NSAIDs

NSAIDs

1. Nonsteroidal antiinflammatory drugs and antipyretic-analgesics Mangesh Bansod Asst. Prof., SDDVCPRC, Panvel

2. Introduction to NSAIDs Chemically diverse, but most are organic acids Grouped together as these drugs have common analgesic (pain reducing) and antipyretic (fever-reducing) effects and which have, in higher doses, anti-inflammatory effects Do not depress CNS – no physical dependence or abuse liability Weaker analgesic than Morphine – except inflammatory pain Also called non-narcotic, nonopioid and aspirin-like analgesics Primarily act on periphera l pain mechanism, and also in CNS (Raise threshold)

3. History of NSAIDs Salix alba or White Willow bark Sodium salicylate – 1875 Acetylsalicylic acid – 1899 – Also phenacetin and antipyrine Phenylbutazone – 1949 Indomethacin - 1963

4. Classification Traditional – Nonselective COX inhibitors Group Drugs Salicylic acids Aspirin Propionic acids Naproxen, Ibuprofen, Ketoprofen, Oxaprozin and Flurbiprofen Anthranilic acid Mefenamic acid Aryl-acetic acid derivative Diclofenac and Aceclofenac Oxicam derivatives Piroxicam and Tenoxicam Pyrrolo-pyrrole derivative Ketorolac, Indomethacin, Nabumetone Indole derivatives Sulindac and Indomethacin Pyrazolone derivative Phenylbutazone, Oxyphenbutazone

5. Nimesulide, Diclofenac, Aceclofenac, Meloxicam and Nabumetone Celecoxib, Etoricoxib and Parecoxib Preferential COX-2 inhibitors Selective COX-2 inhibitors Analgesic-antipyretic with poor antiinflammatory action: Paraaminophenol Pyrazolone derivative Benzoxazocine derivative Paracetamol (acetaminophen) Metamizole and Propiphenazone Nefopam Classification – contd.

6. NSAIDs and Prostaglandins All NSAIDs inhibit PG synthesis Prostaglandins, prostacyclines (PGI2) and Tromboxane A2 (TXA2) are produced from Arachidonic acid The enzyme responsible is prostaglandin synthase , also known as cycloxygenase or COX COX in 2 isoforms : constitutive - COX-1 and inducible COX-2 COX-1 serves house keeping functions COX-2 is generated by cytokines and others during inflammation (constitutive in brain and JG cells) – PG synthesis Most NSAIDs inhibit COX-1 and COX-2 non-selectively and inhibit PG synthesis Aspirin inhibits COX irreversibly – acetylation Other NSAIDs are competitive reversible inhibitors

7. NSAIDs and Prostaglandin Med i i ate i i nf l l amm a a t t i i on , , pain , , and fever C C O O X-2– X-2– s s p p e e c c i i f f i i c c i i n n h h i i b b i i t t ors ors COX-2– specific inhibitors Protect ga s t r o du o d e n al mucosa Su ports p l l ate l l et fun c c t t i i on C O C O X - X - 1 1 COX-1 C O C O X X - - 2 2 COX-2 N N o o n n s s p p e e c c i i f i f i c c N N SA SA ID ID s s Nonsp e c i f i c NSAIDs Prostaglandins Thromboxane Prostaglandins Arachidonic Acid Membrane P hosp h o l i p i d Phospholipase A

8. Major effects of PG synthesis inhibition Analgesia: Prevention of pain nerve ending sensitization Antipyresis: Reduction of Body temperature in hyperthermia Anti-inflammatory action: reduction in signs of inflammation (pain, tenderness, swelling and vasodilatation) Antithrombotic action: Inhibition of platelet aggregation Closure of Ductus arteriosus in Newborn

9. 1. Analgesia What is Pain ? “ An unpleasant sensory and emotional experience associated with actual or potential tissue damage , or described in terms of such damage.” International Association for the Study of Pain (IASP) Merskey and Bogduk. Classification of Chronic Pain. 1994 .

