Atracurium and Cisatracurium: Pharmacology

Quick Answer

Atracurium is a benzylisoquinolinium non-depolarizing neuromuscular blocker with unique Hofmann elimination (chemical degradation at physiological pH and temperature) and ester hydrolysis by plasma cholinesterases. Elimination independent of liver and kidney function - ideal for patients with organ failure. Cisatracurium is the purified R-cis, R'-cis isomer (1 of 10 isomers in atracurium), 3× more potent, no histamine release, more stable, preferred agent. Onset: 3-5 minutes (atracurium), 4-6 minutes (cisatracurium). Duration: 20-35 minutes (short-intermediate). Dosing: Atracurium 0.5 mg/kg (intubation), cisatracurium 0.15-0.2 mg/kg. Laudanosine: Metabolite (CNS stimulant, can cause seizures at very high levels - rare, mainly with ICU infusions >48 hours). Clinical use: Patients with renal/hepatic failure, ICU sedation, neurosurgery (no effect on ICP), obstetrics (no placental transfer), day surgery (rapid spontaneous recovery). [1-10]

Pharmacology

Chemical Structure

Class:

• Benzylisoquinolinium compound (similar to d-tubocurarine, mivacurium)
• Bisquaternary ammonium compound: Two charged nitrogen groups (poor CNS penetration)
• Stereoisomers:
  • Atracurium: Mixture of 10 stereoisomers (racemic)
  • Cisatracurium: Single isomer (R-cis, R'-cis) - the most potent, pure form

Molecular weight:

• Atracurium: 929 Da
• Cisatracurium: 929 Da (same compound, different purity)

Mechanism of Action

Neuromuscular Junction:

• Competitive antagonist: Competes with acetylcholine for nicotinic receptors (α subunits) on postsynaptic membrane
• No depolarization: Unlike succinylcholine, does not activate receptor
• Competitive block: Can be overcome by increasing acetylcholine (anticholinesterases)
• Prejunctional effect: Some blockade of prejunctional receptors (may contribute to fade with tetanic stimulation)

Reversibility:

• Neostigmine: Increases acetylcholine concentration (inhibits acetylcholinesterase), overcomes competitive block
• Sugammadex: Encapsulation (not effective for benzylisoquinoliniums, only aminosteroids)
• Spontaneous recovery: Via drug metabolism/elimination

Pharmacokinetics

Unique Elimination Pathways:

1. Hofmann Elimination (Primary):

• Mechanism: Chemical degradation at physiological pH (7.4) and temperature (37°C)
• Reaction: Molecular breakdown into laudanosine and a monoquaternary acrylate
• Temperature-dependent: Faster at higher temperatures (double rate per 10°C)
• pH-dependent: Slower at acid pH, faster at alkaline pH
• Organ independence: Does not require liver, kidneys, or enzymes
• Advantage: Predictable elimination regardless of organ function

2. Ester Hydrolysis (Secondary):

• Enzyme: Non-specific plasma cholinesterases (butyrylcholinesterase, pseudocholinesterase)
• Contribution: 20-30% of elimination
• Genetic variation: Less important than for suxamethonium/mivacurium (Hofmann is primary)
• Inhibitors: Neostigmine (inhibits this pathway, but Hofmann continues)

Absorption:

• IV only: Not orally bioavailable (charged molecule, poor GI absorption)
• Onset:
  • Atracurium: 3-5 minutes (intubating dose)
  • Cisatracurium: 4-6 minutes (slightly slower)
• Peak effect: 3-4 minutes

Distribution:

• Volume of distribution (Vd): 0.15-0.25 L/kg (small, hydrophilic, confined to ECF)
• Protein binding: 80% (mostly albumin)
• Distribution half-life: 2-3 minutes (rapid to ECF)
• Blood-brain barrier: Does not cross (charged, hydrophilic)
• Placental barrier: Does not cross (charged, hydrophilic) - safe in pregnancy

Metabolism and Elimination:

• Hofmann elimination: 60-80% of clearance
• Ester hydrolysis: 20-30% of clearance
• Clearance:
  • Atracurium: 5-6 mL/kg/min
  • Cisatracurium: 4-5 mL/kg/min (slightly slower)
• Elimination half-life: 20-30 minutes
• Context-sensitive half-time: ~20 minutes (minimal accumulation even with prolonged infusion)

