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Non Steroidal Anti Inflammatory Drugs

This document provides an overview of nonsteroidal anti-inflammatory drugs (NSAIDs). It discusses their classification, mechanism of action involving inhibition of prostaglandin synthesis, beneficial effects, toxicities, and individual drug profiles. NSAIDs are a chemically diverse class of drugs that reduce pain, fever, and inflammation by blocking cyclooxygenase (COX) enzymes and subsequent prostaglandin production. While effective analgesics, NSAIDs can cause adverse effects like gastric irritation, bleeding risks, and interference with other drugs due to competition for protein binding sites.

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NONSTEROIDAL ANTI INFLAMMATORY DRUGS MODERATOR: Dr. M E Sham PRESENTED BY: Dr. Rayan
CONTENTS:  Introduction  Classification  NSAIDs and Prostaglandins  Mechanism of action  Beneficial actions due to PG synthesis inhibition  Shared toxicities due to PG synthesis inhibition  Individual drugs  References
INTRODUCTION
Antiinflammatory drugs  Steroid- Glucocorticoids  Nonsteroidal-Aspirin like
All drugs grouped in this class have three main actions in different measures:  ANALGESIC  ANTIINFLAMMATORY  ANTIPYRETIC They are also called “Nonnarcotic ,Nonopioid ,or Aspirin like analgesics” Definition: NSAIDs are chemically diverse class of drugs(>70 NSAIDs in use) that have antiinflammatory , analgesic, and antipyretic properties.
CLASSIFICATION A) Nonselective Cox inhibitors 1.Salicylates- Aspirin 2.Pyrazolone derivatives- Phenylbutazone, oxyphenbutazone 3.Indole derivatives- Indomethacin, Sulindac,Ketorolac 4.Propionic acid derivatives- Ibuprofen, Naproxen, Ketoprofen 5.Anthranilic acid derivatives- Mephenaimic acid 6.Aryl-acetic acid derivatives- Diclofenac, Aceclofenac 7.Oxicam derivatives- Piroxicam, Tenoxicam 8.Pyrrole derivatives- Ketorolac
B) Preferential cox-2 inhibitor Nimesulide, Meloxicam, Diclofenac C) selective cox- 2 inhibitors- Celecoxib, Etoricoxib, Parecoxib D) Analgesics- Antipyretics with poor anti-inflammatory 1.Paraaminophenol derivative: Paracetamol 2.Pyrazolone derivatives: Metamizol 3.Benzoxazocine derivative: Nefopam
NSAIDs and Prostaglandins  Prostaglandins, Prostacyclins,Thromboxane A2 are produced from arachidonic acid by the enzyme cyclooxygenase  Cyclooxygenase exists in two forms. They are: 1.Cox-1-Constitutive (House keeper) Mucus secretion, Haemostasis, renal functions 2. Cox-2 Inducible- Inflammatory response Sites-brain, JG cells (constitutive)
Normal Tissue Inflammation Site Physiolgical Prostaglandin Production Pathological Prostaglandin Production COX-1 Constitutive COX-2 Inducible Arachidonic Acid Normal Functions Inflammation, pain, fever NSAIDs COX-2 Inhibitors Cytokines Growth factors ILs,TNF +
Biosynthesis of prostaglandins
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
 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 they do by inhibiting cyclo –oxygenase (COX) enzyme in the pathway for PGs synthesis
Beneficial actions due to PG synthesis inhibition  Analgesia  Antipyresis  Antiinflammatory  Antithrombotic  Closure of ductus arteriosus  Dysmenorrohea
Analgesia  PGs---induce hyperalgesia by increasing sensitivity of afferent nerve endings to chemical and mechanical stimuli and thus amplify action of other algesics-bradykinins, histamine, TNF-alpha, ILs.  NSAIDS block this pain sensitizing mechanism induced by these algesics, therefore effective against inflammation associated pain.
Antipyresis  Fever in infection is produced by pyrogens, TNF, ILs, interferon- induce production of PGs in hypothalamus-raise its temprature set point.  NASIDs block the action of pyrogens(cox-2).
Anti-inflammatory  Inhibition of PG synthesis at the site of injury.  Anti-inflammatory action of each drug corresponds with their potency to inhibit COX.
Antiplatelet  Inhibit synthesis of TXA2 by acetylating platelet COX irreversibly.  By inhibiting platelet aggregation lowers the incidence of reinfarction.
Ductus arteriosus closure  PGE2, responsible for maintaining patency in foetal circulation.  At birth ductus closes
Dysmenorrhea Involvement of PG’s in dysmenorrhea is demonstrated by  Increase levels of PGs in menstrual blood flow  Endometrial biopsies  PGF2 metabolite in circulation are raised in dysmenorrhoeic women Myometrial ischemia –menstrual cramps.  NSAIDs-lowers uterine PGs--relief
Renal effects  Conditions like hypovolaemia, decrease renal perfusion, and Na+ loss- induce renal PG synthesis –leading to vasodilatation, inhibition of cl, Na, water reabsorption and opposing Antidiuretic action.  NSAIDs produce renal effects by- 1. Cox-1 dependent impairment of renal blood flow and reduction in gfr- can worsen renal insufficiency. 2. JG Cox 2 dependent Na and water retention. 3. Rare ability to cause papillary necrosis on habitual intake. Renal effects more marked in patients of CHF, hypovolemia, hepatic cirrhosis, renal disease and patients on diuretics and antihypertensives----edema can occur
Parturition  Sudden increase in PG synthesis by uterus triggers labour and facilitate progression.  NSAIDs –delay and retard labour
Shared toxicities due to 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
Gastric mucosal damage  Inhibition of synthesis of gastro protective PGS (E2,I2)- decrease in mucus,HCO3,increases acid secretion, may promote mucosal ischemia.
