Duocetz

Duocetz Mechanism of Action

tramadol + paracetamol

Manufacturer:

Mega Lifesciences

Distributor:

Maxxcare
Full Prescribing Info
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Pharmacology: The following information is based on studies of tramadol alone or paracetamol alone, except where otherwise noted: Pharmacodynamics: Tramadol is a centrally acting synthetic opioid analgesic. Although its mode of action is not completely understood, at least two complementary mechanisms appear applicable: binding of parent and M1 metabolite to U-opioid receptors and weak inhibition of reuptake of norepinephrine and serotonin.
Paracetamol is a non-opiate, non-salicylate analgesic.
Pharmacokinetics: Tramadol is administered as a racemate and both the (-) and (+) forms of both tramadol and M1 are detected in the circulation. The pharmacokinetics of plasma tramadol and paracetamol following oral administration of one tablet are shown in the table. Tramadol has a slower absorption and longer half-life when compared to paracetamol. (See table.)

Click on icon to see table/diagram/image

Absorption: Tramadol hydrochloride has a mean absolute bioavailability of approximately 75% following administration of a single 100mg oral dose of tramadol tablets. The mean peak plasma concentration of racemic tramadol and M1 after administration of two tramadol/Paracetamol combination tablets occurs at approximately two and three hours, respectively, post-dose.
Peak plasma concentrations of paracetamol occur within one hour and are not affected by co-administration with tramadol. Oral absorption of paracetamol following administration occurs primarily in the small intestine.
Distribution: The volume of distribution of tramadol was 2.6 and 2.9 L/kg in male and female subjects, respectively, following a 100mg intravenous dose. The binding of tramadol to human plasma proteins is approximately 20% and binding also appears to be independent of concentration up to 10ug/mL. Saturation of plasma protein binding occurs only at concentrations outside the clinically relevant range.
Paracetamol appears to be widely distributed throughout most body tissues except fat.
Its apparent volume of distribution is about 0.9L/kg. A relative small portion (~20%) of paracetamol is bound to plasma protein.
Metabolism: Following oral administration, tramadol is extensively metabolized by a number of pathways, including CYP2D6 and CYP3A4, as well as by conjugation of parent and metabolites. 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 pathway appears to be N- and O-demethylation and glucuronidation or sulfation in the liver. Metabolite M1 (O-desmethyltramadol) is pharmacologically active in animal models.
Formation of M1 is dependent on CYP2D6 and as such is subject to inhibition, which may affect the therapeutic response.
Approximately 7% of the population has reduced activity of the CYP2D6 isoenzyme of cytochrome P450. These individuals are "poor metabolizers" of debrisoquine, dextromethorphan, tricyclic antidepressants, among other drugs. Based on a population PK analysis of Phase 1 studies in healthy subjects, concentration of tramadol were approximately 20% higher in poor metabolizers versus extensive metabolizers while M1 concentration were 40% lower. In vitro drug interaction studies in human liver microsomes indicates that inhibitors of CYP2D6 such as fluoxetine and its metabolites norfluoxetine, amitriptyline and quinidine inhibit the metabolism of tramadol to various degrees. The full pharmacological impact of these alterations in terms of either efficacy or safety is unknown. Concomitant use of SEROTONIN re-uptake INHIBITORS and MAO INHIBITORS may enhance the risk of adverse events, including seizure and serotonin syndrome.
Paracetamol is primarily metabolized in the liver by first-order kinetics and involves three principal separate pathways: 1. Conjugation with glucuronide; 2. Conjugation with sulfate; and 3. Oxidation via the cytochrome, P450-dependent, mixed function oxidase enzyme pathway to a reactive intermediate metabolite, which conjugates with glutathione and is then further metabolized to form cysteine and mercapturic acid conjugates. The principal cytochrome P450 isoenzyme involved appears to be CYP2E1, with CYP1A2 and CYP3A4 as additional pathways.
In adults, the majority of paracetamol is conjugated with glucuronic acid and, to a lesser extent, with sulfate. These glucuronide sulfate and glutathione-derived metabolites lack biologic activity. In premature infants, newborns, and young infants, the sulfate conjugate predominates.
Elimination: Tramadol is eliminated primarily through metabolism by the liver and the metabolisms are eliminated primarily by the kidneys. The plasma elimination half-lives of racemic tramadol and M1 are approximately 5-6 and 7 hours, respectively, after administration of Tramadol/Paracetamol combination tablet (37.5mg/325mg). The apparent plasma elimination half-life of racemic tramadol increased to 7-9 hours upon multiple dosing of Tramadol/Paracetamol Combination Tablet (37.5mg/325mg).
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 sulfate conjugation in a dose-dependent manner. Less than 9% of paracetamol excreted unchanged in the urine.
Special Populations: Renal: The pharmacokinetics of Tramadol/Paracetamol Combination Tablet (37.5mg/325mg) in patients with renal impairment has not been studied. Based on studies using tramadol alone, excretion of tramadol and metabolite M1 is reduced in patients with creatinine clearance of less than 30mL/min, adjustment of dosing regimen in this patients population is recommended. The total amount of tramadol and M1 removed during a 4 hour period with less than 7% of the administered dose based on studies using tramadol alone.
Hepatic: The pharmacokinetics and tolerability of Tramadol/Paracetamol Combination Tablet (37.5mg/325mg) in patients with impaired hepatic function has not been studied, since tramadol and paracetamol are extensively metabolized by the liver, the use of Tramadol/Paracetamol Combination Tablet (37.5mg/325mg) in patients with hepatic impairment is not recommended.
Geriatric: A population pharmacokinetic analysis of data obtained from a clinical trial in patients with chronic pain treated with Tramadol/Paracetamol Combination Tablet (37.5mg/325mg) which included 55 patients between 65 and 75 years of age and 19 patients over 75 years of age, showed no significant changes in pharmacokinetics of tramadol and paracetamol in elderly patients with normal renal and hepatic function.
Gender: Tramadol clearance was 20% higher in female subjects compared to males on four phase 1 studies of Tramadol/Paracetamol Combination Tablet (37.5mg/325mg) in 50 male and 34 female healthy subjects. The significance of difference is unknown.
Pediatric: Pharmacokinetics of Tramadol/Paracetamol Combination Tablet (37.5mg/325mg) has not been studied in pediatric patients below 16 years of age.
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