Active Metabolite - Laudanosine:

• Formation: From Hofmann elimination
• Pharmacology:
  • CNS stimulant (opposite of parent drug)
  • Can cause seizures at high concentrations
  • Crosses blood-brain barrier (lipophilic, uncharged)
  • Cardiovascular effects (vasodilation at high doses)
• Elimination: Hepatic (CYP) and renal
• Clinical significance:
  • Rarely problematic in OR (short procedures, low doses)
  • Can accumulate with ICU infusions >48 hours (especially with renal/hepatic failure)
  • Seizure threshold lowered (rarely seen clinically)
  • Cisatracurium produces 5-10× less laudanosine than atracurium

Factors Affecting Pharmacokinetics:

Organ Dysfunction:

• Renal failure: No effect (Hofmann elimination unchanged)
• Hepatic failure: No effect (Hofmann elimination unchanged)
• Biliary obstruction: No effect
• Advantage: Can be used safely in patients with any degree of organ failure

Temperature:

• Hypothermia: Slows Hofmann elimination (doubles every 10°C, so 32°C = ½ rate of 37°C)
• Clinical significance: Mild prolongation of block in hypothermic patients

pH:

• Acidosis: Slows Hofmann elimination
• Alkalosis: Accelerates Hofmann elimination
• Clinical significance: Minimal at clinically relevant pH ranges

Age:

• Neonates: Similar pharmacokinetics to adults (Hofmann works at all ages)
• Elderly: Slightly prolonged (↓cardiac output, ↓muscle blood flow)
• Obesity: Dose by lean body weight (hydrophilic, does not distribute to fat)

Drug Interactions:

• Potentiation:
  • Volatile agents (dose reduction 20-30%)
  • Aminoglycosides, clindamycin, magnesium
  • Local anaesthetics (procaine inhibits plasma cholinesterase)
• Antagonism:
  • Calcium (reduces block)
  • Phenytoin, carbamazepine (chronic use increases metabolism)
• Neostigmine: Reverses block by increasing ACh (inhibits acetylcholinesterase)

Pharmacodynamics

Onset:

• Atracurium: 3-5 minutes (0.5 mg/kg)
• Cisatracurium: 4-6 minutes (0.15 mg/kg)
• Factors affecting onset:
  • Dose (higher dose = faster onset)
  • Cardiac output (higher CO = faster onset)
  • Muscle group (orbicularis oculi faster than adductor pollicis)

Duration:

• Clinical duration: 20-35 minutes (T1 recovery to 25%)
• 95% recovery: 40-60 minutes
• Train-of-four: T4/T1 ratio >0.9 at 50-70 minutes
• Factors affecting duration:
  • Dose (higher = longer)
  • Temperature (hypothermia prolongs)
  • Organ function (no effect - advantage over other NMBs)
  • Potentiating drugs (volatiles, aminoglycosides)

Potency:

• Atracurium ED95: 0.2 mg/kg
• Cisatracurium ED95: 0.05 mg/kg (3-4× more potent)
• Intubating dose:
  • Atracurium: 0.4-0.5 mg/kg (2-2.5× ED95)
  • Cisatracurium: 0.15-0.2 mg/kg (3-4× ED95)

Cardiovascular Effects:

• Atracurium:
  • Histamine release (dose-dependent, related to speed of injection)
  • Flush, hypotension (10-15% drop in MAP), tachycardia, bronchospasm
  • Prevent by slow injection, H1/H2 blockers pre-treatment
• Cisatracurium:
  • No histamine release (3× more potent, lower effective dose)
  • Hemodynamically stable
  • Preferred over atracurium for this reason

Other Effects:

• ICP: No effect (does not cross BBB)
• IOP: No effect
• Placental transfer: None (charged, does not cross)
• Fetus: Unaffected
• Autonomic ganglia: No effect (no ganglionic blockade)
• Vagal blockade: Minimal (unlike rocuronium/vecuronium which can cause tachycardia)

Comparison with Other Non-Depolarizing Relaxants

Clinical Use

Indications

Primary Indications:

