Introduction:

Salicylates have been used for more than 100 years. Aspirin (acetylsalicylic acid) and the salicylates are traditionally used in the treatment of pain, inflammation, and fever.

The Mechanism of Action

Aspirin and all newer NSAIDs inhibit cyclooxygenase. As a result, synthesis of prostaglandins and thromboxane is reduced. It is a potent antiplatelet agent, as well as anipyretic analgesic and anti-inflammatory drug.

Pharmacokinetics:

Aspirin:

Aspirin has three therapeutic dose ranges: the low range (<300mg/d) is effective in reducing platelet aggregation; intermediate doses (300-2400mg/d) have antipyretic and analgesic efffects; and high doses (2400-4000 mg/d) are used for their anti-inflammatory effect. Aspirin is readily abosorbed and is hydrolyzed in blood and tissue to acetate and salicylic acid. Salicylate is probably the major active molecule in the anti-inflammatory action of aspirin. Elimination of salicylates is first-order at low doses, with a half-life of 3-5 hours. At high (anti-inflammatory) doses, half-life increases to 15 hours or more and elimination becomes zero-order. Excretion is via the kidney.

Toxicity:

Possible adverse effects from therapeutic anti-inflammatory doses of aspirin are gastrointestinal disturbances and increased risk of bleeding. Chronic aspirin overdosage is associated with reduced synthesis of prothrombin. When prostaglandin synthesis is inhibited by even small doses of aspirn, persons with aspirin hypersensitivity (especially associated with nasal polyps) may experience asthma from the increased synthesis of leukotrienes. At higher doses, tinnitus, vertigo, hyperventilation, and respiratory alkalosis are observed.

Aspirin and Ototoxicity

Salicylates can cause a reversible hearing loss. Apart from that it also causes tinnitus. The incidence rate is less than 1%. Elderly patients are at a significantly high risk of salicylate toxicity even at lower salicylate doses. Tinnitus also occurs with salicylates with the usual frequency of tinnitus being in the 7 to 9 kHz range. Tinnitus may be used as an initial sign of salicylate ototoxicity and may be used as a baseline in patients with normal initial hearing. It is believed that the mechanism of salicylate ototoxicity is related to reversible biochemical or metabolic changes in the cochlear rather than any permanent morphologic abnormality. NSAIDs are a heterogeneous group of compounds that share Quinine ototoxicity is quite similar to salicylate clinical manifestations and has a mechanism distinct from that of salicylates.

It is believed that salicylates uncouple oxidative phosphorylation.

Serum levels of 20 mg/dl can cause hearing loss and tinnitus.

Rarely hearing loss is reported from other types of analgesics, for example hydrocodone/aspirin combination (Friedman et al, 2000; Oh et al, 2000) Mostly the hearing loss is temporary, permanent hearing disturbances are still possible but rare. They are most commonly seen in individuals who take aspirin in large doses for long periods, such as for treatment of arthritis. Occasionally persons with Menieres syndrome will develop a hearing disturbance from a small amount of a aspirin.

Manifestation of Salicylates Ototoxicity:

• Hearing loss (typically mild to moderate and bilaterally symmetric. May be flat or just in the high-frequencies)
• Nausea
• Vomiting
• Tinnitus
• Headache
• Mental changes
• Increased respiration.

Management:

Cessation of the drug and as the salicylate is metabolized, hearing returns to normal (48-72 hours).