Autoimmune disease, antibodies (long-acting thyroid stimulators, LATS) bind to and activate TSH receptors (does not actually increase TSH itself). Symptoms: enlarged goiter, exophthalmos, stare, nervousness, irritability, anxiety, insomnia, heat intolerance, ↑ sweating, ↑ appetite, ↓ weight, muscle tremor / weakness, tachycardia, palpitations, diarrhea. Signs:

Plummer’s disease (toxic nodular goiter) Less common. Common in the elderly. Caused by adenoma nodules autonomously secreting excessive thyroid. Symptoms: same as Grave’s with nodular masses rather than diffusion enlargement.

Other forms Jodbasedow phenomenon: hyperthyroid due to ↑↑ iodine ingestion or amiodarone. Factitious hyperthyroidism: due to abusive ingestion of thyroid replacement drugs to lose weight.

Drugs Beta blockers – propranolol Propranolol ↓ peripheral symptoms (tachycardia, sweating, tremor, nervousness). It also ↓ peripheral T4T3 conversion (deiodonation). Antithyroid drugs Examples: propylthiouracil (PTU), methimazole. Mechanism: interferes with thyroid hormone synthesis by ↓ iodide oxidation. PTU ↓ peripheral T4T3. Dosing: initial dose (2 mo), maintenance dose (12 mo), gradual withdrawal (2 mo). Restart therapy if signs of hyperthyroidism appear. Monitor serum thyroid, FTI and goiter size.

SE: skin rash, urticaria, pruritus, hair loss, skin piementation, drowsiness, myalgia, arthralgia. Severe SE: blood (agranulocytosis, granulocytopenia, thrombocytopenia), monitor blood count. Radioactive iodine (RAI) Mechanism: thyroid gland picks up the radioactive element iodine-131 as it would regular iodine. Radioactivity destroys cells. Advantages: ↑ cure rate (100%), avoid surgical risks, ↓ cost Disadvantages: risk of delayed hypothyroidism, delayed effect. SE: only for women past childbearing years. Response is hard to gauge (too much, too little). Subtotal thyroidectomy Partial removal of the thyroid gland. Last resort. Advantages: ↑ success rate, rapid cure. SE: thyroid storm, permanent hypothyroidism.

Complications Hypothyroidism: may follow Grave’s disease. Thyroid storm (thyrotoxic crisis): is a sudden exacerbation of hyperthyroidism caused by rapid release (leakage) of thyroid hormone (↑↑ T4)  fever, tachycardia, restlessness, tremor, hyper-meabolism  dehydration, shock, death if not treated rapidly. Precipitating factors: thyroid trauma, surgery, radiation, infection, sudden d/c of antithyroid therapy. Treatment: PTU, methimazole, proproanolol, potassium iodide (↓ intrathyroidal iodine intake), supportive therapy (rehydration, cooling, AB, rest, sedation).

54. Cancer Chemotherapy Principles of oncology Cancel cells Tumors arise form a single abnormal cell, which continues to divide indefinitely. Characteristics: no growth control, can invade local tissues, can spread (metastasize).

Incidence Second leading cause of death in the US. Affects 30% of all people at some point in life. Some forms of cancer are curable if detected / treated early.

Etiology Viruses: Epstein-Barr virus, hepatitis B, human papilloma viruses. Environmental / occupational exposures: ionizing / UV radiation, chemicals (benzene, asbestos, vinyl chloride). Life-style: ↑ fat, ↓ fiber diet, ethanol, tobacco. Medications: alkylating agents, immunosuppressants. Genetics: inherited mutations, cancer-causing genes (oncogenes).

Detection / diagnosis Warning signs: CAUTION. Change in bowel / bladder habits, A sore that does not heal, Unusual bleeding / discharge, Tissue thickening or lumps (e.g. breast), Indigestion of difficulty swallowing, Obvious change in a wart or mole, Nagging cough or hoarseness. Guidelines for screening: for asymptomatic people  mammography (breast cancer), fecal occult blood test (colon cancer), Pap smears (cervical cancer). Tumor markers: biochemical indicators of the presence of neoplastic proliferation in serum, plasma, other body fluids. Not definitive. Include: prostate specific antigen (PSA), carcinoembryonic antigen (CEA), alpha fetoprotein (AFP). Tumor biopsy: definitive test for cancer cells is pathology of a biopsy.

Imaging studies: x-ray, computerized tomography scans, MRI, positive emission tomography. Lab tests: complete blood count, blood chemistries.

Staging It is the categorizing of patients according to extent of the disease. Used to determine prognosis. Two system are used for neoplasm staging. TNM: T = tumor size (0-4), N = regional lymph node spread (0-3), M = presence of absence of distant metastases (0-1). Example: T2N1M0. AJC: by the American Joint Committee on staging. Scale: 0-IV.

Survival Depends on tumor size, disease extent, treatment received. 60% survive more than 5 years, but not all survivors are cured. “Complete response or remission” when no evidence of disease after treatment. Slow growing tumors  10-15 disease free years.

Cell life cycle Phases of the cell cycle M phase (mitosis): cell divides into two daughter cells G1 phase (postmitotic gap): synthesis of RNA and proteins S phase (synthesis): synthesis of DNA G2 phase (premitotic / postsynthetic gap): production of RNA and topoisomerisae I/II enzymes (important for DNA replication and RNA transcription). G0 phase (resting): cell is not dividing. Cells now are not sensitive to chemotherapy. Recruitment: resting cells re-enter actively divided cell cycle caused by some chemotherapy agents.

Cell growth kinetics Cell growth fraction: proportion of the cells in the tumor dividing or preparing to divide. Large tumor  ↓ nutrients and blood supply to some cells  ↓ cell growth fraction. Cell cycle time: average time for a cell that has just completed mitosis to grow and again pass through mitosis (divide). Cycle time is specific for each individual tumor. Tumor doubling time: time for the tumor to double in size. Large tumor  ↓ cell growth fraction  ↑ doubling time Gompertzian growth curve: illustrates cell growth kinetics concepts.

Tumor cell burden 9

Number of tumor cells in the body. Number required for clinical symptoms: 10 (large number)  tumor may be in plateau phase of growth curve when detected. Body immunologic defenses may be able to keep tumor cells less than 1000 under control. Each cycle of cancer chemotherapy kills a certain percentage of tumor cells (depending on the dose). When tumor cells are killed  Cells in G0 phase may be recruited to G1 phase  tumor regrowth. Therefore, repeated cycles of treatment are required for complete response or remission.

Drug reliance on cell cycle kinetics for cytotoxic effect Phase specific agents: M  vinca alkaloids / taxanes, G1  asparaginase / prednisone, S  antimetabolites, G2 > bleomycin / etoposide. Phase nonspecific agents: effective when cell are at any phase of the active cycle. Examples: alkylating agents, cisplastin, antitumor antibiotics. Cell cycle nonspecific agents: effective in all phases including G0. Example: nitrosoureas, radiation. Combination of drugs that are active in different cell cycle phases will result in greater cell kill.

Chemotherapy Therapy objectives Cure: sought with aggressive therapy for long time to eradicate all disease. Example for leukemia: remission induction, attempt maximal cell kill and therapy consolidation to eradicate all clinically detectable disease and get tumor cell count ↓ 1000. Palliation: goal is to control symptoms when complete eradication of tumor is unlikely or if patient refuses aggressive therapy. Adjuvant: given after more definitive therapy (e.g. surgery) to eliminate any remaining disease. Neoadjuvant: goal is to ↓ tumor burden before surgery or radiation.

Dosing May be bases on body weight, BSA or AUC. BSA is preferred (correlates with cardiac output which determines renal / hepatic blood flow / elimination). Adjust dose for liver or kidney dysfunction. Dosing is usually given as short courses in cycles.

