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.
Sulfentanil is a potent, short-acting synthetic opioid used in anesthesia and critical care. First synthesized by Janssen Pharmaceutica in 1974. It is the most potent opioid licensed for use in humans.
- OWC 1800
- pKa 8.0
- Potency 5-10x fentanyl, 500x morphine.
- Vd 3 L/kg
- Protein binding 93%
- Clearance 12 mL/kg/min
- tß½ 3 hours
- CSHT(8h) 30 min (alfentanil ~60 m)
- mu agonist, also stimulates serotonin release and at high dose has local anaeshetic effect.
- Structurally different from fentanyl, with a methoxymethyl group on the piperidine ring (increases potency and reduces duration of action) and thiophene instead of phenyl ring.
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.
Pethidine (Meperidine) is a phenylpiperidine synthetic opioid first synthesized in 1938. Although widely used in the 20th century, it has fallen out of favour over the past decade due to abuse potential, limited advantages over other opioids and the existence of toxic metabolites.
- pKa - 8.5 (9% nonionised @ 7.4)
- Octanol water coefficient - 39 (so 40x lipid solubility of morphine)
- phenylpiperidine opioid
- Dose - 25-100 mg (10% morphine potency). Limit 1000 mg 1st day, then 600 mg/day there after.
- Absorption - IV, IM, epidural, po (55% biov)
- Distribution - Vdss 4.5 L/kg. Crosses placenta - foetal 80% of maternal.
- Protein binding - 60%
- Onset 10 min ; Offset 2-3 h
- Metabolism - ß½ 3 h; N-demethylation to norpethidine and then hydrolysis to norpethidinic acid; also direct hydrolysis to pethidinic acid. Renal elimination.
- Norpethidine - ß½ 15 h; 50% analgesic properties, 2x convulsant effects.
- Clearance - 20 mL/kg/min (same as morph & fentanyl)
- Mech - mu and kappa agonist, causing potent spinal and supraspinal analgesia.
- CNS - more euphoria, less N/V than morphine. No miosis, but may cause mydriasis (pupil dilation -atropine-like kappa action). No EEG changes like morphine. ⇡ latency & amplitude of SSEPs.
- NB: has LA action, so can be used as sole agent for neuroaxial block.
- anti-shivering effect (kappa)
- CVS - ⇣ MAP (> than morphine) due to histamine release & alpha adrenergic blockade (vasodilation). Inc HR (atropine like effect). Large doses depress myocardial contractility. May cause hypertensive crisis in those on MAOIs.
- depress myocardial contractility
- Resp - potent resp depressant - greater effect on TV than RR. Histamine release. Chest wall rigidity.
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.
- 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.
- 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.
- 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.
- Distribution - ~8 L/kg (higher than tramadol).
- Protein binding - 20% (low!)
- Onset 30 min; Offset 4-6 h
- 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.
- Clearance - 22 mL/kg/min
- 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.
- CNS - analgesia, good for neuropathic pain, low(er) incidence of tolerance & dependence, lowers seizure threshold, dizziness, sweating, ⇡ ICP.
- CVS - few CVS effects. Some tachycardia and flushing.
- Resp - little respiratory depression.
- Renal - possible caution in renal failure, although no active metabolites even if 99% renal excreted.
- GIT - Nausea & vomiting (less than tramadol), minimal constipation, more biliary spasm than tramadol.
- 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.