NONSTEROIDAL ANTIINFLAMMATORY DRUGS AND ANTIPYRETIC-ANALGESICS MS.NAGESWARARAO

1. NONSTEROIDAL ANTIINFLAMMATORY DRUGS AND ANTIPYRETIC-ANALGESICS MS.NAGESWARARAO DEPT OF MEDICAL PHARMACOLOGY

2. All drugs grouped in this class have analgesic, antipyretic and anti-inflammatory actions in different measures.▪ In contrast to morphine they are weaker analgesics, do not depress CNS, do not produce physical dependence and have no abuse liability.▪They act primarily on peripheral pain mechanisms, but also in the CNS to raise pain threshold . They are more commonly used drugs.

3. CLASSIFICATION • Nonselective COX inhibitors ( traditional NSAIDs ) 1. Salicylates: Aspirin. 2. Propionic acid derivatives: Ibuprofen, Naproxen, Ketoprofen,Flurbiprofen. 3. Anthranilic acid derivatives: Mephenamic acid. 4. Aryl-acetic acid derivatives: Diclofenac, Aceclofenac.5. Oxicam derivatives: Piroxicam, Tenoxicam.6. Pyrrolo-pyrrole derivative: Ketorolac.7. Indole derivative: Indomethacin.8. Pyrazolone derivatives: Phenylbutazone, Oxyphenbutazone.

4. B. Preferential COX-2 inhibitors: Nimesulide, Meloxicam, Nabumetone.C. Selective COX-2 inhibitors: Celecoxib, Etoricoxib, Parecoxib. D. Analgesic- antipyretics with poor anti-inflammatory action 1. Paraaminophenol derivative: Paracetamol (Acetaminophen). 2. Pyrazolone derivatives: Metamizol (Dipyrone), Propiphenazone. 3. Benzoxazocine derivative: Nefopam.

5. MECHANISM OF ACTION: • Prostaglandins, Prostacyclin (PG I2) and thromboxane A2(TXA2) are produced from arachidonic acid by the enzyme cyclooxygenase which exists in a constitutive (COX-1) and an inducible (COX-2 ) isoforms. • Cox-1 is constitutive, found in most tissues such as blood vessels, stomach and kidney. PGs have important physiological role in many tissues.(GI protection, platelet function, kidney function , regulation of blood flow and lowers IOP etc • COX-2 is induced during inflammation by cytokines and endotoxins, and is responsible for the production of prostanoid mediators of inflammation, pain and fever. • Most NSAIDs inhibit COX-1 and COX-2 nonselectively, , but some preferential and selective COX-2 inhibitors have been produced

8. SALICYLATES ASPIRIN (PROTOTYPE)▪ Aspirin is acetyl salicylic acid. It is rapidly converted in the body to salicylic acid which is responsible for most of the actions ▪It is one of the oldest analgesic- anti-inflammatory drugs and is still widely used .MOA: Inhibits irreversibly both the COX nonselectively

9. PHARMACOLOGICAL ACTIONS: • Analgesia- Due to peripheral inhibition of prostaglandin synthesis. • Relieve pain without causing sedation, tolerance or drug dependence. • They are mainly relieving musculoskeletal pain , dysmenorrhea and pain associated with inflammation or tissue damage. • Antipyresis: Inflammation, bacterial infection Increase in PGE2 Hypothalamus – Raises its temperature set point Aspirin by inhibiting PG synthesis decreases temperature They promote heat loss by causing cutaneous vasodilatation and swatting.

10. Anti-inflammatory: • Inhibits PG synthesis at the site of injury . And also affect other mediators of inflammation –bradykinin , histamine , serotonin etc. • Other mechanisms • Produce symptomatic relief • Suppress – Pain swelling, vasodilatation. But they do not affect the progression of underlying disease.

11. Antiplatelet aggregation (Antithrombotic effect ): PGI2 Platelet aggregation TXA2 vasodilatation Vasoconstriction inhibit platelet aggregation promote platelet aggregation • Aspirin (low doses 50-325 mg ) by inhibiting TXA2 it prevents platelet aggregation . • Aspirin in high doses (2-3g/day) inhibits both PGI2 and TXA2 synthesis, hence beneficial effects of PGI2 is lost.

