Propofol

[SH4:p155-163]

Quick summary

 

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

Structure

Structure

• 2,6-diisopropylphenol
• Not a chiral compound
  * Unlike thiopentone, etomidate, and ketamine

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

Respiratory

• 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
• Propofol may decrease hepatic blood flow
  --> May decrease its own clearance
  * [RDM6:p319]

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)
• Propofol is safe in MH and porphyria
• No suppression of cortisol

Side effects / Toxicity

Effects of lipid emulsion

Lipid emulsion is responsible for:

• Bradycardia
• Infection
• Pain on injection
  * 10% in paeds, 18% in adults [Drugs.com]
• Hypertriglyceremia
• Pulmonary embolism (oil)

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

Pain on injection

• Incidence of thrombosis or phlebitis when injecting into large veins is small (<1%)
• Incidence of pain
  = 10% in paediatrics
  = 18% in adults
• Intraarterial injection
  --> Severe pain, but no vascular compromise

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
• Incidence
  = 3-10% in adults
  = 17% in paediatrics
  * [Drugs.com]

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

Pharmacokinetics (PK)

Absorption

• IV administration

Distribution

• Vd of propofol = 3.5 - 4.5 L/kg
• Protein-binding = 98% (to albumin)
  * [PHW2:p96]

Compartmental model

• 3 compartment model:
  * Plasma
  * Rapidly equilibrating tissues
  * Slowly equilibrating tissues

3 phases

• Alpha T1/2 = 2-4 min [PI]
  * Redistribution from plasma to highly perfused brain
  * High metabolic clearance also account for the rapid drop in plasma level
• Beta T1/2 (Rapid elimination phase)
  = 30-60 min [PI]
• Slower final phase [PI]
  * Redistribution from poorly perfused tissues

NB:

[SH4:p156]

• Elimination half-time = 30-90 min

[RDM6:p318]

• A rapid redistribution phase: T1/2 = 1-8 min
• A slow redistribution phase: T1/2 = 30-70 min
• An elimination phase: T1/2 = 4 to 23.5 hours

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
• Clearance of propofol
  = 30-60 mL/kg/min [SH4:p156]
  = 21 to 29 mL/kg/min [PI]
  = 23-50 mL/kg/min [Drugs.com]

Action profile

• Onset of action = <30 seconds
• Time to peak effect = 90 to 100 seconds
  * [RDM6:p319]
• Context-sensitive half-time for propofol infusion up to 8 hours = <40 minutes
  * [SH4:p156;RDM6:p319]
• Context-sensitive half-time for propofol is minimally influenced by duration
  * Rapid metabolic clearance

Pharmaceutics

Physico-chemical properties

• Weak organic acid with pKa = 11
  --> Almost all unionised at pH 7.4
  * [PHW2:p95]

Formulation

• Propofol is insoluble
• The popular formulation uses:
  * Soybean oil as oil phase
  * Egg lecithin as the emulsifying agent
  * Glycerol to adjust tonicity
• 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 or 0.025%), and has lower pH (4.5 - 6.4)
      - Or no preservatives

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)
• Propofol emulsion appears as highly opaque white fluid due to scattering of light from tiny (~150nm) oil droplets

Availability

Propofols are available in (all 1%)

• 20mL
• 50mL
• 100mL vials

Content of an ampule

• 1% propofol
• 10% soybean oil
• 2.25% glycerol
• 1.2% purified egg phosphatide (egg lecithin)

NB:

• Isotonic

Clinical

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
• Healthy adults < 55 y.o. = 40mg every 10sec till onset  (2-2.5mg/kg)
  * [PI]
• Elderly, debilitated, ASA III/IV = 20mg every 10 sec till onset (1-1.5mg/kg)
  * [PI]

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

TCI

• Blood level required for anaesthesia during surgery = 2-5 microgram/mL
  * [RDM6:p319]
  * Awakening usually occurs with levels < 1.5 microgram/mL
• 4-8 microgram/mL [PHW2:p95]

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.

NB:

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

Special consideration

Liver and renal impairment

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

Elderly

• Patients >60 y.o. has decreased plasma clearance of propofol
• Elderly requires a lower induction dose (25-50% decrease)
  * Smaller Vd
  * Decreased clearance

Paediatrics

• Distribution and clearance in children > 3 y.o. are similar to adults
• Not recommended for children < 3 y.o. due to lack of data
  * [PI]
• Children have a larger central compartment volume (50%) and more rapid clearance (25%)
  * [RDM6:p320]

Maternal-foetal

• Propofol readily crosses the placenta
• Propofol is rapidly cleared from the neonatal circulation

Others

According James' notes, propofol interferes with metabolism of alfentanil and sufentanil by inhibiting CYP2B1 and CYP1A1
* [???]

Trivia

History

[Wikipedia]

• Initial clinical trials in 1977
• Solubilised in cremophor EL
  --> Withdrew from market due to anaphylactic reactions
• Relaunched by AstraZeneca in 1986 as Diprivan (DI-isopropyl IV ANaesthetic)

Others

• Propofol emulsion = 1.1 kcal per mL
  * [PI]