Dr. Steven I. Dworkin Drugs for the Treatment of Inflammation and Pain

Dr. Steven I. Dworkin THE SALICYLATES Despite the introduction of many new drugs, aspirin is still the most widely consumed analgesic, antipyretic, and antiinflammatory agent and is the standard for the comparison and evaluation of the others. Prodigious amounts of the drug are consumed in the United States; some estimates place the quantity as high as 10,000 to 20,000 tons annually. Aspirin is the most common household analgesic; yet, because the drug is so generally available, the possibility of misuse and serious toxicity probably is underappreciated, and it remains a cause of fatal poisoning in children.

Dr. Steven I. Dworkin

THE SALICYLATES Asprin – (acetylsalicylic acid) and related drugs –Effects Analgesics - relieve pain Antipyretic – reduce fever Anti-inflammatory Inhibits aggregation of blood platelets –Mechanism of action (not fully understood) Inhibition of prostaglandins

Dr. Steven I. Dworkin THE SALICYLATES Pharmacological Properties of Therapeutic Doses –ANALGESIA The types of pain usually relieved by salicylates are those of low intensity that arise from integumental structures rather than from viscera, especially headache, myalgia, and arthralgia. The salicylates are used more widely for pain relief than are any other classes of drugs. The salicylates alleviate pain by virtue of a peripheral action; direct effects on the CNS also may be involved. –ANTIPYRESIS Salicylates usually lower elevated body temperatures rapidly and effectively. However, moderate doses that produce this effect also increase oxygen consumption and metabolic rate. These compounds have a pyretic effect at toxic doses, and sweating exacerbates the dehydration that occurs in salicylate

Dr. Steven I. Dworkin THE SALICYLATES Pharmacological Properties of Therapeutic Doses –RESPIRATION Salicylates increase oxygen consumption and CO2 production (especially in skeletal muscle) at full therapeutic doses; these effects are a result of uncoupling oxidative phosphorylation. The increased production of CO2 stimulates respiration (mainly by an increase in depth of respiration with only a slight increase in rate). The increased alveolar ventilation balances the increased CO2 production, and thus plasma CO2 tension (PCO2) does not change or may decrease slightly.

Dr. Steven I. Dworkin CARDIOVASCULAR EFFECTS –Low doses of aspirin ( 3 g daily), as might be given for acute rheumatic fever, salt and water retention can lead to an increase (up to 20%) in circulating plasma volume and decreased hematocrit (via a dilutional effect). –There is a tendency for the peripheral vessels to dilate because of a direct effect on vascular smooth muscle. –Cardiac output and work are increased. Those with carditis or compromised cardiac function may not have sufficient cardiac reserve to meet the increased demands, and congestive cardiac failure and pulmonary edema can occur. –High doses of salicylates can produce noncardiogenic pulmonary edema, particularly in older patients who ingest salicylates regularly over a prolonged period.

Dr. Steven I. Dworkin THE SALICYLATES GASTROINTESTINAL EFFECTS –The ingestion of salicylates may result in epigastric distress, nausea, and vomiting. Salicylates also may cause gastric ulceration, exacerbation of peptic ulcer symptoms (heartburn, dyspepsia), gastrointestinal hemorrhage, and erosive gastritis. –These effects occur primarily with acetylated salicylates (i.e., aspirin). Because nonacetylated salicylates lack the ability to acetylate cyclooxygenase and thereby irreversibly inhibit its activity, they are weaker inhibitors than aspirin. –Aspirin-induced gastric bleeding sometimes is painless, and if unrecognized may lead to iron-deficiency anemia. –The daily ingestion of antiinflammatory doses of aspirin (4 or 5 g) results in an average fecal blood loss of between 3 and 8 ml per day, as compared with Approximately 0.6 ml per day in untreated subjects. –Gastroscopic examination of aspirin-treated subjects often reveals discrete ulcerative and hemorrhagic lesions of the gastric mucosa; in many cases, multiple hemorrhagic lesion with sharply demarcated areas of focal necrosis are observed. –The incidence of bleeding may be higher with salicylates that dissolve slowly and deposit as particles in the gastric mucosal folds.

