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Non Steroidal Anti Inflammatory Drugs
- 1. NSAIDS-I Dr. Jessica Dali Departmentof Pharmacology Nobel Medical College and Teaching Hospital
- 2. Inflammation • Reaction toinjury of the living microcirculation and related tissues CARDINAL SIGNS : • Redness (Rubor), • Swelling (Tumour), • Heat (Calor), • Pain (Dolor), • Loss of function
- 3. NSAIDS • Non steroidalanti-inflammatory drugs • One of the most commonly prescribed drugs • Mostly used for: • Anti pyretic • Anti inflammatory • Analgesic action
- 6. COX-1 and COX-2 •Cycloxygenase-1 ( COX-1) • Present in most of the cells • Mediates normal physiological function • Cycloxygenase-2 (COX-2) • Induced during inflammation by cytokines, growth factors, etc. • Not present in all cells at all times • Activated by Interleukin-1 and TNF-α
- 7. • Majority oftissues synthesize all PGH intermediates but the predominant PG in a tissue depends on the enzyme present and their amount • Example: • Lungs and spleen- all PGs • Platelets- Thromboxane synthase • Blood vessels ( vascular endothelium)- Prostacyclin synthase
- 9. Natural Prostaglandins 1. PGE2-many receptors, many functions • Bronchodilation • Vasodilation • Increase mucus secretion in stomach • Patency of ductus arteriosus 2. PGD2 – vasodilation, inhibition of platelet aggregation 3. PGF2α – contracts smooth muscles of uterus, facilitates parturition
- 10. 4. PGI2 orProstacyclin- vasodilation, inhibition of platelet aggregation, prevents platelets adherence to healthy blood vessels wall 5. TXA2- vasoconstriction, platelet aggregation
- 11. Anti- inflammatory effectsof NSAIDs A. Reduce those components of inflammatory response in which PGs play a role: 1. Vasodilation 2. Oedema 3. Pain B. Suppress pain, swelling and increased blood flow due to inflammation but have little action on the actual progress of the underlying chronic disease itself. C. No effect on other aspects of inflammation- leucocyte migration, lysosomal enzyme release and toxic oxygen radical production that contribute to tissue damage in chronic inflammatory conditions
- 12. Fever • Disturbance ofhypothalamic thermostat leads to raised setpoint of body temperature • Normal temperature in humans not affected by NSAIDs • Bacterial endotoxins cause release of IL-1, which stimulates the generation of PGE, that elevate the temperature setpoint
- 13.
- 14. Analgesic effect • Effectiveagainst mild or moderate pain from tissue damage or inflammation • Decrease the production of Prostaglandins that sensitize nociceptors to inflammatory mediators such as bradykinin. Hence effective in arthritis, muscular/vascular pain, toothache, dysmenorrhea – all conditions associated with increased local prostaglandin synthesis • Combined with opioids, they decrease postoperative pain • Ability to relieve headache maybe due to stopping of vasodilator effect of prostaglandins on the cerebral vasculature
- 15. Clinical Implications ofPGs and NSAIDs 1. Patent Ductus Arteriosus- Ductus Arteriosus is kept open by PGE2 and PGI2 in foetal life. Aspirin and Indomethacin are given in high doses to close ductus arteriosus if closure does not occur in usual time. 2. Platelet aggregation- Aspirin in low doses inhibits synthesis of TXA2 and produces antiplatelet action 3. PGE2 and PGF2α are used in induction of labour as they contract uterus, and NSAIDs used to delay the labour. NSAIDS not used for the purpose for the fear of early closure of ductus arteriosus.
- 16. 4. PGF2α constrictsthe sphincter muscle of iris causing miosis, increasing uveoscleral and trabecular outflow, decreasing intraocular pressure. Latanoprost, a synthetic PGF2α has been developed for treatment of open angle glaucoma. 5. PGE2 analogue (Misoprostol) is used in peptic ulcer to increase gastric mucus secretion( gastro-protective effect). 6. TXA2, PGF2α both cause bronchoconstriction. In asthma, LTs are considered to be causative. Hence, NSAIDs might direct all production of AA to LTs increasing the severity of asthma.
