Atracurium

[SH4:p231-235]

Quick summary

 

 

Usage

Non-depolarising intermediate-acting NMBD

Structure

Structure

• Bisquaternary benzylisoquinolinium
• Mixture of 10 geometric isomers
  * One of which is cisatracurium

Pharmacodynamics

Main actions

• Muscle relaxation

Mechanisms of action

• Acts on both presynpatic and postsynaptic nAChRs
  * Same as other nondepolarising NMBDs
• May also directly interfere with passage of ions through nAChR channel by physical presence

Side effects

Cardiovascular system

• Atracurium doses up to 2 x ED95 (i.e. 2 x 0.2 = 0.4mg/kg)
  --> No changes in BP and HR
• Atracurium doses of 3 x ED95 (0.6mg/kg)
  --> Mild tachycardia (8.3%) and moderate drop in MAP (21.5%)
  * Transient (occurs in 60-90 seconds) and disappears within 5 minutes
  * Probably due to histamine release
  * Release of prostacyclin may also contribute (via vasodilation effect mediated by H1 and H2 receptors)

Histamine release

• Responsible for tachycardia, hypotension, and skin flushing
• Dose-related:
  * At 0.5mg/kg --> 15% increase in plasma histamine level
  * At 0.6 mg/kg --> 92% increase in plasma histamine level
  * [PI]
• CVS changes (tachycardia and hypotension) is exaggerated in patients treated with H2 receptor antagonists
  * H3 normally modulates histamine release by H2 (negative feedback)
  * H2 antagonists partially antagonises H3 receptors
  --> Inhibition of modulation --> Exaggerated histamine release
• Histamine release evoked by atracurium (and mivacurium) does not occur with subsequent doses within a short period
  * Tissue histamine stores are not replenished for several days

Other systems

• Brief episode of skin flushing due to histamine release

 

Pharmacokinetics (PK)

Absorption

• IV route only

Distribution

• Protein binding = 82%
  * Presumably to albumin

Metabolism

• Atracurium undergoes
  * Hofmann elimination, AND
  * Hydrolysis
• Both pathways are independent of hepatic and renal function, as well as plasma cholinesterase activity
  --> Lack of cumulative drug effects

Hofmann elimination

• Spontaneous degradation at normal body temperature and pH
• Nonenzymatic
• Base-catalysed reaction
• Essentially a chemical degradation
• More of a safety net
  * Probably accounts for 1/3 of the degradation

(Ester) Hydrolysis

• Hydrolysis by nonspecific plasma esterases
  * Same enzyme which hydrolyse remifentanil
• Essentially a biological degradation
• Main pathway of degradation
  * Accounts for 2/3 of the degradation
  * But according [PI], Hofmann elimination is the principle route

Metabolites

• Laudanosine is the major metabolite of both pathways
  * A tertiary amine
• Hoffmann elimination also produce electrophilic acrylates
  --> Very reactive, but clinical significance is unknown

Laudanosine

• Not active at NMJ
• May cause CNS stimulation at very high concentrations
  --> Increase MAC
• May also cause peripheral vasodilation
• But at clinical relevant concentration, peak level is about 20 times less than the level producing effects in animals
  --> Unlikey to be clinically relevant
  * Even in cases of continuous infusion (<6 days)

Production of laudanosine

• Hofmann elimination produce two molecules of laudanosine
• Ester hydrolysis produce one molecule of laudanosine

Pharmacokinetics of laudanosine

• Peak plasma concentration of laudanosine occurs 2 minutes after atracurium injection
• Concentration of laudanosine remains at approximately 75% of the peak level for about 15 minutes

Effect of pH

• Hofmann elimination is
  * Accelerated by high pH (alkalosis)
  * Slowed by low pH (acidosis)
• Ester hydrolysis is
  * Accelerated by low pH (acidosis)
  * Slowed by high pH (alkalosis)
  * Relationship with pH is opposite to that for Hofmann elimination
• Overall, pH probably does not have too much effect