12. Respiration and Acid-base, electrolyte balance: Anti-inflammatory doses (therapeutic dose) Stimulation of respiration Hyperventilation Respiratory Alkalosis (which is compensated by excretion of alkaline urine )

13. At toxic doses – Respiratory depression CO2 retention Respiratory acidosis (later, there is uncompensated metabolic acidosis )

14. Gastrointestinal tract: • Aspirin irritates the gastric mucosa and produces nausea , vomiting and dyspepsia. • Aspirin also stimulates CTZ and produces vomiting. • Cardiovascular system: • Prolonged use of these drugs Causes sodium and water retention.(inhibit COX-2 in kidney) • Thus can precipitate CCF and they may also compromise the effect of antihypertensive drugs.

15. Urate excretion : • Salicylates in therapeutic doses inhibit urate secretion into the renal tubules and increase the plasma urate levels. • In high doses, salicylates inhibit the reabsorption of uric acid in the renal tubules and produce uricosuric effect.

16. PHARMACOKINETICS • Absorbed from stomach and small intestines • Poor water solubility-micro fining enhances absorption • 80 % bound to plasma proteins • Volume of distribution 0.17L/Kg - 11L • Conjugated with glucuronic acid and glycine • Excreted by glomerular filtration and tubular secretion • In low doses , elimination follows 1st order kinetics and with high doses as the metabolizing enzymes get saturated ,it switches over to zero order kinetics. • Analgesic dose(0.3-1.5 g /day)- t½ 3-5 hours • Antiinflammatory dose(3-5 g /day)-t½ 8-12 hours • Anti platelet dose : 50-325 mg/day.

17. ADVERSE EFFECTS • Side effects-analgesic dose-nausea, vomiting,epigastric distress, increased occult blood in stools-gastric mucosal damage, peptic ulceration. • Ulcerogenic effect is the major drawback of NSAIDs which is prevented / minimized by taking: -After food - buffered aspirin (preparation of aspirin with antacid) - Misoprostol/H2 blockers /PPIs with NSAIDs - selective COX-2 inhibitors

18. Hypersensitivity and idiosyncrasy are more common with aspirin- rashes, urticaria, rhinorrhoea, nasal polyps ,angioedema, bronchospasm and anaphylactoid reaction. • Aspirin induced asthma (due to incresesd production of LT ) LT antagonists are effective to treat aspirin induced asthma. • Anti-inflammatory doses-salicysm-dizziness, tinnitus, vertigo, reversible impairment of hearing and vision, excitement and mental confusion, hyperventilation and electrolyte imbalance. these symptoms are reversible on stoppage of therapy. • Reye’s syndrome- Use of salicylates in children's with viral infection may cause hepatic damage with fatty infiltration and encephalopathy. Hence these drugs are contraindicated .

19. In Pregnancy: These drugs inhibit PG synthesis, there by delaying onset of labour. and Increase chances of PPH. In new-borns inhibition of PG s synthesis results in Premature closure of ductus arteriosus. • Haemostatic effects: Prolonged use of salicylates interfere with action of vitamin K in the liver Decreased synthesis of clotting factors (hypoprothrombinaemia) Predisposes to bleeding (can be treated by administration of vit K)

20. Analgesic nephropathy: mainly seen in renal disease patients. • Slowly progressive renal failure / chronic nephritis occurs on chronic use of high doses of NSAIDs. • This is mainly due to inhibition of PGE2 mediated compensatory vasodilatation that occurs in response to angiotensin-2

22. ACUTE SALICYLATE POISONING • More common in children • Fatal dose in adults is 15-30 g • Vomiting, dehydration, electrolyte imbalance, acidotic breathing, petechial haemorrhages, restlessness,, hallucinations, hyperpyrexia, convulsions, coma - death due to respiratory failure + cardiovascular collapse • TREATMENT symptomatic and supportive • IV fluids with Na, K, HCO3 and glucose • Gastric lavage-alkaline diuresis-haemodialysis • Bleeding-blood transfusion- vit k • External cooling

