Vecuronium

[SH4:p235-p238]

Quick summary

 

 

Usage

• Non-depolarising intermediate-acting NMBDs

Structure

Structure

• Vecuronium is pancuronium without the quaternary methyl group in the A-ring of the steroid nucleus
  * Vecuronium is monoquaternary
  * Pancuronium is bisquaternary

Structure-activity relationship

• Absence of the second quaternary methyl group
  * Less acetylcholine-like character, compared to pancuronium
• Monoquaternary structure
  --> Increased lipid solubility (compared to pancuronium)

Pharmacodynamics

Side Effects/Toxicity

CNS

• NMBD may cause excitement and seizure when injected into CNS
• Vecuronium is a lot less potent than pancuronium or atracurium in producing seizures

CVS

• Typically devoid of circulatory effect even with doses > 3 x ED95
  --> Lack of vagolytic effect or histamine release

Intraocular pressure

• Vecuronium does not increase intraocular pressure
• But it does not prevent increases in intraocular pressure due to tracheal intubation either

Pharmacokinetics (PK)

Absorption

IV

Distribution

Protein-binding = 60-90%
* [SS3:p393]

Vd = 0.18 - 0.27 L/kg
* [SS3:p393]

Metabolism

• Mostly by hepatic metabolism
• Increased lipid solubility --> Better entry into hepatocytes (greater hepatic uptake)
• Increased lipid solubility --> Greater biliary excretion

Deacetylation

• Metabolites include:
  * 3-desacetylvecuronium
  * 17-desacetylvecuronium
  * 3,17-desacetylvecuronium
• 3-desacetylvecuronium has 1/2 the potency of the parent drug
  * But rapidly converted to 3,17-desacetylvecuronium
• 3,17-desacetylvecuronium and 17-desacetylvecuronium have less than 1/10 the potency of the parent drug

BUT,

Miller has very different statement about 3-desacetylvecuronium

[RDM6:p508]

• 3-desacetylvecuronium is
  * Principle metabolite of vecuronium
  * Potent NMBD (80% of vecuronium potency)
  * Low plasma clearance (3.5 mL/kg/min)
  * Longer duration of action than parent compound
  * 1/6 of clearance of this metabolite is renal --> Even longer duration in renal failure

Elimination

• 40% of vecuronium is excreted unchanged in the bile in the first 24 hours
  --> Biliary excretion is the major route of elimination
• 30% excreted in urine (unchanged form and metabolites)
  * Less dependent on renal elimination than pancuronium
• Clearance = 5 - 6 mL/min/kg

Action profile

• First depression of twitch = within 1 minute
• Intubation condition = within 2.5 - 3 minutes
• Maximum NMJ blockade = within 3 - 5 minutes
• Duration of NMJ blockade = 20 to 35 minutes
• Elimination half-time = 60-80 minutes

Physicochemical properties

• Unstable in water (due to hydrolysis)
  --> Supplied as lyophilised powder
• More lipid soluble than pancuronium
• pKa = 8.97 [PI]

Pharmaceutics

Presentation

• Sterile lyophilised powder for reconstitution
• 4mg and 10 mg vials
  --> To be reconstituted to 2mg/mL

Composition

• Active = Vecuronium bromide
• Inactive
  * Citric acid, sodium phosphate
  * NaOH and/or phosphoric acid to buffer and adjust pH
  * Mannitol to adjust tonicity
• After reconstitution, pH = 4

Storage

• Unreconstituted vecuronium can be kept for up to 2 years with stored below 25 degrees Celcius.

Clinical

Administration

• ED95 = 0.05 mg/kg
• Initial dose = 0.1 mg/kg
• Incremental dose = 0.02 - 0.04 mg/kg

Special consideration

Renal dysfunction

• In renal failure, elimination half-time of vecuronium and 3-desacetylvecuronium is prolonged
• Patients with renal failure have an apparent tolerance to vecuronium
  --> Slower onset of action, and higher level of vecuronium during recovery

Hepatic dysfunction

• In patients with hepatic dysfunction, the elimination half-time and duration of action are more prolonged at higher doses

Acid-base disturbance

• Changes in pCO2 which precedes vecuronium administration
  --> No effect
• Increase in pCO2 after NMJ blockade is established with vecuronium
  --> Significant potentiation of vecuronium effect
  --> May be significant in postoperative hypoventilation

Cumulative effect

• Vecuronium has a large Vd
• Redistribution contributes significantly to the decrease in plasma level of vecuronium
• Repeated dosing has a cumulative effect
  * Less than pancuronium
  * Greater than atracurium
• Cumulation of 3-desacetylvecuronium may contribute to prolonged effect
  * Especially in renal dysfunction

Paediatrics

• Potency in infants, children, and adults are similar
• Onset of action is more rapid in infants
  * Due to high cardiac output
• Duration of action is longest in infants
  * Due to immature liver enzyme or increased Vd or smaller biliary clearance
• Duration of action is shortest in children

Elderly

• Elimination half-time and dose-response curves from single dose of vecuronium
  --> Not influenced by age
  * Responsiveness of NMJ is unchanged
• Lower rate of infusion of vecuronium is needed in elderly due to decreased clearance
• Decreased clearance due to
  * Age-related decrease in hepatic blood flow
  * Age-related decrease in renal blood flow
  * Possibly decreased hepatic microsomal enzyme
• Vd is also decreased in 70-80 year olds

Obstetrics

• Clearance of vecuronium may be accelerated during late pregnancy, due to
  * Stimulation of hepatic microsomal enzymes by progesterone
  * Increased cardiac output and fluid shifts
• Duration of action of vecuronium is increased in the immediate postpartum period

Obesity

• Duration of action of vecuronium is prolonged in obesity ( >130% of ideal body weight)
  * Unlike atracurium

Malignant hyperthermia

• Malignant hyperthermia does not follow administration of vecuronium or atracurium