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Home , Edrophonium

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 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 (AchE) N M-

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 • sweating (cholinergic sympathetic) Pilocarpine Nicotine DFP • salivation, • gastric acid secretion (M1) Muscarine Edrophonium Nerve gas

Muscarinic receptor agonists Wild Mushrooms - Amanita

• 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 - Nicotinic receptor agonists

• Adverse reactions: (SLUDE) Ganglionic stimulants - Salivation - Lacrimation - Urination • Clinically not important - Diarrhea - Emesis (vomiting) • (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 – • Two sites: - Ambenonium (synthetic, 4-8 hr) - anionic site that binds the quaternary amine and positions the Ach molecule •

- 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 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

P No cns action - Diisopropyl-fluorophosphate (DFP) R2 X DFP Aging 30-40 min - (low lipid solubility, no CNS) Nerve gas - , Suman (nerve gases) secs / min

- Malathion, (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 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 (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. , 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 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 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: • pesticide poisoning (malathion) ie. atropine - quaternary cholinesterase inhibitor eg. neostigmine or • mushroom poisoning (muscarine) ie. atropine physostigmine (cns action) • nerve gases (sarin) ie. atropine + 2-PAM - for hypotension: sympathomimetics (a-agonist, eg.methoxamine)

Symptoms of Antimuscarinic Toxicity Mad as a

Belladonna (beautiful lady) poisoning Hatter

• mad as a hatter: CNS, delirium Mercury was used to treat hats. It was applied on to the fur to roughen the fibres and make them mat more easily • red as a beet: direct vasodilation • blind as a bat: cycloplegia Mercury is a cumulative poison that causes kidney and brain damage. Physical symptoms include trembling • hot as hell (a hare): ¯sweat, thermoregulation (known at the time as hatter's shakes), loosening of teeth, loss of co-ordination, and slurred speech; mental • dry as a bone: decreased secretions ones include irritability, loss of memory, depression, anxiety, and other personality changes. This was called mad hatter syndrome.

6 Parasympathetic Summary Acetylcholinesterase Inhibitors Type Members Effects

Agonists 1. Ach 1. heart ÞÞ bradycardia, ¯¯ contractility, 2. Bethanecol ¯¯ conduction velocity in the AV node 3. Pilocarpine 2. vasculature ÞÞ mediate vasodilation 4. Methacholine via synthesis of NO by endothelial Rapidly reversible Edrophonium Þ used for myasthenia gravis (aka cells (competitive) Tensilon) 3. smooth muscle ÞÞ •• tone in intestine & bladder; ¯¯ tone in sphincters 4. eye ÞÞ contraction of sphincter Slowly reversible 1. Neostigmine Þ does not cross BBB; affects (miosis) & ciliary muscle for near (competing substrate, skeletal muscle most strongly; used for vision carbamylates enzyme) myasthenia gravis & ileus 5. exocrine glands ÞÞ•• sweating (SNS), 2. Physostigmine Þ crosses BBB, used for salivation & gastric acid secretion glaucoma and for treatment of belladonna Antagonists 1. atropine - non- 1. heart ÞÞ tachycardia, •• AV node poisoning selective, long lasting conduction 3. Pyridostigmine Þ used for myasthenia gravis 2. scopolamine – 2. vasculature ÞÞ no effect (no 4. Ambenonium Þ used for myasthenia gravis centrally acting cholinergic innervation) 3. homatropine – 3. smooth muscle ÞÞ relaxation in GI & 5. Demercarium Þ used for glaucoma shorter acting urinary tract 4. pirenzepine - M1 4. eye ÞÞ mydriasis & cycloplegia Irreversible or very slowly Organophosphate insecticides, nerve gases receptor selective 5. exocrine glands ÞÞ dry mouth, dry (anti-ulcer) reversible Echothiophate Þ used for glaucoma skin, &¯ ¯ gastric acid secretion (phosp horylates enzyme) 6. CNS effects ÞÞ belladonna toxicity (mad as a hatter, red as a beet, blind as a bat, hot as hell)

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