Combination chemotherapy To overcome or prevent resistance, achieve cytotoxicity to resting and dividing cells, enhance biochemical effect, rescue normal cells. Acronyms are often used to indicate certain combinations.

Administration IV is the most common Inrathecal: for methotrexate, hydrocortisone, cytarabine, thiotepa.

Response to chemotherapy Does not always correlate with survival. Complete response: disappearance of all disease (clinical, gross, microscopic). Partial response: > 50 reduction in tumor size for a period of time. Response rate: defined as complete response + partial response. Progression or no response: > 25 increase in tumor size or appearance of new lesions.

Classification of chemotherapeutic agents Alkylating agents Prototype: mechlorethamine (nitrogen mustard) Mechanism: cross-linking and abnormal base-pairing of DNA strands  ↓ DNA replication. Nitrogen mustards: chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine, melphalan. Ethylenimines / methylmelamines: thiotepa, altretamine. Alkyl sulfonates: bisulfan Nitrosoureas: carmustine, lomustine, semustine, streptozocin. Triazenes: dacarbazine Platinum coordination complexes: cisplatin, carboplatin Substituted ureas: hydroxyurea Others: procarbazine, temozolomide.

Antitumor antibiotics Most come from Streptomyces Mechanism: alkylation (mitomycin) or intercalation. Intercalation: drug slides between DNA base pairs and ↓ DNA synthesis. Anthracyclines: daunorubicin (daunomycin), doxorubicin (adriamycin, hydroxydaunorubicin), epirubicin, idarubicin. Anthracendiones: mitoxantrone Others: bleomycin, dactinomycin, mitomycin, plicamycin (mithramycin).

Antimetablites Structural analogs of naturally occurring substrates for biochemical reactions. Mechanism: false substitution in production of nucleic acid  ↓ DNA synthesis. Adenosine analogs: cladribine, fluudarabine, pentostatin (deoxycoformycin). Folic acid analogs (folate antagonists): methotrexate, trimetrexate, raltitrexed. Purine analogs (purine antagonists): mercaptopurine, thioguanine Pyrimidine analogs (pyrimidine antagonists): fluorouracil, capecitabine, cytarabine, gemcitabine.

Plant alkaloids Vinca  prevent formation of the mitotic spindle  arrest cell division. Examples: vinblastine, vincristine, vindesine, vinorelbine. Camptothecins  inhibit topoisomerase I. Examples: irinotecan, topotecan. Podophyllotoxins  inhibit topoisomerase II. Examples: etoposide, teniposide. Taxanes  ↑ microtubule assembly / stabilization  ↓ cell division. Examples: taxol (paclitaxel), taxotere (docetaxel).

Hormones Androgens: testosterone, fluoxymesterone Antiandrogens: bicalutamide, flutamide, nilutammide. Antiestrogens: tamoxifen, toremifene. Aromatase inhibitors: letrozole, anastrozole, exemestane, aminoglutethimide. Corticosteroids: prednisone, dexamthasone Estrogens: ethinyl estradiol, diethylstilbestrol. Estrogen/nitrogen mustard: estramustine Progestins: medroxyprogesterone, megestrol Luteinizing hormone releasing hormone analogs: leuprolide, goserelin

Asparaginase Mechanism: enzyme that causes the degradation of essential AA asparagine to aspartic acid and ammonia. Normal cells can synthesize asparagine but tumor cells can not.

Biologic response modifiers Mechanism: alter the patient’s immune system to fight cancer or to ↓ SE of cancer treatment. Examples: Bacillus Calmette-Guerin (BCG), Colony-stimulating factors (erythropoietin, filgrastim, sargramostim), interferons (alpha, beta, gamma), interleukins (IL-2, IL-11), levamisole, monoclonal antibodies (rituximab, trastuzumab).

Toxicity of chemotherapeutic agents Most toxic to the most rapidly proliferating cells (mucous membranes, cells, hair, GI tract, bone marrow).

Bone marrow depression Most life threatening SE. Effect is dose related. ↓ WBC (especially neutrophils; neutropenia)  serious infections. Colony stimulating factors: used to ↓ extent of neutropenia. ↓ platelets (thrombocytopenia)  bleeding  give platelet transfusion. Anemia is not as common because RBC lifespan is 120 days. Time course: onset  1 week, lowest count point (nadir)  2 weeks, count recovery  3 weeks.

Dermatological Alopecia: partial or complete, can not be prevented. Local necrosis: results from extravasation during administration of vesicant drugs  immediate pain / burning + possible delayed reaction  tissue damage, necrosis, ulceration  require plastic surgery. Treatment: cold for all drugs except vinca and taxanes (use heat). Skin changes: dryness, sun sensitivity (methotrexate, fluorouracil).

GI toxicity Nausea and vomiting Most distressing SE from the patient’s viewpoint. Acute, delayed or anticipatory. Antiemetics are used for prophylaxis. Vomiting  dehydration, electrolyte imbalance, esophageal tears  d/c therapy. Stomatitis Common with methotrexate, fluorouracil (same as skin changes) General inflammation of the oral mucosa or other areas of the GI with rapid turnover of cells. Symptoms: erythema, pain, mouth dryness, lip tingling / burning, ulceration, bleeding  infection, inability to eat. Time course: starts in 1 week, resolve in 2 weeks. Other SE: fluorouracil  diarrhea, vincristine  constipation.

Pulmonary Irreversible and may be fatal. Especially with bleomycin, mitomycin. Symptoms: breath shortness, unproductive cough.

Cardiac Acute: transient ECG abnormalities. Not important. Chronic: irreversible CHF due to drugs or radiation. Dexrazoxane: cardioprotective (use with doxorubicin).

Neurotoxicity Due to intrathecal or systemic therapy. Autonomic / peripheral neuropathy: due to vincristine. Vincristine is fatal if given intrathecally. Peripheral neuropathy / ototoxicity: due to cisplatin. Arachnoiditis: due to intrathecal methotrexate, cytarabine.

Hemorrhagic cystitis Bladder toxicity due to cyclophosphamide and ifosfamide. Acrolein: metabolite of these drugs  chemical irritation of bladder mucosa  bleeding. Prevention: aggressive hydration with frequent urination, mesna (binds to acroltein  prevents it from contacting bladder mucosa).

Other Hypersensitivity: may be life threatening (anaphylaxis). Chills / fever: especially with bleomycin. Hepatoxocity: ↑ liver function tests, jaundice, hepatitis. Nephrotoxicity: ↑ serum creatinine, ↑ BUN, electrolyte imbalance. Use amifostine to protect the kidney if using cisplatin. Secondary malignancies: such as leukemia, solid tumors, lymphoma. Female infertility: may be temporary or permanent .

Other chemotherapeutic modalities Surgery: can be diagnostic or therapeutic Radiation: ↑ doses of ionizing radiation directed at the cancerous tissue. SE: stomatitis, myelosuppression, GI (nausea, vomiting, diarrhea). It’s common to combine drugs, surgery and radiation.

55. Pain Management Definitions Pain: unpleasant sensory and emotional experience that usually is associated with structural or tissue damage. No objective measurement. Acute pain: lasts < 30 days. Occurs after muscle strains and tissue injury. Self limiting, ↓ w/ time as injury heals, linear process with beginning and end, ↑ autonomic NS: ↑ heart rate, ↑ breath rate, ↑ BP, mydriasis, anxiety. Chronic pain: persistent or episodic, > 6 months. Chronic non-malignant pain: complication of acute injury, disease (osteoarthritis, rheumatoid arthritis, fibromyalgia, degenerative disorders). Cyclic, constant, does not improve w/ time. No ANS stimulation. Depression, insomnia, weight loss, sexual dysfunction Chronic cancer pain: similar to non-malignant pain, depression, fear, anger, agony. Due to cancer therapy or tumor (bone metastasis, compression of nerves, occlusion of blood vessels, obstruction of bowel, infiltration of soft tissue). Breakthrough pain: intermittent, transitory ↑ in pain.

