Pyridostigmine

Pyridostigmine is an oral quaternary carbamate cholinesterase inhibitor and the first line symptomatic treatment for myasthenia gravis. It is longer acting and has fewer muscarinic effects than neostigmine. It does not alter the underlying autoimmune disease, which needs immunotherapy.

Classification. Reversible acetylcholinesterase inhibitor; quaternary ammonium; peripheral action only.

Mechanism. Inhibits acetylcholinesterase at the neuromuscular junction, prolonging the action of acetylcholine at the reduced number of functional nicotinic receptors.

Pharmacodynamics. Oral onset 15 to 30 minutes, peak 1 to 2 hours, duration 3 to 6 hours. Improves ocular and limb weakness more reliably than bulbar or respiratory weakness. Muscarinic effects are dose related.

Pharmacokinetics. Oral bioavailability 10 to 20%; food delays absorption without lowering the total. Hydrolysed by cholinesterases and partly metabolised in the liver; mostly excreted unchanged in urine. Half life about 3 to 4 hours, rising several fold in kidney failure.

Myasthenia gravis, adult.

• Start 30 mg orally three or four times daily while awake.

• Titrate by 30 mg each dose every 2 to 3 days against response and muscarinic adverse effects.

• Usual maintenance 60 mg four to six times daily (240 to 360 mg daily), timed 30 to 60 minutes before meals or activity.

• Maximum: product labels allow up to 1.2 g daily, but doses over 450 mg daily rarely add benefit and raise the risk of cholinergic weakness; over this, review diagnosis and immunotherapy.

• Modified release 180 mg at night may be added for early morning weakness; do not use it as the main daytime dose.

• Duration: long term while symptomatic; reduce as immunotherapy takes effect.

Myasthenia gravis, IV, adult (nil by mouth). IV dose is about one thirtieth of the oral dose, for example 2 mg IV for each 60 mg oral, given slowly every 4 hours; or convert to neostigmine (0.5 mg IV roughly equals 60 mg oral pyridostigmine).

Myasthenia gravis, children. 1 mg/kg orally every 4 to 6 hours, titrated; usual maximum 7 mg/kg daily in 5 to 6 divided doses, not over the adult maximum. Neonatal transient myasthenia: specialist dosing.

Orthostatic hypotension and postural tachycardia syndrome, adult (specialist, off label). 30 to 60 mg orally three times daily. Modest effect on standing blood pressure with little supine hypertension.

Nerve agent pretreatment, military use. 30 mg orally every 8 hours before possible exposure; not a treatment after exposure.

Contraindications. Mechanical gut or urinary obstruction; hypersensitivity to pyridostigmine or bromide.

Warnings. Cholinergic crisis with overdose: increasing weakness, fasciculation, bradycardia, bronchorrhoea, sweating, miosis. Distinguish from myasthenic crisis; when unclear in a deteriorating patient, secure the airway and withhold pyridostigmine. Caution in asthma, chronic obstructive pulmonary disease, bradycardia, recent myocardial infarction, epilepsy, parkinsonism and peptic ulcer.

Adverse effects. Abdominal cramp, diarrhoea, nausea, salivation, bronchial secretions, sweating, urinary urgency, fasciculation, muscle cramps, bradycardia. Bromide rash is rare.

Management of muscarinic adverse effects. Glycopyrrolate 1 mg orally two or three times daily or loperamide 2 mg with doses reduces gut effects without blocking nicotinic benefit.

Interactions.

• Suxamethonium: prolonged block. Non-depolarising blockers: variable response; reduce dose and use neuromuscular monitoring.

• Beta blockers and digoxin: additive bradycardia.

• Drugs that worsen myasthenia: aminoglycosides, fluoroquinolones, macrolides, IV magnesium, quinine, chloroquine, hydroxychloroquine, procainamide, beta blockers, botulinum toxin and immune checkpoint inhibitors.

• Antimuscarinics reduce effect.

• High dose corticosteroids at initiation can cause transient worsening of weakness.

Special groups.

• Pregnancy: first line symptomatic treatment; continue throughout. Avoid IV cholinesterase inhibitors in labour because they can trigger uterine contraction. Watch the newborn for transient neonatal myasthenia for 48 to 72 hours.

• Breastfeeding: compatible; small amounts in milk.

• Children: weight based dose; watch for diarrhoea and dehydration.

• Older adults: start at the lower end; bradycardia and falls risk.

• Kidney impairment: reduce dose and lengthen intervals; titrate to effect.

• Liver impairment: no adjustment.

Formulations. Tablets 60 mg; modified release tablets 180 mg; oral syrup 60 mg/5 mL; injection 5 mg/mL in some markets.

Administration. Time doses 30 to 60 minutes before meals to help chewing and swallowing. Do not crush modified release tablets.

Baseline. Diagnosis confirmed by antibodies or neurophysiology, heart rate, respiratory and bulbar function, interacting drugs.

Monitoring.

• Symptom diary showing response timing and wearing off.

• Forced vital capacity and negative inspiratory force in any exacerbation; forced vital capacity under 20 mL/kg or falling quickly needs intensive care review.

• Heart rate and gut adverse effects.

Perioperative. Usually continue on the day of surgery; tell the anaesthetist, who adjusts neuromuscular blocker dosing.

Referral and escalation. Bulbar weakness, rising dose requirement, or respiratory decline needs urgent neurology review for immunotherapy, IV immunoglobulin or plasma exchange.