A Pharmacologic Overview of Tylenol® (acetaminophen)

The information presented here can also be found in the monograph Professional Product Information.
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Physical Properties of Acetaminophen

Structural Formula

Acetaminophen Structural Formula

Solubility

water 1:70
boiling water 1:20
alcohol 1:10
chloroform 1:50
glycerin 1:40
ether slightly soluble

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Molecular Formula

C8H9NO2

Molecular Weight

151.16

Macroscopic Appearance

Acetaminophen is a white, crystalline powder.

Chemical Properties of Acetaminophen

Structural Similarities/Differences of the Drug to Other Available Compounds or Groups of Compounds

Acetaminophen is a synthetic, nonopiate, centrally acting analgesic derived from p-aminophenol. The full chemical name is N-acetyl-p-aminophenol.

pKa

The pKa of acetaminophen is 9.51 at 25°C.

Stability of the Drug to Temperature, Light, and Moisture

Acetaminophen is stable to temperature, light, and moisture.

pH Range over which Drug is Stable in Solution

Acetaminophen is stable at a pH between 4 and 7 at 25°C.

pH of Commercially Available Liquid Products

Acetaminophen oral solution (ie, elixir, adult liquid) has a pH of 3.8 to 6.1 and the oral suspension (ie, infants’ drops, children’s suspension) has a pH of 5.4 to 6.9.

Recommended Storage Conditions

Storage requirements for all TYLENOL® acetaminophen drops, liquids, and solid formulations are as follows: store at room temperature. It is recommended that high humidity and excessive heat (ie, > 40°C [104°F]) be avoided for the gelatin-coated formulations (eg, gelcaps, geltabs). Freezing of the liquid or suspension formulations should be avoided.

Expiration Dating Periods for Commercially Available Products

Under room temperature storage conditions, TYLENOL® acetaminophen solid formulations are generally stable for 3 years and liquid formulations are generally stable for 2 years from the date of manufacture. Refer to product package for specific expiration date.

Osmolarity/Osmolality of Commercially Available Solutions

Extra Strength TYLENOL® acetaminophen Adult Liquid: 3058 ± 152 mmol/kg
Children's TYLENOL® acetaminophen Elixir: 6040 ± 25 mmol/kg
Because of the nature of suspension formulations, osmolarity of the TYLENOL® acetaminophen suspension products cannot be determined.

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Acetaminophen Mechanism of Action

Pharmacologic Classification: 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.

Pharmacologic Class

Acetaminophen is a centrally acting analgesic and antipyretic agent.

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. 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.

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. Inhibition of arachidonic acid metabolism is not requisite for the antipyretic effect of acetaminophen. 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. 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.

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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%.

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.

Pharmacokinetic Profile of Acetaminophen - Figure 1

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 (containing a total of 1300 mg of acetaminophen) release 88% and 95% of the drug within 3 and 5 hours, respectively. Following administration of a single dose of two 650-mg, extended-release caplets, the average maximal plasma concentrations occurred within 0.5 to 3 hours following ingestion and ranged from 6.9 to 14.1 µg/mL.

Figure 2 shows the mean pharmacokinetic profile for 24 fasting subjects who received acetaminophen 1300 mg dosed as two extended-release or four regular-strength caplets (two caplets given at 0 and 4 hours).

Pharmacokinetic Profile of Acetaminophen - Figure 2

Distribution

Acetaminophen appears to be widely distributed throughout most body fluids except fat. The apparent volume of distribution of acetaminophen is 0.95 L/kg. A relatively small proportion (10% to 25%) of acetaminophen is bound to plasma proteins and binding is only slightly increased in plasma concentrations associated with overdose. The sulfate and glucuronide metabolites do not bind to plasma proteins even at relatively high concentrations.

Spinal Fluid
Low protein binding and low molecular weight allow acetaminophen to pass through the blood-brain barrier. The peak concentration of acetaminophen in cerebrospinal fluid is reached after 2 to 3 hours.

Placental Barrier
Analysis of urine samples has demonstrated the passage of unconjugated acetaminophen via placental transfer. When given to the mother in therapeutic doses, acetaminophen crosses the placenta into fetal circulation as early as 30 minutes after ingestion, although the difference in serum concentration between maternal and cord blood is not statistically significant. In the fetus, acetaminophen is effectively metabolized by sulfate conjugation.

Breast Milk
Maternal ingestion of acetaminophen in recommended analgesic doses does not present a risk to the nursing infant. Amounts in milk range from 0.1% to 1.85% of the ingested maternal dose. These studies have established that, even at the time of peak acetaminophen concentration in human breast milk, the nursing infant would receive less than 2% of the maternal dose. Accordingly, breast feeding need not be interrupted because of maternal ingestion of recommended doses of acetaminophen.

Metabolism

Acetaminophen is primarily metabolized in the liver by first-order kinetics and involves three principal separate pathways:

  • conjugation with glucuronide
  • conjugation with sulfate
  • oxidation via the cytochrome, P450 dependent, mixed-function oxidative enzyme pathway to form 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.

Two additional minor pathways also are possibly involved in acetaminophen metabolism:

  • hydroxylation to form 3-hydroxy-acetaminophen
  • methoxylation to form 3-methoxy-acetaminophen.

These metabolites are further conjugated with glucuronide or sulfate.
In adults, the majority of acetaminophen 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.

Excretion

The biologic half-life of acetaminophen in normal adults is approximately 2 to 3 hours in the usual dosage range. It is somewhat shorter in children and somewhat longer in neonates and in patients with cirrhosis. The elimination half-life is approximately 3 hours for the extended-release product. The elimination half-life of acetaminophen in the cerebrospinal fluid according to pooled data is 3.2 hours.

Acetaminophen is eliminated from the body primarily by formation of glucuronide and sulfate conjugates in a dose-dependent manner. Table 1 shows the mean range of acetaminophen urinary metabolite values in healthy subjects using therapeutic doses (10 mg/kg or 1000-mg dose). Less than 9% of acetaminophen is excreted unchanged in the urine.

Other minor metabolites, each accounting for 4% or less of a therapeutic dose, include sulfate and glucuronide conjugates of
3-methoxyacetaminophen, 3-hydroxy-acetaminophen, and
3-methyl-thioacetaminophen. Slight differences have been seen in ethnically distinct populations (eg, Asian, Spanish).

Acetaminophen metabolites found in the urine

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