Bleeding  Inhibition of platelet function  Bleeding time is prolonged  Risk of surgical bleeding is increased
Anaphylactoid reaction  Aspirin precipitates bronchial asthma, angioneurotic swellings, urticaria, rhinitis  By inhibiting COX
Salicylates-Aspirin  Aspirin is acetyl salicylic acid converted in body to salicylic acid.  Mechanism of action - aspirin inhibits COX irreversibly by acetylating one of its serine residue.
Pharmacological actions 1.Analgesic- Relives pain related to inflammation, tissue injury, MOA: -Obtunding peripheral receptors -Prevents PGs mediated nerve ending sensitization. -Raises threshold for pain perception in central sub cortical regions. 2.Antipyretic- Resets the hypothalamic thermostat and reduces fever by promoting heat loss.
3.Antiinflammatory- Signs of inflammation like pain, tenderness, swelling, vasodilatation and leukocyte infiltration are suppressed. 4.Metabolic effects- At anti-inflammatory doses there is: -Increased cellular metabolism -Increased heat production -decrease blood sugar level(especially in diabetics) But in toxic doses hyperglycemia is often seen.
5. Respiration: -At anti-inflammatory doses – respiration is stimulated -In salicylate poisoning- hyperventilation is prominent -Further rise in salicylate level causes respiratory depression 6. Acid – base and electrolyte balance: -Initially increased Co2 production and its washout causes respiratory alkalosis. -Later Co2 retention causes respiratory acidosis (high doses) -Followed by metabolic acidosis. -Dehydration occurs in poisoning.
7. CVS: -In therapeutic doses – no direct effect -At toxic doses –depresses vasomotor centre – BP may fall -CHF may be precipitated 8. GIT: -Causes epigastric distress, nausea and vomiting -Focal necrosis of mucosal cells and capillaries- acute ulcers, erosive gastritis, congestion and microscopic hemorrhages
9. Urate excretion: Dose related effect: < 2g/day - urate retention and antagonism of all other uricosuric drugs. 2-5g/day – often no change >5g/day – increased urate excretion 10.Blood: -TXA2 synthesis inhibition -Interferes with platelet aggregation -Bleeding time is prolonged
Pharmacokinetics  Absorbed from stomach and small intestine  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  Volume of distribution=0.17L/kg  Slowly enters the brain but freely crosses placenta
 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  Taken together with that of 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
Adverse effects a) Gastrointestinal:  Most common  Epigastric distress, Nausea, Vomiting  Increased occult blood loss in stools  Gastric mucosal damage and peptic ulcer b) 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
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
e) Acute salicylate poisoning:  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
Treatment:  Symptomatic and supportive  Gastric lavage  i.v. infusion of Na+, K+, HCO3 and glucose(dextrose-5%)  Vitamin K 10mg i.v.  Haemodialysis
Interactions  Aspirin displaces warfarin, naproxen, phenytoin from its binding sites- toxicity of these agents.  Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to interact with the oral anticoagulant warfarin and can cause a serious bleeding complication. NSAIDs can affect the pharmacologic action of warfarin through their direct interaction. High protein binding and the cytochrome P450 (CYP)-dependent clearance mechanisms of NSAIDs can affect the serum levels of warfarin Choi KH et al. Risk Factors of Drug Interaction between Warfarin and Nonsteroidal Anti-Inflammatory Drugs in Practical Setting. Journal of Korean Medical Science. 2010;25(3):337-341
 Sequential administration of naproxen and low-dose aspirin interferes with the irreversible inhibition of platelet cyclooxygenase 1 afforded by aspirin.  Salicylates displace phenytoin from plasma binding sites, thus raising its level in plasma and producing anticonvulsant effect Anzellotti P et al, Low-dose naproxen interferes with the antiplatelet effects of aspirin in healthy subjects: recommendations to minimize the functional consequences;Arthritis Rheum. 2011 Mar;63(3):850-9
Precautions and contraindications  Peptic ulcer  Sensitive patients  Children suffering from influenza, chickenpox  Chronic liver diseases  Diabetics  CHF, lower cardiac reserve  Pregnancy Delayed or prolonged labor, more postpartum blood loss, premature closure of ductus arteriosus  G6PD deficiency  Before elective surgery  Breastfeeding mothers
Interactions  Aspirin displaces warfarin, naproxen, sulfonylureas, phenytoin from its plasma proteins binding sites-toxicity of these agents.  Inhibits tubular secretion of uric acid and antagonizes action of uricosuric agents.  Blunts action of diuretics