23. PRECAUTIONS AND CONTRAINDICATIONS • Hypersensitivity, peptic ulcer, bleeding tendencies, children suffering from chicken pox or influenza • Chronic liver disease-may cause hepatic necrosis • CHF – sodium and water retention • Stopped one week before surgery –bleeding • Taken at or near term may cause- prolonged labour-greater postpartum blood loss-premature closure of ductusarteriosus (PGE2 &PGI2) • Bronchial asthma patients • Avoid high doses in G-6-PD deficiency-may cause haemolysis

24. Interactions • Displaces warfarin, phenytoin from protein binding sites • Alcohol and glucocorticoids increase the risk of gastritis • Increase risk of bleeding in patients on oral anticoagulant

25. Clinical uses of NSAIDS: • Analgesic-(0.3-0.6 g 6-8 hourly)-headache,toothahe, joint pains etc • Antipyretic-Paracetamol preferred (no Reyes syndrome in children's and GIT symptoms are less) • Acute rheumatic fever-4-5 g/day in divided doses-dose reduction after 4-7 days- it reduce fiver , swelling and joint pain. • Rheumatoid arthritis-(3-5 g/day) • Osteoarthritis-Paracetamol is first choice drug.in severe cases NSAIDs are effective • Post myocardial infarction and post stroke patients-50-150 mg/day –inhibit platelet aggregation. • Primary prevention of myocardial infarction

26. Other uses: • Medical closure of patent ductusarteriosus (indomethacin is preferred) • Colon and rectal cancer: regular use of aspirin is reported to reduce the risk of cancer (COX-2 inhibition in colon) • To control pruritus and flushing associated with the use of nicotinic acid (Aspirin will inhibit PGD2 in he skin)

27. OTHER NSAIDS HAVE SIMILAR MECHANISAM OF ACTION, PHARMACOLOGICAL ACTIONS, THERAPEUTIC USES AND ADVERSE EFFECTS. THEY VARY MAINLY IN THEIR POTENCY, DURATION OF ACTION, ANALGESIC AND ANTIINFLAMMATORY EFFECTS. PROPIONIC ACID DERIVATIVES • Ibuprofen-Naproxen-Ketoprofen-Flurbiprofen • Side effects are milder and incidence is lower • Ibuprofen rated as the safest conventional NSAID • Naproxen more efficacious-better tolerated-longer lasting • Ibuprofen-200,400,600mg tab, 100mg/ml susp-400-600mg TDS • Naproxen-250,500mg tab-250-500mg BD-TDS • Ketoprofen-50,100,200mg tab, 100mg/ml amp-50-100 mg BD-TDS • Flurbiprofen-50,100,200mg tab-50-100 mg BD-QID 0.03% eye drops-1 drop 6 hourly

28. ANTHRANILIC ACID DERIVATIVE • MEPHENAMIC ACID-An analgesic, antipyretic with potent anti-inflammatory action • Diarrhoea is the most important dose related side effect • Haemolytic anaemia is a rare but serious complication • Used primarily as analgesic in muscle, joint and soft tissue pain where strong anti-inflammatory action is needed • 125,250,500 mg tab, 250-500 mg TDS • 50 mg/ml syrp, 100 mg/5 ml susp

29. ARYL-ACETIC ACID DERIVATIVES • DICLOFENAC SODIUM-Similar in efficacy to Naproxen • Most extensively used NSAID • Used in osteoarthritis, bursitis, ankylosing spondylitis,toothache, dysmenorrhoea, post-traumatic and postoperative inflammatory conditions • Affords quick relief of pain and wound edema • 25,50 mg tab-50 mg TDS then BD oral, 25 mg/ml in 3ml amp given deep i.m. 1% topical gel and 0.1% eye drops • ACECLOFENAC-Congener of Diclofenac-longer acting • 100 mg tab-100 mg BD