Dr. Steven I. Dworkin

THE SALICYLATES Use –Relief of mild to moderate pain. –Reduction of elevated temperature. –Treatment of inflammatory conditions Arthritis Rheumatic fever –Reduction in risk of myocardial infarction (asprin). –Reduction risk of transient ischemic attacks or strokes in males.

Dr. Steven I. Dworkin THE SALICYLATES Adverse reactions –Gastric upset, heartburn, nausea, vomiting, anorexia, gastrointestinal bleeding. –Salicylate allergies Hives, rash, …. –Salicylism

Dr. Steven I. Dworkin

Nonsalicylate Analgesics PARA-AMINOPHENOL DERIVATIVES: ACETAMINOPHEN –Acetaminophen (paracetamol; N-acetyl-p-aminophenol; TYLENOL, others) is the active metabolite of phenacetin. –Acetaminophen is an effective alternative to aspirin as an analgesic- antipyretic agent; however, its antiinflammatory effects are much weaker. –While it is indicated for pain relief in patients with noninflammatory osteoarthritis, it is not a suitable substitute for aspirin or other NSAIDs in chronic inflammatory conditions such as rheumatoid arthritis. –Acetaminophen is well tolerated and has a low incidence of gastrointestinal side effects. –It is available without a prescription and is used as a common household analgesic. –Acute overdosage can cause severe hepatic damage, and the number of accidental or deliberate poisonings with acetaminophen continues to grow. –Chronic use of less than 2 g/day is not typically associated with hepatic dysfunction.

Dr. Steven I. Dworkin Nonsalicylate Analgesics HISTORY –Acetanilide is the parent member of this group of drugs. It was introduced into medicine in 1886 under the name antifebrin by Cahn and Hepp, who had discovered its antipyretic action accidentally. – However, acetanilide proved to be excessively toxic. A number of chemical derivatives were developed and tested. –One of the more satisfactory of these was phenacetin. It was introduced into therapy in 1887 and was extensively employed in analgesic mixtures until it was implicated in analgesic-abuse nephropathy and withdrawn in the 1980s. –Acetaminophen was first used in medicine by von Mering in However, it gained popularity only after 1949, when it was recognized as the major active metabolite of both acetanilide and phenacetin.

Dr. Steven I. Dworkin Acetaminophen PHARMACOLOGICAL PROPERTIES –Acetaminophen has analgesic and antipyretic effects similar to those of aspirin. –Has only weak antiinflammatory effects. –Poor ability to inhibit COX in the presence of high concentrations of peroxides, as are found at sites of inflammation. However, this aspect of its action has not been addressed rigorously. –The most commonly consumed daily dose, 1000 mg, results in roughly 50% inhibition of both COX-1 and COX-2 in whole blood assays ex vivo in healthy volunteers. –COX inhibition might be disproportionately pronounced in the brain, explaining its antipyretic efficacy. –Single or repeated therapeutic doses of acetaminophen have no effect on the cardiovascular and respiratory systems, on platelets, or on coagulation

Dr. Steven I. Dworkin Acetaminophen TOXICITY AND COMMON ADVERSE EFFECTS –Acetaminophen usually is well tolerated at recommended therapeutic doses. Rash and other allergicreactions occur occasionally. The rash usually is erythematous or urticarial, but sometimes it is more serious and may be accompanied by drug fever and mucosal lesions. Patients who show hypersensitivity reactions to the salicylates only rarely exhibit sensitivity to acetaminophen. – The use of acetaminophen has been associated anecdotally with neutropenia, thrombocytopenia, and pancytopenia. –The most serious acute adverse effect of overdosage of acetaminophen is a potentially fatal hepatic necrosis. Renal tubular necrosis and hypoglycemic coma also may occur. –In adults, hepatotoxicity may occur after ingestion of a single dose of 10 to 15 g (150 to 250 mg/kg) of acetaminophen; doses of 20 to 25 g or more are potentially fatal. –Symptoms that occur during the first 2 days of acute poisoning by acetaminophen reflect gastric distress (nausea, abdominal pain, and anorexia) and belie the potential seriousness of the intoxication. –Plasma transaminases become elevated, sometimes markedly so, beginning approximately 12 to 36 hours after ingestion.

Dr. Steven I. Dworkin