Aspirin
Aspirin and other nonsteroidal anti-inflammatory drugs are weak organic acids. They all inhibit
prostaglandin biosynthesis. They decrease the production of free radicals and of superoxide
and may interact with adenylyl cyclase to alter the cellular concentration of cAMP. Aspirin is the
drug of choice for treating the majority of articular and musculoskeletal disorders. It is also the
standard against which all anti-inflammatory agents are compared.
Pharmacokinetics: The salicylates are rapidly absorbed from the stomach and upper small
intestine. The acid medium in the stomach keeps a large fraction of the salicylate in the
nonionized form, promoting absorption. However, the drug may damage the mucosal barrier.
Aspirin is absorbed as such and is rapidly hydrolyzed to acetic acid and salicylate by esterases
in tissue and blood. Salicylate is bound to albumin. Ingested salicylate and that generated by
the hydrolysis of aspirin may be excreted unchanged, but most is converted to water-soluble
conjugates that are rapidly cleared by the kidney. Alkalinization of the urine increases the rate of
excretion of free salicylate.
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Pharmacodynamics
Mechanism of Action: Aspirin irreversibly blocks the enzyme cyclooxygenase; the drug
decreases the formation of both the prostaglandins and thromboxane A2 but not the
leukotrienes.
Anti-inflammatory Effects: In addition to reducing the synthesis of eicosanoid mediators, aspirin
also interferes with the chemical mediators of the kallikrein system. Thus, aspirin inhibits
granulocyte adherence to damaged vasculature, stabilizes lysosomes, and inhibits the migration
of polymorphonuclear leukocytes and macrophages into the site of inflammation.
Analgesic Effects: Aspirin is most effective in reducing pain of mild to moderate intensity.
Muscular, vascular, and dental origin, postpartum states, arthritis, and bursitis are alleviated by
aspirin. Aspirin acts peripherally through its effects on inflammation but probably also inhibits
pain stimuli at a subcortical site.
Antipyretic Effects: Aspirin reduces elevated temperature. The fall in temperature is related to
increased dissipation of heat caused by vasodilation of superficial blood vessels. The
antipyresis may be accompanied by profuse sweating. Aspirin blocks the pyrogen-induced
production of prostaglandins and the central nervous system response to interleukin-1.
Platelet Effects: Aspirin inhibits platelet aggregation by inhibition of thromboxane synthesis.
Because its action is irreversible, aspirin inhibits platelet aggregation for up to 8 days (until new
platelets are formed).
Clinical Uses
Analgesic, antipyretics, and anti-inflammatory effects: Aspirin is one of the most frequently
employed drugs for relieving mild to moderate pain of varied origin. Aspirin is not effective in the
treatment of severe visceral pain (acute abdomen, renal colic, pericarditis, or myocardial
infarction). It and other NSAIDs have been combined with opioid analgesics for treatment of
cancer pain. Used in the treatment of rheumatoid arthritis, rheumatic fever, and other
inflammatory joint conditions.
Inhibition of platelet aggregation: Aspirin has been shown to decrease the incidence of transient
ischemic attacks and unstable angina in men. It reduces the incidence of thrombosis in coronary
artery bypass grafts. It may also reduce the incidence of myocardial infarction.
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Adverse Effects
Gastrointestinal Effects: the main adverse effect is gastric upset (intolerance). The gastritis that
occurs with aspirin may be due to irritation of the gastric mucosa by the undissolved tablet, to
absorption in the stomach of nonionized salicylate, or to inhibition of protective prostaglandins.
Central Nervous System Effects: With higher doses, patients may experience “salicylism”
tinnitus, decreased hearing, and vertigo reversible by reducing the dosage. Still larger doses of
salicylates cause hyperpnea through a direct effect on the medulla. At toxic levels, respiratory
alkalosis may occur as a result of the increased ventilation. Later, acidosis supervenes from
accumulation of salicylic acid derivatives and depression of the respiratory center.
