Etomidate

[SH4:p163-167]

Usage

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

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]