Exthegran TD

Uses

Acetaminophen is an analgesic drug used alone or in combination with opioids for pain management, and as an antipyretic agent.

In general, acetaminophen is used for the treatment of mild to moderate pain and reduction of fever. It is available over the counter in various forms, the most common being oral forms.

Acetaminophen injection is indicated for the management of mild to moderate pain, the management of moderate to severe pain with adjunctive opioid analgesics, and the reduction of fever.

Because of its low risk of causing allergic reactions, this drug can be administered in patients who are intolerant to salicylates and those with allergic tendencies, including bronchial asthmatics. Specific dosing guidelines should be followed when administering acetaminophen to children.

Exthegran TD is also used to associated treatment for these conditions: Acute Gouty Arthritis, Acute Musculoskeletal Pain, Allergies, Ankylosing Spondylitis (AS), Arthritis, Chills, Cold, Cold Symptoms, Common Cold, Common Cold/Flu, Cough, Cough caused by Common Cold, Coughing caused by Flu caused by Influenza, Dyskinesia of the Biliary Tract, Dyskinesia of the Urinary Tract, Febrile Convulsions, Febrile Illness Acute, Fever, Fibromyalgia Syndrome, Flu caused by Influenza, Headache, Joint dislocations, Menstrual Distress (Dysmenorrhea), Mild pain, Muscle Inflammation, Muscle Injuries, Muscle Spasms, Musculoskeletal Pain, Nasal Congestion, Neuralgia, Osteoarthritis (OA), Pain, Pollen Allergy, Postoperative pain, Premenstrual cramps, Rheumatoid Arthritis, Rhinopharyngitis, Rhinorrhoea, Severe Pain, Sinusitis, Soreness, Muscle, Spasms, Spastic Pain of the Gastrointestinal Tract, Sprains, Tension Headache, Toothache, Upper Respiratory Tract Infection, Whiplash Syndrome, Acute Torticollis, Mild to moderate pain, Minor aches and pains, Minor pain, Moderate Pain, Airway secretion clearance therapy, Antispasmodic, Bronchodilation

How Exthegran TD works

According to its FDA labeling, acetaminophen's exact mechanism of action has not been fully established - despite this, it is often categorized alongside NSAIDs (nonsteroidal anti-inflammatory drugs) due to its ability to inhibit the cyclooxygenase (COX) pathways. It is thought to exert central actions which ultimately lead to the alleviation of pain symptoms.

One theory is that acetaminophen increases the pain threshold by inhibiting two isoforms of cyclooxygenase, COX-1 and COX-2, which are involved in prostaglandin (PG) synthesis. Prostaglandins are responsible for eliciting pain sensations. Acetaminophen does not inhibit cyclooxygenase in peripheral tissues and, therefore, has no peripheral anti-inflammatory effects. Though acetylsalicylic acid (aspirin) is an irreversible inhibitor of COX and directly blocks the active site of this enzyme, studies have shown that acetaminophen (paracetamol) blocks COX indirectly. Studies also suggest that acetaminophen selectively blocks a variant type of the COX enzyme that is unique from the known variants COX-1 and COX-2. This enzyme has been referred to as COX-3. The antipyretic actions of acetaminophen are likely attributed to direct action on heat-regulating centers in the brain, resulting in peripheral vasodilation, sweating, and loss of body heat. The exact mechanism of action of this drug is not fully understood at this time, but future research may contribute to deeper knowledge.

Toxicity

LD50 = 338 mg/kg (oral, mouse); LD50 = 1944 mg/kg (oral, rat)

Overdose and liver toxicity

Acetaminophen overdose may be manifested by renal tubular necrosis, hypoglycemic coma, and thrombocytopenia. Sometimes, liver necrosis can occur as well as liver failure. Death and the requirement of a liver transplant may also occur. Metabolism by the CYP2E1 pathway releases a toxic acetaminophen metabolite known as N-acetyl-p-benzoquinoneimine(NAPQI). The toxic effects caused by this drug are attributed to NAPQI, not acetaminophen alone.

