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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
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 (<100 mg daily) are used widely for their
cardioprotective effects. At high therapeutic doses (>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
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
Dr. Steven I. Dworkin
Dr. Steven I. Dworkin
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 analgesicantipyretic 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 1893.
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
Dr. Steven I. Dworkin