PM716 Pharmacology I: Ach Blockers PDF

PM716 Pharmacology I Chapter 8 Ach Blockers Cholinolytics RMRocco, PhD PM716 C8 Cholinoceptor Blockers 1  Case Study 63 year old with urinary symptoms, on thiazide diuretic and ACE inhibitor for hypertension. Developed benign prostatic hypertrophy (BHP)...

PM716 Pharmacology I Chapter 8 Ach Blockers Cholinolytics RMRocco, PhD PM716 C8 Cholinoceptor Blockers 1  Case Study 63 year old with urinary symptoms, on thiazide diuretic and ACE inhibitor for hypertension. Developed benign prostatic hypertrophy (BHP) with prostatectomy resulting. Now complains of urinary frequency and urgency. Diagnosis and treatment? PM716 C8 Cholinoceptor Blockers 2  Case Study Urge incontinence may follow prostate removal which may leave the bladder detrusor muscle unstable. Symptoms will resolve with time (as muscle adapts). Patient may use tolterodine or oxybutynin once a day. Slight M3 muscarinic antagonists, reduces detrusor smooth muscle spasms. PM716 C8 Cholinoceptor Blockers 3 Cholinolytics cholinolytics cholinergic antagonists cholinergic blockers anticholinergic drugs acetylcholine blockers Ach Blockers PM716 C8 Cholinoceptor Blockers 4  Cholinolytics Group I Antimuscarinics Group II Ganglionic Blockers (little clinical use) Group III Neuromuscular Blockers (discussed in detail latter in the course) PM716 C8 Cholinoceptor Blockers 5  Receptor Organization Sympathetic Pathway CNS Ach NE Adrenergic Receptors a1a2 b1b2 Parasympathetic Pathway CNS Ach Ach Muscarinic Receptors Somatic Pathway CNS Ach Nicot Recp PM716 C8 Cholinoceptor Blockers Skel Muscle 6  Cholinolytics Includes nicotinic and muscarinic receptor antagonists. NICOTINIC BLOCKERS: ganglion-blockers Group II little clinical use neuromuscular blockers Group III MUSCARINIC BLOCKERS: Group I Drugs block the effects of parasympathetic autonomic discharge. Important group. PM716 C8 Cholinoceptor Blockers 7 Muscarinic Receptor Subtypes M1 CNS, sympathetic postganglionic cell bodies M2 myocardium, smooth muscle M3 effector cell membranes (glands and smooth muscle) PM716 C8 Cholinoceptor Blockers 8  Cholinolytics Drugs that block muscarnic receptors are: Muscarinic antagonists Parasympatholytics Receptor binding to different subtypes of muscarinic receptors may be specific or nonspecific. PM716 C8 Cholinoceptor Blockers 9  Muscarinic Receptor Antagonists All in current use in US are nonselective muscarinic antagonists (M1 M2 M3 etc) Primary clinical targets included CNS, eye, bronchi, GI, and genitourinary tracts. Atropine is the prototypical antimuscarinic blocking drug. PM716 C8 Cholinoceptor Blockers 10  Antimuscarinic Drugs Atropine (Atropa belladonna, deadly nightshade) Scopolamine, po, iv, ophthalmic, transdermal patch Propantheline (Pro-Banthine®) Glycopyrrolate (Robinul®) Tolterodine (Detrol®) Dicyclomine (Bentyl®) Ipratropium (Atrovent®) inhaler PM716 C8 Cholinoceptor Blockers 11 Chapter 8 Cholinoceptor-Blocking Drugs PM716 C8 Cholinoceptor Blockers 12 © The McGraw-Hill Companies, Inc,  Antimuscarinics Block Ach receptors as competitive (surmountable) antagonists. Increase Ach levels and blockade overcome. Block actions of drug agonists more effectively than blocking of endogenous agonists (Ach). Atropine is non-selective for muscurinic receptor subtypes M1, M2, M3 however is selective for muscarinic receptor. Synthetic antimuscarinics are more selective for subtypes. PM716 C8 Cholinoceptor Blockers 13  Antimuscarninics Distribution determined in part by presences of quaternary amine group (permanently charged) which prevents drug from crossing lipid membranes (BBB). These drugs used for antisecretory or antispastic activity in the GI and bronchi with little CNS effects. Distribution into all tissues including CNS with presence