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Description : The action of a drug on the body, including receptor interactions, dose-response phenomena, and mechanisms of therapeutic and toxic action.

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Published on : Aug 07, 2023 | Views : 1015 | Downloads : 8

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Pharmacodynamics The action of a drug on the body, including receptor interactions, dose-response phenomena, and mechanisms of therapeutic and toxic action. 1 By M.D
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Drug action The main ways by which drugs act are via interaction with cell proteins, namely receptors, ion channels, enzymes and transport/carrier proteins. In addition, drugs can work by themselves mechanically or chemically. Its useful to know what are the basic principles of drug action. 2 By M.D
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How does all this happen? 1. Through enzymes: a drug can act by either stimulating or inhibiting an enzyme Receptor action is the most commonest way of producing action. 2. Physical action: E.g. radioisotope I131 and other radioisotopes. 3. Chemical action: E.g. antacids neutralising the gastric acid. 3 By M.D
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Receptor A receptor is a protein on the cell membrane or within the cytoplasm or cell nucleus that binds to a specific molecule (a ligand) such as a neurotransmitter, hormone, or other substance, and initiates the cellular response to the ligand. 4 By M.D
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Major Receptor Families may be divided into four families: ligand-gated ion channels, G protein coupled receptors, enzyme-linked receptors, and intracellular receptors 5 By M.D
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6 By M.D
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Ligand-gated ion channels responsible for regulation of the flow of ions across cell membranes by binding with ligands Response to these receptors is very rapid (durations of a few milliseconds) e.g.Nicotinic receptor 7 By M.D
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G protein coupled receptors comprised of a single peptide that has seven membrane-spanning regions The specific binding sites for agonists occur at the extracellular surface, while the interaction with G proteins occurs with the intracellular portions of the receptor. E.g Muscarinic rec. 8 By M.D
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Second messengers Binding----activation of G protein---change activity of effectors---2nd messengers Effectors: Enzymes-AC, PLC,GC Ion channels 2nd messengers are essential in conducting and amplifying signals coming from G protein receptors. Eg cyclic adenosine monophosphate (cAMP), inositol-1,4,5-trisphosphate and diacylglycerol, cGMP 9 By M.D
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The Whole Signaling Network related to cAMP 10 By M.D
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Enzyme-linked receptors These family of receptors have cytosolic enzyme activity as an integral component of their structure or function Binding of a ligand to an extracellular domain activates or inhibits this cytosolic enzyme activity. Duration of responses to stimulation of these receptors is on the order of minutes to hours. The most common enzyme-linked receptors are those that have a tyrosine kinase activity as part of their structure. Eg insulin 11 By M.D
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Epidermal growth factor 12 By M.D
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Intracellular receptors is entirely intracellular the ligand must diffuse into the cell to interact with the receptor the ligand must have sufficient lipid solubility The time course of activation and response of these receptors is much longer 13 By M.D
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14 By M.D
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Concepts in dose-response relationships Affinity- refers to ability of a drug to bind a receptor Efficacy (intrinsic activity)- is the ability of a drug to produce an effect at a receptor. Potency- a measure of the amount of drug necessary to produce an effect of a given magnitude By M.D 15
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Dose-Response relationship Is the relationship between intensity of drug effect and drug dosage (drug level) When a logarithm of dose as abscissa and responses as ordinate are constructed graphically, the “S” shaped or sigmoid type curve is obtained. 16 By M.D
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DOSE RESPONSE CURVE DOSE of drug % of Response After this point increase in dose doesn’t increase the response 17 By M.D
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Log drug concentration % of response 100% 50% 0% 10mg 20mg 30mg 40mg 50mg 75% 25% 200mg Potency of Drug A >Drug B > Drug C A B C 18 By M.D
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Efficacy and Potency C 19 By M.D
