NSAIDS

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NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAID’s): 

NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAID’s) Dr Rakesh Mittal Asst Professor

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NSAID’s Non-narcotic, non- opioid , aspirin like Weaker analgesics Do not depress CNS Do not produce physical dependence No abuse liability Analgesic, antipyretic and anti-inflammatory actions

CLASSIFICATION: 

CLASSIFICATION NON-SELECTIVE COXINHIBITORS (CONVENTIONAL): Salicylates  Aspirin, Diflunisal PyrazolonePhenylbutazone , Oxyphenbutazone Indole  Indomethacin , Sulindac Proprionic acid Ibuprofen, naproxen, ketoprofen Anthranilic acid Mephenemic acid Oxicam  Piroxicam , Tenoxicam Aryl-acetic acid Diclofenac Pyrrolo - pyrrole  Ketorolac

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PREFERENTIAL COX-2 INHIBITORS Nimesulide , Meloxicam , Nabumetone SELECTIVE COX-2 INHIBITORS Celecoxib , Rofecoxib , Valdecoxib ANALGESIC-ANTIPYRETIC WITH POOR ANTI-INFLAMMATORY ACTION PARAAMINOPHENOL Paracetamol PYRAZOLONE Metamizol , Propiphenazone BENZXAZOCINE Nefopam

MECHANISM OF ACTION: 

MECHANISM OF ACTION

BENEFICIAL EFFECTS OF PROSTAGLANDIN SYNTHESIS INHIBITION: 

BENEFICIAL EFFECTS OF PROSTAGLANDIN SYNTHESIS INHIBITION ANALGESIA ANTIPYRESIS ANTI-INFLAMMATORY ANTI-TROMBOTIC CLOSURE OF DUCTUS ARTERIOSIS

SHARED TOXICITIES DUE PROSAGLANDIN SYNTHESIS INHIBITION: 

SHARED TOXICITIES DUE PROSAGLANDIN SYNTHESIS INHIBITION DAMAGE GASTRIC MUCOSAL BLEEDING (Inhibition of platelet function) LIMITATION OF RENAL BLOOD FLOW (Na & water retention) DELAY/PROLONGATION OF LABOR ASTHMA ANAPHYLACTOID REACTION

ASPIRIN- PHARMACOLOGICAL ACTIONS: 

ASPIRIN- PHARMACOLOGICAL ACTIONS 1) ANALGESIC  weaker action Dose-300-600mg, 8 th hrly Relieves inflammatory, tissue injury related, connective tissue pain etc. Ineffective in ischemic and severe visceral pain

ANTIPYRESIS : 

ANTIPYRESIS Resets hypothalamic thermostat Reduces fever by promoting heat loss ANTI-INFLAMMATORY Dose-3-6 gm/day Suppresses signs of inflammation like pain, tenderness, swelling, vasodilatation and leukocyte infiltration

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RESPIRATION Dose dependent At inflammatory doses - Resp. stimulated (↑ CO2 production & ↑ sensitivity of resp. centre to CO2) Very high - Hyperventilation in poisoning respiratory depression death URATE EXCRETION: Low dose  urate retention Moderate dose no effect High dose uricosuric

ACID-BASE AND ELECTROLYTE BALANCE: 

ACID-BASE AND ELECTROLYTE BALANCE Higher dose ( initially respiratory stimulation) washes out CO 2  resp alkalosis (headache, vertigo, tinnitus, vomiting, hyperventilation – Salicylism Compensated by increased renal excretion of HCO 3 (compensated respiratory alkalosis)

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Still higher doses (Resp. depression) CO 2 retention (Resp. acidosis) addition of metabolic acid etc Development of uncompensated metabolic acidosis. (loss of vision, hyperpyrexia, vasomotor collapse, dehydration, convulsion, coma) Dehydration (due to loss of water)

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CVS Larger dose  increase cardiac output and peripheral vasodilatation Toxic doses depression of VMC fall in BP GIT Irritates gastric mucosa epigastric distress, nausea and vomiting Ion trapping

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BLOOD At low doses – antiplatelet drug – prophylaxis of MI & stroke. Irreversible inhibition of TXA 2 synthesis by platelets and interferes with aggregation. Also inhibits PGI2 (anti- aggregatory ) TXA 2 synthesised by the platelet and are exposed to aspirin in portal circulation. Here it acetylates COX enzymes and irreversibly inhibit generation of TAX 2 Very little aspirin reaches systemic circulation to inhibit PGI 2

PHARMACOKINETICS: 

PHARMACOKINETICS Aspirin is absorbed from stomach and small intestines Limited solubility (can be increased by micro fining) Metabolized in the gut wall by Acetylation 80% PPB Alkalization of urine hastens the excretion T ½ is 15-20 min