Uses: 1. As analgesic- Aspirin 300mg-600mg 6-8.hlly 2. As antipyretic 3. Acute rheumatic fever 4-5 g/day 4. Rheumatoid arthritis 3-5 g/day 5. Osteoarthitiis 6. Post myocardial infraction & post stroke patients Aspirin 60-100mg/day 7. Other- pregnancy induced hypertension preeclampsia to delay labour to close patent ductus arteriosus
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 Trade name: ECOSPRIN(75,150,325 mg tab), DISPRIN(350mg tab) LOPRIN(75,162.5mgtab)
Propionic acid Derivatives These are: Ibuprofen, naproxen, flurbiprofen and ketoprofen  Analgesic, antipyretic and anti-inflammatory efficacy is lower than high dose of aspirin.  All inhibit PG synthesis
Adverse effects Better tolerated than aspirin  Gastric discomfort  Gastric erosion  Nausea & vomiting  Dizziness  Blurring of vision  Tinnitus & depression  Rashes & hypersensitivity reaction
Pharmacokinetics  Well absorbed orally  Highly bound to plasma proteins  Can cross placenta  Metabolised in liver by hydroxylation  Excreted in urine as well as bile
Uses:  As simple analgesic and antipyretic  Dysmenorrhea  Rheumatoid arthritis, osteoarthritis  Soft tissue injuries  Fractures  Tooth extraction  Postpartum & postoperatively
Dosage:  Ibuprofen 400-600mg TDS  Naproxen 250mg BD…(Gout)  Ketoprofen 50-100mg BD  Flurbiprofen- ocular anti inflammatory, 1 drop 6 hourly Trade name: BRUFEN(200,400,600 mg tab) NAPROSYN(250 mg tab) KETOFEN(50,100 mg tab) ARFLUR(50,100 mg tab)
Anthranilic acid derivatives- Mephenamic acid  Analgesic, antipyretic, anti-inflammatory  Inhibits COX  Antagonizes certain actions of PGs  Exerts peripheral as well as central analgesic action  Adverse effects: diarrhea, epigastric distress, skin rashes, dizziness haemolytic anaemia
 Pharmacokinetics:  Oral absorption is slow but complete  Highly bound to plasma proteins.  Excreted in urine as well as bile.  Plasma t1/2 is 2-4 hours  Uses- analgesic, effective in dysmenorrhea  Dose- 250-500mg TDS  Trade name: MEDOL(250, 500mg cap), MEFTAL(250,500mg tab)
Aryl - acetic acid derivative- Diclofenac sodium, Aceclofenac  Analgesic, antipyretic, anti-inflammatory  Similar in efficacy to naproxen  Inhibits PG synthesis and is somewhat cox-2 selective  Anti inflammatory action- reduces neutrophil chemotaxis and superoxide production at the inflammatory site
Pharmacokinetics  Well absorbed orally  99% protein bound  Metabolised and excreted both in urine and bile  Plasma t1/2 is 2 hours  Has good tissue penetrability and concentration in synovial fluid is maintained for 3 times longer than in plasma
 Adverse effects: epigastric distress, skin rashes, dizziness, nausea, headache  Uses: Rheumatoid and osteoarthritis, ankylosing spondylitis, toothache, dysmenorrhea
 Dose: Diclofenac sodium – 50mg bd Aceclofenac - 100mg bd  Trade name: VOVERAN, DICLONAC(50mg,100mg tab) ACECLO, DOLOKIND(100mg tab)
Para-amino phenol Derivatives Paracetamol:(acetaminophen)  Deethylated active metabolite of phenacetin Mechanism of action:  Poor inhibitor of PG synthesis in peripheral tissues  More active on cox in brain  So, poor peripheral antiinflammatory component , more potent as analgesic and antipyretic
Pharmacokinetics:  Well absorbed orally  25% plasma protein bound  Metabolism occurs mainly by conjugation with glucuronic acid and sulfate  Excreted rapidly in urine  T1/2 is 2-3 hours Adverse effects:  In isolated antipyretic doses paracetamol is safe and well tolerated  Rashes and nausea occur occasionally
 Analgesic nephropathy: • Occurs after years of heavy ingestion • Papillary necrosis, tubular atrophy, renal fibrosis occurs • Urine concentrating ability is lost • Kidneys shrink  Acute paracetmol poisoning: • Occurs in small children having low hepatic glucuronide conjugating ability • If a large doses is taken (>150mg/kg or >10 gm in an adult)
Manifestations:  Nausea, vomiting, abdominal pain, liver tenderness  After 12-18 hours centrilobular hepatic necrosis  Hypoglycaemia may progress to coma Treatment:  Vomiting should be induced  Gastric lavage  Activated charcoal is given  N-acetylcysteine(MUCOMIX, ANTIFEN 2OOmg/ml inj)
Uses:  As analgesic for headache, mild migraine, musculoskeletal pain  Dysmenorrhoea  Osteoarthritis  As antipyretic Dose: 0.5-1gm TDS Trade name: CROCIN(0.5,1gm tab), CALPOL(500mg tab)
Oxicam derivatives- Piroxicam  Long acting potent NSAID with anti inflammatory potency similar to Indomethacin  Good analgesic and antipyretic action  Reversible inhibitor of cox  In addition it decreases the production of IgM rheumatoid factor and leucocyte chemotaxis
Pharmacokinetics  Rapidly and completely absorbed  99% plasma protein bound  Metabolised in liver by hydroxylation and glucuronide conjugation  Excreted in urine and bile  Plasma t1/2 is 2 days Adverse effects: • Gastrointestinal side effects are more than ibuprofen, but it is better tolerated and less ulcerogenic than indomethacin. • Less faecal blood loss than aspirin
