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Download Pharmacology introduction Lecture three Dr. nahlah 21-10
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Pharmacology introduction Lecture three Dr. nahlah 21-10-2015 Pharmacodynamic Phase •Describes the biochemical and physiologic action and effects of drugs in the body. •This phase occurs when the medication reaches the target cell, tissue, organ and a therapeutic effect occurs. •It is the study of the biological and therapeutic effects of drugs and their mechanisms of action i.e. effect of drug on the body. Mechanism of drug action: Physical action, alter of the environment of the cell through physical e.g., mannitol induces osmotic diuretics and kaolin adsorbs toxins in diarrhea. Chemical action, alter of the environment of the cell through chemical processes that usually do not affect cell function. e.g,. NaHCO3 in hyperacidity and dimercaprol (BAL) to chelate mercury. Cytotoxic action (stop cell division), e.g., anticancer drugs. Interfere with selective passage of ions as Ca +2 and Na+ entry e.g. local anaesthetics and antiarrhythmic drugs. Interference with normal metabolic pathway, e.g., sulphonamides competes with PABA which is essential for bacterial growth. Action on enzyme either stimulation or inhibition. Enzyme inhibition could be: 1. Reversible which is usually short lasting as allopurinol (xanthine oxidase inhibitor), neostigmine (cholinesterase inhibitor, ....) 2. Irreversible which is usually long-lasting for new enzyme synthesis, e.g., irreversible anticholinesterases. Action on specific receptors (Drug Receptor Interactions): receptors are macromolecular protein structures present on cell membrane or within the cell (cytoplasmic or nuclear) that react specifically with a ligand (drug, hormone or neurotransmitter) to produce a biological response. Receptors transduce (translate) the signal from the ligand to several subcellular elements e.g. enzymes, second messengers or ion channels to produce intracellular biochemical response. Drugs can be categorized into: Agonists are drugs, which stimulate receptors, i.e., initiate changes in cell function producing effects of various types. They have 1 affinity, efficacy and rapid dissociation rate. Agonist potency depends on affinity (i.e. tendency to bind receptors) and efficacy (i.e ability to initiate changes which lead to effect). Antagonists are drugs which block receptors, i.e. they bind to receptors without initiating change in receptors. They have affinity, no efficacy and slow dissociation rate. They have no effect in absence of agonist, but prevent action of agonist. Antagonist may be competitive or non-competitive. A. Reversible competitive antagonist where antagonist competes for the same receptor and can be displaced by an excess agonist. A reversible competitive antagonism causes a parallel shift of the log dose response curve to the right. So slope and maximum effect are not changed. B. Irreversible non competitive antagonist where the antagonist cannot be overcome by excess agonist. A non-competitive antagonist decreases efficacy of the agonist, so it shifts the log dose response curve to the right and changes the slope of the curve e.g. phenoxybenzamine. Competitive antagonism Maximum response (Emax) is the same ED50 is shifted to right 2 Non competitive antagonism Emax is decreased ED50 is constant Partial agonists are drugs which stimulate and block receptors, so they have affinity, efficacy (less than full agonist) and moderate dissociation rate. Inverse agonists: produce effects opposite to that of agonist e.g. benzodiazepines (Bz) are agonists of Bz receptors _ sedation, muscle relaxation and anxiolytic action, while carbolines are inverse agonists of the same receptors_convulsions and anxiety. Affinity Efficacy Dissociation rate Examples Agonist Antagonist Partial agonist Inverse agonist + + + + +++ -+ +++ Rapid Slow Moderate Rapid Diazepam Flumazenil Buprenorphine Carbolines Types of Antagonists 1- Pharmacological Antagonists Competitive Antagonist o They compete for the binding site. o Reversible & Surmountable o The effect of a reversible antagonist can be overcome by more drug (agonist). A small dose of the antagonist (inhibitor) will compete with a fraction of the receptors thus, the higher the concentration of antagonist used, the more drug you need to get the same effect. Non-competitive Antagonist o Bind elsewhere in the receptor (Channel Blockers). o Irreversible & Non-surmountable o The effect of irreversible antagonists cannot be overcome by more drug (agonist). The antagonist inactivates the receptors. 2-Functional Antagonists Physiologic Antagonist 3 •A drug that binds to a non-related receptor, producing an effect opposite to that produced by the drug of interest. •Its intrinsic activity is = 1, but on another receptor. Glucocorticoid Hormones Blood Sugar Insulin Blood Sugar Chemical Antagonist •A chelator (sequester) of similar agent that interacts directly with the drug being antagonized to remove it or prevent it from binding its receptor. •A chemical antagonist does not depend on interaction with the agonist’s receptor (although such interaction may occur). Heparin, an anticoagulant, acidic If there is too much bleeding and haemorrhaging Protamine sulfate is a base. It forms a stable inactive complex with heparin and inactivates it. Receptors and signal transduction mechanism Binding of agonist to receptors activates effectors or signaling mechanisms of different types: (1) Ion-channel linked receptors (Ligand-gated ion channel) e.g. nicotinic andGABAA receptors. The response takes milliseconds. Acetylcholine binds to nicotinic receptors Na+ influx depolarization GABA binds to GABAA receptors Cl- influx hyperpolarization. (2) G-protein Linked Receptors Examples: glucagon, α and β adrenergic receptors and muscarinic receptors. The time elapsed between binding to receptor and cellular response is few seconds. These receptors comprise a seven transmembrane or serpentine receptors because receptor polypeptide chain snakes across cell membrane 7 times. When the 4 agonist binds to the binding domain, G-protein will be activated to transduce the agonist-induced signal to a variety of effector elements (adenylcyclase, phospholipase or ion channel) located either intracellular or in the cell membrane. These effector elements then change the concentration of an intracellular second messenger. Second messengers: include cAMP, Ca++ ion and phosphoinositides and cGMP (3) Membrane tyrosine kinase linked receptors : e.g. receptors for insulin whichact on membrane receptors which can phosp horylate signal transducers and activators of transcription (STAT) molecules, which dimerize and then dissociate from the receptor to cross the nuclear membrane and modulate gene transcription. (4) DNA Linked receptors (intracellular receptor) e.g. corticosteroids, vitamin D and thyroxine. Agonist binds to its domain; the hsp 90 domain is released leaving DNA binding domain that regulates gene transcription, translation and consequently protein synthesis. The response has slow onset (hours) and has long duration. 5