Non- Barbiturate Intravenous Induction AgentsSedative-hypnotics

Question 1

Propofol chemical characteristics

Answer 1

Ampofol-Low lipid formulation 5% soy, 0.6% egg lecithin
Needs no preservative
Higher incidence of pain w/ injection
Non-lipid formulations:
Aquavan-prodrug: adding groups to the parent drug (ie :phosphate monoesters)
Hydrolysis in plasma, can be unpredictable
Slower onset, higher VD, higher potency

Question 2

Mech of action propofol

Answer 2

Receptor interactions
GABAA (major)
Glycine (minor)
Decrease rate of dissociation of GABA from GABAA
No spinal cord depression

Question 3

Propofol Pharmacokinetics

Answer 3

Vd 3.5-4.5 L/kg
Clearance exceeds hepatic blood flow
2-3 compartment model of distribution
Weight, co-existing disease, age, co-administration of other drugs affect pharmacokinetics
T ½ Elimination 0.5-1.5 hours

Question 4

Propofol CNS effect

Answer 4

Chloride Channel activation of 1 subunit of GABA receptor and NMDA inhibition
Rapid onset, one arm-brain circulation
Decreases CBF, ICP, CMRO2 and CPP, cerebral protective
EEG burst suppression
Age affects ED95
Age- ED95 highest in toddlers, decreases with age. In elderly MUST reduce dose.
Hiccoughing, muscle twitching can occur
Hallucinations, opisthotonos
Decreases IOP
Antioxidant effects resemble Vitamin E cerebral protection

Question 5

Propofol resp Effects

Answer 5

Apnea following induction dose
Decreases TV, RR 
Decreases ventilatory response to CO2 and hypoxia
PaCO2 rises, pH decreases
Bronchodilation in COPD patients
HPV remains intact

Question 6

Propofol cardiovascular effects

Answer 6

25-40% decrease in BP
Greater than with STP
Dose dependent myocardial depression and vasodilation result in
Similar decreases in SV, C.O. and SVR
Heart rate unchanged (? baroreceptor inhibition)

Question 7

Other propofol effects

Answer 7

Does NOT potentiate muscle relaxants!!
Myoclonus
Incidence of myoclonus is higher than with TPL but less than with etomidate and brevital.
Pain on injection
Antiemetic and antipruritic at sub-hypnotic doses, 10mg
Mechanism of anti-emetic/pruritic effect unknown.
Amnestic at doses >30 mcg/kg/min
Crosses placenta, rapidly removed from fetal circulation

Question 8

Uses and dose

Answer 8

Induction: 1-2.5 mg/kg*
*As high as 3 mg/kg in toddlers due to pharmacokinetic differences

GA Maintenance Infusion: 100-300 mcg/kg/min

Sedation Infusion: 25-100 mcg/kg/min

Question 9

Propofol metabolism

Answer 9

Conjugated in liver to water soluble compounds
CP-450 system
Liver function does not affect the rate of metabolism
Metabolites mostly inactive
4-hydroxypropofol is ~ 1/3 as potent
Renal Excretion-CRF doesn’t affect clearance.
Highly metabolized, less than 3% excreted unchanged.

Question 10

Etomidate chemical structure

Answer 10

Carboxylated Imidazole derivative
Imidazole refers to the parent compound C3H4N2.
Propylene glycol solvent
pH 6.9- so it is water soluble in solution
At physiologic pH, becomes highly lipid soluble

Question 11

Etomidate mechanism of action

Answer 11

Selective GABAA
Binds to a specific site on the receptor
Increases the affinity of GABA to GABAA

Question 12

Etomidate Pharmacokinetics

Answer 12

Onset of action rapid, one “arm to brain circulation” with
Highly lipid soluble, weak base pH 8.2
Vd 2.5 – 4.5 L/kg
Redistribution terminates hypnotic effect
3 compartment model
Elimination half-life 3-5 hours
High hepatic extraction ratio and clearance
Changes in liver blood flow or function will prolong effects
75% Protein Bound

Question 13

Etomidate Phamacologic effects

Answer 13

Rapid loss of consciousness after single dose

No analgesia

Direct cerebral vasoconstriction results in decreased CBF, ICP and CMRO2

Reduces IOP

Increases EEG activity in epileptogenic foci,

Rare association with Grand Mal Sz

Produces myoclonic movement

Also possesses anticonvulsant properties