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Nsaids
NSAIDs are a class of drugs that provide analgesic, antipyretic, and anti-inflammatory effects by inhibiting the COX enzyme and subsequent prostaglandin production. Aspirin is a prototypical NSAID that is non-selective and irreversibly inhibits both COX-1 and COX-2 isoforms. It is well absorbed but has a short half-life due to rapid metabolism. While effective at reducing pain, fever and inflammation, high doses of aspirin can cause adverse effects like gastric irritation, salicylism, and Reye's syndrome in children. Overdose of aspirin leads to serious toxicity that requires supportive care and dialysis.
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Nsaids
- 1. NSAIDs Non Steroidal AntiInflammatory Drugs
- 2. INFLAMMATION • Inflammation (Latin,inflamatio, to set on fire) is the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. • It is a protective attempt by the organism to remove the injurious stimuli as well as initiate the healing process for the tissue.
- 3. CAUSES • • • • • • • • • Burns Chemical irritants Frostbite Toxins Infection bypathogens Physical injury Immune reactions due to hypersensitivity Radiation Foreign bodies
- 4. The classic signsand symptoms of acute inflammation English Redness Swelling Heat Pain Loss of function Latin Rubor* Tumor/Turgor* Calor* Dolor* Functio laesa**
- 5. Process of Inflammation •Inflammation can be classified as either acute or chronic. • The initial phase of cell injury is known as the acute phase and is mediated by several autacoids like : – – – – Histamine 5-HT Bradykinin Prostaglandins • When a tissue is injured, from any cause, prostaglandin synthesis in that tissue increases.
- 6. Synthesis of Prostaglandins Cyclo-oxygenase(COX) pathway Membrane Phospholipids Phospholipase A2 Arachidonic Acid COX Prostaglandins Thromboxanes Prostacyclin
- 7. NSAIDs • Among themost widely used all therapeutic agents world wide • They are frequently prescribed for ‘rheumatic’ musculo-skeletal complaints and are often taken without prescription for minor aches and pains • More than 50 different NSAIDs on the market and none of these is ideal in controlling or modifying the signs and symptoms of inflammation
- 8. NSAIDs • Analgesic • Antipyretic •Anti-inflammatory actions • Compared to Morphine: – – – – Weaker analgesics Do not depress CNS Do not produce physical dependence No abuse liability Cont..
- 9. NSAIDs Cont.. • They arealso called: – Non norcotic – Non opioid – Aspirin like analgesics • They act primarily on peripheral pain mechanisms but also in CNS to raise pain threshold • These drugs are chemically diverse, but most are organic acids.
- 10. Common characteristics ofall NSAIDs Cont.. • Non of these steroid • All are analgesic, antipyretic, anti-inflammatory (expect paracetamol) • Do not produce CNS, RS depression. • Dose dependent uricosuric action. • Act by inhibition of PGs except Nimesulide, Nefopam
- 11. Classification Non selective COXinhibitors: Salicylates Aspirin, Diflunisal Pyrazolone derivatives Phenylbutazone, Oxyphenbutazone Indole derivatives Indomethacin, Sulindac Propianic acid derivatives Ibuprofen, Naproxen, Ketoprofen, Flurbiprofen Anthranilic acid derivatives Mephenamic acid Aryl-acetic acid derivatives Diclofenac Pyrrolo-pyrrolo derivative ketorolac
- 12. Classification cont.. Preferential COX-2 inhibitors: Nimesulide,Meloxicam, Nabumatone Selective COX-2 inhibitors Celecoxib, Rofecoxib, Valdecoxib Analgesic –Antipyretics with poor Anti inflammatory action Para amino phenol derivatives Pyrazolone derivatives Paracetamol (Acetaminophen) Benzoxazocine derivative Nefopam Metamizol (Dypirone), Propifenazone
- 13. Non selective COXinhibitors: Salicylates Aspirin, Diflunisal Pyrazolone derivatives Phenylbutazone, Oxyphenbutazone Indole derivatives Indomethacin, Sulindac Propianic acid derivatives Ibuprofen, Naproxen, Ketoprofen, Flurbiprofen Anthranilic acid derivatives Mephenamic acid Aryl-acetic acid derivatives Dicofenac Pyrrolo-pyrrolo derivative ketorolac
