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Effect & Sites of Action of Different Agonist Drugs on The Isolated Rabbit Intestine Lab # 1 Purpose of Pharmacological Experiments Qualitative To determine the activity & mechanism of drugs action e.g. analgesic, effect on blood pressure Quantitative To assay (measure) the activity of drugs e.g. toxic level Types of pharmacological experiments In vivo In vitro - Study the action of drugs on the whole body (intact animal) - Study the action of drugs on pieces of tissue - There is interference by compensatory mechanisms of body Easier to study effect of drugs - There is no interference by compensatory mechanisms of body Easier to study MOA & potency of drugs - - In vitro experiments - In vitro experiments involve the use of isolated organ or muscle - Conditions of the experiment should be kept similar to body Experiment conditions: 1- Electrolytes 2- Nutrients 3- Physiological pH 4- Constant temperature 5- Aeration Electrolytes Physiological solution: Ex. Tyrode’s & Kreb’s Ingredients: 1- Nacl → adjust the tonicity 2- Ca+2, K+, Mg+2 → for normal contraction 3- Sodium bicarbonate → to render the pH similar to that of blood 4- NaH2PO4 → to compensate for any change in the pH 5- Glucose → nutrient Aeration Examples - Pure oxygen → for heart tissues Air → for intestine Carbogen (95% O2, 5% CO2) → used for uterus Temperature Temperature should be kept constant during the experiment Physiological temp. (37°C) is needed for mammalian tissues e.g. rabbit intestine The temp. should be reduced in some experiments to decrease spontaneous contraction e.g. isolated guinea-pig ileum Amphibian tissues can survive in room temp. e.g. isolated frog rectus abdominis Intestine Intestine is composed of duodenum, jejunum & ileum It is a smooth muscle & has myogenic contraction The intestine is involuntary structure which undergoes the control of nervous system Autonomic nervous system innervations of the intestine Sympathetic CNS AG e PGF PostGF Key: AG= autonomic ganglion E= effector organ PGF= preganglionic fiber POSTGF= postganglionic fiber Parasympathetic CNS AG e PGF PostGF Autonomic nervous system innervations of the intestine Sympathetic Transmitter: Receptors (intestine): Action (intestine): NA, Adrenaline Parasympathetic Ach adrenergic a1, b2 cholinergic a-central-Nicotinic (Nn) b-periphral-muscarinic(M3) inhibitory (↓cont.) excitatory (↑cont.) Drugs Acting on Intestine 1- STIMULANTS They are called Spasmogenic 2- DEPRESSANTS They are called Spasmolytic Stimulants 1- Autonomic Cholinergic stimulant A- Central nicotinic neuronal (Nn) R agonist (ganglionic stimulant) - Act on Nn R present in autonomic ganglia - Ex. Small dose of nicotine ( dil. Nicotine) - MOA of dil.nicotine: Dil. Nicotine stimulates Gs protein in cell membrane → activates Na channels → rapid ↑ intracellular Na → depolarization and AP → contraction Stimulants B- Muscarinic receptors agonist (cholinomimetic) - Act on muscarinic M3 receptors - Ex.: 1- Ach & its derivatives e.g. methachloine, bethanecol, carbacol 2- Naturally occurring alkaloids e.g. Pilocarpine - MOA of Ach: Ach ++ M3R → ++ Phospholipase C → Splitting of phosphatidylinositol biphosphate (PIP2) into: 1- DAG (diacylglycerol) → ↑opening of Calcium channels 2- IP3 (inositol triphosphate) → mobilization of cal. from its stores 1, 2 lead to ↑ intracellular calcium → contraction Stimulants 2- Direct acting stimulant e.g. Bacl2 - Acts directly on muscle fibers Depressants 1- Autonomic adrenergic stimulants (sympathomimetic) - e.g. adrenaline & noradrenaline - They bind to a1, b2 receptors causing relaxation 2- Direct depressants e.g. Mgcl2 & papaverine Experiment N 0.1 0.1 Dil.nic. Ach 0.1 Bacl2 0.1 adr. 0.1 Mgcl2 Definitions Dose cycle: time between different drug additions Contact time: time from addition of drug until its removal by washing ↑ amplitude ↓ amplitude ↑ tone ↓ tone ↑ tone & amplitude ↓ tone & amplitude