Uses: Rheumatoid and osteoarthritis ankylosing spondylitis, toothache, dysmenorrhea acute gout Dose: 20 mg bd for two days followed by 20 mg od Trade name: DOLONEX, PIROX(10,20 mg cap)
Pyrrolo-pyrrole derivative-Ketorolac  Acetic acid derivative  Potent analgesic and modest anti inflammatory activity.  In post operative pain it has equaled efficacy of morphine but do not have morphine like side effects.  It inhibits PG synthesis
PHARMACOKINETICS:  Rapidly absorbed after oral and IM administration  Highly plasma protein bound  Excreted in urine  Plasma t1/2 is 5-7 hours Adverse effects: Nausea, abdominal pain, dyspepsia, ulceration, ulceration, loose stools drowsiness, pain at injection site
Uses: 1. Post operative pain 2. Acute musculoskeletal pain 3. Renal colic 4. Migraine 5. Pain due to metastasis 6. Dental pain Dose:  15-30mg i.m. or i.v. every 4-6 hours(max. 90mg/day)  Orally 10-20 mg 6 hourly for not more than 5 days Trade name: KETOROL, KETANOV(10mg tab)
Indole derivatives- Indomethacin • Potent anti-inflammatory with prompt antipyretic action • Inhibits PG synthesis • Suppresses the neutrophil motility PHARMACOKINETICS:  Well absorbed orally, rectal absorption is slow  Highly plasma protein bound  Metabolised in liver  Excreted in urine  Plasma t1/2 is 2-5 hours
Adverse effects: • High incidence of GIT and CNS side effects Gastric irritation, nausea, anorexia gastric bleeding, diarrhea frontal headache, dizziness mental confusion, psychosis Uses: Because of prominent adverse effects indomethacin is used as a reserve drug in conditions requiring potent anti-inflammatory action like: Ankylosing spondylitis, acute exacerbation of destructive arthropathies, psoriatic arthritis, acute gout
 Other uses: Malignancy associated fever Bartter’s syndrome For closure of patent ductus arteriosus  Dose: 25-50mg bd orally Three 12 hourly doses of 0.1-0.2 mg/kg for closure of ductus arteriosus  Trade name: INDOFLAM(25, 75 mg cap), IDICIN(25,27 mg cap)
Pyrazolone Derivatives Aminopyrine and antipyrine:  Introduced in 1884  Associated with agranulocytosis, are banned in many countries including India. Phenylbutazone and oxyphenbutazone:  Introduced in 1949  Potent anti-inflammatory drugs  Gastric toxicity is high  Edema and CNS side effects are seen  Hence now it is rarely used
Metamizol:  Derivative of amidopyrine  Potent analgesic and antipyretic  Gastric irritation and pain at injection site occurs  Few cases agranulocytosis were reported  Rarely used now a days  Dose: 0.5-1.5 gm oral/i.m./i.v  Trade name: ANALGIN, NOVALGIN(0.5 gm tab)
Preferential COX-2 inhibitors Nimesulide: Newer NSAID which is relatively weak inhibitor of PG synthesis Mechanism of action:  Preferential COX-2 inhibitor  Antiinflammatory action may be exerted by other mechanisms also such as: -Reduced generation of superoxide by neutrophils -Inhibition of TNF-alpha release
Pharmacokinetics:  Well absorbed orally  99% plasma protein bound  Excreted mainly in urine  T1/2 2-5 hours Adverse effects: Gastrointestinal- epigastralgia, heart burn, nausea, loose motions Dermatological- rash, pruritus CNS- dizziness Liver- hepatic faliure Renal- haematuria in children
Uses:  Used mainly for short-lasting painful conditions- sport injuries, sinusitis, ear nose disorders, dental surgery, bursitis, low backache, dysmenorrhoea, post operative pain, osteoarthritis Dose: 100mg bd Trade name: NIMULID, NIMEGESIC, NIMODOL(100mg tab)
Selective COX-2 Inhibitors  Selectively block COX-2 activity more than COX-1 activity This group includes: Celecoxib, Rofecoxib and Valdecoxib  Celecoxib is available in india  Rofecoxib and Valdecoxib have been withdrawn for increasing cardiovascular risk
Celecoxib:  It exerts anti-inflammatory, analgesic, antipyretic action with low ulcerogenic potential Pharmacokinetics:  Slowly absorbed, 97% plasma protein bound  Metabolised primarily by CYP2C9  T1/2 is 10 hours
Adverse effects: Abdominal pain, dyspepsia, mild diarrhoea Uses: Rheumatoid arthritis Dose: 100-200mg bd Trade name: CELACT, COLCIBRA(100, 200 mg caps.)
REFERENCES - Goodman and Gilman’s: The pharmacological basis of Therapeutics 12th edition - Essentials of medical pharmacology, KD Tripathi - Pharmacology and pharmacotherapeutics, R.S.Satoskar, S.D.Bhandarkar, 19th edition
THANK YOU

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Non Steroidal Anti Inflammatory Drugs

  • 1.
    NONSTEROIDAL ANTI INFLAMMATORY DRUGS MODERATOR:Dr. M E Sham PRESENTED BY: Dr. Rayan
  • 2.
    CONTENTS:  Introduction  Classification NSAIDs and Prostaglandins  Mechanism of action  Beneficial actions due to PG synthesis inhibition  Shared toxicities due to PG synthesis inhibition  Individual drugs  References
  • 3.
