Zegesic (Acetaminophen / Phenyltoloxamine Citrate) - Description and Clinical Pharmacology

DESCRIPTION

Each tablet contains:

Acetaminophen .......................  600 mg

Phenyltoloxamine Citrate ..........  66 mg

In a specially prepared base to provide a prolonged therapeutic effect.

Inactive ingredients in each tablet are: calcium phosphate dibasic, magnesium stearate, methylcellulose, povidone and silicified microcrystalline cellulose.

Acetaminophen, 4'-hydroxyacetanilide, a slightly bitter, white, odorless, crystalline powder, is a non-opiate, non-salicylate analgesic and antipyretic. It has the following structural formula:

Figure 1: Acetaminophen

C₈H₉NO₂                           MW=151.17

Phenyltoloxamine Citrate, N, N-dimethyl-2-(alpha-phenyl-o-tolyloxy) ethylamine dihydrogen citrate, is an antihistamine used to augment analgesia. It occurs as crystals from water or methanol. It is soluble in water. Phenyltoloxamine Citrate has the following structural formula:

Figure 2: Phenyltoloxamine Citrate

C₁₇H₂₁NO•C₆H₈O₇           MW=447.48

CLINICAL PHARMACOLOGY

The analgesic action of acetaminophen involves peripheral influences, but the specific mechanism is as yet undetermined. Antipyretic activity is mediated through hypothalamic heat regulating centers. Acetaminophen inhibits prostaglandin synthetase. Therapeutic doses of acetaminophen have negligible effects on the cardiovascular or respiratory systems; however, toxic doses may cause circulatory failure and rapid, shallow breathing. Acetaminophen blocks the chemical cyclic AMP, a byproduct of prostaglandins, which cause the nerve endings to be more sensitive to pain impulses. Phenyltoloxamine Citrate is an ethanolamine type antihistamine that acts as an adjuvant analgesic, which augments the analgesic effect of acetaminophen. It has been suggested that analgesic effects of antihistamines are related to the modulation of histaminergic and serotonergic pathways. More specific mechanisms that have been postulated include interactions with one or more pain mediators such as substance P, bradykinins, prostaglandins and cyclic nucleotides. Pharmacokinetics: The behavior of the individual components is described below. Acetaminophen is rapidly absorbed from the gastrointestinal tract and is distributed throughout most body tissues. The plasma half-life is 1.25 to 3 hours, but may be increased by liver damage and following overdosage. Elimination of acetaminophen is principally by liver metabolism (conjugation) and subsequent renal excretion of metabolites. Approximately 85% of an oral dose appears in the urine within 24 hours of administration, most as the glucuronide conjugate, with small amounts of other conjugates and unchanged drug. See OVERDOSAGE for toxicity information.

Phenyltoloxamine Citrate is well absorbed following oral administration. It is metabolized in the liver and excreted in the urine predominately, as its metabolites.