3. Old stuff
          3.1. Old pharm stuff (pre 2009)
              3.1.3. Pharmacology
                  3.1.3.7. Neuromuscular blocking drugs
                      3.1.3.7.2. Non-depolarising NMBDs
                          3.1.3.7.2.2. Intermediate-acting nondepolarising NMBDs
 3.1.3.7.2.2.1. Atracurium 

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