Pharmacodynamics Part 2 - 23-9-2024 PDF

PHARMACODYNAMICS PART (∏) BY SAIF A. AL-JUBRAN MSc Pharmacology MRCS-rcseng Objectives : 1. Understanding Agonist, Partial Agonist & Antagonist. 2. Understanding Receptors Up and Down Regulations. 3. Different Types of Antagonism. 4. Factors Affecting Drug Action. 5. Pharmac...

PHARMACODYNAMICS PART (∏) BY SAIF A. AL-JUBRAN MSc Pharmacology MRCS-rcseng Objectives : 1. Understanding Agonist, Partial Agonist & Antagonist. 2. Understanding Receptors Up and Down Regulations. 3. Different Types of Antagonism. 4. Factors Affecting Drug Action. 5. Pharmacogenetic principles  DRUG Agonist: substance combines with the receptor and causes stimulation and pharmacological action as acetylcholine with nicotinic receptors  DRUG Partial agonist: is a drug that has an affinity and some efficacy to the receptors It does not produce maximum effect even when all the receptors are occupied It may antagonize the action of other stronger agonists that have a greater efficacy  DRUG Antagonist : substance has an affinity to the receptors but produces no receptor stimulation The antagonist usually blocks or antagonizes the effect of the agonist. as atropine and muscarinic receptor  HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE RECEPTORS? Unbound Endogenous Activator (Agonist) of Receptor Extracellular Compartment Cell Membrane Inactive Cell Surface Receptor Intracellular Compartment  HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE RECEPTORS? Extracellular Bound Endogenous Activator (Agonist) of Receptor Compartment Cell Membrane Active Cell Surface Receptor Intracellular Compartment Cellular Response  HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE RECEPTORS? Displaced Endogenous Activator (Agonist) of Receptor Extracellular Compartment Bound Antagonist of Receptor (Drug) Cell Membrane Inactive Cell Surface Receptor Intracellular Compartment  RECEPTORS REGULATION The number of receptors is not fixed Continuous administration of the agonist can lead to a reduction in receptor sensitivity and drug effect (tachyphylaxis) Receptors can also be down-regulated (decrease in number ) by continuous agonist drug administration Repeated administration of the antagonist leads to receptors’ up-regulation (increase in number )  TYPES OF ANTAGONISM COMPETITIVE ANTAGONISM: two drugs compete on the same receptors, usually occur between the agonist and its antagonist as epinephrine & propranolol on β receptors. To overcome the effect of the antagonist, the dose of the agonist needs to be increased. PHYSIOLOGICAL ANTAGONISM: two drugs antagonized with each other while acting on two different receptors as histamine and adrenaline  TYPES OF ANTAGONISM ALLOSTERIC ANTAGONISM An allosteric antagonist binds to a site (allosteric site) other than the agonist-binding site and prevents receptor activation by the agonist  HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE RECEPTORS? Displaced Endogenous Activator (Agonist) of Receptor Extracellular Bound Antagonist of Receptor Compartment Cell Membrane Active Receptor Inactive Receptor Intracellular Compartment Allosteric Inhibitor  FACTORS MODIFYING DRUG RESPONSE Age: children, adults & elderly Body weight Food Gender: male or female Race Genetic factors Disease status: Liver and kidneys Drug: dose, route of administration, drug interactions  QUESTIONS 1. If 1 mg of lorazepam produces the same anxiolytic response as 10 mg of diazepam, which is correct? A. Lorazepam is more potent than is diazepam. B. Lorazepam is more efficacious than is diazepam. C. Lorazepam is a full agonist, and diazepam is a antagonist. D. Lorazepam is a better drug to take for anxiety than is diazepam.  QUESTIONS 2. If 10 mg of oxycodone produces a greater analgesic response than does aspirin at any dose, which is correct? A. Oxycodone is more efficacious than is aspirin. B. Oxycodone is less potent than is aspirin. C. Aspirin is a full agonist, and oxycodone is a partial agonist. D. Oxycodone and aspirin act on the same drug target.  QUESTIONS 3. Which is correct concerning the safety of using warfarin (with a small therapeutic index) versus penicillin (with a large therapeutic index)? A. Warfarin is a safer drug because it has a low therapeutic index. B. Warfarin treatment has a high chance of resulting in dangerous adverse effects if the concentration is increased. C. The high therapeutic index makes penicillin a safe drug for all patients. D. Penicillin treatment has a high chance of causing dangerous adverse effects if bioavailability is altered.  PHARMACOGENETICS Pharmacogenetics is the study of the effect of genetic variations on drug response in terms of both drug metabolism (pharmacokinetics) and drug action (pharmacodynamics)  A Given response to fixed dose of drug continuous discontinuous less than the more than the usual response usual response usual response High response Low response 95% 2.5% 2.5%  Mean response 95% Low High 2.5 2.5 Continuous Discontinuous  INHERITED CONDITIONS AFFECT DRUG RESPONSES Acetylation Important route of metabolism for many drugs that contain an amide (-NH2) The population is either rapid or slow acetylators, but the proportion of each varies greatly between races. Isoniazid (INH), a drug used to treat TB is affected by the acetylation status of the patient Vit. B6 Slow acetylators Peripheral neuropathy deficiency hepatotoxic metabolite Rapid acetylators Liver damage (acetyl hydrazine)  GLUCOSE-6-PHOSPHATE DEHYDROGENASE (G6PD) DEFICIENCY G6PD activity is important to the integrity of the red blood cell Individuals who are G6PD deficient may suffer from acute hemolysis if they are exposed to certain oxidant substances, including drugs Drugs are of 2 types: a. Those that carry definite risk. of hemolysis including dapsone, methylene blue, niridazole, nitrofurantoin, pamaquin, primaquine, quinolone antimicrobials, and sulphonamides. b. Those that carry a possible risk of hemolysis including Aspirin (dose> 10 days), probenecid, quinidine, chloroquine, quinine, chloramphenicol  Which of the following is true about slow acetylators of isoniazid? a. They are at a lower risk of Vitamin B6 deficiency. b. They have a higher risk of developing peripheral neuropathy. c. They require higher doses of isoniazid for effective treatment. d. They have higher amounts of metabolic enzymes for INH than rapid acetylators.