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pearl
1
Patients with a history of intraoperative awareness are five-times more likely to experience awareness than those without.
Aranake A, Gradwohl S, Ben-Abdallah A et al. Increased Risk of Intraoperative Awareness in Patients with a History of Awareness. Anesthesiology. 2013 Dec 1;119(6):1275-83.
  Daniel Jolley
reference
1
Collection: 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. 
  Daniel Jolley
reference
1
Collection: 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.
  Daniel Jolley
pearl
1
Oxycodone possesses pharmacologic qualities that render it disproportionately liable to abuse and addiction compared to other commonly used opioids.
Remillard D, Kaye AD, McAnally H. Oxycodone's Unparalleled Addictive Potential: Is it Time for a Moratorium? Curr Pain Headache Rep. 2019 Feb 28; 23 (2): 15.
  Daniel Jolley
reference
1
Collection: 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.
  Daniel Jolley
reference
1
Collection: 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.
  Daniel Jolley
reference
1
Collection: 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
  Daniel Jolley
reference
1
Collection: 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.
  Daniel Jolley
pearl
1
Prophylactic propofol reduces emergence agitation in children after general anesthesia.
van SL, O'Neill ES, Cohen LC et al. Does a prophylactic dose of propofol reduce emergence agitation in children receiving anesthesia? A systematic review and meta-analysis. Paediatr Anaesth. 2015 Jul 1; 25 (7): 668-76.
  Daniel Jolley
reference
1
Collection: 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.
  Daniel Jolley