30. ▪ OXICAM DERIVATIVES • PIROXICAM-long acting potent NSAID • Antiinflammatory efficacy similar to Indomethacin • Good analgesic-anti-inflammatory action • Better tolerated than Indomethacin and aspirin • Used in rheumatoid and osteo-arthritis, ankylosing spondylitis, acute gout, musculoskeletal injuries, dentistry, episiotomy, dysmenorrhoea, etc • 10,20 mg cap-20 mg BD for two days followed by 20 mg OD 20 mg/ml inj in 1 and 2ml amps • TENOXICAM-a congener of Piroxicam –similar properties uses 20 mg tab-20 mg OD

31. PYRROLO-PYRROLE DERIVATIVE • KETOROLAC-A novel NSAID with potent analgesic and modest anti-inflammatory activity • In post operative pain it has equalled the efficacy of morphine • Does not interact with opioid receptors and is free of opioid side effects • Used in postoperative, dental and acute musculoskeletal pain • May also be used for renal colic, migraine and pain due to metastasis • 30 mg in 1 ml amp-15-30 mg im or iv every 4-6 hours (maximum 90mg/day) • 10 mg tab – 10-20 mg 6 hourly • Use for more than 5 days continuously not recommended

32. INDOLE DERIVATIVE • INDOMETHACIN-It is a potent anti-inflammatory drug with prompt antipyretic action • A high incidence (up to 50%) of gastrointestinal and CNS side effects is produced • Gastric irritation, nausea, anorexia, gastric bleeding and diarrhoea are produced • Frontal headache, dizziness, ataxia, mental confusion, hallucination, depression and psychosis can occur • Because of prominent adverse effects, Indomethacin is used as a reserve drug in conditions requiring potent anti-inflammatory action like ankylosing spondylitis, acute exacerbations of destructive arthropathies, and acute gout • 25,75 mg cap 25-50 mg BD-QID • 1% eye drops 50 mg suppository

33. PYRAZOLONES • METAMIZOL(DIPYRONE-ANALGIN) • It is a prompt acting analgesic and antipyretic with poor anti-inflammatory action • It can be given orally, im as well as iv • Few cases of agranulocytosis were reported • 0.5-1-5 g oral/im/iv • 0.5 g tab, 0.5 g/ml in 2 ml and 5 ml amps • PROPIPHENAZONE-Claimed to be better tolerated • Agranulocytosis not reported • SARIDON-Propiphenazone 150 mg +Paracetamol 250 mg tab • DART-Propiphenazone 150 mg + Paracetamol 300 mg + Caffeine 50 mg tab

34. PREFERENTIAL COX-2 INHIBITORS • NIMESULIDE-has relative COX-2 selectivity • Instances of fulminant hepatic failure reported • Withdrawn in Tanzania and many countries • 100 mg tab – 100 mg BD, 50 mg/5 ml susp • MELOXICAM-newer congener of Piroxicam • Long acting can be given once daily • Gastric side effects are milder compared to Piroxicam • Used in osteo arthritis and rheumatoid arthritis • 7.5, 15 mg tab 7.5-15 mg od • NABUMETONE-effective in the treatment of rheumatoid arthritis, osteo arthritis and soft tissue injury • 500 mg tab-1 tab daily

35. SELECTIVE COX-2 INHIBITORS • Cause little gastric mucosal damage • Do not inhibit platelet aggregation-platelet TXA2 not affected • Reduces anti aggregatory endothelial PGI2 • Rofecoxib and Valdecoxib withdrawn for increasing cardiovascular risk (Due to inhibit PGI2 with out effecting TXA2) • CELECOXIB-gastric tolerability better than nonselective NSAIDs • Used in osteo arthritis and rheumatoid arthritis • 100, 200 mg caps,100-200 mg BD • ETORICOXIB-newer COX-2 inhibitor - for once a day treatment • 60, 90, 120 mg,60-120 mg OD • PARECOXIB-suitable for injection-efficacy similar to Ketorolac • 40 mg/vial inj, 40 mg tab • 40 mg oral/ im/ iv, repeated after 6-12 hours

