1. quaternary amine: + charge
2. ester bond for degradation

1. All autonomic ganglia and adrenal medulla
2. parasympathetic POSTganglionic
3. NMJ of somatic and skeletal muscle

most sympathetic POSTganglionic jxns.

Exception: sweat glands in palms of hands are adrenergic; thermorgulatory sweat glands are cholinergic

blocked by botulinum toxin

facilitated to excess by alpha-latrotoxin (black widow venom)

NMJ

Autonomic Ganglia

(NNAg)

Smooth muscle

Heart muscle

Glands

1. mechanism of action: bind 2 ACh to alpha subunits
2. stimulation: all or none switch
3. Can desensitize or not repolarize
4. Ganglionic(N_N N_G) - blocked by hexamethonium
5. Neuromuscular (N_M) - blocked by d-tubocurarine

1. Mechanism of action: M₁, M₃, M₅ - IP3
2. M₂ M₄ - decreased cAMP
3. Slower, graded response

Parasympathomimetic agents

1. dec HR
2. dec arterial tone (promote release of NO)
3. dec BP
4. dec pupil size
5. inc salivation
6. inc lacrimation
7. inc bronchial tone
8. inc intestinal motility
9. inc GI secretions
10. inc urinary bladder body tone
11. dec urinary bladder sphincter tone

Most serious are hypotension, bradycardia, bronchial constriction and exacerbation of ulcers

Most common are SLUDS: salivation, lacrimation, urination, defecation, and sweating

• not used as a drug
• not selective
• brief duration fo action

• b-methyl substitute so muscarinic agonist
• longer duration than ACh
• used diagnostically for pyloric sphincter tests

• Muscarinic & Nicotinic agonist
• long duration of action (2-3 hrs) due to carbamate substitution
• topically for glaucoma - opening canals of Schlemm to facilitate outflow of aqueous humor

• has b-methyl and carbamate groups
• 2-3 hr duration and selective for muscarinic
• oral/sc - mild CV effects, works on GI, bladder
• IV/IM - no specificity, ↑ toxicity

• primarily muscarinic agonist
• 2-3 hr duration
• topically for glaucoma
• SE: sweat glands, CV, CNS effects

• not used as a drug except in gum/patches
• mild CNS stimulant, ↑ respiration and vomiting
• Adrenal medulla stimulant: tachycardia, ↑BP, GI motility
•  SE: high doses cause persistent depolarization --> tremors

Nicotinic agonist

used in smoking cessation treatment

• therapeutic in myasthenia gravis, alzheimers

• used as insectisides and chemical warfare

1. ACh binds ammonium in active site
2. hydrolyzes the ester freeing choline but enzyme is now acetylated
3. acetate residue is rapidly hydrolyzed

• most have carbamyl esters
• carbamylated site persits longer than choline would

• penetrates into CNS
• antidote against atropine poisoning
• topically for acute glaucoma
• AChEI

• Reversible AChEI
• does NOT cross BBB
• stimulate GI/urinary, and improves NMJ fxn
• tx: nonobstructive GI/Urinary atony and myasthenia gravis
• SE: diarrhea, salivation, bronchial secretion, sweating

• reversible AChE inhibitor
• short duration of action
• used in functional tests

• organophosphates

• leave behind alkylphosphorylated site that cant be hydrolyzed

• aging - alkylphophate loses alkyl group and is even more tightly bound

• extremely lipid soluble - readily absorbed and CNS effects

• Irreversible AChEI
• topically for glaucoma
• 100 hr duration
• does not penetrate skin

• military "nerve gas"
• crosses BBB, causes death

• AChEI
• insecticide
• much less toxic to animals than to insects

• life threatening
• CNS effects leading to respiratory failure
• involuntary twitching of muscles and paralysis
• Tx: atropine

• cholinesterase reactivator - treats organophoshpate toxicity
• It is useless if aging has already occured
• only works peripherally