Pharmacology I

1 Learning Objectives: 1. To be able to understand the different branches of pharmacology 2. To be able to understand the basis for classification of drugs 3. A clear understanding of the conditions of drug activity PHARMACOLOGY AND ITS BRANCHES 1. Pharmacology a. It is a science that deals with the study of drugs and their interaction with living systems b. It embraces the knowledge of history, sources, physical and chemical properties, compounding, biochemical and physical effects, mechanisms of action, absorption, distribution, biotransformation, and elimination, and the therapeutics as well as other uses of drugs 2. Pharmacodynamics a. This area of pharmacology describes the effects of drugs on the body. b. It focuses on the characteristics of drugs, their mechanism of actions, and how they produce the pharmacological and physiological effects on living organism or biologic systems (e.g. tissue culture, organ, and intact animal) 3. Pharmacokinetics a. It is the study of the processes and factors, which determine the amount of drug at the site of action. b. It deals with absorption, distribution, biotransformation, and excretion of drugs. 4. Toxicology a. It is the study of the harmful effects or adverse effects of drugs or chemicals in the biologic system. b. It deals with the drugs used in therapy and other chemicals that maybe responsible for household environment or industrial intoxication. 5. Pharmacotherapeutics a. It deals with the application of drugs in the diagnosis, treatment, and prevention of diseases. b. Drugs may be used to provide relief of symptoms or alter the course of disease. c. Drugs may also be administered to alter the physiological processes such as induction of ovulation and synchronization of estrus, pregnancy prevention, and induction of anesthesia 6. Chemotherapy a. It refers to the drugs that destroy the invading microorganisms without destroying the host b. This involves the use of drugs or chemicals to treat or prevent diseases caused by infectious organism (antibacterial, antiviral, antifungal, antiparasitic agents, and antineoplastic.

2 c. Chemotherapeutic agents maybe selectively toxic for invading microorganisms, but are also capable of producing adverse effects on the host. d. The site at which the effects is produced may be located in the same site where the drug acts or it may be located from where the drug is acting. e. Illustration: Aspirin 1)

Action: inhibition of cyclooxygenase enzyme (responsible for the synthesis of prostaglandins that cause fever)

2)

Effect: reduction of fever

Conditions of drug activity: a. Binding of drug molecules to its receptor is not the lone gauge for drug activity, there has to be a biological consequence after attachment. 1) 2)

Affinity - refers to the tendency of a drug to combine with its receptor Intrinsic activity - refers to the inherent ability of the drug to generate a unit of response

b. Drugs that react with specific receptors and produce a defined response are said to possess affinity and intrinsic activity and are termed AGONIST. c. Drugs that have affinity to receptors but have no intrinsic activity are ANTAGONISTS. d. Those that have both agonistic and antagonistic properties are PARTIAL AGONISTS OR DUALISTS 1) 2) 3)

May antagonize agonist that has greater intrinsic activity. Produces a lower response than a full agonist Effect produced is intermediate between the effects produced by a full/pure agonist and a competitive antagonist.

Pharmacologic and Physiologic effects: A. Pharmacologic effect is that which involves a perceptible alteration of biologic functions beyond what is physiological (normal) B. Anything that the body takes in excess can produce pharmacological effects. BASIS OF CLASSIFICATION OF DRUGS 1. Drugs have been classified or grouped into families to reduce various drugs to a manageable number that a generalization can be of these substances.

3 2. Those belonging to one family act on specific receptors and produce similar pharmacologic effects with varying intensify. 3. Drugs can be categorized on the basis of: a. the typical members of their group (e.g. atropine-like drugs) b. Endogenous substances whose action they mimic (e.g. cholinergic drugs) c. Their mechanism of action (cell wall inhibitors) d. Their effects (e.g. diuretics) e. Names of their corresponding agonists (e.g. anticholinergic drugs)

CONCEPT CHECK 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

A science that deals with the study of drugs Describes the effects of drugs in the body Deals with absorption, distribution, biotransformation, and excretion of drugs A study of the harmful or adverse effects of drugs or chemicals in the biologic system Deals with the application of drugs in the diagnosis, treatment, and prevention of diseases Ability of the drug to combine with its receptor A drug that has an affinity and intrinsic activity is said to be an__________ The opposite of agonist The use of drugs that destroy the invading organisms Effect which involves a perceptible alteration of biologic functions beyond what is physiological (normal)

4 LEARNING OBJECTIVES: 1. To be able to understand the concepts of drug-receptor theories 2. To be able to know the basis for classification of receptors DRUG RECEPTOR THEORY 3. An enhanced and excellent understanding of drug-receptor interactions 1. Receptor is a component of a cell or organism that interacts with drug molecules a. The drug-receptor complex initiates a chain of biochemical events that leads to the production of drug’s observed effects b. The receptor was first known as receptive substance which was coined by John Newport Langley c. This concept was developed to identify cellular components to which drug molecules attach before they are able to exert their effects d. The interaction between a drug molecule and its receptor was likened to the lock- and – key model because of the specificity of the interaction. 2. Receptors have been found to be largely made up of proteins a. Several classes of proteins have been identified as drug receptors and these include: 1) Regulatory proteins, which mediate the action of endogenous chemical substances such as neurotransmitters and hormones. 2) Enzymes may be inhibited or activated when bound to a drug (e.g. acetylcholinesterase enzymes, AChE) 3) Transport proteins (e.g. Na +, K+, ATPase, then membrane receptor for digitalis glycosides). 4) Structural proteins (e.g. tubulin; receptors site for certain benzimidazole anthelmintics) b. Cellular sites of receptors 1) 2) 3) 4) 5)

Receptors are located on the surface or within the cells. They occupy only a tiny portion of the cell. If a drug interacts with the receptors that are unique to a few differentiated cells, its effects are more specific If a drug interacts with a receptor common to many cells, its effects will be widespread In some cases, however, the physiological effects of action is localized (e.g. botulinus toxin)

5 3. The receptor theory explains why drugs act on where they do and why one drug can produce different responses from different target tissues. 4. The binding of drugs to their receptors involve any of the following interactions: a. Covalent bonding 1) 2) 3)

A covalent bond is found when an toms which do not differ greatly in electronegativity (valences) share electrons It has very high binding energy and irreversible except at very high temperature and with enzyme intervention This is a very stable bond and is characteristic of drugs with very long duration of action.

b. Ionic bonding 1) An ionic bond is formed when an atom of high electronegativity (anion) unites with an atom of low electronegativity (cation) 2) The transfer of electrons to another atom forms an electrovalent compound 3) The force of attraction decreases with the square of the distance between two atoms of opposing charges. c. Hydrogen bonding 1) This involves hydrogen ions in combination with the other atoms in a molecule or a compound 2) This is a much weaker bond but the presence of a number of H-bonds can stabilize the interaction and reinforce the association d. Van der Waals bonding 1) 2) 3)

Van der Waals bond is a very weak bond between dipoles or induced dipoles and between similar atoms Carbon atoms are usually involved. This type of bonding is believed to be responsible in determining the specificity of drug-receptor interaction.

5. Silent receptors a. Drugs may react with other proteins and the combination does not produce a pharmacodynamic response. b. Such interaction is called silent interaction and the drug receptors are termed “silent receptors” c. Exampels of such drug acceptors are plasma proteins, intracellular proteins, and membrane protein fractions.

6 6. Properties of receptors a. Specificity 1) The molecular shape, form, and configuration of a receptor determine what drug (agonist/antagonist) will bind with avidity to the site 2)

Receptors are responsible for the specificity of drug action

b. Number of receptors can be regulated and is not necessarily fixed. 1) 2)

Their number can be increased by drugs (up-regulation) Certain drugs can also decrease their number or their efficiency to bind with drug molecules (down regulation).

7. Spare receptors a. These are receptors that remain unbound when a maximal response has already been produced. b. Agonists may only need to occupy a small or limited fraction of receptors to produce a maximal response. c. Agents with low affinities can still produced a maximal response at low concentrations when spare receptors are present in target tissues. BASIS OF CLASSIFICATION OF RECEPTORS 1. Receptors are classified primarily on the basis of the substance that stimulates them, the drug effects and the relative potencies based on SAR studies. 2. Examples a. Effects of acetylcholine that are mimicked by muscarine and are selectively blocked by atropine are known as muscarine effects and the receptors that mediate these effects are called muscarinic receptors b. Effects of acetylcholine that are mimicked by nicotine and not antagonized by atropine are nicotinic effects and the receptors that mediate these are called nicotinic receptors c. Since both effects are produced by acetylcholine (cholinergic effects) these receptors can be collectively called cholinergic receptors. 3. Some classes of receptors have sub classifications or subtypes and each exhibit differences which have been utilized for therapeutic purposes. 4. The existence of these receptors subtypes allows the drug to elicit unique or more specific responses in certain cells or tissues.

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a. Some agonists and antagonists are selective for certain sub-populations of receptors. b. A few interact specifically with a single subtype of receptor. 5. This explains why some drug molecule are more specific than the others. a. epinephrine (a neurotransmitter of the sympathetic division) activates both alpha and beta adrenergic receptors. b. Isoproterenol activates only both beta-1 and beta-2 adrenergic c. Dobutamine acts selectively on beta-1 adrenergic receptors d. Metaproterenol acts on beta-2 adrenergic receptors 6. Structure Activity Relationships (SAR) a. The good fit between a drug molecule and its receptor largely depends on the chemical structure of the drug b. Since the drug-receptor interaction does not directly reveal the nature of the receptors, information about its characteristics can be inferred using a structurally related drug that mimic or antagonize the effect of a particular drug (prototype drug). c. If adequate information is given about the structural formulas of drugs that belong to one co generic series and their pharmacological effects, alterations in the chemical structure of the prototype drug and the related changes in effect will insinuate what properties are required for the optimal action of receptors. d. Studies of the relationship between structure and activity of prototype drugs and their antagonists can help identify a species of receptors that mediate a set of pharmacological response. e. SAR studies can also make it possible to develop a drug with higher therapeutic ration but has less toxic effects and more selective to cells that is parent compound. f.

Inferences drawn from the observed physiological response may, however, be compromised by the changes in the pathway from the receptor to the effector site.

g. SAR is an indirect way of gaining information about drug receptors. h. Direct methods of studying drug-binding properties of receptors include: 1) Isolation of receptors (extremely difficult and not always practical) 2) Biochemical and physical means:

8

a)

Electron spin resonance

b)

Fluorescence

c)

High resolution electron microscopy

d)

Nuclear magnetic resonance

e)

X-ray crystallography

F. DRUG-RECEPTOR INTERACTIONS 1. Theories on drug-receptor interactions a)

Occupational theory 1)

Each drug molecule occupies a receptor site and as long as the receptor and the agonist drug combine, there is an effect (ORGAN

2)

The extent of tissue response depends on the proportion of the receptor population occupied by the drug.

EFFECT)

b)

Rate theory 1)

An effect is produced when drug molecule and receptor are combining and dislodging (PIANO EFFECT)

2)

The biologic response depends on the rate at which the agonist and the receptor interact.

3)

The greater the number of associations made per unit of time, the greater is the stimulus.

2) Agonism a.

When an agonist drug binds reversibly with its receptor, the complex formed undergoes a change and becomes different from either the drug or the

receptor. b.

The drug-receptor complex formed provides a stimulus to elicit a response.

3) Pharmacologic antagonism

9 a.

Occurs when an antagonist prevents the attachment of the agonist to the receptor to produce an effect.

b.

The antagonist blocks the interaction of the agonist to the receptor by competitively blocking with the agonist or by altering the structure of the

receptor a.

Competitive antagonism a.

The antagonist competes with the agonist on the same receptor site

b.

The degree of inhibition (reversible) can be overcome by increasing the concentration of the agonist

c.

With the presence of a competitive antagonist, higher concentration of the agonist is required to produce the effect

same b.

4)

Noncompetitive antagonism a.

A noncompetitive (irreversible) antagonist inhibits the action of the agonist at the receptor sites by binding irreversibly to the receptor or to another site that inhibits the response to the agonist.

b.

It may increase the availability of functional receptors or the capacity of the effector organ to respond.

c.

High agonist concentration does not overcome the inhibition by a noncompetitive antagonist.

Physiologic antagonism a.

Antagonism does not occur at the level of receptors.

b.

Two drugs act on different receptors but the effect is observed on the same effector system.

c.

