Table compiled by

B.J. So, Feb 2018 Propofol Thiopentone Ketamine Etomidate Midazolam

Structure and
class1,4
Pharmaceutics

2,6-diisopropylphenol Thiobarbiturate Phencyclidine derivative Carboxylated imidazole derivative Imidazobenzodiazepine

(a phenol derivative)
1% propofol emulsion with: Yellow powder stored with 6% Na2CO3 Clear colourless solution (typically 10mg/ml) Original: clear colourless solution with 35%
10% soybean oil Clear colourless solution with pH 3.5
propylene glycol (pH 6.9)
Distinguishing 2.25% glycerol 500mg reconstituted in 20ml water = 2.5% solution (mostly ring open; protonated)
pH 3.5-5.5
pharmaceutic 1.2% purified egg phosphatide (pH 10.5 to prevent microcrystal formation)
Later: lipid emulsion (pH 7.6)
features Sodium hydroxide Demonstrates tautomerism with open (acidic) and
Racemic mixture: Racemic mixture:
closed (basic) ring forms
Neutral pH 7.4 S- enantiomer more potent at GABAA S(+) has x4 greater affinity for NMDA receptor Enantiopure in the R(+) form
PK: A

Absorption4 N/A N/A 25% (PO), 50% (nasal), 93% (IM) N/A 50% (PO)

pKa1 11.0 (acid) 7.6 (acid) 7.5 (base) pKa 4.2 (base) pKa 6.15 (base)
% non-ionised at
99.7% 61% 44% 99% 90% (ring open; unprotonated)
pH 7.43
PK: D

Protein binding1 98% (very highly bound) 1,4 80% (highly bound) 20% (minimally bound) 75% (highly bound) 98% (very highly bound)
VDss4 4 L/kg 2 L/kg 3 L/kg 4 L/kg1 1 L/kg1
Follows a 3-compartment model Follows 3-compartment model x5-10 more lipid soluble than thiopentone Follows 2 or 3 compartment model Follows 2 compartment model
Comments Offset of clinical effects mainly due to distribution Offset of clinical effects mainly due to distribution Offset of clinical effects mainly due to distribution Offset of clinical effects mainly due to distribution Offset of clinical effects mainly due to distribution
60%: CYP2B6 hydroxylation +
P450 oxidation in liver with low hepatic extraction Hydrolysis by CYP3A4 into active and inactive
glucuronidation and sulfation in liver with high ER Demethylation and hydroxylation in liver
coefficient (15%) ∴ clearance is capacity-limited
PK: M

1 ∴ clearance is flow-dependent Hydrolysis by hepatic and plasma esterases into metabolites.

Metabolism
Zero-order kinetics at high concentrations inactive metabolites
40%: Extra-hepatic metabolism in kidney + small Norketamine metabolite ~25% potency
(Michaelis–Menten elimination) 1-hydromidazolam has 50% potency
intestine
Elimination half-life 0.5 – 1.5 hours3
PK: E

Excretion4 Elimination half-life 3-22 hours4 Elimination half-life 2-3 hours3 Elimination half-life 2-5 hours3 Elimination half-life 2 hours3
CSHT after 8-hour infusion: <40 mins3
Typical Dose 2mg/kg 5mg/kg 1-2mg/kg 0.3mg/kg
0.3 mg/kg1
(range) (1.5-2.5mg/kg) (2-7mg/kg) (0.2-0.5mg/kg for analgesia) (0.2-0.4 mg/kg)
PD: D

Onset1 1 minute2,4 1 minute1 1 minute2 1 minute4 2 minutes1

Duration1 5-10 minutes2 3-7 minutes1 10-15 mins, with ~60 min amnesia3 6-10 minutes4 20 minutes1
(or 4.5 hours after 3-day infusion)
Potentiates GABAA receptor activity Non-competitive antagonist of NMDA
PD: M

Mechanism3 Potentiates GABAA receptor activity (allosteric binding causing ↑GABA affinity) Potentiates GABAA receptor activity Potentiates GABAA receptor activity
(decreases rate of GABA dissociation from receptor)3
receptor (enhances affinity of GABA at receptor)3 (allosteric binding causing ↑GABA affinity)3
*Can directly act on GABAA receptors at high dose* (acts on phencyclidine binding site)
↓CBF, ↓ICP, ↓CMRO2 ↓CBF, ↓ICP, ↓CMRO2 ↑CBF, ↑ICP, ↑CMRO2 ↓CBF, ↓ICP, ↓CMRO2 ↓CBF, ↓ICP, ↓CMRO2
CNS1,3,4 Anticonvulsant Anticonvulsant Anticonvulsant Epileptogenic Anticonvulsant
↓IOP ↓IOP ↑IOP ↓IOP ↓IOP
Potent depressant (*depresses baroreceptor reflex) Mild CVS depressant CVS stimulant + ↑myocardial O2 demand Relatively CVS neutral Mild CVS depressant
CVS1,3,4 (↓contractility, ↓↓SVR, ↓HR*) (↓contractility, ↓SVR, but ↑HR) (↑contractility, ↑HR, but ↔SVR) (MAP, HR, SVR unchanged) (↓contractility, but ↔SVR and ↑HR)
Potent respiratory depressant Potent respiratory depressant No respiratory stimulation/depression
Minimal respiratory depression
Resp1,3,4 Supresses laryngeal reflexes Can cause laryngospasm Preserves airway reflexes + ↑secretions Respiratory depressant
Associated with hiccupping
PD: E

Causes bronchodilation Can cause bronchoconstriction Effective bronchodilator

Painless if given IV Painful in original form
Irritation1,3,4 Pain on injection None None
Highly irritant if extravasates due to alkalinity Painless in lipid emulsion form
“Dissociative anaesthesia” Contraindicated in porphyria
Antiemetic (EEG dissociation between thalamocortical Contraindicated in porphyria
Antipruritic and limbic systems)
Inhibits adrenal steroidogenesis
Contraindicated in porphyria ↓PONV
Other1,3,4 Propofol infusion syndrome ↑PONV ↑PONV
Enzyme inducer Can inhibit platelet aggregation
(in large prolonged doses: metabolic acidosis, Can inhibit platelet aggregation Can inhibit platelet aggregation
rhabdomyolysis, multi-organ failure)
Prolonged use can lead to withdrawal in paeds
Risk of emergence delirium Associated with myoclonic jerks
Sources: 1 Evers Anesthetic Pharmacology 2nd ed., chapter 27-28 / 2 Miller’s Anesthesia 8th ed., chapter 30/ 3 Stoelting Pharmacology and Physiology in Anesthesia 5th ed., chapter 5 / 4 Oxford Handbook of Drugs 5th edition / 5 Peck and Hill Pharmacology 4th edition chapter 9