10. Classification of Pain Acute Chronic v s Duration Nociceptive Neuropathic v s Pathophysiology

11. Acute Pain vs Chronic Pain Acute Chronic Usually accompanied by obvious tissue damage Increased autonomic nervous activity Pain resolves with healing of the underlying injury Serves a protective function Pain that extends 3 or 6 months beyond onset or beyond the expected period of healing 1 Ceases to serve a protective function 2 Degrades health and functional capability 2 Depressed mood 3 v s. 1 Turk and Okifuji. Bonica’s Management of Pain. 2001. 2 Chapman and Stillman. Pain and Touch. 1996. 3 Fields. NNBN. 1991;4:83-92.

12. Nociceptive Neuropathic Classification of Pain • • • Pain that arises from a stimulus that is outside of the nervous system – receptors stimulated Proportionate to the stimulation of the receptor When acute serves a protective function Musculoskeletal disorders are a very common cause of nociceptive pain • Pain initiated or caused by a primary lesion or dysfunction in the nervous system No nociceptive stimulation required Disproportionate to the stimulation of receptor • • v s

13. • • • • • Transduction Transmission Modulation Perception I n t e r p retati o n Pe r i ph e r al N e r v e Pain Behavior • A sce nd i n g Pathways I n j u r y D escen d i n g Pa t h w ay Dorsal Root G a n g l i o n C-Fiber A-beta Fiber A-delta Fiber D o r sal Horn B r ai n Spinal Cord NSAIDs and Analgesia

14. Analgesia PGs induce hyperalgesia by nerve endings NSAIDs do not affect of PGs, but block the pain sensitizing mechanism induced by bradykinin , TNFα , interleukins (ILs) and other algesic substances primarily by inhibiting COX-2. This constitutes the peripheral component of the analgesic action of NSAIDs. They are, therefore, more effective against inflammation associated pain. Lately the central analgesic action of NSAIDs involve inhibition of PG synthesis in the spinal dorsal horn neurones as well as in brain.

15. Antipyresis NSAIDs reduce body temperature in fever, but do not cause hypothermia. Fever during infection and tissue injury is produced through the generation of pyrogens including, ILs, TNFα , interferons which induce PGE2 production in hypothalamus— raise its temperature set point. NSAIDs block the action of pyrogens

16. Antiinflammatory At the site of injury – enhanced COX-2 mediated PG synthesis NSAIDs inhibit PG synthesis at the site of injury – antiiflammatory response of different NSAIDs depend on capacity to inhibit COX (Potency) Also inhibit other mechanisms: PGs are not sole mediators of inflammation - other mediators - LTs, PAF and cytokines etc. - Also, adhesion molecules – ELAM-1 & ICAM-1 – chemotaxis Inflammatory cell express Selectins and Integrins Some NSAIDS also act – inhibition of generation of superoxide/free radicals - also GM-CSF, IL-6 etc.

17. Dysmenorrhoea Involvement of PGs in dysmenorrhoea : level ofPGs in menstrual flow, PGF2α metabolite in circulation are raised in dysmenorrhoeic women. Intermittent ischaemia of the myometrium is probably responsible for menstrual cramps. NSAIDs lower uterine PG levels—afford excellent relief in 60–70% and partial relief in the remaining. Ancillary symptoms of headache, muscle ache and nausea are also relieved. Excess flow may be normalized.

18. Antiplatelet aggregatory NSAIDs inhibit synthesis of both proaggregatory (TXA2) and antiaggregatory (PGI2) prostanoids therapeutic doses of most NSAIDs inhibit platelet aggregation: bleeding time is prolonged. Aspirin is highly active; acetylates platelet COX irreversibly in the portal circulation. Risk of surgical and anticoagulant associated bleeding is enhanced.

19. Ductus arteriosus closure During foetal circulation ductus arteriosus is kept patent by local elaboration of PGE2 by COX-2. Unknown mechanisms switch off this synthesis at birth and the ductus closes. When this fails to occur, small doses of indomethacin or aspirin bring about closure in majority of cases within a few hours by inhibiting PG production. Administration of NSAIDs in late pregnancy has been found to promote premature closure of ductus in some cases. Prescribing of NSAIDs near term should be avoided.

