Tiêu đề 13. NON-STEROIDAL ANTI-INFLAMMATORY DRUGS.pdf ✅

PHARMD GURU Page 1 CLASSIFICATION:  Pyrazolones: oxyphenbutazone, phenylbutazone.  Propionic acids: benoxaprofen, carprofen, fenbufen, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, naproxen, oxaprozin, pirprofen, suprofen, tiaprofenic acid.  Fenamic acids: flufenamic acid, meclofenamic acid, mefenamic acid.  Heterocyclic acetic acids: etodolac, indomethacin, ketorolac, sulindac, tolmetin, zomepirac.  Aryl acetic acids: diclofenac, alclofenac.  Oxicams: isoxicam, piroxicam, tenoxicam.  Sulfonanilide: nimesulide. MODE OF ACTION: The mode of action of all NSAIDs is similar—inhibition of synthesis of prostaglandins, prostacyclins, and thromboxane, by binding to cyclo-oxygenase. Most NSAIDs can cause nephrotoxicity on long-term administration (analgesic nephropathy). Regular monitoring of serum creatinine in patients receiving such drug therapy is advisable. PYRAZOLONES Phenylbutazone was introduced in 1949, followed soon thereafter by its metabolite oxyphenbutazone. Both are potent antiinflammatory drugs, but are associated with significant adverse effects, and hence have been withdrawn from routine use in several countries. They are still available in India. Their use should be restricted to acute gout and acute exacerbations of rheumatoid arthritis and ankylosing spondylitis. Related drugs include aminopyrine, antipyrine, amidopyrine, azapropazone, dipyrone, noramidoprine, phenazone, and sulfinpyrazone. MODE OF ACTION: Phenylbutazone interferes with prostaglandin synthesis via inhibition of the cyclo-oxygenase pathway. It is irritating to the mucosa of the gastrointestinal tract. NON-STEROIDAL ANTI-INFLAMMATORY DRUGS
PHARMD GURU Page 2 CLINICAL FEATURES: 1. Main features of overdose with phenylbutazone/oxyphenbutazone include vomiting, abdominal pain, acid-base and electrolyte disturbances, pulmonary oedema, vertigo, seizures, hypotension, coma, and respiratory and cardiac arrest. 2. Salicylate-like symptoms including stimulation of the respiratory center, respiratory alkalosis, and metabolic acidosis have been reported. 3. Other reported effects include hyperglycaemia, hypocalcaemia, cyanosis, paraesthesias, tinnitus, erythematous rash, profuse sweating, and dyspnoea. 4. Renal, hepatic, and haematological complications soon follow. Renal dysfunction is common, including proteinuria, haematuria, anuria, oliguria and in one fatal case, acute nephritis. Urine may be red due to a pyrazolone metabolite. 5. Blood dyscrasias (agranulocytosis, thrombocytopenia, aplastic anaemia) are more common with dipyrone. Methaemoglobinemia has been reported with antipyrine. Pancytopenia has been reported after overdose with phenylbutazone and oxyphenbutazone. 6. Moderate to marked hepatocellular injury has been reported with chronic ingestion (less than 6 weeks) of therapeutic doses. Gastric ulceration was reported in a few patients. 7. Fatal dose is highly variable (4 to 40 gm). 8. Phenylbutazone enhances the effects of tolbutamide and other sulphonylurea antidiabetic agents, and coumarin anticoagulants, and may enhance the effects of phenytoin and some sulfonamides. DIAGNOSIS: 1. Ferric chloride test. 2. Obtain a baseline CBC, renal and liver function tests, and urinalysis in symptomatic patients. 3. After 24 hours, a red discolouration of the urine may be seen, due to rubazonic acid, a pyrazolone metabolite.
PHARMD GURU Page 3 MODE OF ACTION: 1. Stomach wash, activated charcoal. Ipecac-induced emesis is not recommended because of the potential for CNS depression and seizures. 2. Treat convulsions in the usual manner. 3. It is postulated that the excretion of phenylbutazone, like salicylate, may be enhanced in an alkaline urine. This may be considered in very severely intoxicated patients. However, alkaline diuresis is of questionable value since pyrazoles are extensively metabolised, and only 1 to 5% of the drug is eliminated unchanged by the kidneys. 4. Haemoperfusion in life-threatening cases. Because of the low water solubility and high protein binding, haemodialysis is not likely to be effective. 5. Plasmapheresis is claimed to be beneficial in severe poisoning, and has been tried successfully in a case of phenylbutazone overdose. PROPIONIC ACIDS  The first member of this group to be introduced into pharmacotherapeutics was ibuprofen in 1969. All propionic acids inhibit PG synthesis as well as platelet aggregation (thereby increasing bleeding time). They are widely used today in the relief of musculoskeletal disorders, fractures, sprains, and dysmenorrhoea. Examples include benoxaprofen, carprofen, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, ketorolac, loxoprofen, oxaprozin, pirprofen, suprofen, and tiaprofenic acid.  Angioedema, hives, itching, rash, and swelling have been reported with therapeutic use. GI distress, nausea, and epigastric pain are the most common adverse effects with therapeutic doses; upper GI bleeding may occur after acute or chronic ingestion. Oesophageal stricture may occur with minimal liquid intake. Enteropathy may occur with chronic ingestion. Effective October 1999, the FDA requires an alcohol warning on all over-the-counter pain relievers, which includes aspirin, other salicylates, paracetamol, ibuprofen, ketoprofen, and naproxen sodium. The statement is as follows: If you drink 3 or more alcoholic drinks every day, ask your doctor whether
PHARMD GURU Page 4 you should take ibuprofen or other pain relievers/fever reducers. Ibuprofen may cause stomach bleeding.  Isolated cases of thrombocytopenia, agranulocytosis, haemolysis, lymphopenia, and pancytopenia have been reported after therapeutic use of propionic acids.  Ibuprofen overdoses have been commonly reported in the literature, while the other members of this group are less commonly mentioned. Children ingesting less than 200 mg/kg generally are asymptomatic or have mild effects. Ingestions of 400 mg/kg in children have been associated with severe toxicity. Therapeutic plasma levels should be between 20 to 30 mcg/ml.  Main symptoms include vomiting, abdominal pain, diarrhoea, seizures, apnoea, hypotension, bradycardia, metabolic acidosis, and renal and hepatic dysfunction. Lethargy, drowsiness, headache, nystagmus, diplopia, tinnitus, ataxia, apnoea (particularly in infants), adult respiratory distress syndrome, and hypothermia may develop. Miosis has been reported in acute overdose. Hypokalaemia, hypophosphataemia, hyponatraemia, and hyperkalaemia (associated with renal failure) can occur.  Overdose of ketoprofen produces only mild symptoms, based upon reports from Great Britain. Symptoms include vomiting and drowsiness; ingestion of 5 grams in an elderly male produced no symptoms.  Treatment involves gastric lavage, activated charcoal, and supportive measures. Monitor for signs and symptoms of gastrointestinal ulceration and/or haemorrhage, i.e. stool guaiac test. Antacids may be of some value in patients with GI symptoms. Patients with severe epigastric pain, dysphagia or drooling should be evaluated for possible oesophageal stricture. Management of hypotension, acidosis, and gastrointestinal bleeding may be necessary. Enhanced elimination using urine alkalinisation or haemodialysis has not been shown to be of benefit.  Possible complications of use during pregnancy include delayed labour, complications during delivery, postpartum bleeding, and respiratory depression in the newborn.