Antimuscarinic Agents Parasympathetic Nervous System • Belladonna alkaloids: well absorbed, CNS effects Part II - (7-10 d) - “belladonna” - (1-3 d) - iritis Dr. Edward JN Ishac, Ph.D. - (3-7 d) - motion sickness Professor • Synthetic antimuscarinics

Smith Building, Room 742 - ipratropium (quaternary amine) – asthma, COPD [email protected] - tiotropium - COPD - pirenzepine (tri-cyclic, M1-selective) - ulcer 828-2127 - benztropine - Parkinson’s disease - glycopyrolate (quaternary amine) Department of Pharmacology and Toxicology Medical College of Virginia - (tertiary amine) Campus of Virginia Commonwealth University - propantheline (quaternary amine) Richmond, Virginia, USA

Parasympatholytic Agents Deadly Nightshade Datura

• Antimuscarinic: eg. atropine Approx 5,000 per yr - block Ach in parasympathetic effector junctions (muscarinic receptors)

• Antinicotinic: Ganglia eg. trimethapan - block Ach in ganglia (both parasympathetic and

sympathetic, NN or N1-receptors)

• Antinicotinic: NMJ eg. curare, succinylcholine - block Ach in neuromuscular junctions (skeletal muscle Mainly atropine Mainly scopolamine & relaxants, NM or N2-receptors) Devil’s apple hyoscyamine Stink weed Thorn apple Devil’s cherries Jimson weed

Anticholinergic Effects on Organ Systems Chronic Obstructive Pulmonary Disease (COPD) • Heart: tachycardia, ↑ A-V nodal CV (M2-receptors) Features: - Damage to lungs • Vasculature: no effect, although toxic doses cause pronounced direct vasodilation (red blotches) - Develops slowly - No cure • Smooth muscle - 4th US Cause of death - GI-tract, urinary tract: relaxation, ↓ secretion, ↓ motility - Smoking common cause - Lung: bronchial relaxation & ↓ bronchial secretions - Eye: mydriatic (sphincter relaxation), cyclopegic ( relaxation) Treatment (inhaled): • Secretions - Beta2-agonists - ↓ secretion: dry mouth, dry skin, - M-receptor blockers - ↓ decreased gastric acid secretion (ipratropium, tiotropium) - Glucocorticosteroids • CNS: agitation, delirium, confusion, elderly are more susceptible - Oxygen

1 Other Parasympatholytics Clinical uses of Antimuscarinic Agents

Hemicholinium • respiratory (decrease bronchial secretion) ie. atropine - no clinical use • Asthma, COPD ie. ipratropium, tiotropium - inhibits uptake of choline into nerve terminal (rate • ophthalmologic (, cycloplegia) eg. iritis (ie. atropine) limiting step) • Parkinson’s disease ie. benztropine - leads to decreased Ach synthesis • cardiovascular ie. atropine Botulinus toxin • motion sickness ie. scopolamine • GI disorders (peptic ulcers (pirenzepine), diarrhea) - prevent release of Ach • Rx pesticide poisoning (malathion) ie. atropine + 2-PAM - contamination of improperly prepared food • Rx mushroom poisoning (muscarine) ie. atropine • Rx nerve gases (Vx, sarin) ie. atropine + 2-PAM Clinical use: facial muscle spasms (blepharospasm, eye twitching or eye spasm) , wrinkles

Botulinum toxin Before Toxicity and treatment Inhibits Ach release Single treatment can last 3-4 months • Toxicity: dry mouth, mydriasis, cycloplegia, tachycardia, hot flushed skin, agitation and delirium.

High concentrations may cause ganglionic-blockade leading to hypotension After • Treatment: - quaternary cholinesterase inhibitor eg. neostigmine or physostigmine (cns action) - for hypotension: sympathomimetics (α-agonist, eg.methoxamine)

Facial wrinkles, FDA Approval: Apr 2002

Botulinum toxin - Strabismus Antimuscarinic Toxicity

Belladonna (beautiful lady)

• mad as a hatter: - CNS, delirium • red as a beet: - direct vasodilation • blind as a bat: - cycloplegia • hot as hell (a hare): - ↓sweat, thermoregulation • dry as a bone: - decreased secretions

2 Pharmacology of the Eye Ach effects on smooth muscle in the eye

Contraction of sphincter muscle → “The eye is a good example of an organ with multiple ANS functions, controlled by several different autonomic Contraction of ciliary muscle for near vision receptors.” (Katzung)

Increased intraocular pressure: Untreated → blindness

Glaucoma: - Open-angle (wide, chronic) – treated with beta- blockers and other agents - Closed-angle (narrow-angle) – dilated can occlude outflow. Pilocarpine or surgical removal of part of iris (iridectomy)

Glaucoma Actions on the Glaucoma treatment Increased intraocular pressure: Untreated → blindness Eye 1. α-Agonist Glaucoma:- Open angle (wide, chronic) – treated with beta-blockers and other agents ↑Outflow - Closed angle (narrow-angle) – dilated iris can occlude outflow Pilocarpine or surgical removal of part of iris (iridectomy) 2. M-Agonists/AchEI ↑Outflow

