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Transcript
NSAIDs II (ASPIRIN) LEARNING OBJECTIVES By the end of the lecture students must be able to know about Aspirin regarding: • General properties. • Classification of salicylates. • Pharmacokinetics of aspirin. • Pharmacodynamics. • Aspirin toxicity. • Drug interactions. • Clinical application. • Contraindications. INTRODUCTION • Aspirin is the prototype drug of NSAIDs; hence the other NSAIDs are often referred to as aspirin-like drugs. • Its Chemical name is Acetyl Salicylic Acid. • It is the oldest NSAID. • It belongs to chemical subclass Salicylates. • Its most common clinical use is for the prevention of Ischemic Heart Disease and stroke, as antiplatelet agent. CLASSIFICATION OF SALICYLATES: • Salicylic Acid • Acetylsalicylic Acid (Aspirin) • Sodium Salicylate. PHARMACOKINETICS OF ASPIRIN ABSORPTION • Orally ingested aspirins are absorbed rapidly, partly from the stomach but mostly from the upper small intestine. • Appreciable concentrations are found in plasma in less than 30 minutes; after a single dose, a peak value is reached in about 2 hours and then gradually declines. DISTRIBUTION • After absorption, aspirin is distributed throughout most body tissues and most transcellular fluids, primarily by pHdependent passive processes. • Aspirin is actively transported by a low-capacity, saturable system out of the CSF across the choroid plexus. • The drug readily crosses the placental barrier. BIOTRANSFORMATION AND EXCRETION • The biotransformation of aspirin takes place in many tissues, but particularly in the hepatic endoplasmic reticulum and mitochondria. • The three chief metabolic products are salicyluric acid (the glycine conjugate), the ether or phenolic glucuronide, and the ester or acyl glucuronide. PHARMACODYNAMICS OF ASPIRIN MECHANISM OF ACTION • Irreversible, non-selective COX inhibitor (causes acetylation of COX). • Aspirin covalently modifies both COX-1 and COX-2, thus resulting in an irreversible inhibition of cyclooxygenase activity. • 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. ACTIONS • Platelets are especially susceptible to aspirin-mediated irreversible inactivation of cyclooxygenase because they have little or no capacity for protein biosynthesis and thus cannot regenerate the cyclooxygenase enzyme. • In practical terms, this means that a single dose of aspirin will inhibit the platelet cyclooxygenase for the life of the platelet (8 to 11 days); in human beings, a daily dose of aspirin as small as 40 mg is sufficient to produce this effect. ANALGESIA: • The types of pain usually relieved by aspirin are those of low intensity that arise from integumental structures rather than from viscera, especially headache, myalgia, and arthralgia. • Aspirins are more widely used for pain relief than are any other classes of drugs. • Long-term use does not lead to tolerance or addiction, and toxicity is lower than that of opioid analgesics. • Aspirin alleviates pain by virtue of a peripheral action; direct effects on the CNS also may be involved. ANTIPYRETIC EFFECT: • Aspirin has no effect on temperature in normal persons, but reduces the body temperature when patient is febrile. • The antipyresis is usually associated with profuse sweating, fall in body temperature is partly due to cutaneous vasodilatation. • Aspirin decreases the pyrogen induced synthesis of prostaglandins, inhibits release of IL –I from macrophages and reset the thermoregulatory center in hypothalamus. URICOSURIC EFFECT: • Uric acid filtered by glomerulus is reabsorbed by the proximal tubules and then secreted at distal tubules and is excreted in urine. • In low doses (≤ 2 grams/day) aspirin blocks the secretion of uric acid at distal tubules, this increases uric acid levels in blood. • In high doses (≥ 4 grams/day) aspirin blocks the reabsorption of uric acid by proximal tubules and increase its excretion thus produce uricosuria. NEUROLOGICAL EFFECTS: • Aspirin induces nausea and vomiting, which result from stimulation of sites that are accessible from the cerebrospinal fluid (CSF), probably in the medullary chemoreceptor trigger zone. • In high doses, aspirin has toxic effects on the CNS, consisting of stimulation (including convulsions) followed by depression. Confusion, dizziness, tinnitus, high-tone deafness, delirium, psychosis, stupor, and coma may occur. The tinnitus and hearing loss caused by aspirin poisoning are due to increased labyrinthine pressure or an effect on the hair cells of the cochlea, perhaps secondary to vasoconstriction in the auditory microvasculature. RESPIRATION: • Aspirin stimulates respiration directly and indirectly. Full therapeutic doses of aspirin increase oxygen consumption and CO2 production (especially in skeletal muscle); these effects are a result of aspirin- induced uncoupling of oxidative phosphorylation. The increased production of CO2 stimulates respiration. • Aspirin can directly stimulate the respiratory center in the medulla. This results in marked hyperventilation, characterized by an increase in depth and a pronounced increase in rate. Patients with aspirin poisoning may have prominent increases in respiratory minute volume, and respiratory alkalosis develops. • A depressant effect of aspirin on the medulla appears after high doses or after prolonged exposure. CARDIOVASCULAR