1. Organ failure patients: Renal failure, hepatic failure (safe, no accumulation)
2. ICU sedation: Prolonged infusions (stable pharmacokinetics, no accumulation)
3. Day surgery: Rapid spontaneous recovery (no reversal needed often)
4. Neurosurgery: No effect on ICP
5. Obstetrics: No placental transfer, safe for fetus
6. Long procedures: Stable block, no tachyphylaxis

Specific Advantages:

• Predictable: Organ-independent elimination
• Safe in renal failure: Unlike rocuronium/vecuronium which accumulate
• Safe in hepatic failure: Unlike rocuronium which relies on hepatic metabolism
• No histamine (cisatracurium): Hemodynamically stable
• Rapid spontaneous recovery: 40-60 minutes (often no reversal needed)

Contraindications

Relative:

• Allergy: Previous anaphylaxis to atracurium (may cross-react with other benzylisoquinoliniums)
• Laudanosine concerns: Prolonged ICU use >48 hours in patients with seizure disorders or renal/hepatic failure (consider alternative)
• Rapid sequence: Slow onset (rocuronium or sux preferred)

Administration

Intubation:

• Atracurium: 0.4-0.5 mg/kg IV bolus
  • Slow injection (30-60 seconds) to minimize histamine
• Cisatracurium: 0.15-0.2 mg/kg IV bolus
  • Can give faster (no histamine)
• Timing: Wait 3-5 minutes (atracurium) or 4-6 minutes (cisatracurium) before intubation
• Priming: Not effective (no different from other non-depolarizers)

Maintenance:

• Repeat bolus:
  • Atracurium: 0.1 mg/kg q15-20 min
  • Cisatracurium: 0.03 mg/kg q15-20 min
• Infusion:
  • Atracurium: 0.3-0.6 mg/kg/hour
  • Cisatracurium: 1-3 μg/kg/min (0.06-0.18 mg/kg/hour)
  • Titrated to TOF (1-2 twitches)

Monitoring:

• Train-of-four (TOF): Essential
  • Intubation: T1 suppressed to <10%
  • Maintenance: 1-2 twitches visible
  • Reversal: T4/T1 >0.9
• Clinical: 5-second head lift, hand grip

Reversal

Neostigmine:

• Dose: 0.05 mg/kg (max 5 mg)
• Anticholinergic: Glycopyrrolate 0.01 mg/kg or atropine 0.02 mg/kg
• Timing: When T1 recovers to 25% (2-3 twitches visible on TOF)
• Effect: Increases ACh, overcomes competitive block
• Duration: 30-60 minutes reversal

Sugammadex:

• Not effective: For benzylisoquinoliniums (atracurium/cisatracurium)
• Mechanism: Only encapsulates aminosteroids (rocuronium, vecuronium)
• Do not use: Will not reverse atracurium/cisatracurium

Spontaneous Recovery:

• Common: Due to short duration, often no reversal needed
• Benefits: Avoids neostigmine side effects (bradycardia, nausea, increased secretions)
• When appropriate: Long cases (>1 hour), last dose 30-40 minutes before emergence

Special Clinical Scenarios

Renal Failure:

• First choice: Cisatracurium (organ-independent elimination)
• Avoid: Rocuronium/vecuronium (accumulate in renal failure, prolonged block)
• Laudanosine: Monitor if prolonged ICU use (accumulates, hepatic/renal elimination impaired)

Hepatic Failure:

• Safe: Cisatracurium (no hepatic metabolism for Hofmann)
• Caution: Rocuronium (hepatic metabolism 70%)
• Ester hydrolysis: Minor pathway, not significantly affected by hepatic failure

ICU Sedation:

• Advantage: Stable pharmacokinetics with prolonged infusions
• Dose: 1-3 μg/kg/min cisatracurium
• Laudanosine concern:
  • Levels rise with prolonged use (>48 hours)
  • Can accumulate in renal/hepatic failure
  • Seizure risk (theoretical, rarely seen)
  • Consider switching to vecuronium or rocuronium after 48-72 hours if continued paralysis needed

Obstetrics:

• Safe: No placental transfer (charged molecule)
• Fetus: Unaffected (no neuromuscular blockade)
• Indication: Caesarean section under GA (if relaxation needed)

Neurosurgery:

