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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
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
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
reference
1
Collection: 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.
  Daniel Jolley
reference
1
Collection: 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.
  Daniel Jolley
reference
1
Collection: 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).
  Daniel Jolley