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Anesthesia Pharmacology: Neuromuscular Blocking Agents and Muscle Relaxants
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Overview: Doxacurium (Nuromax)
Nondepolarizing agents; ED95 is about 30 μg/kg.
Time to onset: 4-6 minutes.
Duration of action: about 60-90 minutes.
Renal clearance (similar to pancuronium (Pavulon)).
Extended duration in elderly patients.
No histamine release; no cardiovascular effects.
Drug interactions:
Volatile anesthetics reduce doxacurium (Nuromax) dose requirements by 20%-40% compared to blocking doses for nitrous oxide-fentanyl (Sublimaze) anesthesia.
Stoelting, R.K., "Neuromuscular-Blocking Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, pp 182-219
Overview: pancuronium (Pavulon)
Commonly used long-acting nondepolarizing agent
Low-cost advantage
Cardiovascular side effects (doxacurium (Nuromax) & pipecuronium (Arduan) -- similar to pancuronium (Pavulon) but without cardiovascular side effects)
Pancuronium (Pavulon) and related agents have replaced older, long-acting nondepolarizing drugs such as:
Tubocurarine
Metocurine (Metubine Iodide)
Gallamine (Flaxedil)
No enhancement of histamine release
No autonomic ganglia blockade
General properties: pancuronium (Pavulon)
Nondepolarizing agent: ED95 = 70 ug/kg
Onset: 3-5 minutes
Duration: 60-90 minutes
Pancuronium (Pavulon) block enhanced by respiratory acidosis which opposes neostigmine (Prostigmin) antagonism
Pharmacokinetics: pancuronium (Pavulon)
Renal excretion: 80% of dose excreted unchanged.
Renal dysfunction: pancuronium (Pavulon) clearance may decrease by 33%-50%.
Hepatic metabolism (10%-40%)-with at least one potent metabolite.
Pancuronium (Pavulon) elimination halftime: affected by hepatic cirrhosis/total biliary obstruction.
Aging is associated with decreased pancuronium (Pavulon) plasma clearance.
Mechanism:probably reduced renal function.
Cardiovascular Effects: pancuronium (Pavulon)
Slight increase (10%-15%):
Heart rate.
Mean arterial pressure.
Cardiac output.
Mechanism:
Atropine-like effect on cardiac, muscarinic cholinergic receptors
Sympathetic, autonomic nervous system activation.
Adverse Effects:
Increased incidence of cardiac arrhythmias following pancuronium (Pavulon) (but not succinylcholine (Anectine)) in patients treated chronically with digitalis glycosides.
Increased cardiac arrhythmias may occur due to enhanced sympathetic nervous system activity.
Stoelting, R.K., "Neuromuscular-Blocking Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, pp 182-219; White, P. F. "Anesthesia Drug Manual", W.B. Saunders Company, 1996.
Overview: pipecuronium (Arduan)
Nondepolarizing neuromuscular for; ED95 (50-60 μg/kg).
Time to onset: 3-5 minutes.
duration of action: 60-90 minutes.
Enhanced potency increased/duration of action shortened in infants (relative to adults or children).
No histamine release; no cardiovascular changes associate with pipecuronium (Arduan) administration.
Pharmacokinetics:
Similar to pancuronium (Pavulon) in terms of renal clearance
Hepatic cirrhosis no effect on pipecuronium (Arduan) pharmacodynamics/ pharmacokinetics
Stoelting, R.K., "Neuromuscular-Blocking Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, pp 182-219; White, P. F. "Anesthesia Drug Manual", W.B. Saunders Company, 1996.
Introduction: Intermediate-acting Nondepolarizing Blockers
Overview: Intermediate-acting
Nondepolarizing Blockers
Atracurium (Tracrium), vecuronium (Norcuron), rocuronium (Zemuron), cisatracurium (Nimbex).
Efficient clearance mechanisms (reduced likelihood of significant accumulation following repeated administration).
Useful; but more expensive alternatives to succinylcholine (Anectine) & pancuronium (Pavulon).
