• Neuronal type, ganglion receptor
• Pentamer of (9) α and (3) β subunits
• Located in postganglionic cell body and dendrites, some presynaptic Ach terminals
• Binding --> Open Na, K channel --> depolarization

• Muscle type, end plate receptor
• Found in skeletal muscle end plates
• Binding --> opening of Na, K channels --> depolarization

Located in nerves: CNS, sympathetic postganglionic, some presynaptic

Ligand binding --> formation of IP3 and DAG --> increased intracellular calcium

Located in myocardium, smooth muscle, some presynaptic sites

Acts through Gi

Ligand binding --> opening of K+ channels + inhibition of adenylyl cyclase --> decreased cAMP

Located in exocrine glands, smooth muscle, and vessels with smooth muscle

Act through Gq

Binding --> formation of IP3 and DAG --> increased intracellular calcium

Choline esters - acetylcholine

Cholinomimetic alkaloids - muscarine, pilocarpine

Muscarinic receptor agonist

Permanently charged quarternary ammonium --> poorly absorbed, can't get into CNS

Hydrolyzed by acetylcholinesterase

Binding to nicotinic receptors inhibited by β group --> selective

Not used therapeutically

Muscarinic receptor agonist - choline ester

Used to diagnose asthma

Carbamic acid derivative - resistant to Achesterase hydrolysis

Muscarinic receptor agonist - choline ester

Used topically as miotic agent

Glaucoma treatment

Carbamic acid derivative - resistant to Achesterase hydrolysis

Muscarinic receptor agonist - choline ester

Used to promote GI and urinary tract motility (must be due to non-obstructive cause)

Usually used post-operative or post-partum

Cholinomimetic alkaloids

Quaternary amine --> poorly absorbed

Not used frequently

Muscarine receptor agonist -

Cholinomimetic alkaloid

Tertiary amine --> not hydrolyzed by Achesterase

Well absorbed, penetrates CNS

Excreted by kidney

Used as treatment for Sjogren's (sialogogue), miotic agent

Cardiac slowing, decrease in CO, vasodilation --> fall in arterial pressure

Increase in GI peristalsis, contraction of bladder and bronchial smooth muscle

Stimulation of sweat, lacrimation, salivation, bronchial secretion

Contraction of ciliary muscle (lowers intraocular pressure, good for acute glaucoma)

Nausea and vomiting

Salivation

Sweating

Cutaneous vasodilation

Bronchial constriction

Treat with atropine

Some poisonous mushrooms contain muscarine, effects in 15-30 mins

Little selectivity

Same basic structure as Ach, with aromatic in place of acetyl group

Competitive muscarinic antagonist

Tertiary amine

Found in belladonna/nightshade

Competitive muscarinic antagonist

Similar structure to atropine

Well absorbed from gut, conjunctival membrane

Significant CNS absorptio --> sedation

Formulated for transdermal absorption (motion sickness)

Ameliorate nausea from chemotherapy

Duration of effect: 3 to 7 days

Dry as a bone, blind as a bat, red as a beet, mad as a hatter

Inhibition of secretions - salivary, bronchial, lacrimal, sweat

Tachycardia - inhibits parasympathetic tone

Mydriasis - dilation of pupil

Cycloplegia - paralysis of accomodation

Inhibition of GI motility

Relaxation of bronchial, biliary, urinary smooth muscle

Excitatory effects on CNS

Duration of effects: 7 to 10 days

Induce myadriasis for opthalmologic exam

Reverse sinus bradycardia

Inhibit excessive salivation/mucus 

Prevent vagal reflex

Counteract effects of muscarine poisoning

Competitive muscarinic receptor antagonist

Tertiary amine

Adjunct in therapy of Parkinsons

Used to treat acute dystonia caused by antipsych meds

Competitive antagonist of muscarinic receptor

Quaternary amine --> low CNS penetration

Used to decrease oral secretion

Decrease GI spasm

Treat peptic ulcer

Prevent bradycardia

Competitive antagonist of muscarinic receptor

M3 specificity

Tertiary amine

Relief of bladder spasm of urological surgery

Competitive antagonist of muscarinic receptor

M3 selectivity

Tertiary amine

Similar to darifenacin, xerostomia

Used for urinary incontinence

Competitive inhibitor of muscarinic receptor

Synthetic analog of atropine

Little effect on smooth muscle/CNS

Used in peptic ulcer disease

Cardiovascular - atropine for bradycardia

Opthalmic - tropicamide - dilate a pupil

Neuro - scopolamine for motion sickness, benzotropine for parkinsonism

Respiratory - iaptropium for COPD, asthma

Nicotine

Succinylcholine

Nicotinic receptor agonist

Liquid .: easily absorbed across all surfaces

Acute nicotine toxicity - 40 mg

Ingestion -> vomiting

CNS stimulation: 

seizures, coma, respiratory paralysis, hypertension, arrhythmia

Ganglion blocking drugs

Neuromuscular blocking drugs

Type of nicotinic receptor antagonist

Used to be used for HTN, too much toxicity

Toxicity: cycloplegia, orthostatic hypotension, constipation, urinary retention, sexual dys.

Ganglion blocking drug, nicotinic receptor antagonist

Used occasionally in treatment of hypertensive emergencies or dissecting aortic aneurysm

Neuromuscular Blocking Drugs

Type of nicotinic receptor antagonist

Facilitate surgery, esp intraabd or intrathoracic

Used to control ventilation

Neuromuscular blocking drugs

Nicotinic antagonists

Nondepolarizing neuromuscular blocking drugs

Type of nicotinic receptor antagonist

Block Ach from binding to receptor

Prevent depolarization

Block channel in its closed position

Nicotinic antagonist

Non depolarizing neuromuscular blocking drug

Isoquinoline derivative

Nondepolarizing neuromuscular blocking drug

Nicotinic antagonist

Steroid derivative

More nicotinic agonists → Increased receptor stimulation → Channel stuck open → Continuous depolarization → Inactivation of voltage gated sodium channels → Paralysis

Can occur with anything that overwhelms the receptor

Examples: acetylcholine, succinylcholine

1-2 quaternary nitrogens → poorly lipid-soluble

Limit CNS entry

Highly polar

Inactive orally - must be administered parenterally

Volume distribution only slightly larger than plasma volume

Isoquinoline derivatives - tubocurarine

Steroid derivatives - pancuronium

Two molecules of Ach linked end to end

Slowly hydrolyzed by acetylcholinesterase

Quickly eliminated by plasma cholinesterase

Short duration of action (5 to 10 mins)

Bind to and inhibit acetylcholinesterase

Increase level of acetylcholine in synaptic cleft

Activate cholinergic receptors without directly binding to them

Simple alcohol - edrophonium

Carbamic acid ester - neostigmine, physostigmine

Organophosphates

Simple alcohol - cholinesterase inhibitor

Quaternary ammonium

Reversible inhibitor of AchE

Bnds reversibly via electrostatic interactions and hydrogen bonds

Short duration of action - enzyme inhibitor complex persists for 2 to 10 minutes (allows for tight control)

Diagnostic test for patients with muscle weakness

Assesses adequacy of treatment for myasthenia gravis

Absorption poor due to permanent charge

Negligible CNS distribution

Tacrine

Donepezil

Rivastigmine

Galantamine

Anticholinesterase used for Alzheimer's

Improves cognitive function

Efficacy modest

Significant hepatic toxicity