Carcinogenesis

Long-term studies in mice and rats have been completed by the National Toxicology Program to study the carcinogenic risk of acetaminophen. In 2-year feeding studies, F344/N rats and B6C3F1 mice consumed a diet containing acetaminophen up to 6,000 ppm. Female rats showed evidence of carcinogenic activity demonstrated by a higher incidence of mononuclear cell leukemia at doses 0.8 times the maximum human daily dose (MHDD). No evidence of carcinogenesis in male rats (0.7 times) or mice (1.2 to 1.4 times the MHDD) was noted. The clinical relevance of this finding in humans is unknown.

Mutagenesis

Acetaminophen was not found to be mutagenic in the bacterial reverse mutation assay (Ames test). Despite this finding, acetaminophen tested positive in the in vitro mouse lymphoma assay as well as the in vitro chromosomal aberration assay using human lymphocytes. In published studies, acetaminophen has been reported to be clastogenic (disrupting chromosomes) when given a high dose of 1,500 mg/kg/day to the rat model (3.6 times the MHDD). No clastogenicity was observed at a dose of 750 mg/kg/day (1.8 times the MHDD), indicating that this drug has a threshold before it may cause mutagenesis. The clinical relevance of this finding in humans is unknown.

Impairment of Fertility

In studies conducted by the National Toxicology Program, fertility assessments have been performed in Swiss mice in a continuous breeding study. No effects on fertility were seen.

Use in pregnancy and nursing

The FDA label for acetaminophen considers it a pregnancy category C drug, meaning this drug has demonstrated adverse effects in animal studies. No human clinical studies in pregnancy have been done to this date for intravenous acetaminophen. Use acetaminophen only when necessary during pregnancy. Epidemiological data on oral acetaminophen use in pregnant women demonstrate no increase in the risk of major congenital malformations. While prospective clinical studies examining the results of nursing with acetaminophen use have not been conducted, acetaminophen is found secreted in human milk at low concentrations after oral administration. Data from more than 15 nursing mothers taking acetaminophen was obtained, and the calculated daily dose of acetaminophen that reaches the infant is about 1 to 2% of the maternal dose. Caution should be observed when acetaminophen is taken by a nursing woman.

Volume of Distribution

Volume of distribution is about 0.9L/kg. 10 to 20% of the drug is bound to red blood cells. Acetaminophen appears to be widely distributed throughout most body tissues except in fat.

Elimination Route

Acetaminophen has 88% oral bioavailability and reaches its highest plasma concentration 90 minutes after ingestion. Peak blood levels of free acetaminophen are not reached until 3 hours after rectal administration of the suppository form of acetaminophen and the peak blood concentration is approximately 50% of the observed concentration after the ingestion of an equivalent oral dose (10-20 mcg/mL).

The percentage of a systemically absorbed rectal dose of acetaminophen is inconsistent, demonstrated by major differences in the bioavailability of acetaminophen after a dose administered rectally. Higher rectal doses or an increased frequency of administration may be used to attain blood concentrations of acetaminophen similar to those attained after oral acetaminophen administration.

Half Life

The half-life for adults is 2.5 h after an intravenous dose of 15 mg/kg. After an overdose, the half-life can range from 4 to 8 hours depending on the severity of injury to the liver, as it heavily metabolizes acetaminophen.

Clearance

Adults: 0.27 L/h/kg following a 15 mg/kg intravenous (IV) dose. Children: 0.34 L/h/kg following a 15 mg/kg intravenous (IV dose).

Elimination Route

Acetaminophen metabolites are mainly excreted in the urine. Less than 5% is excreted in the urine as free (unconjugated) acetaminophen and at least 90% of the administered dose is excreted within 24 hours.

Innovators Monograph

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