20. Gastric mucosal damage Gastric pain, mucosal erosion/ulceration and blood loss are produced by all NSAIDs to varying extents Inhibition of COX-1 mediated synthesis of gastroprotective PGs (PGE2, PGI2) is clearly involved, though local action inducing back diffusion of H+ ions in gastric mucosa also plays a role. Deficiency of PGs reduces mucus and HCO3¯ secrection , tends to enhance acid secretion and may promote mucosal ischaemia . selective COX-2 inhibitors are relatively safer. Stable PG analogues ( misoprostol ) administered concurrently with NSAIDs counteract their gastric toxicity.

21. Renal effects During hypovolemia , decreased renal perfusion Particularly important in conditions of CHF, hypovolaemia , cirrhosis and renal impairment (Na+ retention and edema ) Patent under antihypertensives and diuretics PGs cause: ( Intrarenal regulator) Renal vasodilatation and inhibition of tubular reabsorption Frusemide like effect – inhibition of Cl - reabsorption Increased excretion of Na+, K+ and water NSAIDs block these renal effects by inhibition PGs Impairment of renal blood flow Na+ and water retention Papillary necrosis on prolonged use

22. Anaphylactoid reactions Aspirin precipitates asthma, angioneurotic swellings, urticaria or rhinitis in certain susceptible individuals. Inhibition of COX with consequent diversion of arachidonic acid to LTs and other products of lipoxygenase pathway may be involved, but there is no proof.

23. SALICYLATES- Aspirin Aspirin is acetylsalicylic acid. It is rapidly converted in the body to salicylic acid which is responsible for most of the actions.

24. PHARMACOLOGICAL ACTIONS 1. Analgesic, antipyretic, antiinflammatory actions Weaker analgesic than Morphine – 600 mg Vs Codeine 60 mg Aspirin irreversibly inhibits COX-1 & COX-2 activity Inhibits COX irreversibly by acetylation – fresh enzyme synthesis requires for return Mainly effective in pains related to inflammation, tissue injury, connective tissue and integument pain Not much effective in visceral and ischemic pain Mechanism – prevention of PG-mediated sensitization of nerve endings Other mechanisms: Raising of pain threshold by acting centrally – morphine like – but no sedation, subjective effects, tolerance or physical dependence Resetting of hypothalamic thermostat – fever reduction Anti-inflammatory doses are higher than analgesic doses

25. PHARMACOLOGICAL ACTIONS Metabolic effects: Increased cellular metabolism Uncoupling of oxydative phosphorylation → increased heat production Increased utilization of glucose – decreased blood sugar and glycogen depletion Negative Nitrogen balance (increased protein to carbohydrate) Toxic doses: Hyperglycaemia Respiration: Low doses: ↑ CO2 → stimulates respiration Increased sensitivity of Respiratory centre to CO2 In Poisoning - Direct stimulation of respiratory center → Hyperventilation Higher doses - depression of respiratory center →Death due to Respiratory Failure

26. PHARMACOLOGICAL ACTIONS Aspirin – acid-base Balance Analgesic doses (0.3 – 1.0 gm /day) – no effects Anti-inflammatory doses (4 - 5 gm/day) – very important changes in acid-base balance Initially Respiratory stimulation – due to stimulation of respiration and hyperventilation - Increased expelling of CO2 in spite of increased production – Respiratory alkalosis Increased excretion of HCO3- with Na+, K+ and water – Compensated Respiratory Alkalosis Still Higher doses : Respiratory depression – retention of CO2 – Respiratory acidosis Added acids – pyruvic acid, lactic acid and dissociated salicylic acid Net result is – Uncompensated Metabolic acidosis

27. PHARMACOLOGICAL ACTIONS G I T : Salicylic acid – irritant to mucosa causing nausea and vomiting Unionized in stomach and absorbed but upon absorption – ionizes and indiffusible (Ion trapping) Locally – back diffusion of acid – necrosis of mucosa and arteries – ulceration, erosive gastritis etc. Occult blood loss – haematemesis Salicylate -induced gastric bleeding is painless and may lead to an iron deficiency anemia

28. PHARMACOLOGICAL ACTIONS CV S: Therapeutic doses have no significant cardiovascular effect High doses- increased BP - increased CO2 and peripheral vasodilation by exerting a direct effect on smooth muscle Toxic doses - depress circulation directly and by central vasomotor paralysis CHF – low cardiac reserve patients

