Nonsteroidal Anti-Inflammatory Drugs NSAIDs By
Prof. Mohammad Saleh M. Hassan PhD. (Pharma); MSc. (Ped.); MHPE (Ed.)
Nonsteroidal anti-inflammatory drugs NSAIDs • They are divided into: A-Salicylate (e.g. aspirin) and, B-Non-salicylate (e.g. ibuprofen).
Some commonly used NSAIDs are: • • • • •
Aspirin and other salicylates. Acetaminophen. Indomethacin and sulindac Mephenamic acid meclofenamate. Tolmetin.
• Propionic acid derivatives: Ibuprofen. Fenoprofen. Ketoprofen. • Piroxicam. • Diclofenac. • Etodolac. • Nabumatone • Phenylbutazone.
Naproxen. Flubiprofen.
Aspirin (acetylsalicylic acid) Pharmacokinetics: • Oral absorption from stomach but mainly upper GIT. • Starts action in 30 min. peak level at 2 h. • Distribution is pH dependent. • Metabolism by liver metabolizing Enz. salicyluric acid, phenolic glucuronide, acyl glucuronide and free salicylic acid.
• Alkalinization of urine increases excretion. • Rectal absorption is slow and unpredictable.
Pharmacologic effects: A-Antipyretic action: -Rapidly effective in febrile patient through central effect due to inhibited PGE2 synthesis from hypothalamus in response to pyrogens. -Salicylate toxicity hyperpyrexia (increase oxygen consumption and metabolic rate)
B-Anti-inflammatory effects: Due to inhibition of PG synthesis. C-Analgesic effects: -Effective for low-to-moderate pain (musculoskeletal) -Mechanism of pain relief: -Peripheral: inhibition of PGs in inflamed tissue. -Central: the analgesic site in hypothalamus is closer to antipyretic region.
D-Respiratory effects: -Stimulation of respiration ( CO2 production from uncoupling of oxidative phosphorylation). -High doses medullary ++ hyperventilation & respiratory alkalosis ( rapid compensated resp. alkalosis by the kidney) -Toxic doses depress medulla uncompensated respiratory alkalosis accumulation of bicarbonate and organic acids metabolic acidosis.
E-C.V.S. effects: -Therapeutic doses no effects. -Large doses vasodilatation (direct action). -Toxic doses depress circulation (direct & central vasomotor paralysis) -Prolonged use in elderly noncardiogenic pulmonary edema. -Prophylactic use of low dose reduces thromboembolic events.
F-GIT effects: -Epigastric distress, nausea and vomiting (direct irritation and central ++ CTZ in the CNS) -Dose-related gastric ulceration, bleeding, exacerbation of peptic ulcer symptoms and erosive gastritis. -PGI2 has a cytoprotective effects for gastric mucosal cells by decrease of gastric secretion (this effect is inhibited by salicylates). -Salicylate-induces gastric bleeding anaemia.
G-Hepatic effects: -Two forms of hepatic injury: a-One form dose dependent SGOT & SGPT (reversible) b-Second form Reye’s syndrome (rare and often fatal, occur with influenza and chickenpox viruses) (contra indicated in children with these viruses)
H-Hematologic effects:
-Therapeutic doses no effects on WC, Hb. -At low doses prolongation of bleeding time.
-Effects on platelets: - Inactivation of cyclooxygenase affects platelet aggregation: -Vascular injury exposure of subendothelial structures activation of cyclooxygenase Enz activation of thromboxane synthetase production of TXA2 platelet aggregation. -Prostacyclin synthetase (of the endothelial cells) converts the cyclooxygenase products (PGG2 and PGH2) to PGI2 inhibition of platelet clumping.
*Aspirin in appropriate doses inhibits platelet cyclooxygenase system blocking the formation of TXA2 suppressing platelet clumping and prevents release of ADP from platelets further suppression of aggregation.
I-Renal effects: -Salt and water retention (with large doses). -Can exacerbate renal dysfunction. -Low doses decrease urate excretion, high doses uricosuria. Should not be used with treatment of gout.
J-Metabolic effects: -Uncoupling oxidation phosphorylation. -Large doses hyperglycemia, glycosuria and deplete liver and muscle glycogen. -Blocking incorporation of acetates into fatty acids reduction of lipogenesis. -Toxic doses nitrogen loss (aminoaciduria)
K-Endocrine effects: -Very large dose +++ steroid secretion (hypothalamus) -Long term therapy: thyroid uptake and clearance of iodine oxygen metabolism. clearance of T3 & T4 -May prolong the gestational period during pregnancy.
Therapeutic uses: -Antipyretic (not recommended for children). -Analgesic in headache, arthritis, dysmenorrhea. -In acute rheumatic fever (symptomatic). -First-line drug in rheumatoid arthritis. -Low doses in thrombo-embolism, stroke, myocardial infarction (anti-platelets).
Salicylate intoxication: -Mild (salicylism): headache, mental confusion, lassitude, drowsiness, tinnitus, difficult hearing, hyperthermia, sweating, thirst, hyperventilation, vomiting and diarrhea. -More severe: hallucination, vertigo, convulsions, skin eruptions and alteration of acid-base balance. -Fatal intoxication: especially in children (dose 10 g).
*Treatment of toxicity: -Emesis and gastric lavage. -Infusion to correct disturbed electrolyte balance. -Alkalinization of the urine. -Dialysis as required.
Acetaminophen -It is the active metabolite of phenacetin. -It is an analgesic antipyretic drug without significant anti-inflammatory effect. -It is a weak prostaglandin inhibitor.
Pharmacokinetics: -Given orally. -Well absorbed, peak blood concentration in 30-60 min. -Slightly bound to plasma protein and partially metabolized in the liver by conjugation to give acetaminophen sulphate and glucuronide. -Less than 5 % is excreted unchanged. -The half-life is 2-3 h. which is increased in liver disease or toxic doses.
Indications: -It is effective to aspirin as analgesic and antipyretic agent without anti-inflammatory action. -It does not affect uric acid levels. -It has no platelet-inhibitory properties. -It is used for mild to moderate pain. -It may be used as analgesic with an antiinflammatory agent in inflammatory conditions like rheumatoid arthritis.
Indications (cont…): -It preferable to aspirin in patients who are intolerant or allergic to aspirin and in patients with haemophilia, history of peptic ulcer, and in aspirin-induced bronchospasm. -It does not affect the action of uricosuric agents. -It is preferred to aspirin in children with viral infection.
Adverse effects: -Mild reversible increase in hepatic enzymes. -Large doses dizziness, excitement, and disorientation. -Ingestion of 15 gm acetaminophen may be fatal (severe hepato-toxicity with central lobular necrosis with or without acute renal tubular necrosis. -Rare cases of renal damage without hepatic damage may occur with the usual doses.
-Treatment of acetaminophen-induced hepatic injury include supportive measures and administration of donors of sufhydryl groups like acetylcysteine to neutralize the toxic metabolites of the drug. -Rare cases of haemolytic anaemia and methaemoglobinaemia.
Dosage: -For acute pain and fever 325-500 mg four times daily in adults. Small doses are used in children.
Phenacetin -It is not used now for its marked renal toxicity.