Final Pharmacology

Leonila A. Estole-Casanova, MD

Associate Professor 2 Department of Pharmacology and Toxicology May 25, 2010

Each of you has a STUDY & REVIEW METHOD that has worked best for you

GO with WHAT WORKS BEST! 



Prepare yourself Review from your notes and favorite text

It is unnecessary to memorize many of these facts if one learns to predict the behavior of each drug based on a few facts and an understanding of the PRINCIPLES OF PHARMACOLOGY If you can predict the actions, clinical uses, side effects and drug interactions of each drug based solely on its mechanism of action, you will only have to memorize those facts that do not make sense

Be able to IDENTIFY main drug classes and cite a prototype for each or be able to work backward ex. non-selective cyclooxygenase inhibitors prototype drug: aspirin for fever, inflammation and pain propranolol prototype non-selective β- adrenergic blocker* for hypertension, tachycardia, etc

Be able to RECOGNIZE the most common, most important (e.g., serious or life threatening) or unique side effects or adverse responses for the main drugs or drug classes ex. most anti-HPN drugs – hypotension aminoglycoside antibiotics – ototoxicity hydralazine – lupus-like syndrome

Be able to LEARN & RECOGNIZE the intended effects that will give you a good idea re: precautions or contraindications ex.β- adrenergic blocker –

heart rate or contractility contraindicated: bradycardia heart block

PRAY …. PRAY …. PRAY ….

Leonila A. Estole-Casanova, MD

Associate Professor 2 Department of Pharmacology and Toxicology May 25, 2010

t

processes of absorption, distribution, metabolism and elimination “what the Body does to the drug”

mechanisms of action 

“ what the

Drug Does to the body”

Molecular / Cellular level

Organism

Receptors Affinity Dissociation constant (Kd)

Efficacy (Emax) Therapeutic Window Potency ED50 TD50 Graded-dose Therapeutic response Index curve Quantal concentration -effect curve

Agonist, antagonist

Population

1.If you want to achieve a concentration of 5 ug/ml, how much drug must be given via intravenous bolus? The volume of distribution is 50 liters: a.10mg b.10ug c.250 mg d.250 ug

A quantitative estimate of the tissue localization of the drug  Can be determined by measuring the plasma level of the drug total amount of drug in body (D)

Vd = concentration of drug in plasma (C) Vd = D/ C

1.If you want to achieve a concentration of 5 ug/ml, how much drug must be given via intravenous bolus? The volume of distribution is 50 liters: a.10mg b.10ug c.250 mg d.250 ug

Vd = D / C D = C (Vd)

= 5ug/ml (50,000ml) = 250,000ug or 250mg

1.If you want to achieve a concentration of 5 ug/ml, how much drug must be given via intravenous bolus? The volume of distribution is 50 liters: a.10mg b.10ug c.250 mg d.250 ug

87.A patient presents to the emergency room with acute bronchial asthma. The treating physician decides to administer a loading dose of Theophylline. Knowledge of which of the following parameters is needed for proper dosing? a. elimination half-life b. volume of distribution c. elimination clearance d. creatinineclearance

Initial dose of drug administered in order to compensate for drug distribution into the tissues.  may be much higher than would be required if the drug were retained in the intravascular compartment.  may be used to achieve therapeutic levels of drug (i.e. levels at the desired steady state concentration) with only one or two doses of drug

Loading dose = VdxCsteady state Vd – volume of distribution Csteadystate - the desired steady state plasma concentration of the drug

87.A patient presents to the emergency room with acute bronchial asthma. The treating physician decides to administer a loading dose of Theophylline. Knowledge of which of the following parameters is needed for proper dosing? a. elimination half-life b. volume of distribution c. elimination clearance d. creatinineclearance

2.The process by which the amount of orally-administered drug is reduced before it reaches the systemic circulation a. First-order kinetics b. First-pass effect c. Pharmacokinetics d. Excretion e. Metabolism