29. PHARMACOLOGICAL ACTIONS Hematologic effects: It inhibits the platelet aggregation by decreasing the production of TXA2 – lasts for a week In doses greater than 6 gm/day, aspirin may reduce plasma prothrombin levels Prolonged use – decrease in synthesis of clotting factors Urate Excretion: Dose less than 2 gm/day – urate retention 2-5 gm/day – variable effects More than 5 gm/day – increased urate excretion

30. Aspirin Pharmacokinetics Absorbed from stomach and SI Poorly water soluble – limitation Solubility can be increased by alkalizations Converted to salicylic acid in gut, liver and plasma 80-85% bound to plasma protein - can cross placenta and CSF Metabolized in liver by conjugation with glycine – salicyluric acid Excreted as glomerular filtration and tubular secretion T1/2 life is 15-20 minutes 8 – 12 Hrs due to metabolic process saturation High doses have long t1/2

31. Aspirin - ADRs Gastrointestinal disturbances Nausea, vomiting, epigastric distress and gastric mucosal damage Hypersensitivity and Idiosyncrasy: Fixed Drug Eruption ( FDE), rash, urticaria , asthma ( bronchospasm – aspirin sensitive asthmatics) Salicylism : on repeated administration (3-5 gm/day) headache, mental confusion, lassitude, and drowsiness tinnitus and difficulty in hearing hyperthermia, sweating, thirst, hyperventilation, vomiting, and diarrhea Hepatotoxicity Rise in serum transaminases – hepatotoxic Reye`s Syndrome – rare disease of hepatic encephalopathy when given in viral conditions of influenza and varicella Nephrotoxicity : Na+ and water retention, ch . Renal failure Prolongation of bleed time or reduce prothrombin level Respiratory: Asthma, rhinitis

32. Treatment of acute Poisoning - Aspirin Fatal dose: 15 – 30 gm Low in case of children Features: Vomiting, dehydration, acidosis, petechial haemorrhage , hyperglycaemia , hyperpyrexia, confusion and coma etc. Management : Inducing emesis or administering gastric lavage Appropriate infusion measures to correct abnormal electrolyte balance and dehydration – Na+, K+, HCO3 etc. as per need Alkalinization of the urine Dialysis as required Vit.K injection

33. Aspirin – Therapeutic uses Analgesic: Headache, migraine, backache, tothache , dysmenorrhea etc (300 to 600 mg 8 Hrly ) Rheumatoid arthritis: (3-5 gm/day) Used to be standard first line of drug Poorly tolerated – newer NSAIDS Acute Rheumatic Fever: (4-5 gm/day) Osteoarthritis Antipyrretic

34. Aspirin – Contraindications Sensitive Persons Children with viral diseases Peptic ulcer disease and bleeding disorders Chronic liver diseases Diabetes, CHF and juvenile Rh . Arthritis G-6-PD deficient persons Stop prior to surgery, near term pregnancy, breast feeding mothers etc

35. Aspirin – Drug Interactions Aspirin and Probenecid : Antagonize Uricosuric action of probenecid Probenecid become in effective in Gout Aspirin and oral anticoagulants ( warfarin and sulfonylureas ) Toxicity (increased tendency of bleeding) Aspirin and anti-hypertensive: NSAIDs cause fluid retention and oedema – antihypertensive effects are decreased Aspirin and Diuretics: ( furosemide and thiazides ) Blunting of Furosemide effects

36. Aspirin - Uses Analgesic : Backache, myalgia , toothache, joint pain, pulled muscle and dysmenorrhoea Antipyretic : Fever of any origin – Paracetamol safer Acute Rheumatic fever: 75 – 100 mg/kg/day (or, 4 – 5 gm/day) – marked symptomatic relief – all cases – dose reduced after 4 - 7 days and maintained for 2 - 3 weeks till s/s stops - withdrawal should be gradual Rheumatoid Arthritis: Reduction in pain, swelling and stiffness – large dose Osteoarthritis: As and when needed – Paracetamol is the choice Post-myocardial infarction and post stroke: Routinely used – inhibits platelet aggregation (TXA2) at low dose (60 – 100mg/day) – but, high dose can reverse (PGI2 inhibition) – New onset or sudden onset angina (risk of infarction) - 75 to 150 mg/day for 12 weeks …. Also in TIA Other uses:  pregnancy-induced hypertension (PIH), PDA, Familial colonic polyposis and Prevention of colonic cancer

