Sedative-hypnotic drug with anaesthetic and anticonvulsant effects.
- 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
- Dose - 5 mg/kg (methohexitone 2-3x more potent)
- Absorption - IV, oral, rectal (at higher doses)
- 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])
- Protein binding - 75% (prop 98%, methohex 65%)
- Onset within 1 brain-arm circ time (< 60s), Offset 5-15 min
- 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.
- Clearance - 4 mL/kg/min (methohexitone: 3x greater 12 mL/k/m)
- Mech - potentiates GABA inhibition, dec rate of GABA dissociation (like propofol) and at high doses directly activ GABA rec.
- 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 !!)
- 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.
- Respiratory depression (initial ⇡ TV, ⇣ RR)
- Bronchoconstriction & laryngospasm risk (due to ⇣ SNS outflow).
- Renal - ⇣ RBF & GFR 2° ⇣ BP.
- GIT - ⇣ GIT motility, ⇣ HBF, enzyme induction.
- SEs - inhibits neutrophil function; anaphylaxis 1:20,000; porphyria (stims d-ALA synth); inta-arterial injection; thrombophlebitis (> methohexitone 3-4%).
- Crosses placenta; foetal tß½ 11-44h.
Tramadol is a synthetic opioid agonist and neurotransmitter-modulating analgesic.
- 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
- 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
- Absorption - IV, IM, po (80% biov)
- Distribution - 3 L/kg (80% crosses placenta).
- Protein binding - 20%
- Onset 30 min; Offset 6 h
- peak [plasma] after po: 2h
- 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
- Clearance - 9 mL/kg/min
- 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.
- CNS - analgesia, good for neuropathic pain, low(er) incidence of tolerance & dependence, lowers seizure threshold, dizziness, sweating.
- stops shivering?
- CVS - few CVS effects. Some tachycardia and flushing.
- Resp - little respiratory depression.
- Renal - caution in renal failure.
- GIT - Nausea & vomiting (30-40%, like morphine), minimal constipation, minimal biliary spasm.
- 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.
Ketamine is a dissociative anaesthetic & potent analgesic.
- "Dissociative anaesthesia" refers to dissociation of thalamocortical and limbic systems on the EEG.
- 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.
- 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)
- 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).
Morphine is one of the most commonly used opioids worldwide. First isolated in 1803 and commercially marketed by Merck in 1827.
- 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.
- 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).
- Absorption - IV, IM, s/c, po (3x dose as HER 0.69)
- Distribution - Vdcc 0.3, Vdss 3.5 L/kg
- Protein binding - 30% (albumin)
- Onset: peak onset at 20 min when given parenteral, 60 min orally; Offset 4 h
- 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.
- Clearance - 15 mL/kg/min
- Mech - mu, kappa, delta agonist. (GI linked). Effective against visceral, skeletal & joint pain.
- 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.
- 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.
- 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.
- Renal - diuresis (kappa receptors → ADH release)
- GIT - Nausea & vomiting due to stimulation of CTZ (30-40% of subjets); ileus; constipation; sphincter of Oddi spasm.
- Natural phenathrene opioid - plant, animal and even human synthesis identified.
- 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
- 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.
- 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.