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Collections with the topic tag  Drugs

  • Oxycodone

     

    Oxycodone is a semi-synthetic opioid commonly used as an oral, rectal or intravenous analgesic (subcutaneous, intramuscular & intranasal also possible). Trade names include Endone™, OxyContin™ and OxyNorm™.

    A. Physiochemistry

    • Semi-synthetic opioid; thebaine derivative. First synthesised in 1916.

    B. Pharmacokinetics

    1. Dose
      • Oxycodone po conversion from morphine IV 2:1 (oxycodone:morph).
      • (NB: oral to IV morphine 3:1)
      • 10 mg of oral oxycodone is equivalent to 20 mg of oral morphine.
      • 10 mg of oral oxycodone is equivalent to 5 mg of IV/IM morphine.
      • 10-15 mg of parenteral oxycodone (IV/IM) is equivalent to 10-15 mg parenteral morphine (ie. morphine up to 50% more potent)
    2. Absorption - orally up to 87%
    3. Distribution - 2.6 L/kg
    4. Protein binding
    5. Onset - within 10-15 min orally, peak 45-60 minutes; Offset ~2-3h.
    6. Metabolism - ß1/2 ~3-4hrs, metabolised principally to noroxycodone, noroxymorphone and oxymorphone (p450 system). Oxymorphone has some activity
    7. Clearance - 0.8 L/min; predominately renally excreted.

    C. Pharmacodynamics

    • Oxycodone is a full opioid agonist with no antagonist properties whose principal therapeutic action is analgesia.
    • It has affinity for kappa, mu and delta opiate receptors in the brain and spinal cord.
    • Oxycodone is similar to morphine in its action. Other pharmacological actions of oxycodone are in the central nervous system (respiratory depression, antitussive, anxiolytic, sedative and miosis), smooth muscle (constipation, reduction in gastric, biliary and pancreatic secretions, spasm of sphincter of Oddi and transient elevations in serum amylase) and cardiovascular system (release of histamine and/or peripheral vasodilation, possibly causing pruritus, flushing, red eyes, sweating and/or orthostatic hypotension).
    • Strong potentially for tolerance, dependence and abuse.
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  • Etomidate

     

    Etomidate (Amidate™) is short-acting intravenous anesthetic agent first developed in 1964. It is available and used in the United Kingdom, Europe, New Zealand, United States, but not Australia.

    Advocates highlight etomidate's hemodynamic stability when used for induction. Critics point to the well-established adrenocortical suppression, and wide-range of suitable alternatives (propofol, ketamine, thiopentone) in trained hands.

    A. Physiochemistry

    • Carboxylated imidazole
    • 2 isomers - only R(+) hypnotic
    • Haemodynamic stability, minimal respiratory depression, cerebral protection, wide margin of safety.
    • Originally formulated in propylene glycol (painful), now in soybean lipid.

    B. Pharmacokinetics

    1. Dose - 0.3 mg/kg (0.1-0.4 mg/kg)
    2. Absorption - IV
    3. Distribution - 4 L/kg
    4. Protein binding - 75% (like thiopentone)
    5. Onset 30-60s ; Offset
    6. Metabolism - alpha1 ½ 2.5m, alpha2 ½ 30m, tß½ 3.5h; hepatic ester hydrolysis of ester side chain.
    7. Clearance - 20 mL/kg/min

    C. Pharmacodynamics

    1. Mech - probably by GABAa receptors.
    2. CNS - hypnosis; no analgesic action; ⇣ CBF and CMRO2
    3. CVS - stable; may have slight dec MAP 15% due to ⇣ SVR.
    4. Resp - minimal; sometimes brief hypoventilation or apnoea post-induction.
    5. Endo - adrenocortical suppression - inhibits 11ß-hydroxylase (11-deoxycortisol → cortisol). Temporary & reversed by vit C.
      • ⇡ ICU mortality when used for sedation.
    6. SEs - excitatory phenom, involuntary muscle movement (50%), PONV (30%), thrombophlebitis (20%), pain on injection.
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  • 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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  • Propofol

     

