Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: natural opium alkaloid ATC code: N02A A01 Morphine acts as an agonist at opiate receptors in the CNS particularly Mu and to a lesser extent Kappa receptors. Mu receptors are thought to mediate supraspinal analgesia, respiratory depression and euphoria, and Kappa receptors, spinal analgesia, miosis and sedation.
Central Nervous System
The principal actions of therapeutic value of morphine are analgesia and sedation (i.e., sleepiness and anxiolysis). Morphine produces respiratory depression by direct action on brain stem respiratory centres.
Morphine depresses the cough reflex by direct effect on the cough centre in the medulla. Antitussive effects may occur with doses lower than those usually required for analgesia. Morphine causes miosis, even in total darkness. Pinpoint pupils are a sign of narcotic overdose but are not pathognomonic (e.g., pontine lesions of haemorrhagic or ischaemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in the setting of morphine overdose.
Gastrointestinal Tract and Other Smooth Muscle
Morphine causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone is increased to the point of spasm resulting in constipation.
Morphine generally increases smooth muscle tone, especially the sphincters of the gastrointestinal and biliary tracts.
Morphine may produce spasm of the sphincter of Oddi, thus raising intrabiliary pressure.
Cardiovascular System
Morphine may produce release of histamine with or without associated peripheral vasodilation. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.
Endocrine System
Opioids may affect the hypothalamic pituitary adrenal and hypothalamic pituitary gonadal system resulting in adrenal insufficiency or hypogonadism respectively (see section 4.4).
Other Pharmacological Effects
In vitro and animal studies indicate various effects of natural opioids, such as morphine, on components of the immune system; the clinical significance of these findings is unknown.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties
Morphine is well absorbed from MCR tablets and, in general, peak plasma concentrations are achieved 1-5 hours following administration. The availability is complete when compared to an equivalent dose of immediate release oral solution.
Morphine is subject to a significant first-pass effect which results in a lower bioavailability when compared to an equivalent intravenous dose.
The major metabolic transformation of morphine is glucuronidation to morphine 3-glucuronide and morphine-6- glucuronide which then undergo renal excretion. These metabolites are excreted in bile and may be subject to hydrolysis and subsequent re-absorption.
Patients are titrated to appropriate pain control using the wide range of strengths of MCR tablets. Consequently, there is a large inter-patient variation in required dosage, the minimum dosage being 5 mg twelve hourly and a dose of 5.6 g 12 hourly has been recorded.