Algesia Mechanism of Action

Pharmacotherapeutic group: Antipyretic/Opioid Analgesic.
Pharmacology: Pharmacodynamics: Tramadol is a synthetic opioid analgesic that acts on the central nervous system. It is a pure non-selective agonist of the µ, δ, and κ opioid receptors with a higher affinity for the µ receptors. Other mechanisms which contribute to its analgesic effect are inhibition of neuronal uptake of noradrenaline and enhancement of serotonin release.
Paracetamol exhibits analgesic and antipyretic activity by inhibiting prostaglandin synthesis. It produces analgesia by elevating the pain threshold and antipyresis through its action on the hypothalamic heat regulating center. In therapeutic doses, the analgesic and antipyretic action of paracetamol is comparable to that of aspirin. Paracetamol does not adversely affect platelet function and hemostasis.
The combination of tramadol + paracetamol exhibits a synergistic effect. Controlled studies demonstrated that the combination provided analgesia comparable to ibuprofen and superior to that provided by monotherapy of either ingredient or placebo. Onset of pain relief occurred in about 17 minutes (vs. 15 minutes for paracetamol alone and 30 minutes for tramadol alone or placebo), while duration of pain relief was about five hours (vs. two hours with tramadol alone and three hours with paracetamol alone).
Pharmacokinetics: After a single oral dose of tramadol 37.5 mg + paracetamol 325 mg combination tablet, peak plasma concentrations (C_max) of both tramadol enantiomers were 64.3 ng/mL [(+)-tramadol] and 55.5 ng/mL [(-)-tramadol]. These concentrations were achieved after 1.8 hours. Peak plasma concentration of paracetamol achieved after 0.9 hour was 4.2 mcg/mL. The mean elimination half-lives (t1/2) of both tramadol enantiomers were 5.1 hours [(+)-tramadol] and 4.7 hours [(-)-tramadol] and 2.5 hours for paracetamol.
Tramadol is well absorbed with mean absolute bioavailability of approximately 75% after a single oral 100 mg dose. Peak concentrations of tramadol and the M1 metabolite (major metabolite) occur after two and three hours, respectively.
Paracetamol is rapidly and completely absorbed in the small intestine. Peak plasma concentrations are achieved in one hour and are not modified by concomitant administration of tramadol.
The oral administration of tramadol + paracetamol with food has no significant effect on the peak plasma concentration or extent of absorption of either tramadol or paracetamol.
Tramadol has high tissue affinity with a volume of distribution of 2.6 and 2.9 L/kg in male and female subjects, respectively, after intravenous administration. Its affinity for plasma proteins is approximately 20% and saturation occurs at doses beyond the therapeutic range.
Paracetamol is evenly distributed throughout most body fluids, but not in fatty tissue. Volume of distribution is approximately 0.9 L/kg. A relatively small portion (~20%) of paracetamol is bound to plasma proteins.
Tramadol and its metabolites undergo extensive hepatic metabolism via the cytochrome P (CYP) 2D6 and CYP3A4 pathways and conjugation of the parent drug and its metabolites. Most of the drug is excreted in the urine as metabolites (approximately 60%) and the remaining drug fraction is excreted in its unchanged form.
Paracetamol metabolism follows first-order kinetics, and primary metabolic pathways involve conjugation with glucuronide and sulfate; and oxidation via the CYP450 mixed-function oxidase pathway. In adults, most of the drug fraction is transformed into the inactive glucuronide salt, and the remainder is conjugated with sulfate.
Tramadol is cleared from the circulation via renal excretion. The plasma elimination half-lives of racemic tramadol and M1 are approximately five to six, and seven hours, respectively. The plasma elimination half-life of racemic tramadol increased from approximately seven to nine hours upon multiple dosing of tramadol + paracetamol.
Paracetamol has a plasma elimination half-life that ranges from two to three hours in adults, but this may be prolonged in patients with liver disease. It is mainly excreted in the urine in its glucuronide or sulfate form, and less than nine percent is excreted unchanged.
Special Populations: Renal Impairment: Elimination of tramadol and M1 is diminished in patients with renal impairment. In patients with renal failure (creatinine clearance < 5 mL/min), the half-life of tramadol was 11 hours and that of M1 was 17 hours.
Hepatic Impairment: Elimination of tramadol and M1 is diminished in patients with hepatic impairment, the mean half-life of tramadol was 13 hours and the mean half-life of M1 was 19 hours.
Elderly: In the elderly (>75 years old), tramadol's volume of distribution is decreased by 25% and clearance is decreased by 40%. As a result, tramadol's C_max and total exposure are increased by 30% and 50%, respectively. However, the half-life of tramadol is only slightly prolonged by 15%.