Example is the antagonism observed between acetylcholine and epinephrine on the eye: 1)

Acetylcholine acts on the cholinergic receptors in the constrictor muscles of the iris causing miosis (papillary constriction)

10 2) dilation)

Epinephrine stimulates the adrenergic receptors found on the radial muscle of the iris causing mydriasis (papillary

11 5.

6.

7.

Chemical antagonism a.

Known as antagonism by neutralization.

b.

Does not involve drug-receptor interaction

c.

Occurs when one drug inactivates directly the second drug. 1)

Heparin is a systemic anticoagulant.

2)

Protamine sulfate binds to heparin and makes unavailable for interaction with plasma protein in the blood.

3)

Blood coagulation is not prevented by heparin.

Pharmacokinetic antagonism a.

One drug may reduce the potency of another drug by any of the several pharmacokinetic mechanisms.

1) 2) 3) 4) 5)

Altered absorption from the gut Reduced plasma protein binding. Altered renal excretion. Inhibition of metabolic degradation by enzyme inhibition. Promotion of metabolic degradation by enzymatic destruction

Enhancement of drug effects a.

ADDITIVE drug effect occurs when two drugs of the sum effects are given together and produce an effect that is equal in magnitude to the sum of the effects when these drugs are given individually. EAB

b. the

SYNERGISM occurs when two drugs of the same effect are given together and produce an effect which is greater in magnitude than calculated additive effect. EAB

c.

=EA + EB (1+1=2)

=EA + EB (1+1>2)

POTENTIATION is a form of synergism but more appropriate if a drug lacking an effect on its own increases the effect of a second

active drug. EAB

=EA + EB (1+0=2)

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CONCEPT CHECK 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18.

Antagonism by neutralization The antagonist competes with the agonist on the same receptor site Antagonist prevents the attachment of the agonist to the receptor “Organ effect” drug-receptor theory “Piano effect” drug-receptor theory An indirect way of gaining information about the nature of drug receptors A very weak bond Receptors that remain unbound are termed as_______ TRUE OR FALSE. Receptors can be regulated and is not necessarily fixed Receptors that do not produce any pharmacodynamic response Explain the principle behind “up-regulation” The most stable bond The person who coined receptors TRUE OR FALSE. Some proteins can also act as receptors Also known as reversible antagonism Also known as irreversible antagonism Antagonism that does not occur at the level of the receptors EAB =EA + EB (1+1=2). This is a mathematical expression of what type of drug enhancement? 19. EAB =EA + EB (1+1>2). This is a mathematical expression of what type of drug enhancement? 20. Explain drug potentiation.

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LEARNING OBJECTIVES: 1. To be able to understand the concept of dose-response relationship 2. To be able to know the principles of drug evaluation

DOSE-RESPONSE RELATIONSHIP 1. Graded response a. A type of biologic response that is in increasing in a continuous scale b. If drug-receptor combinations and drug effects are governed by the law of mass action, then the clinical responses observed reflect the extent of the combination of drug molecules with the receptors. c. The greater the fraction of receptors occupied by the drug molecules, the greater is the magnitude of effect. d. Maximal effect is achieved when all the receptors are occupied. 2. Quantal response a. Follow the all-or-none principle b. Occurs when an increase in dosage causes a greater percentage of the population to respond at a premeditated intensity. c. This is applicable to pharmacological effects which cannot be measured as graded but occur in full or do not occur at all. d. Quantal dose-response relationship studies determine the dose of a drug that is required to produce a specified magnitude of effect in a large number of experimental animals. DRUG EVALUAITON 1. Drug dose-response curves are very useful in preclinical and clinical tests of the safety and efficacy of drugs before these are marketed 2. Similar dose-response curves can be constructed for any effect produced by chemicals.

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3. Dose-response curves provide the following information: a. Potency 1)Refers to the range of concentrations over which an agonist produces increasing responses. 2)Represented by the distance between the vertical axis and the foot of the curve. 3)Highly potent drugs produce effects at lower concentrations 4)The more potent drug is not necessarily more effective b. Maximal efficacy 1)Obtained when any increase in the dosages will not cause any further increase in the responses. 2)May be achieved even if not all receptors are occupied 3)The receptors that remain unbound after the maximal efficacy is attained are called spare receptors c. Steepness or slope of the curve 1)An increase in the dosage yields a corresponding increase in the response. 2)A steep curve suggests that a small increase in the dose 3)A flat curve suggests that a larger concentration is necessary to obtain a corresponding increase in the responses 4)In drugs that produce flatter curves, a larger concentration of drugs dose is necessary. d. Variability of a point in a curve 1)Depends on the range of: a) b)

Responses for a particular drug dose Doses that produce a particular responses

2)Indicates the reliability of the drug in use 4. New drugs with considerable biologic effects are used in animals studies before these are tried on human objects.

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a. Various doses of a drug given to several groups of test animals b. Only one dose is given to each animal in a group. c. The percentage of animals showing the premeditated effect is plotted against the dose effect is plotted against the dose. d. From this curve, the dose that evokes the desired quantal effect in 50% of the test animals is estimated. 5. In animal studies, the following parameters are used to measure drug safety and effectiveness or its toxicity a. MEDIAN EFFECTIVE DOSE (ED50) is the dose of the drug at which 50% of the animals exhibit the desired quantal effect. b. MEDIAN TOXIC DOSE (MD50) is the dose required to produce toxic effects in 50 % of the animals tested. c. LETHAL DOSE (LD50) is the dose that kills 50% of the animals tested. d. THERAPEUTIC INDEX or THERAPEUTIC RATION is a measure that relates the dose of the drug intended to produce a desirable effect to the dose that produces an undesirable effect. TI=

LD50/ED50 or TI

= TD50/ED50

e. SAFETY FACTOR is the dose lethal to 1% of the animals over the dose effective in all LD1/ED99 or LDmin/EDmax. f.

MARGIN OF SAFETY determines the effectiveness of the drug in relation to toxicity LDmin-EDmax ---------------------x100 EDmax

=%

6. Variations in drug responsiveness a. Idiosyncracy apply to reactions that are qualitatively different from the effects obtained in the majority of the patients. This is usually caused by genetic differences in metabolism of the drug (e.g. enzyme deficiencies. b. Hyporeactive describes a lowered intensity of response to the drug

16 c. Hyperreactive (drug tolerance) describes an increased intensity of response to an ordinary dose of drug. d. Tolerance refers to the decreased responsiveness with continued or chronic drug administration. There is a need for increasing the amount of drug to obtain the same therapeutic effect. e. Tachyphylaxis implies rapid development of tolerance. Responsiveness diminishes rapidly after drug administration. f.

Hypersensitivity (drug allergy) is a response that results from a previous sensitizing exposure and is mediated by an immunologic mechanism. 1)Anaphylaxis is an acute, systemic life-threatening reactions characterized by bronchospasm, angioedema, urticaria, erythema, pruritus, cardiac arrythmias, vomiting, colic, and hyperperistalsis.

after

2)Serum sickness is a systemic reaction manifested by lymphadenopathy, neuropathy, vasculitis, nephritis, arthritis,urticaria, fever (onset is usually delayed until 10-20 daus receiving the drug; a type III hypersensitivity). 3)Contact dermatitis is a type IV hypersensitivity initiated by local exposure to drugs that act as hapten; delayed reaction may develop at the site of drug application

CONCEPT CHECK 1. Is the dose of the drug at which 50% of the animals exhibit the desired quantal effect. 2. Is a measure that relates the dose of the drug intended to produce a desirable effect to the dose that produces an undesirable effect. 3. Refers to the range of concentrations over which an agonist produces increasing responses. 4. A type of biologic response that is in increasing in a continuous scale 5. Follow the all-or-none principle 6. Is the dose that kills 50% of the animals tested 7. Obtained when any increase in the dosages will not cause any further increase in the responses 8. Apply to reactions that are qualitatively different from the effects obtained in the majority of the patients. This is usually caused by genetic differences in metabolism of the drug 9. Implies rapid development of tolerance 10. Determines the effectiveness of the drug in relation to toxicity

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LEARNING OBJECTIVES: 1. To be able to know the actions of non-specific drugs 2. To be able to know the factors that affects the transport of drugs across cell membranes

There are drugs that do not require receptors to bring about the pharmacologic response. These drug actions are accomplished through any of the following mechanisms A.

Interactions with small molecules or ions 1.Some drugs (e.g. chelating agents) interact with small molecules or ions normally or abnormally found in the body. 2.Chelating agents are accomplished are compounds that bind metal cations and are often used to as antidotes for metal intoxications. 3.Chelating agents form stable coordinate complexes with these metals which are often eliminated by the body 4.Examples

B.

a.

Ethylenediamine-tetraacetic acid (EDTA)

b.

Dimercaprol or BAL (british and antile-wisite )

c.

Penicillamine

Incorporation of drugs into macromolecules 1.Drugs having structural similarity with normal biological substances may become incorporated into cellular components and alter their function. 2.This process is called “counterfeit” incorporation mechanism.

18 3.A drug replaces a normal metabolite in the synthesis of cellular components resulting to the change in the biological responses 4.A typical example in the replacement of dihydrofolate C.

Nonspecific actions and membrane perturbation 1.This group includes drugs that act by virtue of their: a.

Osmotic properties (e.g. osmotic diuretics)

b.

pH (e.g. antacids, urine acidifiers)

c.

Non-specific actions (e.g. detergents actions, anesthetics)

DRUG TRANSPORT ACROSS CELL MEMBRANES 1.

Nature of cell membranes

a.Davson and Danielli (1952) described the cell membranes as a thin bilayer of phospholipids molecules, oriented in a manner perpendicular to the plane of the phospholipids molecules, with polar groups (hydrophilic) aligned at both surface and long hydrocarbon (hydrophobic) chains extending inwards. b.Singer and Nicholson (1972) established the presence of proteins embedded on the bilayer of phospholipids in the Fluids Mosaic Model. These proteins are either embedded on one side or entirely through the phospholipids bilayer while some are loosely attached to the surfaces 2. Drug molecules move across these membranes, by passive transfer or through some specialized transport processes. a.Passive diffusion 1.

Characterized by movement of drug molecules down a concentration gradient

2.

It is the most important mechanisms of drug transfer across membrane barriers

3.

Passage affected by: a)

Molecule size and charge of drug

b)

Lipid-water partition coefficient

c)

Concentration gradient

19

4.

Types of passive diffusion a)

Simple diffusion

b)

Filtration

20 b.Carrier-mediated transport (facilitated diffusion and active transport) 1)

Drug molecules are moved across the membrane by a carrier which is a component of the membrane.

2)

This kind of transport is relative to the structure that is moved across the membrane.

DOSAGE SCHEDULES AND REGIMENS 1.Dosage refers to the amount of medication for a patient or a condition 2.It represents a decision about four variables a.

Amount of drug to be administered

b.

Route of administration

c.

Interval between doses

d.

Duration of therapy

3.Single dose a.

Some drugs are given only once to produce the desired effect such as those used in pre-anesthetic medication, anesthetics, and prevention of vomiting

b.

Others, however, produce effects longer than the period they are present in the plasma (“hit-and-run” drugs).

c.

Examples of “hit-and-run” drugs are organophosphate compounds, which produce inhibitory effects that persist even when the drugs are already eliminated.

4.Repetitive dosing a.

Necessary for drugs that must be given more frequently to produce and maintain a desired effect.

b.

The drug concentration in the plasma must fall within and maintained in a therapeutic range, below which no effect may be produced and above effects may be manifested

which, toxic c.

There are two ways this is achieved:

21

d.

1)

Through continuous intervention infusion

2)

Through repetitive or multiple dosing

Repetitive dosing, using a fixed dose and fixed frequency interval, is the most common method of keeping plasma drug concentration in the therapeutic

range. 5.Plateau principle a. b. c. replenished d.

Drugs that are administered repetitively over a period of time have tendency to accumulate in the system. A plateau (steady-state) is reached after 4-5 half-lives and the rate of drug entering the body is equal to the rate leaving the body. Drug concentration then fluctuates about a mean concentration with each dose administered: the amount of drug that is lost from the previous dose is by the next dose. The degree of fluctuation about desired concentration is related to the maintenance dose, drug’s half-life, and dose interval

6.Loading dose is one or series of large doses given at the onset of therapy so that the target concentration is achieved in a short time. a. b.

Applicable in drugs with wide margin of safety. May expose sensitive individuals to toxic concentrations of the drug.

7.Maintenance dose refers to series of repetitive doses or a continuous infusion of drug given to maintain a steady state concentration in the plasma within a given therapeutic range. CONCEPT CHECK 1. 2. 3. 4. 5.

