Anti-Inflammatory Drugs (2025)

Anti-Inflammatory Drugs

Inflammation is a normal, protective response to tissue injury caused by physical trauma, noxious chemicals, or microbiologic agents.
Inflammation is the body's response to inactivate invaders, remove irritants, and prepare for tissue repair

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

NSAIDs primarily inhibit COX enzymes, reducing prostaglandin production.
NSAIDs' adverse effects include GI issues due to COX-1 inhibition, increasing the risk of bleeding and peptic ulcers.
COX-1 inhibition decreases TXA2, promoting an anti-platelet effect and increasing bleeding risk.
Selective COX-1 enzyme inhibitors are linked to prolonged bleeding times.
Renal prostaglandins E2 and I2 dilate the renal afferent arteriole, which is crucial for glomerular filtration.
NSAIDs reduce renal prostaglandin production, raising the risk of kidney injury in susceptible individuals.
Aspirin with high COX-1 selectivity can offer cardiovascular protection due to antiplatelet properties.
Agents with high COX-2 selectivity can have opposite cardiovascular effects.
Prostacyclin, mainly from COX-2 in the endothelium, causes vasodilation and inhibits platelet activation.
TXA2, primarily from COX-1 in platelets, promotes vasoconstriction and platelet aggregation.
Selectively inhibiting COX-2 favors TXA2 formation, increasing vasoconstriction and platelet aggregation, raising the risk of cardiovascular events.

Selective COX-1 Inhibitors

Salicylates

Aspirin is a weak organic acid, a common drug for fever and pain relief serving as a benchmark for NSAID comparisons
Aspirin and related salicylates treat mild to moderate pain, including headaches, joint and muscle pain, and dysmenorrhea.
Higher doses of salicylates are effective for rheumatoid arthritis, gout, and rheumatic fever.
Most salicylates are potent antipyretics, except for Diflunisal, which is weakly active.
Low-dose aspirin selectively inhibits COX-1, reducing the risk of transient ischemic attacks, myocardial infarction, and stroke.
Higher doses of aspirin inhibit both COX-1 and COX-2 isoforms.
Salicylic acid treats corns, calluses, and warts topically.
Methyl salicylate (oil of wintergreen) is a cutaneous counterirritant in liniments.
Aspirin is used for cardiovascular applications to inhibit platelet aggregation
Salicylate side effects include upper GI disturbances that are common (epigastric distress, N&V) use Misoprostol or a PPI
Salicylates must be avoided in children and teenagers under 15 years old or a risk of Reye's syndrome
Aspirin can cause bleeding due to reduced TXA2 levels and inhibition of platelet aggregation.
Aspirin can cause hypersensitivity reactions including urticaria, angioedema, fatal anaphylactic shock
Aspirin interacts with drugs like warfarin, phenytoin, or valproic acid by displacing highly-protein bound drugs, and Ketorolac and Aspirin should not be used together due to increase risk of GI bleeding and platelet aggregation inhibition
Salicylate intoxication (Salicylism) symptoms include nausea, vomiting, hyperventilation, dizziness, and tinnitus.
Diflunisal has less GI irritation than aspirin and no antipyretic effect.

Indoles and Related Compounds

Indomethacin is very potent for use only when less toxic agents are ineffective, and toxicity limits use for acute gouty arthritis, ankylosing spondylitis & osteoarthritis
Sulindac is an inactive prodrug related to Indomethacin, used for RA, ankylosing spondylitis, osteoarthritis, and acute gout

Etodolac

Etodolac produces analgesic, antipyretic, and anti-inflammatory effects.
Etodolac has a long half-life allowing for daily or twice-daily dosing, with CNS disturbances as side effects.

Non-Selective COX Inhibitors

p-Aminophenol Derivatives

Acetaminophen is an active metabolite with fewer toxic effects.
Acetaminophen is effective for mild to moderate pain and fever, like aspirin.
Acetaminophen is suitable for patients with gastric complaints or those needing to avoid aspirin's anti-inflammatory action.
Acetaminophen is the choice for children with viral infections or chickenpox.
A portion of acetaminophen is hydroxylated to form N-acetylbenzoiminoquinone.
Acetaminophen can cause skin rash and minor allergic reactions infrequently.
Large acetaminophen doses may cause hepatic necrosis and renal tubular necrosis, countered by N-acetylcysteine administration.
Those with severe hepatic impairment should avoid acetaminophen.

Fenamates

Meclofenamate and Mefenamic Acid (Ponstan) are analgesic, antipyretic, and anti-inflammatory agents used for mild to moderate pain, dysmenorrhea, rheumatoid arthritis, and osteoarthritis, and are associated with inflammation bowel & hemolytic anemia

Arylpropionic Acid Derivatives

Ibuprofen, Flurbiprofen, Oxaprozin, Fenoprofen, Ketoprofen & Naproxen are 2-substituted propionic acid derivatives, that block prostaglandin production via COX inhibition for analgesia, antipyresis, and anti-inflammatory effects similar to salicylates
Arylpropionic acids are more potent than aspirin with fewer side effects like gastric irritation
Used for rheumatoid arthritis, osteoarthritis, mild to moderate pain and fever, and dysmenorrhea
Side effects include dyspepsia, bleeding, and CNS disturbances, but have lower toxicity and better acceptance.