Principles of pain management Comprehensive pain management: chronology, history, symptomatology, onset, location, intensity, duration, quality, distribution, provoking factors, underlying disease / trauma, allergies, analgesic response, side effects. Pain management targets: ↑ patient comfort (may aid healing in acute pain), break pain cycle (chronic pain), ↓ breakthrough pain, improve sleep, well-being, self-esteem, mobility, psychology, etc. Individual management regimens: dose, intervals, mode of administration, adjunct therapy. Avoid narcotics for chronic non-malignant pain. Long acting analgesics (round the clock) for cancer pain. Intermittent prn short-acting analgesics for breakthrough and acute pain. Reassess and change regiment as needed.

Analgesics Non narcotic analgesics General uses: antipyretic, anti-inflammatory (except acetaminophen), analgesic ceiling effect, no tolerance, no dependence. OTC: aspirin, acetaminophen, ibuprofen, ketoprofen, naproxen (low doses). General SE 1. Gastro-intestinal: Due to PG inhibition. With all except acetaminophen, COX-II inhibitors, choline magnesium trisalicylate, etanercept. Symptoms: dyspepsia, ulceration, bleeding, perforation. Especially in the elderly, ulcers, smokers, alcoholics. Avoid by combo therapy with GI protectants (PPI, misoprostol, H2-antagonists, antacids, sucralfate) or enteric coating (aspirin). 2. Hematologic: Exceptions: acetaminophen, choline mg trisalicylate, etanercept. Inhibit platelet aggregation by reversibly inhibiting PG synthase. Aspirin is an irreversible inhibitor. Contraindicated with anticoagulants (warfarin, heparin, etc) 3. Renal:

PG inhibition, interstitial nephritis, impaired renin secretion, ↑ tubular water/Na reabsorption  reversible abrupt oliguria Salicylates Chemistry: derivatives of salicylic acid (from Willow bark). Weak acids with excretion ↑ by ↑ pH. Aspirin is acetyl salicylic acid, hydrolyses easily, unstable in water, moisture. Other salicylates: diflunisal, methyl salicylate (topical, wintergreen oil), salsalate, mesalamine, olsalazine, sulphasalazine, sodium thiosalicylate (injection), choline salicylate (oral liquid). Pharmacology: ↓ cyclooxygenase (COXI/II)  ↓ local PG  analgesic, antipyretic, anti-inflammatory. Aspirin is the only salicylate that ↓ COX irreversibly by covalent acetylation. Also, ↓ platelet COX  ↓ thromboxane A2 formation  ↓ platelet aggregation / thrombus formation. Indications: analgesics (skeletal muscle pain, headache, neuralgia, myalgia, spasmodic dysmenorrhea), anti-inflammatory (arthritis, rheumatic fever), antipyretic (avoid in children with viral infection  Rye’s syndrome), prophylaxis of MI. Mesalamine, sulphasalazine, olsalazine  ↓ inflammation in inflammatory bowel disease, Crohn’s disease. Methyl salicylate  topical counter irritant. SE: GI upset (nausea, vomiting, discomfort, irritation, ulceration, hemorrhage), ↑ bleeding, delayed labor, ↑ depth of respiration, hyperglycemia, glycosuria. Low dose (2 g)  ↓ urate excretion (↑ blood level). High dose (5 g)  opposite. Toxicity: salicylism (tinnitus). Oral methyl salicylate can be fatal. Sulphasalazine  male infertility. Acute hypersensitivity (asthma, rhinitis, urticaria, shock, etc). May have cross-sensitivity to other NSAID DI: Oral anticoagulants (due to platelet inhibition and gastric mucosal damage ↑ bleeding). Methotrexate: ↑ toxicity with salicylates by blocking methotrexate renal tubular secretion. NSAIDs Examples: (x-profen) ibuprofen, ketoprofen, fenoprofen, flurbiprofen, naproxen (sodium), indomethacin, piroxicam, diclofenac, ketorolac (oral, IM), etodolac, oxyprazocin, tolmetin, sulindac, meclofenamate, mefanemic acid, nabumetone. COXII inhibitors: celecoxib, rofecoxib, valdecoxib. Chemistry: Many are acid derivatives. Most are from propionic (x-en) or acetic acid. Others: fentamates, oxicams or anthanilic acid derivatives. COX-II inhibitors  pyrazole derivatives. Pharmacology: COX-I produces PG cytoprotective of stomach lining. COX-II produces PG for pain / inflammation. NSAIDs: ↓ COXI/II  ↓ local PG synthesis. COX-II inhibitors: ↓ COXII only. Indications: NSAIDs: mild to moderate pain, rheumatoid arthritis, osteoarthritis, gout, additive analgesia with narcotics. COX-II inhibitors: rheumatoid arthritis and osteoarthritis. Ketorolac IM: for moderate to severe pain (strongest NSAID for analgesia) when narcotic are undesirable (addicts, respiratory depression, sedation). Indomethacin: strongest NSAIDS for inflammation, ↑ CNS SE. Use for ductus arterisous in premature infants. SE: NSAIDs: GI upset (dyspepsia, mucosal erosion), CNS depression / drowsiness, ↓ platelet function, skin rash, kidney damage. COX-II inhibitors: kidney damage, ↓ GI upset. DI: NSAIDs ↓ effect of diuretics (due to ↓ renal perfusion). COXII inhibitors are CI in allergy to sulfonamides, aspirin, NSAID’s p-Aminophenols Acetaminophen is the prototype (APAP, acetyl para-amino phenol). Also, phenacetin. Mechanism: ↓ central PG  analgesic, antipyretic. No peripheral PG blocking  no effect on inflammation, platelets. Use: alternative antipyretic, analgesic to salicylate. Unlike aspirin, safe as antipyretic for children with viral infections. SE: ↓ at normal doses (skin rash). Acute overdose  liver failure. Antidote: N-acetyl cysteine. CI: alcoholism. Pyrazolones Chemistry: prototype is phenylbutazone, its metabolite is oxyphenbutazone. Also sulfinpyrazone. Mechanism: ↓ PG synthesis, stabilize lysosomal membrane  analgesic, antipyretic, anti-inflammatory, uricosuric. Sulfinpyrazone  only uricosuric ↓ hyperuricemia in gout.

Use: (oxy)phenylbutazone  short term treatment of rheumatoid arthritis and gout (not first choice). SE: ↑ SE. blood dyscrasias (agranulocytosis, thrombocytopenia, anemias), GI uspet, ulceration, kidney damage, hyperglycemia, skin rash, CNS (drowsiness, headache).

