Aspirin or other Salicylates + Carbonic anhydrase inhibitors - Drug Interactions

A severe and even life-threatening toxic reaction can occur in patients taking high-dose salicylates if they are given carbonic anhydrase inhibitors (acetazolamide,diclofenamide).

An 8-year-old boy with chronic juvenile arthritis, taking prednisolone, indometacin and aloxiprin, was admitted to hospital with drowsiness, vomiting and hyperventilation (diagnosed as metabolic acidosis) within a month of aloxiprin dosage being increased from 3 to 3.6 g daily and starting to take diclofenamide 25mg three times daily for glaucoma (See reference number 1).

Other cases of toxicity (metabolic acidosis) have included a 22-year-old woman taking salsalate with acetazolamide 250 mg four times daily,(See reference number 1)and 2 elderly women taking large doses of aspirin with acetazolamide or diclofenamide (See reference number 2). A 50-year-old woman taking acetazolamide for glaucoma was admitted to hospital with confusion and cerebellar ataxia,associated with hyperchloraemic acidosis, 14 days after starting to take aspirin for acute pericarditis (See reference number 3). A man taking diclofenamide developed salicylate poisoning within 10 days of starting to take aspirin 3.9 g daily (See reference number 4). Coma developed in an 85-year-old woman taking aspirin 3.9 g daily when her dosage of acetazolamide was increased from 500mg to 1 g daily,(See reference number 5,6) and toxicity was seen in a very elderly man given both drugs: levels of unbound acetazolamide were found to be unusually high (See reference number 6). An elderly man became confused,lethargic, incontinent and anorexic while taking acetazolamide and salsalate. He needed intravenous hydration (See reference number 7).

Not fully established. One idea is that these carbonic anhydrase inhibitors (acetazolamide, diclofenamide) affect plasma pH, so that more of salicylate exists in un-ionised (lipid-soluble) form, which can enter CNS and other tissues more easily, leading to salicylate toxicity (See reference number 2). However, carbonic anhydrase inhibitors also make urine more alkaline, which increases loss of salicylate(See reference number 8) (see also Aspirin or other Salicylates + Antacids interaction). Animal studies confirm that carbonic anhydrase inhibitors increase lethal toxicity of aspirin (See reference number 4). An alternative suggestion is that because salicylate inhibits plasma protein binding of acetazolamide and its excretion by kidney, acetazolamide toxicity, which mimics salicylate toxicity, may occur (See reference number 6).

Although there are few clinical reports on record, interaction between carbonic anhydrase inhibitors and salicylates is established, well confirmed by animal studies, and potentially serious. One study recommended that carbonic anhydrase inhibitors should probably be avoided in those receiving high-dose salicylate treatment (See reference number 6). If they are used, patient should be well monitored for any evidence of toxicity (confusion, lethargy, hyperventilation, tinnitus) because interaction may develop slowly and insidiously (See reference number 2). In this context NSAIDs may be a safer alternative. Naproxen proved to be a satisfactory substitute in one case (See reference number 1). The authors of one study suggest that methazolamide may possibly be a safer alternative to acetazolamide because it is minimally bound to plasma proteins. They also suggest paracetamol (acetaminophen) as an alternative to salicylate in patients taking acetazolamide (See reference number 6). The reports cited here concern carbonic anhydrase inhibitors given orally,not as eye drops. It is not known whether latter interact similarly, but there appear to be no reports.

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