2.The process by which the amount of orally-administered drug is reduced before it reaches the systemic circulation a. First-order kinetics b. First-pass effect c. Pharmacokinetics d. Excretion e. Metabolism

FIRST-ORDER rate is directly proportional to the concentration of free drug  constant FRACTION of drug is metabolized per unit time  linear kinetics  half-life is constant

ZERO-ORDER rate remains constant over time, e.g. ASA , Ethanol, Phenytoin  constant AMOUNT of drug is metabolized per unit time  non-linear kinetics  half-life increases with dose

12. The kinetics characteristic of elimination of ethanol and high doses of phenytoin and aspirin is known as a. Distribution b. Excretion c. First-pass effect d. First-order elimination e. Zero-order elimination

12. The kinetics characteristic of elimination of ethanol and high doses of phenytoin and aspirin is known as a. Distribution b. Excretion c. First-pass effect d. First-order elimination e. Zero-order elimination

13. If the plasma concentration of a drug declines with “first order kinetics,” this means that: a. The half-life is the same regardless of plasma concentration b. The drug is largely metabolized in the liver after oral administration and has low bioavailability c. The rate of elimination is proportionate to the rate of administration at all times d. The drug is not distributed outside the vascular system

13. If the plasma concentration of a drug declines with “first order kinetics,” this means that: a. The half-life is the same regardless of plasma concentration b. The drug is largely metabolized in the liver after oral administration and has low bioavailability c. The rate of elimination is proportionate to the rate of administration at all times d. The drug is not distributed outside the vascular system

PHASE I t functions to convert lipophilic materials into more polar molecules

PHASE II t consists of conjugation reactions that result in polar, usually water soluble compounds that are therapeutically inactive

PHASE I P450-dependent oxidations  P450 independent oxidations (alcohol or aldehyde dehydrogenation deamination, decarboxylation)

 

Hydrolysis Reductions

PHASE II  glucuronidation  acetylation  glycine conj.  sulfate conj.  glutathione conj  N- or Omethylation

 Not

all drugs undergo Phase I and Phase II reactions in that order.

 For

example, isoniazid is first acetylated (a phase II reaction) and then hydrolyzed to isonicotinicacid (a phase II reaction)

11. Which of the following is NOT a Phase II reaction of drug metabolism a. Deamination b. Acetylation c. Glucuronidation d. Methylation e. Sulfate conjugation

11. Which of the following is NOT a Phase II reaction of drug metabolism a. Deamination b. Acetylation c. Glucuronidation d. Methylation e. Sulfate conjugation

84.The rate of acetylation is important with respect to the duration of action of: a. atropine b. cocaine c. isoniazid d. acetaminophen

84.The rate of acetylation is important with respect to the duration of action of: a. atropine b. cocaine c. isoniazid d. acetaminophen

drugs induce P450   Increased rate of metabolism

drugs inhibit P450   potentiate the actions of other drugs

 Phenytoin

 omeprazole

 carbamazepine



barbiturates  rifampicin  ritonavir  griseofulvin  chronic ethanol toxicity 

DISULFIRAM  erythromycin  valproic acid  isoniazid  cimetidine  ciprofloxacin  acute ethanol toxicity

14.The drug interaction of alcohol and disulfiram would be an example of which of the following? a.Induction of metabolizing enzymes b.Displacement from serum albumin c.Inhibition of metabolizing enzyme d.Inhibition of uptake into adrenergic neuron

14.The drug interaction of alcohol and disulfiram would be an example of which of the following? a.Induction of metabolizing enzymes b.Displacement from serum albumin c.Inhibition of metabolizing enzyme d.Inhibition of uptake into adrenergic neuron

86.The expected effect of toxic hepatitis on the rate of drug metabolism by the liver: a. Increased b. Decreased c.Unchanged d.Changed from a Type I to Type II process

86.The expected effect of toxic hepatitis on the rate of drug metabolism by the liver: a.Increased b.Decreased c.Unchanged d.Changed from a Type I to Type II process

