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  1. Nonsteroidal antiinflammatory drugs and antipyretic-analgesics Dr. D. K. Brahma Associate Professor Department of Pharmacology NEIGRIHMS, Shillong
  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 peripheral 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 Traditional – Nonselective COX inhibitors Group Drugs Salicylic acids Aspirin Propionic acids Propionic acids Naproxen, Ibuprofen, Ketoprofen, Oxaprozin and Flurbiprofen Anthranilic acid Anthranilic acid Mefenamic acid Aryl-acetic acid derivative Aryl-acetic acid derivative Diclofenac and Aceclofenac Oxicam derivatives Oxicam derivatives Piroxicam and Tenoxicam Pyrrolo-pyrrole derivative Pyrrolo-pyrrole derivative Ketorolac, Indomethacin, Nabumetone Indole derivatives Indole derivatives Sulindac and Indomethacin Pyrazolone derivative Pyrazolone derivative Phenylbutazone, Oxyphenbutazone
  5. Classification – contd. Preferential COX-2 inhibitors Nimesulide, Diclofenac, Aceclofenac, Meloxicam and Nabumetone Selective COX-2 inhibitors Celecoxib, Etoricoxib and Parecoxib Analgesic-antipyretic with poor antiinflammatory action: Paraaminophenol derivative Pyrazolone derivative Benzoxazocine derivative Paracetamol (acetaminophen) Metamizole and Propiphenazone Nefopam
  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. Proposed Mechanism: COX-1, COX-2, & COX-3 Arachidonic acid COX-2 (inducible) Body homeostasis • Stomach • Intestine • Kidney • Platelet Inflammatory Site • Macrophages • Synoviocytes • Endothelial cells X X Selective COX-2 inhibitor COX-1 (normal constituent) X Normal Constituent • CNS • Kidney • Female U/G tract Glucocorticoids (block mRNA expression) X X Acetaminophen COX-3 (normal constituent) Pain Fever ?HTN ?GI • CNS, Heart, Aorta Nonselective NSAID
  8. NSAIDs and Prostaglandin Mediate Mediate inflammation, inflammation, pain, and fever pain, and fever Mediate Mediate inflammation, inflammation, pain, and fever pain, and fever COX-2– COX-2– specific inhibitors specific inhibitors COX-2– COX-2– specific inhibitors specific inhibitors Protect Protect gastroduodenal gastroduodenal mucosa mucosa Protect Protect gastroduodenal gastroduodenal mucosa mucosa Supports platelet Supports platelet function function Supports platelet Supports platelet function function COX-1 COX-1 COX-1 COX-1 COX-2 COX-2 COX-2 COX-2 Nonspecific Nonspecific NSAIDs NSAIDs Nonspecific Nonspecific NSAIDs NSAIDs Prostaglandins Thromboxane Prostaglandins Arachidonic Acid Membrane Phospholipid Phospholipase A
  9. Major effects of PG synthesis inhibition 1. Analgesia: Prevention of pain nerve ending sensitization 2. Antipyresis: Reduction of Body temperature in hyperthermia 3. Anti-inflammatory action: reduction in signs of inflammation (pain, tenderness, swelling and vasodilatation) 4. Antithrombotic action: Inhibition of platelet aggregation 5. Closure of Ductus arteriosus in Newborn
  10. 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.
  11. Classification of Pain Acute Chronic vs Duration Nociceptive Neuropathic vs Pathophysiology
  12. 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 healing1  Ceases to serve a protective function2  Degrades health and functional capability2  Depressed mood3 vs. 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.
  13. 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 vs
  14. • Transduction • Transmission • Modulation • Perception • Interpretation • Pain Behavior Peripheral Peripheral Nerve Nerve Ascending Ascending Pathways Pathways Injury Injury Descending Descending Pathway Pathway Dorsal Dorsal Root Root Ganglion Ganglion C-Fiber C-Fiber A-beta Fiber A-beta Fiber A-delta Fiber A-delta Fiber Dorsal Dorsal Horn Horn Brain Brain Spinal Cord Spinal Cord NSAIDs and Analgesia
  15. NSAIDs induced Analgesia • Peripheral component: – PGs (especially E2 and I2) sensitize afferent nerve endings to pain – induces chemical and mechanical stimuli – Induce hyperalgesia – by affecting transducing property of free nerve endings – normal stimuli may become painful – NSAIDs do not block direct PG application related pain and tenderness – But, block the pain sensitizing mechanism induced by – Bradykinin, TNF and Interleukins (IL) and others – by inhibiting COX-2 – More effective against pain due to inflammation • Central Component: Antihyperalgesic (analgesic) effects through inhibition of PGs release in spinal dorsal horn and CNS
  16. Peripheral & Central Sensitization Peripherally & Centrally Induced COX-2 Trauma/inflammation Release of arachidonic acid COX-2 COX-2  Prostaglandins E2 Pain sensitization COX-2 COX-2  Prostaglandins sensitization Pain IL-1ß IL-6?
