Propofol
Chemical
Non-barbiturate phenol derivative IV anaesthetic agent
Use
- Induction & maintenance anaesthesia
- Sedation
- Cerebral protection in ICU
- PONV
- Hx of malignant hypertension
Presentation
20mL lipid emulsion
1% propofol (200mg)
- Egg lethicin 1% → emulsify intralipid
- Glycerol 2.25% → isotonicity
- Soyabean 10% → intralipid
- NaOH → brings pH >7
- Benzyl alcohol / EDTA / sodium metabisulfide → retards bac / fungal growth
- PPF is insoluble in H2O → must be mixed in a lipid emulsion to make it soluble (this is expensive)
- pKa 11 (50% ionised, 50% unionised) = weak organic acid = 99% UNIONISED at pH 7.4
- A weak acid moving into a more acidic enviro becomes less ionised
- Highly lipid soluble
Dose
Induction → 2mg/kg
Maintenance → 6 – 10mg/kg/hr
Sedation → 2 – 4mg/kg/hr
PONV → 0.6mg/kg/hr
Route
IV only → pain on injection
Onset
- Extremely rapid
- 1-arm-brain-circulation time ~15secs
- Short effect site equilibration ∴ LOC ~30 sec
- Peak effect 2 mins
DoA
Rapid distribution & elimination = rapid recovery
Awakening occurs at [PPF] 1mcg/mL
Short C5HT <40 mins for 8hr infusion
MoA
- Unclear → ∴ no antidote
- Potentiates actions of GABA & Glycine (main inhibitory NT of CNS/SC)
PD
CNS
- Sedation & hypnosis
- NO ANALGESIA
- Amnesia (same as midaz, Fent has more)
- Anticonvulsant
- Cerebral protection: ↓CMRO2 → coupled to metabolic rate, there is a ↓CBF & ∴ ↓ICP
- ↓intraocular P
CVS
- ↓BP (myocardial depression & ↓SVR)
- ↓SVR
- ↓CO
- Direct -ve inotrope (↓Ca2+ release)
NB: ↓ symp CV & ↓ Ca2+ availability
Resp
- ↓Resp depression (dose related)
- ↓ventilatory response to ↑PCO2 & ↓PO2
- Suppresses laryngeal & cough reflexes
GI
- Anti-emetic (D2 receptor antagonism)
GU
- ↓RBF 2° ↓CO
- Green urine (prolonged infusions, due to phenols in urine)
NB: does not affect renal function (the green or the ↓ RBF)
PK
A
IV admin only
D
- Short effect site equilibrium time (2 mins)
- Mixes rapidly in central blood volume
- Distributed to tissues quickly according to BF & diffusion
- After a single bolus, plasma levels ↓rapidly due to redistribution & elimination
- High VD = 4L/kg → prolonged clearance
*** huge, the largest of all IV induction agents
- PPB = 98%
- Crosses placenta rapidly (but rapidly cleared)
M
- Clearance = 30mL/kg/min
- Exceeds HBF → ∴ extrahepatic metabolism
- Hepatic metabolism → rapid + extensive
- All metabolites inactive → H2O soluble sulphate & glucuronic acid metabolites
E
- Inactive sulphate & glucuronic acid metabolites excreted by kidney
- Organ dependent metabolism → liver & extra-hepatic
- <1% excreted unchanged
- ↓elimination with renal disease
Adverse Effects
Ceutical
- Expensive → complex mixture requiring lipid emulsion due to low H2O solubility
- High E content → caution with prolonged infusion & disorders of fat metabolism
- Formulation supports growth & needs to because discarded quickly following being drawn up (<6hrs)
- Glass ampoule! Accidents! Occupational hazard!
- Preservatives → allergic potential
- Pain on injection
PD
MoA unclear so no antidote
CNS
- Narrow therapeutic index: sedation → GA
- ↓CPP
- Excitatory phenomena → vivid dreams
- Abuse potential & addiction described
CVS
- HR unaffected → but 1/100,000 → profound brady + asystole on induction
- ↓myocardial contractility
- Bradycardia → asystole (SNS > PNS suppression)
- ↓HBF/RBF/CBF 2° ↓BP
- Direct -ve inotrope (↓Ca2+ release)
Resp
- ↓Resp depression (dose related)
- ↓ventilatory response to ↑PCO2 & ↓PO2
- Suppresses laryngeal & cough reflexes
Immuno
- Allergy → should not be given to patients with soya/egg allergy
Other
- Pain on injection
- Anaphylaxis
- Propofol infusion syndrome: metabolic acidosis, rhabdo, MOF
PK
- IV admin only
- High PPB → ∴ affected by [plasma proteins] & other drugs with high PPB
- High lipid solubility → crosses placenta (but this is what allows it to act rapidly in lipid-rich CNS neurons which mop it up to drive the [ ] gradient)
- High VD → prolonged clearance
- Decreased elimination w renal disease