This kind of transport is relative to the structure that is moved across the membrane. Described the cell membranes as a thin bilayer of phospholipids molecules This process is called “counterfeit” incorporation mechanism Refers to series of repetitive doses or a continuous infusion of drug given to maintain a steady state concentration in the plasma within a given therapeutic range. Characterized by movement of drug molecules down a concentration gradient

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LEARNING OBJECTIVES: 1. To be able to know the different routes of drug administration. 2. To be able to know the principles of pharmacokinetics and pharmacodynamics. DRUG ADMINISTRATION AND ABSORPTION 1.

The route of drug administration determines the rate and efficiency of absorption.

2.

Alimentary routes (oral and rectal routes) a.Oral route is the oldest from of drug administration and considered the safest. b.These routes allow the use of absorption and bioavailability of drug administered. c. There is variable degree of absorption and bioavailability of drug administered. d.Some drugs may affect normal gut flora, cause irritations, or become destroyed or inactivated.

3.

Parenteral routes a.Intravenous routes (IV) 1)

Accurate and rapid high blood and tissue levels reached.

2)

Useful for administering large volumes of drugs or painful and/or irritant injections.

3)

Administration requires specific formulations and good techniques.

4)

Acute toxic reactions, perivascular and intravascular thrombosis can occur

b.Intramascular route (IM) 1)

The most common route of drug administration in large animals

2)

Some injections are painful and may cause muscle damage.

3)

Accurate blood and tissue levels not obtained.

c. Subcutaneous route (SC)

23 1)

Allow for administration of large drug volumes.

2)

Drug may be slowly absorbed and provoke a marked fluid reaction.

3)

Less speed of absorption than IM

d.Other parenteral routes include: 1)

Intraperitoneal route (IP)

2)

Intramammary

3)

INtraarticular

4)

Intrapleural

5)

Subconjunctival

e.Miscellaneous routes include:

4.

1)

Topical

2)

Inhalation

Absorption of drugs from parenteral sites a.Introduction of drug into the bloodstream is equal to the actual rate of absorption. b.Drug concentration is inversely proportional to absorption rate from IM and SC sites: the greater the dose administered the slower is the rate of absorption. 1)

The rates of blood flow and diffusion limit absorption.

2)

Degree of ionization, lipid solubility and molecular weight of drug affect the rate of absorption.

c. In intraperitoneal and rectal, the absorption, drugs may undergo first-pass effect. However, first-pass effect is lessened in drugs absorbed per rectum because 50% of these will by-pass the liver. d.Percutaneous drug absorption is largely dependent on the lipid solubility of the compound. 5.

Absorption from the gut is more complicated than absorption from parenteral sites. a.It is governed by physiologic factors, such as:

24

1)

Surface area for absorption

2)

Blood flow to the site of absorption

3)

pH of gastrointestinal contents

4)

Presence of food in the stomach

5)

Species differences among animals

b.It is also affected by the physicochemical properties of drugs 1)

2)

Lipid solubility a)

Solubility is expressed in terms of partition cooeficient , the ration of drug solubility in oil to its solubility in water.

b)

Drugs with high partition cooefficient are more lipid soluble and therefore, readily absorbed from the gut.

Physical state of the drug a)

Solid drug formulations need to be released from its dosage and become transported across the gastrointestinal barrier.

b)

Rate of absorption of solid forms (e.g. tablets) depend on the rate of its dissolution in the gastrointestinal fluids.

3)

Molecular weight limits the degree of absorption of non-lipid soluble drugs.

4)

Degree of ionization in a given pH a)

Nonionization drug molecules pass with relative ease through the GI epithelium

b)

Ionized or charged molecules having limited ability to cross biological membranes due to ion trapping.

c)

Ion trapping refers to the accumulation of ions in one compartment because of the difference in pH

d)

Weak acids ionize in a basic pH while weak bases ionize in an acidic pH.

25

N.

e)

Absorption of weak acids is favored in acidic environment while that of weak bases is favored in basic environment.

f)

Obligate ions (e.g. Curare) are administered IV because these favor poor gut absorption.

DISTRIBUTION 1.As soon as drug is absorbed into the bloodstream, it is distributed to various interstitial and cellular fluids. 2.Distribution of drug in the body is affected by: a.

b.

Blood flow 1)

Tissue perfusion is one important determinant of drug distribution.

2)

Less perfused tissue requires longer period before the steady-state concentration is attained in these areas.

Physico-chemical properties of drug 1)

Lipid solubility

2)

Ionization constant

3)

pH (weak acids/weak base)

4)

Molecular weight

c. Concentration gradient 1)

Drugs easily diffuse down a concentration gradient.

2)

Movement against a concentration gradient requires sufficient metabolic energy.

d.Drug reservoirs 1)

Plasma proteins a)

Drug molecules attach to plasma proteins (e.g. albumin, globulins) until an equilibrium is reached between the free drug and bound drug.

26 b)

Free drug molecules interact with receptors and produce an effect while those bound to plasma proteins remain in the circulation and can biotransformed or excreted.

c)

Drugs may compete for binding sites in plasma proteins.

d)

This binding is saturable and if the dose and administered exceeds the amount the plasma proteins can hold the amount of free drug in circulation increases and may lead to manifestation of toxic

not be

the effects. 2)

3)

Cellular reservoirs a)

Muscles, fat, bone, and other tissues can accommodate drug molecules at concentrations greater than that in ECF (extracellular fluid)

b)

If the tissue involved has a large fraction of body mass, it may represent a sizable drug reservoir.

c)

Fat can serve as important for lipid soluble drugs.

d)

Bone can serve as important reservoir for tetracyclines and heavy metals.

Transcellular reservoirs a)

The major transcellular is the GIT especially for orally administered drugs that have slow absorption rate.

b)

Some may be excreted and temporarily stored in the bile.

c)

Others: CSF, aqueous humor, endolymph joint fluids.

3.Redistribution or sequestration refers to the accumulation of drug molecules in sites where they do not have pharmacological action. a.

This is one way of terminating drug activity

b.

These sites may serve as reservoirs for the maintenance of plasma drug concentration.

c.

Elimination of drug from these sites depend on its biotransformation and excretion.

4.Potential transfer of drugs a.

In general, drugs administered to the dam reach the fetus.

27 b.

Factors affecting drug transfer. 1)

Surface area and diffusion characteristics of placenta

28 2)

3) c.

Properties of drugs that promote diffusion a)

High lipid solubility

b)

Low molecular weight

c)

Decreased degree of ionization

d)

Decreased plasma protein binding

Relative maternal and fetal drug concentrations

Sink effect describes the transfer of drugs across the placenta 1)

Free drug molecules that cross the placenta bind with the macromolecules in the blood and organs of fetus

2)

This causes a lowered concentration gradient of free drug in the fetal circulation.

3)

Further transfer of drug molecules into the fetus by simple diffusion is promoted.

5.Drugs transfer across the blood-brain barrier a.

The blood-brain barrier normally excludes entry of drugs and other foreign agents into the CSF and the brain.

b.

Factors that affect distribution of drugs to the brain 1)

Lipid-solubility of the drug

2)

Damage to the blood-brain barrier (BBB)

c.

Highly lipid-soluble drugs readily penetrate the barrier while less lipid-soluble drugs are pharmacologically altered to be able to reach the brain.

d.

Latentation is the process by which a lipophilic group is attached to the drug to enable it to pass through the BBB

e.

Damage to the barrier removes the restrictions.

29

O.

BIOTRANSFORMATION OF DRUGS

1.Biotransformation refers to the various enzymatically mediated chemical changes that a compound or drug undergoes in a living system that terminates or alters drug activity. 2.This process generally transforms a biologically active compound into an inactive or less active one (DETOXIFICATION) 3.It may also transform an inactive or less active compound to its more active form (LETHAL SYNTHESIS) and the resulting metabolite may or may not cause death. 4.Lethal synthesis often involves PRO-DRUGS which are inactive or with low level of activity that are metabolized to the active form in the body (e.g. probenzimidazoles). 5.Sites of biotransformation a.

The liver is the principal site of drug metabolism

b.

Other organs like the GIT, lungs, skin, and kidneys have considerable activity.

c.

Drugs absorbed from the gut pass via the hepatic portal system to the liver and thus undergo a first-pass effect.

d.

First-pass effect refers to the partial metabolism/biotransformation of drugs as they pass through the liver before they reach their sites of action.

e.

First-pass effect limits the bioavailability of orally administered drugs.

6.Liver microsomes (microsomal mixed functions oxidase system) a.

Microsomes are smooth endoplasmic reticulum vesicles containing enzymes called cytochromes are smooth endoplasmic reticulum vesicles containing enzymes called cytochrome P-450, mixed function oxidase or

monooxidases. b.

These are complex of proteins and hemeprotein.

c.

The soluble cytoplasmic fractions of hepatic contain NADPH which serves as the reducing agent.

d.

Microsomal oxidation reduction reactions are mediated by: 1)

Flavoprotein (NADPH-cytochrome P-450 reductase)

30

2)

Hemoprotein (cytochrome P-450)

7.Biochemical reactions involved are grouped into two major categories. a.

b.

Phase I reactions (metabolic biotransformations) 1)

Convert the parent drug into a more polar metabolic product by introduction or removal of a functional group.

2)

This involve oxidation, reduction, and hydrolic reactions.

Phase II reactions (conjugation reactions) 1)

Proceed combining endogenous substances with phase I metabolites which are not rapidly eliminated.

2)

Examples of endogenous substrates include glucuronic acid, sulfuric acid, acetic acid or amino acid (glycine)

3)

If the parent drug already possess a functional group, it may proceed directly to phase II.

8.Non-microsomal biotransforming enzymes include: a.

Plasma: butrylcholinesterase/pseudocholinesterase

b.

Neurons and neuromuscular junctions: acetylcholinesterase

c.

Mitochondria or cytosol: monoamine oxidase (MAO), alcohol dehydrogenase

d.

Intestines:

glucoronidases, glycosidases, aminodases.

9.Factors affecting biotransformation a.

b.

Physicochemical property of drug 1)

lipid solubility

2)

molecular weight

3)

Ionic charge

Route of administration: oral route can cause extensive hepatic metabolism of some drugs due to first-pass effect.

31 c.

Dosage:

d.

Age of animal 1) Very young animals or neonates lack well developed drug metabolizing. 2)

e.

toxic dose can deplete detoxifying enzymes

Very old patients have decreased activity of metabolic enzymes or reduced availability of essential endogenous cofactors

Species 1)

Most species have different pathways of drug biotransformation.

2)

This difference is believed to be responsible for the difference in response to drugs

3)

Species variations in drug biotransformation are classified into: a)

Qualitative difference to the variation in the pathways of drug metabolism (e.g. glucoronic, glutathione, sulfate

b)

Quantitative difference refers to the variation in the rates of biotransformation (e.g. chloramphenicol half life: dogs 4.2 man 1.5 to 3.5 hours)

conjugation

hours,

the co

f.

Disease, particularly that in the liver reduces drug metabolism.

g.

Starvation usually decreases rate of biotransformation because the cofactors needed for biotransformation are decreased

h.

Gender-associated differences is associated with androgenic hormone (testosterone)

i.

A genetic factor variation in drug metabolism of animals belonging to the same species

j.

Drug-to-drug interaction during metabolism 1)

Enzyme induction refers to the enhancement of enzymatic activity of one drug by another drug to hasten its rate of biotransformation

2)

Enzyme inhibition refers to the inhibition of cytochrome P-450 enzyme activity causing reduction of the rate of degradation of one drug or administered drug

32

P.

EXCRETION 1.

Excretion refers to the removal or elimination of drugs metabolites from the living system.

2.

The kidney is the primary organ for excretion although drugs can be excreted in the urine, bile, feces, sweat, saliva, milk, and even expired air.

3.

Renal excretion

4.

a.

Glomerular filtration applies to the drugs with MW 70,000 or less

b.

Tubular secretion of many drugs is an active process and a saturable

c.

Reabsorption of drugs in he tubular fluid depends on the lipid solubility of or polarity of the drug and urine pH.

d.

Urine pH can be manipulated to enhance drug elimination or reabsorption.

Biliary extension (enterohepatic recycling) a.

Biliary excretion of drugs is a carrier-mediated process.

b.

Drugs or endogenous metabolite conjugates which enter the gut via the bile are reabsorbed in the process called enterohepatic recycling

c.

When higher concentration of drug dose undergoes enterohepatic recycling, its elimination is delayed and its duration of action is

prolonged. 5.

Fecal excretion a.

