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Collections with the topic tag  Thiopentone

  • Thiopentone

     

    Sedative-hypnotic drug with anaesthetic and anticonvulsant effects.

    A. Physiochemistry

    • Thiobarbiturate
    • Highly lipophilic
    • Presented in glass ampoule containing 2.5% powdered form: a. 500 mg thiopentone (anhydrous yellow powder) b. 30 mg sodium carbonate (buffer) c. 0.8 atm of N2 (reduces oxidation)
    • made up with H2O to 20 mL
    • pH 10.8, pKa 7.6 (ie. ~ pH 11 pKa 7)
    • Weak acid
    • 60% non-ionised @ pH 7.4 (vs. methohexitone 75%)
    • Racemic mixture (l potency > d)
    • Demonstrates tautomerism, with water soluble enol form (double bond) in solution → lipid sol keto form at pH 7.4.
    • First administered 1934

    B. Pharmacokinetics

    1. Dose - 5 mg/kg (methohexitone 2-3x more potent)
    2. Absorption - IV, oral, rectal (at higher doses)
    3. Distribution - Vdcc 0.4 L/kg, Vdss 2.5 L/kg
      • fat:blood coeff 11:1 (ie. thio will move into fat until [fat] 11x [blood])
    4. Protein binding - 75% (prop 98%, methohex 65%)
    5. Onset within 1 brain-arm circ time (< 60s), Offset 5-15 min
    6. Metabolism - alpha1 ½ 5 min, alpha2 ½ 1 h, ß ½ 8-11 h, CSHT-8h: 3 h; phase I p450 side-arm oxidation, desulfuration to pentobarbitone (t½ 40h) and ring cleavage to urea and 3-carbon fragments.
      • some extrahepatic (renal) metab.
      • NB: alpha1 ½ (fast-alpha) is equilibration with/from effect site - alpha2 ½ (slow-alpha) with slow compartments.
    7. Clearance - 4 mL/kg/min (methohexitone: 3x greater 12 mL/k/m)

    C. Pharmacodynamics

    1. Mech - potentiates GABA inhibition, dec rate of GABA dissociation (like propofol) and at high doses directly activ GABA rec.
    2. CNS - anaesthetic, anticonvulsant, sedative, ant-analgesic.
      • Dec CBF, CMRO2 (max 55%), ICP, IOP.
      • EEG (alpha → theta → delta) ⇣ freq, ⇡ ampl → burst suppression → isoelectric.
      • Some focal cerebral protection (requires 40 mg/kg !!)
    3. CVS - Negative inotrope (direct effect and indirect dec SNS outflow), dec CO 20%, vasodilation, dec venous return → ⇣ MAP 20-30%. Compensatory ⇡ HR.
      • Histamine release & dysarrythmias rarely occur.
    4. Resp
      • Respiratory depression (initial ⇡ TV, ⇣ RR)
      • Bronchoconstriction & laryngospasm risk (due to ⇣ SNS outflow).
    5. Renal - ⇣ RBF & GFR 2° ⇣ BP.
    6. GIT - ⇣ GIT motility, ⇣ HBF, enzyme induction.
    7. SEs - inhibits neutrophil function; anaphylaxis 1:20,000; porphyria (stims d-ALA synth); inta-arterial injection; thrombophlebitis (> methohexitone 3-4%).
    8. Crosses placenta; foetal tß½ 11-44h.
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