- 14. Mechanism of action •When a tissue is injured, from any cause, prostaglandin synthesis in that tissue increases. • PGs have TWO major actions: • They are mediators of inflammation • They also sensitize pain receptors at the nerve endings, lowering their threshold of response to stimuli and allowing the other mediators of inflammation
- 15. Mechanism of action Cont.. •Naturally, a drug that prevents the synthesis of PGs is likely to be effective in relieving pain due to inflammation of any kind • In 1971 Vane and coworkers made the landmark observation that aspirin and some NSAIDs blocked PG generation. • This is they do by inhibiting cyclo –oxygenase (COX) enzyme in the pathway for PGs synthesis
- 16. Synthesis of Prostaglandins Cyclo-oxygenase(COX) pathway Membrane Phospholipids Phospholipase A2 Arachidonic Acid NSAIDs COX Prostaglandins Thromboxanes Prostacyclin
- 17. COX • Exists intwo isoforms: 1. COX-1 (constitutive) 2. COX-2 (inducible) – – – – Oxidative stress Injury Ischemia Neurodegenerative diseases
- 18. Beneficial actions dueto PG synthesis inhibition • • • • • Analgesia Antipyresis Antiinflammatory Antithrombotic Closure of ductus arteriosus
- 19. Shared toxicities dueto PG synthesis inhibition • Gastric mucosal damage • Bleeding • Limitation of renal blood flow/Na+ & water retention • Delay/prolongation of labour • Asthma and anaphylactoid reactions in susceptible individuals
- 20. Salicylates - Aspirin •Prototype • Acetylsalicylic acid • It was obtained from „willow bark‟ (Salicaceae) but is now synthesized • Methyl salicylate is a volatile liqiud derivate. • Irreversible inhibitor of COX • Nonselective inhibitor of COX (Counter irritant)
- 21. Aspirin – Pharmacologicalactions 1. Antiinflammatory action: Potent Exerted at high doses (3-6g/day or 100mg/kg/day) Signs of inflammation are suppressed Acts mainly by inhibiting PG synthesis
- 22. Aspirin – Pharmacologicalactions 2. Analgesic action: • • • Mild analgesic effect ≤ codeine Effective in non visceral pain Inhibition of peripheral PG synthesis
- 23. Aspirin – Pharmacologicalactions 3. Antipyretic action: • • • • Reduces body temperature in fever Resets the hypothalamic thermostat Rapidly reduces fever by heat loss But does not decrease heat production 4. Metabolic effects: • • • • These are significant at only at antiinflammatory doses ↑ Cellular metabolism increased heat production ↑ Utilization of glucose
- 24. Aspirin – Pharmacologicalactions 3. Respiration: • • • Stimulated at therapeutic doses by peripheral and central actions Hyperventilation is prominent in salicylate poisoning Further raise causes respiratory depression and death due to respiratory failure 4. Acid -base and electrolyte balance: • • Significant changes at antiinflammatory doses Hypokalemia, Respiratory alkalosis(400µg500µgstimulation of respiratory centre inc. pO2), compensated respiratory alkalosis(most pts), respiratory acidosis(higher doses500µg to 1mg medullary depress,inc.pCO2 ), uncompensated metabolic acidosis(poisoning) and dehydration(poisoning).
- 25. Aspirin – Pharmacologicalactions 5. CVS: • • • No direct effect in therapeutic doses Larger doses increase Cardiac Output (3g) Toxic doses depress VMC 6. GIT: • Acid • • • Irritate gastric mucosa and cause epigastric distress, nausea and vomiting pH 7.1 Gastric pH 1.5 Also stimulates CTZ A mucosal cell s “Ion trapping” Asp p Heart burn, dyspepsia, gers.astritis, erosion, Gastric ulcers.
- 26. Aspirin – Pharmacologicalactions 7. Effect on platelets/coagulation: • • • TXA2 enhances platelet aggregation PGI2 decreases it Low doses(80-100mg/day) An anticoagulant effect with a prolonged BT
- 27. Aspirin – Pharmacologicalactions 8. Urate excretion: • • • • • Dose related effect is seen <2gm/day- urate retention and antagonism of all other uricosuric drugs 2-5gm/day- variable effects, often no change >5gm/day- increased urate excretion Not suitable in chronic gout- high doses are not tolerated
- 28. Aspirin – Pharmacologicalactions 9. Local irritant effect: • • Cause irritating to the skin & mucosa and destroys epithelical cells Keratolytic effects 10. Endocrine effect: • • Large dose stimulate adrenal cortex by hypothalamus inc adrenocortico steroid production L.Dose dec. thyroid uptake of iron cause goitre.