  17. 2. Antipyresis • Against Pyrexia (Fever) • Reduction in body temperature in case of hyperthermia - not in normothermic individuals • MOA: During infection and tissue injury  Fever – by generation of Pyrogens - Interleukins, TNF-alpha and Interferones – induce production of PGE2 in Hypothalamus – raise its temperature set point  COX-2 and COX-3 (?) isoforms • NSAIDs block the action of PG production in hypothalumus and reduce temperature
  18. 3. 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.
  19. 4. Antiplatelet aggregator • TXA2 is pro-aggregator (COX-1) • PGI2 is anti-aggregator • Most NSAIDs - effects on TXA2 predominates and inhibits aggregation – prolonged bleeding time • Aspirin is highly active and acetylates COX in circulation – before hepatic 1st pass metabolism • Even small dose Antithrombotic effect – Myocardial Infarction and other cardiac conditions
  20. 5. Ductus arteriosus • It is a shunt connecting the pulmonary artery to the aortic arch • Maintained by local PGE2 and PGI2 • Closes at birth • Failure to close – small doses of NSAIDs (aspirin or indomethacin) – closes (No NSAIDs in late pregnancy – premature closure)
  21. Dysmenorrhoea • Severe pain during menstruation – may precede menstruation or during menstruation • Caused by increased release of PGs (PGF2α) due to increased destruction of endometrial cells and release of their contents • Intermittent ischaemia of myometrium – cramps • NSAIDs - decrease PG release
  22. Gastric Mucosa • All NSAIDs produce gastric mucosal damage, ulceration and blood loss – varying extent • Due to inhibition of COX-1 mediated synthesis of gastro protective PG (PGE2 and PGI2) – Also back diffusion of H+ in gastric mucosa • Deficiency of PGs reduces mucus and HCO3 secretion – promote mucosal ischaemia • Enhance aggressive factors over defensive factors - Ulcerogeic Paracetamol – free of gastric toxicities Selective COX-2 inhibitors Misoprostol
  23. 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 •
  24. From Last Class
  25. Salicylates •ASPIRIN is acetylsalicylic acid, the Prototype - converted in the Body to Salicylic acid – Oldest analgesic •Other important salicylates – Sulfasalazine, Diflunisal •Natural Sources - fruits, vegetables, herbs, spices, nuts, and tea
  26. Pharmacological – analgesic, antipyretic and antiinflammatory • 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
  27. Pharmacological actions – contd. • 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
  28. 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
  29. Aspirin – contd. • GIT: – 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 • CVS: – Therapeutic doses have no significant cardiovascular effect – High doses- increased BP - increased CO and peripheral vasodilation by exerting a direct effect on smooth muscle – Toxic doses - depress circulation directly and by central vasomotor paralysis – CCF – low cardiac reserve patients
  30. Aspirin – contd. • 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
  31. Aspirin Pharmacokinetics • Absorbed from stomach and SI • Poorly water soluble – limitation – Solubility can be increased by alkalizations – but ??? • 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
  32. Aspirin - ADRs • Gastrointestinal disturbances – Nausea, vomiting, epigastric distress and gastric mucosal damage • Hypersensitivity and Idiosyncrasy: 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
  33. 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
  34. Aspirin – Therapeutic uses 1. Analgesic: Headache, migraine, backache, tothache, dysmenorrhea etc (300 to 600 mg 8 Hrly) 2. Rheumatoid arthritis: (3-5 gm/day)  Used to be standard first line of drug  Poorly tolerated – newer NSAIDS 1. Acute Rheumatic Fever: (4-5 gm/day)  First drug of choice – other drugs are added when it fails  Dose is reduced after 1 week therapy  Continued for 3-4 weeks  gradual withdrawal for over 2 weeks 1. Osteoarthritis 2. Antipyrretic
  35. Aspirin and Myocardial infarction • Routinely prescribed for post myocardial infarction patients – prophylaxis purpose to prevent re-infarction • MOA - TXA2 (pro-aggregator) inhibition • Dose is very low (60 – 100 mg/day) • High doses inhibit PGI2 (anti-aggregator) • Primary prophylaxis (100 to 150 mg – more useful) • Reduces TIA and lowers incidence of stroke Aspirin preparations: Tablets of various strength – 75 mg, 100 mg, 325 mg, 650 mg etc. Aspirin, Disprin, Loprin, Ecospirin etc.