Oxicam Derivatives

Piroxicam treats inflammatory and rheumatoid conditions
Meloxicam inhibits both COX-1 and COX-2, with preferential binding for COX-2 causing less GI irritation than Piroxicam
At high doses, meloxicam is a nonselective NSAID

Acetic Acid Derivatives

Diclofenac and Tolmetin are more potent than indomethacin or naproxen, approved for long-term use in treating RA, ankylosing spondylitis, and osteoarthritis
Ketorolac is a potent analgesic with moderate anti-inflammatory effects
Ketorolac is indicated for short-term relief of moderate to severe pain up to 5 days after the first dose and should be avoided in pediatric patients because it can cause fatal peptic ulcers and GI bleeding

Selective COX-2 Inhibitors

Celecoxib and Rofecoxib are selective COX-2 inhibitors
Rofecoxib is more selective for COX-2 than COX-1, treats RA, osteoarthritis, and pain, and does not inhibit platelet aggregation or increase bleeding time
Rofecoxib is extensively metabolized in the liver by cytochrome P450 (CYP2C9) and should be avoided in patients with severe hepatic and renal disease
Rofecoxib's side effects include common HA, dyspepsia, diarrhea and abdominal pain, and is contraindicated in patients who are allergic to sulfonamides.

Disease Modifying Antirheumatic Agents

Rheumatoid Arthritis is a chronic inflammatory disorder affecting joints and other organs like skin and lungs

Methotrexate

Used alone or in combination, it treats rheumatoid or psoriatic arthritis.
Common side effects are mucosal ulceration and nausea
Chronic Methotrexate administration can induce cytopenias, liver cirrhosis, and acute pneumonia like syndrome
Leucovorin taken daily after methotrexate reduces adverse effects' severity.

Leflunomide

Leflunomide is an immunomodulatory agent, it causes cell cycle arrest of autoimmune lymphocytes via dihydroorotate dehydrogenase (DHODH) action
Leflunomide has been approved for treating RA
Leflunomide reduces pain and inflammation and appears to slow the progression of structural damage
Leflunomide can be used alone or with methotrexate

Hydroxychloroquine

Hydroxychloroquine treats malaria and early mild RA.
Hydroxychloroquine is used with methotrexate or alone.
Hydroxychloroquine's mechanism may include inhibiting phospholipase A2 and platelet aggregation, membrane stabilization, immune system effects, and antioxidant activity
Hydroxychloroquine may cause renal toxicity

Sulfasalazine

Sulfasalazine treats early mild RA with methotrexate and hydroxychloroquine
It has an onset of activity of 1-3 months.
Sulfasalazine is associated with leukopenia

D-Penicillamine

D-Penicillamine is an analog of the amino acid cysteine
It slows bone destruction progression from RA
D-Penicillamine is used as add-on therapy to NSAID/glucocorticoid therapy
D-Penicillamine's serious side effects include nephritis and aplastic anemia
D-Penicillamine acts as a chelating agent for heavy metal poisoning and treats cystinuria

Gold Salts

Gold salts cannot repair existing damage but prevent further injury
Gold salts are taken up by macrophages, suppressing phagocytosis and lysosomal activity, retarding bone and articular destruction
Gold salts can cause serious toxicity: myelosuppression

Biologic Therapies In Rheumatoid Arthritis

TNF Inhibitors

Etanercept, Infliximab and Adalimumab binds to TNF-alpha, blocking its interaction with cell surface TNF receptors
TNF Inhibitors reduce structural damage progression and improve physical function
When combined with methotrexate, TNF inhibitors are standard therapy for rheumatoid and psoriatic arthritis
Side effects include increased risk for infections (tb & sepsis), fungal opportunistic infections and pancytopenia, thus liver vaccinations should be avoided

Anakinra

Anakinra acts as an IL-1 receptor antagonist, preventing IL-1 actions.

Abatacept

Abatacept is a soluble recombinant fusion protein of human CTLA4 that inhibits full T-cell activation by competing with CD28 for binding on CD80/CD86.

Rituximab

Rituximab is a genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 antigen to deplete B-cells

Drugs Employed In The Treatment of Gout

Treatment of Acute Gout

Treated with NSAIDs to decrease movement of granulocytes into the affected area to reduce pain and inflammation
Aspirin is contraindicated because it competes with uric acid for organic acid secretion in the proximal tubule
Administer Intra-articular glucocorticoids, when only one or two joints are affected
Double the initial NSAID dose within the first 24 to 48 hours

Colchicine

It inhibits phagocytosis, preventing additional accumulation of urate crystals
Colchicine does not prevent the progression of gout to acute gouty arthritis but has a suppressive effect to reduce frequency of acute attacks and relieves pain
Colchicine is used to prevent recurrent attacks.
Colchicine treatment might cause nausea, vomiting, diarrhea and abdominal pain
The drug should not be used in pregnancy, and the chronic administration might lead to agranulocytosis aplastic anemia.

Lower Uric Acid Concentrations

Hypouremic acids

Function to inhibit the action xanthine oxidase thus preventing formation of uric acid
Are first line agents for patients with gout and are used in the treatment of chronic gout
Febuxostat and Allopurinol are examples of hypouremic acids
Allopurinol reduces uric acid production by inhibiting the last two steps in uric acid biosynthesis catalyzed by xanthine oxidase
Allopurinol is the drug of choice in those with a history of kidney stones or if the creatinine clearance is less than 50 ml/day.
Allopurinol's side effects include hypersensitivity reactions
Allopurinol interacts with the metabolism of 6-mercaptopurine and azathioprine, so a reduction in dosage may be needed for these drugs because allopurinol interferes with the metabolism

Uricosuric agents

Are weak organic acids that promote renal clearance of uric acid by inhibiting the urate-ion exchanger in the proximal tubule that mediates urate reabsorption
Probenecid blocks tubular secretion of penicillin to increase antibiotic levels and inhibits excretion of naproxen, ketoprofen, and indomethacin
Sulfinpyrazone is a derivative of phenylbutazone and has the side effect of gastric distress