Nsa Ids

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Non-Steroidal Anti-inflammatory drugs

(Analgesic, Anti-pyretic and Anti-inflammatory drugs OR Non-narcotic analgesics or non-opioid analgesics) These are chemically diverse but most are organic acids. They are different from opioid analgesics in several respects. 1. Effective only in superficial pain of somatic origin but not of deep visceral origin. 2. Effective in pain of low to moderate intensity. 3. Cause respiratory depression only in very high doses. 4. Have no abuse liability. C L A S S I F I C AT I O N A) Analgesics and Anti-inflammatory a. Salicylates i. Aspirin ii. Salicylamide iii. Benorylate iv. Diflunisal b. Pyrazolone derivatives i. Phenylbutazone ii. Oxyphenbutazone c. Indole derivatives i. Indomethacin ii. Sulindac d. Propionic acid derivatives i. Ibuprofen ii. Ketoprofen iii. Naproxen e. Anthranilic acid derivatives i. Mefenamic acid f. Aryl-acetic acid derivatives i. Diclofenac ii. Tolmetin g. Oxicam derivatives i. Piroxicam ii. Tenoxicam iii. Meloxicam h. Pyrrolo-pyrrole derivatives i. Ketorolac i. Sulfonanilide derivatives i. Nimesulide j. Alkanones i. Nabumetone

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B) Analgesic but poor anti-inflammatory a. Para-aminophenol derivatives i. Paracetamol (acetaminophen) b. Pyrozolone derivatives i. Metimazol (Dipyrone) ii. Propiphenazone c. Benzoxazocine derivatives i. Nefopam INHIBITION OF PROSTAGLANDIN SYNTHESIS BY NSAIDs The principal therapeutic effects of NSAIDS derive from their ability to inhibit prostaglandin production. The first enzyme in the prostaglandin synthesis is prostaglandin endoperoxidase synthase, or fatty acid cyclooxygenase. Prostaglandins, Prostacyclin (PGI2) and thromboxane A2 (TXA2) are produced from arachidonic acid by the enzyme cyclo-oxygenase. There are two forms of cyclooxygenase, termed COX-1 and COX- 2. The COX- 1 is a constitutive isoform found in most normal cells and tissues. The COX-2 is induced in settings of inflammation by cytokines and inflammatory mediators. The eicosanoids produced by COX-1 participate in the physiological functions such as secretion of mucus in the gastric mucosa, hemostasis and maintenance of renal function, while those produced by COX-2 lead to inflammatory and other pathological changes. In stomach COX-1 is constitutively expressed but not COX-2. This accounts for the markedly reduced occurrence of gastric toxicity with the use of selective inhibitors of COX-2. Arachidonic acid also can be converted, via the 5-lipoxygenase pathway, to a variety of leukotrienes. Inhibition of synthesis: Synthesis of cyclo-oxygenase products can be inhibited by NSAIDs. Aspirin causes irreversible inhibition while other NSAIDs are competitive and reversible inhibitors. Most NSAIDs are non-selective and inhibit both COX-1 and COX-2 but some newer ones are relatively selective for COX-2, such as Nimesulide, Nabumetone, Meloxicam. Aspirin and NSAIDs inhibit cyclooxygenase and prostaglandin production, but do not inhibit lipoxygenase and leukotrienes formation. Glucocorticoids suppress the expression of COX-2 and thus COX-2 mediated prostaglandin production. This effect may contribute in part to the antiinflammatory actions of glucocorticoids. Aspirin covalently modifies both COX-1 and COX-2 and irreversibly inhibits cyclooxygenase. Thus duration of effects of aspirin is related to the turnover rate of cyclooxygenases. In the structure of COX-1, aspirin acetylates serine 530, preventing the binding of arachidonic acid to the active site of the enzyme and thus the ability of the enzyme to make prostaglandins. In COX-2, aspirin acetylates a homologous serine at position 516. Although aspirin also blocks COX-2, an interesting property of COX-2, not shared by COX-1, is that acetylated COX-2 now synthesizes 15 ( R )-HETE. Interestingly, this aspirin-induced product can undergo trans-cellular metabolism by the 5-lipoxygenase enzyme to yield 15epilipoxin A4, which exerts potent antiinflammatory actions and therefore may potentiate the antiinflammatory action of aspirin. Beneficial actions due to inhibition of PG synthesis. Analgesia – prevention of pain nerve ending sensitization Anti-pyresis Anti-inflammatory Anti-thrombotic Closure of ductus arteriosus