- 17. 7. PGE2 andPGI2 are vasodilators, increase renal blood flow due to direct action on renal tubules, causing natriuresis, diuresis and kaliuresis. NSAIDs, hence, cause retention of sodium and water and may block the effect of diuretics.
- 19. Common adverse effectsof NSAIDs 1. Effect on gastric mucosa: PGs like PGE2 and PGI2 protect gastric mucosa by inhibiting gastric acid secretion, increasing mucus, and increasing the gastric blood flow. Loss of these actions damages gastric mucosa causing ulcers.
- 20. 2. Renal toxicity:In hypovolemia or decreased renal perfusion, PGs synthesized in the kidneys maintain perfusion by vasodilation, antagonizing action of ADH and other mechanisms. NSAIDs block this mechanism and give rise to analgesic nephropathy – a slow developing renal failure. Avoid by • short course or after gap of few weeks • Only one NSAID at a time
- 21. 3. Cardiovascular adverseeffects: a) Inhibition of PG production in the kidney may retain sodium and water. NSAIDs are therefore associated with risk of hypervolemia- hence worsening heart failure, especially if controlled by diuretics b) Risk of increase in BP. c) Increased stroke and Myocardial infarction due to inhibition of prostacyclins
- 22. Classification 1. Non- selectiveCOX inhibitors • Salicylic acids: Aspirin • Propionic acid derivatives: Ibuprofen, Naproxen, Ketoprofen • Fenamate: Mephenamic acid • Enolic acid derivatives: Piroxicam • Acetic acid derivatives: Ketorolac, Indomethacin • Pyrazolone derivatives: Phenylbutazone
- 23. 2. Preferential COX-2inhibitors: Nimesulide, Diclofenac, Meloxicam 3. Selective COX-2 inhibitors: Celecoxib, Etoricoxib
- 24. Aspirin (Acetyl SalicylicAcid) • Derived from Willow bark, which used for centuries • Prototype drug with a range of actions • Used for 1. Pain- sp. Tension headache 2. Fever 3. Acute Rheumatic Fever 4. Post myocardial infarction and post stroke patients
- 25. Actions 1. Pain, fever,inflammation • Inflammatory, connective tissue related pain • Peripheral pain receptors desensitized, PG- mediated sensitization of nerve endings prevented. Also, pain threshold increases. • Resets hypothalamic thermostat, rapidly reduces fever by promoting sweating, cutaneous vasodilation • Inhibits PG synthesis, suppress signs and symptoms of inflammation but do NOT affect the progression of the disease
- 26. 2. Antiplatelet effect: •In lower doses( 50-325 mg) Irreversibly inhibits platelet TXA2 synthesis producing antiplatelet effect, which lasts for 8-10 days, i.e. the lifetime of platelets. • In high doses (2-3 g/day) inhibits both PGI2 and TXA2 synthesis, hence beneficial effect of PGI2 is lost. • Aspirin should be withdrawn 1 week prior to elective surgery because of this risk of bleeding. 3. At high doses, increased respiration/ hyperventilation is stimulated by Aspirin. Even higher doses can cause respiratory failure.