- 29. Aspirin – Pharmacokinetics • • • • Wellabsorbed Poor water solubility is the limiting factor Solubility is more at higher pH Rapidly deacetylated in the gut wall, liver, plasma and other tissues to salicylic acid • 80% bound to proteins • Vd=0.17L/kg • Slowly enters the brain but freely crosses placenta
- 30. Aspirin – Pharmacokinetics •Conjugated in the liver by glycine and glucuronic acid • Excreted by glomerular filtration as well as tubular secretion • t1/2 of aspirin as such is 15-20min • Together that released salicylic acid is 3-5hrs • Metabolic processes get saturated over therapeutic range • t1/2 of antiinflammatory doses may be 8-12hrs • While that during poisoning may be upto 30hrs • Thus elimination is dose dependant
- 31. Aspirin – Adverseeffects a) Gastrointestinal: • • • • b) • • • • Most common Epigastric distress, Nausea, Vomiting Increased occult blood loss in stools Gastric mucosal damage and peptic ulcer Rey‟s syndrome Occurs in infants and children Occurs when aspirin given during viral infections Characterized by liver damage and encephalopathy Replaced by acetaminophen in such condition to reduce fever
- 32. Aspirin – Adverseeffects c) Hypersensitivity: • • Though infrequent, these can be serious Reactions include; rashes, urticaria, angioedema, rhinorrhoea, asthma and anaphylactoid shock d) Salicylism • • High doses(at antiinflammatory doses) or chronic use of aspirin may induce a syndrome characterised by tinnitus, hearing defects, blurring of vision, dizziness, headache and mental confusion Effects are reversible
- 33. Aspirin – Adverseeffects
- 34. Aspirin – Adverseeffects e) Acute salicylate poisonig: • • More common in children Fatal dose in adults estimated to be 15-30gm, but considerably low in children • Serious toxicities seen at serum levels >50mg/dl Manifestations are: vomiting, dehydration, electrolyte imbalance, acidotic breathing, hyper/hypoglycemia, petecheal hemorrhages, restlessness, delirium, hallucinations, hyperpyrexia, convulsions, coma and death due to respiratory and cardiovascular failure
- 35. Aspirin – Adverseeffects Treatment: • • • • • Symptomatic and supportive Gastric lavage i.v. infusion of Na+, K+, HCO3 and glucose(dextrose-5%) Vitamin K 10mg i.v. Peritoneal dialysis or hemodialysis
- 36. contraindications Aspirin – Contraindications •Peptic ulcer • Ulcerative colitis • Gout • Renal failure • Patients hypersensitive to salicylates • Hemophilias
- 37.
- 38. Uses Aspirin – Uses 1.As analgesic 2. As antipyretic 3. Antiinflammatory i. Acute rheumatic fever ii. Rheumatoid arthritis iii. Osteoarthritis 4. Cardio protective
- 39. Aspirin – Doses(oral) •As analgesic and antipyretic: 0.3-0.6gm, 6-8 hourly • Acute rheumatic fever: 75-100mg/kg/day in divided doses/4-6 days 50mg/kg/day/2-3wks- maintenance dose • Rheumatoid arthritis: 3-5gm/day • Cardio protective: 80-100mg/day
- 40. Other clinically usedSalicylates a) • • b) • Sodium salicylate: Aspirin alternative in rheumatic fever But now is obsolete Methylsalicylate (Topical): Used topically as a counterirritant in muscle and joint pain, in the form of liniments and ointments • Systemic absorption can lead to toxicity c) Salicylic acid (Topical): • Used as keratolytic and corn remover • Combined with benzoic acid (Whitefield ointment) for local use in epidermophytosis
- 41. Pyrazolone Derivatives These are: •Aminopyrine and antipyrine • Phenylbutazone and oxyphenbutazone • Analgin (dipyrone) Phenylbutazone: • Potent antiinflammatory drug • Poorly tolerated by many patients • Causes GI, hepatic, renal and fatal hematologic, agranulocytosis toxic effects • Gives rise to various drug interactions • Hence now it is rarely used
- 42. Pyrazolone Derivatives Cont… Oxyphenbutazone: • Metabolicdegradation product of phenylbutazone • Less gastric irritation than phenylbutazone • It shares all toxic effects of phenylbutazone Analgin (Dipyrone, Novalgin): • Has potent analgesic antipyretic but no antiinflammatory actions • Has no advantage over aspirin • Toxic effects are similar to phenylbutazone
- 43. Indole Derivatives Indomethacin: • Potentantiinflammatory agent • Has antipyretic, analgesic and anti-inflammatory actions • Effective in gout, rheumatoid arthritis, ankylosing spondylitis and osteoarthritis. • Given orally, absorbed well • Mainly metabolized by liver and excreted by kidneys • Its action is more prolonged than its t1/2 • Headache is the most common adverse effect, followed by giddiness, mental confusion, blurring of vision, depression and psychotic disturbances. • Total daily dose is 50-150mg in divided doses (Indomethacin 25mg cap) after food.
