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Pharmacology of the Parasympathetic Nervous System

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Pharmacology of the Parasympathetic Nervous System Autonomic Nervous System Pharmacology of the Parasympathetic Nervous System Edward JN Ishac Smith Building, Room 742 [email protected] 8-2127 8-2126 Department of Pharmacology and Toxicology Medical College of Virginia Campus of Virginia Commonwealth University Richmond, Virginia, USA ANS Diagram Neurons of the ANS Key Points Key Points Preganglionic fibers Division – Anatomical – mylinated Usually dual innervation Postganglionic fibers – non mylinated Usually antagonistic SNS pre : post 1:20 Usually one dominates PNS pre : post 1:1 Usually some ANS “tone” (exception 1:10,000 Auerbachs plexus) Key role of Ach Motor fiber not part of ANS Cholinoceptors Cholinergic Neurotransmission Muscarinic M 1- Ganglia cells Rate limiting step M 2- Cardiac muscle Uptake of cholineinto nerve terminal M 3- Sweat glands M /M Termination 4 5 Enzymatic by Nicotinic N N- Ganglia cells acetylcholinesterase (AchE) N M- Neuromuscular junction 1 Cholinergic Receptors True Acetylcholinesterase (AchE) Na+ - in (Other: Pseudocholinesterase, circulating, plasma, K+ - out butylcholinesterase) AchE BuChE Nerves Yes Little NMJ Yes Little • Muscarinic (7 transmembrane) • Nicotinic (ion channel) Circul n Little Yes - M1 -autonomic ganglia, CNS - pentamer, 5 subunits - M2 -heart - NN or N1 -ganglia, adrenal - M -smooth muscle, glands 3 medulla (a2b 3, a3b 2) Quaternary group Acyl carbon - M , M 4 5 - NM or N2 -skeletal muscle - M135 • PLC, M 24 ¯AC (infant a bde, adult a2bdg ) 2 AchE: 300,000 Ach / enzyme / min (0.15 msec/cycle) - G-protein coupled - a subunit, Ach binding (2) Muscarinic effects on organ systems Cholinergic Stimulants • Heart (M2) - ¯ HR, ¯ contractility, ¯conduction velocity • Vasculature (not innervated) - vasodilation: nitric oxide (NO) • Other smooth muscle • - Eye: pinpoint pupil (miosis), focus for near vision • - GI-tract: •tone to intestine, bladder, ¯ tone to sphincters • - Lung: contract bronchial SM. ® •resistance, • secretions - Exocrine glands: • Ach Ach Physostigmine Malathion • sweating (cholinergic sympathetic) Pilocarpine Nicotine Neostigmine DFP • salivation, • gastric acid secretion (M1) Muscarine Edrophonium Nerve gas Muscarinic receptor agonists Wild Mushrooms - Amanita • Choline esters 10,000 cases per year - ACH (muscarinic & nicotinic action) - bethanechol (oral or sc, never iv or im ® cardiac arrest) - methacholine (not common) Muscarine poisoning - carbachol (direct/indirect; muscarinic & nicotinic) 5,000 mushroom species 100 “bad”, 10 “deadly” • Alkaloids: - muscarine (mushrooms) - pilocarpine (DOC, used in glaucoma emergence) - oxotremorine (synthetic) CNS action (basal ganglia) • Uses: - ophthalmic (Ach, brief miosis) - diagnostic for belladonna poisoning (methacholine) - urinary retention (bethanechol) - reverse GIT depression (bethanechol) 2 Adverse Reactions - Cholinergics Nicotinic receptor agonists • Adverse reactions: (SLUDE) Ganglionic stimulants - Salivation - Lacrimation - Urination • Clinically not important - Diarrhea - Emesis (vomiting) • Acetylcholine (natural transmitter) - cardiac slowing (arrest, esp. bethanechol) • DMPP (experimental) - nausea, cramps • Nicotine (alkaloid, tobacco) - bronchoconstriction, can precipitate asthma - involuntary defecation, urination • Lobeline (tobacco) - tremor, CNS induced convulsions Indirectly-Acting Parasympathomimetics Reversible inhibitors • Interact with acetylcholinesterase • Quarternary ammonium compounds True and/or pseudocholinesterase (serum) - Edrophonium (synthetic, water stable, 5-10 min) Tensilon test – Myasthenia gravis • Two sites: - Ambenonium (synthetic, 4-8 hr) - anionic site that binds the quaternary amine and positions the Ach molecule • Carbamates - esteratic site which attacks the acyl carbon - Physostigmine (0.5-2 hr) (tertiary amine, well absorbed, cns activity, • Inhibitors of cholinesterase: can give topically) - Reversible inhibitors (eg. physostigmine) - Neostigmine (0.5-2 hr) - Irreversible inhibitors (eg. organophosphates) (quaternary amine, no cns activity, synthetic, some direct action) Myasthenia gravis Acetylcholinesterase and Reversible inhibitors Autoimmune disease ACH Neostigmine Ach very fast 0.15msec Neostigmine 1:10,000 (250,000 USA) undergoes • antibodies to NMJ nicotinic receptors metabolism leads to degradation 0.5 – 6 hr • simplified synaptic folds • normal nerve terminal and transmitter • wider synaptic junction • Diagnosis: Edrophonium (Tensilon, short Enzyme acting) is used for diagnosis and becomes determination of maintenance dose operational again • Treatment: Neostigmine has direct (stimulates receptor) and indirect actions (inhibition of AchE). No cns activity. 