Particularly useful for tracheal intubation/skeletal muscle relaxation for short procedures (e.g. outpatient).
Properties:
Intermediate-acting agents (compared to long-acting agents):
Similar time to onset (exception: roncuronium (Zemuron) -- rapid onset, similar to succinylcholine (Anectine)).
Duration of action -- about one-third of long-acting agents.
30%-50% more rapid recovery rate.
Minimal/absent cardiovascular effects.
Intermediate duration, due to rapid/efficient plasma clearance.
Special considerations:
Rocuronium (Zemuron): rapid onset (similar to succinylcholine (Anectine)).
Rapid onset -- within one-minute; good choice for tracheal intubation facilitation.
Method for accelerating onset for other "intermediate acting" agents.
Use a small, subparalyzing dose (about 10% of ED95); followed about four minutes by the larger dose (2-3 X ED95).
Divided dose technique = priming principal (neuromuscular-blockade:two-step process).
Initial binding of spare receptors (no clinical effect)-- but reduces safety factor for neuromuscular transmission.
Deeper blockade.
Priming dose technique may be less valid now with the availability of single, large IV roncuronium (Zemuron) dose -- providing rapid onset -- no risk of drug-induced weakness in awake patients
Antagonism of
blockade cause by intermediate-acting
nondepolarizing drugs:
Anticholinesterase agents: effective (within 20 minutes of administration of the paralyzing intermediate-acting nondepolarizing drug dose).
Pharmacologic antagonism (administration of anticholinesterase drugs) coupled with rapid clearance of the blocker results in enhanced, recovery rates.
Stoelting, R.K., "Neuromuscular-Blocking Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, pp 182-219; White, P. F. "Anesthesia Drug Manual", W.B. Saunders Company, 1996.
Overview: atracurium (Tracrium)
Nondepolarizing, neuromuscular blocker (multiple isomers).
ED95: 0.2 mg/kg.
Time to onset: 3-5 minutes.
Duration of action: about 20-35 minutes.
Site of action:
Presynaptic & postsynaptic membrane nicotinic receptors.
Degradation: spontaneous, in vivo (Hofmann elimination)
More stable in acid pH (storage range is pH 3.25-3.65).
Should not mix atracurium (Tracrium) with alkaline drugs (e.g. barbiturates) or expose to solutions of more alkaline pH.
Alkaline pH: accelerated breakdown.
Clearance involves two mechanisms:
Hofmann elimination -- nonenzymatic; accounts for one-third of the degradation
Hydrolysis catalyzed by plasma esterases (nonspecific, i.e. not plasma cholinesterase); accounts for about two-thirds of degraded atracurium (Tracrium)
Clearance not dependent on hepatic or renal function
Clearance not affected in patients with atypical cholinesterase
Laudanosine is a major metabolite of both catabolic atracurium (Tracrium) pathways
Laudanosine is a CNS stimulant, however, even with long, continues atracurium (Tracrium) infusions in the surgical setting, laudanosine concentrations remain below those apparently required for cardiovascular/CNS action/
In the ICU setting with longer durations Seizure potential becomes much more likely.
Cumulative effects
No significant cumulative effect due to rapid clearance from plasma (hydrolysis + Hofmann elimination).
Cardiovascular Effects:
With these background anesthetics: nitrous oxide, fentanyl (Sublimaze), halothane (Fluothane), isoflurane (Forane).
no BP/heart rate change associated with rapid IV atracurium (Tracrium) up to (2 X ED95).
With nitrous oxide-fentanyl (Sublimaze) anesthesia, IV atracurium (Tracrium) (3 X ED95): slight increase in heart rate (8%); decreased in mean arterial pressure (20%).
Cardiovascular effects: transitory (< 5 minutes).
Facial/truncal flushing may be due to histamine release (no circulatory effects if patients are pretreated with H1/H2 receptor blockers)
H1/H2 receptors may be activated by prostacyclin (not histamine).
Special Patient Populations
Pediatric patients
Similar atracurium (Tracrium) doses in adults and children (2-16 years old) when doses are calculated using mg/m2 rather than on a mg/kg basis.