37. Propionic acid derivatives Ibuprofen, Naproxen, Ketoprofen , Flurbiprofen Analgesic, antipyretic and anti-inflammatory efficacy is lower than aspirin ( low potency ) – all inhibits PG synthesis (Naproxen – most potent) – Antiplatelet activity – short with Ibuprofen but longer with naproxen Adverse Effects: Better tolerated than aspirin and Indomethacin – milder – gastric discomfort, nausea, vomiting, gastric erosion rarely CNS effects - headache, dizziness, blurring of vision, tinnitus and depression Rash, itching and hypersensitivity are less Precipitates aspirin induced asthma

38. Propionic acid derivatives – contd. Pharmacokinetics: All are well absorbed orally – 90-99% plasma protein bound But lesser displacement of other drugs Inhibits platelet function – use with anticoagulants are avoided Decreases antihypertensive and diuretic actions of furosemide , thiazides and beta-blockers Uses: Not given in pregnancy and Peptic ulcer patient Ibuprofen: Simple analgesic and antipyretic – like low dose aspirin – dysmenorrhoea Also in Rh . Arthritis, OA and musculoskeletal disorders – pain prominent conditions Also in STI, fractures, vasectomy, tooth extraction, postpartum and post operative pain Naproxen – preferred in acute gout – stronger anti-inflammatory and inhibition of leucocyte migration – longer half-life (12-16 hours)

39. Fenamates - Mephenamic acid Analgesic, antipyretic and weak anti-inflammatory – inhibition of certain PG synthesis – peripheral + central analgesic ADRs: Diarrhoea , epigastric distress, skin rash, dizziness and other CNS ADRs Kinetics: Slow oral absorption, but complete, bound to plasma protein – displacement reactions Uses: as analgesic in muscle, joint and soft tissue pain ---- Dysmenorrhoea

40. Enolic acid derivatives - Piroxicam Multiple action NSAID, Long acting, good anti-inflammatory, good analgesic-antipyretic action Reversible, non-selective COX inhibition lowers PG synthesis and inhibits platelet aggregation Decreases IgM rheumatoid factor and leucocyte chemotaxis ADRs: Contrast COX-1 blocking action - More GI effects than Ibuprofen - but less than Indomethacin , lesser ulcerogenic – lesser occult blood than aspirin - also rash, pruritus and serious skin reactions Kinetics: Rapid complete absorption, 99% plasma bound, t 1/2 – 2 days ( ss – 1 week); excreted in bile and urine – EH circulation Uses: Long term anti-inflammatory – rheumatoid arthritis, osteo -arthritis, ankylosing spondylosis , acute gout etc. – Not first choice for any conditions … Relative higher toxicity than Others

41. Acetic acid - Indomethacin Indole acetic acid derivative - Potent anti-inflammatory and prompt antipyretic Relieves only inflammatory and injury related pain Highly potent inhibitor of PG and neutrophil motility Use: Reserve drug - ankylosing spondylitis , destructive arthropathies , psoriatic arthritis, postoperative pain, malignancy associated fever, medical closure of PDA Kinetics: well absorbed orally, 90% PP bound and t 1/2 2 – 5 Hours ADRs: High incidence of gastric and CNS side effects ( COX-1 related ) – gastric, irritation, nausea, anorexia, bleeding and diarrhoea CNS: Frontal headache, dizziness, ataxia, mental confusion, hallucination, depression and psychosis Leucopenia, hypersensitivity, rash etc. Increased risk of bleeding – low platelet aggregation Contraindications: machinery operators, drivers, psychiatric & epileptic patients kidney disease, pregnancy & children