of tertiary amine (highly lipid soluble), like atropine. PM716 C8 Cholinoceptor Blockers 14  Antimuscarinics CNS: sedative in normal low doses, higher doses induce excitation, agitation, hallucinations, coma. EYE: Atropine blocks Ach activation of pupillary constrictor muscle. Belladonna (“beautiful lady”) Renaissance eye drops to induce mydriasis (pupil dilation). CARDIAC: Sinoatrial (SA) node, atropine blocks vagus nerve slowing of heart rate. PM716 C8 Cholinoceptor Blockers 15 Chapter 8 Cholinoceptor-Blocking Drugs PM716 C8 Cholinoceptor Blockers 16 © The McGraw-Hill Companies, Inc, Chapter 8 Cholinoceptor-Blocking Drugs PM716 C8 Cholinoceptor Blockers 17 © The McGraw-Hill Companies, Inc,  Antimuscarinics RESPIRATORY: Vagus innervation of secretory glands and smooth muscles blocked by atropine (reduced secretions and bronchodilation). GI: Motility and secretion are blocked. Enteric ANS compensates. GENITOURINARY TRACT: Relaxation of smooth muscles of ureters and bladder walls with reduced urine output. PM716 C8 Cholinoceptor Blockers 18  Antimuscarinics ORGAN EFFECT RECEPTOR(S) Blocked Eye Mydriasis M3 Bronchi Dilation M3 GI Relaxation M1 M3 Genitourinary Relaxation bladder M3 wall, urinary retention Heart Tachycardia* M2 Bradycardia** * Moderate to high dose (blocks the Ach at vagal nerve which slows rate) ** Low dose PM716 C8 Cholinoceptor Blockers 19  Antimuscarinics CNS: Limited use in Parkinson’s (replaced with better drugs) Inhibition of unbalanced Ach activity due to loss of DA. Motion sickness, scopolamine patches cause dry mouth and some sedation. OPHTHALMOLOGIC: mydriasis (pupil dilation) for retina examination. PM716 C8 Cholinoceptor Blockers 20  Antimuscarinics RESPIRATORY: Ipratropium (atropine analog) used as inhalant in asthma patients for broncodilation. CARDIOVASCULAR: reflex vagal discharge in MI is blocked with atropine-like drugs. GASTROINTESTINAL: Traveler’s diarrhea, Lomotil® (atropine + diphenoxylate, an opioid). The added atropine helps keep the opioid dose low. URINARY: Oxybutynin to reduce involuntary voiding. PM716 C8 Cholinoceptor Blockers 21  Atropine Belladonna plant, jimsonweed and others. Used in the renaissance by women to make their eyes “beautiful” Atropine blocks Ach receptors. Cardiac slowing, dry mouth, sweat inhibition, pupil dilation, blurred vision, up to coma in higher doses. PM716 C8 Cholinoceptor Blockers 22  Atropine Atropine competes with Ach for binding sites on the muscarinic receptor. Atropine can be replaced with more Ach neurotransmitter. Treat atropine overdose by increasing Ach at receptor. Use the inhibition of AchE which degrades Ach (anticholinesterase drugs). Favorite exam question. PM716 C8 Cholinoceptor Blockers 23 Clinical Applications of Atropine Heart:treat excess stimulation of vagus nerve block releases excess Ach which causes bradycardia (< 60/min). Eye: block Ach contraction of pupillary muscle, cause dilation (mydriasis) GI: Ach increases motility, block in irritable colon. PM716 C8 Cholinoceptor Blockers 24 Clinical Applications of Atropine Motion Sickness: scopolamine patch to block Ach stimulation of nausea and vomiting. Anticholinesterase Poisons: overcome wild mushroom’s, insecticide’s, and chemical warfare agent’s increase in Ach by their inhibition of AchE and the increase of Ach. PM716 C8 Cholinoceptor Blockers 25  Antimuscarinic Therapy Mechanisms Agents inhibit AchE which raises Ach levels and Ach in excess causes paralysis. Drugs that block nicotinic and muscarninc Ach receptors block excess Ach which can lead to paralysis. Treat with Atropine (1-2 mg every 5-15 min iv until atropine effects appear (dry mouth etc). Atropine for up to a month every day may be required (following overdose, nerve gas in war etc) PM716 C8 Cholinoceptor