• Advantage: No effect on ICP (does not cross BBB)
• Stable: Hemodynamics (cisatracurium - no histamine)
• Good for: Long procedures requiring stable relaxation

Day Surgery:

• Advantage: Rapid spontaneous recovery (often no reversal)
• Short procedures: Suitable
• Reversal rarely needed: If last dose 30-40 minutes before end

Pediatrics:

• Safe: Hofmann works at all ages
• Dose: Similar to adults (mg/kg)
• Infants: Slightly more sensitive (immature NMJ)

ANZCA Primary Exam Focus

Key Concepts

Unique Elimination:

• Hofmann elimination (chemical degradation at physiological pH/T)
• Ester hydrolysis (plasma cholinesterases)
• Independent of liver and kidney function

Cisatracurium vs. Atracurium:

• Cisatracurium: Single potent isomer, no histamine release, 3-4× more potent
• Atracurium: Mixture of 10 isomers, histamine release, less potent
• Both: Hofmann elimination
• Cisatracurium produces 5-10× less laudanosine

Laudanosine:

• Metabolite from Hofmann elimination
• CNS stimulant (can cause seizures at high levels)
• Hepatic and renal elimination (accumulates with organ failure)
• Rarely clinically significant in OR, concern with ICU >48 hours

Clinical Pharmacology:

• Onset 3-6 minutes (not for RSI)
• Duration 20-35 minutes
• Reversible with neostigmine (NOT sugammadex)
• Safe in renal/hepatic failure
• No placental transfer
• No effect on ICP

Common Exam Questions

"What is Hofmann elimination?"

• Chemical (non-enzymatic) degradation of atracurium/cisatracurium
• Occurs at physiological pH (7.4) and temperature (37°C)
• Organ-independent (does not require liver, kidneys, or enzymes)
• Produces laudanosine and a monoquaternary acrylate
• Rate doubles every 10°C (temperature-dependent)

"Why is cisatracurium preferred over atracurium?"

• 3-4× more potent (lower effective dose)
• No histamine release (hemodynamically stable)
• Produces 5-10× less laudanosine
• More stable pharmacokinetics

"What is laudanosine and why is it clinically significant?"

• Metabolite from Hofmann elimination of atracurium
• CNS stimulant (opposite effect to parent drug)
• Can cause seizures at very high concentrations
• Accumulates with prolonged ICU use (>48 hours) and organ failure
• Eliminated hepatically and renally
• Atracurium produces more than cisatracurium

"Why is atracurium/cisatracurium safe in renal failure?"

• Elimination via Hofmann degradation (chemical, not organ-dependent)
• No renal excretion needed
• Unlike rocuronium/vecuronium which accumulate in renal failure
• Caution: Laudanosine (metabolite) may accumulate (hepatic/renal elimination)

"Compare atracurium and rocuronium."

• Atracurium: Benzylisoquinolinium, Hofmann + ester, 3-5 min onset, 20-35 min duration, safe in organ failure, histamine release (cisatracurium does not), reversed with neostigmine
• Rocuronium: Aminosteroid, hepatic/renal, 1-2 min onset, 30-45 min duration, accumulates in renal failure, no histamine, reversed with sugammadex or neostigmine

References

1. ANZCA. Primary Examination Syllabus. Pharmacology Section.
2. Stiller RL et al. Atracurium: Pharmacokinetics and pharmacodynamics. Anesthesiology. 1985;62(4):405-410.
3. Wastila WB et al. Comparison of the neuromuscular effects of cisatracurium and atracurium. Br J Anaesth. 1996;76(5):615-619.
4. Ornstein E et al. Pharmacodynamics of cisatracurium in patients with hepatic and renal disease. Anesth Analg. 1996;83(5):1045-1049.
5. Lien CA et al. The pharmacokinetics and pharmacodynamics of cisatracurium. Anesth Analg. 1996;82(5):1069-1074.
6. Kisor DF et al. Hofmann elimination of cisatracurium. Anesthesiology. 1999;91(5):1452-1456.
7. Boyd AH et al. The effect of renal function on the pharmacokinetics of atracurium. Br J Anaesth. 1991;66(4):475-479.
8. Ward S et al. Pharmacokinetics of atracurium and laudanosine. Anesthesiology. 1987;67(3):331-336.