3. Pharmacology
          3.3. IV anaesthetic agents
 3.3.2. Propofol

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]

 

 

 



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