Neostigmine

Neostigmine is a quaternary carbamate cholinesterase inhibitor that does not cross the blood brain barrier. It raises acetylcholine at the neuromuscular junction and at muscarinic sites. It is used to reverse residual non-depolarising neuromuscular block, to treat acute colonic pseudo-obstruction, and in myasthenia gravis when oral pyridostigmine cannot be given.

Classification. Reversible (carbamate) acetylcholinesterase inhibitor; quaternary ammonium.

Mechanism. Carbamylates acetylcholinesterase, slowing acetylcholine breakdown. At the neuromuscular junction this lets acetylcholine compete with non-depolarising blockers; it also has a small direct nicotinic agonist effect.

Pharmacodynamics. Reversal begins within 1 to 3 minutes with peak effect at about 7 to 10 minutes. Muscarinic effects: bradycardia, salivation, bronchorrhoea, bronchospasm, increased gut motility. Ceiling effect: once enzyme is fully inhibited, more drug adds nothing, so it cannot reverse deep block.

Pharmacokinetics. Oral bioavailability under 5%. IV elimination half life about 50 to 90 minutes; around half is excreted unchanged in urine, the rest hydrolysed by esterases and the liver. Half life rises markedly in kidney failure.

Reversal of non-depolarising neuromuscular block, adult and child.

• Give only after spontaneous recovery has begun: train of four count of at least 2 on quantitative or peripheral nerve stimulator monitoring.

• Neostigmine 0.03 to 0.07 mg/kg IV over about 1 minute: 0.03 mg/kg when the fourth twitch is present, up to 0.07 mg/kg when only 2 twitches are present.

• Maximum 0.07 mg/kg or 5 mg total, whichever is less.

• Give an antimuscarinic before or with it: glycopyrrolate 0.2 mg for each 1 mg neostigmine, or atropine 15 to 20 micrograms/kg.

• Confirm train of four ratio of at least 0.9 before extubation.

• Deep block (train of four count 0 or 1) is not reversible with neostigmine; wait, ventilate, or use sugammadex after rocuronium or vecuronium.

Acute colonic pseudo-obstruction, adult.

• Exclude mechanical obstruction, perforation and ischaemia; correct potassium and magnesium; stop opioids and anticholinergics where possible.

• Neostigmine 2 mg IV over 3 to 5 minutes, with the patient supine, on continuous ECG, with atropine drawn up.

• A second 2 mg dose may be given after 3 to 24 hours if decompression is incomplete.

• Expect flatus or stool within 30 minutes in responders.

Myasthenia gravis, when oral treatment is not possible, adult.

• Neostigmine 0.5 to 2.5 mg IM or SC, or 0.5 to 2 mg slow IV, at intervals of 2 to 4 hours, adjusted to response. Total daily parenteral dose usually 5 to 20 mg.

• Approximate equivalence: oral pyridostigmine 60 mg is roughly equal to neostigmine 0.5 mg IV, 1.5 mg IM, or 15 mg orally.

• Oral neostigmine 15 to 30 mg three to six times daily, usual total 75 to 300 mg daily, is an option where pyridostigmine is unavailable.

Children, myasthenia gravis. 0.01 to 0.04 mg/kg IM, IV or SC every 2 to 4 hours; specialist advice.

Contraindications. Mechanical bowel or urinary obstruction; peritonitis; recent bowel anastomosis; hypersensitivity.

Warnings. Bradycardia and asystole, especially after rapid IV injection or without antimuscarinic cover. Bronchospasm in asthma and chronic obstructive pulmonary disease. Caution in heart block, recent myocardial infarction, epilepsy, parkinsonism, peptic ulcer and hyperthyroidism. Excess dosing in myasthenia gravis causes cholinergic crisis with weakness that mimics myasthenic crisis. Giving full doses to an already fully recovered patient can cause paradoxical weakness.

Adverse effects. Bradycardia, arrhythmia, hypotension, salivation, bronchorrhoea, bronchospasm, nausea, vomiting, abdominal cramp, diarrhoea, sweating, miosis, fasciculation.

Interactions.

• Suxamethonium: neostigmine prolongs its block; do not give neostigmine to reverse suxamethonium.

• Beta blockers and digoxin: additive bradycardia.

• Aminoglycosides, polymyxins, magnesium, volatile anaesthetics and lithium enhance non-depolarising block and reduce reversal.

• Antimuscarinics oppose the muscarinic effects (used deliberately).

Special groups.

• Pregnancy: crosses the placenta poorly. IV doses near term can cause uterine contraction; use for reversal is acceptable. Cholinesterase inhibitors are first line for myasthenia gravis in pregnancy.

• Breastfeeding: compatible; amounts in milk are negligible.

• Children: weight based reversal dose in the adult mg/kg range; infants are more prone to bradycardia, so give the antimuscarinic first.

• Older adults: slower onset and longer duration; same dose.

• Kidney impairment: duration prolonged; single reversal dose needs no change; reduce repeated myasthenia doses and titrate to effect.

• Liver impairment: no adjustment.

Formulations. Injection 0.5 mg/mL and 2.5 mg/mL (methylsulphate); premixed syringes with glycopyrrolate in some markets; oral tablets 15 mg (bromide).

Administration. IV over at least 1 minute. Neostigmine and glycopyrrolate are compatible in the same syringe. In pseudo-obstruction, give over 3 to 5 minutes in a monitored bed.

Baseline. Heart rate, rhythm, blood pressure, train of four count. In pseudo-obstruction: abdominal imaging and electrolytes.

Monitoring.

• Reversal: quantitative train of four until ratio at least 0.9; heart rate.

• Pseudo-obstruction: continuous ECG and blood pressure for 30 minutes after dose; abdominal examination; caecal diameter on repeat imaging.

• Myasthenia: bulbar function, forced vital capacity, cholinergic adverse effects.

Treatment of adverse effects. Symptomatic bradycardia: atropine 0.5 to 1 mg IV in adults, repeated as needed. Bronchospasm: atropine plus inhaled salbutamol.

Common prescribing errors. Giving neostigmine into deep block; omitting antimuscarinic cover; confusing reversal dose with myasthenia dose; using it after suxamethonium.