Tramicet Mechanism of Action

Pharmacotherapeutic group: Analgesics, Opioids in combination with non-opioid analgesics. ATC code: N02AJ13.
Pharmacology: Pharmacodynamics: Tramadol is a centrally acting analgesic compound. At least two complementary mechanisms appear applicable, binding of parent and M1 metabolite to μ-opioid receptors and weak inhibition of reuptake of norepinephrine and serotonin. Paracetamol is another centrally acting analgesic. The exact site and mechanism of its analgesic action is not clearly defined. When evaluated in a standard animal model, the combination of tramadol and paracetamol exhibited a synergistic effect.
Pharmacokinetics: Tramadol has a slower absorption and longer half-life when compared to paracetamol. Single and multiple dose pharmacokinetics of Tramicet showed no significant drug interactions between tramadol and paracetamol.
After a single oral dose of one Tramadol/Paracetamol combination tablet (37.5 mg/325 mg) peak plasma concentrations of 64.3/55.5 ng/ml [(+)Tramadol/(-)-Tramadol] and 4.2 μg/ml (paracetamol) are reached after 1.8 h [(+)Tramadol/(-)-Tramadol] and 0.9 h (Paracetamol), respectively. Mean elimination half-lives t1/2 are 5.1/4.7 h [(+)Tramadol/(-)-Tramadol] and 2.5 h (paracetamol).
Absorption: Tramadol hydrochloride has a mean absolute bioavailability of approximately 75% following administration of a single 100 mg oral dose of tramadol tablets. The mean peak plasma concentration of racemic tramadol and M1 after administration of two Tramicet tablets occur at approximately two and three hours, respectively, post-dose in healthy adults.
Oral absorptions of paracetamol following administration of Tramicet is rapid and almost complete and occurs primarily in the small intestine. Peak plasma concentrations of paracetamol occur within 1 hour and are not affected by co-administration with tramadol.
Food effects: The oral administration of Tramicet with food has no significant effect on the peak plasma concentration or extent of absorption of either tramadol or paracetamol, so Tramicet can be taken independently of meal times.
Distribution: The volume of distribution of tramadol was 2.6 and 2.9 L/kg in male and female subjects, respectively, following a 100 mg intravenous dose. The binding of tramadol to human plasma protein is approximately 20%. Paracetamol appears to be widely distributed throughout most body tissue except fat. Its apparent volume of distribution is about 0.9 L/kg. A relatively small portion (~20%) of paracetamol is bound to plasma protein.
Metabolism: Plasma concentration profiles for tramadol and its M1 metabolite measured following dosing of Tramicet showed no significant change compared to dosing with tramadol alone. Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. The major metabolic pathways appear to be N- and O-demethylation and glucuronidation of sulfation in the liver. Tramadol is extensively metabolized by a number of pathways, including CYP2D6. Patients who are CYP2D6 ultra-rapid metabolizers may convert tramadol to its active metabolite (M1) more rapidly and completely than other patients.
Paracetamol is primarily metabolized in the liver by first-order kinetics and involves three principle separate pathways: a) Conjugation with glucuronide, b) Conjugation with sulphate, c) Oxidation via cytochrome P450 enzyme pathway.
Excretion: Tramadol and its metabolite are eliminated primarily by the kidneys. The plasma elimination half-lives of racemic tramadol and M1 are approximately six and seven hours, respectively. The plasma elimination half-life of racemic tramadol increased from approximately six hours to seven hours upon multiple dosing of Tramicet.
The half-life of paracetamol is about 2 to 3 hours in adults. It is somewhat shorter in children and somewhat longer in neonates and in cirrhotic patients. Paracetamol is eliminated from the body primarily by formation of glucuronide and sulphate conjugates in a dose-dependent manner. Less than 9% of paracetamol is excreted unchanged in the urine.