42. Acetic acid derivatives - Ketorolac Potent analgesic – but modest anti-inflammatory – post operative pain – equal efficacy with Morphine (but no receptor interaction) Inhibits PG synthesis – inhibits pain peripherally Uses: Given IM and orally - Post-operative, dental, musculo -skeletal pain also in renal colic, migraine – short term management of moderate pain rated superior to aspirin and paracetamol and equivalent to ibuprofen – Concurrent use with morphine (reduce dose) – but not used with anticoagulant – not to be used for more than 5 days Kinetics: Well absorbed orally and IM – highly plasma protein bound; t 1/2 5 7 Hrs – 60% excretes unchanged in urine ADRs: Nausea, abdominal pain, dyspepsia, ulceration, dizziness, nervousness, pain in injection site, rise in serum transaminase , fluid retention etc.

43. Pyrazolones Metamizole ( Analgin ) is a derivative of Amidopyrine . It is a potent and promptly acting analgesic, antipyretic, and spasmolytic - but poor antiinflammatory and not uricosuric activity – Analgin can be given orally, i.m . as well as i.v . (very slowly) ADRs: Agranulocytosis

44. Preferential COX-2 inhibitors - Nimesulide Weak PG synthesis inhibitor, moderate COX-2 selective Other Mechanisms: reduced superoxide generation by neutrophils , inhibition of PAF, TNF α release & free radical scavenging Completely absorbed and 99% plasma protein bound Half life – 4-5 hours and excreted in urine Uses: sports injuries, sinusitis, dental surgeries, renal colic, arthritis, postoperative inflammatory condition, fever, low back pain, ENT disorders– no cross reaction of aspirin and other NSAIDS related bronchospasm – specific usefulness ADRs: epigastric pain, nausea, loose motion, heart burn, rash, pruritus , somnolence and dizziness – GIT tolerant but Ulceration - Fulminant hepatic failure

45. Preferential COX-2 inhibitors – Diclofenac Analgesic- antipyrretic and antiinflammatory – efficacy similar to naproxen Inhibits PG synthesis – somewhat COX-2 selective Reduced Neutrophil chemotaxis and reduced superoxide generation No antiplatelet action (COX-1 sparing) 99% plasma protein bound – 2 hours half-life Good tissue and synovial fluid penetration Uses: Most widely used drug – RA, OA, Bursitis, ankylosin spondylitis , bursitis, toothache, dysmenorrhoea , renal colic, post trauma and post inflammatory conditions ADRs: Mild epigastric pain, nausea, headache, dizziness and rashes – less gastric ulceration and bleeding - Risk of heart attack and stroke

46. Selective COX-2 inhibitors - Celecoxib , Etoricoxib and Parecoxib Inhibit COX-2 without inhibiting COX-1 - benefits Less peptic ulcer occurrence, less ulcer bleeds Do not depress TXA2 production (COX-1) of platelets Do not inhibit platelet aggregation , & do not prolong bleeding time – But reduce PGI2 production Disadvantage: Reduce PGI2 production by vascular endothelium leading to increase prothrombotic effect & enhance cardiovascular risks Uses : Patients with high risks of PU, perforation at lowest dose and shortest period Contraindications: History of IHD, hypertension, CHF and CVA

47. Coxibs – contd. Other concerns of selective COX-2 inhibition: Efficacy: COX-1 generated PGs may play role in inflammation – broad range action (??) Gostroprotectivity disturbed: Injury and H. pylori induce COX-2 – gatsroprotective PG synthesis locally …. Delay in ulcer healing Concern over COX-2 Physiological Role: Constitutive in JG renal cells – Na+ and water retention, oedema , precipitation of CHF and rise in BP

48. Para-amino phenol derivatives - Paracetamol (acetaminophen) Phenacetin 1887 – banned now (Nephropathy) Its deethylated active metabolite of Phenacetin Analgesic – Like aspirin - Antipyretic , raises pain threshold but no PG inhibition except COX inhibition in brain – no peripheral anti-inflammatory action Good promptly acting antipyretic Additive analgesic action with Aspirin (central + peripheral) Negligible antiinflammatory action Poor inhibition of PG in peripheral tissues – but high in CNS !! Explanation: Inflammatory area – peroxide generation – cannot inhibit COX in its presence at periphery – centrally its lacking – also COX-3 (??) No stimulation of respiration or affect acid base balance (unlike aspirin) …no increase in cellular metabolism No Gastric erosion or platelet function alteration

