Autonomics - Cholinergic System

Where is acetylcholine used?

• Somatic nervous system (NMJ)

• Autonomic pregang and parasympathetic postgang

• CNS

Acetylcholine synthesis

• Acetyl CoA (mitochondria)

• Choline (dietary)

• Catalyzed by choline acetyl transferase (ChAt)

Target for drugs

Acetylcholinesterase

Breaks down ACh

Target for drugs

Cholinergic receptors

Nicotinic: Excitation

Muscarinic: Excitation or inhibition

Nicotinic AChR

Mediate fast synaptic transmission

5 polypeptide subunits

Vary in subunit structure, agonist sensitivity, distribution

Muscarinic AChR

Slower synaptic transmission via intracellular signaling cascade

5 subtypes, G protein coupled

Cholinergic agonists (Parasympathomimetics)

Direct acting: Act like ACh

Indirect acting: Inhibit AChE, more ACh available

Cholinergic agonist effects SLUD

Salivation

Lacrimation

Urination

Defecation

Direct acting cholinergic agonists

Esters of choline: Structurally related to ACh, “-chol”

Alkaloids: Similar shape, not metabolized by cholinesterase

Effects are mostly muscarinic (SLUD)

Bethanechol (Urecholine)

Stimulates bladder or GI musc

Short duration of action

Carbachol (Miostat)

Produces miosis during eye surgery

Decrease IOP after surgery

Pilocarpine (Salagen)

Causes miosis and Tx for glaucoma

Greater affinity for muscarinic than nicotinic

Indirect acting cholinergic agonists

Anticholinesterases

Inhibit AChE → Increase ACh

Neostigmine (Bloxiverz) and Pyridostimine (Mestinon)

Reverse effects of nicotinic antagonists like curare

Tx for myasthenia gravis

Reversible

Alzheimer’s

ACh is important for learning and memory, low levels

Aricept Tx to block AChE

Reversible inhibitors (Anticholinesterases)

Compete with ACh for active site on AChE

“-stigmine” and “-nium”

Irreversible inhibitors (Anticholinesterases)

Phosphorylate AChE and inactivate it

Toxicity of cholinergic stimulants DUMBBELS

Diarrhea

Urination

Miosis

Bradycardia

Bronchocontrictions

Excitation (CNS → Paralysis, ataxia, seizures)

Lacrimation

Salivation, sweating

Cholinergic toxidrome muscarinic

SLUDGE

Salivation, Lacrimation, Urination, Defecation, GI cramping, Emesis

Cholinergic toxidrome nicotinic

MTWTF

Muscle cramps, Tachycardia, Weakness, Twitching, Fasiculations

Cholinergic antagonists

Parasympatholytics

Antagonized the effects of ACh by inhibiting receptors or blockign release

Cholinergic antagonists muscarinic blockers

Relax smooth muscle, decrease gland secretion, increase HR

Cholinergic antagonists nicotinic blockers

Relax skeletal musc during surgery

Muscarinic antagonist effects

• Dry mouth

• Mydriasis

• Increase HR

• Bronchodilation

• Reduced GI motility

• Urinary retension

• Drowsiness

Muscarinic antagonist uses

• Dilate pupils

• COPD Tx

• Prevent salivation during surgery

• Antinausea, antispamodics

• Atropine counteracts toxic muscarinic effects from AChE inhibitors

Can you target ganglion nicotinic receptors and block them?

No, too many side effects

Will block ALL autonomics

Neuromuscular blockeres

Skeletal muscle relaxation

Block ACh by competitively interacting with nicotinic receptors are NMJ and ganglia

Depolarizing neuromuscular blockers

Bind receptor and open ion channel → Depolarization of the end plate

Succinylcholine (Quelecin)

Non-depolarizing neuromuscular blockers

Bind receptor but don’t open channel

Competitive antagonist at nicotinic receptors

Pancuronium and curare

Why is a muscarinic antagonist co-administered with AChE inhibitors when reversing neuromuscular blockers?

More ACh in cleft that can start binding to muscarinic receptors and cause more muscarinic signaling

Prevent SLUD toxicity

Botulinum toxin (Botox)

Block the release of ACh at NMJ

Tx for muscle spasms