Compare the pharmacology of Aspirin, Diclofenac, and Paracetamol.

Aspirin (Acetylsalicylic acid):

• Mechanism of Action: Aspirin inhibits both COX-1 and COX-2 enzymes, which are responsible for the production of prostaglandins (PGF2alpha), substances that mediate pain and inflammation. It also inhibits the conversion of arachidonic acid to thromboxane A2, a potent inducer of platelet aggregation.

Low-dose aspirin use irreversibly blocks the formation of thromboxane A₂ in mature platelets by inhibiting the COX-1 enzyme, producing an inhibitory effect on platelet aggregation during the lifetime of the affected platelet (8–9 days) and acts as a blood thinner.

• Indications: Aspirin is used to treat pain, fever, and inflammation associated with various conditions. It is also used as antiplatelet agent sometimes in low doses.
• Pharmacokinetics: Aspirin is rapidly and completely absorbed after oral administration. It is widely distributed in the body in protein-bound form.
• Prevention of Toxicity: Sodium bicarbonate and gastric lavage

Diclofenac: 

• Mechanism of Action: Diclofenac, like other NSAIDs, inhibits COX-1 and COX-2 enzymes (but COX - 2 preferably), which are involved in prostaglandin synthesis. This results in analgesic, anti-inflammatory, and antipyretic properties. (As COX -2 dependent pathway is majorly and Principally involved in inflammatory response is is better selective Analgesic and anti-inflammatory agent) 
• Indications: Diclofenac is used to treat the signs and symptoms of osteoarthritis and rheumatoid arthritis.
• Pharmacokinetics: Diclofenac is well-absorbed from the gastrointestinal tract and readily inactivated in the liver by conjugation to its glucuronide and sulfate.
• Treatment for Toxicity: Gastric lavage, charcoal

Paracetamol (Acetaminophen):

• Mechanism of Action: Paracetamol is thought to act primarily in the CNS, increasing the pain threshold by inhibiting both isoforms of cyclooxygenase, COX-1, COX-2, and COX-3 enzymes involved in prostaglandin synthesis.
• Indications: Paracetamol is used for the relief of mild to moderate pain, and for relieving fever.
• Pharmacokinetics: Paracetamol is well-absorbed from the gastrointestinal tract. Its systemic bioavailability is dose-dependent and ranges from 70 to 90%.
• Toxicity Treatment: N acetylcysteine

	Aspirin	Diclofenac	Paracetamol
Class	Non-selective COX inhibitor NSAID	Preferential COX – 2 Inhibitor NSAID	Analgesic, Antipyretic with poor Anti-inflammatory Action (Non-NSAID)
Mode of Action	Blocks both COX-1 and COX-2 irreversibly and inhibits the production of -        Inflammatory Mediators (PGE2, PGF, PGI2) -        Thromboxane A2	Inhibits COX- 2 preferentially. And inhibits the production of Inflammatory Prostaglandins MAJORLY.	Inhibits Both COX-1 and COX-2 and inhibits PG synthesis in BRAIN.   Modulation in Endocannabinoid System
Indication	Analgesic, Anti-inflammatory, Blood Thinner	Anti-inflammatory, Analgesic (STRONG)	Analgesic, Anti-pyretic, Anti-inflammatory (MILD)
Onset of Action	30 – 60 min	15 – 60 min	30 – 60 min
Dose in adult	325 – 650 mg/4-6hrs	50 – 100 mg/8 – 12hrs	325 – 650 mg/4-6hrs
MAX daily dose	4000 mg	150 mg	4000 mg
Toxicity Treatment	Sodium bicarbonate/ Gastric lavage	Activated Charcoal / gastric lavage	N-acetylcysteine
Contraindications	Gastric Ulcer, Asthma, Major surgery	Hepatic Disorder, Renal Disorder	Hepatic Disorder
Metabolism (In liver)	ENZYME: COX – 1 METABOLITE: Salicylic Acid	ENZYME: CYP2C8, CYP2C9 METABOLITE: Glucuronide, Sulphate conjugates.	ENZYME: CYP2E1, CYP3A4 METABOLITE:  Glucuronide, Sulphate conjugates.
Interactions	­ Risk of Bleeding with Anticoagulants and Thrombolytics.	­ Risk of Bleeding with Anticoagulants and Thrombolytics.	May Cause Hepatotoxicity with interaction to other drugs.