Tramado1 is a centrally acting synthetic analgesic compound. Although its mode of action is not completely understood, from animal tests, at least two complementary mechanisms appear applicable: binding of parent and M1 metabolite to mc-opioid receptors and weak inhibition of reuptake of norepinephrine and serotonin. Opioid activity is due to both low affinity binding of the parent compound and higher affinity binding of the O-demethylated metabolite M1 to mc-opioid receptors. In animal models, M1 is up to 6 times more potent than tramado1 in producing analgesia and 200 times more potent in mc-opioid binding. Tramado1-induced analgesia is only partially antagonized by the opiate antagonist naloxone in several animal tests. The relative contribution of both tramado1 and M1 to human analgesia is dependent upon the plasma concentrations of each compound (see Pharmacokinetics).
Tramado1 has been shown to inhibit reuptake of norepinephrine and serotonin in vitro, as have some other opioid analgesics. These mechanisms may contribute independently to the overall analgesic profile of tramado1 HCl. Analgesia in humans begins approximately within one hour after administration and reaches a peak in approximately two to three hours.
Apart from analgesia, tramado1 administration may produce a constellation of symptoms (including dizziness, somnolence, nausea, constipation, sweating and pruritus) similar to that of an opioid. However, tramado1 causes less respiratory depression than morphine at recommended doses (see OVERDOSAGE). In contrast to morphine, tramado1 has not been shown to cause histamine release. At therapeutic doses, tramado1 has no effect on heart rate, left-ventricular function or cardiac index. Orthostatic hypotension has been observed.
Pharmacokinetics
The analgesic activity of tramado1 HCl is due to both parent drug and the M1 metabolite (see Pharmacodynamics). Tramado1 is administered as a racemate and both the [-] and [+] forms of both tramado1 and M1 are detected in the circulation. Tramado1 is well absorbed orally with an absolute bioavailability of 75%. Tramado1 has a volume of distribution of approximately 2.7 L/kg and is only 20% bound to plasma proteins. Tramado1 is extensively metabolized by a number of pathways, including CYP2D6 and CYP3A4, as well as by conjugation of parent and metabolites. One metabolite, M1, is pharmacologically active in animal models. The formation of M1 is dependent upon Cytochrome P-450(2D6) and as such is subject to both metabolic induction and inhibition which may affect the therapeutic response (see DRUG INTERACTIONS). Tramado1 and its metabolites are excreted primarily in the urine with observed plasma half-lives of 6.3 and 7.4 hours for tramado1 and M1, respectively. Linear pharmacokinetics have been observed following multiple doses of 50 and 100 mg to steady-state.
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