INTRODUCTION Lecture 3

Pharmacodynamics Receptor: macromolecule that interacts with a drug and initiates the chain of biochemical events leading to the drug’s observed effects. Receptor: macromolecule that interacts with a drug and initiates the chain of biochemical events leading to the drug’s observed effects. –Receptors are determine the dose or concentration of drug required to form a significant of drug-receptor complexes. –Types and location of receptors: 1-type I :on external surface of cell like catechol amine. 2-type II: in cytoplasm of cell like steroid hormones 3-typeIII: in nucleus like thyroid hormones

General Type of Drugs Interactions 1-AGONIST A drug is binds to a receptor and causes a response or effect. A drug is binds to a receptor and causes a response or effect. Eg phenylephrine is an agonist at adrenoceptor. Eg phenylephrine is an agonist at α 1 adrenoceptor. It has intrinsic activity = 1 It has intrinsic activity = Depolarization

2-Antagonists A drug is binds to a receptor and prevents (blocks or inhibits) a natural compound A drug is binds to a receptor and prevents (blocks or inhibits) a natural compound i:e Antagonist : prevent the action of agonist on receptor but dose not have any effect on its own i:e Antagonist : prevent the action of agonist on receptor but dose not have any effect on its own An antagonist has NO activity. Eg Prazocin (antihypertensive ) competes with the endogenous ligand norepinephrine at – adrenoceptor. An antagonist has NO activity. Eg Prazocin (antihypertensive ) competes with the endogenous ligand norepinephrine at α 1 – adrenoceptor. Its intrinsic activity is = 0

3- PARTIAL AGONIST A drug is said to be a partial agonist when it binds to a receptor and causes a partial response. A drug is said to be a partial agonist when it binds to a receptor and causes a partial response. i:e Partial agonist: activate a receptor to produce a submaximal effect but antagonizes the action of a full agonist i:e Partial agonist: activate a receptor to produce a submaximal effect but antagonizes the action of a full agonist It has intrinsic activity < 1. It has intrinsic activity < 1. i:e partial agonist that act on the same receptor as a full agonist but do not produce the same maximum response in large concentration or dose, because it has a high affinity with very low intrinsic activity

4- Inverse agonists 4- Inverse agonists Typically, unbound receptors are inactive and require interaction with an agonist to assume an active conformation. Typically, unbound receptors are inactive and require interaction with an agonist to assume an active conformation. However, some receptors show a spontaneous conversion from Ri to Ra in the absence of agonist (that is, they can be active without the presence of agonist). However, some receptors show a spontaneous conversion from Ri to Ra in the absence of agonist (that is, they can be active without the presence of agonist). inverse agonists reverse the constitutive activity of receptors and exert the opposite pharmacological effect of receptor agonists. inverse agonists reverse the constitutive activity of receptors and exert the opposite pharmacological effect of receptor agonists. inverse agonists exert an opposite effect by reducing the Ra/Ri ratio and inhibiting a normally active pathway. inverse agonists exert an opposite effect by reducing the Ra/Ri ratio and inhibiting a normally active pathway.

In this example, all the drugs are assumed to have the same receptor affinity. In this example, all the drugs are assumed to have the same receptor affinity.

inverse agonist Such agents (e.g. β-carboline) have been described for the benzodiazepine receptor. (these experimental drugs (β-carboline) cause anxiety and CNS arousal. In contrast to sedative benzodiazepines such as diazepam), Flumazenil, a competitive antagonist of the benzodiazepine receptor, reverses the effects of agonists and inverse agonists.

Types of antagonist (Mechanisms of receptor antagonism) 1- Pharmacological A- Competitive. The antagonist reversibly competes or displaces the agonist from the receptor. The antagonist reversibly competes or displaces the agonist from the receptor. Since occupancy by an antagonist produces no response, the action of the agonist is blocked. Since occupancy by an antagonist produces no response, the action of the agonist is blocked. Higher concentrations of agonist, however, can overcome this competition and restore the full response. Higher concentrations of agonist, however, can overcome this competition and restore the full response.

Competitive antagonism : occurs when the agonist (A )and antagonist (I)compete for the same binding site on the receptor. Response curves for the agonist are shifted to the right in a concentration- related manner by the antagonist.

a. Competitive They compete for the binding site ReversibleReversible

B-Non-Competitive The antagonist changes the receptor to decrease the efficacy of the agonist The antagonist changes the receptor to decrease the efficacy of the agonist or irreversibly blocks the agonist from combining with the receptor. or irreversibly blocks the agonist from combining with the receptor. If the antagonist binds to the same site as the agonist ; it causes a shift of the dose–response curve to the right, with further depression of the maximal response. If the antagonist binds to the same site as the agonist ; it causes a shift of the dose–response curve to the right, with further depression of the maximal response.

