Table compiled by

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

s

t
Structure and
u

e
class1,4
c

2,6-diisopropylphenol
(a phenol derivative) Thiobarbiturate Phencyclidine derivative Carboxylated imidazole derivative Imidazobenzodiazepine

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

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

K
pKa1 11.0 (acid) 7.6 (acid) 7.5 (base) pKa 4.2 (base) pKa 6.15 (base)
P

% non-ionised 99.7% 61% 44% 99% 90% (ring open; unprotonated)

at pH 7.43

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

Comments 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
Offset of clinical effects mainly due to distribution Offset of clinical effects mainly due to distribution Offset of clinical effects mainly due to Offset of clinical effects mainly due to distribution Offset of clinical effects mainly due to distribution
distribution
M

Metabolism1 60%: CYP2B6 hydroxylation + P450 oxidation in liver with low hepatic Demethylation and hydroxylation in liver Hydrolysis by hepatic and plasma esterases Hydrolysis by CYP3A4 into active and
glucuronidation and sulfation in liver with high extraction coefficient (15%) ∴ clearance is into inactive metabolites inactive metabolites.
K

ER ∴ clearance is flow-dependent capacity-limited Norketamine metabolite ~25% potency

1-hydromidazolam has 50% potency
40%: Extra-hepatic metabolism in kidney + Zero-order kinetics at high
small intestine concentrations (Michaelis–Menten
elimination)
E

K
Excretion4 Elimination half-life 0.5 – 1.5 Elimination half-life 3-22 hours4 Elimination half-life 2-3 hours3 Elimination half-life 2-5 hours3 Elimination half-life 2 hours3
hours3 CSHT after 8-hour infusion:
P

<40 mins3
D

D
Typical Dose 2mg/kg 5mg/kg 1-2mg/kg 0.3mg/kg 0.3 mg/kg1
P

(range) (1.5-2.5mg/kg) (2-7mg/kg) (0.2-0.5mg/kg for analgesia) (0.2-0.4 mg/kg)

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

M

Mechanism3 Potentiates GABAA receptor Non-competitive antagonist of Potentiates GABAA receptor Potentiates GABAA receptor
(decreases rate of GABA dissociation from activity (allosteric binding causing activity (enhances affinity of GABA at activity (allosteric binding causing
D

receptor)3
NMDA receptor
↑GABA affinity) (acts on phencyclidine binding site) receptor)3 ↑GABA affinity)3

*Can directly act on GABAA receptors at high dose*

:
CNS1,3,4 ↓CBF, ↓ICP, ↓CMRO2 ↓CBF, ↓ICP, ↓CMRO2 ↑CBF, ↑ICP, ↑CMRO2 ↓CBF, ↓ICP, ↓CMRO2 ↓CBF, ↓ICP, ↓CMRO2
D

P
Anticonvulsant Anticonvulsant Anticonvulsant Epileptogenic Anticonvulsant
↓IOP ↓IOP ↑IOP ↓IOP ↓IOP

CVS1,3,4 Potent depressant (*depresses baroreceptor Mild CVS depressant CVS stimulant + ↑myocardial O2 Relatively CVS neutral Mild CVS depressant
reflex) (↓contractility, ↓↓SVR, ↓HR*) (↓contractility, ↓SVR, but ↑HR) demand (↑contractility, ↑HR, but (MAP, HR, SVR unchanged) (↓contractility, but ↔SVR and ↑HR)
↔SVR)

Resp1,3,4 Potent respiratory depressant Potent respiratory depressant No respiratory stimulation/depression Minimal respiratory depression Respiratory depressant
Supresses laryngeal reflexes Can cause laryngospasm Preserves airway reflexes + Associated with hiccupping
Causes bronchodilation Can cause bronchoconstriction ↑secretions Effective bronchodilator

Irritation1,3,4 Pain on injection Painless if given IV None Painful in original form None
Highly irritant if extravasates due to alkalinity Painless in lipid emulsion form

Other1,3,4 Antiemetic Contraindicated in porphyria “Dissociative anaesthesia” Contraindicated in porphyria Contraindicated in porphyria
Antipruritic Enzyme inducer (EEG dissociation between thalamocortical Inhibits adrenal steroidogenesis ↓PONV
Propofol infusion syndrome and limbic systems) ↑PONV Can inhibit platelet aggregation
(in large prolonged doses: metabolic acidosis, ↑PONV Can inhibit platelet aggregation Prolonged use can lead to withdrawal in paeds
rhabdomyolysis, multi-organ failure) Can inhibit platelet aggregation Associated with myoclonic jerks
Risk of emergence delirium

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