Propofol

[SH4:p155-163]

Structure

 

 

Structure

2,6-diisopropylphenol

Not a chiral compound
* Unlike thiopentone, etomidate, and ketamine

 

 

Pharmacokinetics (PK)

Absorption

IV administration

Distribution

3 phases

Distribution T1/2 = 2-4 min [PI]

Elimination T1/2
= 30-60 min [PI]
= 30-90 min [SH4:p156]

Slower final phase [PI]
* Redistribution from poorly perfused tissues

Metabolism

Clearance of propofol from plasma EXCEEDS hepatic blood flow
--> Hepatic and extra-hepatic clearance
* But still primarily metabolised in liver [PI]

Glucuronidation is the major metabolic pathway
--> Produces inactive metabolites (quinols, glucuronide conjugates, and sulfites)

Some propofol undergoes ring hydroxylation by CYP450 (?hepatic)
--> 4-hydroxypropofol (has 1/3 the hypnotic activity of propofol)
--> Later on glucuronidated or sulfated to inactive metabolite

Extra-hepatic clearance of propofol

Pulmonary uptake of propofol
--> Influence initial availability
* Most released back into circulation
* Some transformed into 2,6,-diisopropyl-1,4-quiniol

Isoforms of UDP-glucuronosyltransferase (enzyme for glucuronidation) are present in brain and kidney 
* Significant renal metabolism of propofol

Elimination

0.3% of propofol is excreted unchanged in urine

Inactive metabolites are renally excreted

Action profile

Onset of action = <30 seconds

Vd of propofol = 3.5 - 4.5 L/kg

Clearance of propofol
= 30-60 mL/kg/min [SH4:p156]
= 21 to 29 mL/kg/min [PI]

Context-sensitive half-time for propofol infusion up to 8 hours = <40 minutes

Context-sensitive half-time for propofol is minimally influenced by duration
* Rapid metabolic clearance

Pharmacodynamics (PD)

Mechanisms of action

Propofol activates GABAa receptors
--> Decrease the rate of dissociation of GABA from the receptor
--> Increased the duration of Cl- channel opening
--> Increased hyperpolarisation of membrane

Immobility during propofol anaesthesia is not caused by drug-induced spinal cord depression
* Unlike volatile anaesthetics

Effects by systems

CNS

Propofol decreases
* Cerebral metabolic rate for oxygen (CMRO2)
* Cerebral blood flow
* Intracranial pressure (ICP)

CBF autoregulation to BP and PaCO2 are not affected

NB:

When used for sedation, propofol has similar degree of memory impairment as midazolam
* Thiopentone has mild effect on memory
* Fentanyl has no effect on memory

Uniformly depresses CNS structures, including subcortical centres
* Possible antiemetic effect by possible depression of subcortical

Anticonvulsant property, especially in ECT patients

No tolerance after repeated exposure

CVS

Heart

Propofol decreases BP
* More than thiopentone
* Relaxation of vascular smooth muscle mainly due to inhibition of sympathetic vasoconstrictor nerve activity

HR is unchanged
* c.f. thiopentone can cause reflex tachycardia

Propofol also has negative inotropic effect
* Possibly due to decreased intracellular calcium availability

NB:

Hypotensive effect is exaggerated in:
* Elderly
* Hypotensive
* Impaired LV function

Autonomic nervous system

Propofol blunts the pressor response to LMA and direct laryngoscopy
* More effective than thiopentone

Propofol induction may depress sympathetic nervous system more than parasympathetic nervous system
--> Predominance of parasympathetic nervous system

Propofol increases ephedrine's pressor effect

Bradycardia

Propofol induction can rarely result in bradycardia or asystole
* Risk of bradycardia-related death during propofol anaesthesia = 1.4 in 100,000

Propofol results in decreased HR response to atropine
* Cannot be overcome effectively by larger dose of atropine
* May require beta-agonists such as isoproterenol

Other CVS-related

OK for use in accessory pathway ablation operations

No change in QTc
* c.f. Sevoflurane increases QTc interval

Resp

Propofol causes dose-dependent depression of ventilation
* 25-35% apnoea after induction
* Decreased ventilatory response to CO2 and hypoxemia

During maintenance infusion of propofol
--> Both tidal volume and RR are decreased

Depression of hypercapnia drive is mostly due to effect on central chemoreceptor

Hepatic and renal

Propofol has no adverse effects on liver and kidney

BUT,

Prolonged infusion can produce hepatocellular injury, causing propofol infusion syndrome
(See "Propofol infusion syndrome" below)

NB:

Prolonged infusion can result in green urine
* Due to presence of phenolic metabolite or quinol [PHW2:p84] in urine
* The metabolite has not been identified [anaesthesia-az.com]
* No clinical significance

Propofol can also result in cloudy urine
* Due to increased uric acid excretion
* Uric acid crystallize in urine with low pH and temperature
* Not detrimental or indicative of renal damage

Other systems

Propofol does not inhibit gastric emptying and not prokinetic either

Propofol REDUCES intraocular pressure

Propofol has no effect on coagulation or platelet function
* But inhibits platelet aggregation induced by proinflammatory lipid mediators (e.g. thromboxane A2, platelet activating factors)

Usage

Hypnosis

Induction
* Especially where rapid and complete awakening is desirable
* Produce unconsciousness within 30 seconds