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Shared toxicities due to inhibition of PG synthesis Gastric mucosal damage Bleeding due to inhibition of platelet function Limitation of renal blood flow: Na+ and water retention Delay / prolongation of labour Asthma and anaphylactoid reaction in susceptible individuals Respiration: the effects are dose-dependant. At anti-inflammatory doses respiration is stimulated by peripheral increased CO2 production and central action causing increased sensitivity of respiratory centre to CO2. Hyperventilation is prominent in salicylate poisoning. Acid-Base and electrolyte balance: Anti-inflammatory doses produce significant changes. Initially respiratory stimulation washes out CO2 despite increased production Respiratory alkalosis, which is compensated by increased renal excretion of HCO3 (with accompanying Na+, K+, water). Most adults treated with 4-6g/day of aspirin stay in a state of compensated respiratory alkalosis, still higher doses cause respiratory depression with CO2 retention. While excess CO2 production continues Respiratory acidosis. To this is added dissociated salicylic acid as well as metabolic acids (lactic, pyruvic, acetoacetic) which are produced in excess. All these combine to cause Uncompensated Metabolic Acidosis, since plasma HCO3- is already low. Dehydration occurs in poisoning due to increased water loss in urine, increased sweating, hyperventilation. Cardiovascular system: Therapeutic doses have no effect. Larger doses increase cardiac output to meet increased peripheral O2 demand and cause direct vasodilatation. Toxic doses depress vasomotor centre. GIT: Aspirin and released salicylic acid irritate mucosa, cause epigastric distress and nausea. Aspirin remains unionized and diffusible in acid gastric juice because its pKa = 3.5. But on entering the mucosal cell (pH 7.1) it ionizes and becomes indiffusible. This ‘ion trapping’ in gastric mucosal cell enhances gastric toxicity. Further, aspirin particle coming in contact with gastric mucosa promotes local back diffusion of acid focal necrosis of mucosal cells and capillaries acute ulcers. The occult blood loss in stools is increased with any dose of aspirin. Soluble aspirin tablets containing CaCO3 + citric acid are less liable to cause gastric ulceration. Urate excretion: Dose related effect is seen --- < 2g/day – urate retention and antagonism of uricosuric drugs. 2-5g/day – often no change > 5g/day increase urate excretion. Aspirin in not suitable for use in chronic gout because high doses are required. Blood: Aspirin, even in small doses, irreversibly inhibit TXA2 synthesis by platelets. Thus it interferes with platelet aggregation and bleeding time is prolonged to nearly twice the normal value. This effect lasts for about a week (turn-over time of platelets). Analgesia: PGs (E2 and I2) sensitize afferent nerve endings to pain. They affect the transducing property of nerve endings – stimuli that normally do not elicit pain are able to do so. Thus PGs induce hyperalgesia. NSAIDs block the pain sensitizing mechanism. Antipyresis: NSAIDs reduce body temperature in fever but do not cause hypothermia in normothermic individuals. Fever, during infection is produced

