Neurons of the ANS Parasympathetic Nervous System Part II Dr. Edward JN Ishac Smith Building, Room 742 eishac@vcu.edu 8-2127 8-2126 Department of Pharmacology and Toxicology Medical College of Virginia Campus of Virginia Commonwealth University Richmond, Virginia, USA Parasympatholytic Agents Anticholinergic Effects on Organ Systems • Heart: tachycardia, ↑ A-V nodal CV (M2-receptors) • Antimuscarinic: eg. atropine • Vasculature: no effect, although toxic doses cause - block Ach in parasympathetic effector junctions pronounced direct vasodilation (red blotches) (muscarinic receptors) • Smooth muscle - GI-tract, urinary tract: relaxation, ↓ secretion, ↓ motility • Antinicotinic: Ganglia eg. trimethapan - Lung: bronchial relaxation & ↓ bronchial secretions - block Ach in ganglia (both parasympathetic and - Eye: mydriatic (sphincter relaxation), cyclopegic (ciliary sympathetic, N N or N 1 -receptors) muscle relaxation) • Secretions • Antinicotinic: NMJ eg. curare, succinylcholine - ↓ secretion: dry mouth, dry skin, - block Ach in neuromuscular junctions (skeletal muscle - ↓ decreased gastric acid secretion relaxants, N M or N 2 -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 1
Virginia Beach Officials Investigate Rash of Jimsonweed Poisonings - Jan 2006 Other Parasympatholytics • 12 teenagers were diagnosed with Hemicholinium Jimsonweed poisonings - no clinical use • Jimsonweed, also known as thorn - inhibits uptake of choline into nerve terminal (rate apple, stinkweed, and Jamestown weed limiting step) - leads to decreased Ach synthesis • it is sometimes eaten - or made into a tea - and ingested by young people in an Botulinus toxin attempt to get high - prevent release of Ach • they displayed symptoms such as - contamination of improperly prepared food combative behavior, dry mouth/thirst, blurred vision hallucinations and Clinical use: facial muscle spasms, strabismus, wrinkles elevated body temperature Botulinum toxin Botulinum toxin - Strabismus Inhibits Ach release Before Single treatment can last 3-4 months After 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, cycloplegia, tachycardia, hot flushed skin, agitation and delirium. • ophthalmologic (mydriasis, cycloplegia) eg. iritis (ie. atropine) • Parkinson’s disease ie. benztropine High concentrations may cause ganglionic-blockade • cardiovascular ie. atropine leading to hypotension • motion sickness ie. scopolamine • GI disorders (peptic ulcers (pirenzepine), diarrhea) • Treatment: - quaternary cholinesterase inhibitor eg. neostigmine or • pesticide poisoning (malathion) ie. atropine + 2-PAM physostigmine (cns action) • mushroom poisoning (muscarine) ie. atropine - for hypotension: sympathomimetics ( α -agonist, • nerve gases (sarin) ie. atropine + 2-PAM eg.methoxamine) 2
Pharmacology of the Eye Symptoms of Antimuscarinic Toxicity “The eye is a good example of an organ with multiple ANS Belladonna (beautiful lady) poisoning functions , controlled by several different autonomic receptors.” ( Katzung) • mad as a hatter: CNS, delirium Increased intraocular pressure: Untreated → blindness • red as a beet: direct vasodilation Glaucoma: • blind as a bat: cycloplegia - Open-angle (wide, chronic) – treated with beta- ↓ sweat, thermoregulation • hot as hell (a hare): blockers and other agents - Closed-angle (narrow-angle) – dilated iris can • dry as a bone: decreased secretions occlude outflow. Pilocarpine or surgical removal of part of iris (iridectomy) Glaucoma Ach effects on smooth muscle in the eye Increased intraocular pressure: Untreated → blindness Glaucoma:- Open angle (wide, chronic) – treated with beta-blockers and other agents Contraction of sphincter muscle → miosis - Closed angle (narrow-angle) – dilated iris can occlude outflow Pilocarpine or surgical removal of part of iris (iridectomy) Contraction of ciliary muscle for near vision Glaucoma treatment 1. α -Agonist: ↑ Outflow 