Salicylates

Chemical Properties

Aspirin is a weak organic acid and is one of the oldest known drugs for the relief of fever and pain. Aspirin remains the standard to which most NSAIDs are compared for efficacy.

Indications

The salicylates are useful in the treatment of minor musculoskeletal disorders such as bursitis, synovitis, tendinitis, myositis, and myalgia.They may also be used to relieve fever and headache. They can be used in the treatment of inflammatory disease, such as acute rheumatic fever, rheumatoid arthritis, osteoarthritis, and certain rheumatoid variants, such as ankylosing spondylitis, Reiter’s syndrome, and psoriatic arthritis. However, other NSAIDs are usually favored for the treatment of these chronic conditions because of their lower incidence of GI side effects. Aspirin is used in the treatment and prophylaxis of myocardial infarction and ischemic stroke.

Mechanism of action

Aspirin and related salicylates produce their pharmacological effects predominantly by inhibiting the synthesis of prostaglandins and to a lesser extent synthesis of the thromboxanes (implicated in platelet aggregation). The prostanoids are mediators of inflammatory responses in many cell types. Aspirin is unique among NSAIDs in that it irreversibly acetylates COX-1 and COX-2, which are required for the synthesis of prostanoids from arachidonic acid. COX-2 is induced during inflammation and is therefore considered to mediate most inflammatory responses. Aspirin acetylation of COX-1 permanently inactivates the enzyme, while acetylated COX-2 is capable of producing 15-HETE. New enzyme must be synthesized to overcome the effects of aspirin, which in the case of platelets can take as long as 11 days. The metabolite of aspirin, salicylic acid, is a reversible inhibitor of COX. Other NSAIDs have reversible effects at different sites on COX-1 and on COX-2. In addition, aspirin interferes with kinin-induced modulation of the inflammatory response.

Clinical Use

Aspirin and related salicylates are the primary treatment for mild to moderate pain, such as that associated with headache, joint and muscle pain, and dysmenorrhea. At higher doses aspirin is an effective analgesic in rheumatoid arthritis.The analgesic effects of salicylates are thought to be due to the inhibition of prostaglandin synthesis in the periphery and to a less well documented mechanism at cortical areas.
The salicylates are also potent antipyretic agents, with the exception of diflunisal, which is only weakly active. Aspirin acts at two distinct but related sites. It decreases prostaglandin-induced fever in response to pyrogens and induces a decrease in interleukin-1 modulation of the hypothalamic control of body temperature. Thus, the hypothalamic control of body temperature returns, vasodilation occurs, heat dissipates, and fever decreases. Other uses of aspirin include inhibition of platelet aggregation via inhibition of thromboxanes, which has been shown to decrease the incidence of blood clots, myocardial infarction, and transient ischemic attacks.

Side effects

The most commonly observed side effects associated with the use of salicylates relate to disturbances of the GI tract. Nausea, vomiting, epigastric discomfort, intensification of symptoms of peptic ulcer disease (e.g., dyspepsia and heartburn), gastric ulcerations, erosive gastritis, and GI hemorrhage occur in individuals on high doses of aspirin. The incidence of these side effects is more rare at low doses, but a single dose of aspirin can cause GI distress in 5% of individuals.

Drug interactions

The salicylates displace a number of drugs from plasma protein binding sites, thereby leading to potential adverse effects by these agents. Since aspirin is an over-thecounter medication, patients may fail to inform the doctor of their aspirin consumption. Anticoagulants are potentiated by aspirin by displacement of the anticoagulants from plasma proteins and the intrinsic anticoagulant effect of aspirin. Thus, the dosage of drugs such as coumarin and heparin should be reduced in patients taking aspirin. A similar effect is observed in patients taking oral sulfonylureas (Orinase, DiaBeta) for non–insulin-dependent diabetes or phenytoin (Dilantin) for seizures. Displacement of the sulfonylureas or phenytoin from plasma binding necessitates a decrease in dosage to prevent an acute hypoglycemic event or sedation, respectively.Aspirin enhances the effects of insulin (leading to hypoglycemia), penicillins and sulfonamides (increasing acute toxicity), and corticosteroids. Aspirin increases the hypotensive effects of the cardiac drug nitroglycerin but decreases the effectiveness of the loop diuretics. In patients taking methotrexate for cancer chemotherapy, aspirin may increase retention of the drug, and severe toxicity may result.
Conversely, certain drugs modify the effectiveness or side effects of aspirin. Phenobarbital, occasionally used for seizures, induces liver enzymes that increase the metabolism and excretion of aspirin, β-adrenoceptor– blocking drugs, such as propranolol, and decrease the antiinflammatory effects of aspirin, whereas reserpine decreases its analgesic effects. Antacids decrease the absorption of aspirin. Alcohol consumption in combination with aspirin increases the latter’s ulcerogenic effects.

Metabolism

Aspirin itself is an acid with a pKa of 3.5 and is relatively insoluble in water, while its sodium or calcium salts have enhanced solubility.Aspirin and related salicylates are rapidly absorbed upon oral administration, with most absorption occurring in the small intestine. The pH of the stomach, a secondary site of drug absorption, along with the gastric emptying time of the stomach, determines the rate of absorption of the drug. Thus, food, which alters gastric emptying time and possibly the pH of the stomach, will alter absorption of the drug. Buffering of the drug decreases irritation in the stomach, increases drug solubility, and therefore may increase the rapidity of absorption. Enteric-coated aspirin tablets have a variable rate of dissolution depending on the preparation but are somewhat useful for prevention of stomach ulceration and gastric distress. Absorption of aspirin from rectal suppositories is slower and more variable than from oral administration. The peak plasma concentration of aspirin occurs 1 to 2 hours following oral administration. Aspirin is immediately hydrolyzed by various esterases in the stomach and in the liver to acetate and salicylic acid. Salicylic acid is glucuronidated, conjugated to glycine to form salicyluric acid (the major metabolic pathway), oxidized to gentisic acid (a minor metabolic pathway), or remains free as salicylic acid, which is secreted in the proximal tubule of the kidney. Diflunisal (Dolobid) differs from other salicylates in that it is not metabolized to salicylic acid but is rapidly glucuronidated. The conjugated metabolites of salicylates are inactive.
Salicylic acid is highly plasma protein bound, an effect that alters the pharmacokinetics of other drugs taken in combination with aspirin. Salicylates passively diffuse to all tissues, including breast milk, fetal tissues, and the CNS.They tend to accumulate, since increases in dose decrease renal clearance and prolong the half-life of the drug. Clearance at high doses (>2–4 g/day) is via zero order kinetics, and the half-life can approach 15 hours.At lower doses (600–1000 mg/day), clearance depends on the concentration of glucuronide or glycine available for conjugation and is a first-order process (half-life of approximately 3–6 hours). However, renal clearance is highly dependent on the pH of the urine; the higher the pH of the urine, the greater the clearance of the drug. Alkalinization of the urine is used to increase clearance of the salicylates in the case of toxicity or overdose.

Raw materials

Preparation Products