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through generation of pyrogens, ILs etc. which induce production of PG in hypothalamus – raise its temperature set point. NSAIDs block the action of pyrogens. Anti-inflammatory: NSAIDs inhibit PG synthesis at the site of injury. NSAIDs inhibit COX, but inhibition of COX does not depress the production of other mediators like LTs, PAF, cytokines etc. Dysmenorrhoea: PGs are involved in dysmenorrhoea. NSAIDs lower utrine PG levels and afford relief. Ductus arteriosus closure: During feotal circulation the ductus arteriosus is kept patent by local PGE2 and PGI2. At birth the synthesis of PG is switched off and the ductus closes. If this fails to occur, small doses of aspirin or indomethacin bring about closure in majority of cases. Administration of NSAIDs in late pregnancy may promote premature closure of the ductus arteriosus. Parturition: Sudden spurt of PG synthesis by uterus triggers labour. NSAIDs may delay and retard labour. Gastric mucosal damage: NSAIDs inhibit the synthesis of gastro-protective PGs ( PGE2 and PGI2). Deficiency of PGs reduces mucus and HCO3 – secretion, tends to enhance gastric acid secretion. Thus NSAIDs are ulcerogenic. Paracetamol, a very week inhibitor of COX is free of gastric toxicity and selective COX-2 Pharmacokinetics: Aspirin is absorbed from stomach and intestine. Its poor water solubility is the limiting factor in its absorption. Microfining the drug and inclusion of an alkali (solubility is more at higher pH) enhances absorption. However, higher pH also favours ionization thus decreasing the diffusible form. Aspirin is deacetylated in liver and plasma. It is conjugated with glycine and with glucoronic acid. Adverse Effects: a) Side-effects that occur at analgesic dose (0.3-1.5g/day) are nausea, epigastric distress, increased occult blood loss in the stools, peptic ulceration. b) Hypersensitivity: Infrequent; urticaria, angioedema, anaphylactic reaction. c) Anti-inflammatory doses (3-6g/day) produce the syndrome called ‘salicylism’ – dizziness, tinnitus, vertigo, excitement, hyperventilation, electrolyte imbalance. In children having viral infections (vericella, influenza), salicylate therapy may cause ‘Reye’s syndrome’ (hepatic encephalopathy) d) Acute salicylate poisoning: It is more common in children, manifestations are : vomiting, dehydration, acidotic breathing, electrolyte imbalance, delirium, hallucinations, hyperpyrexia, convulsions, coma, death. Treatment: It is symptomatic and supportive. Most important is external cooling and I.V fluids with Na+, K+, HCO3-, and glucose. Gastric levage. Forced alkaline diuresis.

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Precautions and contraindications: 1. Contraindicated in patients who are sensitive to it and in peptic ulcer, bleeding disorders, in children suffering from chicken pox or influenza ( risk of Reye’s Syndrome) 2. Aspirin should be avoided in diabetes, CHF 3. Aspirin should be stopped one week before elective surgery 4. Given during pregnancy it may be responsible for low birth weight babies. If taken near term, aspirin may cause prolonged labour, greater blood loss (post-partum) and premature closure of ductus arteriosis. Interactions: 1. Aspirin displaces warfarin, naproxen, phenytoin, sulphonyl ureas, and methotrexate from plasma protein binding sites; toxicity of these drugs may occur. Its anti-platelet action increases the risk of bleeding in patients on oral anti-coagulants. 2. It inhibits tubular secretion of uric acid, at low doses and antagonizes uricosuric action of probenecid. 3. It decreases the diuretic action of furosemide and thiazides and blocks the action of spironolactones. Uses: 1. 2. 3. 4. 5.

As analgesic. Headache, toothache, myalgia. An antipyretic. Effective in fever of any origin. Acute rheumatic fever. Dose 4-6g/day Rheumatoid arthritis. Dose 3-5g/day Osteoarthritis 6. Post myocardial infarction and post stroke patients. Aspirin inhibits TXA 2 synthesis in platelets. 7. Pregnancy induced hypertension and pre-eclampsia – imbalance between TXA2 and PGI2. 8. Patent ductus arteriosis. Aspirin can bring about closure.

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THE SALICYLATES These comprise two classes.1: Esters of salicylic acid, obtained by substitution in carboxyl group., e.g., methyl salicylate. 2: Salicylate esters of organic acids, in which substitution is made in hydroxyl group, e.g.,aspirin, which is an ester of acetic acid. Pharmacological Properties: Analgesia: Salicylates relieve pains of low intensity that arise from integumental structures, rather than from viscera, especially headache,myalgia and arthralgia.