3. If a drug is repeatedly administered at dosing intervals equal to its elimination half-life, the number of doses required for the plasma concentration of the drug to reach the steady state is: a. 2 to 3 b. 4 to 5 c. 6 to 7 d. 8 to 9 e. 10 or more

input (rate of infusion) = output (rate of elimination)

3. If a drug is repeatedly administered at dosing intervals equal to its elimination half-life, the number of doses required for the plasma concentration of the drug to reach the steady state is: a. 2 to 3 b. 4 to 5 c. 6 to 7 d. 8 to 9 e. 10 or more

5.The dose or concentration required to bring about 50% of a drug’s maximal effect a. Potency b. ED50 c. Efficacy d. Kd e. Therapeutic index

Molecular / Cellular level

Organism

Receptors Affinity Dissociation constant (Kd)

Efficacy (Emax) Therapeutic Window Potency ED50 TD50 Graded-dose Therapeutic response Index curve Quantal concentration -effect curve

Agonist, antagonist

Population

Kd A

measure of a drug’s affinity for a given receptor  The concentration of drug required in solution to achieve 50% occupancy of its receptors

Molecular / Cellular level

Organism

Receptors Affinity Dissociation constant (Kd)

Efficacy (Emax) Therapeutic Window Potency ED50 TD50 Graded-dose Therapeutic response Index curve Quantal concentration -effect curve

Agonist, antagonist

Population

Emax 

maximal response produced by the drug

 Refers

to the concentration (EC50) or dose (ED50) of a drug required to produce 50% of the drug’s maximal effect

Molecular / Cellular level

Organism

Receptors Affinity Dissociation constant (Kd)

Efficacy (Emax) Therapeutic Window Potency ED50 TD50 Graded-dose Therapeutic response Index curve Quantal concentration -effect curve

Agonist, antagonist

Population

the range of doses of a drug that elicits a therapeutic response, WITHOUT unacceptable side effects (toxicity), in a population of patients  quantified by the

THERAPEUTIC INDEX (TI) or THERAPEUTIC RATIO

Single number that quantifies the relative margin of safety of a drug in a population of people  Ratio of the TD50 to the ED50 Median toxic /lethal dose TD50 (LD50)- the dose of a drug required to produce a toxic/lethal effect in 50% of the population Median effective dose (ED50) – the dose of a drug that is therapeutically effective in 50% of the population

5.The dose or concentration required to bring about 50% of a drug’s maximal effect a. Potency b. ED50 c. Efficacy d. Kd e. Therapeutic index

6. The maximum effect of the drug may be produced even if not all receptors are bound in the presence of which of the following: a. Full agonist b. Partial agonist c. Spare receptors d. Inert binding site

e. Effector

The receptor theory assumes that all receptors should be occupied to produce a maximal response. In that case at half maximal effect EC50= Kd.

 Sometimes,

maximal response is seen at a fractional receptor occupation  allow maximal response without total receptor occupancy – increase sensitivity of the system  EC50 2 additive 1 +1 = 2 ; potentiation 0 +1 >1

8.Which of the following terms is best described as a rapid reduction in the effect of a given dose of a drug after only one or two doses a. Supersensitivity b. Tachyphylaxis c. Tolerance d. Anaphylaxis e. Synergism

100.The interaction between an acetylcholinesterase inhibitor and acetylcholine at the neuromuscular junction would be an example of: a.Addition b.Potentiation c.Competitive antagonism d.Non-competitive antagonism

100.The interaction between an acetylcholinesterase inhibitor and acetylcholine at the neuromuscular junction would be an example of: a.Addition b.Potentiation c.Competitive antagonism d.Non-competitive antagonism

9. Aspirin is a weak organic acid with a pKaof 3.5. What percentage of a given dose will be in the lipid soluble form at a stomach pH of 2.5? a. About 1% b. About 10% c. About 50% d. About 90% e. About 99%

 About

90%- a weak acid is protonated when ph