NSAIDs and Inflammation

• Non-steroidal anti-inflammatory drugs (NSAIDs) are used to treat inflammation, pain, and fever by decreasing the production of prostaglandins.
• Prostaglandins are pro-inflammatory chemicals.

Inflammation and Arachidonic Acid

• Inflammation is the body’s response to a harmful stimulus like infection or injury.
• Immune cells use phospholipase A2 to convert membrane phospholipids into arachidonic acid during inflammation.
• Arachidonic acid is a 20-carbon polyunsaturated fatty acid.
• Arachidonic acid is a substrate for cyclooxygenase (COX).

Cyclooxygenase (COX) Isoforms

• COX exists in two isoforms: COX-1 and COX-2.
• COX-1 is a constitutive enzyme, always active.
• COX-2 is an inducible enzyme, activated by immune cells and vascular endothelial cells during inflammation.

Prostaglandin Production

• Both COX-1 and COX-2 produce prostaglandin E2 (PGE2) and prostacyclin (PGI2).
• PGE2 and PGI2 cause vasodilation and attract immune cells to the affected area.
• These prostaglandins act on nociceptors (pain-detecting neurons), increasing their sensitivity by lowering their activation threshold.
• They stimulate the hypothalamus to increase body temperature, causing fever.
• Prostaglandin E2 causes uterine contractions, decreases acid secretion, and increases protective mucus production in the stomach.

NSAID Groups

• NSAIDs inhibit cyclooxygenase to decrease prostaglandin production.
• NSAIDs are subdivided into irreversible COX inhibitors (aspirin) and reversible COX inhibitors (non-aspirin NSAIDs).
• Non-aspirin NSAIDs are further divided into non-selective COX inhibitors (ibuprofen) and selective COX-2 inhibitors (celecoxib).

Aspirin (Acetylsalicylic Acid)

• Aspirin works by irreversibly inhibiting both COX-1 and COX-2.
• Aspirin is mainly absorbed in the ileum, after peroral intake.
• Aspirin irreversibly inhibits COX-1 in platelets through covalent acetylation, decreasing thromboxane A2 production.
• Aspirin's effects persist until new platelets are produced due to irreversible COX-1 inhibition and increases bleeding time.
• In the liver, aspirin is metabolized into salicylate, which has anti-inflammatory properties but no antiplatelet effect.
• Salicylate inhibits COX-2, reducing prostaglandin production and decreasing inflammation, pain, and fever.
• Salicylate is used for headaches, musculoskeletal pain, osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis.

Aspirin Dosage

• Low doses (under 300 mg/day) of aspirin work as an antiplatelet medication.
• Medium doses (300-2400 mg/day) of aspirin work as an antipyretic and analgesic.
• High doses (over 2400 mg/day) of aspirin work as an anti-inflammatory medication.
• Low-dose aspirin (81 mg) is used long-term to prevent heart attacks, strokes, and blood clot formation.

Non-Selective COX Inhibitors

• Non-selective COX inhibitors reversibly inhibit both COX-1 and COX-2.
• Common medications include ibuprofen, naproxen, ketorolac, indomethacin, sulindac, and meloxicam.
• Ketorolac, ibuprofen, and indomethacin are available in parenteral form.
• These medications inhibit COX-1 and have a temporary antiplatelet effect.
• They compete with aspirin for binding sites on COX-1, reducing aspirin’s antiplatelet effect.
• Non-selective COX inhibitors also inhibit COX-2, reducing inflammation, pain, and fever.

Specific Uses of Non-Selective COX Inhibitors

• Ibuprofen, naproxen, and indomethacin reduce inflammation during acute gout attacks.
• Aspirin is avoided during gout attacks because it competes with uric acid for excretion.
• Indomethacin is used to close patent ductus arteriosus in neonates and premature infants.
• Ketorolac is used to treat severe acute pain, usually after surgery.

Selective COX-2 Inhibitors

• Celecoxib is the main medication in this group.
• Celecoxib reversibly inhibits COX-2, treating pain and inflammation.
• Celecoxib lacks the antiplatelet effect seen in aspirin.
• Celecoxib doesn’t compete with aspirin for COX-1, so they can be combined without decreasing aspirin's antiplatelet effect.

Side Effects of NSAIDs

• Aspirin and nonselective COX inhibitors can cause gastric issues by blocking COX-1 in the stomach.
• Inhibition of COX-1 leads to decreased cytoprotective prostaglandins, which can result in gastritis, ulcers, or bleeding.
• Reversible inhibitors of COX-1 cause fewer gastrointestinal problems than aspirin.
• Selective COX-2 inhibitors like celecoxib cause the least GI side effects.
• All NSAIDs inhibit COX-2 in the kidneys, decreasing prostaglandins that dilate the renal artery and reducing renal blood flow.
• Reduced renal blood flow activates the renin-angiotensin-aldosterone system, leading to hypertension.
• Low doses of aspirin can lower blood pressure if taken before bedtime, but high doses increase blood pressure.
• Reduced kidney blood flow can lead to acute kidney injury, especially in the elderly and those with heart, liver, or kidney disease.
• Chronic NSAID abuse can lead to analgesic nephropathy, manifesting as chronic nephritis or renal papillary necrosis.
• Hypersensitivity reactions, such as Stevens-Johnson Syndrome, toxic epidermal necrolysis, and anaphylactic reactions may occur.
• Cross-hypersensitivity means that individuals hypersensitive to one NSAID may react to others.
• People with nasal polyps and asthma are more likely to experience NSAID hypersensitivity, which is known as Samter’s triad or aspirin exacerbated respiratory disease.

Aspirin-Specific Side Effects

• Aspirin should not be given to children with viral infections due to the risk of Reye’s syndrome.
• Reye’s syndrome is characterized by liver damage and encephalopathy.
• Aspirin can be used in children to reduce fever in Kawasaki’s disease.
• An aspirin overdose can be fatal.
• Early symptoms of salicylate poisoning include tinnitus, deafness, headache, and vomiting.
• High doses of salicylate directly stimulate the respiratory center, causing hyperventilation and respiratory alkalosis.
• Increased salicylate doses inhibit oxidative phosphorylation, leading to anaerobic metabolism and lactic acid production.
• Lactic acid buildup causes an elevated anion gap metabolic acidosis.
• Decreased blood pH causes more salicylate to convert to its non-ionized form (salicylic acid), which crosses the blood-brain barrier and causes seizures or coma.

Treatment for Aspirin Overdose

• There is no specific antidote for aspirin overdose.
• Treatment includes administration of activated charcoal to prevent absorption.
• Alkalization of urine using sodium bicarbonate facilitates salicylate excretion.
• Ventilatory support and management of acid-base imbalance are also required.