USES: 

USES 1) AS ANALGESIC Headache, backache, myalgia , joint pain, pulled muscle, toothache, neuralgia, dysmenorrhea Dose 300-600mg 8 th hrly 2) AS ANTI-PYRETIC Paracetamol is preferred

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3) ACUTE RHEUMATIC FEVER Dose is 4-6g/day (100mg/kg/day) in divided doses Relieves symptoms in 1-3 days Dose can be reduced after 4-7 days Maintenance doses (50mg/kg/day) continued for 2-3 weeks 4) RHEMATOID ARTHRITIS 3-5gm/day Relief of pain, swelling and morning stiffness Synovial proliferation and bony erosions are delayed but not prevented

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5) OSTEOARTHRITIS Relieves symptoms SOS (As and when required basis) 6) POST MYOCARDIAL INFARCTION low doses (100-300mg/day) Reduces transient ischemic attacks Platelet lack nuclei and cannot synthesize new COX enzyme once it is inhibited whereas endothelium can regenerate COX to produce PGI..

OTHER USES……: 

OTHER USES…… Pregnancy induced hypertension, pre- eclampsia (suppresses TAX2) To delay labor Patent Ductus Arteriosis ( aspirin & indomethacin ) Familial colonic polyposis Prevention of colon cancer To prevent flushing following nicotinic acid ingestion

ADVERSE EFFECTS: 

ADVERSE EFFECTS Analgesic dose nausea, vomiting, epigastric distress, occult blood loss. Hypersensitivity and idiosyncrasy  rashes, fixed drug eruptions, urticaria , rhinorrhoea , angioedema , asthma, anaphylactoid reaction etc. At therapeutic doses – hyperuricemia (not to be used in gout pt.)

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Anti-inflammatory doses ” Salicylism ” Dizziness, vertigo, tinnitus, reversible impairment of hearing, excitement and mental confusion, electrolyte imbalance. Liver damage  increase in transaminases Reye’s Syndrome (hepatic encephalopathy) in children (<12yrs). Salt and water retention

Acute salicylate poisoning : 

Acute salicylate poisoning Fatal dose is 15-30gm; toxic levels >50mg/dl Vomiting, dehydration, electrolyte imbalance, acidotic breathing, hyper/hypo glycaemia, petechial hemorrhages, restlessness, delirium, hallucinations, hyperpyrexia, convulsions and coma, death due to respiratory failure and CVS collapse. Rx External cooling, i.v fluids with Na,K, HCO3, glucose Gastric lavage, forced alkaline diuresis/hemodialysis Blood transfusion and Vitamin K (if bleeding)

Precautions and contraindications…: 

Precautions and contraindications … Peptic ulcer Bleeding tendencies Chronic liver cases Avoided in DM, frank CCF, juvenile rheumatoid arthritis Should be stopped 1 week before elective surgery Pregnancy  LBW babies Delayed/prolonged labor, premature closure of ductus Avoid in G-PD deficiency  hemolysis

INTERACTIONS: 

INTERACTIONS It displaces warfarin, naproxen, sulfonylurea's, phenytoin, methotrexate. Inhibits tubular secretion of uric acid (low dose) while antagonizes uricosuric action of probenecid. Blunts diuretic action of furosemide and thiazides

PYRAZOLONES: 

PYRAZOLONES Phenylbutazone , oxyphenbutazone , METAMIZOL Potent anti-inflammatory but weak analgesic and anti-pyretic More toxic than aspirin Edema (Na retention)  major drawback Fatal agranulocytosis Use limited RA, AS, acute gout.

INDOLE DERIVATIVES: 

INDOLE DERIVATIVES Indomethacin inhibits PLPA 2 and apart from COX inhibit also possess immunosuppressive property Potent anti-inflammatory , Good analgesic S/E  CNS (C/I in machinery operators, drivers, psychiatric patients, epileptics), GIT, Leucopenia, rashes, hypersensitivity More GIT upset, headache ( analgesic causing pain) sedation USES: RA, AS, Malignancy associated fever, PDA

PROPRIONIC ACID: 

PROPRIONIC ACID Ibuprofen - safe Naproxen – inhibits leucocytic migration - gout Ketoprofen – lysosomal stabilising & inhibit LOX Flurbiprofen – Ocular inflammatory - topical eye drops Better tolerated USES: Simple analgesic ( dysmenorrhea ) RA, OA, Musculoskeletal disorders, Soft tissue injuries, fractures, tooth extraction,

ANTHRANILIC ACID: 

ANTHRANILIC ACID MEPHENEMIC ACID Weak antiinflammatory Possess PG receptor antagonism, PLPA 2 inhibitory activity as well as antagonize certain actions of PG’s Diarrhea is the commonest s/e Uses : Dysmenorrhoea , Muscle, joint, soft tissue pain

ARYL-ACETIC DERIVATIVE: 

ARYL-ACETIC DERIVATIVE DICLOFENAC Additional action on neutrophil chemotaxis and super oxide formation Milder git effects Used extensively for RA,OA, AS, dysmenorrhea, post-traumatic pain

OXICAMS: 

OXICAMS PIROXICAM, TENOXICAM Long acting ( enterohepatic circulation ) ↓ PG in synovial fluid Potent anti-inflammatory, ↓ IgM , rheumatoid factor Common s/e  git Uses RA, OA, AS, Acute gout, dentistry, episiotomy, dysmenorrhea .