  • 4.
    Antiinflammatory drugs  Steroid-Glucocorticoids  Nonsteroidal-Aspirin like
  • 5.
    All drugs groupedin this class have three main actions in different measures:  ANALGESIC  ANTIINFLAMMATORY  ANTIPYRETIC They are also called “Nonnarcotic ,Nonopioid ,or Aspirin like analgesics” Definition: NSAIDs are chemically diverse class of drugs(>70 NSAIDs in use) that have antiinflammatory , analgesic, and antipyretic properties.
  • 6.
    CLASSIFICATION A) Nonselective Coxinhibitors 1.Salicylates- Aspirin 2.Pyrazolone derivatives- Phenylbutazone, oxyphenbutazone 3.Indole derivatives- Indomethacin, Sulindac,Ketorolac 4.Propionic acid derivatives- Ibuprofen, Naproxen, Ketoprofen 5.Anthranilic acid derivatives- Mephenaimic acid 6.Aryl-acetic acid derivatives- Diclofenac, Aceclofenac 7.Oxicam derivatives- Piroxicam, Tenoxicam 8.Pyrrole derivatives- Ketorolac
  • 7.
    B) Preferential cox-2inhibitor Nimesulide, Meloxicam, Diclofenac C) selective cox- 2 inhibitors- Celecoxib, Etoricoxib, Parecoxib D) Analgesics- Antipyretics with poor anti-inflammatory 1.Paraaminophenol derivative: Paracetamol 2.Pyrazolone derivatives: Metamizol 3.Benzoxazocine derivative: Nefopam
  • 8.
    NSAIDs and Prostaglandins Prostaglandins, Prostacyclins,Thromboxane A2 are produced from arachidonic acid by the enzyme cyclooxygenase  Cyclooxygenase exists in two forms. They are: 1.Cox-1-Constitutive (House keeper) Mucus secretion, Haemostasis, renal functions 2. Cox-2 Inducible- Inflammatory response Sites-brain, JG cells (constitutive)
  • 9.
    Normal Tissue InflammationSite Physiolgical Prostaglandin Production Pathological Prostaglandin Production COX-1 Constitutive COX-2 Inducible Arachidonic Acid Normal Functions Inflammation, pain, fever NSAIDs COX-2 Inhibitors Cytokines Growth factors ILs,TNF +
  • 10.
  • 11.
    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
  • 12.
     Naturally, adrug 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 they do by inhibiting cyclo –oxygenase (COX) enzyme in the pathway for PGs synthesis
  • 13.
    Beneficial actions dueto PG synthesis inhibition  Analgesia  Antipyresis  Antiinflammatory  Antithrombotic  Closure of ductus arteriosus  Dysmenorrohea
  • 14.
    Analgesia  PGs---induce hyperalgesiaby increasing sensitivity of afferent nerve endings to chemical and mechanical stimuli and thus amplify action of other algesics-bradykinins, histamine, TNF-alpha, ILs.  NSAIDS block this pain sensitizing mechanism induced by these algesics, therefore effective against inflammation associated pain.
  • 15.
    Antipyresis  Fever ininfection is produced by pyrogens, TNF, ILs, interferon- induce production of PGs in hypothalamus-raise its temprature set point.  NASIDs block the action of pyrogens(cox-2).
  • 16.
    Anti-inflammatory  Inhibition ofPG synthesis at the site of injury.  Anti-inflammatory action of each drug corresponds with their potency to inhibit COX.
  • 17.
    Antiplatelet  Inhibit synthesisof TXA2 by acetylating platelet COX irreversibly.  By inhibiting platelet aggregation lowers the incidence of reinfarction.
  • 18.
    Ductus arteriosus closure PGE2, responsible for maintaining patency in foetal circulation.  At birth ductus closes
  • 19.
    Dysmenorrhea Involvement of PG’sin dysmenorrhea is demonstrated by  Increase levels of PGs in menstrual blood flow  Endometrial biopsies  PGF2 metabolite in circulation are raised in dysmenorrhoeic women Myometrial ischemia –menstrual cramps.  NSAIDs-lowers uterine PGs--relief
  • 20.
    Renal effects  Conditionslike hypovolaemia, decrease renal perfusion, and Na+ loss- induce renal PG synthesis –leading to vasodilatation, inhibition of cl, Na, water reabsorption and opposing Antidiuretic action.  NSAIDs produce renal effects by- 1. Cox-1 dependent impairment of renal blood flow and reduction in gfr- can worsen renal insufficiency. 2. JG Cox 2 dependent Na and water retention. 3. Rare ability to cause papillary necrosis on habitual intake. Renal effects more marked in patients of CHF, hypovolemia, hepatic cirrhosis, renal disease and patients on diuretics and antihypertensives----edema can occur
  • 21.
    Parturition  Sudden increasein PG synthesis by uterus triggers labour and facilitate progression.  NSAIDs –delay and retard labour
  • 22.
    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
  • 23.
    Gastric mucosal damage Inhibition of synthesis of gastro protective PGS (E2,I2)- decrease in mucus,HCO3,increases acid secretion, may promote mucosal ischemia.
  • 24.
    Bleeding  Inhibition ofplatelet function  Bleeding time is prolonged  Risk of surgical bleeding is increased
  • 25.
    Anaphylactoid reaction  Aspirinprecipitates bronchial asthma, angioneurotic swellings, urticaria, rhinitis  By inhibiting COX
  • 26.
