Neostigmine and Pyridostigmine

Mechanism

Mechanism of Action

Reversible inhibitors of the enzyme acetylcholinesterase (AChE) through the formation of a slowly dissociating carbamyl-enzyme complex. By covalently binding to the ester active site of AChE, they prevent the hydrolysis of endogenous acetylcholine in the synaptic cleft and at the neuromuscular junction. This causes the accumulation and prolongation of the action of the neurotransmitter at the nicotinic and muscarinic receptors. At the level of the motor plate, they enhance neuromuscular transmission, facilitating voluntary muscle contraction in myasthenia gravis and reversing non-depolarizing competitive neuromuscular blockade.

Neostigmine

• Structure: Polar quaternary ammonium; It does not cross the blood-brain barrier.
• Indications: Reversal of non-depolarizing neuromuscular blockade; postoperative paralytic ileus; Ogilvie syndrome (acute colonic pseudo-obstruction).
• Pharmacokinetics: Short half-life (1 to 1.5 hours). Rapid onset of action via IV route (1-3 minutes).

Pyridostigmine

• Structure: Quaternary ammonium; without significant central penetration.
• Indications: Chronic symptomatic treatment of myasthenia gravis; prophylaxis against exposure to organophosphate nerve gases (military use).
• Pharmacokinetics: Longer elimination half-life (3 to 4 hours); Duration of oral effect of 4-6 hours.

Pharmacokinetics

Key Pharmacokinetics

• Routes: Neostigmine: Intravenous, intramuscular, subcutaneous. Pyridostigmine: Oral (conventional and delayed-release tablets), intravenous (exceptional).
• Oral absorption: Poor for both compounds (10-20%) due to their ionized nature in the digestive tract.
• Metabolism: Hepatic by hydrolysis of the ester linkage and conjugation of minor active metabolites.
• Excretion: Renal dominant, with elimination of 50-70% of the unchanged drug in urine.

Indicators and dose

Approved and Off-label Indications

Approved: Myasthenia gravis (oral symptomatic treatment of choice for pyridostigmine); postoperative reversal of nondepolarizing muscle relaxants (IV neostigmine); non-obstructive paralytic ileus.

Off-label: Moderate postural orthostatic tachycardia syndrome (POTS); severe chronic constipation of idiopathic origin.

Dosage and Adjustments

Reversal of Neuromuscular Blockade (Neostigmine IV): 0.03 to 0.07 mg/kg IV administered slowly (maximum 5 mg per dose), *always* administering atropine previously or concomitantly (0.01-0.02 mg/kg IV) to prevent severe bradycardia.

Myasthenia Gravis (Oral Pyridostigmine): Start with 30 to 60 mg orally every 4-6 hours, adjusting individually according to muscle strength. The maintenance dose ranges from 120 to 600 mg/day in divided doses.

Renal adjustment: Reduce the initial dose by 25-50% in moderate renal failure (eGFR < 50 mL/min); imminent accumulation of unchanged drug.

Hepatic adjustment: No specific systematic reduction recommendations have been established.

Security

Contraindications

Absolute: Mechanical obstruction of the urinary or gastrointestinal tracts, active bacterial peritonitis.

Relative: Bronchial asthma or reactive COPD, severe bradyarrhythmias (AV node disease or AV block), Parkinson's disease.

Adverse Effects (ADR)

Common: Hyperperistalsis, diffuse intestinal cramps, motor diarrhea, profuse hypersalivation, excessive lacrimation, fixed pupillary miosis, peripheral muscle fasciculations.

Serious: Generalized systemic cholinergic crisis with paralysis of respiratory muscles, severe bronchospasm with cyanosis, complete heart block with asystole, extreme bradycardia.

Interactions

Ester local anesthetics and halogenated hydrocarbons: May prolong the blockade by mutual inhibition of plasma cholinesterases.

Antimuscarinic (Atropine): Frequently used prophylactically together to mitigate undesirable muscarinic cholinergic effects (salorrhea, bradycardia) without altering the nicotinic motor reversal effect of neostigmine.

Pregnancy and Breastfeeding

FDA Classification: Category C. Due to their polar quaternary ionized structure, they do not cross the placental barrier significantly, being considered safe in controlled therapeutic doses for pregnant women with myasthenia. They are not excreted appreciably in breast milk.

Cholinergic crisis vs myasthenic crisis

Extreme generalized muscle weakness in a patient diagnosed with myasthenia gravis may be due to a dose deficit (Myasthenic Crisis) or an overdose of cholinesterase inhibitors that induces persistent depolarization at the nicotinic receptor (Cholinergic Crisis). The classic differential diagnosis is made using the Edrophonium test (tensilon test, ultra-short-acting inhibitor). If muscle strength improves noticeably after the injection, it is a myasthenic crisis; If it worsens or is associated with fasciculations and diffuse hypersalivation, it is an imminent cholinergic crisis.