K2i / 17B11 / 15B14: Describe the pharmacology of Propofol

17B11: Exam Report

Describe the pharmacology of propofol.

76% of candidates passed this question.

A structured approach proved a good basis to answer this question. It was expected candidates would outline the uses such as anaesthesia, more prolonged sedation or possible additional roles in patients with seizures or head injuries. Discussion of the presentation and pharmaceutics, including a comment on antibacterial preservatives or lack thereof was expected. The mechanism of action should have been described. It was expected candidates could provide an indication of the usual dose (and how it differs in the more unwell / elderly patient population). A maximal rate and possible toxicity was expected.

A discussion on the pharmacodynamics by major organ systems was expected and credit was given for additional comments about hyperlipidaemia, urine colour changes or metabolic alterations. It was expected that candidates would mention propofol infusion syndrome at some point in their answer with some mention of clinical features or pathophysiology.

The important aspects of its pharmacokinetics should have been mentioned (high protein binding, large volume of distribution, termination of effect by redistribution, hepatic metabolism, context sensitive half life). A mention of adverse effects would complete the answer.

15B14: Exam Report

Describe the pharmacology of propofol.

60% of candidates passed this question.

Those candidates who did poorly lacked any structure for answering a pharmacology question. Pharmacokinetics was generally poorly handled and many answers revealed a lack of knowledge about this drug. Adverse effects and mechanism of action were generally well
known. Doses of the drug were often incorrectly stated.

Important aspects such as dose or pharmacodynamics were often omitted and a structured approach helps avoid this.

K2i / 17B11 / 15B14: Describe the pharmacology of 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 → 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

Anti-emetic (D₂ receptor antagonism)

↓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 V_D = 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

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

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 V_D → prolonged clearance
Decreased elimination w renal disease