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Collections of knowledge containing reference notes.

  • 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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  • Tramadol

     

    Tramadol is a synthetic opioid agonist and neurotransmitter-modulating analgesic.

    A. Physiochemistry

    • Synthetic analgesic of 'amino-cyclo-hexanol' group.
    • Racemic mixture of two enantiomers + and -:
      • (-) Inhibits NAd reuptake
      • (+) Enhances 5HT release, inhibits 5HT reuptake, weak mu (& less kapaa/delta) agonist.
    • Oral (50 mg capsules, 100 mg tablets) & parenteral (100 mg/2mL) preparations.
    • pKa 9.4

    B. Pharmacokinetics

    1. Dose - 5-10x less potent than morphine: 50-100 mg q6h, max 400-600 mg/day.
      • 2-3 mg/kg loading, then 1-2 mg/kg q6h.
      • PCA IV tramadol: 20 mg/mL then step down to oral (Prof Schug, Perth: 25-50 mg q1h PCA, using up to 1500 mg/24h).
      • analgesic efficacy and potency comparable to pethidine
      • Caudal: 2 mg/kg
    2. Absorption - IV, IM, po (80% biov)
    3. Distribution - 3 L/kg (80% crosses placenta).
    4. Protein binding - 20%
    5. Onset 30 min; Offset 6 h
      • peak [plasma] after po: 2h
    6. Metabolism - t½ 6h (12h in renal impairment);
      • 85% p450 (CYP-2D6 - also converts codeine → morphine & metabolises ondansetron!)
      • Demethylation to 'O-demethyl-tramadol' (M1) t½ 9h - has some activity as it has 6x greater mu affinity than tramadol. Some consider tramadol a prodrug because of this.
      • 90% excreted in urine, 10% in faecies.
      • metabolism inhibited by quinidine
    7. Clearance - 9 mL/kg/min

    C. Pharmacodynamics

    1. Mech - weak mu agonists (30% of action) (very weak kappa & delta); inhibits NAd reuptake (through indirect activation of post-synaptic alpha-2 adrenoreceptors) and stimulates 5HT release, so activates desc NAd and 5HT pathways (70%), modulating pain pathways.
      • Naloxone antagonises only 30% tramadol analgesic effect. Ondansetron antagonises a further 30% of tramadol analgesic effect.
    2. CNS - analgesia, good for neuropathic pain, low(er) incidence of tolerance & dependence, lowers seizure threshold, dizziness, sweating.
      • stops shivering?
    3. CVS - few CVS effects. Some tachycardia and flushing.
    4. Resp - little respiratory depression.
    5. Renal - caution in renal failure.
    6. GIT - Nausea & vomiting (30-40%, like morphine), minimal constipation, minimal biliary spasm.
    7. SEs - interacts with MAOI, SSRIs.
    • Quinidine may decrease efficacy of tramadol by inhibiting CYP-2D6, thus decreasing production of M1. Codeine my compete for the same enzyme with a similar result.
    • Carbamazepine induces CYP-2D6 decreasing effect by increasing metabolism.
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  • Morphine

     

    Morphine is one of the most commonly used opioids worldwide. First isolated in 1803 and commercially marketed by Merck in 1827.

    A. Physiochemistry

    • Natural phenathrene opioid - plant, animal and even human synthesis identified.
      • Synthesized by mammalian cells from dopamine, although exact role unclear.
    • pKa - 7.9 (20% nonionised @ 7.4)
    • Octanol water coefficient - 1.4 (relatively low lipid solubility compared with other opioids)
    • 3 rings attached to piperidine ring with a tertiary amine.

    B. Pharmacokinetics

    1. Dose - 50 mcg/kg IV
      • analgesia @ [plasma] 0.05 mcg/mL
      • epidural: 10-20 mcg/mL
      • PCA adult: 50 mg in 50 mL; 1 mL (1 mg) bolus 5 min lockout, commonly used.
      • PCA paeds: 1 mg/kg in 50 mL; 1 mL (20 mcg/kg) bolus; background 0.5-1 mL/h (10-20 mcg/kg/h).
    2. Absorption - IV, IM, s/c, po (3x dose as HER 0.69)
    3. Distribution - Vdcc 0.3, Vdss 3.5 L/kg
    4. Protein binding - 30% (albumin)
    5. Onset: peak onset at 20 min when given parenteral, 60 min orally; Offset 4 h
    6. Metabolism - t½α 10-20 min, t½ß 2-4 h
      • 75% metabolised by conjugation → 90% morphine-3-glucuronide (no activity)
      • 10% morphine-6-gluc (13x potency of morphine). MAOIs inhibit glucuronidation.
    7. Clearance - 15 mL/kg/min