3. β-Blocker ↓Secretion

4. α2-Agonist ↓Secretion Glaucoma treatment 5. Prostaglandins 1. α-Agonist: ↑Outflow ↑Outflow 2. M-Agonists: ↑Outflow 3. β-Blocker: ↓Secretion 4. α2-Agonist: ↓Secretion 6. Carbonic acid 5. Prostaglandins: ↑Outflow inhibitors 6. Carbonic acid inhibitors: ↓Secretion ↓Secretion

Prostaglandin analogues Open Angle vs Closed Angle Glaucoma (Latanoprost, Bimatoprost, Travoprost, Unoprostone)

Side effects: - darkening of the iris - lengthening and thickening of - intraocular inflammation

3 Drugs used in glaucoma Question 3

Cholinomimetics Ciliary muscule contraction Topical Pilocarpine (acute DOC), → opening of trabecular Right Left physostigmine, echothiophate meshwork →↑outflow The circles represent the size of the of a patient's right Without Alpha Agonists: Unselective: ↑ Outflow Topical and left eyes, both without treatment Epinephrine, Dipivefrin, PE treatment and with two different Alpha2-Selective Agonists: ↓ Aqueous secretion from Topical treatments. Which of the Apraclonidine, Brimonidine the ciliary epithelium following is compatible with the findings shown for the left eye? Treatment Beta-Blockers: ↓ Aqueous secretion from Topical With TYR Timolol, betaxolol, carteolol the ciliary epithelium A. Blockade of α-adrenergic rec. B. Blockade of ß-adrenergic rec. Diuretics: Carbonic acid inhib. Acetazolamide, Methazolamide ↓ Secretion due to lack of Oral C. Blockade of muscarinic rec. Treatment HCO - Topical Dorzolamide, Brinzolamide 3 D. Inhibition of cholinesterase With EPI E. Sympathetic denervation Prostaglandins: (PGF2α) ↑ Outflow Topical Latanoprost, Bimatoprost USMLE Step 1: 1998, 2003, 2005

Effects of pharmacological agents on the Parasympathetic Summary

Clinical Setting Drug Agents Effects Agonists 1.Ach 1.heart ⇒ bradycardia, ↓ contractility, ↓ Normal Alpha agonist Dilation (mydriasis) 2.Bethanecol conduction velocity in the AV node ie. 3.Pilocarpine 2.vasculature ⇒ mediate vasodilation via Normal Muscarinic agonist Constriction (miosis) 4.Methacholine synthesis of NO by endothelial cells ie. pilocarpine cycloplegia 3.smooth muscle ⇒↑tone in intestine & bladder; tone in sphincters Normal Mydriasis, ↓ 4.eye contraction of sphincter (miosis) & ie. atropine cycloplegia ⇒ ciliary muscle for near vision 5.exocrine glands ⇒↑ sweating (SNS), Horner’s syndrome Cocaine No dilation salivation & gastric acid secretion

Preganglionic Horner’s Hydroxyamphetamine Dilation Antagonists 1.atropine - non-selective, 1.heart ⇒ tachycardia, ↑ AV node conduction long lasting 2.vasculature ⇒ no effect (no cholinergic Postganglionic Horner’s Hydroxyamphetamine No dilation 2.scopolamine – CNS innervation) 3.homatropine – shorter 3.smooth muscle ⇒ relaxation in GI & urinary Adie’s pupil Pilocarpine Constriction acting 4.eye ⇒ mydriasis & cycloplegia 4. ipratropium - asthma 5.exocrine glands ⇒ dry mouth, dry skin, & ↓ 5. pirenzepine - M1 gastric acid secretion Normal Opioids (oral or Pinpoint pupils receptor selective (ulcer) 6.CNS effects ⇒ belladonna toxicity (mad as a intravenous) hatter, red as a beet, blind as a bat, hot as hell

Eye - Horners Syndrome Acetylcholinesterase Inhibitors Destruction of Sympathetic innervation to the iris - loss of preganglionic fibers - loss of postganglionic fibers Rapidly reversible Edrophonium ⇒ used for myasthenia gravis - parasympathetic innervation left unopposed (competitive) (aka Tensilon) Slowly reversible 1.Neostigmine ⇒ does not cross BBB; affects Horners Syndrome (note sagging left and miosis) (competing substrate, skeletal muscle most strongly; used for carbamylates enzyme) myasthenia gravis & ileus 2.Physostigmine ⇒ crosses BBB, used for glaucoma and for treatment of belladonna poisoning 3.Pyridostigmine ⇒ used for myasthenia gravis 4.Ambenonium ⇒ used for myasthenia gravis 5.Demercarium ⇒ used for glaucoma

Irreversible or very Organophosphate insecticides, nerve gases slowly reversible Echothiophate ⇒ used for glaucoma (phosphorylates enzyme)

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