- 44. Indole Derivatives Cont.. Tocolytic agent:As effective as MgSo4 It dec. preterm birth significantly by arresting premature uterine contractions Dose; 25mg 2-3 times a day. Sulindac: • Fluorinated derivative of indomethacin • It is a prodrug and has a longer duration of action • Given orally in the dose of 100-200mg twice a day
- 45. Propionic acid Derivatives Theseare: Ibuprofen, naproxen, flurbiprofen and ketoprofen • Analgesic, antipyretic and anti-inflammatory properties similar to Aspirin • Better tolerated orally • Adverse effects are lower than aspirin and indomethacin • Highly bound to plasma proteins (92-99%) • ADR: cause GI disturbances such as epigastric pain, nausea, sensation of fullness in the stomach and heartburn • Less frequently they may cause CNS symptoms
- 46. Anthranilic acid Derivatives(Fenamates) Mefenamic acid: • • • • Useful in chronic and dull aching pains No advantages over other NSAIDs Weaker analgesic than aspirin Adverse reactions include gastric upset, diarrhoea, dizziness, headache, skin rashes, hemolytic anemia • Dose is 500mg 2-3 times a day • Used in Dysmenorrhoea
- 47. Arylacetic acid Derivatives Diclofenac: •Probably has greater activity than other NSAIDs • Extensively bound to plasma proteins, t1/2 is 1-2hrs • Accumulates in the synovial fluid- probably responsible for its longer duration of action than its t1/2 • Incidence of adverse reactions is 20% • Adverse effects similar to propionic acid derivatives+elevation of liver enzymes
- 48. Oxicam Derivatives Piroxicam: • Structurallydifferent from other NSAIDs • Given orally, well absorbed, has long t1/2 (38-45hrs) – administered OD • Commonly causes GI and CNS disturbances • Has been used to treat rheumatoid arthritis, ankylosing spondylitis, osteoarthritis and acute gout • Has no advantages except a longer duration of action
- 49. Pyrollo pyrollo Derivatives Ketorolac: •Has less antiinflammatory activity • IM. 20-30mg (single dose) is a moderately effective analgesic in patients with moderate to severe postoperative pain • IV ketorolac has been as effective as, and have fewer side effects than morphine in surgical and chronic cancer pain • Has longer duration of action (t1/2 5hrs) • Metabolised in liver and excreted by kidneys
- 50. Para aminophenol Derivatives •The commonly used drug is Paracetamol (Acetaminophen) • Potent antipyretic and equianalgesic with aspirin in therapeutic doses but devoid of significant antiinflammatory effect • Does not produce gastric irritation, acid –base imbalance, electrolyte disturbances nor does it affect blood clotting • Hence is preferred to aspirin as an analgesic antipyretic • Absorption, fate and excretion: • Rapidly absorbed on oral administration • Peak plasma levels are reached within ½ an hour to 1hour
- 51. Para aminophenol Derivatives Cont.. •Metabolised in the liver and excreted in urine as conjugation products of glucuronic and sulfuric acids • Poor metabolism in infants- enhanced toxicity Adverse effects: • At recommended therapeutic doses (500-1000mg) in healthy subjects is well tolerated Hepatic and renal toxicity: • Larger doses (7-10gm) produce extensive hepatocellular damage and renal tubular necrosis, and may cause death
- 52. Para aminophenol Derivatives Cont.. •This is a major problem in paracetamol poisoning • Liver toxicity is due to N-acetyl-P- benzoquinone imine which normally turns harmless by conjugation with glutathione • Early manifestations are just nausea, vomiting, abdominal pain and live tenderness with no impairment of consciousness • After 12-18hrs centrilobular hepatic necrosis occurs which may be accompanied by renal tubular necrosis and hypoglycemia that may progress to coma