36. PARA-AMINO PHENOL DERIVATIVE • PARACETAMOL(ACETAMINOPHEN) • Recent evidences suggests that paracetamol may act by inhibiting cox-3 in CNS. cox-3 is involved in pain perception and fever but not in inflammation. • Has analgesic, antipyretic actions • Weak anti-inflammatory action • Does not stimulate respiration or affect acid base balance • Does not increase cellular metabolism • Has no effect on CVS • Gastric irritation is insignificant • Does not affect platelet function

37. PARACETAMOL • Well absorbed on oral administration • 1/4th is plasma protein bound • Uniformly distributed in body • Metabolism mainly conjugation with glucuronic acid and sulfate • Conjugates excreted rapidly in urine • Plasma t ½ is 2-3 hours • Effects after an oral dose lasts 3-5 hours • ADVERSE EFFECTS-Safe and well tolerated • Nausea and rashes occur occasionally • Hepatotoxicity and nephrotoxicity is seen on chronic use.

38. ACUTE PARACETAMOL POISONING • Occurs commonly in small children having low glucuronide conjugating capacity • 15-20 g in an adult fatal • Hepatic necrosis, renal tubular necrosis, hypoglycemia –may progress to coma and death • Minor metabolite N-acetyl-p-benzoquinoneimine is detoxified by conjugation with glutathione • Toxicity manifests when glutathione is depleted • Specific antidote N-acetylcysteine replenishes glutathione stores of liver and prevents binding of toxic metabolite to proteins in the liver and kidney. • Activated charcoal is administered to decrease the absorption of paracetamol from the GIT • Hemodialysis may be required in case with acute renal failure.

39. PARACETAMOL-USES • One of the most commonly used over the counter analgesic • Used for headache, mild migraine, musculoskeletal pain, dysmenorrhoea • First choice analgesic for osteo arthritis • Is best drug to be used as antipyretic • 500 mg tab 0.5-1 g TDS • 125 mg/ 5 ml syrup, infants 50 mg, 1-3 years 80-160 mg, 4-9 years 240-320 mg, 9-12 years300=600 mg TDS

40. TOPICAL NSAIDs • Topical formulations for application over painful muscles or joints • Believed that drug penetrates subjacent tissues attaining high concentrations in the affected muscles/joints, while maintaining low blood levels • Strong placebo effect of local application-massaging • Presence of counter irritants like menthol, methyl salicylate, etc. • Diclofenac 1% gel, Ibuprofen 10% gel, Naproxen 10% gel, Ketoprofen 2.5% gel, Flurbiprofen 5% gel, Nimesulide 1% gel, Piroxicam 0.5% gel

41. CHOICE - NONSTEROIDAL ANTIINFLAMMATORY DRUG • Mild to moderate pain with little inflammation: Paracetamol or low dose Ibuprofen • Postoperative or similar acute but short lasting pain: Ketorolac, Propionic acid derivative, Diclofenac, Nimesulide, Aspirin • Acute musculoskeletal, osteoarthritic, injury associated pain: Paracetamol, propionic acid derivative, Diclofenac • Exacerbation of rheumatoid arthritis, ankylosing spondylitis, acute gout, acute rheumatic fever: Naproxen, Piroxicam, Indomethacin, high dose aspirin • Gastric intolerance to traditional NSAIDs or predisposed patients: a selective COX-2 inhibitor or paracetamol

42. CHOICE – NONSTEROIDAL ANTIINFLAMMATORY DRUG • Patients with history of asthma or anaphylactoid reaction to aspirin/other NSAIDs: Nimesulide, COX-2 inhibitor • Paediatric patients: Only Paracetamol, Aspirin, Ibuprofen, Naproxen have been adequately evaluated in children. Due to risk of Reye’s syndrome Aspirin should be avoided • Pregnancy: Paracetamol is the safest; Low dose Aspirin is probably the second best • Hypertensive, diabetic, ischaemic heart disease, epileptic and other patients receiving long term regular medication: possibility of drug interaction with NSAIDs should be considered

43. ANALGESIC COMBINATIONS • Additive synergism • Aspirin + Paracetamol • Ibuprofen + Paracetamol • Diclofenac + Paracetamol • Aspirin + Codeine • Paracetamol + Codeine

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