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
 3.1.3.7.2.2.3. Vecuronium 

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