Drugs reach the intestinal tract via its wall, its secretions, on the bile.

b.

The amount that can be recovered in the feces consists of the unabsorbed drug and drug that has reentered the gut.

c.

Excretion by the other route:

33 1)

Drugs can be excreted into sweat, saliva, tears, milk, expired air (via lungs), hair, and skin, in insignificant amounts.

2)

Rate of excretion is dependent on diffusion or non-ionized, lipidsoluble substances and their pH.

6.

Drug residue refers to the concentration of drug present in tissues or killed animals

7.

Withdrawal period refers to the time which must elapse between the first dosing and slaughter of food animal for human consumption.

effect on

a.

It does not define the time between last dosing and total elimination of the drug or other substances.

b.

It defines the time needed to achieve a drug concentration in the tissues, which on the basis of toxicological studies will not have adverse the consumer.

CONCEPT CHECK 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17.

Determines the rate and efficiency of absorption Oldest from of drug administration and considered the safest Route of drug administration in which accurate and rapid high blood and tissue levels reached The most common route of drug administration in large animals. Introduction of drug into the bloodstream is equal to the actual rate of__________ Drug concentration is inversely proportional to absorption rate from____________ It is expressed in terms of partition cooefficient, the ration of drug solubility in oil to its solubility in water. Factor that limits the degree of absorption of non-lipid soluble drugs. Refers to the accumulation of ions in one biological because of the difference in pH. Two plasma proteins useful for distributing drugs to the different sites in the body Major transcellular reservoirs of the body Refers to the accumulation of drug molecules in sites where they do not have pharmacological action. Describes the transfer of drugs across the placenta Excludes the entry of drugs and other foreign agents into the CSF and the brain Is the process by which a lipophilic group is attached to the drug to enable it to pass through the BBB Refers to the various enzymatically mediated chemical changes that a compound or drug undergoes in a living system that terminates or alters drug

activity. 18. Refers to the partial metabolism/biotransformation of drugs as they pass through the liver before they reach their sites of action

34 19. 20.

Process that transforms an inactive or less active compound to its more active form. Phase I reactions is also termed as _________________.

AUTONOMIC AND SOMATIC PHARMACOLOGY A.

MAJOR DIVISIONS OF THE NERVOUS SYSTEM 1.

Central Nervous System a. b.

2.

Brain Spinal Cord

Peripheral Nervous System a.

Autonomic division 1) 2) 3)

Activities are not under the direct conscious control Concerned primarily with visceral functions Subdivided into: a) b)

b.

Somatic division 1) 2)

B.

Activities are under the direct conscious control Concerned with functions like locomotion, respiration, and posture.

ANATOMY OF THE AUTONOMIC NERVOUS SYSTEM 1.

Parasympathetic autonomic nervous system a.

Consists of two nerve fibers, one (preganglionic) arising from the CNS and the other (postganglionic), from the terminal the first.

b.

Parasympathetic preganglionic fibers leave the CNS through the cranial nerves (especially III, VI, IX, X) and the sacral (S3, spinal roots.

portion of

S4)

Parasympathetic (craniosacral) Sympathetic (thoracolumbar)

35

c. or near 2.

Sympathetic autonomic nervous system a.

Sympathetic preganglionic fibers leave the CNS through the thoracic and lumbar spinal nerves.

b.

Sympathetic preganglionic fibers synapse at the sympathetic ganglia located in the paravertebral ganglia arranged in both sides of the spinal column.

chains on 3.

Parasympathetic preganglionic fibers synapse with the postganglionic fiber at parasympathetic ganglia located in the wall of the innervated organ.

Comparative features of the two divisions:

Criteria Length of fiber: Preganglionic Postganglionic Ganglionic synapse Function

C.

Parasympathetic

Sympathetic

Long Short Discrete (1:1) Energy conservation

Short Long Diffuse (1:20) Massive energy discharge

NEUROTRANSMITTERS 1.

Neurotransmitters is chemical substance released in small amounts from the nerve terminals of presynaptic cell into the synaptic cleft.

2.

The chemical transmitter diffuses along the synaptic cleft and binds to specialized receptor molecules on the postsynaptic cell, resulting to the activation of the

3.

There are two common neurotransmitters in the autonomic nervous system:

latter.

4.

a.

Acetylcholine (AcH) is the main neurotransmitter of the parasympathetic division.

b.

Norepinephrine is the predominant neurotransmitter of the sympathetic division.

Autonomic nerve cells are also classified according to the neurotransmitter they release: a.

Cholinergic fibers are those which synthesize and release acetylcholine (AcH) at their terminal and they include: 1) 2)

All parasympathetic and sympathetic preganglionic fibers Parasympathetic postganglionic fibers

36 3) b.

Somatic (nonautonomic) fibers are those which synthesize and release norepinephrine

Adrenergic (or noradrenergic) fibers are those which synthesize and release norepinephrine (noradrenaline). 1.

Most sympathetic postganglionic fibers release norepinephrine.

2.

Adrenal medullary cells (chromaffin cells) which are modified sympathetic postganglionic neurons release both

3.

Dopamine is released by some peripheral sympathetic fibers.

norepinephrine.

D.

PHYSIOLOGY OF JUNCTIONAL TRANSMISSION 1.

When the action potential reaches the axonal terminals, a series of events proceed in a manner that allows transmission of an excitatory or inhibitory in pulse across the

synapse. 2.

Release of neurotransmitters a.

Neurotransmitters are synthesized in axonal terminals (nonpeptides) or cell body (peptides) and stored in large quantities in vesicles found at the axon

b.

These are released at the resting phase in quantities enough to produce electrical responses of the postsynaptic membranes (miniature

c.

Depolarization of the axonal terminal causes the entry of large concentration of calcium ions which promote the fusion of synaptic vesicles containing neurotransmitters.

d.

Vesicular contents are released into the synaptic cleft by exocytosis

terminals.

endplate).

these

3.

4.

Combination with presynaptic receptors a.

The neurotransmitter released may bind with presynaptic receptors (receptors found in the presynaptic axonal membrane).

b.

Binding may inhibit (e.g. alpha 2-adrenergic receptor) or enhance (e.g. beta2 adrenergic receptor) further release of the neurotransmitter.

c.

Regulatory effects are believed to be associated with the function of the calcium channels.

Combination with the postsynaptic receptors

37 a.

Binding of the neurotransmitter with the postsynaptic receptors changes the ionic permeability or conductance of the membrane

b.

If the change favors the entry of large quantities of cations (Na+, Ca++) across the postsynaptic membrane, this can lead to the production of an postsynaptic potential (EPSP).

c.

If the entry of anions is promoted, this results to hyperpolarization (more negative membrane potential) which constitutes inhibitory postsynaptic potential (PSP).

d.

If permeability to K+ is increased (K+ is increased (K+ leaves the cell), this also lead to hyperpolarization.

excitatory

5.

Initiation of postsynaptic activity a.

6.

E.

EPS in the postsynaptic membrane that reaches the threshold causes a series of activity depending on the nature of the postsynaptic cell. 1)

Neuron, skeletal, cardiac fiber: depolarization and propagation of action potential.

2)

Smooth muscle fiber: increased rate of spontaneous depolarization and increase in muscle tone.

3)

Gland cell:

b.

IPSP opposes excretory potential of other neurons.

c.

The continuation of the propagated impulse depends on the algebraic sum of excitatory and inhibitory effects.

Removal of the neurotransmitter from the synaptic cleft occur through the following: a.

Enzymatic degradation

b.

Simple diffusion

c.

Reuptake by the axon terminals

AUTONOMIC RECEPTORS 1.

Cholinergic receptors (Cholinoreceptors) a.

Muscarinic 1)

gland)

increased secretory activity.

Usually found in effector cells innervated by the parasympathetic postganglionic fiber (eg. cardiac muscle, smooth muscle, and

38 2) b.

2.

Some are also present in the CNS neurons and presynaptic sites.

Nicotinic 1)

Autonomic ganglia

2)

Skeletal muscle

Adrenergic receptors (adrenoreceptors) a.

Alpha-adrenoreceptors 1)

Alpha 1 (postsynaptic effector cells esp. smooth muscles)

2)

F.

Alpha2 (presynaptic adrenergic nerve terminals, platelets, lipocytes, smooth muscles) ACETYLCHOLINE BIOSYNTHESIS 1.

Acetylcholine (AcH) is synthesized from choline and acetylcoenzyme A by choline acetyltransferase enzyme in the cytoplasm of cholinergic fibers. a.

Choline actively gets into the cytoplasm by a carrier that cotransports Na+.

b.

Acetylcoenzyme A is synthesized in the mitochondria

2.

The newly synthesized ACh is transported down the terminal portion of the axon and stored in the vesicles by quanta (1 quantum= 1,000 to 5,000 ACh molecules).

3.

Release of ACh occurs when the action potential coming from the body of the neuron reaches the terminal portion.

4.

The released ACh molecules diffuse across the synaptic junction and activate the ACh receptors on the postsynaptic cell.

5.

Activity is terminated when acetylcholinesterase enzymes so the half-life of ACh is very short.

6.

Cholinergic synapse is rich with these enzymes so the half-life of ACh is very short

G. ACETYLCHOLINE HYDROLYSIS

enzyme.

1.

The action of ACh and its cogeners on the receptors are terminated by cholinesterase ( ChE) enzymes.

2.

Cholinesterase have ionic and esteratic sites similar to those of cholinergic receptors.

3.

The quaternary N+ atom or the choline molely is attracted to the anionic site of AChE while the C atom of the carbonyl group interacts with the hydroxyl group of the

39 4.

The ester bond between choline and acetate breaks and the acetate remains attracted to the enzyme now termed as acetylated enzyme.

5.

The acetylated enzyme reacts with the water to rproduce acetic acid and regenerates the enzyme.

6.

The regenerated enzyme is capable of cleaving another ACh molecule.

7.

Since AChE enzymes are responsible for terminating ACh activity, inhibition of these would lead to: a. b. c.

8.

Accumulation of ACh in the receptor site Prolongation of ACh action Exaggeration of cholinergic responses.

Types of cholinesterases a.

b.

Acetylcholinesterase (true cholinesterase) 1)

Hydrolyzes acetylcholinesterase

2)

Found in nerve terminals of peripheral nervous system, neuromuscular junctions, gray matter of the CNS, and in erythrocytes

Butyrylcholinesterase (pseudocholinesterase) 1) 2)

H.

Hydrolyzes butyrylcholine Localized in the plasma and white matter of the CNS

PHARMACOLOGICAL PROPERTIES OF ACETYLCHOLINE 1.

ACh generates types of effects, classified according to the receptors that mediate these effects: a.

Muscarinic effects are produced by the action of ACh and its cogeners on cholinergic receptors in autonomic effector cells such as smooth cardiac muscles and glands.

b.

Nicotinic effects are produced when the cholinergic receptors in the autonomic ganglia and NMJ are stimulated.

muscles,

2.

Muscarinic effects of ACh and its cogeners include: a.

Cardiovascular system 1) 2)

Vasodilation (reduced peripheral vascular resistance) Decreased rate of conduction of sinoatrial (SA) and atrioventricular (AV) node

40 3) b.

Gastrointestinal system 1) 2) 3)

c.

3.

Narrowing of bronchial lumen due to contraction of smooth muscles Increased secretory activity of tracheobronchial glands

Eye 1) 2) 3)

f.

Increased ureteral peristalsis Contraction of detrusor muscles Relaxation of trigone and sphincter muscles

Respiratory system 1) 2)

e.

Increased peristaltic activity of the stomach and intestines Relaxation of sphincter muscles Increased secretory activity of the gut

Urinary tract 1) 2) 3)

d.

Decreased rate and force of cardiac contraction

Contraction of the circular smooth muscles of the iris (miosis) Contraction of the ciliary muscles (accommodation for near vision) Opening of the canal of Schlemm (relief of increased intraocular pressure or glaucoma)

Miscellaneous secretory glands stimulation of secretory activity of sweat, lacrimal, and nasopharyngeal glands.

Nicotinic effects a.

Central nervous system 1) 2)

b.

Mild alerting action at lower concentration Tremor, emesis, and convulsion at higher concentration

Peripheral nervous system 1)

Simultaneous discharge of sympathetic and parasympathetic neurotransmitters due to activation of nicotinic receptors in the

2)

Effects in the cardiovascular system are predominantly sympathetic while that in the GIT are predominantly parasympathetic

ganglia

c.

Neuromuscular junction (NMJ) 1) 2)

I.