Narcotic analgesics (opioids) Chemistry Include natural opiate alkaloids and synthetic analogs Derived from opium (oldest drug) from poppy seed capsule. Morphine: phenolic hydroxyl group is critical for activity. Most important alkaloid (pharmacologically and quantitatively). Amphoteric structure  erratic oral absorption. Agonists: morphine, codeine, heroin, oxycodone, oxymorphone, hydromorphone, hydrocodone, dihydrocodone, meperidine, fentanyl (transdermal), propoxyphene, loperamide, methadone / levorphanol (both long t1/2), diphenoxylate, sufentanil, dezocine. Antagonists: methyl group on nitrogen atom is replaced by bulkier group. Examples: naltrexone, naloxone, levallorphan (?). Mixed agonists-antagonists: nalbuphine, buprenorphine, butorphanol, pentazocine, can ppt withdrawal symptoms if used after agonists. Mechanism Endogenous peptides (enkephalins, endorphins, dynorphins) provide self-pain relief. Opioid receptors: in the brain / spinal cord (Types: μ, κ, σ, δ, ε) Effects of mu receptor stimulation (morphine-like): analgesia, sedation, miosis, euphoria, physical dependence, respiratory depression, bradycardia Other actions: cough suppression, CTZ stimulation (nausea, vomiting). Opioids mimic the action of endogenous opioid peptides at CNS opioid receptors  ↑ pain threshold and tolerance. Clinical use Moderate to severe pain, acute or chronic, of visceral or somatic origin, e.g. MI, cancer, labor, etc. Preanesthesia and adjuncts during anesthesia. Anti-tussives (codeine, dextromethorphan). Antidiarrheal (loperamide, diphenoxylate). Pure antagonists are used as antidotes to reverse SE of agonists or agonists-antagonists (respiratory depression, CV depression, drowsiness). Naltrexone is used for opioid addition. Dose is increased gradually until the appearance of limiting SE Mixed agonist-antagonist preferred for acute pain respiratory depression risk is ↑. Avoid with chronic opioids  withdrawal. Oral: preferred esp. for chronic stable pain. CR morphine and oxycodone available for continuous pain (e.g. cancer) IM, SC: used post-operatively. Absorption is not predictable. IV bolus: most rapid, predictable onset for breakthrough pain IV infusion: to titrate pain relief rapidly for unstable chronic pain, esp. morphine. IV PCA: for acute post-operative pain. Small doses delivered at frequent intervals (10 min). Epidural / intrathecal: for acute post-operative pain and chronic cancer pain. Intrathecal dose = 0.1 epidural dose. Must be preservative free due to neurotoxicity of parabens and benzyl alcohol. Intrathecal local SE: itching, urinary retention. Epidural: ↓ brain level  ↓ SE  give if respiratory depression risk is ↑. Labor  meperidine (less neonatal respiratory depression). Rectal: alternative to oral. Patient un-preferred, poor absorption. Transdermal: CR fentanyl (3 days). Alternative to oral for chronic pain. Slow onset, require oral supplement. Adverse effects Constipation: due to ↓ intestinal tone and peristalsis. After several days (↑ with codeine). Prophylaxis: laxative / stool softener combo (bisacodyl / docusate) if to be used chronically. Respiratory depression: most serious. Monitor respiratory rate if at risk. Use IV naloxone (antagonist) to reverse life-threatening depression, but may ppt withdrawal if on chronic opiates.

Nausea / vomiting: due to central stimulation of chemoreceptor trigger zone, esp. in parenteral dosing for acute pain. May need anti-emetic (hydroxyzine, prochlorperazine), but may ↑ sedation. Sedation: dose-related and ↑ with other sedatives (BZD, anti-emetics). Tolerance develops if chronically used. May need CNS stimulant (methylphenidate, dextroamphetamine). Different from physiological sleep (pain is controlled  patient rests). Anticholinergic: dry mouth, urinary retention. Hypersensitivity: not true allergy. Itching or wheel at injection site due to histamine release, esp. with intrathecal or epidural. Meperidine  CNS excitation: seizure-like, esp. in renal failure patients. Due to accumulation of normeperidine metabolite. Tolerance: to analgesic, sedative and euphoric effects. Combo with NSAID may help overcome this problem. Other SE: miosis, euphoria, confusion / hallucinations, coma, orthostatic hypotension, arrhythmias, histamine release (itching, vasodilation  ↓ BP, bronchoconstriction). Dependence: Withdrawal symptoms: anxiety, irritability, insomnia, chills, salivation, rhinorrhea, diaphoresis, nausea, vomiting, GI cramping, diarrhea, piloerection. Long t 1/2  less intense / delayed withdrawal. Reduce acute withdrawal by using antagonist (naloxone) or agonist-antagonist (pentazocine). Drug interactions: additive CNS depression (alcohol, anesthetics, antidepressants, antihistamines, barbiturates, benzodiazepines, phenothiazines). Meperidine with MAO inhibitors  hypertension, excitation, rigidity.

Tramadol Oral, centrally acting, non-controlled, analgesic with weak opiate (mu) activity for moderate to severe pain. Chemically unrelated to opioids. Mechanism: bind to opiate receptors  ↓ norepinephrine, serotonin reuptake. Naloxone is a partial antagonist. SE: GI (nausea, constipation, dry mouth), CNS (dizziness, drowsiness, headache), ↓↓ respiratory depression, histamine release. DI: ↑ sedation with alcohol and hypnotics. Inhibits MAO  avoid with MAO inhibitors ( seizures)

Miscellaneous agents Glucosamine sulfate and chondroitin sulfate For degenerative joint disease (arthritis) Glucosamine: substrate and stimulant for biosynthesis of hyalouronic acid and glucosaminoglycans forming proteoglycans in structural matrix of joints. SE: GI, drowsiness, headache, rash. Chondroitin: substrate for formation of healthy joint matrix Analgesic adjuncts Other drugs affect non-opiate pain pathways  may help with certain types of pain (e.g. neurogenic / neurologic), or to ↓ SE Examples: tricyclic antidepressants, anticonvulsants, BZD, neuroleptics, corticosteroids, antihistamines, amphetamines. Non-pharmacological pain management Include Cognitive Behavioral Interventions (education, instruction, relaxation, biofeedback, hypnosis), and Physical methods (acupuncture, physical therapy, compression gloves, orthotic devices, heat / cold, massage, immobilization, exercise, rest, transcutaneous electrical nerve stimulation (TENS)

56. Nutrition and the Hospitalized Patient I. Nutritional problems in hospitalized patients a. Malnutrition: Pathologic state resulting from the relative or absolute deficiency or excess of one or more essential nutrients.

b. Marasmus: Chornic state (over months or years) that result from deficiency in the total calorie intake  depletion of fat stores and skeletal proteins to meet metabolic needs. Visceral protein is preserved (normal serum albumin, prealbumin, transferrin). Immune competence, wound healing and ability to handle short term stress are preserved Aggressive nutritional repletion can result in metabolic distrubances (e.g. hypokalemia, hypophosphatemia)

c. Kwashiorkor Acute pricess (within weeks) due to inadequate protein intake Visceral protein depletion, impaired immune function Hypermetaboism (e.g. trauma, infection, surgery) + protein deprivation  kwashiorkor malnutrion, hypoalbuminemia, edema Aggressive nutritional protein repletion is warranted

d. Mixed marasmus kwashiorkor Severe protein-calorie malnutrition when marasmic patients are hypermetabolic

II. Nutritional assessment of metabolic requirements A. Nutritional assessment 1. Subjective global assessment (SGA): relies on patient history 2. Prognostic nutritional index (PNI) Derived from a formula that quantifies patient’s risk of developing complications based on markers of nutritional status such as: serum albumin (visceral protein), triceps skn fold thickness and delayed hypersensitivity skin-test reactivity (immune competence). PNI50%  high risk. 3. Body composition analysis: measure and compares the ratios of body compartments. a. Bioelectrical impedence: calculates lean body mass based on resistance to electrical current. Inaccurate in critically ill patients, and those with fluid or electrolyte abnormalities. b. Dual energy x-ray absorptiometry: measures fat and lean body mass. Depend on hydration status c. Total body potassium: uses whole body counter to measure potassum isotope concentrated in lean tissue  measures lean body mass d. Total body water: measures lean body mass from deuterium total body water (impractical). e. In-vivo neutron activation analysis: divides the body into compartments. Requires large dose of radiation. 4. Test of physiologic function: Quantify malnutrition based on decrease in muscle strength due to amino acid mobilization. a. Maximum voluntary grip strength: measured with isokinetic dynamometry and correlates to total body protein. b. Electrical stimulation of the ulnar nerve: measures muscle contraction.

