Cholinergic muscle stimulants

Overview
Cholinergic muscle stimulants are agents that enhance neuromuscular transmission by increasing the availability or action of acetylcholine (ACh) at the neuromuscular junction. They act primarily by inhibiting acetylcholinesterase, the enzyme that breaks down ACh, thereby increasing ACh concentration and prolonging its effect on nicotinic receptors at the skeletal muscle end plate. These drugs are mainly used in the management of myasthenia gravis, for the reversal of non-depolarizing neuromuscular blockade after surgery, and occasionally in certain gastrointestinal or urinary tract motility disorders.

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Mechanism of Action

• Inhibit acetylcholinesterase at the neuromuscular junction, preventing ACh breakdown.

• The elevated ACh concentration increases stimulation of nicotinic receptors on skeletal muscle, improving muscle contraction strength.

• In the parasympathetic nervous system, the same mechanism enhances muscarinic receptor stimulation, causing side effects such as increased secretions, bradycardia, and gastrointestinal hypermotility.

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Therapeutic Uses

1. Myasthenia Gravis

   • Chronic therapy to improve muscle strength

   • Agents: Pyridostigmine, Neostigmine

2. Reversal of Non-Depolarizing Neuromuscular Blockade (e.g., rocuronium, vecuronium) after anesthesia

   • Agent: Neostigmine (given with an antimuscarinic such as atropine or glycopyrrolate to counteract muscarinic side effects)

3. Postoperative or Neurogenic Ileus, Urinary Retention

   • Rarely used now for these indications; Neostigmine sometimes used under close monitoring

4. Diagnostic Use

   • Edrophonium (short-acting) historically used in the Tensilon test to diagnose myasthenia gravis or differentiate myasthenic from cholinergic crisis (now largely replaced by antibody testing and other methods)

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Common Agents and Properties

Drug	Onset	Duration	Main Uses
Pyridostigmine	30–60 min (oral)	3–6 h	Myasthenia gravis maintenance
Neostigmine	1–20 min (IV), 30 min (oral)	2–4 h	Myasthenia gravis, reversal of non-depolarizing block
Edrophonium	30–60 sec (IV)	5–15 min	Diagnostic (historical)
Ambenonium	1–2 h	4–8 h	Myasthenia gravis (less commonly used)

Contraindications

• Mechanical obstruction of the gastrointestinal or urinary tract

• Peritonitis

• Known hypersensitivity to the agent

• Caution in asthma, COPD, bradycardia, hypotension, peptic ulcer disease, or seizure disorders

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Precautions

• Dose must be individualized to avoid cholinergic crisis (excess ACh leading to muscle weakness, respiratory distress, and parasympathetic overstimulation)

• When used perioperatively, always combine with an antimuscarinic to prevent severe bradycardia and secretions

• Regular monitoring in myasthenia gravis to adjust for disease fluctuations

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Adverse Effects (mostly due to muscarinic stimulation)

• Common: Nausea, vomiting, diarrhea, abdominal cramps, increased salivation, sweating, miosis, urinary urgency

• Cardiovascular: Bradycardia, hypotension

• Respiratory: Bronchospasm, increased bronchial secretions

• Neuromuscular: Muscle cramps, fasciculations, weakness (with excessive dosing)

• Serious: Cholinergic crisis with risk of respiratory failure

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Drug Interactions

• Anticholinergic drugs (e.g., atropine, scopolamine, TCAs) antagonize effects

• Other cholinergic drugs (bethanechol, pilocarpine) increase risk of cholinergic toxicity

• Neuromuscular blockers: May reduce the effect of non-depolarizing agents (used intentionally in reversal) but prolong depolarizing block with succinylcholine