3 Acetylcholinesterase & Irreversible Inhibition Irreversible inhibitors DFP, Isoflurophate • Organophosphates 2-PAM (highly lipid soluble, >50,000 compounds) R1 O Pralidoxime P No cns action - Diisopropyl-fluorophosphate (DFP) R2 X DFP Aging 30-40 min - Echothiophate (low lipid solubility, no CNS) Nerve gas - Sarin, Suman (nerve gases) secs / min - Malathion, Parathion (more toxic) Inactive, converted to active compound Malathion 4 – 6 hr in body (S O) pesticides, very lipid soluble US Military 2-PAM / Atropine Injector Clinical use: Acetylcholinesterase Inhibitors • Eye: miosis (sphincter contraction), accommodation block (ciliary 2.5 mg Atropine, 600mg 2-PAM muscle contraction) Use: Glaucoma (wide-angle or secondary glaucoma) Physostigmine or echothiophate(long acting) • GI tract: •motility in paralytic ileus (post-op) or atony of urinary bladder. Neostigmine (bethanechol better) • Neuromuscular junction: - Neostigmine in Myasthenia gravis - Edrophonium as diagnostic Myasthenia gravis - Reverse NMJ block after surgery, Neostigmine • Reverse toxicity by anticholinergic agents: - ie. atropine, tricyclic antidepressants (high doses) - Physostigmine is preferred (CNS action) Actions on the Eye Acetylcholinesterase Inhibitors Glaucoma treatment Approximate Uses Duration 1. a-Agonist of Action •Outflow Alcohols Edrophonium (Tensilon) Myasthenia gravis, 5 -15 minutes 2. M-Agonists ileus, arrhythmias •Outflow Carbamates and related agents Neostigmine (Prostigmine, ) Myasthenia gravis, 1/2 -2 hours 3. b-Blocker ileus ¯Secretion Pyridostigmine (Mestinon) Myasthenia gravis 3 -6 hours Physostigmine (Eserine) Glaucoma 1/2 -2 hours 4. a2-Agonist Ambenonium (Mytelase) Myasthenia gravis 4 -8 hours ¯Secretion Demecarium (Humorsol) Glaucoma 4 -6 hours Organophosphates 5. Carbonic acid Echothiophate , DFP Glaucoma 100 hours inhibitors (Phospholine), etc .) ¯Secretion 4 Toxicity & Treatment of AchE Inhibitors Toxicity of AchEInhibitors • Adverse reactions: (SLUDE) - Salivation (muscarinic) - Lacrimation (muscarinic) SLUDGE DUMBBELS - Urination (muscarinic) - Diarrhea (muscarinic) D - Diarrhea - Emesis (vomiting) (muscarinic) S - Salivation U - Urination - cardiac slowing (muscarinic) L - Lacrimation M - Miosis/muscle weakness - hypertension / hypotension (nicotinic) U - Urination B – Bronchorrea (mucus) - NMJ paralysis (nicotinic) D - Diarrhea B - Bradycardia - cramps (muscarinic) G - Gastric upset E - Emesis - bronchoconstriction (muscarinic) E - Emesis L - Lacrimation - tremor, nausea, CNS induced convulsions S - Salivation/sweating • Treatment: Muscarinic antagonist ie. Atropine AchE reactivator (Pralidoxime, 2-PAM) mechanical respiration Parasympatholytic Agents AnticholinergicEffects on Organ Systems • Heart: tachycardia, • A-V nodal CV (M2-receptors) • Antimuscarinic: eg. atropine - block Ach in parasympathetic effector junctions • Vasculature: no effect, although toxic doses cause pronounced vasodilation (red blotches) (muscarinic receptors) • Smooth muscle • Antinicotinic: Ganglia eg. mecamylamine - GI-tract, urinary tract: relaxation, ¯ secretion, ¯ motility - block Ach in ganglia (both parasympathetic and - Lung: bronchial relaxation & ¯ bronchial secretions - Eye: mydriatic (sphincter relaxation), cyclopegic (ciliary sympathetic, NN or N1-receptors) muscle relaxation) Antinicotinic: NMJ • Secretions • eg. curare, succinylcholine - ¯ secretion: dry mouth, dry skin, - block Ach in neuromuscular junctions (skeletal muscle - ¯ decreased gastric acid secretion relaxants, NM or N2-receptors) • CNS: agitation, delirium, confusion, elderly are more susceptible Antimuscarinic Agents Deadly Nightshade Datura • Belladonna alkaloids: well absorbed, CNS effects Approx 5,000 per yr - atropine (7-10 d) - “belladonna” - homatropine (1-3 d) - iritis - scopolamine (3-7 d) - motion sickness • Synthetic antimuscarinics - ipratropium (quaternary amine) - asthma - pirenzepine (tri-cyclic, M1-selective) - ulcer - benztropine - Parkinson’s disease - glycopyrolate (quaternary amine) Mainly atropine Mainly scopolamine & - cyclopentolate (tertiary amine) Devil’s apple hyoscyamine - propantheline (quaternary amine) Stink weed Thorn apple Devil’s cherries Jimson weed 5 Botulinum toxin Other Parasympatholytics Inhibits Ach release Before Single treatment can last 3-4 months Hemicholinium - no clinical use - inhibits uptake of cholineinto nerve terminal (rate limiting step) - leads to decreased Ach synthesis After Botulinus toxin - prevent release of Ach - contamination of improperly prepared food Clinical use: facial muscle spasms, strabismus, wrinkles Facial wrinkles, FDA Approval: Apr 2002 Clinical uses of Antimuscarinic Agents Toxicity and treatment • respiratory (decrease bronchial secretion) ie. atropine • Toxicity: • asthma ie. ipratropium dry mouth, mydriasis, tachycardia, hot flushed skin, • ophthalmologic (mydriasis, cycloplegia) ie. iritis agitation and delirium. • Parkinson’s
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