Blockers 26  Mushroom Poisoning Rapid onset type poisoning from ingestion of muscarine found in Amanita muscaria (the source for muscarine). Signs of toxicity consistent with muscarinic (Ach) excess. Treatment is with atropine. Delayed onset type occurs with many many other species of Amanita and other genus. Fungus contains amatoxins which cause liver failure. Transplant required. PM716 C8 Cholinoceptor Blockers 27  FOOD Button mushrooms (Agaricus bisporus) and Mold used to make cheese, Stilton or Blue Cheese (Penicillium roqueforti). PM716 C8 Cholinoceptor Blockers 28 Edible Mushrooms Shiitake mushrooms (Lentinula edodes) Oyster mushrooms (Pleurotus ostreatus) PM716 C8 Cholinoceptor Blockers 29 Poison Mushrooms Rapid Poisons Amanita muscaria. Musrooms produce hallucinogens, and muscarine. Muscarine is a potent acetylcholine (Ach) agonist. Muscarine receptors in numerous organs stimulated by muscarine. Symptoms include diarrhea, sweating, miosis (pupil constriction), nausea and urinary urgency. Recovery is usual. PM716 C8 Cholinoceptor Blockers 30 Poison Mushrooms Slow Poisons Amanita virosa and Amanita phalloides (Death Caps). Induce slow toxic reactions (days to weeks). Mushrooms contain alpha- amanitin, a peptide (MW 900) which binds to RNA polymerase in liver hepatocytes, shut down protein synthesis in the liver. Liver failure results. No treatment, always fatal and liver transplant required. PM716 C8 Cholinoceptor Blockers 31  Antimuscarinics POISONING WITH CHOLINESTERASE INHIBITORS: insecticides wild mushroom consumption nerve gas (chemical warfare) (1) Antimuscarinics: atropine treats PNS and CNS cholinesterase inhibition. Up to 1 g/day to reverse severe poisonings. PM716 C8 Cholinoceptor Blockers 32 Nerve Agents Sarin (GB) Tabun (GA) Potent AchE inhibitors, resulting in excess Ach and paralysis. PM716 C8 Cholinoceptor Blockers 33 Antidote for Nerve Agents Atropine injection. Block excess Ach actions nicotinic and muscarinic receptors. PM716 C8 Cholinoceptor Blockers 34  AchE Inhibitor Nerve Agents Newmark, J. The Birth of Nerve Agent Warfare Lessons From Syed Abbas Foroutan Neurology 62:1590-1596 (2004) S. A. Foroutan, the world’s first physician to report on the treatment of Sarin nerve gas. PM716 C8 Cholinoceptor Blockers 35  Nerve Gas During a three year period between 1984-1987 Iraq used Sarin nerve gas in their war with Iran. The UN confirmed 450 000 casualties. During the conflict, Dr. S. A. Faroutan was sent by Iran to the front to set up field hospitals to treat the wounded. Between 1996 -1999 Faroutan published 11 papers describing his experience. They were published in Farsi in the Kowsar Med. Journal. PM716 C8 Cholinoceptor Blockers 36  Nerve Gas Foroutan noted that some of the patients were exposed to mustard gas (1, 1-thiobis 2- chloroethane) which smells like mustard or garlic. This is the gas of WWI. He claimed that these patients were so disfigured and untreatable that he managed to have many of them airlifted to European hospitals. PM716 C8 Cholinoceptor Blockers 37 Mustard Gas Mustard Gas classified as a blistering agent. It is a direct contact poison developed in WWI (~1914). PM716 C8 Cholinoceptor Blockers 38  Nerve Gas (AchE Inhibitors) Foroutan described the cholinergic crisis: miosis; bronchospasm, increased bronchus secretions, muscle twitching, flaccid paralysis, coma, convulsions, death. Treatment consists of atropine and 2PAM, two drugs which act synergistically. Foroutan has only atropine. PM716 C8 Cholinoceptor Blockers 39  Treatment Atropine: competes with Ach (excess) for binding to muscarinic receptors. US, NATO and Iranian forces carry 3 each of a 2 mg autoinjector of atropine. 