    A. Physiochemistry

    • A highly lipid-soluble alkylphenol.
    • 2,6 di-isopropyl phenol
    • 20 mL ampoules contain:
      1. 200 mg 1% propofol
      2. 10% soybean oil (solubiliser)
      3. 1.2% egg lecithin (emulsifier)
      4. 2.25% glycerol (make isotonic)
      5. Sodium hydroxide (buffer)
    • pKa 11, pH 7
    • 90% non-ionised @ pH 7.4
    • weak acid
    • stable at room temp, not light sensitive
    • 1 mL = 0.1 g fat = 1.1 kcal

    B. Pharmacokinetics

    1. Dose
      • 2 mg/kg induction -> 2-6 mcg/mL
      • 3-4 mg/kg in children
      • 1 mg/kg load then: 10, 8, 6 mg/kg/h infusion (10m, 10m, cont) after 1 mg/kg loading - aims for blood conc of 3 ug/mL.
      • Children: 15 mg/kg/h for 15 min, 13 mg/kg/h for 15 min, 11 mg/kg/h for 30 min then 9 mg/kg/h for 1-2 h, then 9 mg/kg/h for 2-4 h -> 3 ug/mL.
      • Sedation 25-100 mcg/kg/min
      • Plasma levels:
      • major surg 4 mcg/mL (4-8 ug/mL)
      • minor surg 3 mcg/mL
      • 50% wake @ 1.07 mcg/mL (decrement lvl: 1.2 mcg/mL on TCI)
      • 50% orientated @ 0.95 mcg/mL
      • Psychomotor perfomance pre-op levels @ 0.3 mcg/mL
    2. Absorption - IV
    3. Distribution - Vdcc 0.5 L/kg, Vdss 2-10 L/kg
    4. Protein binding - 98% albumin
    5. Onset < 60s, peak 60-90s (slightly slower than thio: peak 30-60s); Offset 5-10 min (faster than thio).
    6. Metabolism - alpha1∆ 2 min, tß∆ 1h, CSHT-8h: 30 min. Conjugated to glucuronide & sulphate - water sol and renally excreted. 0.3% excreted unchanged.
    7. Clearance - 30 mL/kg/min.
      • Children - larger central vol; longer CSHT (10m@1h & 20m@4h cf. 7m@1h & 10m@4h for adults); slower recovery; but require higher infusion rates and have higher clearance (req. same blood (=effect) conc as adults).
      • NB: children have primarily pharmacokinetic differences not pharmacodynamic.
      • Women - higher clearance.

    C. Pharmacodynamics

    1. Mech - potentiates GABA inhibition.
    2. CNS - anaesthetic, anticonvulsant (?), antiemetic, antipruritic, amnesic.
      • Not ant-analgesic like thio.
      • Inc interthreshold range for temp
    3. CVS - 25-45% dec MAP, dec CO, dec SVR (dec SNS outflow; direct effect on veins, dec intracellular Ca mobilisation), HR unchanged (resets barorec response).
    4. Resp - resp depression (apnoea in 30% alone, 100% + narcotic), dec TV, inc RR, bronchodilation (slight), dep laryngeal reflexes.
    5. Renal - dec RBF, green urine.
    6. GIT - antiemetic, no hepatic effects.
    7. Haem - intralipid dec platelet aggregation.
    8. SEs - anaphylaxis rare; sig hypotension in volume depleted; hallucinations; abuse.
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  • Methohexitone

     

    A barbiturate derivative (Brevital™, Brietal™) intravenous anaesthetic agent, no longer available in Australia although still used in other parts of the world.

    Preferred for use in electroconvulsive therapy for its pro-seizure effects and comparatively short duration.

    Compared to thiopentone

    • Oxybarbiturate
    • Made up in 50 mL to 1% solution
    • 3x more potent
    • 3x clearance (12 mL/kg/min)
    • tß½ 3 h (STP 8h)
    • Greater ionised proportion
    • Less protein binding (65%)
    • More rapid recovery: 2-3 min (smaller fat compartment, no active metabolites, ⇡ clearance)
    • Higher incidence of pain on injection
    • Pro-convulsant/epileptiform EEG (excitatory in 30%)
    • PONV (30%)
    • Less dec MAP, more inc HR than STP
    • More pronounced resp depression
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