Depolarization of skeletal muscle fibers Muscular contraction, tremors and fasciculation

CHOLINERGIC RECEPTOR STIMULANTS (CHOLINERGIC AGENTS)

41 1.

Direct-acting cholinergic agonists act directly on cholinergic receptors a.

Muscarinic or PARASYMPATHOMIMETIC agents are drugs which mimic the action of ACh on muscarinic sites and are blocked by atropine.

1)

Choline esters a)

These have similar absorption and distribution but have longer duration of action than ACh Poorly absorbed and distributed into the CNS (low lipid solubility) Differ in their susceptibility to AChE and their muscarinic and nicotinic effects. Examples are methacholine, carbachol, and bethanecol Used cilinically in the treatment of gut hypomotility (such as in grain overload), urinary bladder paralysis, and esophageal achalasia

b) c) d) e)

CHOLINE ESTERS

SUSCEPTIBILITY TO AChE

MUSCARINIC ACTION

NOCTINIC ACTION

ANTAGONISM BY ATROPINE

+ + -

++++ ++ ++

+ +++ -

+++ + +++

Methacholine Carbachol Bethanechol 2.

Cholinomimetic alkaloids a)

MUSCARINE i.

Isolated from a mushroom species, Amanita muscaria

ii.

Major importance in toxicologic studies

iii.

Mushroom poisoning is exhibited by overstimulation of the muscarinic receptors: salivation, lacrimation, nausea, vomiting, disturbances, diarrhea, bronchodilation

visual b)

c)

PILOCARPINE i.

Chief alkaloid from the leaflets of Pilocarpus sp. A North American shrub

ii.

Marked effect on the muscarinic receptors of the eye and exocrine glands

iii.

Used to treat glaucoma (causes opening of the canal of Schlemm)

ARECOLINE i.

An alkaloid from the seeds of Areca catechu (betel nut)

ii.

Has both muscarinic and nicotinic effects

42

b.

iii.

Causes increased waves of peristalsis

iv.

Has been used to eradicate tapeworms (causes paralysis of the scolex)

Nicotinic agonists 1)

NICOTINE a)

2)

2.

A depolarizing ganglionic blocker i.

Competes with ACh at receptor sites

ii.

Causes powerful, persistent stimulation of cholinergic receptors on autonomic ganglia

iii.

Large amounts produces subsequent blockade after initial stimulation.

b)

It stimulates the CNS and causes increased bowel motility (parasympathetic stimulation)

c)

Has been used in vet. Med. As wildlife capture drug and as an insecticide (40% nicotinic sulfate)

SUCINYLCHOLINE a)

A depolarizing neuromuscular blocker

b)

Causes initial stimulation and subsequent blockade due to fatigue

c)

Rapidly hydrolyzed by pesudocholinesterase

Indirect-acting cholinergic agonists act on the cholinesterase enzymes that degrade acetylcholine and its cogeners a.

These agents react covalently with the cholienesterase in the same manner as ACh. 1)

The difference lies in the rate of regeneration of these enzymes

2)

Regeneration of carbamoylated enzyme (AChE- acetate + water) is slower

3)

Regeneration of carbamolyated enzyme (carbamate-AChE + water) is slower.

4)

Regeneration of phosphorylated enzyme (OP- AChE + water) occurs at a much slower rate

43 b.

There are two types of indirect-acting cholinergic agents: reversible and irreversible.

c.

Reversible cholinesterase inhibitors inactive cholinesterase for a few hours only. 1)

2)

PHYSOSTIGMINE/ESERINE a)

An alkaloid from the Calabar bean, an ordeal bean

b)

Inhibition, in vivo, lasts for 3 to 4 hours

c)

Effects are mainly muscarinic and is used clinically to

ii)

Counter the effects of atropine in the eye

a)

A synthetic analogue of physostigmine

b)

It inhibits AChE and also stimulates cholinergic receptors

c)

Used clinically to treat hypomotility of the gut and urinary bladder, myasthenia gravis, and counteract muscle caused by myasthenia gravis, and caused by drugs like curare or

ENDROPHONIUM a)

A simple analogue of neostigmine but does not have a carbamyl group

b)

Less potent and has a shorter duration of action

c)

Used in diagnostic test to differentiate between muscle weakness due to myasthenia gravis and muscle patients with myasthenia gravis exhibit improvement for 5 minutes

fatigue: that lasts 4)

Relieve glaucoma

NEOSTIGMINE

paralysis counteract muscle paralysis aminoglycoside antibiotic 3)

i)

CARBAMATE INSECTICIDES a)

These are heterocyclic aromatic, napthyl carbamates synthesized to produce selective toxicity against

b)

These are also potent anticholinesterase agents.

insects

44

d.

c)

Mainly used in vet. Med. For the control of external parasites of both large and small animals

d)

Signs of poisoning similar to those of organophosphate poisoning

e)

Examples: CARBARYL (SEVIN) PROPOXUR (BAYGON), MOBAN ALDICARB AND ZECTRAN

IRREVERSIBLE CHOLINESTERASE INHIBITORS 1)

These are organophosphorous compounds or organophosphates (OP) and include: a) b) c) d) e)

Toxic “nerve gases” Agricultural pesticides Herbicides Acaricides Dewormers The general formula for this class of AChE inhibitors is:

R1-O

O or S P

R2-O

X

Legend: a) b) c) d)

R= any group (alkyl-amino-intercaptan- etc.) X= leaving group (e.g. halide, cyanide, phosphate) O= phosphate compound (active) S= phosphothionate compound (inactive)

4)

Examples a)

War gases : DIISOPROPYL-PHOSPHO-FLUORIDATE (DFP)

b)

Nerve gases: TABUN, SARIN, SOMAN

c)

Insecticides: COUMAPHOS (Asuntol), DICHLORVOS (DVVP), TRICHLORFON(Neguvon), MALATHION, RONNET,

TUELENE 5)

Ops have high lipid solubility and so they are well absorbed and widely distributed.

45

6)

Volatile gases like “nerve gases” can be readily absorbed through the lungs and skin

7)

OPS are extensively metabolized in the liver

8)

e.

a)

Removal of the leaving group X (dealkylation) leads to inactivation or activation of the compound

b)

Dealkylation reaction is inhibited in mammals and birds, but not in insects which accounts for the selective toxicity in insects

There are two classifications of Ops a)

Directly-acting Ops those which inhibit ChE enzyme without prior metabolism

b)

Indirectly-acting Ops require biotransformation before they can inhibit ChE enzymes

Cholinesterase inhibition by Ops 1)

2)

Phosphorylation of ChE enzyme a)

OP forms a powerful covalent linkage ChE on the esteratic site of the latter

b)

The degree and duration of binding depends on the nature of the specific OP involved

c)

This is also characterized by the removal of the leaving group X from the ChE-OP group

Dephosphorylation of ChE a)

Removal of OP from its attachment to the enzyme or spontaneous dephosphorylation occurs even without the intervention of

b)

The rate of removal (recovery of the enzyme) depends on the nature of the OP: those with more complex R groups usually have spontaneous recovery period

c)

When the OP is already dislodged from the esteratic site, the ChE (recovered or regenerated) can act at once more on another molecule

d)

Recovery of enzymes can be induced using:

medicines

longer

ACh

46

1.

HYDROXYLAMINE (NH2OH) i. ii.

2.

A very toxic compound and not used clinically Act directly on the OP attached to the esteratic site of ChE

PRALIDOXIME (2-PAM) i.

A relatively nontoxic compound and has been used for counter-acting OP toxicosis

ii.

Attaches itself to the anionic site of ChE before attacking the OP attached to the esteratic

site. 3)

Aging a)

Refers to the stage at which ChE enzyme can no longer be activated.

b)

If after the removal of the leaving group X, one of the alkyl groups is removed (dealkylation of R1 or R2), there is a rearrangement electron cloud..

of the

f.

i.

The electronegative group repels the (OH-from the water or 2PAM) necessary for spontaneous/induced recovery

ii.

The bond between the esteratic site and OP becomes stronger.

c)

The enzyme at this stage is considered to be dead, it cannot recover or regenerate

d)

Aging takes place longer in compounds with more complex R groups.

e)

IN cases of OP poisoning, 2PAM should be administered before aging takes place

f)

It usually takes weeks or months to restore normal ChE, levels in the body after OP poisoning

Pharmacological effects of OP 1)

Observable signs are due to stimulation of both muscarinic and nicotinic cholinergic receptors.

2)

Effects in the CNS include excitation (or mania) which may progress to convulsions and coma

3)

Cause of death is usually due to respiratory failure: bronchoconstriction, dyspnea, excessive salivation, and paralysis of respiratory

47

g.

Drugs used in the treatment of poisoning include: 1)

2)

J.

ATROPINE i.

Most important antidote for carbamate and OP poisoning

ii.

Blocks only the muscarinic effects

PRALIDOXIME i.

Activity is limited by aging

ii.

No longer effective if aging has already taken place between the time of poisoning and treatment

PARASYMPATHOLYTICS 1.

2.

These are the drugs which competitively inhibit ACh at muscarine sites: a.

These are specifically muscarinolytics.

b.

No action on the nicotinic sites.

Atropine sulfate a.

The prototype parasympatholytic drug

b.

An active substance from deadly nightshade, Atropa belladonna

c.

Physiologic disposition

d.

1)

Well absorbed orally and parenterally

2)

Widely distributed in tissues, reaches the CNS

3)

Metabolized by atropinase, an enzyme which is present in goats and rabbits at high concentrates

4)

Horses and cattle are quite resistant to oral doses of atropine but may be responsive to parenteral injections

Pharmacologic effects 1)

Mainly due to ACh inhibition a)

Heart: tachycardia

b)

Blood pressure: little effect because the blood vessels are primarily under sympathetic control

48

e.

K.

Smooth muscle: relaxation

d)

Secretion: decreased]

e)

GIT: decreased peristaltic activity

f)

Eye:

g)

CNS: stimulation in large doses, followed by depression

dilation, relaxation of ciliary muscles, closure of canal of Schelemm

Clinical uses 1)

3.

c)

Preanesthetic great a)

To decrease salivary secretions associated with the use of anesthetic agents

b)

Prevent heart block

2)

Mydriasis

3)

OP poisoning antidote

4)

Antispasmodic

5)

Counteract cholinergic drug overdose

Other atropine-like drugs a.

SCOPOLAMINE

b..

HOMATROPINE

c.

EUCATROPINE

d.

HYOSCINE

e.

GLYCOPYROLATE

BIOSYNTHESIS OF CATECHOLAMINES 1.

Catecholamines are endogenous adrenergic neurotransmitters a.

Norepinephrine is the transmitter of most of the sympathetic postganglionic and certain tracts of the CNS

49

2.

b.

Epinephrine is the major hormone of the adrenal medulla and mesolimbic neuronal pathway

c.

Dopamine is the major hormones of the adrenal medulla and mesolimbic neuronal pathway

Catecholamines synthesis occurs in nerve terminal varicosities a.

b.

c.

Hydroxylation of tyrosine into dihydroxy-phenylamine (DOPA) 1)

This step determines the rate of catecholamine synthesis

2)

Catalyzed by tyrosine hydroxylase

3)

This step can be inhibited by alpha-methyldopa

DOPA is decarboxylated into dopamnine 1)

Catalyzed by DOPA decarboxylase

2)

Can be inhibited by alpha-methyldopa

3)

Dopamine the moves into the vesicles, movement can be inhibited by reserpine

Dopamine is hydroxylated at beta-carbon to form norepinephrine 1)

Catalyzed by dopamine beta-hydroxylase

2)

Can be inhibited by disulfiram

3)

Norepinehprine may diffuse out of the terminal varicosities, or back into the cytoplasm, or stored until released by exocytosis in the an action potential.

presence of d.

I.

Methylation of norepinehprine into epinephrine 1)

Occurs in chromaffin cells of adrenal medulla

2)

Catalyzed by6 phenyl-ethanol-amine N-methyltransferase

3)

Norepinephrine leaves the vesicles by diffusion and is methylated to epinephrine which reenters the vesicles

4)

Rate of epinephrine synthesis largely depends on the level of glucocorticoids secreted by the adrenal cortex

TERMINATION OF THE ACTIONS OF CATECHOLAMINES

50 1.

2.

3.

M.

Reuptake into nerve terminals (uptake I) a.

The most common mechanisms for termination of catecholamine action.

b.

Removes 65% of the released catecholamine.

c.

Uptake 1 refers to reuptake from the synaptic cleft into the cytoplasm.

d.

Uptake -2 refers to the reuptake from the cytoplasm into dense core vesicles.