B. Metabolic requirments: 1. Energy requirments Determined as nonprotein calories (NPC). Can be measued by:

a. Indirect calorimetry or Measured Energy Expendure (MEE) Most accurate. Directly measures O2 consumption and CO2 production. Energy requirment is directly related to oxygen consumption. Respiratory quotient (RQ) = CO2 produced / O2 consumed Oxidation of nutrients: carobohyrates RQ = 1.0, fat RQ = 0.7, Lipogenesis: conversion of excess carbohyrate calories to fat, produces more CO2 than oxidation. b. Estimated energy expendure (EEE) Requires calculation of basal energy expendure (BEE) from Harris-Benedict equation. BEE is then multiplies by stress and substrate utilization factors. c. Simple nomogram Based on patient weight, least accurate. Range from 2535 Kcal/kg/day depending on degree of stress. 2. Protein (nitrogen) requirments a. Nitrogen balance techniques 16% of protein is comprised of nitrogen Nitrogen balance = 24hr nitrogen intake – 24hr nitrogen output Nitrogen output = urine urea nitrogen + nonurea urine nitrogen (ammonia, creatinine) + nonurine nitrogen loss (skin/feces) Positive nitrogen balance of 3-6 g is the goal (not for the renally impaired) b. Nomogram method: estimates protein needs based on lean body weight (1.5-2.0 g protein/kg/day) c. Nonprotein calorie to nitrogen (NPC:N) ratio: normally 125-150:1 3. Essential fatty acids (EFAs): EFAs are polyunsaturated fatty acids not synthesized by humans. Linoleic acid: principal EFA. It’s omega-6 polyunsaturated fatty acid. Linoleic acid deficiency  diarrhea, dermatitis, hair loss Prevent EFAs deficiency by giving ~5% of patient’s calorie intake as linoleic acid from lipid emulstion. 4. Vitamins: Fat soluble: A, D, E, K; Water soluble: B, C Vitamin A: essential for vision, growth, reproduction. IV form binds to plastic and glass. Vitamin D: regulate calcium / phosphorous homeostasis together with calcitonin and parathormone. Vitamin E: antioxidant, ↓ oxidation of free unsaturated fatty acids. Need to ↑ Vitamin E in diets ↑ in unsaturated fatty acids. Vitamin K: critical for synthesis of clotting factors. Vitamin B1 (thiamine): coenzyme in phosphogluconate, structural component of nervous system membranes. Deficiency  acute pernicious beriberi. Prolonged deficiency  Wernicke’s encephalopathy. Vitamin B2 (riboflavin): coenzyme in oxidative phosphorylation. No intracellular stores maintained. Vitamin B3 (niacin): conenzyme in oxidative phosphorylation. Deficiency  pellagra. Vitamin B5 (pantothenic acid): functional form is coenzyme A, essential for all acylation reactions. Vitamin B6 (pyridoxine): coenzyme in enzymatic reactions. Deficiency when taking isonizid, penicillamine, cycloserine. Vitamin B7 (biotin): synthesized by intestinal floar. Involved in carboxylation reactions. Vitamin B9 (folic acid): folate cofactors are needed for purien and pyrimidine (DNA) synthesis. Deficiency in B12  deficiency in (B9) folate  megaloblastic anemia. Deficiency during pregnancy  neural tube fetal defects. Vitamin B12 (cyanocobalamin): large stores  deficiency develops in years. Deficiency: megaloblastic (pernicious) anemia, peripheral neuropathy (needed for myelin synthesis). 5. Trace minerals Iron: necessary for hemoglobin and myoglobin production, enzymatic reactions (cofactor). Deficiency: hypochromic, microcytic anemia, immune deficiency. Zinc: necessary for RNA, DNA synthesis and enzymatic reactions (cofactor). Deficiency: imparied wound healing, growth retardation, hair loss, anorexia.  risk of deficiency in long-term steroid therapy, malabsorption, surgery. Copper: necessary for heme synthesis, electron transport, wound healing. Deficiency: anemia, leukopenia, neutropenia.

Manganese: involved in protein synthesis Selenium: for antioxidant reactions. Deficiency: muscle pain, cardiomyopathy. Iodine: component of thyroid hormones. Deficiency: goiter Chromium: critical for glucose use,  insluin effect. Deficiency: hyperglycemia, glucose intolerance. Molybdenum: essential to xanthine oxidase

100. The Patient Behavioral Deterimants 102. Drug Education 103. Patient compliance Definition: extent to which an individual’s behavior coincides with medical or health advice. Noncompliance can be intentional or unintentional. About 50% of the population is noncompliant with drug therapy in some way. Causes in the elderly: complicated drug regimen, inability to read labels, difficulty opening lids, etc. Noncompliance can affect and bias the results of clinical studies.

Types of noncompliance Not filling Rx: because they do not feel they need or want the Rx. Example: an infection with Tylenol is feeling better and improving. May be because of cost. Omission of doses: common for drug that are taken frequently for long time. Wrong dose: amount of does or frequency of administration is incorrect. Incorrect administration: for example, not using the right technique with aerosols, or wrong route of administration. Wrong time: for example, drug taken at the wrong time in relationship to meals. Drugs such as tetracycline, fluoroquinolones, erythromycin should be taken on empty stomach. Diuretic should be taken in the morning. Premature d/c: common with antibiotics (symptoms subside) or chronic drugs such as for ↑ BP (asymptomatic). Storage: improper storage and improper disposal of unused drugs.

Consequences of noncompliance Over and under utilization have major economic impact. Always, the benefits from ↑ compliance outweigh the costs of compliance enhancing programs. Overutilization: may cause toxicity. Examples: double dose to make up for missed dose, if one pill is good then more must be even better. Noncompliance is one of the most commonly missed diagnoses (e.g. poorly controlled BP). Consequences of noncompliance are not always negative. Some patients are “intelligent noncompliant” where they alter the dose based on SE emergence while treatment goals is still achieved.

Detection of noncompliance Diagnosis of the problem is a key. Behavior may change with time. Ideal detection takes place at the time and place of taking the medication.

Indirect measures: Self-reports and interview: simplest, but overestimates compliance. “Most people have trouble remembering to take their medicine. Do you have trouble remembering to take yours?” Pill count: commonly used in clinical studies. Pill dumping is a common problem (study participants try to deceive physicians). Overestimate compliance. Change of weight of MDI can be used. Achievement of treatment goal: examples: normal BP, BG, intraocular pressure. However, patients may load-up on medication or use other regimens (diet) before doctor visit. This is called toothbrush effect (people toothbrush before dentist visit).

Computerized compliance monitors: most reliable indirect method. Started with electronic eye-drop dispensers. A microprocessor is located in the cap of the container. Time and date are recorded every time the patient removes the cap. Very useful in clinical studies. Refill rate: commonly used in community pharmacy settings.

Direct measured: Direct methods are more reliable. Use of at least 2 methods is recommended. Biological markers and tracer compounds: indicate patient compliance over extended period. Example: glycosylated hemoglobin assesses BG control over the preceding 3-months. Tracer compounds: small amounts of agents such as Phenobarbital or digoxin (long half life, indicate compliance for past weeks) are added to drugs and measured in biological fluids. Drug concentration in biological fluids: limited usefulness due to variability between individuals, does not indicate the timing of the dose, can be fooled by loading-up prior to biological fluid sampling.

The noncompliant patient No consistent pattern has been observed regarding noncompliance with certain age, education, occupation, socioeconomic status, personality, race, severity or type of illness, etc. Intentional noncompliance is more common in patients who used two or more drugs or two or more physicians. Health Belief Model: developed initially to explain preventative health behaviors such as immunizations and prophylactic dental care. It also applies to compliance with prescribed medical regimen. Third Generation Model: focuses on health decisions. Health Decision Model: combines decision analysis, behavioral decision theory, and health beliefs to give a model for health decisions and resultant behavior. Compliance and health beliefs: patient has to believe that: he has the illness diagnosed, illness can cause severe consequences to daily functioning, treatment will ↓ present and future severity of condition, benefits or regimen outweigh perceived disadvantages and costs. Stimulus to trigger positive health behavior can be internal (patient’s concern) or external (interaction with physician or pharmacist). Myths: “need to take medication only when experiencing symptoms”, “need to d/c medication occasionally to prevent dependence and maintain efficacy”. Other factors: patient who live alone are more noncompliant. Patient may have fear of dependence for any drug that is used chronically. They may d/c or ↓ dose occasionally to prevent this or to prove to themselves that is not the case.

