Cholinergic drugs
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Cholinergic Drugs
Cholinergic drugs are agents that mimic, enhance, or prolong the actions of acetylcholine (ACh) at cholinergic synapses. They are broadly divided into direct-acting (act on cholinoceptors themselves) and indirect-acting (inhibit acetylcholinesterase, thereby increasing ACh at the synapse).
1. Cholinoceptors: The Targets
Two receptor families mediate ACh effects:
Muscarinic Receptors (G protein-coupled, 7-TM)
| Subtype | Location | Signaling | Key Effect |
|---|---|---|---|
| M1 | Nerves, CNS | Gq/11 → IP3, DAG | Slow EPSP in ganglia |
| M2 | Heart, nerves, smooth muscle | Gi/o → ↓cAMP, ↑K⁺ | Bradycardia, decreased contractility |
| M3 | Glands, smooth muscle, endothelium | Gq/11 → IP3, DAG | Secretion, smooth muscle contraction |
| M4 | CNS | Gi/o → ↓cAMP | CNS modulation |
| M5 | CNS | Gq/11 → IP3, DAG | CNS modulation |
Nicotinic Receptors (ligand-gated ion channels, pentameric)
| Subtype | Location | Effect |
|---|---|---|
| NM (muscle type) | Skeletal NMJ | Na⁺/K⁺ depolarization → muscle contraction |
| NN (neuronal type) | Autonomic ganglia, CNS | Na⁺/K⁺ depolarization → ganglionic transmission |
2. Direct-Acting Cholinomimetics
These drugs bind directly to muscarinic and/or nicotinic receptors.
A. Choline Esters
| Drug | Muscarinic | Nicotinic | AChE Hydrolysis | Key Features |
|---|---|---|---|---|
| Acetylcholine | +++ | +++ | Very rapid | No therapeutic use (too short-acting) |
| Methacholine | +++ | + | Slow | Bronchial challenge test |
| Carbachol | ++ | ++ | Resistant | Glaucoma, GI motility |
| Bethanechol | ++ | Minimal | Resistant | Urinary retention, GI atony |
Bethanechol is the most clinically used: given orally (10-25 mg 3-4x/day for GI disorders) or subcutaneously (5 mg for urinary retention). It is resistant to AChE hydrolysis, giving it a longer duration of action than ACh.
B. Cholinomimetic Alkaloids
| Drug | Receptor Selectivity | Key Use |
|---|---|---|
| Pilocarpine | Muscarinic (M3) | Glaucoma (topical), Sjögren syndrome (dry mouth) |
| Muscarine | Muscarinic | Toxin (mushroom poisoning) - no therapeutic use |
| Nicotine | Nicotinic | Smoking cessation |
| Cevimeline | Muscarinic (M1, M3) | Dry mouth in Sjögren syndrome |
Pilocarpine is notable: IV administration can paradoxically cause hypertension via M1 receptor activation at sympathetic ganglia, causing slow EPSP and ganglionic discharge.
3. Indirect-Acting Cholinomimetics (Anticholinesterases)
These drugs inhibit acetylcholinesterase (AChE), the enzyme that hydrolyzes ACh, causing ACh to accumulate at all cholinergic synapses.
A. Reversible (Noncovalent) Inhibitors
| Drug | Key Properties | Uses |
|---|---|---|
| Edrophonium | Quaternary amine, short-acting (minutes), renal elimination | Diagnosis of myasthenia gravis (Tensilon test) |
| Tacrine | Lipophilic, crosses BBB | Alzheimer's disease (largely obsolete due to hepatotoxicity) |
| Donepezil | Lipophilic, crosses BBB, long-acting | Alzheimer's disease (first-line) |
B. Reversible Carbamate Inhibitors
| Drug | Key Properties | Uses |
|---|---|---|
| Physostigmine | Tertiary amine, crosses BBB | Glaucoma (topical), atropine overdose reversal |
| Neostigmine | Quaternary amine, does NOT cross BBB | Myasthenia gravis, postoperative ileus, reversal of NMJ blockade |
| Pyridostigmine | Quaternary amine | Myasthenia gravis (longer-acting than neostigmine) |
| Rivastigmine | Lipophilic, crosses BBB | Alzheimer's disease, Parkinson's dementia |
| Galantamine | Crosses BBB; also allosteric nicotinic modulator | Alzheimer's disease |
Carbamates form a covalent but reversible carbamylated intermediate at the AChE active site (hydrolysis in minutes to hours).
