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Pharmacology: Pharmacodynamics: Tramadol hydrochloride is a centrally acting analgesic. It is non selective pure agonist at mu, delta and kappa opioid receptors with a higher affinity for the mu receptor. Other mechanisms which may contribute to its analgesic effect are inhibitor of neuronal reuptake of noradrenaline and enhancement of serotonin release.
Pharmacokinetics: After oral administration, tramadol is almost completely absorbed. Mean absolute bioavailability is approximately 70% following a single dose and increases to approximately 90% at steady state. Plasma protein binding of tramadol is approximately 20%. When C14 labelled tramadol was administered to humans, approximately 90% was excreted via the kidneys with the remaining 10% appearing in the faeces.
Tramadol has a linear pharmacokinetic profile within the therapeutic dosage range. The half life of the terminal elimination phase (t½β) was 6.0±1.5 h in young volunteers. Tramadol pharmacokinetics show little age dependence in volunteers up to the age of 75 years. In volunteers aged over 75 years, t½β was 7.0±1.6 h on oral administration.
Following a single oral dose administration of tramadol 100 mg as capsules or tablets to young healthy volunteers, plasma concentrations were detectable within approximately 15-45 minutes with a mean Cmax of 280 to 308 mcg/L and Tmax of 1.6 to 2h.
Tramadol is metabolized by the cytochrome P450 iso-enzyme CYP2D6. It undergoes biotransformation to a number of metabolites mainly by means of N- and O-demethylation. O-desmethyl tramadol appears to be the most pharmacologically active metabolite, showing analgesic activity in rodents. As humans excrete a higher percentage of unchanged tramadol than animals it is believed that the contribution made by this metabolite to analgesic activity is likely to be less in humans than animals. In humans the plasma concentration of this metabolite is about 25% that of unchanged tramadol.
Since tramadol is eliminated both metabolically and renally, the terminal half-life t½β may be prolonged in impaired hepatic or renal function. In patients with liver cirrhosis t½β tramadol was a mean of 13.3±4.9 h; in patients with renal insufficiency (creatinine clearance < 5 ml/min) it was 11.0±3.2 h.
