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Collections with the topic tag  Drugs

  • Buprenorphine

     

    A. Physiochemistry

    • Semi-synthetic thebaine derivative (like oxycodone).
    • Partial µ-agonist.

    B. Pharmacokinetics

    1. Dose: 0.5 mg q6h IV/IM
      • 30x morphine potency
      • 200mcg-400mcg sublingual qid  for analgesia
    2. Absorption - IV, IM, s/l, epidural (po undesirable as ++ 1st pass met)
    3. Distribution - 3 L/kg
    4. Protein binding - 96%
    5. Onset 30 min; Offset 4 h (longer latency & duration than morph)
    6. Metabolism - ß½ 5 h; hepatic dealkylation & glucuronidation. Excreted in bile & hydrolysed by GIT bacteria.
    7. Clearance - 14 mL/min/kg (dec 30% by GA)

    C. Pharmacodynamics

    1. Mechanism: µ partial agonist.
      • 50x greater mu rec affinity than morphine.
      • May be used to treat heroin/morphine dependence.
      • Greater lipid solubility than morphine.
      • Ceiling effect to both analgesia & respiratory depression.
      • Long duration as slow to dissociate from receptor & thus difficult to reverse.
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  • Remifentanil

     

    A. Physiochemistry

    • pKa - 7.3 (58% nonionised @ 7.4)
    • Octanol water coeff - 18
    • phenylpiperidine opioid
    • contain 2 ester bonds so hydrolysed by non-specific tissue esterases.
    • Preparation contains 'glycine', so cannot be used epidurally.
    • White powder for reconstitution with water - 1, 2, 5 mg packs

    B. Pharmacokinetics

    1. Dose: (100x morphine potency, ~equal to fent)   - TCI: 3-8 ng/mL     - (up to 15 ng/mL for very stimulating procedures)     - Spontaneous ventilation returns @ 1-2 ng/mL   - 0.1-0.3 mcg/kg/min infusion (with propofol 80 mcg/kg/min (= 34 mL/h for 70 kg).
      • 0.01-0.05 mcg/kg/min spont vent
      • dilute 1 mg to 50 mL = 20 mcg/mL, or 5 mg in 50 mL = 100 mcg/mL.
      • paeds: 0.03 mg/kg in 50 mL then 1 mL/h = 0.01 mcg/kg/min.
      • Or paediatric whole-ampoule dilutions when advanced pumps are unavailable:
      • 1mg in 16.7mLs
      • or 2mg in 33.3 mLs
      • or 3mg in 50mLs 
      • → to give a dilution of 60mcg/mL
      • then for a patient of XYkg running at X.Y mLs/hr is 0.1mcg/kg/min. eg. for a 42kg patient running at 0.1mcg/kg/min will be 4.2mLs/hr which over 4 hrs uses 16 mL so a 1mg ampoule would be sufficient.
      • 1 mcg/kg IV bolus to blunt pressor resp to intubation, better than fentanyl. (equiv. fent 2 mcg/kg, alfent 20 mcg/kg)
      • 3-5 mcg/kg for intubation with propofol 2 mg/kg.
      • 0.2-0.8 mcg/kg bolus for PCA analgesia (++SEs: sedation, desaturation)
    2. Absorption - IV
    3. Distribution - 0.5 L/kg (small)
    4. Protein binding - 70-90%
    5. Onset 1-4 min; Offset 4 min (offset due to metab not redist)
    6. Metabolism - ß½ ~10 min. (CSHT-8h only 4 min!) Metabolised by non-specific plasma esterases to almost-inactive metabolites (GR90291: 1/4600 activity! / t½ 2h).
      • Minor pathway - N-dealkylation. NOT metabolised by plasma cholinesterase.
    7. Clearance - 42 mL/min/kg (30-50% CO)