EFFECTS: • Ordinary therapeutic doses of aspirins have no important direct cardiovascular actions. The peripheral vessels tend to dilate after large doses because of a direct effect on their smooth muscle. • Toxic amounts depress the circulation both directly and by central vasomotor paralysis. • Antithrombotic effect of low dose acetyl salisylic acid helps in prevention of IHD. GASTROINTESTINAL EFFECTS: • The ingestion of aspirin may result in epigastric distress, nausea, and vomiting. • Aspirin also may cause gastric ulceration; exacerbation of peptic ulcer symptoms (heartburn, dyspepsia), gastrointestinal hemorrhage, and erosive gastritis. • All have been reported in patients on high-dose therapy but also may occur even when low doses are administered. HEPATIC AND RENAL EFFECTS: • At least two forms of hepatic injury. • In one form, hepatotoxicity is dose- dependent and usually is associated with plasma concentrations that are maintained above 150 mg/ml. • Severe hepatic injury and encephalopathy observed in Reye's syndrome (Combined encephalopacy and liver disorder – 20-40% lethality). This syndrome is a rare but often fatal consequence of infection with varicella and various other viruses, especially the influenza virus. It has been proposed that aspirin and the viral illness may act to damage mitochondria. • The use of aspirins in children or adolescents with chickenpox or influenza is contraindicated. MISCELLANEOUS EFFECTS: • Salicylates decrease the ESR in rheumatic fever, they increase the adrenaline release from adrenal medulla. • In large doses they can produce hyperglycemia, and glycosuria in normal persons. ADVERSE EFFECTS • Most common side effects of salicylates are nausea & vomiting, epigastric distress, gastric ulceration, gastrointestinal hemorrhage. • Gastric irritation can be reduced by giving the drug after meals and by using enteric-coated preparation. • Prostaglandin derivative misoprostol and proton pump inhibitor omeprazole are used for prevention and treatment of aspirin induced ulcer. • Salicylates increase bleeding time, they increase the serum uric acid levels and can precipitate the attack of acute gout. They also produce fluid electrolyte and respiratory disturbances. In high doses salicylates produce hyperpyrexia. Salicylates also produce hepatitis and hypersensitivity reactions. • Prolonged administration of salicylates in the treatment of rheumatic fever/arthritis may produce a condition of mild salicylate poisoning termed as SALICYLISM. • It is characterized by headache, dizziness, tinnitus, drowsiness, mental confusion, nausea & vomiting and respiratory alkalosis. • Chronic use of salicylates also produces iron deficiency anemia due to chronic blood loss. ASPIRIN TOXICITY SIGNS AND SYMPTOMS: • Mild chronic aspirin intoxication is termed salicylism. • When fully developed, the syndrome includes headache, dizziness, ringing in the ears, difficulty in hearing, dimness of vision, mental confusion, lassitude, drowsiness, sweating, thirst, hyperventilation, nausea, vomiting, and occasionally diarrhea. • A more severe degree of aspirin intoxication is characterized by more pronounced CNS disturbances (including generalized convulsions and coma), skin eruptions, and marked alterations in acid-base balance. Fever is usually prominent • Treatment: The treatment is directed at cardiovascular and respiratory support and correction of acid-base abnormalities plus use of measures to speed excretion of aspirin. DRUG INTERACTIONS • Aspirin displaces many drugs from plasma proteins and increase the toxicity of the drugs like tolbutamide, chlorpropamide, methotrexate, phenytoin and other salicylates. • Probenecid and sulphinpyrazone decrease the urinary excretion of salicylates. • Antacids decrease the absorption of salicylates. • Salicylates potentiate the effects of anticoagulants. CONTRAINDICATIONS • Aspirin is contraindicated in patients with bleeding disorders like hemophilia, pregnancy, peptic ulcer, gout, and in infants with viral infections (as there are chances of development of Reyes syndrome that is a type of fatal encephalopathy). THERAPEUTIC USES • ANALGESIC: For relieving mild to moderate pain of varied origin. Aspirin and other NSAIDs are often combined with opioid analgesics for treatment of cancer pain. • ANTIPYRETIC: Aspirin is an effective antipyretic agent in febrile conditions. • ANTI-INFLAMMATORY: Aspirin in large doses is effective for the management of rheumatoid arthritis, rheumatic fever and other inflammatory conditions. • ANTITHROMBOTIC: Aspirin in low doses decreases the incidence of stroke, coronary artery thrombosis, unstable angina, myocardial infarction and thrombosis after coronary artery bypass grafting. • ANTIRHEUMATIC: Antirheumatic application of aspirin requires high doses. CNS effects of its high dose are possible (tinnitus, nausea, etc.) So other NSAIDs have been developed as alternative. Differences b/w Aspirin & Paracetamol ASPIRIN PARACETAMOL It has anti-inflammatory properties. It has no significant anti-inflammatory activity. Inhibits platelet aggregation. It has no effect on platelets. It interferes with uric acid excretion. No such effect. Produces gastric irritation. Does not produce gastric irritation. It is bound to plasma proteins. It is less bound to plasma proteins. Thank You