NSAIDs PDF

Non-steroidal anti-inflammatory drugs They have 3 pharmacological actions:  Antipyretic  Analgesic  Antiinflammatory Antipyretic action:  Fever raises the set temperature in hypothalamus  NSAIDs decrease this set temperature  Pyrogens released by macrophages (for example IL-1)  T...

Non-steroidal anti-inflammatory drugs They have 3 pharmacological actions:  Antipyretic  Analgesic  Antiinflammatory Antipyretic action:  Fever raises the set temperature in hypothalamus  NSAIDs decrease this set temperature  Pyrogens released by macrophages (for example IL-1)  These pyrogens will stimulate prostaglandin PG production in hypothalamus.  PG raises the set point in hypothalamus —> fever  NSAIDs inhibits production of PG  NSAIDs have no action on normal temperature (37.2°) Analgesic action:  They are effective in pain associated with inflammation. Antiinflammatory action:  They inhibits cyclooxygenase enzyme (COX) —> decrease production of PG  They decrease production of oxygen radicals (ROS) —> ↓ tissue damage.  They have no effects on lysosomal enzyme release. Mechanism of action: 3 types of COX enzyme:  COX-1: constitutively expressed , widely distributed, maintains the normal physiological ‘housekeeping’ function.  COX-2: inducible in inflammatory cells by inflammatory stimuli.  Expression is stimulated by growth factors, tumor promotersmers, cytokines, and endotoxins.  COX-3: implicated in fever, expressed in the brain  Indomethacin & sulindac primarily inhibit COX-1.  Meclofenamate & ibuprofen have equally action on COX-1 &COX-2.  Celecoxib & rofecoxib inhibit COX-2  Drugs with short half-lives in the plasma remain in the joints for a long time and vice versa; long half-life acting drugs last longer in the plasma, and have a proportional level with that of the intrarticular concentration.  COX-2 inhibitors have no effect on platelet function (thus no cardioprotctive properties), but of importance, have less effect on the GI system.  NSAIDs decrease sensitivity of the vessels to bradykinin and histamine and reduce the incidence of colon cancer by about 50%. Common adverse effects: 1. Gastrointestinal effects:  result mainly from inhibition of the COX-1 isoform.  dyspepsia, diarrhea, nausea, vomiting, gastric bleeding, and ulceration. 2. Adverse renal effects: This figure illustrates the action of PG on the kidney  NSAIDs inhibit the action of PG in the kidney thus impeding renal vascular auto- regulation.  In susceptible pt. —> acute renal insufficiency. 3. Skin reactions (caused by mefenamic acid and sulindac.)  Include: mild rash, urticaria, and photosensitivity reactions.  Classification of NSAIDS Another Classification of NSAIDs Nonselective COX inhibitors COX-2 selective inhibitors  COX-1 inhibition, in general, is instantaneous and competitively reversible.  COX-2 inhibition is time dependent, i.e. its effect increases with time.  The COX-2-selective drugs have minimal gastrointestinal toxicity.  COX-2 inhibitors no impact on platelet aggregation.  Cardiovascular thrombotic events seen in COX-2 inhibitors.  COX-2 is constitutively active within the kidney. Salicylates (aspirin) Mechanism of action:  Non-selective Inhibitor of both COX isoforms  Irreversibly inhibits COX and inhibit platelet aggregation PK:  Weak acid  Most of it is protein bound  T1/2= low dose: 3h high dose: 15h  Hydrolyzed by plasma and tissue esterases.   Metabolism:  25% oxidized  25% excreted unchanged  some conjugated to glycine, glucuronic , & sulfuric acid  Rate of excretion is higher in alkaline urine (Henderson-Hasselbalch equation). Adverse effects:  Contraindicated in hemophilic pt.  GIT side effects: dyspepsia, nausea, vomiting, mucosal damage —> peptic ulcers.  Analgesia-associated nephropathy  Bronchospasm in aspirin-sensitive asthmatics  Skin reactions  Impaired homeostasis.  Reye’s syndrome: occurs in aspirin consumption by children with viral diseases such as chickenpox. (fatal disease) Acute toxicity:  Local effects: Gastritis with focal erosion  Systemic effects: Salicylism: Large therapeutic doses alter acid-base balance —> hyperventilation & respiratory alkalosis. In larger doses —> respiratory acidosis. Also Causes:  Interference with carbohydrate metabolism —> metabolic acidosis  Hyperpyrexia  Dehydration  CNS effects: initially stimulation with excitement then coma & respiratory depression. Treatment of toxicity:  Correction of acid-base balance  Rehydration and treat hyperthermia  Maintenance of kidney function  Gastric lavage & forced alkaline diuresis Drug interaction:  Aspirin increases concentrations of: warfarin, phenytoin, valproic acid  Avoid aspirin use with probencid & sulfinpyrazone because they increase uric acid excretion while aspirin does the opposite  Ketorolac + aspirin = ↑ risk of GI bleeding and platelet inhi- bition Clinical uses:  Minor musculoskeletal disorders → bursitis, synovitis, tendinitis, myositis, and myalgia  Fever and headache  Inflammatory disease, such as acute rheumatic fever, rheumatoid arthritis, osteoarthritis, and certain rheumatoid variants, such as ankylosing spondylitis  Prophylaxis of myocardial infarction and ischemic stroke.  