Factors associated with noncompliance Disease Psychiatric patient are more noncompliance due to an attitude or inability to cooperate. Patients with chronic asymptomatic disease are more noncompliant (hypertension, hypercholesterolemia, tuberculosis). Occurrence of significant symptoms upon d/c may ↑ compliance. ↑ disability caused by the disease  ↑ compliance. No general correlation between disease severity and compliance.

Therapeutic regimen Multiple drug therapy: ↑ number of drugs  ↑ noncompliance (e.g. in geriatrics). The similarity in appearance of drugs may lead to confusion. Combination drugs may help but therapy should start with individual drugs and then switched to the combo when optimum dose is reached. Frequency of administration: may cause interruption of normal routine or work schedule  inconvenience, embarrassment, forget. Very critical factor in compliance. However, patient may be skeptical about the effective of a QD drug. Duration of therapy: rate of noncompliance ↑ as duration ↑. Adverse effects: change dosage or use alternative drugs if possible. Big problem when the medication makes the patient feel worse than before (e.g., BP drugs). Sexual dysfunction is common cause (e.g.

with antipsychotics, antihypertensives). Just communicating potential SE may cause the patient not to take the drug. Asymptomatic conditions: includes lack of symptoms before the drug, lack of appearance of symptoms if drug is d/c, disappearance of symptoms (antibiotics). Cost: ↑ cost  Rx not filled, ↓dose is taken, ↓frequency, prematurely d/c. Administration: for example, incorrect measure of liquid medications, MDI use, oral antibiotic drops for ear infection instilled in the ear, using suppository by the oral route. Taste: common for oral liquid in children (e.g. liquid KCl).

Patient/pharmacist interaction Psychological support should be provided in a compassionate manner. Patients are ↑ compliance with a physician they know and respect. Not appreciating importance of therapy: if therapy does not meet their own or taught expectations  noncompliance. Poor understanding of instructions: “as directed” should be avoided on label. “every 8 hours” is more specific than “three times a day”. Auxiliary instructions are also key. Example: apply one nitroglycerin patch a day, patient got confused and added a new patch without removing the old ones.

Improving compliance Identification of risk factors All patients should be viewed as potential noncomlpiers. Evaluate the probability of being noncompliant based on the risk factors.

Development of treatment plan Recommend longer acting drugs or dosage forms. The more actively participating patient in the plan is more compliant. Plan should be individualized. Tailor regimen to ↓ inconvenience and forgetfulness by fitting it to regular activities in the patient’s schedule. Indicate specific times of the day to take medications if possible.

Patient education Effective communication is the key for ↑ compliance. Patients should be asked to repeat the instructions to show understanding. Key points: name of medication, action, how much to take, when, for how long, food interactions, possible SE, what to do about SE, information sheet. Oral communication / counseling: more important than written, as it gives patient a chance to interact and ask questions. Ensure privacy and ↓ distractions. Separate consultation area is ideal. Call the patient if possible if face to face is not possible. Written communication: important is a future reference for the patient as he is not expected to remember all details. Written info ↑ compliance only for short term therapy (e.g. antibiotics). Audiovisual materials: very useful in certain situations (e.g. insulin, sumatriptan, MDI). Controlled therapy: it is recommended that patients start self-medication before hospital discharge to transition them from complete dependence in the hospital to complete independence at home. Special compliance programs: example: behavioral program for schizophrenics. Training include learning on obtaining information about drug benefits, correct self-administration and evaluation of effects, identify SE, talking about issue with professionals. Programs may be useful also for sight or hearing impaired patients.

Patient motivation Good knowledge about the illness and medication does not necessarily translate to ↑ compliance. Patients need to be motivated not only educated. Information must be presented in a manner that is not coercive, threatening, or demeaning. Use special packaging or reminder systems if possible. A contract approach may be useful with some patients where agreement is reached on specific actions.

Compliance aids Labeling / auxiliary: must be clear, accurate and specific Calendars / Reminder charts: helps the patient understand which medication to take and when to take it. Special containers / caps: for example, system with four compartments for different time periods (morning, noon, evening, bedtime) for each day of the week. Special caps can display the time of the day when the last dose was taken. It flashes / beeps when it is time for the next dose. Compliance packaging: defined as pre-packaged unit that provides one treatment cycle of the medication. Usually based on blister packages. A good example is special packaging for birth control pills. Another example: prednisone decreasing dose regimen. Child-proof caps may be a problem for the elderly or patients with arthritis. Dosage forms: for example ER, XR and transdermal patches.

Monitoring therapy Self monitoring: by the patient of the treatment regimen, response parameters. Pharmacist monitoring: based on inadequate frequency of refills, follow up by phone or mail reminders. Automatic phone call reminder systems have been used. Brown bag program: elderly pull all medications in a bag and take them to a professional for review. Directly observed treatment: watch patient swallow drug (e.g. in TB).

112. Pharmacoeconomics Innovative roles for pharmacists: home IV therapy, drug level monitoring, parenteral nutrition management, self-care counseling. Pharmacy services may provide positive outcomes by ↓ morbidity, ↑ therapeutic control, ↓ cost of treatment by using efficient therapy, ↓ # of physician visits, ↓ rate of drug related hospitalization, ↓ incidence and intensity of SE. Extra years of life for a patient population can be converted to dollars for society. Economic methods Technique Inputs Outputs Classical operations analysis Units (e.g. pharmacy hrs) Units (e.g. patients monitored) Cost effectiveness analysis Dollars Natural units Cost benefit analysis Dollars Dollars Cost utility analysis Dollars Utiles/preferences Cost minimization analysis Dollars Assumed equal

Cost benefit analysis Medical care is an investment good (in human capital) and a consumption good. Measure of investment benefit: present value of a person’s lifetime productivity. Both inputs (costs) and outputs (benefits) have to be quantified in dollars. Both $ amounts are discounted to their present value at a certain interest rate. Economic value = present value of benefits – present value of costs. Benefits may be difficult to measure or to convert to $, or both.

Benefits Benefits: defined as the ↓ in costs realized due to program implementation. Can be direct, indirect, or intangible. Direct benefits: savings on direct costs in medical care. Easy to measure. Indirect benefits: savings on indirect costs in the medical care. Difficult to measure. It’s avoidance of earnings and productivity losses which would have been incurred without the health program. Intangible benefits: difficult, if not impossible, to measure. Intangible costs are psychological (pain, suffering and grief).

Discount rates Discount rate is the conversion of dollar amount to present values through the use of interest rate. ↑ discount rate: favors projects with benefits occurring in distant future. ↓ discount rate: favors projects with costs occurring in distant future.

Commonly used discount rate is the yield rate on long term gov bonds. Mathematical models are used to calculate benefit/cost ratio. Net Present Value (NPV): a new model for calculating benefits-costs. Very popular and currently recommended by many economists. Rate of Return on Investment: calculates the interest rate from an initial program investment over a potential stream of benefits over time.

Cost effectiveness analysis Alternative ways are compared for achieving results (↓BP, life expectancy). Similar output measurements must be achieved to compare programs. Cost Benefit Analysis Cost Effectiveness Analysis Output: dollar values Output: units not dollars Determines maximum benefit or investment Determines least cost combination Assumes limited resources Assumes adequate resources Fast comparison of programs Different ways to reach same objectives Less flexible More flexible

Economic perspectives A pharmacy service with positive benefit/cost ratio may be good for the society as a whole but not to every segment of the society. Example: drug regiment that ↓ # of patient days in acute care is good for the society but may not be good for the hospital that depends on patient stays for revenue. Always consider who pays the costs and who receives the benefits.

