Propofol

History

۱۹۷۰'s: from hypnotic substituted "hindered" phenols arose:

2,6-diisopropylphenol

1977: First clinical trial.
Initially in cremaphor EL -> anaphylactoid reaction.
So, new formulation developed: emulsion in use today.

Physicochemical Considerations

2,6-diisopropylphenol

SAR: increasing length of 2,6 side chains up to about 7 or 8 C atoms:

• increased sleep time
• increased potency
• decreased induction time

Further increase in length of side chains longer than about 8 C atoms:

• decreased potency
• slower induction
• prolonged recovery

Present form:

• 20 ml amps or 50 ml vials:
  • propofol 1%
  • soybean oil 10%
  • glycerol 2.25%
  • egg phosphatide 1.2%
• pH 7-8
• isotonic
• no antimicrobial preservatives
• compatible with D5W

 

Metabolism

Liver glucuronate & sulfate conjugation -> excreted in urine (70% in 24 hours, 90% in 5 days).
Metabolites probably inactive.

Cl exceeds hepatic blood flow. Extrahepatic metabolism has been shown during liver transplantation.

Pharmacokinetics

2 and/or 3 compartment models
3 compartment model (2 distribution phases)

• T_1/2(distrib) = 2-8 minutes
• T_1/2(redistrib) = 30-60 minutes
• T_1/2(elim) = 4-7 hours ("deep" compartment allows accumulation with prolonged infusion)
• V_dss = 2-10 L/kg
• V_d(peak effect) = 300 ml/kg
• Cl = 20-30 ml/kg/min
• older age: decreased Cl (so reduce dose)

 

Pharmacodynamics

CNS

• NOT an analgesic (but not antanalgesic as thiopental)
• in fact, causes local pain on injection
• hypnosis in 1 arm-brain time (2.5 mg/kg)
• Mechanism of Action: Probably related to action at or near the GABA receptor that enhances the inhibitory effect of GABA on neurotransmission.
• lower doses -> slower onset (but less bad side effects)
• duration 5-10 minutes (2-2.5 mg/kg)
• subhypnotic doses -> sedation and amnesia and antemesis
• alter mood less than thiopental
• general sense of well being; 'amorous' ideation reported
• hallucination and opisthotonus have been reported
• EEG: 2.5 mg/kg + infusion ->
  • log blood concentration proportional to %delta/%beta
  • seizure effect unclear
    • has been used effectively to treat seizures
    • briefer seizure activity after ECT compared to Brevital
• lowers ICP (normal and patients with high ICP)
  • + fentanyll -> less ICP response to ETT
  • normal CO₂ response
  • patients with high ICP: MAP may drop more than ICP -> decreasing CPP
• lowers IOP 35% acutely (> thiopental)
• relevant Cp's (depends also on age and concurrent medications)
  • Cp₅₀ for loss of response to verbal commands = 2.3 - 3.5 mcg/ml
  • maintenance: 1.5-6 mcg/ml
  • awakening: < 1.6 mcg/ml
  • orientation: < 1.2 mcg/ml

Respiratory

• qualitatively similar to barbiturates
• apnea after induction dose: 25-40%
  • more likely to last longer than 30 seconds
  • function of dose, speed of injection, other medications
• 2.4 mg/kg ->
  • slower respiratory rate for 2 minutes
  • smaller V_T for 4 minutes
• 100 mcg/kg/min ->
  • slightly less CO₂ response (compared to 3 mg/kg thiopental)
  • V_T 40% less, respiratory rate 20% greater
• 200 mcg/kg/min ->
  • only slightly more depression of V_T
  • expect p_aCO₂ low 50's

Cardiovascular System

• Induction bolus 2-2.5 mg/kg:
  • BP DOWN: systolic, diastolic, and mean: 24-40%
  • CI, SV DOWN 15-20%
  • LVSWI down 30%
  • HR little changed or significant bradycardia *
  • vasodilation + myocardial depression
• Less depression of CI with spontaneous ventilation (compared to controlled ventilation)
• More CV depression in the elderly and debilitated
• Less CV depression with an induction infusion (avoid boluses)
• Maintenance
  • systolic BP 25% less than preop
  • 100 mcg/kg/min + spontaneous ventilation on room air:
    • CI and SV unchanged
    • HR relatively unchanged
  • MVO₂ and myocardial blood flow lower
  • Myocardial O₂ supply:demand ratio probably preserved
  • ETT: returns BP to baseline

Other -- some nice negatives:

Does NOT:

• potentiate NM blockers
• trigger MH
• cause nausea or vomiting
• affect steroid synthesis or ACTH response
• alter hepatic or fibrinolytic function
• cause histamine release

Uses, Doses

Induction and Maintenance of General Anesthesia

• Induction: 1-2.5 mg/kg
• Maintenance: 50-200 mcg/kg/min +/- N₂O or opioid or ketamine
• ED₉₅ 2.25-2.5 mg/kg
• Onset 1 arm-brain time
• Duration: 3-6 minutes
• Pediatrics: not much change
  • maybe 3 mg/kg induction dose in healthy young children
  • slightly higher maintenance doses may be expected
• Fast recovery and return of psychomotor function
  • within 8-10 minutes after up to 2 hours infusion
  • almost as fast as desflurane and with less nausea and vomiting
• Cardiac surgery
  • not associated with hypotension if boluses are avoided
  • no change in coronary sinus flow, MVO₂, or myocardial lactate extraction
• Cp required: 2.5-6 mcg/ml
• TIVA: propofol + ketamine
  • propofol:ketamine = 4:1 (or even 8:1 for less painful procedures)
  • stable hemodynamics
  • no negative dreaming or abnormal behavior

Sedation

• Readily titratable, rapid recovery, by infusion
• ICU: 4 days sedation ->
  • 10 minutes to recover
  • Cp for sedation stable 96 hours (no tolerance)
• 25-60 mcg/kg/min
• amnesia - yes
• compared to midazolam
  • equal or better control
  • more rapid recovery (and extubation)
• PCS, patient controlled sedation, has been reported effective

Precautions

Side effects

• Pain on injection
  • less than or equal to etomidate pain but greater than usually painless thiopental
  • minimize by mixing with lidocaine or pre-administering lidocaine (0.5-1 mg/kg)
• Significantly increased risk of bradycardia compared with other anesthetics (Tramer et al, 1997)

  Overall NNH (number-needed-to-harm) = 11.3
  Pediatric strabismus surgery: NNH = 4.1

• Myoclonus (thiopental < propofol < etomidate or methohexital)
• Apnea (less with infusion; avoid boluses)
• Hypotension (especially with narcotics; less with infusion)
• Phlebitis (rare)
• Reported to cause tissue necrosis on subcutaneous extravasation in small children *

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Texts

Hemelrijck JV and White PF: Nonopioid Intravenous Anesthesia. In Clinical Anesthesia, Third Edition. Lippincott-Raven, 1997

Reeves JG, Glass PSA, Lubarsky DA: Nonbarbiturate intravenous anesthetics. In Anesthesia, Fifth Edition. Churchill Livingstone, 2000

Journals

Sebel PS: Propofol. Curr Rev Clin Anesth 12(14):113-120, 1992

White PF: Propofol: Pharmacokinetic and Pharmacodynamics. Seminars in Anesthesia VII(1,sup1):4-20, 1988

Roth W, Eschertzhuber S et al: Case report. Extravasation of propofol is associated with tissue necrosis in small children. Pediatric Anesthesia 16:887-889, 2006

Tramer MR, Moore RA, McQuay JH: Propofol and bradycardia: causation, frequency and severity. British Journal of Anaesthesia 78:642-651, 1997