PHARMACO DYNAMICS II Dr Abdul Latif Mahesar Department

PHARMACO DYNAMICS -II Dr. Abdul Latif Mahesar Department of Medical Pharmacology King Saud University 1

AGONIST: • When a drug binds to a receptor , there is conformational change which initiates chain of chemical events , leading to response , the drug is said to be AGONIST. • FULL AGONIST: have a high efficacy and are able to produce maximum response, while occupying only small percentage of receptors. • It has afffinity and efficacy both 2

• PARTIAL AGONIST: Have low efficacy and are unable to elicit maximum response , even if they occupy all available receptors, regardless of concentration e. g. Pindolol ( β-adrenoceptor blocker) • Inverse agonist: substances produce effects 's that are? ? ? opposite to those of the agonist. e. g. β-carbolines (at Benzodiazepine receptor) 3

Antagonist • The drug binds to receptor but don't activate it , don't induce a conformational change , no efficacy. it has affinity but no efficacy. • They inhibit the binding of agonist drugs or endogenous agonists. • There is often structural similarity b/w the chemical structures of the agonist and antagonist molecules. 4

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Competitive antagonist: • They bind to receptor reversibly, • The effect can be overcome by increasing the concentration of agonist. • In graph the curve in the presence of competitive antagonist is shifted to the right when concentration of agonist is increased 6

• But the curves are parallel. • Maximum effect can be obtained by increasing the dose of agonist. • It is direct mechanism by which one drug can reduce the effect of other drug 7

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• • Inverse agonist can be regarded as drug with negative efficacy, to distinguish it from agonist (+ve efficacy ) and competitive antagonist (zero efficacy) 9

Non-competitive antagonists (irreversible) • Their presence also produce parallel shift to the right of agonist dose response curve. but the maximum response is depressed , reflecting the fact that antagonist effect can not be over come by the addition of greater dose of agonist. 10

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Spare receptors • Many full agonists are capable of eliciting maximal response at very low occupancies, often less than 1% , such system is said to be possess spare receptors. • This means response can be achieved with a lower concentration of hormone or neurotransmitter , than if fewer receptors were present. • Economy of hormone/neurotransmitter is thus achieved at expense of providing more receptors 12

EFFICACY • it is the capacity of the drug to activate the receptor and response produced by a drug called intrinsic activity Ability of the drug to produce maximum response It depends on the number of drug-receptor complexes formed and the efficiency with which the activated receptor produces cellular action. • Affinity it is the ability of the drug to bind with receptor. • Note: agonist has both affinity and efficacy where 13 as antagonist has only affinity.

• POTENCY: • It is the amount (weight) of a drug in relation to its effect • Eg. Weight for weight it is a measure (in weight) of how much drug is required to elicit a given response. drug of high potency will generally have a high affinity for the receptors and the occupancy a significant proportion of the receptors even at low concentration How ever efficacy is more important than potency. 14

Difference b/w efficacy and potency • Amiloride(low efficacy) can cause no more than 5% of filtered sodium to be excerted • Benzofluride ( moderate efficacy) cause about 10 % excretion of filtered sodium • Frusamide ( high efficacy ) cause 25% excretion of filtered sodium. 15

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• THERAPEUTIC INDEX • this is related to safety of drug It is the ratio between lethal dose and effective dose. Therapeutic index = lethal dose effective dose If therapeutic index is more than one the drug is safe. If it is one or less it is not safe e. g lithium Digoxin 17

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ANTAGONISM: when two drugs are give together, the action of one drug opposes the action of other drug. • Chemical antagonism • simple chemical interaction b/w two drugs • no receptor involved e. g. Antacids and tetracycline given together form unabsorbed solutes. 19

• Physiological antagonism • Drugs act on different receptors antagonizes the physiological effect e. g. Noradrenaline α 1 -receptors VC ↑ B. P Histamine H 1 receptors relaxes vascular smooth muscles 20

Pharmacodynamic antagonism In this type of antagonism drugs compete for the same receptor and antagonize the effects of each other. This may be reversible or irreversible. a) Reversible ( competitive) o binding is loose o Effect can be over come by increasing the concentration of agonist o In the presence of antagonist bu increasing the concetration of agonist , the graph is shifted to the right eg. Acetylcholine acts on muscrinic receptors at smooth muscles of intestine and causes 21 contraction.

eg. Acetylcholine acts on muscrinic receptors at smooth muscles of intestine and causes contraction. where as Atropine acts on same receptors and causes relaxation. b ) Irrevrsible ( non competitive) eg. Phenoxybenzamine 22

• Synergism: correlated action or cooperation on the part of two or more drugs • ADDITIVE EFFECT (summation): When effect of two drugs having the similar action are additive i-e 2+2=4 eg. β-adrenocptor blocker plus a thiazide diuretics have an additive antihypertensive effect. 23

• POTENCIATION( to make more powerful) when one drug increases the action of other drug i. e 2+2=5 e. g trimethoprim plus sulphonamide. or when one drug have no effect as own but increases the effect of other drug i. e 0+2 =5 eg. levodopa and carbidopa. 24

• Dose: • It represents the amount of a drug to produce an effect • Therapeutic dose: • A dose which is required to produce a therapeutic effect • Toxic dose: • The dose which produces a toxic effect • Loading dose: • A large initial single or multiple doses are given for some drugs to achieve a rapid steady state concentration 25

• Maintenance dose: • The dose which is used to maintain the steady – state concentration or to maintain therapeutic effect of a drug. It is given at a fixed interval time 26

• ED 50 (Effective dose 50): • The dose or concentration which produces effect in 50% of the population in a group. • TD 50 (Toxic dose 50): • The dose or concentration which produces toxic effects in 50% of the population in a group. • LD 50 (Lethal dose 50): • The dose or concentration which kills 50% of the animals in a group 27

Pro-drug • it is a drug which is pharmacologically inactive • , after administration, by the action of enzymes , it is chemically altered • To active form in the body. e. g Enalapril to Enalaprilat Aspirin to Salicylates Levodopa to Dopamine Valcicovir to Acyclovier 28