2. M-Agonists: ↑ Outflow 3. β -Blocker: ↓ Secretion 4. α 2-Agonist: ↓ Secretion 5. Prostaglandins: ↑ Outflow 6. Carbonic acid inhibitors: ↓ Secretion Actions on the Eye Drugs used in glaucoma Glaucoma treatment 1. α -Agonist Cholinomimetics Ciliary muscule contraction Topical Pilocarpine, physostigmine, → opening of trabecular ↑ Outflow echothiophate meshwork → ↑ outflow 2. M-Agonists ↑ Outflow Alpha Agonists: Unselective: Tropical ↑ Outflow Epinephrine 3. β -Blocker ↓ Aqueous secretion from Alpha2-Selective Agonists: Topical ↓ Secretion Apraclonidine the ciliary epithelium ↓ Aqueous secretion from Beta-Blockers: Topical 4. α 2-Agonist Timolol, betaxolol, carteolol the ciliary epithelium ↓ Secretion Diuretics: Carbonic acid inhib. 5. Prostaglandins ↓ Secretion due to lack of Oral Acetazolamide, Methazolamide ↑ Outflow - HCO 3 Topical Dorzolamide, Brinzolamide 6. Carbonic acid ↑ Outflow Topical Prostaglandins: inhibitors Latanoprost (PGF2 α ) ↓ Secretion 3
Effects of pharmacological agents on the pupil Innervation of the iris Clinical Setting Drug Pupillary Response Normal Alpha agonist Dilation (mydriasis) ie. phenylephrine Normal Muscarinic agonist Constriction (miosis) ie. pilocarpine cycloplegia Normal Muscarinic antagonist Mydriasis, ie. atropine cycloplegia Horner’s syndrome Cocaine No dilation Preganglionic Horner’s Hydroxyamphetamine Dilation Postganglionic Hydroxyamphetamine No dilation Horner’s Adie’s pupil Pilocarpine Constriction Normal Opioids (oral or Pinpoint pupils intravenous) Eye - Horners Syndrome Question 3 Destruction of Sympathetic innervation to the iris - loss of preganglionic fibers Left Right - loss of postganglionic fibers The circles represent the size of - parasympathetic innervation left unopposed Without the pupils of a patient's right treatment and left eyes, both without Horners Syndrome (note sagging left eyelid and miosis) treatment and with two different treatments. Which of the following is compatible with the Treatment findings shown for the left eye? With TYR A. Blockade of α -adrenergic rec. B. Blockade of ß-adrenergic rec. C. Blockade of muscarinic rec. Treatment D. Inhibition of cholinesterase With EPI E. Sympathetic denervation USMLE Step 1: 1998, 2003, 2005 Parasympathetic Summary Acetylcholinesterase Inhibitors Agents Effects 1.heart ⇒ bradycardia, ↓ contractility, ↓ Rapidly reversible Edrophonium ⇒ used for myasthenia gravis Agonists 1.Ach 2.Bethanecol conduction velocity in the AV node (competitive) (aka Tensilon) 3.Pilocarpine 2.vasculature ⇒ mediate vasodilation via 4.Methacholine synthesis of NO by endothelial cells 1.Neostigmine ⇒ does not cross BBB; affects Slowly reversible 3.smooth muscle ⇒ ↑ tone in intestine & (competing substrate, skeletal muscle most strongly; used for bladder; ↓ tone in sphincters 4.eye ⇒ contraction of sphincter (miosis) & carbamylates enzyme) myasthenia gravis & ileus ciliary muscle for near vision 2.Physostigmine ⇒ crosses BBB, used for 5.exocrine glands ⇒↑ sweating (SNS), glaucoma and for treatment of belladonna salivation & gastric acid secretion poisoning 3.Pyridostigmine ⇒ used for myasthenia gravis Antagonists 1.atropine - non-selective, 1.heart ⇒ tachycardia, ↑ AV node conduction 4.Ambenonium ⇒ used for myasthenia gravis 2.vasculature ⇒ no effect (no cholinergic long lasting 5.Demercarium ⇒ used for glaucoma 2.scopolamine – centrally innervation) acting 3.smooth muscle ⇒ relaxation in GI & urinary 3.homatropine – shorter 4.eye ⇒ mydriasis & cycloplegia Irreversible or very Organophosphate insecticides, nerve gases acting 5.exocrine glands ⇒ dry mouth, dry skin, & ↓ Echothiophate ⇒ used for glaucoma 4.pirenzepine - M1 gastric acid secretion slowly reversible 6.CNS effects ⇒ belladonna toxicity (mad as a receptor selective (anti- (phosphorylates ulcer) hatter, red as a beet, blind as a bat, hot as hell enzyme) 4
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