C. Irreversible Organophosphate Inhibitors
These form covalent phosphorylated complexes with AChE that are extremely long-lasting ("aging" locks in the bond over time).
| Drug | Use/Context |
|---|---|
| Echothiophate | Glaucoma (topical) |
| Malathion, Parathion | Agricultural insecticides |
| Sarin, VX, Tabun | Chemical warfare nerve agents |
| Soman | Nerve agent with fastest "aging" |
Treatment of organophosphate poisoning:
- Atropine (0.5-5 mg IV) - blocks muscarinic excess (dyspnea, lacrimation, bradycardia, secretions). Titrate until signs of muscarinic excess resolve.
- Pralidoxime (2-PAM) - reactivates AChE if given before "aging." Initial 1-2% solution IV over 15-30 min, then 1% infusion (200-500 mg/h) until fasciculations cease. Does not enter CNS.
- Oxygen, airway support, decontamination (remove clothing, wash skin).
4. Organ System Effects of Cholinomimetics (DUMBELS/SLUDGE)
| System | Effect |
|---|---|
| Eye | Miosis, accommodation spasm (ciliary contraction → near vision), decreased intraocular pressure |
| Heart | Bradycardia (M2), decreased AV conduction, decreased force (atria) |
| Blood vessels | Vasodilation via endothelial NO release (M3); direct contraction of denervated vessels |
| Lungs | Bronchoconstriction, increased secretions (M3) |
| GI tract | Increased motility, secretions, defecation (M3) |
| Urinary bladder | Detrusor contraction, sphincter relaxation → urination (M3) |
| Glands | Increased salivation, lacrimation, sweating |
| Skeletal muscle | Fasciculations, weakness (NM at NMJ) |
| CNS | Anxiety, seizures (at toxic doses) |
The classic mnemonics:
- SLUDGE: Salivation, Lacrimation, Urination, Defecation, GI distress, Emesis
- DUMBELS: Diarrhea/Diaphoresis, Urination, Miosis, Bradycardia/Bronchospasm, Emesis, Lacrimation, Salivation
5. Clinical Applications Summary
| Indication | Drug of Choice |
|---|---|
| Myasthenia gravis (chronic) | Pyridostigmine |
| Myasthenia gravis (diagnosis) | Edrophonium |
| Alzheimer's disease | Donepezil, rivastigmine, galantamine |
| Glaucoma (acute angle-closure) | Pilocarpine + topical β-blocker |
| Urinary retention / postoperative ileus | Bethanechol, neostigmine |
| Acute colonic pseudo-obstruction (Ogilvie syndrome) | Neostigmine IV 2 mg |
| Dry mouth (Sjögren, radiation) | Pilocarpine, cevimeline |
| Reversal of NMJ blockade (post-anesthesia) | Neostigmine + glycopyrrolate (to block muscarinic side effects) |
| Organophosphate poisoning | Atropine + pralidoxime (2-PAM) |
| Atropine/anticholinergic overdose | Physostigmine |
6. Indirect Modulators of ACh Release
- Amifampridine (3,4-DAP) and 4-aminopyridine (dalfampridine): block K⁺ channels on nerve terminals → prolonged depolarization → increased ACh release. Used in Lambert-Eaton myasthenic syndrome (amifampridine) and multiple sclerosis walking impairment (dalfampridine).
Sources:
- Katzung's Basic & Clinical Pharmacology, 16th Ed. - Chapters 7 & 8 (Cholinomimetics)
- Goodman & Gilman's Pharmacological Basis of Therapeutics, Chapter 12 (Anticholinesterase Inhibitors)
- Katzung's Basic & Clinical Pharmacology, 16th Ed., Chapter 62 (GI pharmacology)
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