FRCA Notes

Propofol

  • Propofol, or 2, 6 - di-isopropylphenol, is an alkyl phenolic derivative
  • It is highly lipid but poorly water soluble
  • As such it presents as a milky-white lipid-in-water emulsion containing:
    • 1% or 2% propofol
      • Some preparations contain medium and long chain triglycerides to reduce pain on injection (propofol-lipuro)
    • 10% soya bean oil [NB unlikely to trigger soy protein allergy]
    • 2.25% glycerol
    • 1.2% purified egg phosphatide [NB unlikely to trigger egg protein allergy]
    • NaOH to adjust pH
    • ± EDTA or sodium metabisulphite to reduce bacterial growth

Potential additives

  • 1% lidocaine immediately prior to use to reduce pain on injection
  • 5% dextrose
  • Alfentanil in a ratio of 20 - 50:1 e.g. for 'dirty TIVA'
  • Other drugs may crack the emulsion, alter pharmacokinetics or spontaneously degrade the drug

  • Induction of anaesthesia
    • IV bolus e.g. 1-2mg/kg
    • IV TCI e.g. Marsh, Shnider, Eleveld or Bristol models
  • Maintenance of anaesthesia including sedation of ventilated patients on ICU
  • Procedural sedation e.g. for endoscopy
  • Control of status epilepticus
  • Anti-emetic in ondansetron-resistant chemotherapy patients

  • The emulsion is stable at room temperature and in light
  • Has a pH of 7.0 - 8.5
  • Isotonic
  • Has a molecular weight of 178.28

Absorption

  • It is a weak organic acid with a pKa of 11
  • Therefore at physiological pH is almost entirely unionised

Distribution

  • 98% albumin bound
  • Volume of distribution is >4L/kg
    • Volume of distribution very large as essentially wholly unionised at physiological pH and very lipophilic
  • Uses a 3-compartment model with a central compartment of 20-40L

  • Has a very high hepatic extraction ratio and is therefore hepatic blood flow-dependent and hepatic enzyme capacity-independent
    • Its hepatic extraction will be increased by drugs increasing hepatic blood flow and vice-versa
    • Hepatic extraction ratio not increased by drugs that induce its metabolising CYP2C9 enzymes

Metabolism

  • Metabolism is primarily hepatic by the CPY2C9 subfamily and CYP2B6
    • 60% to a quinol, which is excreted in the urine as an inactive glucuronide/sulphate metabolite
    • 40% to a glucuronide directly

  • Some metabolism is extra-hepatic (as clearance exceeds hepatic blood flow):
    • <1% excreted unchanged in urine
    • 2% excreted in faeces
    • Some excreted via lungs

Excretion

  • Clearance 30-60ml/min/kg
  • Steady state half life of 5-12hrs
  • Context sensitive half-time for infusions <8hrs is 40mins
  • Bolus half-time about 2-5mins

Respiratory

  • Dose-dependent respiratory depression, leading to apnoea
  • Suppresses airway reflexes so rare to cause cough or laryngospasm
  • Can cause a small degree of bronchodilation in those with COPD

Cardiovascular

  • Reduces SVR
    • Reduces sympathetic activity, causing vasodilation
    • Stimulates NO pathway
    • 15 - 20% reduction in SVR (although one study found ∽85% reduction in total peripheral resistance)

  • Reduces cardiac output (approx. 15%)
    • 25% reduction in stroke volume
    • 30% reduction in LV stroke work index
    • Reduces myocardial contractility
    • Effect on SV appears to be:
      • Age-dependent; greater effect in older patients
      • Dose-dependent; greater effect at lower doses (plasma conc. <1.1μg/ml) and lesser at higher doses due to the baroreceptor feedback mechanism
  • May attenuate reperfusion injury

Neurological

  • Mediates its effects primarily through GABAA receptor (hypnotic effect) and glycine receptor agonism
  • Does antagonise neuronal nAChR (sedative effect)
  • Can cause excitatory effects in up to 10% of patients
    • Due to subcortical excitatory-inhibitory imbalance
    • Dystonic movements with choreiform elements and opisthotonos

Gastrointestinal & metabolic

  • Anti-emetic properties thought to be due to D2 receptor antagonism
  • Can cause propofol infusion syndrome
  • Antioxidant and free radical scavenger

Other effects

  • Pain on injection, reduced by using a larger vein/cannula, slower injection, 1% lidocaine, lipuro preparation

  • Can turn urine and hair green

  • Synergistic effect with opioids