CHOLINERGIC DRUGS — STUDY NOTES

 CHOLINERGIC DRUGS-STUDY NOTES

Cholinergic drugs act by enhancing acetylcholine (ACh) activity at muscarinic and/or nicotinic receptors.
They are divided into:

1. Direct-acting agonists – bind directly to cholinergic receptors (mimic ACh)

2. Indirect-acting agonists (AChE inhibitors) – inhibit acetylcholinesterase, increasing ACh concentration at synapses

DIRECT-ACTING CHOLINERGIC AGONISTS

1. Acetylcholine

• MOA: Non-selective agonist at both muscarinic and nicotinic receptors

• Effect: Decreases HR, BP (via M2), increases GI motility, miosis

• Clinical use: Rarely used (rapid hydrolysis by AChE)

Bethanechol

• MOA: Muscarinic (M3) agonist — ↑ bladder detrusor tone & GI motility

• Use: Post-op or postpartum urinary retention, neurogenic atony of bladder

• Mnemonic: “Bethany, call (Bethanechol) your bladder to contract.”

• Adverse: Diarrhea, sweating, salivation, bradycardia

3. Carbachol

• MOA: Muscarinic & nicotinic agonist (resistant to AChE)

• Use: Glaucoma — causes miosis & ↓ intraocular pressure

• Adverse: If systemically absorbed → bradycardia, bronchospasm

4. Methacholine

• MOA: Muscarinic agonist (M2, M3)

• Use: Methacholine challenge test to diagnose bronchial hyperreactivity (asthma)

• Adverse: Bronchoconstriction, hypotension, bradycardia

5. Pilocarpine

• MOA: Muscarinic (M3) agonist — ↑ glandular secretion, miosis

• Use: Open-angle and acute angle-closure glaucoma; xerostomia (dry mouth) in Sjögren’s

• Mnemonic: “Pile on the sweat, tears, and saliva.”

• Adverse: Diaphoresis, flushing, bronchospasm, bradycardia

6. Cevimeline

• MOA: Selective M3 receptor agonist

• Use: Xerostomia in Sjögren’s syndrome

• Note: Longer duration than pilocarpine

7. Muscarine (toxin)

• MOA: Natural M receptor agonist found in mushrooms (Inocybe, Clitocybe)

• Toxicity: DUMBBELLS symptoms (see below)

Toxicity of Direct Cholinergic Agonists

Mnemonic: DUMBBELLS

• Diarrhea

• Urination

• Miosis

• Bradycardia

• Bronchoconstriction

• Emesis (vomiting)

• Lacrimation

• Lethargy

• Salivation / Sweating

INDIRECT-ACTING CHOLINERGIC AGONISTS (AChE INHIBITORS)

🩸 Reversible Inhibitors

1. Edrophonium

• MOA: Short-acting (5–10 min) AChE inhibitor

• Use: Dx of myasthenia gravis (Tensilon test); historically used to distinguish MG crisis vs cholinergic crisis

• Adverse: Bradycardia, bronchospasm

2. Neostigmine

• MOA: AChE inhibitor; also directly stimulates nicotinic receptors at NMJ

• Use:

  • Reversal of non-depolarizing NMJ blockade (post-surgery)

  • Tx of myasthenia gravis

  • Urinary retention, paralytic ileus

• Does not cross BBB

• Adverse: Muscarinic effects (give with atropine or glycopyrrolate)

3. Pyridostigmine

• MOA: Reversible AChE inhibitor (longer-acting)

• Use: Maintenance therapy for myasthenia gravis

• Note: “PyRIDostigmine gets RID of myasthenia gravis.”

• Adverse: Cholinergic excess if overdosed

4. Physostigmine

• MOA: Reversible AChE inhibitor; crosses BBB

• Use: Anticholinergic toxicity (e.g., atropine overdose)

• Mnemonic: “PHYSostigmine fixes atropine overdose.”

• Adverse: Seizures, bradycardia, bronchospasm

5. Donepezil, Rivastigmine, Galantamine

• MOA: Centrally acting AChE inhibitors

• Use: Alzheimer’s disease, dementia

• Adverse: GI upset, dizziness, bradycardia

6. Ambenonium

• MOA: Reversible AChE inhibitor

• Use: Myasthenia gravis (alternative to neostigmine)

Irreversible AChE Inhibitors (Organophosphates)

1. Echothiophate

• MOA: Irreversible AChE inhibitor

• Use: Long-term management of glaucoma (rarely used)

• Toxicity: Cholinergic crisis, paralysis

2. Malathion, Parathion

• MOA: Irreversible AChE inhibitors (insecticides)

• Toxicity: Severe cholinergic excess → DUMBBELLS + respiratory failure

• Tx: Atropine (blocks muscarinic receptors) + Pralidoxime (2-PAM) (reactivates AChE if given early)

3. Sarin, Soman, Tabun

• MOA: Nerve gases (organophosphates)

• Effect: Fatal respiratory paralysis due to continuous ACh stimulation

• Antidote: Atropine + Pralidoxime + Benzodiazepines (for seizures)

SUMMARY TABLE

Category	Drug Examples	MOA	Main Uses
Direct-Acting (Muscarinic)	Bethanechol, Pilocarpine, Methacholine, Carbachol, Cevimeline	Stimulate M receptors	Urinary retention, glaucoma, xerostomia
Direct-Acting (Nicotinic)	Nicotine, Varenicline	Stimulate N receptors	Smoking cessation
Reversible AChE inhibitors	Neostigmine, Pyridostigmine, Physostigmine, Edrophonium, Donepezil	Inhibit AChE to ↑ ACh	MG, Alzheimer’s, reversal of NMJ block
Irreversible AChE inhibitors	Echothiophate, Organophosphates	Covalent inhibition of AChE	Glaucoma (rare), toxins/pesticides
Antidote	Atropine + Pralidoxime	Blocks M receptors, regenerates AChE	Organophosphate poisoning

CHOLINERGIC CRISIS

• Cause: Excess ACh (from overdose of AChE inhibitors)

• S/S: Severe DUMBBELLS + muscle weakness → respiratory paralysis

• Tx: Atropine (muscarinic block) + mechanical ventilation