2PAM (2-pralidoxime): reactivates AchE restoring its catalytic activity. US and NATO forces carry 3 each of a 600 mg dose of 2PAM autoinjector. Iran, none. Diazepam: used to counteract seizures. All US and NATO forces carry a 10 mg autoinjector. Iran none. PM716 C8 Cholinoceptor Blockers 40  Foroutan’s Recommendations All treated (and recovered) troops be allowed 2-3 weeks rest before being sent back to the field. Logic was to allow AchE to become fully replaced with newly synthesized AchE. Rejected. The standard 3x2 mg Atropine dose carried by US and NATO forces can treat only mild to moderate cases. Higher doses required. Titrate the atropine dose to the pulse rate: < 60 - 70 beats/min increase the dose, > 110 beats/min, decrease the dose. PM716 C8 Cholinoceptor Blockers 41  Foroutan’s Recommendations Higher casualties among the Pasdaran whose beards prevented the gas mask from fitting properly. Nerve gas attacks occur on a large scale (air born agent) and triage is required. Foroutan would see up to 2000 victims in a five hour period. PM716 C8 Cholinoceptor Blockers 42 Tolterodine (Detrol®) Tolterodine is a potent muscarinic antagonist that shows some selectivity for the bladder. Drug indicated for overactive bladder. PM716 C8 Cholinoceptor Blockers 43  Antimuscarinics Atropine is not specific, induces unwanted mydriasis and cycloplegia (paralysis of ciliary muscles). Atropine overdose blocks all parasympathetic functions (dry as a bone, blind as a bat, red as a beet, mad as a hatter). Dry mouth, mydriasis, tachycardia, hot/flushed skin, agitation, delirium. PM716 C8 Cholinoceptor Blockers 44  ADRs and Toxicity Antimuscarinics Mnemonic for atropine toxicity: dry as a bone, red as a beet, mad as a hater. (1) Drugs block thermoregulation (atropine fever). The hyperthermia is potentially lethal in children. (2) Atropine “dry as a bone” because sweating, salivation and lacrimation reduced. (3) Constipation and blurred vision. All of the above toxicities predictable from peripheral autonomic blockade. PM716 C8 Cholinoceptor Blockers 45  ADRs and Toxicity CNS toxicity includes sedation, amnesia, delirium or hallucinations (“mad as a hater”). Convulsions may occur. Cutaneous blood vessels of the arms, legs, head, neck, and trunk resulting in atropine flush (“red as a beet”). This may be diagnostic of overdose from these drugs. PM716 C8 Cholinoceptor Blockers 46 “mad as a hatter” The Mad Hatter from Lewis Carroll’s Alice in Wonderland “How do you know I’m mad?” said Alice, “You must be, said the Cat, “or you wouldn’t have come here.” PM716 C8 Cholinoceptor Blockers 47  Nicotinic Antagonists Two Groups Neuromuscular Blocking Drugs (Group III) Nondepolarizing Drugs (tubocurarine) Depolarizing Drugs (succinylcholine) Ganglion-Blocking Drugs (Group II) PM716 C8 Cholinoceptor Blockers 48  Receptor Organization Sympathetic Pathway CNS Ach NE Adrenergic Receptors a1a2 b1b2 Parasympathetic Pathway CNS Ach Ach Muscarinic Receptors Nicotinic Receptors PM716 C8 Cholinoceptor Blockers 49  Organization of the ANS Preganglionic Postganglionic Organ Sympathetic Parasympathetic Ganglia embedded in organ PM716 C8 Cholinoceptor Blockers 50 PM716 C8 Cholinoceptor Blockers 51  Ganglion Blocking Drugs Block the action of Ach and other agonists at nicotinic receptors in both parasympathetic and sympathetic autonomic ganglia. Seldom used clinically because they block all sympathetic outflow with no selectivity. PM716 C8 Cholinoceptor Blockers 52  Ganglion Blocking Drugs Hexamethonium (“C6”) world’s first antihypertensive, no longer used. Mecamylamine Trimethaphan (short acting given iv). PM716 C8 Cholinoceptor Blockers 53 Hexamethonium Ganglion blocking drug used to lower blood pressure. Introduced in the 1950’s but no longer used. Drug blocks nerve impulses that lead to vasoconstriction. PM716 C8 Cholinoceptor Blockers 54 