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Agonist Agonists are the chemicals that interact with a receptor, thereby initiate a chemical reaction in the cell and produces effect . Example—ACh is agonist at muscarinic receptor in heart cell. Will have both Affinity and maximal Intrinsic activity 20 By M.D
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Antagonist A drug that binds to the receptor and blocks the effect of an agonist for that receptor Atropine is antagonist of ACh at Muscarinic receptors. Will have only Affinity but no Intrinsic activity 21 By M.D
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Inverse agonist Inverse Agonists are the chemicals that interact with a receptor, but produces opposite effect of the well recognized agonist for that receptor Will have Affinity and negative Intrinsic activity Example: Flumazenil is an inverse agonist of Benzodiazepine 22 By M.D
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Partial agonist Partial agonist activates receptor to produce an effect which is less than a full agonist . Partial agonist blocks the agonist action. Will have Affinity but sub maximal Intrinsic activity E.g Pindolol 23 By M.D
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Graded dose effect: As the dose administered to a single subject or tissue increases, the pharmacological response also increases in graded fashion up to ceiling effect. It is used for characterization of the action of drugs. The concentration that is required to produce 50 % of the maximum effect is termed as EC50 or ED50. A drug with low ED50 is more potent than a drug with larger ED50 24 By M.D
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Quantal dose effect It is all or none response The sensitive objects give response to small doses of a drug while some will be resistant and need very large doses for a given effect It is characterized by stating the median effective dose (ED50), the dose at which 50% of individuals exhibit the specified quantal effect. It generate information regarding the margin of safety(TI) 25 By M.D
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Drugs with a low TI should be used with caution and needs a periodic monitoring (less safe) E.g. warfarin, digoxin, theophylline Drugs with a large TI can be used relatively safely and does not need close monitoring (highly safe) E.g. penicillin, paracetamol 26 By M.D
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Combined effect of drugs A. Synergism Two types: Additive effect: the effect of two drugs are in the same direction and simply add up. Effect of drug A + B = effect of drug A and B Supraadditive effect (potentiation): the effect of combination is greater than the individual effect of the components. Effect of drug A + B > effect of drug A + effect of drug B 27 By M.D
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B. Antagonism Different types of antagonism Physical: based on physical property of a drug. E.g. activated charcoal adsorbs alkaloids and prevents their absorption (in alkaloid poisoning) Chemical: based on chemical properties resulting in an inactive product. E.g. chelating agents complex metals (used in heavy metal poisoning) 28 By M.D
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Contd.. Physiological antagonism: two drugs act on different receptors or by different mechanisms, but have opposite effects E.g. histamine and adrenaline on bronchial smooth muscle and BP E.g. glucocorticoid VS. insulin. 29 By M.D
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4. Receptor antagonism This is when an antagonist interferes with the binding of the agonist with its receptor and inhibits the generation of a response Receptor antagonism is specific E.g. an anticholinergic will decrease the spasm of intestine induced by cholinergic agonists but not the one induced by histamine It can be competitive and noncompetitive 30 By M.D
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Competitive antagonism Competitive -Surmountable Competes with agonist in reversible fashion for same receptor site Necessary to have higher concentration of agonist to achieve same response 31 By M.D
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Noncompetitive antagonism Noncompetitive -Insurmountable Antagonist binds to a site different to that of an agonist No matter how much agonist -- antagonism cannot be overcome 32 By M.D
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Comparison of Competitive Vs Noncompetitive Antagonist binds with same receptor Chemical resemblance with agonist Parallel rightward shift of DRC(EC50%) Apparently reduces potency of agonist Intensity of response depends both on antagonist and agonist concentration Eg: Ach and Atropine Another site of receptor binding Does not resemble Flattening of DRC (Emax50%) Apparently reduces efficacy of agonist Intensity of response depends mainly on antagonist concentration Eg: phenoxybenzamine vs Adr (for pheochromocytoma) 33 By M.D
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Tolerance Gradual reduction in response to drugs is called as tolerance Requirement of higher dose to produce a given response It occurs over a period of time E.g. tolerance to sedative-hypnotics Many reasons for tolerance Pharmacokinetic reasons-chronic use leads to enhanced clearance-less effective concentration Pharmacodynamics reasons (reduced number and/or affinity of the receptors to the drugs)-down regulation 34 By M.D