    C. Pharmacodynamics

    1. Mech - highly selective mu agonist.
    2. CVS - dec MAP & HR 20-30%. (? low dose glycopyrrolate to attenuate brady).
      • No histamine release.
    3. CNS
      • max MAC reduction ~ 85% (0.1-0.2 mcg/kg/min = 60-70% MAC reduction).
      • To avoid awareness keep propofol @ at least 80 mcg/kg/min or volatile 0.3 MAC.
      • Sedation.
      • Beware rapid Opioid Induced Hyperalgesia.
    4. Resp - ⇣ RR & MV; apnoea. Spontaneous respiration occurs at blood concentrations of 4 to 5 nanogram/mL in the absence of other anaesthetic agents; for example, after discontinuation of a 0.25 microgram/kg/minute infusion of remifentanil, these blood concentrations would be reached in two to four minutes.
    5. GIT - dec CTZ stimulation as rapidly metabolised; no ion trapping.
    6. Muscle - muscle rigidity similar to alfentanil, though more than fentanyl.
      • May cause chest wall rigidity (inability to ventilate) after single doses of > 1 microgram/kg administered over 30 to 60 seconds or infusion rates > 0.1 microgram/kg/minute.
      • Administration of doses < 1 microgram/kg may cause chest wall rigidity when given concurrently with a continuous infusion of remifentanil.
    7. Foetal - little effect as rapidly metabolised by foetus.
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  • Ketamine

     

    Ketamine is a dissociative anaesthetic & potent analgesic.

    • "Dissociative anaesthesia" refers to dissociation of thalamocortical and limbic systems on the EEG.

    A. Physiochemistry

    • phenylcyclidine (PCP) derivative
    • pKa 7.5, weak acid (like thiopentone 60% nonionised @ pH 7.4)
    • highly lipid soluble (4x thio)
    • ampoule: 200 mg in 2 mL
    • acidic solution of i) ketamine hydrochloride with ii) benzethonium chloride (preservative - neurotoxic !)
    • 2 optical isomers - S(+)d ketamine has i) more rapid emergence due to higher metab, ii) less emergence SEs, iii) less cardiac depression, iv) 3x analgesic potency.

    B. Pharmacokinetics

    1. Dose - 1.5-2 mg/kg IV, 10 mg/kg IM
      • oral premed: 6-7 mg/kg po (15-30 min onset)
      • Rx: asthma 20 mcg/kg/min
      • analgesia: 0.1-0.3 mg/kg/h (no dysphoria @ 0.1, sometimes pleasant dreams @ 0.2 mg/kg/h). -[HPH 400mg in 50mL]
      • TIVA: 10-50 mcg/kg/min
    2. Absorption - IV, IM, oral or PR
    3. Distribution - 8 L/kg
    4. Protein binding - 25% (thiopentone 75%, propofol 98%)
    5. Onset IV: 45-60s, peak 60s; IM: 3-5 min; Offset 15-30 min
    6. Metabolism - alpha∆ 11 min, ß ∆ 2.5 h. Hepatic p450 to N-demethylation to norketamine, hydroxylated to hydroxynorketamine, conjugated to water sol glucuronide derivatives.
      • Norketamine has 1/5 activity of ketamine (? post-op S/Es).
    7. Clearance - 18 mL/kg/min (prop 25, thio 4 mL/kg/min)

    C. Pharmacodynamics

    1. Mech - non-competitive NMDA antagonism (PCP site on NR1 subunit); anti-muscarinic; anti-monaminergic; inhibits peripheral reuptake of catecholamines; S+ enantiomer has some mu receptor activity; inhibits NO synthesis; inh non-NMDA glutamate rec.
    2. CNS - analgesia, amnesia, dissociative anaesthetic (thalamocortical - limbic system); inc CBF, CMRO2, ICP & IOP.
    3. CVS - direct cardiac depressant, but inc SNS outflow - inc CO, HR, MAP. Variable Vc & Vd.
    4. Resp - unaltered response to CO2; bronchodilator; inc salivary secretions; airway reflexes intact.
    5. GIT- inc BSL
    6. SEs - PONV, emergence delerium, ++ secretions, uterine hypertonicity at > 1.5 mg/kg
    7. Interactions - halothane prolongs duration by delaying its redistribution and metabolism.

    Ketamine produces a dissociative state (unconsciousness where in cataleptic state, disconnected from surroundings associated with functional and electrophysiological dissociation between thalamo-neocortical and limbic system)

    • Characteristically : eye open, slow nystagmus, varying purposeful movement and hypertonus unrelated to stimuli
    • Advantages: sympathetic stimulation with preservation of BP esp in hypovolaemic state, preservation of airway reflexes, bronchodilation and intense analgesia
    • Disadvantages: can theoretically precipitate myocardial ischaemia (increasing both workload and O2 requirements) increases CBF, increases PVR, emergence delirium (also anaesthetic end-point unclear and uncontrolled movements).
    reference

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