Hexamethonium Ach causes bronchial constriction (nicotinic) Drug is antagonistic at nicotinic ganglionic receptors, given iv. Does not cross BBB. No effect on muscarinic (smooth muscle) receptors. PM716 C8 Cholinoceptor Blockers 55  Ganglion Blockers Mecamylamine (Inversine®) Trimethaphan (Arfonad®) PM716 C8 Cholinoceptor Blockers 56  Ganglion Blocking Drugs Nondepolarizing competitive antagonists. Blocking overcome by increasing concentration of Ach at the receptor. PM716 C8 Cholinoceptor Blockers 57  Ganglion Blocking Drugs CNS: Mecamylamine crosses BBB, trimethaphan does not. Mecamylamine causes sedation, tremor, mental aberrations. Eye: Ciliary muscle receives both symp and parasymp innervation, cycloplegia (paralysis) results. Cardiac: Vasoconstrictor sympathetic fibers blocked and blood pressure drops PM716 C8 Cholinoceptor Blockers 58  Ganglion Blocking Drugs Trimethaphan used on occasion for treating hypertension. Very limited clinical uses. PM716 C8 Cholinoceptor Blockers 59  Cholinergic Poisoning Sever excess of Ach or Ach agonist activity due to (a) Excess AchE inhibitor agents (organophosphate pesticides and nerve gas agents). (b) Mushroom poisoning PM716 C8 Cholinoceptor Blockers 60  AchE Regenerator Drugs Pralidoxime hydrolyzes the phosphorylated AchE-organophosphate complex and regenerate AchE. Pralidoxime does not cross BBB and does not reverse CNS actions of organophosphates. PM716 C8 Cholinoceptor Blockers 61  AchE Regenerator Drugs Pralidoxime (Protopam®) PM716 C8 Cholinoceptor Blockers 62  Antimuscarinics (2) Cholinesterase Regenerator Drugs pralidoxime (PAM) Used to reverse the PNS effects of organophosphate poisonings (does not cross BBB due to its positive charge). PM716 C8 Cholinoceptor Blockers 63 Pralidoxime (2PAM) Regenerates AchE through hydrolysis of the phosphorylated Ach-organophosphate complex. PM716 C8 Cholinoceptor Blockers 64  Summary Muscarinics Muscarinic Agonists CAUSE: 1. Smooth muscle contraction (gut, bladder) 2. Pupillary constriction, ciliary muscle contraction 3. Decreased rate and force of heart beat 4. Glandular secretion (salivary), sweat 5. Gastric acid secretion 6. Vasodilation via nitric oxide 7. Inhibition of neurotransmitter release 8. Slow excitation of ganglia PM716 C8 Cholinoceptor Blockers 65  Summary Muscarinics Muscarinic Antagonists CAUSE: 1. Inhibiton of secretion (dry mouth) 2. Tachycardia 3. Pupillary dilation 4. Relaxation of smooth muscles 5. Inhibition of gastric acid secretion 6. CNS excitation (atropine) or depression 7. Anti-emetic actions 8. Anti-Parkinson actions PM716 C8 Cholinoceptor Blockers 66  Summary I (1) Group I, II, III drugs (2) Sympath vs parasympath receptor organization (3) Muscarinic receptor subtypes (4) Antimuscarnic drugs (Slide 9) (5) Antimuscarinic Drug distribution, pharmacological actions. (6) Atropine clinical applications (7) Mushroom poisoning (rapid vs slow onset). PM716 C8 Cholinoceptor Blockers 67  Summary II (8) Toxicity of muscarinics (9) Nicotinic antagonists (Group III) (10) Ganglionic Blocking Drugs (Group II) Slide 41, pharmacological actions. (11) Cholinergic poisoning causes (12) Cholinergic poisoning treatment, pralidoxime. (13) Muscarinic agonists vs antagonists. PM716 C8 Cholinoceptor Blockers 68  Cholinomimetics methacholine echothiophate bethanechol donepezil carbachol physostigmine pilocarpine edrophonim muscarine PM716 C8 Cholinoceptor Blockers 69  Cholinomimetics carbamate insecticides propoxur organophosphate insecticides parathion malathion nerve gas suman sarin tabun (GA) PM716 C8 Cholinoceptor Blockers 70  Cholinolytics atropine hexamethonium scopolamine mecamylamine propantheline trimethaphan glycopyrrolate tolterodine tropicamide pralidoxime dicyclomine ipratropium PM716 C8 Cholinoceptor Blockers 71