Acetaminophen | Mechanism of Action | USES | Adverse Effecs

Acetaminophen

Acetaminophen is also known as paracetamol. Acetaminophen doesn't increase clotting time of blood and does not have an effect on platelet function. It's an antipyretic and analgesic drug recommended especially in those patients who are already suffering from gastric disease. A drug for mild to moderate pain and to reduce fever. This drug is recommended especially for osteoarthritis patients as a first-line therapy group of the knee and hip. It has minimal anti-inflammatory activity and can't be used to reduce swelling or stiffness during rheumatoid arthritis.

1. Antipyretic Activity of Acetaminophen 

Acetaminophen and Aspirin decrease the increased temperature of the body by interfering with the release and synthesis of PGE2 that causing an increase in the body temperature. Acetaminophen and Aspirin lower the body temperature of patients by resetting the Thermostat towards a normal state by the release of heat in the form of sweat and peripheral vasodilation.

2. Analgesic Activity of Acetaminophen 

When inflammation occurs, Prostaglandin E2 causes the sensitization of Nerve ending in the action of histamine, bradykinin, and other chemical mediators that are released locally as a result of the inflammation. Acetaminophen and Aspirin decrease the synthesis of Prostaglandin E2, thus results repress the pain sensation. 

Dosage of Acetaminophen 

Acetaminophen is available in 325mg and 500mg. A prolonged dosage form caplet of 650 mg is also available.

Dose for Adults 

1. 500mg to 1000mg dose is recommended three times a day. 
2. Maximum 4000mg dose per day for pain. It should be given not more than 10 days for the pain and not more than 3 days for fever.
3. For Osteoarthritis patients 4000mg four times can be given.

Dose for children (6 years or above)

1. 325mg is recommended every 4 to 6 hours as needed.
2. Maximum dose is 1600mg per day for no longer than 5 days for the pain and 3 days for fever and 2 days for sore throat.

Note:
1. Acetaminophen is recommended for Gastrointestinal Disturbance sensitive patients.
2. The patients having bleeding problems 
3. The patients hypersensitive to Salicylates 

Adverse effects of Acetaminophen 

At normal Doses 
When we talk about the adverse effects of acetaminophen at normal therapeutic doses it's virtually free of any significant adverse effect. But infrequently 
I. Skin rash 
II. Allergic reaction may occur 
III. Altered leukocytes count (minor and transient)

At High Doses 
When high doses of Acetaminophen are used it causes the following:
I. Depletion of glutathione in the liver 
II. Hepatic necrosis 
III. Renal tubular necrosis 
IV. Hypoglycaemic coma

Note: High doses of acetaminophen required periodic monitoring of liver enzymes test.

Precautions 
Chronic administration of Acetaminophen is contraindicated in Liver diseases, Viral hepatitis, and active alcoholism. Chronic 5 g or acetaminophen used for one month or more on a daily basis leads to liver damage. Acute administration of 10g or more is hepatotoxic.

How does Acetaminophen cause toxicity when overdosed?

Acetaminophen form inactive glucuronidated or sulfated metabolites by conjugation in the liver. On the other side, Acetaminophen is also hydroxylated to form N-acetylbenzoiminoquinone. This hydroxylated form is a very dangerous metabolite of Acetaminophen that reacts with sulfhydryl groups of glutathione during normal doses and circumstances. 
When high doses of acetaminophen are used then the glutathione available in the liver is depleted and N-acetylbenzoiminoquinone reacts with the sulfhydryl group of hepatic proteins by forming covalent bonds. This leads to hepatic necrosis.

How does N-acetylcysteine work as an antidote?

NAC also contains sulfhydryl groups to which toxic metabolites start reacting. When NAC is administered these metabolites like N-acetylbenzoiminoquinone start reacting with sulfhydryl groups of NAC instead of reacting with sulfhydryl groups of hepatic proteins. This drug should be administered within 10 hours of the Acetaminophen overdose.

Why does acetaminophen have weak anti-inflammatory activity?

Acetaminophen has very less and weak anti-inflammatory activity because acetaminophen has less effect on cyclooxygenase in peripheral tissues.

Why Acetaminophen is preferred over Aspirin?

Aspirin causes damage to the stomach lining thus causing GI bleeding and this adverse effect is universal when patients are treated with Salicylates. That's why Acetaminophen is the preferred drug in those patients who already are suffering from stomach disease and gastric complaints.

Antidote of Acetaminophen

Introduction
Acetaminophen has antipyretic and analgesic properties because it inhibits prostaglandin synthesis in the CNS leading to a decrease in body temperature. Acetaminophen lacks the property of anti-inflammatory or has a very less effect. Acetaminophen is an alternative therapy to aspirin. The patients who do not need anti-inflammatory effects acetaminophen is a perfect choice. It does not have antiplatelet activity so it's a good choice in patients who do not need prolongation of bleeding time.

Clinical Presentation
There are  3 phases of clinical presentation after acetaminophen toxicity.
1. Phase I ( 12 to 24 hours post-ingestion)

• Nausea, Vomiting, anorexia, diaphoresis

• Asymptomatic

• Nausea, abdominal pain, progressive evidence of hepatic failure, coma, and death

The antidote to Acetaminophen: 
N-Acetyl Cysteine
Acetaminophen Half-Life:
Acetaminophen has a half-life of 2-3 Hours and is well absorbed from the GIT.
Causes: 
Liver Failure, Coma, Diaphoresis
Acetaminophen USES:
Acetaminophen is an antipyretic and analgesic agent. Acetaminophen produces dangerous liver toxicity because of toxic metabolites.
NAC is an antioxidant. It’s a prodrug to L-cysteine. NAC provides cysteine for Glutathione synthesis. This glutathione reacts with N-Acetyl-P-Benzoquinone imine to protect tissues. NAPQI is a byproduct that is produced during the metabolism of Acetaminophen. Normally, When a drug is taken this NAPQI is Produced in small amounts. Then soon after its production quickly detoxified the Liver. But when acetaminophen is taken in large quantities or used excessively, then the reserved glutathione is not enough to deactivate this N-Acetyl-P-Benzoquinone imine. Thus the presence of NAPQI in large quantities reacts with the tissues of the liver and causes damage to the liver. This NAC maintains the quantity of glutathione in the body.
Adverse effects
With normal dose, 

1. Skin Rash

1. Minor allergic reaction

1. Minor alteration in leukocyte count

1. Hepatic necrosis

1. Renal Tubular necrosis

2. Phase II ( 1 to 4 days post-ingestion)

3. Phase III ( 2 to 3 days in untreated patients)

With a large dose,