- 27. 3. Acid- baseand electrolyte balance: • At high doses, hyperventilation drives out CO2 causing respiratory alkalosis, which is compensated by increased renal excretion of HCO3 -. • Still higher doses- depressed respiration- more CO2 produced in the body- respiratory acidosis. • Metabolic acids produced in excess + metabolites of salicylic acid present, decreased HCO3 - in the body- uncompensated metabolic acidosis
- 28. 4. GIT: Iontrapping prominent • Aspirin is easily absorbed into the gastric mucosal cells as it remains unionized in the acidic medium of the stomach. But once inside the gastric cells, most part of it gets ionized and cannot cross the cell membrane to reach the bloodstream • Irritates gastric mucosa, causing nausea, v vomiting and epigastric distress. • Also stimulates CTZ
- 29. 5. Urate excretion: <2g/day- urate retention, antagonize other uricosuric drugs 2-5g/day- variable effects >5 g/day- increased urate excretion 6. Metabolic effects: At high doses, • Uncoupling of oxidative phospholylation → increased heat production • Increased utilization of glucose → hyperglycemia
- 30. Pharmacokinetics • Rapidly absorbedfrom upper GIT • Metabolized in liver • Low dose- 1st order kinetics of elimination • High doses- 0 order kinetics of elimination, as the metabolizing enzymes are saturated
- 31. Adverse effects 1. GIT:Nausea, vomiting, epigastric pain, gastric ulcer and bleeding. 2. Hypersensitivity: Patients with asthma, nasal polyps, recurrent rhinitis or urticarial 3. Reye’s syndrome: Children with viral infection- Avoid NSAIDs as they can cause liver damage with fatty infiltration and encephalopathy 4. Pregnancy: Delay natural contractions of labour, increase chances of postpartum hemorrhage. Also in the newborn, inhibition of PG synthesis results in premature closure of ductus arteriosus. 5. Analgesic nephropathy: Renal failure
- 32. Aspirin poisoning • Symptoms: •CNS: headache, tinnitus, vertigo, convulsions, coma • GIT: nausea, vomiting, diarrhoea • Sweating and hyperventilation • Hypo/hyperglycemia • Hyperpyrexia • Death by respiratory failure/ Cardiovascular collapse
- 33. Treatment: NO ANTIDOTE, Symptomatictreatment 1. Gastric lavage + activated charcoal 2. Fluid and electrolytes, acid-base balance 3. IV sodium bicarbonate to treat metabolic acidosis, also alkalinizes urine and increases excretion of salicylates 4. External cooling 5. Hemodialysis in severe cases 6. Vitamin K1 and blood transfusion if there is bleeding
- 34. Dose of Aspirin •Antiplatelet effect- 50-325 mg/day • Analgesic effect- 2-3 g/day • Anti-inflammatory effect- 4-6 g/day • Anti- gout effect (uricosuric effect)- >4-5g/day
- 35. Paracetamol • COX-3 isa variant of COX-1, sensitive to Paracetamol • Weak inhibitor of PG synthesis of COX-1 and COX-2 Adverse effects 1. Rare, occasionally causes skin rashes and nausea 2. Hepatotoxicity 3. Nephrotoxicity Chronic use
- 36. Paracetamol 1. NO ANTIINFLAMMATORY ACTION: Increases pain threshold; produces analgesic and antipyretic action due to action in CNS. Weak inhibitor of cyclooxygenase in presence of high concentration of cyclic endoperoxides at peripheral inflammatory sites 2. No effect on cardiovascular/ respiratory function 3. No acid base imbalance 4. No gastric irritation/ bleeding 5. No effect on platelets, bleeding time and uric acid
- 37.
- 39. • Alcohol isan inducer of CYP2E1, increases conversion of paracetamol to NAPQI, increasing paracetamol toxicity • Fatal dose reduced to 5-6 g in chronic alcoholics • Overdose occurs when high dose (>8 g/day) is consumed • Symptoms: Nausea, vomiting, abdominal pain, liver tenderness, jaundice, unconsciousness • ANTIDOTE: N-acetylcysteine (NAC)- repletes the glutathione • Alternatively, methionine can be used- avoid with charcoal as it will get bound in charcoal particles hence useless • Supportive measures: Activated charcoal, gastric lavage
- 40. Diclofenac • Used for •Rheumatoid arthritis, • Osteoarthritis • Ankylosing spondylitis • Toothache, • Renal colic, • Postoperative inflammatory pain
- 41. Ketorolac • Good forpostoperative pain ( analgesic action equal to morphine) • Reduces the dose of opioids in severe pain • Renal toxicity more than other NSAIDs • Continuous use >5 days orally and >2 days i.m/i.v. not recommended due to high incidence of GIT bleeding and bleeding at surgical site
- 42. Indomethacin • Drug ofchoice for Acute Gout • Rheumatoid arthritis • Ankylosing spondylitis • Antipyretic in Hodgkin’s disease- fever refractory to other antipyretics • Medical treatment of Patent Ductus Arteriosus
- 43. Ibuprofen • Safest amongthe traditional NSAIDs • Effective and safe antipyretic as paracetamol • Well tolerated in patients who cannot tolerate other NSAIDs
- 44. Nimesulide • Partially selectiveCOX-2 inhibitor, less gastric effects • Serious life threatening toxic effect- hepatic damage and agranulocytosis • BANNED IN MANY COUNTRIES