Metabolic biotransformation or enzymatic degradation. a.

Removes about 20% of the released catecholamine

b.

Monoamine Oxidase (MAO) is mitochondrial enzyme.

c.

Catechol-O-Methyltransferase (COMT) is found in the cytoplasm

Dilution by diffusion out of the junctional cleft and uptake at extraneuronal sites (removes about 15% of the released catecholamine)

PHARMACOLOGICAL EFFECTS OF EPINEHPRINE 1.

Epinephrine is the prototype adrenergic stimulant.

2.

Effects caused by other adrenergic stimulants differ in intensity.

3.

Major effects a.

Peripheral excitatory effects (alpha adrenoreceptors) 1) 2) 3)

b.

Peripheral inhibitory effects 1) 2) 3)

c.

Vasodilation Relaxation of the smooth muscles in the gut Bronchodilation

Cardioexcitatory effects (alpha and beta adrenoreceptors) 1) 2)

d.

Vasodilatation Mydriasis Mucoid and thick salivation

Increased heart rate Increased force of myocardial contraction

Metabolic effects (alpha and beta adrenoreceptors)

51

1) 2) 3) e.

CNS effects (alpha and beta adrenoreceptors) 1) 2) 3)

N.

Hyperglycemia Hyperlipidemia Increased blood lactic acid

Transient respiratory stimulation Wakefulness Anxiety

ADRENERGIC DRUGS 1.

Directly-acting (act directly on adrenergic receptors) a.

EPINEPHRINE (ADRENALINE) stimulates both the alpha and beta receptors.

b.

Alpha stimulants 1) 2) 3)

c.

Alpha-2 stimulants 1) 2) 3) 4)

d.

Dopamine Dobutamine

Beta-2 stimulants 1) 2) 3)

g.

Isoproterenol Mehtoxyphenamine

Beta-1 stimulants 1) 2)

f.

Clonidine Oxymethazoline Xylazine Detomidine

Beta stimulants 1) 2)

e.

Norepinephrine (Noradrenaline) Phenylephrine Methoxamine

Metproterenol Albuterol Terbutaline

Others 1) 2)

Phenylpronanolamine Terahydrozoline

52 3) 4) 5) 2.

Indirectly-acting (promote the discharge of norepinehrine from varicosities of nerve terminals) a.

AMPHETAMINE 1) 2) 3) 4)

b.

c.

3) 4)

Resembles ephedrine but lacks CNS stimulating action Used principally as mydriatic

METARAMINOL 1) 2) 3)

Effects similar to norepinephrine but less potent and prolonged Has both direct and indirect actions Principally used to treat hypotensive states

Clinical use of sympathomimetics a. b. c. d. e. f.

O.

Obtained from plant Ma huan (ephedra shrubs) Has direct and indirect action and the alpha and beta adrenergic receptors and enters the brain. Resistant to the effects of MAO and COMT Used as bronchodilator, cardiac stimulant, mydriatic, and CNS stimulant

HYDROXYTRYPTAMINE 1) 2)

e.

Similar to amphetamine Greater central than peripheral effects

EPHEDRINE 1) 2)

d.

Readily enters the CNS Stimulates mood and alertness; depresses appetite Peripheral effects are mediated through the release of catecholamines Blocks monoamine oxidase

METAMPHETAMINE 1) 2)

3.

Oxymethazoline Porpylhexedrine Tuaminopheptane

Adjunct to local anesthesia Hemostatic Mydriatic Treatment in anaphylactic reactions Bronchodilation Decongestant

SYMPATHOLYTIC AGENTS (ADRENERGIC BLOCKERS) 1.

Alpha adrenergic blockers

53 a.

Examples 1) 2) 3)

2.

b.

Cause hypotension due to loss of compensatory mechanism which is dependent upon the sympathetic tone.

c.

Used to reverse compensatory vasoconstriction in cardiovascular shock

Beta adrenergic blockers a.

Examples 1) 2) 3) 4)

Pronanolol Timolol Metoprolol (beta-1 selective) Butoxamine (beta-2 selective)

b.

Cause cardiac depression and bronchoconstriction

c.

Clinical uses include: 1) 2) 3)

3.

Phenoxybenzamine, Dibenamine, Phentolamine, Prazosin Ergot alkaloid: Ergocristine, Ergocryptine Tranquilizers: Chlorpromazine, Acepromazine, Haloperidol

Treatment of hypotension Reverse digitalis-induced cardiac arrythmias Treatment of obstructive cardiomyopathy in dogs and cats

Inhibition at various stages of catecholamines synthesis a.

Interference of catecholamine release form the vesicles by blocking action potential 1) 2)

b.

c.

Guanithidine and Bretylium Effect: adrenergic inhibition

Inhibition of vesicular storage of catecholamine (uptake-2) 1)

Reserpine and Guanithidine

2)

Effect: initial stimulation followed by depression due to depletion of norepinephrine

3)

Effect: the amines becomes free in the axoplasm and is susceptible to attack by MAO

Inhibition by uptake into varicosity (uptake-1) through inhibition of the uptake pump 1) 2)

Imipramine, Cocaine Effects: adrenergic stimulation, antidepression

54

d.

1)

Alpha-methyl-tyrosine (inhibits tyrosine hydroxylase)

2)

Disulfiram (inhibits dopamine beta-oxidase)

3)

Inhibition of metabolic enzyme

e.

MAO inhibitors: Parygline, Isocarboxacid (antidepression )

f.

COMT inhibitor: Pyrogallol (no striing pharmacological effect)

g.

Effect: protect the release of catecholamines from inactivation

h.

Synthesis of false neurotransmitter

i.

P.

Inhibition of enzyme synthesis

1)

Alpha-methyl-dopa and octopamine

2)

Hypotension

Degeneration of adrenergic nerve fibers 1)

6-hydroxydopamine

2)

Effect: decreased sympathetic function

MUSCLE RELAXANTS 1.

Muscle relaxants are agents that induce skeletal muscle relaxation

2.

Uses

3.

a.

Relief of muscular spasms

b.

Restrain animal patients

c.

Adjunct to anesthetic agents

Sites of action a.

Central (brain) 1)

General anesthetic a)

Cause CNS depression, consequently depressing outflow of impulse to the skeletal muscle

55 b) 2)

Not routinely used for muscle relaxation only because of concurrent loss of consciousness

Skeletal muscle relaxants a) MOA: block internuncial neurons which are responsible for polysynaptic reflexes b)

No marked CNS depression and loss of consciousness but some degree of sedation or tranquilization may occur

c)

Clinical use: relief of skeletal muscles spasm as in intervertebral disk protrusion

d)

Examples: i. ii. iii. iv.

b.

Mephenesin Glyceryl, Guaiacolate/Guaphenesin Melprobamate Methocarbamol

Motor nerve fibers 1)

Local anesthetics a)

Produce desensitization and analgesia of skin surfaces, local tissues, and regional structure

b)

Main site of action is the cell membrane i.

Bind to voltage-gated Na+ channels and prevent the transient increase in the permeability to

ii.

Blockade of Na+ channels block all subsequent ionic flow

iii.

Depolarization is prevented and therefore conduction of impulses is stopped or retarded

these ions

c)

Ester-linked drugs i. ii. iii. iv.

d)

Cocaine Procaine HCL Chlorprocaine HCL Tetracaine HCL

Amide-linked drugs

56

i. ii. iii. iv. c.

Lidocaine HCL Mepivacaine HCL Dibucaine HCL Bupivacaine HCL

Neuromuscular junction 1)

At presynaptic site a)

Inhibition of ACh synthesis (e.g. inhibition of choline uptake by Hemicholinum)

b)

Inhibition of ACh release by i. ii. iii. iv.

c)

Promotion of ACh release depletion of ACh stores i. ii.

2)

Calcium deficiency, magnesium increase Procaine Tetracycline and Aminoglycoside antibiotics Botulinum toxin and tetrodotoxin (puffer fish poisoning)

Black widow spider venom Grayanotoxin (Rhododendron spp.)

At postsynaptic site a)

Depolarizing drugs (noncompetitive neuron muscular blockers ) i.

Succinylcholine Decamethonium

ii.

MOA persistent i)

Depolarization leading to Na+ inactivation preventing electrical impulses

ii)

Dual block prolonged exposure of cholinergic receptors to large doses depolarizing drugs reduces the these drugs to cause conduction.

iii)

Characteristics

conduction.

of ability of

(i)

Transient muscle fasciculation caused by asynchronous depolarization

57 (ii)

Paralysis is caused by prolonged depolarization of the motor plate

(iii)

Paralysis is not reversed by anticholinesterase drugs

(iv)

Paralysis is terminated by metabolism with

end-

pseudocholinesterase b)

Nondepolarizing drugs (competitive neuromuscular blockers) i.

Examples: i)

d-Tubocurarane chloride (Curare, MetubimineR)

ii)

Galammine Triethiodide (Flaxedil R)

iii)

Pancuronium Bromide (PavulonR)

iv)

Vecuronium Besulate (Tracrium R)

v)

Atracurium Besulate (TracriumR)

ii.

MOA: complete with ACh for postsynaptic receptors thereby reducing depolarization caused by

iii.

Characteristics

ACh

d.

i)

No muscle fasciculation occurs before muscle paralysis

ii)

There is no depolarization of motor end-plate

iii)

The animal gradually relaxes

iv)

Neuromuscular nondepolarizing drug can be reversed by anticholinesterase drugs

Skeletal muscle fiber 1) 2) 3) 4)

Dantrolene This drug counteracts muscular rigidity by limiting the release of calcium form the sarcoplasmic reticulum Used in the treatment and prevention of malignant hyperthermia Adverse effects

58

a) b) c) d)

Generalized muscle weakness Sedation Gastrointestinal disturbances Hepatitis

DRUGS ACTING ON THE CENTRAL NERVOUS SYSTEM A.

CENTRAL NEUROTRANSMITTERS 1.

Excitatory amino acids a. b c.

2.

Examples: glutamate and aspartate Found in the interneuron at all levels of the CNS Effects: reduced by dissociative agents (e.g. ketamine)

Inhibitory amino acids a.

Gamma- aminobutyric acid (GABA) 1)

Major inhibitor neurotransmitter at all levels of the brain in mammals

2)

Present in short inhibitory neurons

3)

Utilized by certain animal parasites as peripheral neurotransmitter

59 4) b.

3.

MOA: binds with its receptors and causes opening of chloride channels in nerve

Glycine 1)

Found in interneurons in the brain stem and spinal cord

2)

MOA: causes hyperpolarization of postsynaptic flexor neurons

3)

Effects:

4)

Antagonized by:

suppression of flexor movements

a)

Strychnine:

titanic contractions of skeletal muscles

b)

Brucine:

(from Strychnos nox vomica) causes enhancement of spinal reflexes

Amino neurotransmitters a.

b.

Acetylcholine 1)

Transmitters between motor neurons and Renshaw cells in the spinal cords

2)

Central action antagonized by parasympatholytics

3)

Release is enhanced by calcium and suppressed by magnesium

Norepinephrine/Epinephrine 1)

Location a)

Norepinephrine: all levels of the brain

b)

Epinephrine: primarily in the midbrain and brain stem

c)

Degradation inhibited by MAO inhibitors

d)

Presence in synaptic cleft is prolonged by drugs that prevent reuptake of these substances presynaptic nerve terminal

into the c.

Dopamine 1)

An intermediate in the synthesis of Norepinehprine

2)

Receptors:

60

d.

a)

D1 receptors activate adenylcyclase

b)

D2 receptors inhibit adenyccyclase

c)

Dopamine receptors in CTZ mediate vomiting

3)

Inhibits secretion of prolactin from anterior pituitary gland

4)

Antagonized by tranquilizer-sedative phenothiazines and butyrophenones

5-Hydroxytryptine/serotin 1)

A putative transmitter for the midbrain and pons

2)

5-HT receptors regulate feed intake

3)

Hallocinogenic effects are mediated by 5-HT2 receptors

4)

Functions: a) b) c) d)

5) e.

B.

Agonists like LSD (lysergic acid, a hallucinogen) stimulates 5-HT2 receptors

Histamine 1)

A neurotransmitter in the hypothalamus, the limbic system, and other parts of the cortex

2)

Formed by decarboxylation of amino acid histidine

3)

There are three known types of histamine receptors:

4) pituitary

Sleep Excitatory role in regulation of prolactin secretion Inhibit transmission of pain in the dorsal horns Probable involvement in regulation of circadian rhythms

a)

H1-activates phospholipase C

b)

H2 increases intracellular cyclic AMP

c)

H3-mediates inhibition of histamine secretion

Function in the brain is uncertain but believed to be related to arousal and regulation of the secretion of some anterior hormones

CORTICAL STIMULANTS

61

1.