- 53. Para aminophenol Derivatives Cont.. paracetamol Glutathione N-acetylbenzoquinone imine For normal therapeutic doses In toxic doses Treatment Oxidation of SH group Of hepatic and renal Cell proteins Glutathione Glutathione conjugate of toxic metabolite (non toxic, excreted) Methionine or N-acetylcysteine Conjugates of toxic metabolite Cell proteins get covalently Bound to toxic metabolite →cell death
- 54. Para aminophenol Derivatives Cont.. Treatment: •Patient is brought early (within 16hrs of ingestion) • Vomiting should be induced or gastric lavage done • Activated charcoal is given orally or through tube to prevent further absorption • Other supportive measures, as needed, should be taken Specific: • N- acetylcysteine 150mg/kg should be infused i.v. over 15min, followed by the same dose i.v. over next 20hrs
- 55. Benzoxazocine Derivatives Nefopam: • Differentfrom other NSAIDs since it has atropin like actions • Effective in traumatic and post operative pain, and in musculoskeletal pain not responding to other NSAIDs • Atropine like adverse effects • Contraindicated in epilepsy
- 56. Pref COX-2 inhibitors Theseare: Nimesulide, Meloxicam, Nabumatone Nimesulide: • Relative weak PGs inhibitor with COX-2 selective action • Other mechanisms implicated are reduced superoxide generation by neutrophils, inhibition of PAF synthesis and free radical scavenging action • Gastric and other adverse effects are similar to other NSAIDs Has been reported to cause nephrotoxicity and hepatotoxicity Not licensed in some developed countries And it has been withdrawn from others Use should be avoided especially in children and old persons
- 57. Selective COX-2 Inhibitors •Selectively block COX-2 activity more than COX-1 activity • Less action on stomach, blood vessels and kidneys This group includes: Celecoxib, Rofecoxib and Valdecoxib • Given orally, absorption is complete • Established analgesic- antiinflammatory NSAIDs • They have to be shown effective in treatment of osteoarthritis and rheumatoid arthritis • Their major advantage is that they cause fewer gastric ulcers and do not inhibit platelet aggregation • Stomach friendly
- 58. Selective COX-2 Inhibitors Cont.. Adverseeffects: • The most common adverse effects are nausea, vomiting, dyspepsia, abdominal pain, diarrhoea and edema of the lower extremities • Share some of the renal adverse effects of non selective COX inhibitors and renal toxicity • Hence their use should be restricted to patients who do not tolerate other NSAIDs
- 59. Selective COX-2 Inhibitors Cont.. Recently, the use of rofecoxib and valdecoxib has been reported to be associated with increased incidence of MI and stroke Hence, they have been withdrawn by the original manufacturers Currently all the selective COX -2 inhibitors are under suspicion regarding their long term toxicity They have been described as drugs with “marginal efficacy, heighted risk and excessive cost compared with traditional NSAIDs”
- 60. Topical NSAIDs • • • • • • • Diclofenac 1%gel Ibuprofen 10% gel Naproxen 10% gel Ketoprofen 2.5% gel Flurbiprofen 5% gel Nimesulide 1% gel Piroxicam 0.5% gel
- 61.
Editor's Notes
- #4 Frost=Manchu
- #5 Acute; vasodilatation & increased capillary permeability, Sub acute phase: infiltration Chronic phase: tissue degeneration and fibrosis
- #44 It inhibits the motility of polymorphonuclear leukocytes and dec synthesis of mucopolysaccharides rheumatoid arthritis
- #47 It has PG receptor blocker in addition to inhibition to PG synthesis