  36. Aspirin – Contraindications 1. Sensitive Persons 2. Children with viral diseases 3. Peptic ulcer disease and bleeding disorders 4. Chronic liver diseases 5. Diabetes, CHF and juvenile Rh. Arthritis 6. G-6-PD deficient persons 7. Stop prior to surgery, near term pregnancy, breast feeding mothers etc
  37. Aspirin – Drug Interactions • Aspirin and Probenecid: – Antagonize Uricosuric action of probenecid – Probenecid become ineffective 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
  38. 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: PIH, PDA, Familial colonic polyposis and Prevention of colonic cancer
  39. 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
  40. 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)
  41. 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
  42. Enolic acid derivatives - Piroxicam • Multiple action NSAID, Long acting, good anti-inflammatory, good analgesic-antipyretic action – Reversible, non-selective COX inhibition – Synovial fluid – 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, t1/2 – 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
  43. 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 t1/2 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
  44. 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; t1/2 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.
  45. 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 • Analgin, Novalgin, Baralgan, Ultragin etc
  46. Preferential COX-2 inhibitors - Nimesulide • Weak PG synthesis inhibitor, moderate COX-2 selective – Other Mechanisms: reduced superoxide generation by neutrophils, inhibition of PAF, TNFα 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
  47. 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 boung – 2 hours half-life • Good tissue and synovial fluid penetration • Uses: Most widely used drug – RA, OA, Bursitis, ankylosin spondi;it is, 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
  48. 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
  49. 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
  50. 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
  51. Paracetamol – contd. • Kinetics: orally absorbed, 1/4th 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
  52. 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
  53. Paracetamol poisoning - Mechanism N- acetylparabenzoquinoneimine Acetaminophen glutathione conjugate Acetaminophen glucuronide Urine Acetaminophen Acetaminophen sulfate Phenosulfotransferase UDP- glucuronosyl- transferase 50% 40% <5% 5-15% CytoP450 Glutathione (GSH) Binds covalently with liver cells and renal tubules
  54. Paracetamol Uses • Most commonly used – over the counter drug • Headache, mild migraine, musculoskeletal pain dysmenorrhoea etc. • 1st 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
  55. Topical NSAIDS • NSAIDS are also effective topically – gel/spray etc. • Advantages: 1. Attains higher conc. Locally in muscles and joints – low blood levels 2. GI and other systemic ADRs are minimized 3. 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
  56. 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
  57. Choices of NSAIDS 1. Mild to moderate pain – Paracetamol or low dose Ibuprofen 2. Post operative acute short lasting pain – Ketorolac, Propionic acid derivatives, diclofenac or nimesulide 3. Acute musculo-skeletal, osteoarthritic or injury pain – Paracetamol or propionic acid 4. Exacerbation of Rh. Arthritis, acute gout, ankylosing spondylosis – naproxen, piroxicam, indomethacin 5. Gastric intolarance to NSAIDS - Selective COX-2 inhibitors 6. H/o asthma – nimesulide or selective COX-2 inhibitors 7. Hypertension or risk of heart attack – COX-2 inhibitors and PA derivatives 8. Paediatric – paracetamol, elderly – low dose of NSAIDS 9. Pregnancy – Paracetamol 10. Fast acting ones – fever, headache and other short lasting pain SR preparations for chronic long lasting pain 11. IHD, hypertension, DM – consider drug interactions
  58. Combinations • Aspirin + Paracetamol – Supra-additive • Also Paracetamol + Ibuprofen and • Diclofenac + Paracetamol
  59. Summary • Everything about aspirin • Individual drugs – Mephenemic acid, Ketorolac, Indomethacin and Diclofenac • Selective COX-2 inhibitors • Everything about Paracetamol including poisoning
  60. Thank you