    Salicylates-Aspirin  Aspirin isacetyl salicylic acid converted in body to salicylic acid.  Mechanism of action - aspirin inhibits COX irreversibly by acetylating one of its serine residue.
  • 27.
    Pharmacological actions 1.Analgesic- Relivespain related to inflammation, tissue injury, MOA: -Obtunding peripheral receptors -Prevents PGs mediated nerve ending sensitization. -Raises threshold for pain perception in central sub cortical regions. 2.Antipyretic- Resets the hypothalamic thermostat and reduces fever by promoting heat loss.
  • 28.
    3.Antiinflammatory- Signs of inflammationlike pain, tenderness, swelling, vasodilatation and leukocyte infiltration are suppressed. 4.Metabolic effects- At anti-inflammatory doses there is: -Increased cellular metabolism -Increased heat production -decrease blood sugar level(especially in diabetics) But in toxic doses hyperglycemia is often seen.
  • 29.
    5. Respiration: -At anti-inflammatorydoses – respiration is stimulated -In salicylate poisoning- hyperventilation is prominent -Further rise in salicylate level causes respiratory depression 6. Acid – base and electrolyte balance: -Initially increased Co2 production and its washout causes respiratory alkalosis. -Later Co2 retention causes respiratory acidosis (high doses) -Followed by metabolic acidosis. -Dehydration occurs in poisoning.
  • 30.
    7. CVS: -In therapeuticdoses – no direct effect -At toxic doses –depresses vasomotor centre – BP may fall -CHF may be precipitated 8. GIT: -Causes epigastric distress, nausea and vomiting -Focal necrosis of mucosal cells and capillaries- acute ulcers, erosive gastritis, congestion and microscopic hemorrhages
  • 31.
    9. Urate excretion:Dose related effect: < 2g/day - urate retention and antagonism of all other uricosuric drugs. 2-5g/day – often no change >5g/day – increased urate excretion 10.Blood: -TXA2 synthesis inhibition -Interferes with platelet aggregation -Bleeding time is prolonged
  • 32.
    Pharmacokinetics  Absorbed fromstomach and small intestine  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  Volume of distribution=0.17L/kg  Slowly enters the brain but freely crosses placenta
  • 33.
     Conjugated inthe liver by glycine and glucuronic acid  Excreted by glomerular filtration as well as tubular secretion  t1/2 of aspirin as such is 15-20min  Taken together with that of 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
  • 34.
    Adverse effects a) Gastrointestinal: Most common  Epigastric distress, Nausea, Vomiting  Increased occult blood loss in stools  Gastric mucosal damage and peptic ulcer b) 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
  • 35.
    c) Hypersensitivity:  Thoughinfrequent, 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
  • 36.
    e) Acute salicylatepoisoning:  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
  • 37.
    Treatment:  Symptomatic andsupportive  Gastric lavage  i.v. infusion of Na+, K+, HCO3 and glucose(dextrose-5%)  Vitamin K 10mg i.v.  Haemodialysis
  • 39.
    Interactions  Aspirin displaceswarfarin, naproxen, phenytoin from its binding sites- toxicity of these agents.  Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to interact with the oral anticoagulant warfarin and can cause a serious bleeding complication. NSAIDs can affect the pharmacologic action of warfarin through their direct interaction. High protein binding and the cytochrome P450 (CYP)-dependent clearance mechanisms of NSAIDs can affect the serum levels of warfarin Choi KH et al. Risk Factors of Drug Interaction between Warfarin and Nonsteroidal Anti-Inflammatory Drugs in Practical Setting. Journal of Korean Medical Science. 2010;25(3):337-341
  • 40.
     Sequential administrationof naproxen and low-dose aspirin interferes with the irreversible inhibition of platelet cyclooxygenase 1 afforded by aspirin.  Salicylates displace phenytoin from plasma binding sites, thus raising its level in plasma and producing anticonvulsant effect Anzellotti P et al, Low-dose naproxen interferes with the antiplatelet effects of aspirin in healthy subjects: recommendations to minimize the functional consequences;Arthritis Rheum. 2011 Mar;63(3):850-9
  • 41.
    Precautions and contraindications Peptic ulcer  Sensitive patients  Children suffering from influenza, chickenpox  Chronic liver diseases  Diabetics  CHF, lower cardiac reserve  Pregnancy Delayed or prolonged labor, more postpartum blood loss, premature closure of ductus arteriosus  G6PD deficiency  Before elective surgery  Breastfeeding mothers
  • 42.
    Interactions  Aspirin displaceswarfarin, naproxen, sulfonylureas, phenytoin from its plasma proteins binding sites-toxicity of these agents.  Inhibits tubular secretion of uric acid and antagonizes action of uricosuric agents.  Blunts action of diuretics
  • 43.
    Uses: 1. As analgesic- Aspirin300mg-600mg 6-8.hlly 2. As antipyretic 3. Acute rheumatic fever 4-5 g/day 4. Rheumatoid arthritis 3-5 g/day 5. Osteoarthitiis 6. Post myocardial infraction & post stroke patients Aspirin 60-100mg/day 7. Other- pregnancy induced hypertension preeclampsia to delay labour to close patent ductus arteriosus
  • 44.
    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 Trade name: ECOSPRIN(75,150,325 mg tab), DISPRIN(350mg tab) LOPRIN(75,162.5mgtab)
  • 45.
