Cholinergic junction

Choline + Acetyl CoA = Ach (packaged into vesicles)

Membrane depolarization leads to opening of Ca2+ channels and binding of the Ach vesicles w/ the membrane

Once in the junction it can bind to receptors (muscarinic or nicotinic), be metabolized by AchE, or diffuse back and bind to autoreceptor M2 

Botulinum toxin

Inhibits synaptobrevin and other proteins to prevent ACh release

AChE

Target for inhibitory drugs (indirect acting cholinomimetic)

Reversible AChE's: edrophonium, physostigmine, neostigmine

Irreversible AChE's: echothiophate, malathion, parathion

Muscarinic receptor activation (Eye)

Sphincter -- M3 -- contraction, miosis

Ciliary muscle -- M3 -- contraction, accomodation

Muscarinic Receptor activation (heart)

SA node -- M2 -- decrease HR (neg. chronotropy)

AV node -- M2 -- decrease conduction velocity (neg. dromotropy)

Muscarinic receptor activation (lungs)

Bronchioles -- M3 -- contraction, bronchospasm

Glands -- M3 -- secretion

muscarinic receptor activation (GI)

Stomach -- M3 -- increased motility, cramps

Glands -- M1 -- Secretion

Intestine -- M3 -- contraction, diarrhea

muscarinic receptor activation (bladder)

muscarinic receptor activation (sphincters)

muscarinic receptor activation (glands)

Sweat glands -- M3 -- really sympathetic pathway

Salivation, lacrimation -- M3 -- rest of glands parasympathetic

muscarinic receptor activation (blood vessels)

Endothelium -- M3 -- dilation via NO relaxing factor (no innervation, no effects of indirect agonists)

Only pharmacologically stimulated M3 muscarinic agonists will cause this dilation

Muscarinic agonists (cholinomimetics)

Bethanechol = used to Rx ileus, urinary retention (people complaining of decreased GI/GU activity)

Methacholine = Dx bronchial hyperreactivity

Pilocarpine = Rx glaucoma (topical), xerostomia (dry mouth esp. in Sjogren's pts)

Muscarinic agonists (AChE's inhibitors)

Endrophonium = Dx myasthenia, (also to differentiate myasthenia from cholinergic crisis)

Physostigmine = tertiary amine, Rx glaucoma, antidote to atropine overdose

Neostigmine = quaternary amine, Rx ileus, urinary retention, myasthenia, reversal of NM blockers

Donepezil = CNS entry, Rx alzheimer's dz (b/c loss of ACh neurons in Meynert's nucleus

Organophosphates = irreversible, lipid soluble, Rx glaucoma (MC used as insecticides malathion, parathion and nerve gas sarin)

Toxicity of AChE inhibitors

SLUDGE or DUMBBELSS

D = diarrhea

U = urination

M = miosis

B = bradycardia

B = bronchoconstriction

E = excitation (muscle/CNS)

L = lacrimation

S = salivation

 Management of the muscarinic effects = atropine

Regeneration of AChE = pralidoxime (wedges in b/n drug and enzyme)

S = sweating

Muscarinic antagonists

Atropine = bella donna alkaloid, tertiary amine that enters CNS (antispasmodic, antisecretory, antidiarrheal, manage AChE inhibitor OD)

Effects = decreased secretions, mydriasis, hyperthermia, tachycardia, sedation, urinary retention, constipation, behavioral excitation/hallucinations

Other drug classes that are antimuscarinic

Antihistamines

TCA's

Antipsychotics (chlorpromazine, thioridazine)

Quinidine

Amantadine

Meperidine

M blocker (tropicamide)

Used for ophthalamology (topical)

M blocker (Ipratropium)

M blocker (Scopolamine)

M blocker (Benztropine, trihexyphenidyl)

M blocker (Tolterodine, Oxybutynin)

Nicotinic receptor angatonists (ganglion blocking agents)