Aspirin VS Acetaminophen Mechanism Of Action

Acetaminophen

Acetaminophen is also known as paracetamol. Acetaminophen don't increase clotting time of blood and does not have effect on platelet function. It's a 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 an first line therapy group of the knee and hip. I has minimal anti inflammatory activity and can't be used to reduce swelling or stiffness during rheumatoid arthritis.

Antipyretic Activity of Acetaminophen 
Acetaminophen and Aspirin decrease the increased temperature of the body by interfering with the release and synthesis of PGE2 that causes an increase in the body temperature. Acetaminophen and Aspirin lowers 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.

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 decreases 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 in a day. 
2. Maximum 4000mg dose per day for pain. It should be given not more than 10 days for 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 not longer than 5 days for 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 are following:
At normal Doses 
When we talk about 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 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 to on daily basis it leads to liver damage. Acute administration of 10g or more is hepatotoxic.

How does Acetaminophen causes toxicity when overdosed?
Acetaminophen form inactive glucuronidated or sulfated metabolites by conjugation in the liver. On the other side, Acetaminophen 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 depleted and N-acetylbenzoiminoquinone reacts with 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 with sulfhydryl groups of NAC instead of reacting with sulfhydryl groups of hepatic proteins. This drug should be administered within the 10 hours of the Acetaminophen overdose.


Why acetaminophen has 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 stomach lining thus causing GI bleeding and this adverse effect is universal when patient treated with Salicylates. That's why Acetaminophen is preferred drug in those patients who already are suffering from stomach disease and gastric complaints.

ASPIRIN

 Aspirin 

Introduction 
Aspirin is a weak organic acid. Aspirin is the only one among  NSAIDs that effects irreversibly results in the inactivation of the cyclooxygenase enzyme. Aspirin is also called Acetylsalicylic acid. When a tablet of Aspirin is taken, aspirin is converted to salicylates by the esterase enzyme because of rapid deacetylation inside the body. These salicylates work as have anti-inflammatory, antipyretic, and analgesic effects.

Function of Salicylates 

Blockage of prostaglandin synthesis at thermoregulatory centers.
Inhibition of prostaglandins at peripheral target sites.
Prevents pain sensitization receptors to both chemical stimuli and mechanical stimuli.
Salicylates (Aspirin) depress pain stimuli at subcortical sites ( thalamus and hypothalamus).
Important Note:
Salicylate at low doses exhibit analgesic activity but at higher doses, it shows the anti-inflammatory activity as well.
Aspirin 
Mechanism of Action 
Aspirin is a weak organic acid and inhibits cyclooxygenase irreversibly. Salicylate that has analgesic, antipyretic and anti-inflammatory properties is produced in the body by rapid deacetylation by esterases.  These salicylates block the synthesis of prostaglandins leading to the prevention of pain receptors sensitization, block prostaglandin synthesis at thermoregulatory centers in the hypothalamus and at peripheral target sites.
Aspirin has the following three major therapeutic activities:

Antipyrexia
Analgesic 
Anti-inflammatory 

1. Antipyretic Action 
Aspirin decrease the increased temperature of the body by interfering with the release and synthesis of PGE2 that causes an increase in the body temperature. Aspirin lowers 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.

Note: Body temperature is controlled by the hypothalamus whenever a pyrogen such as a cytokine is released from white cells because of any infection inside the body, this causes an increase in the synthesis of PGE2. Thus fever occurs when the anterior hypothalamic thermoregulatory center set point is increased.
2. Analgesic 
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. Aspirin decreases the synthesis of Prostaglandin E2, thus results repress the pain sensation. 
3. Anti-inflammatory 
Aspirin inhibits the activity of cyclooxygenase leading to a decrease in the level and synthesis of prostaglandins. As the prostaglandins synthesis diminishes, Aspirin inhibits the inflammatory response of prostaglandins.

Difference between Low dose aspirin and high dose Aspirin
Low Dose Aspirin (60-80 mg daily)
Effects of Aspirin on Platelets
The low dose of Aspirin irreversibly inhibits thromboxane production in platelets. This occurs by acetylation of cyclooxygenase. Due to the inhibition of thromboxane, platelet aggregation is reduced. Because thromboxane increases the aggregation of platelet along with other factors. This lack of thromboxane in the platelet remains till the lifetime of the platelet (3-7 days) because the platelet doesn't have nuclei so they can not synthesize new thromboxane.
Low dose Aspirin also inhibits endothelial cells cyclooxygenase resulting in a reduction of prostacyclin also called PGI2 formation. Prostacyclin decreases platelet aggregation naturally. On the other hand, endothelial cells have nuclei so they are able to produce new cyclooxygenase. So PGI2 effect of antiplatelet remains available naturally.

High dose Aspirin (more than 325mg, 650mg to 4 gram/day)
we already have studied the function of Salicylates that Salicylates show analgesic and anti-inflammatory activity. It totally depends on the number of doses. At low doses, aspirin shows an analgesic effect but by increasing doses, it shows the anti-inflammatory activity as well. That's why a higher dose of aspirin is used in Rheumatoid arthritis and osteoarthritis with an initial dose of 3 grams/day.

Effects of Aspirin on Cardiovascular system 
Aspirin is used as platelet aggregation inhibitor along with other pharmacological effects. 
1. When Aspirin is used as a low dose it causes reduction of stroke and Also reduce the risk of recurring transient ischemic attacks (TIAs) or death especially in those people who already had suffered single or multiple episodes of stroke or TIA.
2. Low dose of Aspirin is used to reduce deaths in those patients having an acute myocardial infarction.
3. Low doses of Aspirin reduce myocardial infarction and also reduce the death in patients with previous unstable angina pectoris.
4. Reduce risk of recurrent neofatal myocardial infarction.
5. Reduce cardiovascular risk in revascularization procedures.
Effects of Aspirin on GIT
When aspirin is taken for it's pharmacological actions, some of the prostanoids (PGE2 and PGF2à) that stimulates synthesis of mucus that protects stomach and small intestine are not formed in the presence of Aspirin. Because of this gastric acid secretion is increased resulting in diminished mucus protection. This leads to epigastric distress, iron deficiency, hemorrhage and ulceration. 

Note: PGI2 also called prostacyclin inhibits secretion of gastric acid, Whereas PGE2 and PGF2à stimulates protective mucus synthesis. 

Effects of Aspirin on Kidney 
As Aspirin is a cyclooxygenase inhibitor, So cyclooxygenase inhibitors stop the synthesis of PGE2 and PGI2 prostaglandins that are needed to maintain the renal blood flow in the presence of circulating vasoconstrictors. Thus decrease in the synthesis of these prostaglandins results in retention of water and sodium leading to edema and hyperkalemia.
Other effects of Aspirin 
Aspirin increases alveolar ventilation at therapeutic doses. 
Adverse effects of Aspirin
a. Urticaria
b. Bronchoconstriction
c. Peptic ulcer disease 
d. Metabolic acidosis



In high doses, Aspirin lacks anti-platelet activity by which of the following phenomena
a. Stimulates thromboxanes
b. Stimulates prostacyclins
c. Inhibits prostacyclins
d. Stimulates leukotrienes
e. Inhibits leukotrienes


Answer: c. Inhibit prostacyclins