    Propionic acid Derivatives Theseare: Ibuprofen, naproxen, flurbiprofen and ketoprofen  Analgesic, antipyretic and anti-inflammatory efficacy is lower than high dose of aspirin.  All inhibit PG synthesis
  • 46.
    Adverse effects Better toleratedthan aspirin  Gastric discomfort  Gastric erosion  Nausea & vomiting  Dizziness  Blurring of vision  Tinnitus & depression  Rashes & hypersensitivity reaction
  • 47.
    Pharmacokinetics  Well absorbedorally  Highly bound to plasma proteins  Can cross placenta  Metabolised in liver by hydroxylation  Excreted in urine as well as bile
  • 48.
    Uses:  As simpleanalgesic and antipyretic  Dysmenorrhea  Rheumatoid arthritis, osteoarthritis  Soft tissue injuries  Fractures  Tooth extraction  Postpartum & postoperatively
  • 49.
    Dosage:  Ibuprofen 400-600mgTDS  Naproxen 250mg BD…(Gout)  Ketoprofen 50-100mg BD  Flurbiprofen- ocular anti inflammatory, 1 drop 6 hourly Trade name: BRUFEN(200,400,600 mg tab) NAPROSYN(250 mg tab) KETOFEN(50,100 mg tab) ARFLUR(50,100 mg tab)
  • 50.
    Anthranilic acid derivatives- Mephenamicacid  Analgesic, antipyretic, anti-inflammatory  Inhibits COX  Antagonizes certain actions of PGs  Exerts peripheral as well as central analgesic action  Adverse effects: diarrhea, epigastric distress, skin rashes, dizziness haemolytic anaemia
  • 51.
     Pharmacokinetics:  Oralabsorption is slow but complete  Highly bound to plasma proteins.  Excreted in urine as well as bile.  Plasma t1/2 is 2-4 hours  Uses- analgesic, effective in dysmenorrhea  Dose- 250-500mg TDS  Trade name: MEDOL(250, 500mg cap), MEFTAL(250,500mg tab)
  • 52.
    Aryl - aceticacid derivative- Diclofenac sodium, Aceclofenac  Analgesic, antipyretic, anti-inflammatory  Similar in efficacy to naproxen  Inhibits PG synthesis and is somewhat cox-2 selective  Anti inflammatory action- reduces neutrophil chemotaxis and superoxide production at the inflammatory site
  • 53.
    Pharmacokinetics  Well absorbedorally  99% protein bound  Metabolised and excreted both in urine and bile  Plasma t1/2 is 2 hours  Has good tissue penetrability and concentration in synovial fluid is maintained for 3 times longer than in plasma
  • 54.
     Adverse effects: epigastricdistress, skin rashes, dizziness, nausea, headache  Uses: Rheumatoid and osteoarthritis, ankylosing spondylitis, toothache, dysmenorrhea
  • 55.
     Dose: Diclofenac sodium– 50mg bd Aceclofenac - 100mg bd  Trade name: VOVERAN, DICLONAC(50mg,100mg tab) ACECLO, DOLOKIND(100mg tab)
  • 56.
    Para-amino phenol Derivatives Paracetamol:(acetaminophen) Deethylated active metabolite of phenacetin Mechanism of action:  Poor inhibitor of PG synthesis in peripheral tissues  More active on cox in brain  So, poor peripheral antiinflammatory component , more potent as analgesic and antipyretic
  • 57.
    Pharmacokinetics:  Well absorbedorally  25% plasma protein bound  Metabolism occurs mainly by conjugation with glucuronic acid and sulfate  Excreted rapidly in urine  T1/2 is 2-3 hours Adverse effects:  In isolated antipyretic doses paracetamol is safe and well tolerated  Rashes and nausea occur occasionally
  • 58.
     Analgesic nephropathy: •Occurs after years of heavy ingestion • Papillary necrosis, tubular atrophy, renal fibrosis occurs • Urine concentrating ability is lost • Kidneys shrink  Acute paracetmol poisoning: • Occurs in small children having low hepatic glucuronide conjugating ability • If a large doses is taken (>150mg/kg or >10 gm in an adult)
  • 59.
    Manifestations:  Nausea, vomiting,abdominal pain, liver tenderness  After 12-18 hours centrilobular hepatic necrosis  Hypoglycaemia may progress to coma Treatment:  Vomiting should be induced  Gastric lavage  Activated charcoal is given  N-acetylcysteine(MUCOMIX, ANTIFEN 2OOmg/ml inj)
  • 60.
    Uses:  As analgesicfor headache, mild migraine, musculoskeletal pain  Dysmenorrhoea  Osteoarthritis  As antipyretic Dose: 0.5-1gm TDS Trade name: CROCIN(0.5,1gm tab), CALPOL(500mg tab)
  • 61.
    Oxicam derivatives- Piroxicam Long acting potent NSAID with anti inflammatory potency similar to Indomethacin  Good analgesic and antipyretic action  Reversible inhibitor of cox  In addition it decreases the production of IgM rheumatoid factor and leucocyte chemotaxis
  • 62.
    Pharmacokinetics  Rapidly andcompletely absorbed  99% plasma protein bound  Metabolised in liver by hydroxylation and glucuronide conjugation  Excreted in urine and bile  Plasma t1/2 is 2 days Adverse effects: • Gastrointestinal side effects are more than ibuprofen, but it is better tolerated and less ulcerogenic than indomethacin. • Less faecal blood loss than aspirin
  • 63.
