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Morphine is one of the most commonly used opioids worldwide. First isolated in 1803 and commercially marketed by Merck in 1827.
A. Physiochemistry
- 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.
B. Pharmacokinetics
- 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
C. Pharmacodynamics
- 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
- Natural phenathrene opioid - plant, animal and even human synthesis identified.
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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
- 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)
- Absorption - orally up to 87%
- Distribution - 2.6 L/kg
- Protein binding
- Onset - within 10-15 min orally, peak 45-60 minutes; Offset ~2-3h.
- Metabolism - ß1/2 ~3-4hrs, metabolised principally to noroxycodone, noroxymorphone and oxymorphone (p450 system). Oxymorphone has some activity
- 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.