Quality of life outcomes and patient decisions Quality of life and satisfaction with service are critical. Elements may include: probability of success, associated pain, likely outcomes, etc. Example: the quality of years within life extension (healthy years?). Example: untreated hypertension may not critical affect daily life, but a MI would ↓ quality of life. Health-related quality of life (HRQL) is a humanistic outcome. Using decision-analysis techniques, a decision tree can be made of what happens to the patient from diagnosis to cure. The FDA has been leery of drugs that ↑ quality but ↓ life expectancy. Diseases are associated with physical, mental and social impairments (which can be difficult to measure).

Pharmacy Management (PDF files) Basic accounting Accounting: process of collecting, recording, summarizing, using financial data Auditing: accounting that deals with verifying that records are kept and computations are made. Bookkeeping: process that documents flow of resources ($$, goods) into / out of the business, and claims of creditors / owners to those resources Dual effects of accounting: most transactions are recorded twice with the result of a balanced sheet. T Account: with debt on the left and credit on the right. Debits = Credits. Transactions: fiscal / financial events that are recorded. Accounting period: period of time over which transactions are recorded, at the end of which income is measured. Usually 1 year. Not always a calendar year. Methods of recording transactions: Accrual: transactions are recorded at the time they occur. Cash: transactions are recorded when cash transfers hands. Revenue: measurement of goods sold or services rendered for which the business receives cash or the promise of cash. Expenses: resources used up during a period of time to earn revenue. Types of accounts: owner equity = assets - liabilities. Assets: resources owned by the business, e.g. cash, account receivable, buildings, inventory, equipment, furniture, prepaid insurance.

Liabilities: debt owned by the business to creditors. It arises when business borrows cash (e.g. bank loan) or purchases goods or services on credit. Examples: accounts payable, notes payable. Owner equity (Net Worth): claim of the owners to the assets of the business after all creditors have been paid. It ↑ when owners make investments in business or when revenue is earned. It ↓ when expenses are paid. Examples: contributed capital, sales revenue, service revenue, expense accounts. Expenses: not a liability because they are used up resources that require the immediate payment of cash for the amount in full, otherwise  liability. Prepaid expenses are assets because they’re resources that have not yet been used up. Income = revenues – expenses. Cost of Goods on Hand: on last day of accounting period  physical inventory to determine cost of inventory not sold. No physical inventory is needed if perpetual inventory is kept by computer systems. Fixed assets: tangible, long-lived resources used in business operation, e.g. building, machinery, fixtures, equipment, etc. Current assets: resources owned by the business which are expected to be realized in cash, sold or consumed in one year, e.g. account receivable, inventory, etc. Depreciation: wear and tear that occurs on fixed assets calculated as an expense. Most fixed assets, except land, are depreciated. Contra (offset) accounts: reside directly below the fixed asset account to which they pertain.

Income statement Summary of operations, income earned during accounting period. Constructed using revenue and expense account balances. Revenue: sales of good and services Cost of goods sold: such as inventory and transportation expenses. Gross margin = revenue – cost of goods sold. Net profit (income) = revenue – all expenses. Net income = net profit – income tax

Balance sheet Presents the financial position of the business at a certain point in time Constructed using all asset account, liability accounts, OE accounts Retained earnings: link income statement and balance sheet.

Purchasing and inventory Inventory management Involves planning, organizing, controlling inventory for profitability Inventory control objectives: ↓ investment, ↓ purchasing / carrying costs, balance supply and demand. Inventory is the largest pharmacy investment  critical to manage. Total inventory costs = acquisition costs + stock out costs + carrying costs + procurement costs. Acquisition costs: amount the pharmacy pay for the product. Stock out costs: cost of not having the product available when needed Carrying costs: storage, handling, insurance, loss/theft, damage, capital Procurement costs: cost of placing orders, receiving items, stocking shelves, processing documentation Objective of holding inventory: to guard against fluctuations in demand and later delivery, take advantage of bulk discount. Goals of inventory management: minimize investment in carrying and procuring inventory by balancing supply and demand. Inventory costs  significant impact on financials. ↓ procurement and carrying costs, ↑ sales by avoiding stock-outs Cash flow: prompt payment, ↓ COGS, ↑ gross margin Inventory turn-over rate (ITOR) = COGS/average inventory. Target: ↑ ITOR to ↑ return on investment in inventory, ↓ investment in inventory to free up capital for other ventures. Inventory return on investment = net profit/average inventory. What to buy? product, manufacturer, competitor consideration. Where to buy? consider order cycle time, minimum order required. How much and when to buy? difficult to determine.

Cycle stock: inventory kept on hand to fulfill orders Buffer/safety stock: inventory for case of supply/demand fluctuations. Anticipatory/speculative stock: inventory for expected ↑ in demand

Steps of purchasing Cost of goods sold (COGS): have dramatic effect on profits Purchasing objectives: right product / variety, quality, quantity, price, time 1. Market research: to determine needs/wants of patients / prescribers, identify pharmacy image and business goals, space limitations, potential sales. Determining needs: usage reports, other pharmacies, pharmacy employees, questionnaires, sales reps, published top X drugs, formularies. Example: area with young families  children items, older families  elderly items. Consider special disease management areas, e.g. asthma, diabetes. 2. Effective purchasing policies: Use “open-to-buy purchase budget”. Control total $ investment in inventory. Use prior year data to forecast purchase budget for each month in the upcoming year, based on sales and COSG. Adjust (↑ / ↓) each month purchases based on previous month sales and purchases. Gross margin = sales – COGS. 3. Selecting supply sources: must be dependable, prompt, frequent delivery, good return policy, ↓ frequency of out-of-stock, customer service, price, financing arrangement. Options: wholesales, manufactures, buying groups, rack jobbers, etc. Wholesales: advantages include storage of good until needed, rapid delivery, financing options, help with advertising promotions, store layout and design. Rack jobbers: stock and maintain a specified assortment of goods (e.g. eyeglasses) in a fixture in the pharmacy. Manufacturers: not common, large minimum purchases. Central purchasing groups: pool buying power of independent pharmacies for better terms. 4. Negotiating terms: price, discounts, dating, return policy. Pharmacy margin = suggested retail price – pharmacy cost. Quantity discounts: cumulative (generic rebate) or non-cumulative ($ or % per quantity). Cash discount: for prompt payment (typical: 2% if paid in 10 days, net amount due in 30 days), or discount for Electronic Fund Transfer. Final price is calculated after subtracting trade, quantity and cash discounts. Dating: time for discount and payment (prepayment, collect-on-delivery (COD), delayed). Returned goods policy: full credit within x days, partial credit after y days, non-returnable after z days. Check shelves regularly for items not sold. Consider using a returned goods service company (charge a fee). 5. Transferring merchandise title (?) 6. Receiving, marking, stocking: count shipment, check for damage, check invoices, mark prices (merchandise, computer), stock. Stock depth considerations: average demand, review time, lead time, safety stock. Inventory control includes the following: 1. Visual: look at # of units in inventory and compare with how many should be carried, order more if needed. 2. Periodic: count stock on hand at certain intervals, compare to minimum target levels, order more if needed. 3. Perpetual: monitor inventory all the time (usually using a computer). Computer systems: sales, analysis, trends, perpetual, automatic ordering, interface inventory and dispensing systems at point of sale.