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Tachyphylaxis Rapid desensitization to a drug produced by inoculation with a series of small frequent doses. A rapidly decreasing response to a drug following its initial administration E.g. ephedrine, tyramine, nicotine,NG. 35 By M.D
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Adverse drug reactions(ADR) ADR is any response to a drug that is noxious and unintended and that occurs at doses used in human for prophylaxis, diagnosis or therapy. Unpredicted and harmful Side effects :produced with therapeutic dose of the drug/predictable/extended form MOA or not E.g. dryness of mouth with atropine 36 By M.D
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allergic reactions : may be mild or very severe like anaphylaxis Idiosyncratic reactions : are one’s peculiar response to drugs (genetically determined) glucose -6 phosphate dehydrogenase defeciency Vs primaquine teratogenic effects: congental abnormalities on the fetus. eg thalidomide cause absence of limbs in new born babies Other drugs with teratogenic potential include anti convulsants, lithium, tricyclic antidepressants and warfarin. 37 By M.D
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Drug -drug interactions It is a phenomenon which occurs when the effects of one drug are modified by the prior or concurrent administration of another drug(s). It may result in beneficial or harmful effects It may be classified into: a) Pharmaceutical drug interactions: E.g. diazepam if added to infusion fluid there will be a precipitate formation → loss of therapeutic effect. 38 By M.D
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b) Pharmacokinetic drug interactions: Interaction during absorption-Tetracycline + Calcium → Decreased absorption of tetracycline. Interaction during distribution-eg Sulfonamide by salicylates Interactions during biotransformation:-Affects biotransformation rate, intensity and duration of action as well as toxicity ii) Enzyme induction---Warfarin (anticoagulant) + Barbiturate (enzyme inducer) → decreased anticoagulation 39 By M.D
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Enzyme inhibition Warfarin + Metronidazole (enzyme inhibitor) → Haemorrhage. Interactions during excretion e.g. Penicillin (antibiotic) + Probenecid (antigout drug) → Increases the duration of action of penicillin (Both drugs excreted through tubular secretion). 40 By M.D
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C. Pharmacodynamic interactions: Additive effect( A+B = AB) e.g. Combination of ephedrine and theophylline in the treatment of bronchial asthma. Potentiation effect(AB > A + B) Trimethoprim + sulfamethoxazole Antagonism Doxycycline vs.pencillin Lamivudine vs emtricitabine 41 By M.D
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Factors affecting Drug Action Body Size/Wt. The average adult dose refers to individuals of medium built For exceptionally obese and lean and for children the dosage should be calculated based on body wt. Individual Dose = BW (Kg)/70 x average adult dose Dosage calculation based on surface area more appropriate for children 42 By M.D
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Contd.. Age Extreme care has to be taken while administering drugs to children and elderly Drug metabolizing enzymes are very poor and in case of elderly they might have some other diseases Reduced doses are ideal for these age groups. 43 By M.D
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Contd.. Genetics Deficiency of some enzymes may lead to drug toxicity because of poor or absence of metabolism Route of drug administration IV route has quicker and prominent action when compared to oral route 44 By M.D
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Psychological Factors Psychological factors can influence individual responses to drugs. When placebo drugs are given patients receiving them can report therapeutic and adverse effects. Another factor can be patient’s willingness to follow prescribed dosage regimens. 45 By M.D
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Contd.. Pathological states Any underlying pathology may alter the drug response Special care is taken if the patient has renal or hepatic impairment as the drugs are not eliminated and it may lead to severe drug toxicity. Alzheimer’s disease – memory loss- failure to take medications
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Contd.. Co-administration of other drugs One drug may affect the drug action of others, it may be useful or it may be harmful. Drug interactions play a very important part of therapeutics. Diet & environmental factors too play an important role in deciding the drug action. Tolerance 47 By M.D
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Sex Responsiveness to certain drugs is different for men and women Pregnancy – induction of certain drug metabolizing enzymes occurs in second and third trimester Hormonal changes during development have a profound effect on drug metabolism 48 By M.D