Chapter: Modern Pharmacology with Clinical Applications: Opioid and Nonopioid Analgesics


Aspirin is a weak organic acid and is one of the oldest known drugs for the relief of fever and pain. Aspirin re-mains the standard to which most NSAIDs are com-pared for efficacy.



Aspirin is a weak organic acid and is one of the oldest known drugs for the relief of fever and pain. Aspirin re-mains the standard to which most NSAIDs are com-pared for efficacy.


Aspirin itself is an acid with a pKa of 3.5 and is rela-tively insoluble in water, while its sodium or calcium salts have enhanced solubility. Aspirin and related sali-cylates are rapidly absorbed upon oral administration, with most absorption occurring in the small intestine. The pH of the stomach, a secondary site of drug ab-sorption, 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 pos-sibly 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 as-pirin tablets have a variable rate of dissolution depend-ing on the preparation but are somewhat useful for pre-vention of stomach ulceration and gastric distress. Absorption of aspirin from rectal suppositories is slower and more variable than from oral administra-tion. The peak plasma concentration of aspirin occurs 1 to 2 hours following oral administration. Aspirin is im-mediately hydrolyzed by various esterases in the stom-ach 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 re-mains free as salicylic acid, which is secreted in the proximal tubule of the kidney. Diflunisal (Dolobid) dif-fers from other salicylates in that it is not metabolized to salicylic acid but is rapidly glucuronidated. The con-jugated 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 de-crease renal clearance and prolong the half-life of the drug. Clearance at high doses (>2–4 g/day) is via zero or-der 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 ap-proximately 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.

Mechanism of Action and Pharmacological Effects

Aspirin and related salicylates produce their pharmaco-logical 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 inflamma-tion and is therefore considered to mediate most in-flammatory 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 ef-fects at different sites on COX-1 and on COX-2. In ad-dition, aspirin interferes with kinin-induced modulation of the inflammatory response.

Clinical Uses

Aspirin and related salicylates are the primary treat-ment for mild to moderate pain, such as that associated with headache, joint and muscle pain, and dysmenor-rhea. At higher doses aspirin is an effective analgesic in rheumatoid arthritis . The analgesic ef-fects of salicylates are thought to be due to the inhibi-tion 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 ac-tive. Aspirin acts at two distinct but related sites. It de-creases prostaglandin-induced fever in response to py-rogens and induces a decrease in interleukin-1 modulation of the hypothalamic control of body tem-perature. Thus, the hypothalamic control of body tem-perature returns, vasodilation occurs, heat dissipates, and fever decreases. Other uses of aspirin include inhi-bition of platelet aggregation via inhibition of throm-boxanes, which has been shown to decrease the inci-dence of blood clots, myocardial infarction, and transient ischemic attacks.

Overdose and Other Adverse Effects

The major consequence of aspirin overdose, which of-ten occurs in children, results from actions on respira-tory centers in the medulla. Salicylate-induced stimula-tion of respiration leads to hyperventilation. In addi-tion, salicylates uncouple oxidative processes leading to increased carbon dioxide production and metabolic aci-dosis. The onset of acidosis, if not treated less than 1 hour after ingestion of aspirin, will lead to loss of rhyth-micity of respiration and eventually loss of breathing. Treatments include alkalinization of the urine, fluid re-placement, gastric lavage with activated charcoal, dialy-sis, and artificial ventilation.

Some patients exhibit hypersensitivity to aspirin in the form of salicylism, which is accompanied by ringing in the ears (tinnitus), vertigo, and bronchospasm (espe-cially in asthmatics). The use of salicylate-containing preparations is not the only source of this drug. Those sensitive to salicylates should be aware of salicylates in a number of foods, such as curry powder, licorice, prunes, raisins, and paprika.

The use of aspirin in children and teenagers with ei-ther chickenpox or influenza is contraindicated, since there is evidence linking the use of the salicylates in such diseases to Reye’s syndrome, a potentially fatal disease accompanied by liver damage and encephalopa-thy. The mechanism by which the use of salicylates in-creases the chances for development of Reye’s syn-drome is not known.


Other potential adverse effects of the drugs include the use of aspirin by patients who anticipate surgery or dental procedures. Such patients should be closely mon-itored and the salicylate stopped at least 1 week prior to surgery because of the possibility of increased clotting time and excessive bleeding. Similarly, the use of salicy-lates in pregnant women may increase bleeding upon delivery and prolong delivery. In addition, adverse fetal effects have been documented, such as low birth weight, fetal intracranial bleeding, and possible teratogenic ef-fects. Due to the ulcerogenic effects of the drugs, pa-tients with a history of ulcers or other GI disturbances should be carefully monitored for increased blood in the feces while taking salicylates.

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-the-counter medication, patients may fail to inform the doctor of their aspirin consumption. Anticoagulants are potentiated by aspirin by (1) displacement of the antico-agulants from plasma proteins and (2) the intrinsic anti-coagulant 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 de-crease in dosage to prevent an acute hypoglycemic event or sedation, respectively. Aspirin enhances the effects of insulin (leading to hypoglycemia), penicillins and sulfon-amides (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 can-cer 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 an-tiinflammatory effects of aspirin, whereas reserpine de-creases its analgesic effects. Antacids decrease the ab-sorption of aspirin. Alcohol consumption in combination with aspirin increases the latter’s ulcerogenic effects

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Modern Pharmacology with Clinical Applications: Opioid and Nonopioid Analgesics : Salicylates |

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