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Etomidate (Amidate™) is short-acting intravenous anesthetic agent first developed in 1964. It is available and used in the United Kingdom, Europe, New Zealand, United States, but not Australia.
Advocates highlight etomidate's hemodynamic stability when used for induction. Critics point to the well-established adrenocortical suppression, and wide-range of suitable alternatives (propofol, ketamine, thiopentone) in trained hands.
A. Physiochemistry
- Carboxylated imidazole
- 2 isomers - only R(+) hypnotic
- Haemodynamic stability, minimal respiratory depression, cerebral protection, wide margin of safety.
- Originally formulated in propylene glycol (painful), now in soybean lipid.
B. Pharmacokinetics
- Dose - 0.3 mg/kg (0.1-0.4 mg/kg)
- Absorption - IV
- Distribution - 4 L/kg
- Protein binding - 75% (like thiopentone)
- Onset 30-60s ; Offset
- Metabolism - alpha1 ½ 2.5m, alpha2 ½ 30m, tß½ 3.5h; hepatic ester hydrolysis of ester side chain.
- Clearance - 20 mL/kg/min
C. Pharmacodynamics
- Mech - probably by GABAa receptors.
- CNS - hypnosis; no analgesic action; ⇣ CBF and CMRO2
- CVS - stable; may have slight dec MAP 15% due to ⇣ SVR.
- Resp - minimal; sometimes brief hypoventilation or apnoea post-induction.
- Endo - adrenocortical suppression - inhibits 11ß-hydroxylase (11-deoxycortisol → cortisol). Temporary & reversed by vit C.
- ⇡ ICU mortality when used for sedation.
- SEs - excitatory phenom, involuntary muscle movement (50%), PONV (30%), thrombophlebitis (20%), pain on injection.
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Sedative-hypnotic drug with anaesthetic and anticonvulsant effects.
A. Physiochemistry
- Thiobarbiturate
- Highly lipophilic
- Presented in glass ampoule containing 2.5% powdered form: a. 500 mg thiopentone (anhydrous yellow powder) b. 30 mg sodium carbonate (buffer) c. 0.8 atm of N2 (reduces oxidation)
- made up with H2O to 20 mL
- pH 10.8, pKa 7.6 (ie. ~ pH 11 pKa 7)
- Weak acid
- 60% non-ionised @ pH 7.4 (vs. methohexitone 75%)
- Racemic mixture (l potency > d)
- Demonstrates tautomerism, with water soluble enol form (double bond) in solution → lipid sol keto form at pH 7.4.
- First administered 1934
B. Pharmacokinetics
- Dose - 5 mg/kg (methohexitone 2-3x more potent)
- Absorption - IV, oral, rectal (at higher doses)
- Distribution - Vdcc 0.4 L/kg, Vdss 2.5 L/kg
- fat:blood coeff 11:1 (ie. thio will move into fat until [fat] 11x [blood])
- Protein binding - 75% (prop 98%, methohex 65%)
- Onset within 1 brain-arm circ time (< 60s), Offset 5-15 min
- Metabolism - alpha1 ½ 5 min, alpha2 ½ 1 h, ß ½ 8-11 h, CSHT-8h: 3 h; phase I p450 side-arm oxidation, desulfuration to pentobarbitone (t½ 40h) and ring cleavage to urea and 3-carbon fragments.
- some extrahepatic (renal) metab.
- NB: alpha1 ½ (fast-alpha) is equilibration with/from effect site - alpha2 ½ (slow-alpha) with slow compartments.
- Clearance - 4 mL/kg/min (methohexitone: 3x greater 12 mL/k/m)
C. Pharmacodynamics
- Mech - potentiates GABA inhibition, dec rate of GABA dissociation (like propofol) and at high doses directly activ GABA rec.
- CNS - anaesthetic, anticonvulsant, sedative, ant-analgesic.
- Dec CBF, CMRO2 (max 55%), ICP, IOP.
- EEG (alpha → theta → delta) ⇣ freq, ⇡ ampl → burst suppression → isoelectric.
- Some focal cerebral protection (requires 40 mg/kg !!)
- CVS - Negative inotrope (direct effect and indirect dec SNS outflow), dec CO 20%, vasodilation, dec venous return → ⇣ MAP 20-30%. Compensatory ⇡ HR.
- Histamine release & dysarrythmias rarely occur.
- Resp
- Respiratory depression (initial ⇡ TV, ⇣ RR)
- Bronchoconstriction & laryngospasm risk (due to ⇣ SNS outflow).
- Renal - ⇣ RBF & GFR 2° ⇣ BP.
- GIT - ⇣ GIT motility, ⇣ HBF, enzyme induction.
- SEs - inhibits neutrophil function; anaphylaxis 1:20,000; porphyria (stims d-ALA synth); inta-arterial injection; thrombophlebitis (> methohexitone 3-4%).
- Crosses placenta; foetal tß½ 11-44h.