Non-steroidal anti-inflammatory drugs (NSAIDs) Dr Sasan Zaeri (PharmD, PhD) Department of Pharmacology

Inflammatory cascade Triggers Infection Tissue and/or vessel damage Inflammatory Mediators Acute Inflammatory Response Note this is a common & non-specific response - Redness - Heat - Swelling - Pain

Drugs block production or effect of inflammatory mediators Tissue and/or vessel damage Infection Inflammatory Mediators Vasoactive peptides: Histamine,serotonin The kinin system Coagulation cascade The complement system Arachidonic Acid metabolites NSAIDs Corticosteroids

Inflammatory Enzymes: PLA2 & COX 3. Zileuton Montelukast, zafirlukast 2.NSAIDS 1. Steroids Phospholipase A2 Arachidonic acid (AA) Lipoxygenase Cyclooxygenase (COX) Lipoxygenase products (leukotrienes) Prostaglandins & thromboxanes Inflammatory effects (inducible) Homeostatic Functions (stomach mucus) Inflammatory effects (esp. in asthma)

COX-1 vs. COX-2

NSAIDs- MeChanism OF ACTION Non –Selective NSAIDs inhibit both COX-1 & COX-2 reversibly Ibuprofen, Diclofenac, Indomethacin, Naproxen, Mefenamic acid etc. Aspirin (irreversible COX inhibitor) Selective NSAIDs inhibit only COX-2 reversibly Celecoxib

Pharmacological Actions of Non-Selective NSAIDs Analgesic Antipyretic (Drug that lowers the elevated body temperature to normal) Anti-inflammatory Anti-platelet Exceptions: celecoxib, non-acetylated salicylates

THERAPEUTIC USES SHARED BY NS-NSAIDs Fever Analgesic Headache Migraine Dental pain Common cold

THERAPEUTIC USES SHARED BY NS-NSAIDs Rheumatoid arthritis Osteoarthritis Myositis or other forms of inflammatory conditions Dysmenorrhea

Adverse effects shared by NS-NSAIDs GIT upsets ( nausea, vomiting) GIT bleeding & ulceration Bleeding Hypersensitivity reaction Inhibition of uterine contraction Salt & water retention

Dose Dependent Therapeutic Effects Of Aspirin Antithrombotic Antipyretic, Analgesic Anti-inflammatory Daily dose of aspirin (g) 1 2 3 4 5

Normal physiologic interaction between PGI2 and TXA2 Blood Vessel Wall Endothelial Cell (COX-2) Platelet (COX-1) Arachidonic acid PGH2 Prostacyclin (PGI2) Arachidonic acid PGH2 Thromboxane (TXA2)  cAMP/vessel smooth muscle relaxes  Ca2+  aggregation cAMP  aggregation  Ca2+/vessel smooth muscle constricts Normal physiologic interaction between PGI2 and TXA2 in platelet and endothelial cell biology

Added Clinical uses Antiplatelet/Antithrombotic effect Decreases platelet production of TXA2 by COX-1 irreversibly to limit platelet aggregation and vasoconstriction Cardioprotective (reducing the risk of MI)

Acute rheumatic fever Prevention of pre-eclampsia Chronic gouty arthritis with large doses Chronic use of small doses , reduce the incidence of cancer colon

Adverse Effects Related to : (A) Therapeutic Doses Of Aspirin Aspirin asthma Reye's syndrome Syndrome of hepatic injury & encephalopathy in kids treated with aspirin after a viral illness

Aspirin-induced asthma

Adverse Effects Related to ( B) Large doses or prolonged use of aspirin Salicylism ( ringing of ear( tinnitus) , vertigo) Hyperthermia GI ulcer and bleeding Metabolic acidosis

ADVERSE effects Related to High doses

Contraindications Children with viral infections Patients with GI ulcer or upper GI bleeding Patients with hemophilia Patients with Aspirin-induced asthma

PARACETAMOL (acetaminophen) Commonly used as analgesic antipyretic drug

Clinical uses of paracetamol Can be used safely in patients with: Peptic or gastric ulcers Bleeding tendency Allergy to aspirin Viral infections in children Pregnancy

Adverse Effects Mainly on liver due to its active metabolite ( N-acetyl-p-benzoquinone) Large doses cause liver necrosis Treatment Of toxicity of paracetamol: N- acetylcysteine : SH- donor to neutralize the toxic metabolite

Acetaminophen Toxicity induction alcohol

DICLOFENAC Clinical uses Treatment of rheumatoid arthritis , osteoarthritis (accumulates in synovial fluid in Long-term use ) Analgesic Antipyretic Acute gouty arthritis Locally to prevent post-operative ophthalmic inflammation

Selective COX-2 inhibitors General advantages : Adverse effects are slighter than other NSADs No effect on platelet aggregation (COX-1) Long-term studies of the incidence of clinically significant gastrointestinal ulcers and bleeding are not yet completed

Adverse effects Renal toxicity Cardiovascular (high risk of MI) Rofecoxib and valdecoxib were withdrawn

STILL ON THE MARKET

GENERAL CLINICAL USES Rheumatoid arthritis Osteoarthritis Acute musculoskeletal pain Dysmenorrhea They can also be used in patients with gastric ulcer , haemophilia for the above indications