Medical Pharmacology Chapter 20:  Neuromuscular Blocking Agents and Muscle Relaxants

• Doxacurium (Nuromax)

  • 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

• Pancuronium (Pavulon)

  • 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.

• Pipecuronium (Arduan)

  • 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).

        1. Initial binding of spare receptors (no clinical effect)-- but reduces safety factor for neuromuscular transmission.

        2. 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.

• Atricurium (Tracrium)

  • 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.

• Cisatracurium (Nimbex)

  • 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.

• Vecuronium (Norcuron)

  • 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.

• Rocuronium (Zemuron)

  • 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.

• 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.