49. Paracetamol – contd. Kinetics: orally absorbed, 1/4 th PP bound, t1/2: 3 – 5 hours; Metabolism by conjugation with glucoronic acid and sulfate ADRs: Safe and well tolerated – analgesic nephropathy (after years) ACUTE PARACETAMOL POISONING Commonly occur in Children – low hepatic glucoronidation conjugation capacity – also in adults Large dose - >150 mg/kg or >10 gm in adults Manifestations: Nausea, vomiting, abdominal pain and liver tenderness After 12 – 18 hours – centrilobular hepatic necrosis, renal tubular necrosis and hypoglycaemia … and coma Jaundice after 2 days High dose poisoning – fulminating hepatic failure and DEATH

50. Paracetamol toxicity N-acetyl-p- benzoquinoneimine (NAQBI) – highly reactive arylating minor metabolite – normally detoxified by conjugation with glutathione Large dose of Paracetamol – glucoronidation capacity gets saturated – more NAQBI formed Hepatic glutathione depleted – metabolites bind covalently to proteins in liver and renal tubular cells – necrosis 5-6 gm in alcoholics (CYP2E1) - dangerous Treatment: Early cases - Induction of vomiting (activated charcoal) and other supportive measures N- acetylcysteine – 150 mg/kg IV for 15 min – followed by same dose for 20 hours … replenishes glutathione store and prevents further binding with cellular contents

51. Paracetamol Uses Most commonly used – over the counter drug Headache, mild migraine, musculoskeletal pain dysmenorrhoea etc. 1 st choice in osteoarthritis , not effective in Rheumatoid arthritis Safest Antipyretic in children – no Reye`s syndrome Advantages – 1) lesser gastric irritation, ulceration and bleeding (can be given in ulceration) 2) does not prolong bleeding time 3) Hypersensitivity rarely 4) no metabolic disturbances 5) can be given in all age group – pregnancy- lactation 6) No significant drug interactions

52. Topical NSAIDS NSAIDS are also effective topically – gel/spray etc. Advantages: Attains higher conc. Locally in muscles and joints – low blood levels GI and other systemic ADRs are minimized First pass metabolism avoided Kinetics: slow absorption – 10 times longer time to attain peak plasma conc. to oral dosing Highest blood level – 15% of the same oral dose, Local conc. Upto 4 - 6mm high (dermis); 25 mm in muscles (low) Overall efficacy depends on site Uses: Osteoarthritis, sprains, sports injuries, spondylitis and soft tissue rheumatism etc. – safety no issue but efficacy (!) local application, massaging – counter irritant - menthol and methyl salicylate More efficacious in short lasting musculo -skeletal pain

53. Choices of NSAIDS ??? H/o asthma Selective COX-2 inhibitors Hypertension or risk of heart attack COX-2 inhibitors Paediatrics Paracetamol , elderly – low dose of NSAIDS Pregnancy Paracetamol

54. Choices of NSAIDS Mild to moderate pain – Paracetamol or low dose Ibuprofen Post operative acute short lasting pain – Ketorolac , Propionic acid derivatives, diclofenac or nimesulide Acute musculo -skeletal, osteoarthritic or injury pain – Paracetamol or propionic acid Exacerbation of Rh . Arthritis, acute gout, ankylosing spondylosis – naproxen, piroxicam , indomethacin Gastric intolarance to NSAIDS - Selective COX-2 inhibitors H/o asthma – nimesulide or selective COX-2 inhibitors Hypertension or risk of heart attack – COX-2 inhibitors and PA derivatives Paediatric – paracetamol , elderly – low dose of NSAIDS Pregnancy – Paracetamol Fast acting ones – fever, headache and other short lasting pain SR preparations for chronic long lasting pain IHD, hypertension, DM – consider drug interactions

55. Combinations Aspirin + Paracetamol – Supra-additive Also Paracetamol + Ibuprofen and Diclofenac + Paracetamol

56. Thank you