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