Analab Mechanism of Action

Tramadol is a centrally acting opioid analgesic. It is a nonselective pure agonist at μ, δ and κ opioid receptors with a higher affinity for the μ receptor.
Other mechanisms which contribute to its analgesic effect are inhibition of neuronal re-uptake of noradreneline and enhancement of serotonin release.
Tramadol has an antitussive effect. In contrast to morphine, analgesic doses of tramadol over a wide range have no respiratory depressant effect. Also, gastrointestinal motility is not affected. Effects on the cardiovascular system tend to be slight. The potency of tramadol to be 1/10-1/6 that of morphine. The onset of the analgesic effect of tramadol hydrochloride is rapid and the effect lasts for several hours. Tramadol hydrochloride is a potent drug and should not be used for minor pain.
It does not have an anti-inflammatory effect.
Tramadol hydrochloride has an analgesic effect in all the usual test models for centrally acting analgesics. On parenteral administration, the intensity of the effect of is equivalent to that of other opioid analgesics, e.g pentazocine and pethidine. On oral administration, tramadol hydrochloride is practically as effective as on parenteral application. The onset of activity is rapid and the duration of the effect is similar to that of morphine. Tramadol hydrochloride is a pure opiate agonist. The morphine antagonist, naloxone, neutralizes the analgesic effect of tramadol hydrochloride.
Pharmacokinetics: Capsule: More than 90% of tramadol is absorbed after oral administration. The mean absolute bioavailability is approximately 70%, irrespective of the concomitant intake of food. The difference between absorbed and non-metabolised available tramadol is probably due to the low first-pass effect. The first-pass effect after oral administration is a maximum of 30%.
Tramadol has a high tissue affinity (Vd, β= 203+40 l). It has a plasma protein binding of about 20%.
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 to 45 minutes within a mean Cmax 280 to 208 mcg/L and Tmax of 1.6 to 2 h.
Tramadol passes the blood-brain and placental barriers. Very small amounts of the substance and derivative are found in the breast-milk.
Elimination half-life t_½ β is approximately 6 h, irrespective of the mode of administration. In patients above 75 years of age it may be prolonged by a factor of approximately 1.4.
Tramadol is mainly metabolised by means of N-and O-demethylation and conjugation of the O-demethylation products with glucuronic acid. Only O-desmethyltramadol is pharmalogically active. There are considerable interindividual quantitative differences between the other metabolites. So far, eleven metabolites have been found in the urine. The inhibition of one or both types of the isoenzymes CYP3A4 and CYP2D6 involved in the biotransformation of tramadol may affect the plasma concentration of tramadol or its active metabolite. Up to now, clinically relevant interactions have not been reported.
Tramadol and its metabolites are almost completely via the kidneys. Cumulative urinary excretion is 90% of the total radioactivity of the administered dose, in cases of impaired hepatic and renal function the half-life may be slightly prolonged.
In patients with cirrhosis of the liver, elimination half-lives of 13.3+4.9 h (tramadol) and 18.5+9.4 h (o-desmethyltramadol), in an extreme case 22.3 h and 36 h respectively, have been determined. In patients with renal insufficiency (creatinine clearance < 5 ml/min) the values were 11+3.2 h and 16.9+3 h, in an extreme case 19.5 h and 43.2 h respectively.
Tramadol has a linear pharmacokinetic profile within the therapeutic dosage range.
The relationship between serum concentrations and the analgesic effect is dose-dependent, but varies considerably in isolated cases. A serum concentration of 100-300 ng/ml is usually effective.
Injection: Serum protein-binding is low (about 20%). The elimination half-life in the terminal phase is 6 hours with about 1/4-1/3 of the active substance appearing unchanged in the urine. One of the metabolites is pharmacologically active, but the concentration in the blood is lower than that of Tramadol hydrochloride itself.
Excretion: Tramadol hydrochloride and its metabolites are almost completely eliminated via the kidneys.