3. Old stuff
          3.1. Old pharm stuff (pre 2009)
              3.1.3. Pharmacology
                  3.1.3.3. IV anaesthetic agents
 3.1.3.3.3. Etomidate 

Etomidate

[SH4:p163-167]

Usage

  • Alternative drug for induction of anaesthesia
    * Especially with unstable cardiovascular system

Structure

Structure

  • Carboxylated imidazole-containing compound
  • Similar to midazolam
    * Water soluble at low pH
    * Lipid soluble at physiological pH
  • Etomidate is unique amongst IV and inhaled anaesthetics in that it is administered as single isomer R(+)
    * R(+) has 5 times the potency as S(-)

Pharmacodynamics

Mechanisms of action

Etomidate is a relatively selective modulator of GABAa receptor
--> Binds directly to site(s) on the receptor protein
--> Enhance affinity of GABA transmitter for GABAa receptors

Effects by system

CNS

  • Potent direct vasoconstrictor
    --> 35-45% decrease in CBF and CMRO2
    * Comparable to thiopentone
  • Frequency of excitatory spikes on EEG is greater with etomidate than with thiopentone or methohexitone
    --> Use with caution in patients with history of seizures or focal epilepsy

CVS

  • CVS stability
    * with induction dose of 0.3 mg/kg of etomidate
    * HR, SV, CO remains constant
  • Small drop in MAP
    * Up to 15%
    * Due to similar drop in SVR
  • Within higher dose (0.45 mg/kg)
    --> Significant decrease in CO and MAP
  • No negative inotropic effect at clinically relevant concentration
  • Etomidate does NOT greatly decrease renal blood flow
    * Other IV anaesthetic agents greatly decrease renal blood flow

Respiratory

  • Depressant effects of etomidate is LESS than barbiturates
  • In most cases, decreases in tidal volume is compensated by increase in RR
  • Effects on ventilation are transient
    * Lasts 3-5 minutes
  • May also stimulate ventilation independently of medullar centres

Other systems

  • Hepatic and renal function unaffected
  • Intraocular pressure decreased
    * Comparable to thiopentone
  • No detrimental effect when injected arterially
  • No pain on injection with lipid emulsion formulation
  • Very low incidence of allergy
  • May increase incidence of PONV
  • Does not cause histamine release

Side effects / Toxicity

Depression of adrenocortical function

  • The main limiting factor in clinical usage of etomidate
  • Dose-dependent inhibition of conversion of cholesterol into cortisol
    * Via inhibition of 11-beta-hydroxylase
    * Evidenced in accumulation of 11-deoxycorticosterone
    * Unresponsive to ACTH
  • Inhibition lasts 4-8 hours after induction dose
  • Some reports no suppression after one induction dose
  • Reason for etomidate not being used for maintenance of sedation in ICU

NB:

Adrenocortical failure could lead to:

  • Hypotension
  • Hyponatremia
  • Hypoglycaemia
  • Hyperkalaemia
    * Excess resorption of urinary K+

Involuntary myoclonic movements

  • IV anaesthetics (including etomidate) can cause excitatory movements
    * Myoclonus
    * Dystonia
    * Tremour
  • With etomidate, spontaneous movement (esp myoclonus) occurs in 50-80% of patients without premedications.
  • Incidence reduced by prior administration of opioid, benzodiazepine, or small dose of etomidate
Mechanism of myoclonus
  • Etomidate reduces subcortical inhibition which normally suppress extrapyramidal motor activity

Pharmacokinetics (PK)

Absorption

  • IV
  • Transmucosal

Distribution

  • Protein-binding = 76% (to albumin)
    * But decrease in albumin will still increase unbound fraction of etomidate significantly
  • Vd = 2.2 - 4.5 L/kg

Metabolism

  • High hepatic extraction
  • Hydrolysis by
    * Hepatic microsomal enzyme
    * Plasma esterase
  • Hydrolysis of the ethyl ester side-chain
    --> Carboxylic acid ester metabolites (inactive)

Elimination

  • <3% of etomidate is excreted in urine unchanged
  • Metabolites are excreted:
    * 85% in urine
    * 10-13% in bile
  • Clearance = 10-20 mL/kg/min
    * Clearance is about 5 times that for thiopentone

Action profile

  • Peak level within 1 minute
  • Elimination half-time = 2-5 hours
  • Duration of action is dose-dependent
    * Usually 3-5 minutes with induction dose of 0.3mg/kg
    * [Drugs.com]

 

NB:

  • Prompt awakening is due to:
    * Redistribution
    * Rapid clearance

Pharmaceutics

Formulation

[SH4:p164]

  • Original formulation = 35% propylene glycol (pH 6.9)
    * High incidence of pain on injection
  • Later changed to fat emulsion
    * No pain on injection
    * Same incidence of myoclonus
  • Also available as transmucosal preparation
    * Bypass first-pass metabolism

NB:

[SS3:p152]

  • pH 8.1 for aqueous solution ?fat emulsion

Physicochemical properties

  • Weak base with pKa of 4.2
    --> 99% unionised at physiological pH

Clinical

Administration

  • Induction dose = 0.2-0.4 mg/kg IV
  • At smaller dose (0.15-0.3mg/kg), etomidate has minimal effect on seizure duration
    * Unlike propofol

Indications/contraindication/precautions

Contraindication

  • Not to be used for maintenance of anaesthesia

Precautions

Use with caution in patients with

  • History of seizures or focal epilepsy
  • Immunosuppression/transplantation
  • Sepsis

Special consideration

Paediatrics

Only for children >10 year old