Colon cancer  Paracetamol (acetaminophen) Has no significant antiinflammatory effects and is usally used as an analgesic. PK:  Well absorbed orally  Peak plasma concentration 30-60 m  Variability in protein binding  T1/2= 2-4 h  Drug is inactivated in the liver by conjugation with gluco  uronic & sulfuric acid  T1/2 for toxic dose= 4-8 h Adverse effects  Allergic skin reactions  Toxicity:  The drug is metabolized to N-acetyl-p- benzoquinone.  In normal doses the previous compound binds with glutathione, and is converted to mercaptopuric acid (nontoxic)  With high doses N-acetyl-p-benzoquinone will cause necrosis in the liver and kidney  Initial symptoms: nausea and vomiting  Treatment: 1. Gastric lavage, oral activated charcoal. 2. Agents that ↑ glutathione formation e.g. acetylsystine (orally or IV) 3. Agents that ↑ conjugation reaction (methionine & cystamine) 4. After 12 hours these agents are useless and they may precipitate hepatic coma Clinical uses  Allergy to aspirin  When slicylates are poorly tolerated  Hemophilia  History of peptic ulcer  Bronchospasm precipitated by aspirin  Children with certain viral infection  Is usually combined with probencid Ibuprofen A nonselective COX inhibitor PK:  T1/2= 2 h  Oral, cream preperation, and IV  Hepatic metabolism and urinary excretion  Clinical uses:  As an analgesic, antipyretic, in treatment of rheumatoid arthritis and degenerative joint disease.  Closing patent ductus arteriosus in preterm infants  A liquid gel preparation → postsurgical dental pain.  Ibuprofen + aspirin = no platelet inhibition Adverse effect Nausea, heartburn, epigastric pain, rash, and dizziness, visual changes, prolongation of bleeding times Diclofenac Piroxicam Meloxicam Equal action on COX-1,2 Mechanism of action:  Nonselective COX Mechanism of action: PK inhibitor COX-2 selective  Oral, IM, ophthalmic, topical,  In high concentrations it inhibitor but less  T1/2= 1.1 h inhibits selective than celecoxib polymorphonuclear or rofecoxib for COX-2 Clinical uses leukocyte migration,  Used for rheumatoid arthritis, decreases oxygen radical Clinical uses: osteoarthritis, ankylosing production, and inhibits Osteoarthritis, spondylitis, dysmenorrhea. lymphocyte function. rheumatoid arthritis and  Topical for solar keratosis certain acute conditions  Usually combined with PK misoprostol or omeparazole T1/2= 57 h Adverse effects to prevent upper GI bleeding Low frequency GI  Ophthalmic preparation → Clinical uses: effects postoperative ophthalmic Rheumatoid arthritis and inflammation. osteoarthritis  Rectal suppository for preemptive analgesia and Adverse effects: postoperative nausea GI reactions, edema, dizziness, headache, rash, and changes in Adverse effects hematological parameters.  GI disturbances  Headache  Reversible elevation of serum transaminases.  Nabumetone Celecoxib PK:  The only nonacid NSAID  T1/2= 26 h A COX-2 Selective inhibitor  A prodrug metabolized in the liver to 6- PK: methoxy-2-naphthylacetic acid, a strong  T1/2= 11 h COX inhibitor, which is chemically simi-  27% urinary excretion lar to naproxen  Renal impairment may double its t ½. Clinical uses Osteoarthritis and rheumatoid arthritis Clinical uses Rheumatoid arthritis, osteoarthritis, and pain Contraindications: management.  Hypersensitivity to sulfonamides or other NSAIDs. Adverse effects:  Used with caution in persons with  Less damage to the stomach hepatic disease  Pseudoporphyria and photosensitivity in some patients Drug interactions:  lower-bowel complaints, rashes, and with other drugs that induce CYP2C9 (e.g CNS disturbances. rifampin) or compete for metabolism by this enzyme (e.g. warfarin, fluconazole, leflunomide). Adverse effects:  Mild to moderate GI effects such as dyspepsia, diarrhea, and abdominal pain.  Serious GI and renal effects have occurred rarely  hypertension and edema