NSAIDs

Introduction One of the most commonly used in the world 17000000 regular users, 50% over the age 60 Will increase in the future 5 to 7 percent of hospital admissions

Main actions 1.) Analgesic -effective against mild to moderate pain, do not cause dependence 2.) Anti-inflammatory 3.) Anti-pyretic 4.)Anti-platelet- prevent thromboxane production, derived from prostaglandins and cause platelet aggregation Others 5.) Useful in treatment of dysmenorrhea, associated with increased prostaglandin synthesis and increased uterine contractility 6.) Used to close the patent ductus arteriosus

Familiar NSAIDs Acetylsalicylic acid Ibuprofen Naproxen Indomethacin Diclofenac Piroxicam Celecoxib

Pharmacokinetics NSAID absorbed in stomach and small intestine into bloodstream 90% - 95% of NSAID is bound to plasma proteins 5% - 10% dissolved into plasma and exerts clinical effects Metabolized in liver and excreted by kidney, but not on first pass through

NSAIDs Mechanism of action Inhibits cyclo-oxygenase (prostaglandin synthase) that is responsible for conversion of arachidonic acid to cyclic endoperoxides 2 isoforms of enzyme - COX-1 constitutive, present in platelets, stomach and kidney - COX-2 inducible by cytokines & endotoxins at sites of inflammation e.g., joints

Eicosanoid Cascade

COX-2: Regulated COX-1: Constitutive Homeostatic Protection of gastric mucosa Platelet activation Renal functions Macrophage differentiation Pathologic Inflammation Pain Fever

Selective VER Non-Selective Similar to non-specific COX inhibitors Anti-inflammatory Analgesic Some renal effects, e.g. sodium excretion, blood pressure Different from non- specific COX-inhibitors No anti-platelet effects Reduced endoscopic GI erosion and ulceration Bronchial spasm

NSAID Effects Complete effects are achieved in two weeks in acute inflammatory conditions Analgesia achieved with 50% - 75% dosage needed for anti-inflammatory effects

Side Effects In 2001: 100,000 hospitalizations (estimated) 17,000 deaths (estimated) $2 billion dollars in medical care

Side Effects GI Irritation Renal Damage or Dysfunction Liver Damage or Dysfunction Anemia Skin reactions CNS Effects: Nervousness, Tinnitus, HA

GASTROINTESTINAL Dyspepsia, peptic ulcer disease, and bleeding 103000 hospitalization and 16500 deaths 2% peptic ulcer

Who is at risk peptic ulcer? Increasing age, particularly >60 Higher NSAID dose A past history of gastroduodenal toxicity from NSAIDs or peptic ulcer disease Concurrent use of glucocorticoids, anticoagulants, bisphosphonates, or other NSAIDs

How can decrease peptic ulcer? Use of alternative analgesics Lowest dose Selective COX2 Misoprostol PPI

HEPATIC INJURY Elevations of serum aminotransferases Liver failure is quite rare Cholestasis

RENAL EFFECTS Acute renal failure ACUTE INTERSTITIAL NEPHRITIS AND NEPHROTIC SYNDROME CHRONIC KIDNEY DISEASE

CARDIOVASCULAR EFFECTS Coronary risk Exacerbate heart failure Hypertension

PULMONARY EFFECTS Bronchospasm Pulmonary infiltrates

HEMATOLOGIC EFFECTS Neutropenia Antiplatelet effects

CENTRAL NERVOUS SYSTEM Aseptic meningitis Psychosis Cognitive dysfunction Headaches Tremor

SKIN REACTIONS Various skin reactions Toxic epidermal necrolysis (TEN) and the Stevens-Johnson syndrome

Minimizing toxicity with: Patient evaluation for risk of developing NSAID-induced toxicity

The "safest" NSAID Nonacetylated salicylates, ibuprofen

PREGNANCY AND LACTATION It is best to avoid NSAIDs if possible during pregnancy Miscarriage Aspirin has a role in prevention of preeclampsia and the treatment of the antiphospholipid syndrome NSAIDs are excreted in breast milk in very small amounts