    C. Pharmacodynamics

    1. Mech - mu, kappa, delta agonist. (GI linked). Effective against visceral, skeletal & joint pain.
    2. CNS - little CNS penetration (cf. heroin, which readily crosses BBB), although alkalisation (⇣pCO2) ⇡ non-ionised fraction, and ⇡pCO2 ⇡CBF. Both ⇡ cerebral morphine concentration.
      • 'Ceiling effect' on EEG reaching high voltage, slow frequency (delta 2-4 Hz) waves.
      • ⇣ CMRO2 & ⇣ ICP.
      • ⇡ cortical stimulation of Edinger-Westphal nucleus → miosis.
    3. CVS - ⇣ SNS & ⇡ PNS tone. Bradycardia, venodilation, histamine release (causes ⇣ MAP). Orthostatic hypotension due to depression of SNS responses. Direct depressant effect on SA node, slowing conduction (⇡ VF risk).
      • Administration with N2O results in CVS depression.
    4. Resp - Respiratory depression & response to CO2 & hypoxia (shift pCO2/VA curve to right).
      • Bronchoconstriction due to histamine release (similar with pethidine). Depresses airway reflexes & ciliary reflexes.
    5. Renal - diuresis (kappa receptors → ADH release)
    6. GIT - Nausea & vomiting due to stimulation of CTZ (30-40% of subjets); ileus; constipation; sphincter of Oddi spasm.
    7. Pruritus
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  • Sufentanil

     

    Sulfentanil is a potent, short-acting synthetic opioid used in anesthesia and critical care. First synthesized by Janssen Pharmaceutica in 1974. It is the most potent opioid licensed for use in humans.

    • OWC 1800
    • pKa 8.0
    • Potency 5-10x fentanyl, 500x morphine.
    • Vd 3 L/kg
    • Protein binding 93%
    • Clearance 12 mL/kg/min
    • tß½ 3 hours
    • CSHT(8h) 30 min (alfentanil ~60 m)
    • mu agonist, also stimulates serotonin release and at high dose has local anaeshetic effect.
    • Structurally different from fentanyl, with a methoxymethyl group on the piperidine ring (increases potency and reduces duration of action) and thiophene instead of phenyl ring.
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  • Tapentadol

     

    Tapentadol (Paliex™, Nucynta™) is a synthetic opioid agonist and noradrenaline-reuptake inhibitor. Similar to and based upon tramadol, although with much weaker inhibition (by design) of serotonin reuptake.

    A. Physiochemistry

    • Synthetic analgesic of 'amino-cyclo-hexanol' group.
    • Unlike tramadol, prepared as only the (R,R) stereoisomer (weakest opioid activity).
    • Oral: 50, 75 & 100 mg immediate release, and 50,100,150 & 200 mg extended release preparations.
    • No parenteral preparation is approved for use.

    B. Pharmacokinetics

    1. Dose: 50-200 mg bd/qid for immediate release preparations, 50-200mg bd for extended release.
      • approximately double potency of tramadol, similar to oxycodone and between tramadol and morphine.
    2. Absorption - po (only 32% biov)
      • increasing doses have a non-linear effect on increasing peak plasma concentration, thus higher doses result in disproportionately higher Cmax.
    3. Distribution - ~8 L/kg (higher than tramadol).
    4. Protein binding - 20% (low!)
    5. Onset 30 min; Offset 4-6 h
    6. Metabolism - t½ 4h
      • hepatic conjugation with glucuronic acid → glucuronides is main pathway (tapentadol-O-glucuronide); p450 metabolism to N-desmethyl tapentadol and hydroxyl tapentadol.
      • No known active metabolites
      • 99% excreted in urine, 1% in faecies.
    7. Clearance - 22 mL/kg/min

    C. Pharmacodynamics

    1. Mech - weak mu agonists (30% of action / 18x less affinity than morphine) ; inhibits NAd reuptake (through indirect activation of post-synaptic alpha-2 adrenoreceptors), activating descending NAd (70%) modulating pain pathways.
    2. CNS - analgesia, good for neuropathic pain, low(er) incidence of tolerance & dependence, lowers seizure threshold, dizziness, sweating, ⇡ ICP.
    3. CVS - few CVS effects. Some tachycardia and flushing.
    4. Resp - little respiratory depression.
    5. Renal - possible caution in renal failure, although no active metabolites even if 99% renal excreted.
    6. GIT - Nausea & vomiting (less than tramadol), minimal constipation, more biliary spasm than tramadol.
    7. SEs - interacts with MAOI (adrenergic storm), SSRIs (serotonin syndrome).
    • Although thought to have less abuse potential than other common opioids, it is still classed as a Schedule 2 drug in the US, Schedule 1 in Canada, Class A controlled drug in the UK and S8 in Australia.
    • Safety of tapentadol in pregnant, lactating women, and pediatric patients is not yet established. 
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