Infants who are 1-6 months require about 50% of the atracurium (Tracrium) dose given to older children.
Continuous infusion rate (to maintain steady-state blockade): 25% less during the first month of life.
Elderly patients
Increasing age: no effect on atracurium (Tracrium) continuous infusion rate required for constant degree of neuromuscular-blockade.
Mechanism -- age independence of Hofmann elimination & plasma ester hydrolysis inactivation processes (enal/hepatic state independent).
Stoelting, R.K., "Neuromuscular-Blocking Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, pp 182-219; White, P. F. "Anesthesia Drug Manual", W.B. Saunders Company, 1996.
Overview: cisatracurium (Nimbex)
Nondepolarizing neuromuscular blocker
ED95: 50 μg/kg
Time to onset: 3-5 minutes.
Duration of action: 25-30 minutes.
Similar pharmacological profile to atracurium (Tracrium) compared atracurium (Tracrium).
Cisatracurium (Nimbex)(Tracrium) onset slightly slower.
Cisatracurium (Nimbex) much less likely to cause histamine release, compared atracurium (Tracrium).
Spontaneous neuromuscular blockade recovery not affected by prolonged infusion (80 hr) to patients requiring ventilation in the intensive care environmen, by contrast to vecuronium (Norcuron)
Recovery: accelerated by the use of anticholinesterase agents.
Clearance: cisatracurium (Nimbex)
Hofmann elimination (77% cisatracurium (Nimbex) clearance).
16%: renal.
Neuromuscular-blockade characteristics not affected by hepatic or renal dysfunction.
Cisatracurium (Nimbex) pharmacokinetics: not appreciably affected by advanced age (slight delay in time to onset).
Cardiovascular Effects: cisatracurium (Nimbex)
No histamine-releasing effects (by contrast to atracurium (Tracrium)).
Large doses (8 X ED95, IV) do not typically induce cardiovascular changes.
Less change in cerebral hemodynamics compared to equal potent atracurium (Tracrium) dosage.
Stoelting, R.K., "Neuromuscular-Blocking Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, pp 182-219; White, P. F. "Anesthesia Drug Manual", W.B. Saunders Company, 1996.
Overview: vecuronium (Norcuron)
Nondepolarizing neuromuscular blocker
ED95: 50 μg/kg
Time to onset: 3-5 minutes.
Duration of action: 20-35 minutes.
Structurally resembles pancuronium (Pavulon); vecuronium (Norcuron) exhibits reduced anti-vagal properties compared to pancuronium (Pavulon).
Unstable in solution; supplied as lyophilized powder.
Clearance
Overview
Hepatic metabolism and renal excretion.
Metabolites generally much less active than vecuronium (Norcuron)
More lipid-soluble compared pancuronium (Pavulon) promotes biliary excretion and significant hepatic uptake.
Rapid hepatic uptake may be responsible for short duration of action.
Reduced renal function.
Vecuronium (Norcuron) action prolonged in patients with renal failure
Increased concentration of metabolites also contribute to prolonged skeletal muscle paralysis following long-term vecuronium (Norcuron) infusion.
Reduced liver function
When used in patients with hepatic cirrhosis, vecuronium (Norcuron) at 0.2 mg/kg IV, longer duration of action (longer elimination halftime); not observed that the 0.1 mg/kg IV dose level.
In patients with cholestasis, undergoing biliary surgical procedures: vecuronium (Norcuron) duration of action is increased (at the 0.2 mg/kg IV dosage).
Cardiovascular Effects
Minimal even at 3 X ED95, with rapid IV administration.
No vagolytic action.
Apparently no/minimal histamine release.
Possible vagotonic vecuronium (Norcuron) effect if administered nearly concurrently with potent opioids (e.g. sufentanil (Sufenta)).
Vagotonic action may be serious, promoting sinus nodal exit block & cardiac arrest.
Use in pediatric patients
Vecuronium (Norcuron) potency (during nitrous oxide-halothane (Fluothane) anesthesia) is similar in the following:
Infants (7-45 weeks).