Conscious sedation

TIVA

Non-hypnotic use

Antiemetic
* Somewhat controversial
* Mechanism unclear

Antipruritic
* No effect on analgesia
* Mechanism may be depression of spinal cord

Anticonvulsant

Attenuation of bronchoconstriction
* Except in allergy or where metabisulfite is used as preservatives
* Metabisulfite alone causes bronchoconstriction

NB:

Propofol does not have any analgesic property

Pharmaceutics

Formulation

Propofol is insoluble

The popular formulation uses
* Soybean oil as oil phase
* Egg lecithin as the emulsifying agent

Sometimes preservative is used
* Diprivan uses disodium edetate 0.005%, with NaOH to adjust the pH to 7 - 8.5
* Generic formulation uses sodium metabisulfite (0.25 mg/mL), and has lower pH (4.5 - 6.4)

Other formulation includes:

Low-lipid emulsion of propofol
* 5% soybean oil, 0.6% egg lecithin, and no preservatives

Prodrug
* Slower, larger Vd, and higher potency

Cyclodextrin as solublilising agent

NB:

Disodium edetate is also EDTA (ethylenediaminetetraacetic acid)

Content of an ampule

1% propofol

10% soybean oil

2.25% glycerol

1.2% purified egg phosphatide (egg lecithin)

 

 

Price

Physicochemical properties

 

pKa = 11

Administration

Induction

Induction dose of propofol = 1.5 to 2.5 mg/kg IV
* Equivalent to thiopentone 4 to 5 mg/kg IV
* Unconsciousness produced at blood level of 2-6 microgram/mL

Conscious sedation

Conscious sedation dose of propofol = 0.025 - 0.1 mg/kg/min IV

Maintenance of anaesthesia

Maintenance of anaesthesia dose of propofol = 0.1-0.3 mg/kg/min IV

Antiemesis

Antiemesis dose = 10mg bolus, followed by 0.01 mg/kg/min IV

Anticonvulsant

Anticonvulsant dose = >1mg/kg
* Decreases sezure duration by 35-45% in ECT

Indications/contraindication/precautions

Indication

A short acting anaesthetic agent for induction and maintenance in children > 3 y.o. and in adults

Contraindication

Allergy

For sedation in < 16 y.o.

 

 

 

When should the drug be used?

When should the drug NOT be used?

When should the drug be used, but only with caution?

 

 

Propofol is ok for use in MH and porphyria

No suppression of cortisol

 

Propofol may abolish tremour in Parkinson's
--> Not suitable for use in stereotactic neurosurgery (e.g. pallidotomy)

 

Adverse reactions

Effects of lipid emulsion

Lipid emulsion is responsible for:

Bradycardia

Infection

Pain on injection

Hypertriglyceremia

Pulmonary embolism (oil)

Allergy

Allergenic components include:
* Phenyl nucleus
* Diisopropyl side chains

Diisopropyl radicals are present in many dermatological preparations
--> Can cause anaphylaxis in patients sensitised with diisopropyl radical

Increased risk of allergy if allergic to neuromuscular blocker

Lactic acidosis (aka Propofol infusion syndrome)

Seen in large dose infusions ( >0.075 mg/kg/min)

Unexpected increase in HR
--> Should raise suspicion of metabolic acidosis

Mechanism is unclear
* May be due to poisoning of the electronic transfer chain and impaired oxidation of long-chain fatty acid

 

Characterised by

Lactic acidosis

Bradyarrhythmia

Rhabdomyolysis

Hyperkalaemia
* [Drug.com]

Heart failure
* [Drug.com]

 

Differential diagnosis include

Hyperchloremic metabolic acidosis
* From large normal saline infusion

Metabolic acidosis
* Ketone from diabetes
* Lactate from release of tourniquet

Excitatory movements

Spontaneous excitatory movement of subcortical origin
* c.f. Cortical activity in seizures

Does NOT induce seizure in epilepsy
* Similar to thiopentone

Bacterial growth

Supports growth of:
* Escherichia Coli
* Pseudomonas Aeruginosa

Discard open ampule after 6 hours

Discard tubing and unused propofol after 12 hours in ICU

Antioxidant properties

Similar to vitamine E

Phenolic hydroxyl group scavenges lipid peroxyl radicals
--> Stops lipid peroxidation

Phenolic hydroxyl group also scavenges peroxynitrite
* May thus contribute to suppression of phagocytosis

Propofol attenuates lipid peroxidation during coronary bypass

Pain on injection

Incidence of thrombosis or phlebitis when injecting into large veins is small (<1%)

Intraarterial injection
--> Severe pain, but no vascular compromise

 

 

Interactions

What other things can the drug interact with?

Special consideration

What issues should be considered when the drug is used in special circumstances, e.g.:

Pregnancy/lactation

Elderly

Paediatrics

 

 

 

Despite rapid metabolism of propofol and elimination of inactive metabolite by kidney
--> Clearance is not impaired in liver cirrhosis and renal dysfunction

Patients >60 y.o. has decreased plasma clearance of propofol

Elderly requires a lower induction dose (25-50% decrease)
* Smaller Vd
* Decreased clearance

 

Distribution and clearance in children > 3 y.o. are similar to adults

 

Propofol readily crosses the placenta

Propofol is rapidly cleared from the neonatal circulation

 

Trivia

History

Other tidbits

 

Propofol emulsion = 1.1 kcal per mL