Cholinergics ANSLect 16_2010BbF

Cholinergics ANSLect 16_2010BbF - Cholinergics Agonists and...

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Unformatted text preview: Cholinergics Agonists and Antagonists Lecture Objectives • Review • Examine drug manipulation of cholinergic system I. Cholinomimetics A. Natural and synthetic Ag B. Cholinesterase and inhibitors A. Reversible B. Irrerversible II. Muscarinic R ANT Atropine, Scopolamine & synthetic compounds III. Nicotinic R Ag IV. Nicotinic R ANT- ganglionic blockers • FOCUS: mechanism/effects therapeutic use adverse effects In review: • Neurotransmitter...? – Selectivity between n &m R: – BBB: – Absorption and degradation: – IV dose: all observed effects target “postganglionic” • Role in periphery – NMJ – Role in ANS • nACh and mACh R’s – Physiological importance Acetylcholine Choline Choline Acetyl Coenzyme A Choline transporter + Acetyltransferase Acetylcholinesterase (AChE) ACh m or n Ach R Fig. 11.3 Kalant et al. Hemicholine Vesamicol Figure 14.24 Effects of ANS on Pacemaker Potentials in SA Node Slowing via? Physiology review I. Cholinomimetics A. Structural analogs of ACh – Directly mimic Ach via binding Natural: Muscarine A manita muscaria . (mAChR) Pilocarpine Pilocarpus jaborandi (m>n Ach R) Synthetic: Carbachol (m>n AchR,) Methacholine (mAChR) Bethanechol- substitution at acetyl group or methyl group at b carbon (figure 12.1) changes selectivity and sensitivity to Achase – Therapeutic use • Ocular surgery/glaucoma • Post-surgery urinary retention I. Cholinomimetics B. Indirectly via inhibition of degradation – Cholinesterase inhibitors Reversible (carbamate derivatives) vs Irreversible (organophoshates) – Inhibit both acetylcholinesterase and plasma cholinesterase – Increase ACh activity only where ACh actively released – Cholinergic Crisis Cholinesterase and its inhibitors • Lethal AChase-I – restlessness, abdominal distress, spasms, defecation, urination, pupils constricted, muscle twitches- paralysis, salivation, sweating, difficulty breath (bronchiole constriction, secretion),convulsions and respiratory failure • AChase – selective site interacts with N and esteric site hydrolyzes ester group _ Active site: anionic Esteratic site N H O H Reversible Cholinesterase Inhibitors • Competitive inhibitors but chemically diverse 1. Physostigmine ( Eserine- Alkaloid of calabar bean) • Crosses BBB • Used for glaucoma (eye drops) decreasing intraocular P (IOP) 2. Neostigmine • Quaternary ammonium compounds- do not cross BBB • Direct nAChR activity • Taken po to treat myasthenia gravis • Stimulates GI contractions and gastric secretions 3. Edrophonium • Short acting & given IV to diagnose myasthenia gravis Reversible Cholinesterase Inhibitors 4. Donepezil ( Aricept ) • Maintain or improve cognitive function with AD (PD) • Crosses BBB • Specificity • Fewer side effects...
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This note was uploaded on 12/03/2010 for the course PHAMACOLOG pcl470 taught by Professor Arnot during the Fall '10 term at University of Toronto.

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Cholinergics ANSLect 16_2010BbF - Cholinergics Agonists and...

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