Children (1-8 years).
Adults (18-38 years).
Onset of action: more rapid in infants compared to adults; (infants have high cardiac output, promoting rapid onset).
Duration of action: longest in infants; shortest in children-- (infants have less/immature enzyme systems and have increased drug volume of distribution).
Use in Elderly patients
With increased age: decreased continuous infusion rate required to maintain a given level of block.
Mechanism:
Age-related hepatic blood flow decrease.
Age-related decreased renal blood flow.
Age-related reduced hepatic microsomal enzyme system activity (possibly).
With increased age: prolonged recovery time if vecuronium (Norcuron) was administered by continuous infusion (recovery from individual IV doses of vecuronium (Norcuron) is not age sensitive).
Use in Obstetric patients
Clinically significant fetal effects not observed with nondepolarizing neuromuscular-blocking drugs.
Vecuronium (Norcuron) clearance: increased during late pregnancy; possibly due to enhance microsomal enzyme activity (by progesterone).
Vecuronium (Norcuron)-induced neuromuscular blockade: prolonged immediately postpartum.
Obesity:
Vecuronium (Norcuron) duration of action (but not atracurium (Tracrium)) prolonged in obese (> 130% of ideal body weight) compared with nonobese adults.
Malignant Hyperthermia
Not associated with vecuronium (Norcuron) or atracurium (Tracrium) administration in animal models.
In a patient susceptible to malignant hyperthermia and therefore pretreated with dantrolene (Dantrium): duration of vecuronium (Norcuron) action prolonged.
Mechanism: Dantrolene (Dantrium) may prolonged action of neuromuscular-blocking agents secondary to dantrolene (Dantrium)-mediated impairment of presynaptic calcium release.
Stoelting, R.K., "Neuromuscular-Blocking Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, pp 182-219; White, P. F. "Anesthesia Drug Manual", W.B. Saunders Company, 1996.
Overview: rocuronium (Zemuron)
Nondepolarizing agent; ED95 is about 0.3 mg/kg.
Time to onset: 1-2 minutes.
Duration of action: 20-35 minutes.
reduced potency (relative to vecuronium (Norcuron)) probably responsible for relatively rapid onset [lower potency requires higher dose {more molecules administered} -- more molecules increased the likelihood of initial blockade]
Time to onset: Clinical implications --
Time to onset of maximal single twitch depression (following 3-4 X ED95): similar to time to onset for succinylcholine (Anectine) (when mg/kg, IV).
Rocuronium (Zemuron): only nondepolarizing agent which may substitute for succinylcholine (Anectine) when:
Succinylcholine (Anectine) is contradicted.
Rapid onset is required to promote tracheal intubation.
Differences between rocuronium (Zemuron) & succinylcholine (Anectine)
Laryngeal muscles more resistant to rocuronium (Zemuron) than adductor pollicis: large dose rocuronium (Zemuron) effects resemble succinylcholine (Anectine) at adductor pollicis but will be delayed relative to succinylcholine (Anectine) effects at laryngeal adductors.
Duration of action:
Similar to other intermediate-acting agents at normal doses.
With large dose rocuronium (Zemuron) --3-4 X ED95-- to achieve onset rates similar to succinylcholine (Anectine)-- duration is prolonged (more similar to long-acting nondepolarizing drugs, e.g. pancuronium (Pavulon))
Large IM doses (rocuronium (Zemuron)) -- 1-8 mg/kg given to infants/children to support rapid tracheal intubation results in relatively long durations (sixty minutes). This long duration may limit clinical utility.
Effects on muscle groups
Laryngeal adductor muscles and diaphragm are more resistant to rocuronium (Zemuron) than adductor pollicis muscles.
Therefore, complete single twitch response suppression of adductor pollicis is not sufficient to ensure paralysis of laryngeal muscles and diaphragm.
Maximal paralysis of laryngeal muscles may not be recognized if suppression of adductor pollicis single twitch response is being monitored as the clinical sign for optimal conditions supporting intubation.
