Article Notes
Article pearls, summaries and comments.
- 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.
- Pruritus
- 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.
Collection: Morphine
Morphine is one of the most commonly used opioids worldwide. First isolated in 1803 and commercially marketed by Merck in 1827.
A. Physiochemistry
B. Pharmacokinetics
C. Pharmacodynamics
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.