Financial analysis / planning Comparative analysis: express each financial statement component as percent of sales, and compare with Digest data. Ratio analysis: compare financial ratios with ratios for the same company during recent years, and similar group of pharmacies in NCPA Pharmacia Digest. Solvency: overall ability to pay legal debts. Calculate Current and Acid Test ratio Current Ratio = current assets / current liabilities. Target > 2 Acid Test Ratio = (Cash + account receivable) / current liabilities. Target > 1 Other solvency ratios: current liabilities / inventory, total liabilities / net worth, long-term liabilities / net working capital, fixed assets / net worth, Efficiency: how well available capital is used. Inventory turnover ratio. Inventory turn over ratio = COGS / average inventory. Target: 5-6. Other efficiency ratios: net sales / inventory, account receivable and account payable collection period, net working capital turnover.

Profitability: the bottom line, important but not the only measure of success. Return on net worth = net profit / net worth. Target 25%. Net worth = total assets – total liabilities. Net profit / net sales: target 5%. Net profit / total assets. Target 15%. Net profit / inventory. Target 20%. Expenses: salaries, wages, rent, utilities, accounting / legal fees, taxes, licenses, insurance, interest, equipment, depreciation. Balance sheet: includes assets and liabilities. Current assets: cash, account receivables, inventory. Current liabilities: account payable, accrued expenses.

Pricing Components of price = ingredient cost + service cost (dispensing) + income. Actual Acquisition Cost (AAC): price the pharmacy pays for the product. Varies depending on source, volume, incentives and deals, type of pharmacy Average Wholesale Price (AWP): NOT (?) the average price the wholesalers sell the product at. Cost assigned to product by manufacturer, overstates AAC Estimated Acquisition Cost (EAC): established by third party payers to estimate AAC. Usually a percentage of AWP (e.g. 90%). Service cost: average or per unit cost of providing a service. Covers expenses such as salaries, rent, utilities, depreciation. Includes cost to dispense. Direct costs: results directly from providing the service. No direct cost if service is not provided. Dispensing direct costs: labels, containers, computer, delivery costs, patient education materials, pharmacy licenses. Indirect costs: costs shared by all services, e.g. rent, utilities, salaries, benefits, advertising, etc. Cost of providing a service = all direct costs + “fair share” of indirect costs. Cost allocation: determining the fair share of indirect costs. Difficult. Estimate % of employees time and facility space devoted to dispensing. Cost to dispense (COD): total dispensing costs / expected Rx volume. It is an estimation of the average cost to dispense Rx. Sensitive to volume. Differential costs; differ among alternative courses of action, i.e. additional costs the pharmacy incurs for providing a new service. Non-cost factors: demand, competition, image, quality signaling, goals, non-monetary costs. Demand: quantity consumers will be at a certain price. Function of price. Elasticity of demand: measures sensitivity of demand to price ∆. Elastic demand: small ↓ in price results in big ↑ in demand. Sellers make money by lowering the price. Inelastic demand is opposite (↑ price  ↑ profit) Consumers are more sensitive to price when: cost of product is large part of total cost, ↓ differences among products, comparisons are easy, consumers can judge quality, switching costs are small, commodity. Image: consumers can select based on perceptions of pharmacy image. Image is affected by: prices, size, location, services offered, personnel, promotions, etc Price as a signal of quality: more likely when consumers cannot judge quality, more for services than products. Penetration pricing: ↓ price to ↑ sales volume. Loss leader pricing: ↓ Rx prices to ↑ OTC sales. Price skimming: ↑ price for superior service.

Basic Management Management components: self, controllable surroundings, uncontrollable surroundings, external environment. Management activities: satisfy various entities, deal with emergencies, purchasing, recruiting, accounting, training, planning, negotiating, sales, dealing with regulatory officials. Management actions: identify tasks, organize resources, monitor performance / task completion, plan for future requirements, deal with problems. Functions of management actions: target setting, problem solving, leadership, team building, dealing with emergencies. Management functions: controlling, directing, organizing, planning, staffing

Controlling: establish standards based on objectives, measure / report performance, take corrective / preventative actions. Directing: motivation, communication, performance appraisal, discipline, conflict resolution. Organizing: division of labor, delegation of authority, departmentalization, span of control, coordination. Planning: vision, mission, objectives, coals Staffing: recruiting, selecting, hiring, training, retaining Know self, who we are, what we aspire to become, new info, what we need to know, who else need to work with us, etc. Manager’s skills: intellectual, technical, ethical, interactive, emotional. Intellectual skills: logical thinking, problem solving Ethical skills: define right from wrong Interactive skills: communicate intelligently and create an atmosphere that facilitates communication. Most problematic issues: poor communication, developing people, empowerment, lack of alignment, entitlement, balancing work / personal life, confronting poor performance, coaching senior management, cross-functional strife, fascination with programs. Decision making: identify objectives, analyze relevant factors, consider all alternatives, selection best option, implement the decision, evaluate the results Management style: depends on organization, situation, personal values, personality, chance. Self-development methods: observation, reflection, guided readings, attachments / visits, seeking feedback, seeking challenges. Strategic planning: must complement strategic thinking / acting. Includes where we are going (mission) and how we get there (strategy). SWOT analysis: strengths, weaknesses, opportunities, threats. Vision of success: mission, basic philosophy, core values, goals, strategies, performance criteria, decision rules, ethical standards. Environment: stability, complexity, market diversity, hostility, competition Cascade of information: should flow not only downward, but also upward Project management failures: lack of focus / attention, inability to cope with different project characteristics, feeling being used / exploited, lack of experience Project management process: develop ideas and proposals, approve the project, project kick-off / start, monitoring / reporting / managing, termination. Project management 10 commandments: concentrate on interfacing, organize project team, plan strategically / technically, remember Murphy’s law, identify stakeholders, manage conflict, expect the unexpected, listen to intuition, apply behavioral skills, take corrective actions. Project management functions: scope / quality / time / cost management PDCA Cycle: Plan, DO, Check, Act Problem solving: define the problem  identify the criteria  weight importance of criteria  generate alternatives  rate alternatives on each criterion  compute the optimal decision Continuous Quality Improvement (CQI): philosophical / structural / healthcare-specific elements. Use PDCA cycle. Philosophical elements: strategic focus (mission, values, objectives), customer focus (patient, provider, payer), systems focus. Structural elements: process improvement teams, top management commitment, statistical analysis, customer satisfaction measures, benchmarking, seven tools (flow charts cause/effect diagrams, check sheets, histograms, etc). Healthcare specific elements: epidemiological studies, governance processes (QA, committees, peer review), risk-adjusted outcome measures, cost-effectiveness analysis. Barrier to quality transformation: lack of constancy of purpose, emphasis on short-term profits, personal view system, management mobility, using only visible figures, ↑↑ cost of employee healthcare, ↑↑ cost of warranty / insurance.

5. Extemporaneous Prescription Compounding 18. Nuclear Pharmacy 19. Pharmaceutical Care and Disease Management 21. Adverse Reactions and Post Market Surveillance 34. Clinical PK and Therapeutic Drug Monitroing 53. Renal Failure 57. Immunosuppressants in organ transplantation 58. Outcomes Research and Pharmacoeconomics Health care system Preferred Provider Organization (PPO): Broad network of providers available, generally management is less strict. 52% Point of Service (POS): HMO plan with the option of going outside the narrow provider network if willing to pay higher cost-sharing. 18% HMO: Narrow choice of providers, tighter management. 26% Types of outcomes: Humanistic outcomes: Health Related Quality of Life, Patient Satisfaction, Caregiver Impact, Patient Preferences, Functional Status Economic: Cost Analysis, Cost-of-Illness, Cost-Minimization, Cost-Benefit, Cost-Effectiveness, CostUtility Clinical: Efficacy, Safety, Impact of therapy on “natural history” of the disease Methods for setting health insurance rates Experience rating: everyone in a specific area is charged the same premium based on the average cost of providing health services to all people in the area Community rating: premium adjusted individually according to a person’s or group’s average health history, risk, and past claim experience