Direct laryngoscopy for intubation performed at peak laryngeal muscle paralysis may result in abdominal muscle/diaphragmatic motion when the tracheal tube is positioned -- because the diaphragm and abdominal muscles are not yet fully paralyzed:
This condition is undesirable especially in those cases when pulmonary aspiration gastric contents is considered a risk.
Pharmacokinetics: Clearance:
Rocuronium (Zemuron)
Up to 50% excreted in the bile {animal studies}
> 30% renal excretion (in 24 hours)
Liver disease: possible increased drug effect duration due to increased volume of distribution
Elderly patients:
Similar time to onset (compared to young adults)
Prolonged duration (compared to young adults)
Cardiovascular Effects:
No histamine released (as with other non-polarizing agents)
Small anti-vagal effect which may be useful in certain surgical procedures which cause vagal stimulation (e.g. opthalmological, laproscopic procedures).
Bradycardia (reflex) may occur with atracurium (Tracrium) or vecuronium (Norcuron) in patients undergoing these procedures
Stoelting, R.K., "Neuromuscular-Blocking Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, pp 182-219; White, P. F. "Anesthesia Drug Manual", W.B. Saunders Company, 1996.
Short-acting nondepolarizing neuromuscular blocker: Mivacurium (Mivacron)
Overview: mivacurium (Mivacron)
Clinically useful nondepolarizing agent classified as short acting.
ED95: 80 μg/kg.
Time to onset: 2-3 minutes.
Duration of action: 12-20 minutes (about 2 X longer than succinylcholine (Anectine); about 30%-40% that of intermediate-acting neuromuscular-blocking agents).
Mivacurium (Mivacron): no malignant hyperthermia likely (based on swine model).
Pancuronium (Pavulon), then mivacurium (Mivacron) leads to prolonged mivacurium (Mivacron) duration of action.
Muscle effects: mivacurium (Mivacron)
Mivacurium (Mivacron) (2 X ED95):
Maximal depression (single twitch) of orbicularis oculi prior to maximal depression at adductor pollicis (different from succinylcholine (Anectine) which produces maximal depression at the sites concurrently).
Loss of orbicularis oculi function (but not adductor pollicis) correlates with maximal laryngeal adductor muscle and diaphragm paralysis.
Clearance: mivacurium (Mivacron)
Short duration of action due to: plasma cholinesterase-mediated hydrolysis
Hydrolytic rate for mivacurium (Mivacron) about 90% that observed for succinylcholine (Anectine).
Mivacurium (Mivacron) hydrolysis is decreased with increased duration of action in the presence of atypical plasma cholinesterase.
In patients with atypical plasma cholinesterase: mivacurium (Mivacron) blockade is intense in prolonged.
Effective antidote: administration of human plasma cholinesterase (anticholinesterase agents appear ineffective).
Renal status: renal excretion is a minor pathway for mivacurium (Mivacron) clearance
Hepatic status:
Patients with liver cirrhosis may experience prolonged mivacurium (Mivacron) blockade if the liver disease is associated with reduced plasma cholinesterase activity
Increase volume of distribution associate with liver disease because reduced neuromuscular-blockade
Pharmacological Antagonism:
May not be needed given rapid spontaneous recovery from mivacurium (Mivacron) blockade
Anticholinesterase agents (e.g. neostigmine (Prostigmin)) because they inhibit plasma cholinesterase may interfere with normal recovery mechanism
Moderate mivacurium (Mivacron)-mediated blockade may respond to neostigmine (Prostigmin)
Deep mivacurium (Mivacron)-mediated blockade maybe antagonized by edrophonium (Tensilon)
Cardiovascular Effects: mivacurium (Mivacron)
Minor at doses up to 2 x ED95
Rapid IV administration of 3 x ED95 may provoked a decrease in BP (10%-20%), secondary to histamine release
Stoelting, R.K., "Neuromuscular-Blocking Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, pp 182-219; White, P. F. "Anesthesia Drug Manual", W.B. Saunders Company, 1996.
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