2.

Cocaine a.

An alkaloid from South American shrub, Erythroxylon coca

b.

MOA: potentiates catecholamine action by blocking their reuptake into the axonal nerve terminals

c.

A weak MAO inhibitor

d.

Effects: 1)

Enhanced mental activity and increased work performance

2)

Convulsion with subsequent depression (large doses)

Xanthines (Methylxanthines) a.

A group of naturally occurring alkaloids in beverages 1) 2) 3)

Tea (Caffeine, Theophylline) Coffee (Caffeine) Cocoa (Caffeine, Theobromate)

b.

MOA: inhibition of phosphodiesterase, which inactivate cAMP (accumulation of cAMP in tissues to high levels of activity)

c.

Effects:

metabolic

1) 2) 3) d.

Myocardial stimulation (positive inotropic effect) Smooth muscle relaxation Diuresis

Potency ranking of natural xanthines Heart

Theophylline Theobromine Caffeine 1-

2 3

greatest 3

Smooth Muscle 1 2 3

3

Kidney 1 2 3

-least

Sympathomimetics (indirectly acting) a. b. c.

Examples: Ephedrine, Amphetamine More potent CNS stimulants than epinephrine Effects

CNS 2 3 1

62 1) 2) 3) 4) 4. C.

D.

E.

Increased alertness and wakefulness in man A feeling of euphoria Improvement in physical work Dizziness and disorientation (large doses)

No longer used in veterinary medicine

MEDULLARY STIMULANTS 1.

These are physiological antagonists of CNS depressants

2.

Mainly used to antagonize effects of excessive does of CNS depressants

3.

Doxapram (Dopram) a.

Clinically used in veterinary medicine

b.

Primarily acts as stimulant of peripheral (aortic and carotid bodies) chemoreceptors

c.

Has a wide margin of safety between respiratory stimulant dose and convulsant dose.

SPINAL STIMULANTS 1.

Examples:

strychnine and brucine

2.

MOA: block glycine in the spinal cord

3.

Effect enhancement reflex responses (a lower doses) and painful, tonic convulsions (at higher doses)

4.

Can cause death due to asphyxia

5.

Used as poison

6.

Antidote: Central muscle relaxant (e.g. gauifenesin) or barbiturate

ANTICONVULSANTS (ANTIEPILEPTICS) 1.

These are CNS depressants which act primarily by suppressing convulsions arising from CNS stimulation

2.

Their principal use in veterinary medicine is in the treatment of epilepsy including status epilepticus

63

3.

Commonly used anticonvulsants a.

b.

c.

d.

Phenobarbitone/Phenobarbital 1)

First antiepileptic used

2)

Has widest spectrum of activity in different types of seizures (general anticonvulsant)

3)

MOA: raises seizure threshold but does not prevent spread of seizure activity

4)

A general non-selective CNS stimulant

Primidone 1)

2-deoxyanalogue of phenobarbitone

2)

Converted to phenobarbitone and phenylethylmalonamide (PEMA)

3)

Does not produce hypnosis at anticonvulsant

Phenytoin (Diphenylhydantoin) 1)

MOA: Inhibits the spread of seizure activity from a focus to adjacent neural tissue.

2)

Not a general anticonvulsant; depresses motor centers without depressing sensory areas.

3)

Properties a)

membrane-stabilizing activity

b)

local anesthetic property

c)

antiarrythmic

Diazepam 1)

A benzodiazepine tranquilizer-sedative

2)

Has a short duration of action (rapid hepatic biotransformation)

3)

Primarily used for emergency treatment of status epilepticus

64 4)

4.

a)

Minimal depressant action on respiration and cardiovascular system

b)

Rapidly penetrates the CNS than other antiepileptic drugs

Other anticonvulsants a.

b.

c.

d.

e.

F.

Advantages:

Trimethadone 1)

Formerly used to treat canine epilepsy

2)

Causes photopobia

3)

Converted to dimethadone, which is an effective anticonvulsant

Valproic acid 1)

Short half-life renders it unsuitable for maintenance

2)

Rapidly absorbed and distributed to CNS

3)

May be valuable when used with other agents

Carbamazepine 1)

Used to treat grand mal seizures in man

2)

Rapidly excreted in dog

3)

Not suitable for maintenance

Ethosuxamide 1)

Used for treatment of epilepsy in man

2)

May be effective for myclonic epilepsies

Clonazepam 1)

A benzodiazepine

2)

Used primarily in the dog for emergency treatment of status epilepticus

PREANESTHETHIC MEDICATION

65

1.

Purposes: a. b. c. d. e. f. g. h.

2.

Aid in restraint of animal by modifying behavior (calming effect or sewdation) Reduce stress Eliminate or minimize pain Produce relaxation of muscles Decrease the amount of anesthetic drugs For safe and uncomplicated induction, maintenance, and recovery from anesthesia Minimize the potentially toxic and adverse effects of concurrently administered drugs to produce general anesthesia Minimize autonomic reflex activity, whether sympathetic or parasympathetic in origin

Drug categories a.

Anticholinergic 1)

2)

placental b.

Primarily to: a)

Prevent salivary secretions

b)

Inhibit bradycardic effects of vagal stimulation caused by anesthetic drugs

Ability to cause CNS effects a)

Atropine and Scopolamine may produce drowsiness and potentiate effects of CNS depressants

b)

Glycopyrolate (a quaternary ammonium drug) dos not cross the blood-brain barrier or, barrier

Tranquilizer, neuroleptics, and sedatives 1)

Tranquuilizer-sedatives a) b) c)

2)

Phenothiazine derivatives Butyrophenone derivatives Benzodiazepine

Sedative-hypnotic a) b) c)

Alpha-2 agonists Barbiturates Chloral hydrate

66 3)

Tranquilization, sedation, pharmacological hypnosis and general anesthesia are considered increasing depth of CNS

depression a)

There is no clear cut demarcation between each stages

b)

Some drugs may be used to induce sedation, hypnosis, or attain general anesthetic state by increasing the

dose G.

PHENOTHIAZINE TRANQUILIZERS 1.

Mechanism of action a.

Block central excitatory dopaminergic pathways causing depression reticular activity system (RAS)

b.

Suppression of the sympathetic nervous system (depresses mobilization of catecholamine centrally and peripherally)

c.

Lower seizure threshold in animals with epilepsy

d.

Inhibit dopamine interaction in the chemoreceptor trigger zone (CTZ) in the medulla 1)

2.

There are two central dopaminergic pathways a)

Excitatorystimulated by apomorphine and blocked by neurolepsis (drugs used in the treatment of mental disorders)

b)

Inhibitoryblocked by ergometrine, not affected by neuroleptics

Effects a.

Blocked by the RAS alerting route results in reduced alertness or tranquil mental state. 1) 2) 3)

b.

Produce mental calming Decreases motor activity Increase threshold for responding to external stimuli

Calms vicious or nervous animals 1)

Calming effect can be temporarily reversed with adequate stimulus

2)

Most evident in excitable or apprehensive animals

67 c.

Cardiopulmonary effects 1)

Alpha-adrenergic blocakade; hypotension

2)

Reflex tachycardia or centrally induced bradycardia

3)

Antiarrythmic effects

4)

Direct depression of myocardium and vascular smooth muscles

d.

Extrapyramidal (involuntary) musculoskeletal effects and hallucinatory activity in some animals (horses) in large

e.

Does not have analgesic effects

doses

3.

Uses a. b. c.

4.

Calming effect on vicious animal Antiemetic Preanesthetic

Examples a.

Chlorpromazine 1)

Prototype drug of this group

2)

Superseded by acepromazine (less potent but has larger

3)

Not recommended as preanesthetic medication in cattle; may cause relaxation of cardiac sphincter resulting regurgitation

to b.

c. 5. debilitated 6.

Acepromazine maleate 1)

Extensively used in veterinary medicine for preanesthetic medication and tranquilization

2)

Extremely potent; duration of action depends on the dose

Others include promazine, propionylpromazine, Methotrimeprazine, Promethazine

Phenothiazine tranquilizers can produce penile paralysis in horses, particularly propionyl-promazine (Should not be given to old, male horses) Horses under phenothiazine tranquilization are hypersensitivities to noise and may react violently (make sure the surrounding is quiet)

68

H.

BUTYROPHENONE DERIVATIVES 1.

The same MOA with phenothiazine

2.

Pharmacological effects

3.

a.

Reduced motor activity

b.

May produce cataleptic state

c.

Reduced mortality from stress and trauma

d.

Prevention of fatal effects of catecholamines

Examples a.

b.

c.

I.

Haloperidol 1)

First one introduced

2)

Not used in veterinary medicine (of historical importance only)

Droperidol 1)

More potent in dogs than chlorpromazine

2)

Shortest duration of action among butyrophenones

3)

Most potent antiemetic activity

4)

Combine with fentanyl (an opioid) to produce neurolepanalgesia

Azaperone (Stresnil) 1)

Most suitable sedative for pigs (2-3 hours duration)

2)

Can cause violent excitement in horses

3)

Pharmacological effects

BENZODIAZEPINES

a)

Antagonizes respiratory depression induced by anesthetics

b)

Slight drop in blood pressure

69 1.

These are selective neuronal depressants

2.

Do not produce true general anesthesia

3.

4.

5.

a.

Awareness usually persists

b.

Not completely paralysis

c.

Relaxation (decreased muscle tone) sufficient to allow surgery cannot be achieved

MOA a.

Entrance activity of inhibitory neurotransmitters in the CNS (GABA, glycine) and open chloride channels causing hyperpolarization.

b.

Depresses the limbic system, thalamus, and hypothalamus thereby including a mild calming effect

c.

Reduces polysynaptic reflex activity, leading to muscle relaxation

Pharmacological effects a.

Muscle relaxation

b.

Anticonvulsant effect (increases seizure threshold)

c.

Analgesic effect (diazepam)

d.

Marked calming effect in sick, depressed, or debilitated animals

Examples a.

b.

Chlordiepoxide (Librium R) 1)

First one introduced

2)

Has taming effect on wild animals after oral administration

Diazepam 1)

Most widely used benzodiazepine in veterinary medicine

2)

Pharmacological effects a)

Prevalent convulsions

b)

Sedative, hypnotic, and tranquilizing effects

70

3)

c.

d. J.

c)

Muscle relaxation

d)

Increase duration of anesthetic action

Clinical use a)

Anticonvulsant

b)

Control of behavioral problems

c)

Pre-and-post-anesthetic sedation

Lorazepam (AtivanR) 1)

Long-acting but has slow onset of action

2)

More potent than diazepam

3)

Use preanesthetic before ketamine administration

Zolazepam: Available in combination with tiletamine (a dissociative agent)

ALPHA-2 RECEPTOR AGONISTS 1.

MOA a.

Produce CNS depression by stimulation of presynaptic alpha-2 adrenoreceptors in the CNS and peripheral nervous

b.

This decreases the release of norepinephrine centrally and peripherally.

c.

Results to decreased circulating catecholamines and other stressrelated substances.

system.

2.

Pharmacological effects a.

Inhibition of postsynaptic reflexes by blocking internuncial neuron transmission of impulses at the CNS

b.

Induction of sleep-like state more profound than phenothiazines 1) 2) 3)

c.

Profound sleep in dogs, cats, foals, and small ruminants Horses may remain standing In cattle, decreased motor activity (low doses) and recumbency (large doses)

Produce analgesia by stimulating CNS alpha-2 receptors

71

3.

d.

Central emetic effect: cause vomiting in cats, sometimes in dogs

e.

Initial transient hypertension followed by hypotension and bradycardia

f.

Suppression insulin release (alpha 2 receptor stimulation in pancreas) leading to hyperglycemia and glucosoria

g.

Depress swallowing reflex

h.

Ecbolic effect (contraindicated in late pregnancy)

Side effects a. b. c. d. e. f.

4.

Severe respiratory depression/respiratory acidosis Bradycardia/bradyarrhythmias Hypotension Ataxia (large animals0 Sweating in horses Diuresis

Official names a. b.

Clonidine (used in humans to treat hypertension) Xylazine 1) 2)

c.

Detomidine 1) 2) 3)

d.

5.