Effect of temperature

• Low temperature reduces the rate of atracurium inactivation

Elimination

• Laudanosine relies on liver for clearance
  * 70% is excreted in bile
  * Rest excreted in urine
  * Biliary and urinary excretion account for >90%
• Liver cirrhosis does NOT alter clearance of laudanosine
• Biliary obstruction impairs clearance of laudanosine

Action profile

• Onset of action = 3 to 5 minutes
  * Suitable intubating condition reached within 2 - 2.5 min [PI]
• Duration of blockade = 20 - 35 minutes (before recovery starts)
  * Recovery to 25% takes about 35 - 45 minutes [PI]
  * 95% recovery within 60-70 minutes [PI]
• Time from the start of recovery (from complete block) to complete recovery (tetanic response 95% normal) is 30 minutes
  * Regardless of the dose of atracurium
  * 40 minutes if halothane, enflurane, or isoflurane were used
• Similar or slightly longer in duration than vecuronium [PI]
• With increasing dose
  * Decreased onset time
  * Prolonged duration
  * Same as other nondepolarising NMBDs [PI]

Pharmaceutics

Presentation

• 25 mg in 2.5 mL
• 50 mg in 5 mL

Composition

• Active = Atracurium besylate
• Inactive = Benzenesulfonic acid (to adjust pH)
• pH
  = 3.25 - 3.65 [SH4]
  = 3.2 - 3.7 [PI]

NB:

• Iodide salt besylate --> improve solubility in water
• pH adjusted to minimise the likelihood of in vitro degradation

Storage

• Potency of atracurium stored at room temperature decreases by 5% every 30 days

Clinical

Administration

• ED95
  = 0.2 mg/kg [SH4]
  = 0.23 mg/kg [PI]
• An initial dose of 0.4-0.5 mg/kg is generally used (1.7 - 2.2 of ED95)
  * Maximum blockade within 3-5 minutes
  * Suitable intubation condition within 2-2.5 minutes
• Subsequent maintenance dose = 0.08 - 0.10 mg/kg
  * First maintenance dose is required within 20 to 45 minutes
  * Every 15 - 25 minutes
• Continuous IV infusion = 0.3 - 0.6 mg/kg/hr
  * Should not be commenced until early recovery from inital bolus is evident

Interactions

Drugs which potentiate atracurium

• Some inhalational anaesthetics
  * Isoflurane and enflurane increase potency by about 35%
  * Halothane has only marginal effect (20%)
  * No information on any potential interaction with sevoflurane or desflurane
• Antibiotics (aminoglycosides, tetracycline, clindamycin, vancomycin)
• Antiarrhythmic drugs (lignocaine, procainamide, quinidine)
• Beta-blocker (propranolol)
• Calcium channel blockers (verapamil)
• Diuretics (frusemide, thiazides, acetazolamide)
• Others (magnesium, ketamine, lithium, quinine)

Drugs reducing NMJ effect of atracurium

• Chronic anticonvulsant therapy (carbamazepine and phenytoin) [PI]
  * Not so according to [SH4:p226]

Special consideration

Paediatrics

• Doses of atracurium (mg/m2) are similar from > 2 years old
• Infants 1 to 6 months old:
  * Are more sensitive to atracurium (requires only 1/2 the dose)
  * But also recover faster
• Safety and effectiveness not established in children < 1 month old

Elderly patients

• Age has NO effect on the pharmacokinetics or pharmacodynamics aspects of atracurium

Pregnancy

• Atracurium crosses the placenta, but no demonstrated adverse effects in the fetus or newborn infant
• Atracurium has been shown to be potentially teratogenic
• If patient is receiving magnesium sulfate
  --> The reversal of neuromuscular blockade may be unsatisfactory

Renal dysfunction

• Patients with renal failure have an apparent tolerance to atracurium
  --> Slower onset of action, and higher level during recovery
  * Not as prominent as in the case of vecuronium
  * [SH4:p236]

Trivia

History

• First synthesized in 1974 by George Dewar