Pharmacologic Classification

a. General

Acetaminophen is an analgesic and antipyretic agent and has been clinically proven to be effective for the temporary relief of minor aches and pains associated with the common cold, headache, toothache, muscular aches, backache, for the minor pain of arthritis, for the pain of menstrual cramps, and for the reduction of fever. Acetaminophen is an effective antipyretic in infants, children, and adults.

b. Pharmacologic Class

Acetaminophen is a centrally acting analgesic and antipyretic agent.

c. Mechanism of Action

Analgesia

Although the exact site and mechanism of analgesic action is not clearly defined, acetaminophen appears to produce analgesia by elevation of the pain threshold.^2-4 The potential mechanism may involve inhibition of the nitric oxide pathway mediated by a variety of neurotransmitter receptors including N-methyl-D-aspartate and substance P.⁵

Antipyresis

Investigations indicate that endogenous pyrogens produced by leukocytes cause an elevation of prostaglandin E (PGE) in the cerebrospinal fluid. Fever results when the elevated PGE acts on the preoptic area of the anterior hypothalamus to decrease heat loss and increase heat gain. Acetaminophen has been shown to inhibit the action of endogenous pyrogens on the heat-regulating centers in the brain by blocking the formation and release of prostaglandins in the central nervous system.^6-9 Inhibition of arachidonic acid metabolism is not requisite for the antipyretic effect of acetaminophen.¹⁰ Acetaminophen does not depend upon the activation of the arginine vasopressin V-1 receptor to induce antipyresis as has been noted in rats treated with indomethacin and salicylates.^11,12 This has been demonstrated in animals by observing a decrease in both fever and PGE activity following administration of acetaminophen to unanesthetized cats, and in rabbits and dogs when brain prostaglandin synthetase was inhibited by the administration of acetaminophen.^13,14

d. Pharmacokinetic Data

Absorption

Regular-Release

Oral acetaminophen is rapidly and almost completely absorbed from the gastrointestinal tract primarily in the small intestine. This absorption process occurs by passive transport. The relative bioavailability ranges from 85% to 98%.¹⁵

Figure 1 shows the mean pharmacokinetic profile for 24 fasting subjects who received acetaminophen 1000 mg dosed as liquid or caplets. For individual subjects, maximal plasma concentrations occurred within 10 to 90 minutes following ingestion and ranged from 8 to 32 µg/mL. Acetaminophen plasma concentrations range from 1 to 4 µg/mL 6 hours after ingestion.

Extended-Release

Each bilayered acetaminophen extended-release, 650-mg caplet contains 325 mg of immediate-release acetaminophen on one side and, on the other side, 325 mg of acetaminophen in a matrix formulation designed to slowly release. In vitro data indicate that two 650-mg extended-release caplets

FIGURE 1. Mean plasma concentrations of acetaminophen in 24 male subjects following oral administration of 1000 mg of acetaminophen dosed as either 30 mL of Extra Strength TYLENOL® acetaminophen Adult Liquid Pain Reliever or as two Extra Strength TYLENOL® acetaminophen Caplets.

FIGURE 2. Mean plasma concentrations of acetaminophen in 24 male subjects following oral administration of 1300 mg acetaminophen dosed as either two caplets of TYLENOL® Arthritis Extended Relief or four Regular Strength TYLENOL® acetaminophen (two caplets given at 0 and 4 hours).

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