Most commonly used in veterinary medicine Duration of action 20 to 40 minutes

Licensed for use in horses More potent than xylazine or clonidine Duration of action 90 to 120 minutes

Medetomidine 1)

Used in cats and dogs

2)

Twenty times more potent than xylazine

3)

Duration of action 45 to 90 minutes

Antagonists a.

Yohimbine (especially vs. xylazine)

b.

Tolazoline

c.

Atipamazole (especially vs. medetomidine)

72

K.

BARBITURATES 1.

These are derivatives of barbituric acid

2.

Barbiturates are classified according to the duration of their action

3.

4.

5.

a.

Long-acting (8 to 12 hours): Phenobarbital sodium, barbital sodium

b.

Intermediate acting (2 to 6 hours): Amobarbital sodium

c.

Short-acting (45 minutes to 1.5 hours): Pentobarbital sodium, secobarbital sodium

d.

Ultrashort-acting (5 to 15 minutes): Thiopental sodium, Thiamylal sodium, Thialbarbitone sodium, Mehtohexital

Classification according to chemical structure a.

Oxybarbiturates have oxygen atom attached to C2

b.

Thiobarbiturates have sulfur atom attached to C2 which increases lipid solubility of the compound

General anesthetic actions a.

A slow-acting sedative-hypnotic which depresses the cerebral cortex, resulting in hyporeflexia

b.

CNS depression is attributed to trichlorethanol. 1)

Subanesethetic doses cause mild sedation and depression of motor and sensory nerves

2)

Anesthetic doses cause deep sleep that lasts for several hours with prolonged period (6 to 24 hours)

Pharmacological effects a.

b.

Cardiovascular system 1)

Myocardial depression (decreased contractility)

2)

Potentiates vagal (parasympathetic) activity

3)

Cardiac arrythmias and fibrillation

GI system

73

1) 2) 6.

L.

Increased motility and secretory activity Nausea, vomiting, salivation, diarrhea/defecation

Clinical Uses a.

Presently used as sedative and adjunct to surgical anesthesia in horses and cattle

b.

Generally used in combination with pentobarbital and magnesium sulfate in small animals in inducing anesthesia

DISSOCIATIVE AGENTS 1.

Agents which cause cataleptic (muscular rigidity), analgesic (absence of pain), and anesthetic (state of insensibility) action without hypnotic producing effect)

2.

This group includes the arylcyclohexylamines

(sleep

a. b. c. 3.

Phencylidine Ketamine Tiletamine

Pharmacological effects a.

Anesthesia is characterized by profound amnesia, superficial analgesia, and catalepsy 1) 2) 3)

Oral, ocular, and swallowing reflexes intact Muscle tone generally increases Large doses can cause convulsions (can be controlled by pentobarbital thiobarbiturates, diazepam)

b.

Hallucinations, confusion, agitation, and fear (psychosomatic effects) that occur in man seem to occur in animals when doses are given

c.

Muscle rigidity (minimized by tanquilizers, barbiturates, or benzodiazepines)

d.

Copious salivation and lacrimation

e.

Selective analgesia; visceral pain not abolished

f.

Animals are hyperresponsive and ataxic during recovery

g.

Irregular pattern of breathing

h.

Cardiovascular system

large

74

4.

1)

Increased heart rate and blood pressure

2)

Decreased cardiac contractility

3)

Sensitize the heart to catecholamines

Specific agents a.

b.

c.

Phencylidine 1)

First one introduced

2)

Not recommended anymore for use in veterinary medicine

Tiletamine 1)

A new cataleptic agents for cats

2)

Similar to phencyclidine

3)

Does not produce analgesia of the skin

4)

Available in 1:1 fixed combination with Zolazepam (TelazolR)

Ketamine (VetalarR, KetasetR) 1)

Has a shorter duration of action than phencyclidine

2)

Produce profound analgesia without muscle relaxation.

3)

Tonic-clonic spasm can occur even without surgical stimulation

4)

Increases salivation and causes mild respiratory depression

5)

Blocks reuptake or norepinephrine by adrenergic nerve terminals a) b)

5.

Increases circulating catecholamine Results to increased blood pressure

Clinical Uses a.

Chemical restrain

b.

Induction of anesthesia

75 c.

M.

Production of general anesthesia either alone or in combination with xylazine, acepromazine, or diazepam

NARCOTIC ANALGESICS 1.

Analgesics, substances that minimize or abolishes the sensation of pain, are divided into two groups: a.

Narcotic-analgesic (e.g. morphine)

b.

Non-narcotic-analgesic or antipyretic- analgesic (e.g. aspirin)

2.

Narcotic analgesics are more potent and are referred to as opioids because they are derived from opium

3.

Opium is a dried milky exudate from the unripe seed capsules or Oriental poppy plant, Papaver somniferum

4.

Opium contains the following alkaloids: a.

Phenantrene derivatives (analgesic and spasmogenic) 1) 2) 3)

b.

Morphine Codeine Thebaine

Benzylisoquinoline (non-analgesic and spasmolytic) 1)

Papaverine

2)

Narcotine

3)

Narceine

5.

MOA: reversible combination with one or more specific opiate receptors in the brain and spinal cord

6.

Pharmacological effects: a.

Analgesia 1)

Used before during or after surgery

2)

Analgesic action produced at doses lower than needed for sedation

b.

Behavioral changes (e.g. sedation, euphoria, dysphoria)

c.

Reduction of responses to external stimuli

76

d.

Miosis in dogs and pigs, mydriasis in cats and horses

e.

sweating in horses

f.

Excellent sedation in dogs (excitation if given rapid IV), excitation in cats and horses

g.

Cardiopulmonary

h.

i.

1)

Bradycardia

2)

Hypotension due to histamine release

3)

Respiratory depression

GI effects 1)

Salivation

2)

Nausea

3)

Vomiting (stimulates CTZ)

4)

Segmental intestinal motility

Decreased urine production (ADH release)

77 7.

Opioid agonists a. b. c. d. e. f. g. h. i.

8.

Mixedagonist-antagonist (partial agonist) a. b. c.

9.

Morphine Codeine Diamorphine (Diacetylmorphine or Heroin) Methadone Theambutene Pethidine (Meperidine, USA) Apomorphine Dextromethorphan Ethorphine (M99)

Pentazocine Buprenorphine Butorphanol

Antagonists (act by competing with opioids for their receptor sites) a.

With slight (agonist activity) a) Nalorphine b)

b.

10.

Diprenorphine (vs. ethrophine)

Pure antagonists 1)

Naloxone

2)

Naltrexone

Side effects a.

Excitement, dysphoria

b.

Apnea

c.

Bradycardia

d.

Ataxia and incoordination

e.

Excessive vomiting

f.

Excessive sweating in horses

78 N.

NEUROLEPTANALGESIA 1. 2.

3.

A state of CNS depression and analgesia produced by the combination of an opioid analgesic and a neuroleptic tranquilizer. Results of drug combination a.

Heavy preanesthetic medication (low doses)

b.

Surgical anesthesia (high doses)

c.

Depression of ventilation or respiratory depression

d.

Bradycardia

e.

Defecation and flatulence

f.

Analgesia for periods up to 40 minutes

Commercial combination a.

Fentanyl (opioid)- Droperidol (tranquilizer) combination 1)

2)

Fentanyl a)

Actions similar to morphine but 100 times more potent

b)

Respiratory and cardiovascular depressant

Droperidol a)

Potent antiemetic: action comparable to phenothiazines (not recommended for

b)

Exerts adrenergic blocking action on the heart (prevents arrhythmia)

horses)

3)

b.

Uses a)

Used in dogs, primates and small rodents

b)

Contraindicated in cats (causes violent excitement)

c)

Deep sedation with profound analgesia for minor surgeries

Ethorpine-phenothiazine tranquilizer mixtures 1)

Ethorpine and Acepromazine

79

P.

2)

Ethorpine and Methotrimeprazine

3)

Uses a)

CNS depression with considerable analgesia that allows major surgery

b)

For capture of wild animals (not recommended for wild felidae and domestic cats)

INHALATION ANESTHETICS 1.

These are vapors or gases administered directly into the bloodstream through respiratory route.

2.

Stages of Anesthesia (ether anesthesia) a.

Stage I (Stage of Analgesia) 1) 2) 3) 4) 5) 6)

b.

Stage II (Stage of delirium or involuntary excitement) 1) 2) 3) 4) 5) 6)

c.

Describes the period from the beginning of induction to the loss of consciousness. Disorientation, with normal reflexes or hyperflexia Animal exhibit fear and apprehension. Increased heart rate and rapid respiration. Excessive salivation. Voiding of urine and feces may occur.

Represents the early period of unconsciousness Involuntary reflexes are present (exaggerated response) Respiration is irregular in depth and rate (breath-holding may occur) Eyelids are wide open and iris is dilated because of sympathetic stimulation Reflex vomiting, defecation and urination The duration of this stage should be decreased if possible to avoid depressing the respiratory center.

Stage III (Stage of Surgical Anesthesia) 1)

Plane 1

a)

Marked by appearance of full rhythmic and mechanical respiration. Responses to pain are still present Cardiovascular function is minimally affected Irregular automatic breathing

b) c) d)

80 2)

Plane 2 a) b) c) d) e) f) g)

3)

Plane 3 a)

between b) c) d.

Breathing is still automatic but respiratory depression is marked (noticeable pause inspiration and expiration) Cardiovascular function is noticeably depressed Orthopedic and abdominal operations can be done

Stage IV (Overdose) 1) 2) 3) 4)

4.

Tidal volume is slightly decreased Respiratory rate may be increased or decreased Cardiovascular function is minimally affected Eyeballs fixed in the center (horse, cats, sheep, and pigs) or downwards (dogs) Laryngeal reflexes persist until the middle of plane 2 Progressive muscle relaxation Adequate for all surgeries except abdominal surgery

Respiratory arrest (jerky diaphragmatic movement) Circulatory collapse Wide dilation of pupils Death within 1 to 5 minutes

INHALTION ANESTHETICS a.

DIETHYLETHER 1) 2) 3) 4) 5) 6) 7) 8)

b.

Transparent, colorless liquid (boiling point 35°F) Lighter than chloroform but twice heavier than air May cause death if liquid, light, heat, and explosion is a possibility May cause death if liquid is aspirated in nasal passages May cause respiratory and cardiac arrest Irritate the respiratory tract and causes salivation, coughing, and breatholding Produces a curare-like effect at neuromuscular junction Does not affect the medullary center

CHLOROFORM 1) 2) 3) 4) 5)

A powerful anesthetic Heavy, sweat smelling liquid Noninflammable and not explosive Vapor is not irritating Decomposed by air and light

81 6) 7) 8) 9) c.

HALOTHANE 1) 2) 3) 4) 5) 6) 7) 8) 9) 10) 11) 12)

d.

Fluorinated hydrocarbon Heavy liquid (boiling point 50°C) Noninflammable and not explosive Decomposes slowly, relatively safe Nervous effect is twice as ether Not irritating to respiratory mucosa, inhibits respiratory secretions Decreases tidal volume, blood pressure, slow pulse rate, bradycardia Increases sensitivity of myocardium to epinephrine Potentiates activity of nondepolarizing drugs Antagonizes activity of depolarizing drugs Has a minimal muscular effect; may interfere with the normal involution of uterus after hysterectomy May cause hepatic dysfunction

ENFLURANE 1) 2) 3) 4) 5) 6) 7) 8)

e.

Depresses sensitivity to carbon dioxide Causes slow and shallow breathing May cause respiratory failure during anesthesia Affects heart, medullary center of brain, peripheral blood vessels

Halogenated ether Noninflammable and nonexplosive liquid Its vapor reacts with soda lime Low blood-gas partition coefficient May cause twitching or seizures activity Dose-dependent respiratory and cardiovascular depression Inhibits epinephrine secretion by the adrenal medulla Potentiates nondepolarizing drugs such as pancuronium

METHOXYFLURANE 1) 2) 3) 4) 5) 6) 7) 8)

Halogenated-ethyl methyl ether Clear, colorless, liquid (boiling point 104°C) Noninflammable and not explosive Stable, not decomposed by air or light Low vapor pressure (not recommended for induction) Causes respiratory depression with minimal stimulation of respiratory tract secretions Resembles ether in cardiovascular effects Can cause polyuric renal dysfunction

82 f.

NITROUS OXIDE 1) 2) 3) 4) 5) 6)

A colorless gas with faint sweet smell; nontoxic Noninflammable and not explosive but can support combustion of other agents even without oxygen Considered a weak anesthetic but has analgesic property Does not cause respiratory depression not harmful cardiovascular effects Stimulates sympathoadrenal system May cause bloat