Pancuronium

BRAND NAME: Pavulon.

INDICATIONS: Adjunct to general anesthesia to facilitate endotracheal intubation. Skeletal muscle relaxation during surgery or mechanical ventilation.

CLASS: Synthetic bisquaterary aminosteroid non-depolarizing neuromuscular blocker. Long-acting, non-depolarizing skeletal muscle relaxant.

MODE OF ACTION:

	Competitive antagonist of acetylcholine on the alpha subunit of the nicotinic post-junctional receptor. Prevents opening of the ion channel of the receptor.
	Interferes with the mobilization of acetylcholine presynaptically.
	May block the open receptor and interfere with the passage of ions.
	Blocks muscarinic M2 receptors in the heart and sympathetic nerve endings.
	Increases release of noradrenaline and decreases its reuptake from the sympathetic nerve endings.
	Increase heart rate, arterial blood pressure and cardiac output (by about 15%). These effects are related to vagolytic and sympathomimetic effects.
	Does not cause histamine release or blockade of autonomic ganglia.

ONSET: ED₉₅ (dose producing 95% of maximum block at the adductor pollicis): 0.07 mg/kg. Onset time (to maximum effect): 3-4 min at 2 ×  ED₉₅ (more rapid in infants and children).

DURATION:

	Clinical duration of action (to 25% recovery): 90 min at 2 × ED95.
	Total duration of action (to 90% recovery):120 min at 2 × ED95.
	Recovery index (from 25 to 75% recovery): 30-40 min.

CLEARANCE:

	Protein binding 87%, clearance 1.9 mL/kg/min.
	Pancuronium is metabolized mainly by acetylation in the liver to 3-OH and 17-OH derivatives, which are excreted in the urine. The 3-OH metabolite is 40-50% as potent as pancuronium.
	Elimination is mainly by the kidney (70-80%). In case of renal failure, clearance is decreased resulting in a prolonged duration of action because biliary excretion (normally 15-20%) cannot compensate for the decrease in glomerular filtration rate.

ADULT DOSE:

	Intubation: 0.07-0.1 mg/kg IV.
	Dose following an initial bolus of succinylcholine: 0.07 mg/kg IV.
	Maintenance dose: 0.01 mg/kg IV (administer carefully using a nerve stimulator). Avoid continuous infusion.
	Pretreatment/priming: 10% of intubating dose, 3-5 min before full dose.
	If Clcr 10-50 mL/min give 50% of normal dose. If < 10 mL/min, avoid use!
	Dosage should be based on ideal body weight in obese patients.

PEDIATRIC DOSE: > 1 month, children, dosage requirements as in adults.

NEONATAL DOSE:

	In preterm infants, pancuronium causes a sustained tachycardia, hypertension and increased plasma epinephrine level.
	< 1 week: 0.04 mg/kg IV.
	1-3 weeks: 0.06 mg/kg IV.
	> 3 weeks: 0.06-0.09 mg/kg IV.
	Repeat doses should not exceed one-sixth of the initial dose.

CAUTION:

	Priming may cause hypoventilation, airway obstruction and diplopia.
	Use of pancuronium with tricyclic antidepressants and with volatile anesthetics (especially halothane) may cause serious cardiac dysrrhythmias.
	Verify recovery from NMB after succinylcholine before administration.
	Respiratory acidosis enhances NMB, opposes antagonism with neostigmine.
	Patients with total biliary obstruction and hepatic cirrhosis have increased volume of distribution, decreased clearance and prolonged elimination time.
	Cardiac stimulating effects may increase incidence of myocardial ischemia.
	Hypothermia prolongs action (slower hepatic enzyme activity and clearance).
	Reduce dose in elderly (decreased clearance).
	Increased resistance to NMB in burns (BSA > 30%), 5-70 days post-injury.
	Severe aortic stenosis.
	Precipitates with thiopental; may occlude IV line without flush.

NEUROMUSCULAR DISEASES:

	Myasthenia gravis, Eaton-Lambert syndrome: increased sensitivity.
	Myotonia: response to non-depolarizing drugs is normal.
	Duchenne muscular dystrophy: increased sensitivity.
	Familial periodic paralysis: hypokalemic state is especially sensitive, avoid!
	Guillain-Barré syndrome: variable sensitivity or resistance.
	Upper motor neuron lesions: hemiplegic patients may be more resistant. Monitoring of the affected site shows that the block is less intense and recovery is more rapid than on the unaffected site.

CONTRAINDICATIONS:

	Hypersensitivity to pancuronium and bromide.
	Renal failure.
	Patients with total biliary obstruction or severe hepatic cirrhosis.
	Surgery < 60 min.
	Pheochromocytoma.

INTERACTIONS:

	Halogenated anaesthetic agents shift the dose-response curve to the left, an effect that is dependent on the concentration and duration of administration. The potentiating effects of enflurane are greater than those of isoflurane, sevoflurane or desflurane.
	Most IV induction agents may potentiate neuromuscular block in animals, but this is of limited clinical importance.
	Antibiotics: aminoglycosides, polymyxins, clindamycin and vancomycin (especially on high doses) may potentiate neuromuscular block.
	Local anesthetics produce block in their own right and enhance neuromuscular blockade (dose-dependent).
	Antiarrhythmics: quinidine, procainamide, bretylium - no significant interaction.
	Magnesium potentiates neuromuscular blockade of non-depolarizing NMBs (severity correlates with serum magnesium, caution in pre-eclampsia).
	Lithium: potentiates neuromuscular blockade.
	Phenytoin, carbamazepine: chronic use causes resistance to NMB.
	Cyclosporine may prolong the duration of NMB.
	Ganglion blockers (trimethaphan) delays onset and prolongs action.
	Other drugs that potentiate NMB include prior succinylcholine, diuretics (related to serum K), ketamine, dantrolene, amphotericin B, beta agonists, beta blockers, CCBs and steroids (chronic use).
	Other drugs that antagonize NMB include azathioprine, carbamazepine, theophylline, anticholinesterases and cholinergics.
	Tricyclic antidepressants: risk of arrhythmias with coadministration.
	Severe hyponatremia, hypocalcemia, hypokalemia, hypermagnesemia and acidosis potentiate NMB.
	Hypercalcemia and alkalosis antagonize NMB.
	Combination of pancuronium with vecuronium is additive.

ADVERSE REACTIONS:

	CVS: tachycardia, hypertension.
	Other: rash, salivation, pruritus.
	Rare: bronchospasm, anaphylactoid reactions, flushing, prolonged block.
	Critical illness myopathy with prolonged paralysis in ICU patients.

Pregnancy: Category C.

MUSCLE SENSITIVITY: from vocal cords (most resistant), to diaphragm, to orbicularis oculi, to adductor pollicis (most sensitive).

ANTAGONISM OF NMB:

	Atropine 0.02 mg/kg or glycopyrrolate 0.01 mg/kg with neostigmine 0.04 mg/kg.
	Atropine 0.007-0.01 mg/kg followed by edrophonium 0.5 mg/kg (adult).
	Atropine 0.02 mg/kg followed by edrophonium 1 mg/kg (pediatric).
	Neostigmine can be given when four visible twitches following train-of-four stimulation can be observed at the adductor pollicis. For all intermediate-acting neuromuscular-blocking agents (atracurium, cisatracurium, rocuronium, vecuronium) and mivacurium, neostigmine can be given when two twitches are detected at the adductor pollicis without any risk of recurarization.
	Never use edrophonium for reversal of intense neuromuscular block (less than four twitches at the adductor pollicis).
	Use neostigmine for reversal of dense block.
	Atropine with neostigmine may cause tachycardia followed by bradycardia.