Knowledge
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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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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
- 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)
- Absorption - orally up to 87%
- Distribution - 2.6 L/kg
- Protein binding
- Onset - within 10-15 min orally, peak 45-60 minutes; Offset ~2-3h.
- Metabolism - ß1/2 ~3-4hrs, metabolised principally to noroxycodone, noroxymorphone and oxymorphone (p450 system). Oxymorphone has some activity
- 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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A. Physiochemistry
- Semi-synthetic thebaine derivative (like oxycodone).
- Partial µ-agonist.
B. Pharmacokinetics
- Dose: 0.5 mg q6h IV/IM
- 30x morphine potency
- 200mcg-400mcg sublingual qid for analgesia
- Absorption - IV, IM, s/l, epidural (po undesirable as ++ 1st pass met)
- Distribution - 3 L/kg
- Protein binding - 96%
- Onset 30 min; Offset 4 h (longer latency & duration than morph)
- Metabolism - ß½ 5 h; hepatic dealkylation & glucuronidation. Excreted in bile & hydrolysed by GIT bacteria.
- Clearance - 14 mL/min/kg (dec 30% by GA)
C. Pharmacodynamics
- 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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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
- 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
- Absorption - IV, IM, oral or PR
- Distribution - 8 L/kg
- Protein binding - 25% (thiopentone 75%, propofol 98%)
- Onset IV: 45-60s, peak 60s; IM: 3-5 min; Offset 15-30 min
- 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).
- Clearance - 18 mL/kg/min (prop 25, thio 4 mL/kg/min)
C. Pharmacodynamics
- 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.
- CNS - analgesia, amnesia, dissociative anaesthetic (thalamocortical - limbic system); inc CBF, CMRO2, ICP & IOP.
- CVS - direct cardiac depressant, but inc SNS outflow - inc CO, HR, MAP. Variable Vc & Vd.
- Resp - unaltered response to CO2; bronchodilator; inc salivary secretions; airway reflexes intact.
- GIT- inc BSL
- SEs - PONV, emergence delerium, ++ secretions, uterine hypertonicity at > 1.5 mg/kg
- 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).
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A. Physiochemistry
- A highly lipid-soluble alkylphenol.
- 2,6 di-isopropyl phenol
- 20 mL ampoules contain:
- 200 mg 1% propofol
- 10% soybean oil (solubiliser)
- 1.2% egg lecithin (emulsifier)
- 2.25% glycerol (make isotonic)
- 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
- 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
- Absorption - IV
- Distribution - Vdcc 0.5 L/kg, Vdss 2-10 L/kg
- Protein binding - 98% albumin
- Onset < 60s, peak 60-90s (slightly slower than thio: peak 30-60s); Offset 5-10 min (faster than thio).
- Metabolism - alpha1∆ 2 min, tß∆ 1h, CSHT-8h: 30 min. Conjugated to glucuronide & sulphate - water sol and renally excreted. 0.3% excreted unchanged.
- 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
- Mech - potentiates GABA inhibition.
- CNS - anaesthetic, anticonvulsant (?), antiemetic, antipruritic, amnesic.
- Not ant-analgesic like thio.
- Inc interthreshold range for temp
- 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).
- Resp - resp depression (apnoea in 30% alone, 100% + narcotic), dec TV, inc RR, bronchodilation (slight), dep laryngeal reflexes.
- Renal - dec RBF, green urine.
- GIT - antiemetic, no hepatic effects.
- Haem - intralipid dec platelet aggregation.
- SEs - anaphylaxis rare; sig hypotension in volume depleted; hallucinations; abuse.