PYRRALO-PYRROLE: 

PYRRALO-PYRROLE KETOROLAC Potent analgesic and modest anti-inflammatory (post-operative pain) Only NSAID to be used i.v. Also available as eye drops

PREFERRENTIAL COX 2 INHIBITOR: 

PREFERRENTIAL COX 2 INHIBITOR Nimesulide, Meloxican, Nabumetone (prodrugs), etodolac, diclofenac. All NSAIDs’ are acidic in nature except nabumetone Relative COX-2 selective Additional anti-inflammatory action Used for short lasting painful conditions Adverse effects: Fulminant hepatic failure (withdrawn)

The search for safer NSAIDs – the COX-2 selective NSAIDs: 

The search for safer NSAIDs – the COX-2 selective NSAIDs COX exists in two forms - constitutive COX-1 and inducible COX-2 The anti-inflammatory effects of NSAIDs are believed to be attributable to inhibition of COX-2, whereas the gastrotoxic effects have been attributed to inhibition o f COX-1 COX-2-selective NSAIDs may offer a reduced risk of gastrointestinal toxicity

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Selective COX 2 Inhibitors Renal toxicity is similar & chances of thrombosis (acute MI) are increased on prolonged use. Celecoxib, Roficoxib & valdecoxib sulfonamide derivative – rash & hypersensitivity. Etoricoxib – longest acting coxib and monitoring of hepatic function is must during use. Lumiracoxib – Newer COX2 inhibitor that has more activity in the acidic medium.

PARACETAMOL: 

PARACETAMOL Active metabolite of Phenacetin PHARMACOLOGIAL ACTIONS Analgesia (raises pain threshold) No/Weak anti-inflammatory action  ineffective in presence of peroxides generated at site of inflammation, selective COX 3 inhibitor in brain. Good anti-pyretic No effect on respiration and electrolyte and acid-base balance platelet function

PHARMACOKINETICS: 

PHARMACOKINETICS Well absorbed orally 1/3 rd is PPB Uniformly distributed in the body Conjugated with glucuronic acid Excreted rapidly in the urine Produces very little GIT toxicity

USES: 

USES Analgesic for headache, musculoskeletal pain, dysmenorrhea Osteoarthritis Fever (Can be used in pregnant and lactating mothers)

ADVERSE EFFECTS: 

ADVERSE EFFECTS Rashes, nausea, leucopenia Analgesic nephropathy  chronic use heavy dose of analgesics Papillary necrosis, tubular atrophy, renal fibrosis Loss of urine concentrating power Shrinkage of the kidney

ACUTE PARACETAMOL POISONING: 

ACUTE PARACETAMOL POISONING Occurs mainly in children and patients with low glucuronide conjugating ability. alcohol is potent enzymes inducer - ↑ NABQ level dose>10gm Early manifestations  nausea, vomiting, abdominal pain and liver tenderness with no impairment of consciousness. 12-18 hrs later centrilobular hepatic necrosis, renal tubular necrosis and hypoglycemia Jaundice in 2 days Fulminating hepatic failure and death

MECHANISM OF TOXICITY: 

MECHANISM OF TOXICITY N- acetly -p- benzoquononeimine (NABQI)  de- toxified by conjugation with glutathione saturated in poisoning metabolite binds covalently to liver proteins, enzymes and renal tubules necrosis. Rx Induce vomiting/gastric lavage , activated charcoal, supportive measures. Antidote N-acetyl cysteine ( sulfhydryl donor) 150mg/kg iv infusion over 15 mins same dose over next 20 hours

CHOICE OF NSAID’S: 

CHOICE OF NSAID’S Mild to moderate pain with little inflammation PCT or ibuprofen Acute musculoskeletal, osteoarthritis, inflammatory pain  diclofenac, ibuprofen Post-operative, short lasting pain with minimal inflammationketorolac, nefopam Gastric intolerance to conventional NSAID’s rofecoxib, celecoxib Exacerbation of RA, AS, acute gout, acute RF aspirin, indomethacin, naproxen, piroxicam Combination of 2/> NSAID’s is not superior to single agents

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