Neostigmine

INDICATIONS:

	Neuromuscular blockade reversal after non-depolarizing agents.
	Myasthenia gravis.
	Urinary retention.
	Severe postoperative ileus (non-obstructive).
	Adjunctive treatment of refractory supraventricular tachycardia (SVT) (rare, where all other routine treatment fail).

CLASS: Anticholinesterase (cholinergic) agent.

MODE OF ACTION: Reversible inhibition of acetylcholinesterase, leading to the greater availability of acetylcholine at preganglionic sympathetic (nicotinic), parasympathetic nerve endings (muscarinic) and at the neuromuscular junction (nicotinic).

ONSET: IV < 3 min, peak effect 7-11 min. Assess residual neuromuscular blocking (NMB) effect with a nerve stimulator.

DURATION: IV: Normal half-time 77 min with a dose of 0.043 mg/kg; in anephric patients 181 min.

CLEARANCE: Hepatic metabolism; renal clearance accounts for 50% of elimination.

ADULT DOSE:

	Reversal of neuromuscular blockade: 0.04-0.07 mg/kg IV, based on nerve stimulator findings; mix with atropine 0.015 mg/kg or glycopyrrolate 0.01 mg/kg IV; maximal total dose not to exceed 5 mg.
	Myasthenia gravis: 15-375 mg PO daily, 0.5-2 mg slow IV; individualize dose, consult neurologist.
	Supraventricular tachycardia: 0.25-0.5 mg IV; treat precipitating cause.
	Postoperative ileus, urinary retention: 0.25-1 mg IM/SC every 4-6 h.

PEDIATRIC DOSE:

	Infants and children, antagonism of neuromuscular blockade: neostigmine 0.05 mg/kg IV, mixed with atropine 0.02-0.025 mg/kg IV or glycopyrrolate 0.01 mg/kg IV, administer slowly.
	Neostigmine dose range: Infants: 0.025-0.1 mg/kg/dose IV; children: 0.025-0.08 mg/kg/dose IV.
	Monitor effect with a nerve stimulator.
	Myasthenia gravis (consult pediatric neurologist).

NEONATAL DOSE: See pediatric dose.

CAUTION:

	Asthma, bradycardia, recent myocardial infarction, epilepsy, hyperthyroidism, peptic ulcer.
	Administration to patients with an absolute contraindication to succinylcholine (e.g. myotonia).
	Beta-adrenergic blockade.

CONTRAINDICATIONS:

	Hypersensitivity to neostigmine or bromides.
	Gastrointestinal or genitourinary tract obstruction.
	After administration of succinylcholine.

INTERACTIONS:

	May prolong the 'phase I block' of depolarizing muscle relaxants.
	No antagonism of the 'phase I block' of succinylcholine.
	May reverse the 'phase II block' associated with succinylcholine.
	Cholinesterase inhibitors may provoke a cholinergic crisis.
	Factors that may inhibit antagonism of NMB  by anticholinesterases include aminoglycosides, hypothermia, respiratory acidosis (PaCO2 > 50 mmHg (6.7 kPa), hypokalemia and metabolic acidosis.

ADVERSE REACTIONS:

	CNS: seizures, dysarthria, headache, dizziness, drowsiness.
	CVS: bradycardia, tachycardia,  AV block, nodal rhythm, cardiac arrest, hypotension.
	Pulmonary: increased respiratory secretions (oral, pharyngeal and bronchial), bronchospasm. Respiratory depression, respiratory paralysis.
	GIT: diarrhea, nausea, increased salivation, abdominal cramps (increased peristalsis).
	GU: urinary frequency.
	Other: anaphylaxis, allergic reactions, rash and urticaria.

Cholinergic Crisis (due to neostigmine overdose): Overdose with an anticholinesterase manifests as muscarinic and nicotinic symptoms in peripheral and central nervous system sites. 

	Muscarinic symptoms: miosis, lacrimation, unfocused vision, hypersalivation, nausea, vomiting, diaphoresis, bronchospasm, bradycardia, abdominal cramps, and loss of bladder and rectal control.
	Nicotinic symptoms range from skeletal muscle weakness to full paralysis and apnea. CNS effects include confusion, ataxia, seizures, coma, respiratory depression.
	Treatment of cholinergic crisis: Discontinue neostigmine. Administer atropine 0.01 mg/kg IV every 3-10 min; assess by disappearance of muscarinic symptoms; cardiorespiratory support as indicated. Treat seizures with diazepam or thiopental. Very rare cases may require pralidoxime 15 mg/kg IV over 2 min, for reversal of nicotinic effects.

PREGNANCY: Category C.

COMMENTS:

	Administer neostigmine when spontaneous recovery from neuromuscular blockade starts to occur.
	Neostigmine is more effective than either edrophonium or pyridostigmine in antagonizing intense neuromuscular block.
	Combination of atropine with neostigmine may lead to an initial tachycardia, followed by a mild bradycardia. Slow administration may avoid this.
	Factors affecting NMB reversal: block intensity, anticholinesterase dose, specific muscle relaxant, age, renal failure, hypothermia, acidosis.
	Dose adjustment in renal failure: creatinine clearance (Clcr) 10-50 mL/min - decrease dose by 50%; Clcr < 10 mL/min - decrease dose by 75%.