Cholinergic Agonists (8-21-15)

Question 1

Nicotine

Answer 1

*Indication: Withdrawal symptoms of smoking cessation
*MOA: Activation of neuronal nicotinic receptors
Elimination: Urine
1/2 life: 1-2 hrs

Question 2

Acetylcholine

Answer 2

• Indication: NOT USED CLINICALLY
• MOA: Nicotinic and muscarinic agonist
• Elimination: AchE
• 1/2 life: ~150 msec

Quaternary Nitrogen Analog

Question 3

Methacholine

Answer 3

*Indication: Diagnosis of subclinical asthma, or test for severity of asthma
*MOA: Muscarinic agonist
Elimination: AchE
1/2 life: relatively short
*Contraindications: Pts given B blockers (antidote to overdose is B-agonist)
*Toxicity/side-effects: bronchiolar constriction

Quaternary Nitrogen Analog

Question 4

Carbachol

Answer 4

*Indication: Miotic agent in ocular surgery, intraocular injection reduces pressure after surgery
*MOA: Muscarinic and nicotinic agonist
Elimination: not degraded by AchE (increases 1/2 life)
1/2 life: duration 4-8hrs topically or 24hrs intraocularly
*Contraindications: ???
*Toxicity/side-effects: bronchoconstriction, decreased cardiac conduction (excessive N and M receptor activation)

Quaternary Nitrogen Analog

Question 5

Bethanechol

Answer 5

*Indication: Post-op and postpartum non-obstructive urinary retention, neurogenic bladder atony
*MOA: Muscarinic agonist
Elimination: not degraded by AchE or PChE (increases 1/2 life)
1/2 life: ~1 hr
*Contraindications: asthma, peptic ulcer, bradycardia
*Toxicity/side-effects: ???

Quaternary Nitrogen Analog

Question 6

Pilocarpine

Answer 6

*Indication: Dry mouth due to head & neck radiotherapy or Sjogren’s Syndrome; Open and Angle-closure Glaucoma
*MOA: Muscarinic agonist
Elimination: not degraded by AchE (inc 1/2 life)
*1/2 life: ~1 hr
*Contraindications: Administer with care to pts on B blockers due to exacerbation of conduction slowing
*Toxicity/side-effects: Excess muscarinic activation slows AV conduction, hypotension (dec BP), salivation, bronchoconstrict

*Crosses BBB therefore many CNS effects
Sjogrens=autoimmune attack on glands that decreases secretions

Naturally Occuring Tertiary Amine

Question 7

Neostigmine

Answer 7

*Indication: Myasthenia gravis, reverse neuromuscular block
*MOA: REVERSIBLE AchE inhibitor
Elimination: AchE and plasma esterases
1/2 life: 50-90 mins
*Contraindications: intestinal obstruction
*Toxicity/side-effects: nicotinic & muscarinic excess

• Does NOT cross BBB
• Note that neostigmine and other indirects have effect on NM endplate that M-Directs do not

Reversible Cholinesterase Inhibitor (Indirect Cholinergic Agonist)

Question 8

Edrophonium

Answer 8

*Indication: Diagnosis of MG or to distinguish btwn progression of myasthenic weakness and a cholinergic crisis (excess Ach) due to cholinesterase toxicity
*MOA: REVERSIBLE AchE inhibitor
Elimination: Bile
*1/2 life: ~10 mins (rapid onset, very SHORT duration of action (minutes))
*Contraindications: ???
*Toxicity/side-effects: bradycardia

Note: excess cholinesterase inhibition can cause neuromuscular block resulting in muscle weakness which can mimic and be mistaken for MG progression

Reversible Cholinesterase Inhibitor (Indirect Cholinergic Agonist)

Question 9

Physostigmine

Answer 9

*Indication: Delirium from anticholinergic drugs; glaucoma
*MOA: REVERSIBLE AchE inhibitor
Elimination: AchE
1/2 life: 45-60 mins
*Contraindications: asthma, cardiac insufficiency, intestinal obstruction
*Toxicity/side-effects: convulsions, respiratory & CV depression (excess M and N receptors)

*Crosses BBB, inactivated by plasma ChE but slow (long duration)

Reversible Cholinesterase Inhibitor (Indirect Cholinergic Agonist)

Question 10

Donepezil

Answer 10

*Indication: Alzheimer’s diagnosis
*MOA: Reversible AchE inhibitor IN THE CNS
Elimination: Liver
1/2 life: ~70 hrs
*Contraindications: ???
*Toxicity/side-effects: ???

Reversible Cholinesterase Inhibitor (Indirect Cholinergic Agonist)

Question 11

Echothiophate

Answer 11

• Indication: Long-term miosis to treat open angle glaucoma
• MOA: IRREVERSIBLE AchE inhibitor
• Elimination: unknown
• 1/2 life: 1/2 life is about a week b/c it is IRREVERSIBLE (time to regenerate)
• Contraindications: ???
• Toxicity/side-effects: ???

Constricts pupil and increase outflow of aqueous humor to decrease IOP; administered topically to reduce systemic effects

Irreversible Cholinesterase Inhibitos (Indirect Cholinergic Agonist)

Question 12

Organophosphates

Answer 12

• Indication: insecticide, toxic nerve gas
• MOA: IRREVERSIBLE AchE inhibitor; phosphorylate esteratic site on AChE molecule which becomes a stable complex with time
• Elimination: recovery depends on synthesis of new AChE
• 1/2 life:
• Contraindications: ALWAYS (not used clinically)
• Toxicity/side-effects: DUMBBELLS (severe toxicity)

“Cholinergic crisis”; treatment with ventilation (effects on Nm), suction of oral secretion, atropine, 2-Pralidoxime Chloride (2-PAM) (reactivates P-AChE)

DUMBBELLS: toxicity of organophosphates	
D	diarrhea
U	urination
M	miosis
B	bradycardia
B	bronchorrhea
E	emesis
L	lacrimation
L	lethargy
S	salivation