14 Competitive non competitive 1- antagonist binds with the same receptor as the agonist 2-antagonist resembles chemically with agonist 3-antagonist reduces affinity of agonist 4-intensity depend on conc. Of both agonist and antagonist 5-e.g. Ach - atropine 1- bind to another 2- not 3-antagonist reduces efficacy of agonist 4-intensity depend only on conc. Of antagonist 5- Aspirin with cyclooxygenase

2- Physiologic ANTAGONIST (functional ) A drug that binds to a non-related receptor, producing an effect opposite to that produced by the drug of interest. A drug that binds to a non-related receptor, producing an effect opposite to that produced by the drug of interest. Eg : histamine induced bronchoconstriction, antagonist by epinephrine Glucocorticoid Hormones  Blood Sugar Insulin  Blood Sugar 3- Chemical ANTAGONIST A chelater of similar agent that interacts directly with the drug being antagonized to remove it or prevent it from binding its receptor. A chelater of similar agent that interacts directly with the drug being antagonized to remove it or prevent it from binding its receptor.

16 synergism Synergism in a Greek mean : work together Synergism in a Greek mean : work together When the action of one drug is facilitated or increased by the other When the action of one drug is facilitated or increased by the other It can be: It can be: 1- Additive e.g. aspirin + paracetamol 1- Additive e.g. aspirin + paracetamol drug A+ drug B = effect of A + effect of B drug A+ drug B = effect of A + effect of B 2- supra – additive (potentiation): 2- supra – additive (potentiation): the effect of combination is greater than individual effect e.g.adrenaline + cocaine (as a vasoconstrictor ) e.g.adrenaline + cocaine (as a vasoconstrictor ) Effect of drug A+B > effect of drug A + effect of drug B

Drug Concentration Response DOSE-EFFECT RELATIONSHIP The intensity and duration of a drug ’ s effects are a function of the drug dose and drug concentration at the effect site.

Drug Concentration Response SEMILOG DOSE-RESPONSE CURVE ED50 50% Effect Maximal Effect Effect or

Types of Dose-Effect (response) Graded Quantal Continuous scale (  dose   effect)Continuous scale (  dose   effect) Relates dose to intensity of effectRelates dose to intensity of effect All-or-none pharmacologic effectAll-or-none pharmacologic effect Relates dose to frequency of effectRelates dose to frequency of effect

Therapeutic index Is the ratio of the dose that produce toxicity to the dose that produce effective response. Is the ratio of the dose that produce toxicity to the dose that produce effective response.

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Drug effects cont. –Efficacy of a drug : refers to the maximal effect produced by a drug, it depend on the number of drug- receptor complexes formed. –Ceiling dose : Additional doses produce no further beneficial effects this concept is called ceiling dose –Potency of a drug : is the dose of drug which required to produce response. –Potency is influenced by absorption, distribution, biotransformation, excretion, and ability to combine with receptors. Or defined as the pharmacological activity of dose of drug compared with a dose of a different drug producing the same effect Or defined as the pharmacological activity of dose of drug compared with a dose of a different drug producing the same effect

Comparison of different drugs at the same dose to determine which is stronger

24Affinity When a drug molecule moves so close to it is receptor that the attractive force between them (the drug binds to the receptor) When a drug molecule moves so close to it is receptor that the attractive force between them (the drug binds to the receptor) drug and receptorTypes of reaction between drug and receptor : 1- noncovalent binding. 2- covalent binding. 3- hydrogen binding. 4- electron transfer 5- enzyme reaction Note: potency is related to affinity of drug to it is receptor,where as efficacy is related to the intrinsic activity of the drug drug-receptor complex is formed Note: potency is related to affinity of drug to it is receptor,where as efficacy is related to the intrinsic activity of the drug drug-receptor complex is formed

Maximal Effect: greatest response that can be produced by a drug, above which no further response can be created (sometimes called “peak effect”. Onset: how long time before a drug is able to exert a therapeutic effect Duration: how long a drug effect lasts.

Factors affecting the safety and effectiveness of drug A-host related factor B-drug related factor

A-host related factor 1-biological variation include tolerance or cross-tolerance Tolerance : Tolerance : is characterized by the need to increase the dose continually to achieve the desired effect due to decrease response by the time. is characterized by the need to increase the dose continually to achieve the desired effect due to decrease response by the time.

2- age (weight and surface area) In children –Size of body are small –Have lower albumin and renal blood flow –Have lower GFR In old age In old age.- decrease in body weight - Low blood flow - Impaired hepatic function 3-bioavailability Is an immunological mediated adverse reaction to chemical resulting from previous sensitization to that chemical. 4-allergy : Is an immunological mediated adverse reaction to chemical resulting from previous sensitization to that chemical. Allergy not doses related because allergic reaction may result from exposure to relatively low doses. Allergy not doses related because allergic reaction may result from exposure to relatively low doses.

5- Idiosyncrasy idiosyncratic response Some people has deficient in G 6 phosphate dehydrogenase so when taken antimalarial drug (primaquine) cause genetic abnormality and result hemolytic anemia. 6-Sex generally, men metabolize faster than women (ex: alcohol)

B-drug related factor 1-side effect 2-secondary effect 3-toxic effect 4-interaction with other drug

32 Adverse drug effects Is any undesirable effects of drug administration. - Predictable (type A ):depend on pharmacological properties of drug ( include side effect toxic effects and consequence of drug withdrawal) - Unpredictable (type B):depend on patient (include allergy and idiosyncrasy)

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34 Severity of adverse effects graded as: Minor : no therapy Minor : no therapy Moderate: change the drug therapy Moderate: change the drug therapy Sever : need medical Rx Sever : need medical Rx Lethal : lead to death Lethal : lead to death

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