Other Adverse Effects: Aspirin in a low daily dose usually increases serum uric acid levels,
whereas doses exceeding 4 g daily decrease urate levels below 2.5 mg/dL. Salicylates may
cause reversible decrease of glomerular filtration rate in patients with underlying renal disease.
Asprin is contraindicated in children with viral upper respiratory tract infections, because it may
precipitate Raye syndrome.
Newer Nonsteroidal Anti-Inflammatory Drugs
The newer NSAIDs inhibit of biosynthesis of prostaglandins. In addition they inhibit chemotaxis,
down-regulate interleukin-1 production, and interfere with calcium-mediated intracellular events.
These drugs are reversible inhibitors of cyclooxygenase.
Most of these drugs are well absorbed. Most of the NSAIDs are highly metabolized, some by
phase I and phase II mechanisms and others by direct glucuronidation (phase II) alone. While
renal excretion is the most important route, all undergo varying degrees of biliary excretion and
reabsorption (enterohepatic circulation). All of the NSAIDs are highly protein-bound, usually to
albumin.
Ibuprofen
Ibuprofen is extensively metabolized in the liver, and little is excreted unchanged.
Gastrointestinal irritation and bleeding occur, though less frequently than with aspirin. In addition
to the gastrointestinal symptoms, rash, pruritus, tinnitus, dizziness, headache, and fluid
retention have been reported. Rare hematologic effects include agranulocytosis and aplastic
anemia. Effects on the kidney include acute renal failure, interstitial nephritis, and nephrotic
syndrome, occurring very rarely.
Diclofenac
Diclofenac is a potent cyclooxygenase inhibitor with antiinflammatory, analgesic, and antipyretic
properties. The drug is rapidly absorbed following oral administration and has a half-life of 1-2
hours. It accumulates in the synovial fluid. The potency of diclofenac as a cyclooxygenase
inhibitor is greater than that of naproxen. The drug is recommended for chronic inflammatory
conditions such as rheumatoid arthritis and osteoarthritis and for the treatment of acute
musculoskeletal pain. Adverse effects include gastrointestinal distress, occult gastrointestinal
bleeding, and gastric ulceration.
Sulindac
Sulindac is a prodrug. Its active metabolite is, like diclofenac, an acetic acid derivative. The drug
is effective only after it is converted by liver enzymes to a sulfide, which is excreted in bile and
then reabsorbed from the intestine. The enterohepatic cycling prolongs the duration of action to
12-16 hours. The indications and adverse reactions are similar to those of other NSAIDs.
Among the more severe reactions, Stevens-Johnson epidermal necrolysis syndrome,
thrombocytopenia, agranulocytosis, and nephrotic syndrome have all been observed. Like
diclofenac, sulindac may have some propensity to cause elevation of serum aminotransferase; it
is also sometimes associated with cholestatic liver damage.
Mefenamic Acid
Mefenamic acid, another fenamate, possesses analgesic properties but is probably less
effective than aspirin as an anti-inflammatory agent and is clearly more toxic.
Piroxicam
It is rapidly absorbed in the stomach and upper small intestine and reaches 80% of its peak
plasma concentration in 1 hour. Gastrointestinal symptoms are encountered in 20% of patients.
Other adverse reactions include dizziness, tinnitus, headache, and rash.
Nimesulide: It is a new NSAID and after oral administration it is rapidly and almost completely
absorbed. Highly bound to plasma proteins. It is a weak inhibitor of prostaglandin synthesis.The
advantage of nimesulide over other NSAIDs is that it causes minimal gastric irritation.
Rofecoxib: Rofecoxib is a highly selective and specific COX-2 inhibitor. It inhibits prostaglandin
synthesis via inhibiting cyclooxygenase- 2. It is about 90% bound to plasma proteins. The main
adverse effects are nausea, dyspepsia, epigastric discomfort, heart burn, diarrhea, fluid
retention etc. It is mainly useful in osteoarthritis, acute pain like dental pain & primary
dysmenorrhoea.
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