Antimuscarinics 2014 PDF

Antimuscarinic agents & drugs acting on the autonomic ganglia Dr. Khairun Nain Bin Nor Aripin  Learning outcomes Describe the prototype of antimuscarinic agents i.e. atropine and some alkaloid and synthetic atropine substitutes e.g. scopolamine, hyoscine, ipratopiu...

Antimuscarinic agents & drugs acting on the autonomic ganglia Dr. Khairun Nain Bin Nor Aripin  Learning outcomes Describe the prototype of antimuscarinic agents i.e. atropine and some alkaloid and synthetic atropine substitutes e.g. scopolamine, hyoscine, ipratopium bromide, tropicamide, pirenzepine and benztropine in terms of pharmacokinetic and pharmacodynamic properties. Describe the clinical uses of these drugs and the possible adverse effects. Describe the treatment for overdose of antimuscarinic drugs. Describe the drugs that stimulate the ganglia selectively (nicotine) and non-selective (acetylcholine, carbachol, pilocarpine, anticholinesterases). Describe the property of nicotine which stimulate ganglia in low dose but causes blockage in large dose List other ganglion blocking agents i.e. competitive (hexamethonium) and persistant depolarising blockers (nicotine, anticholinesterase) and briefly describe their mechanism of action. Antimuscarinics Recap Atropine & Scopolamine  Atropine & Scopolamine Naturally occurring alkaloid Extremely potent anticholinergic (esp muscarinic) PHARMACOKINETICS A: Well absorbed via gut, membranes and even skin (scopolamine patches) D: Lipophilic, widely distributed and penetrate CNS esp scopolamine (treatment for motion sickness) M: hydrolysis & conjugation E: 60% excreted unchanged via urine, rest as metabolites. *Eye effects may persist up to 72 hours  Atropine & Scopolamine PHARMACODYNAMICS Mechanism of action http://www.pharmacologycorner.com/drugs-acting-on-the-autonomic-nervous-system-animation-showing- their-mechanism-of-action/ Atropine binds reversibly to muscarinic receptors Highly selective for muscarinic receptors Prevents downstream actions eg release of IP3 or release of adenylyl cyclase Salivary,bronchial,sweat glands more sensitive to atropine compared to gastric acid secretion  Organ system effects & Clinical uses CNS Sedation esp scopolamine Reduces Parkinsonian tremor and rigidity o Reducing excess cholinergic activity Reduces vestibular overactivity/motion sickness esp scopolamine  Organ system effects & Clinical uses EYE Inhibit pupillary constrictor muscles Inhibit ciliary contraction Unable to accommodate/focus But may induce acute glaucoma  Organ system effects & Clinical uses EYE Mydriasis allow ophthalmic examination Anti-muscarinics used second line to α-agonists o Prolonged mydriasis and cycloplegia (inability to accommodate/focus) Tropicamide, cyclopentolate  Organ system effects & Clinical uses CVS - Increase heart rate - Little effect on BP - Useful to counter-act muscarinic agonists (cholinomimetics)  Organ system effects & Clinical uses Respiratory Inhibit bronchoconstriction =bronchodilation Useful for asthma & COPD o Ipratropium & tiotropium o Often in combination with β- agonists Reduce secretion o Used prior to inhalant anaesthetic agents  Organ system effects & Clinical uses GI Tract Salivation inhibited = dry mouth Gastric acid secretion is less inhibited o Pirenzepine & telenzepine selectively block gastric acid secretion Motility and peristalsis is reduced o Useful in diarrhoea o In combination with opioids Local mechanisms of the enteric nervous system counteract antimuscarinic actions  Organ system effects & Clinical uses GU Tract Inhibit detrusor muscle contraction Inhibit sphincter opening = inhibit voiding Useful for incontinence & bladder spasm Oxybutinin – M3-selective  Organ system effects & Clinical uses Cholinergic poisoning Insecticide or mushroom poisoning Nerve gas use Large doses of atropine needed Pralidoxime can regenerate Acetylcholinesterase.  Adverse effects ATROPINE EXCESS DRY AS A BONE – dry mouth, reduction of secretions BLIND AS A BAT – cycloplegia/loss of accommodation RED AS A BEET – tachycardia, hot & flushed skin MAD AS A HATTER – CNS effects, delirium Overall safe in adults and can be treated symptomatically. Children may suffer from atropine fever and cholinomimetics esp acetylcholinesterase-inhibitor eg neostigmine/physostigmine may be given carefully. Drugs acting on autonomic ganglia  Ganglia-acting drugs Ganglia stimulants – nicotine, acetylcholine etc (revisit previous lecture) Ganglia blockers Block acetylcholine at the nicotinic receptors of autonomic ganglia Examples include hexamethonium, decamethonium, mecamylaminme and trimethapan Limited clinical use due to limited selectivity Broad range of undesirable effects “There is at present no clinical relevance of ganglion blockers” KD Tripathi, Essentials of Medical Pharmacology 6th Edition.