    Uses: Rheumatoid and osteoarthritis ankylosingspondylitis, toothache, dysmenorrhea acute gout Dose: 20 mg bd for two days followed by 20 mg od Trade name: DOLONEX, PIROX(10,20 mg cap)
  • 64.
    Pyrrolo-pyrrole derivative-Ketorolac  Aceticacid derivative  Potent analgesic and modest anti inflammatory activity.  In post operative pain it has equaled efficacy of morphine but do not have morphine like side effects.  It inhibits PG synthesis
  • 65.
    PHARMACOKINETICS:  Rapidly absorbedafter oral and IM administration  Highly plasma protein bound  Excreted in urine  Plasma t1/2 is 5-7 hours Adverse effects: Nausea, abdominal pain, dyspepsia, ulceration, ulceration, loose stools drowsiness, pain at injection site
  • 66.
    Uses: 1. Post operativepain 2. Acute musculoskeletal pain 3. Renal colic 4. Migraine 5. Pain due to metastasis 6. Dental pain Dose:  15-30mg i.m. or i.v. every 4-6 hours(max. 90mg/day)  Orally 10-20 mg 6 hourly for not more than 5 days Trade name: KETOROL, KETANOV(10mg tab)
  • 67.
    Indole derivatives- Indomethacin •Potent anti-inflammatory with prompt antipyretic action • Inhibits PG synthesis • Suppresses the neutrophil motility PHARMACOKINETICS:  Well absorbed orally, rectal absorption is slow  Highly plasma protein bound  Metabolised in liver  Excreted in urine  Plasma t1/2 is 2-5 hours
  • 68.
    Adverse effects: • Highincidence of GIT and CNS side effects Gastric irritation, nausea, anorexia gastric bleeding, diarrhea frontal headache, dizziness mental confusion, psychosis Uses: Because of prominent adverse effects indomethacin is used as a reserve drug in conditions requiring potent anti-inflammatory action like: Ankylosing spondylitis, acute exacerbation of destructive arthropathies, psoriatic arthritis, acute gout
  • 69.
     Other uses: Malignancyassociated fever Bartter’s syndrome For closure of patent ductus arteriosus  Dose: 25-50mg bd orally Three 12 hourly doses of 0.1-0.2 mg/kg for closure of ductus arteriosus  Trade name: INDOFLAM(25, 75 mg cap), IDICIN(25,27 mg cap)
  • 70.
    Pyrazolone Derivatives Aminopyrine andantipyrine:  Introduced in 1884  Associated with agranulocytosis, are banned in many countries including India. Phenylbutazone and oxyphenbutazone:  Introduced in 1949  Potent anti-inflammatory drugs  Gastric toxicity is high  Edema and CNS side effects are seen  Hence now it is rarely used
  • 71.
    Metamizol:  Derivative ofamidopyrine  Potent analgesic and antipyretic  Gastric irritation and pain at injection site occurs  Few cases agranulocytosis were reported  Rarely used now a days  Dose: 0.5-1.5 gm oral/i.m./i.v  Trade name: ANALGIN, NOVALGIN(0.5 gm tab)
  • 72.
    Preferential COX-2 inhibitors Nimesulide: NewerNSAID which is relatively weak inhibitor of PG synthesis Mechanism of action:  Preferential COX-2 inhibitor  Antiinflammatory action may be exerted by other mechanisms also such as: -Reduced generation of superoxide by neutrophils -Inhibition of TNF-alpha release
  • 73.
    Pharmacokinetics:  Well absorbedorally  99% plasma protein bound  Excreted mainly in urine  T1/2 2-5 hours Adverse effects: Gastrointestinal- epigastralgia, heart burn, nausea, loose motions Dermatological- rash, pruritus CNS- dizziness Liver- hepatic faliure Renal- haematuria in children
  • 74.
    Uses:  Used mainlyfor short-lasting painful conditions- sport injuries, sinusitis, ear nose disorders, dental surgery, bursitis, low backache, dysmenorrhoea, post operative pain, osteoarthritis Dose: 100mg bd Trade name: NIMULID, NIMEGESIC, NIMODOL(100mg tab)
  • 75.
    Selective COX-2 Inhibitors Selectively block COX-2 activity more than COX-1 activity This group includes: Celecoxib, Rofecoxib and Valdecoxib  Celecoxib is available in india  Rofecoxib and Valdecoxib have been withdrawn for increasing cardiovascular risk
  • 76.
    Celecoxib:  It exertsanti-inflammatory, analgesic, antipyretic action with low ulcerogenic potential Pharmacokinetics:  Slowly absorbed, 97% plasma protein bound  Metabolised primarily by CYP2C9  T1/2 is 10 hours
  • 77.
    Adverse effects: Abdominal pain,dyspepsia, mild diarrhoea Uses: Rheumatoid arthritis Dose: 100-200mg bd Trade name: CELACT, COLCIBRA(100, 200 mg caps.)
  • 78.
    REFERENCES - Goodman andGilman’s: The pharmacological basis of Therapeutics 12th edition - Essentials of medical pharmacology, KD Tripathi - Pharmacology and pharmacotherapeutics, R.S.Satoskar, S.D.Bhandarkar, 19th edition
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