Acetazolamide toxicity

Acetazolamide toxicity was suspected, because of the temporal association between drug treatment and the onset of the neurological sjmptoms, together with metabolic acidosis. Gerstmann sjmdrome is usually due to an acute stroke. Although a brain CT scan was negative, such an event was likely in this patient, who had a history of cerebrovascular disease and multiple risk factors, and a causal relation to acetazolamide must be considered tenuous. 

Not fully established. One idea is that these carbonic anhydrase inhibitors (acetazolamide, diclofenamide) affect the plasma pH, so that more of the salicylate exists in the un-ionised (lipid-soluble) form, which can enter the CNS and other tissues more easily, leading to salicylate toxicity. However, carbonic anhydrase inhibitors also make the urine more alkaline, which increases the loss of salicylate (see also Aspirin or other Salicylates + Antacids , p.l35). Animal studies confirm that carbonic anhydrase inhibitors increase the lethal toxicity of aspirin. An alternative suggestion is that because salicylate inhibits the plasma protein binding of acetazolamide and its excretion by the kidney, acetazolamide toxicity, which mimics salicylate toxicity, may occur. ... 

There is an increased risk of cyclosporine toxicity when the drug is administered with acetazolamide. Decreased serum and urine concentrations of primidone occur when the drug is administered with acetazolamide. 

Drowsiness and paresthesias are common following large doses of acetazolamide. Carbonic anhydrase inhibitors may accumulate in patients with renal failure, leading to nervous system toxicity. Hypersensitivity reactions (fever, rashes, bone marrow suppression, and interstitial nephritis) may also occur. 

Acetazolamide, others Inhibition of the enzyme prevents dehydration of H2CO3 and hydration of CO2 Reduces reabsorption of HC03 in the kidney, causing self-limited diuresis hyperchloremic metabolic acidosis reduces body pH, reduces intraocular pressure Glaucoma, mountain sickness, edema with alkalosis Oral and topical preparations available duration of action 8-12 h Toxicity Metabolic acidosis, renal stones, hyperammonemia in cirrhotics... 

Carbonic anhydrase inhibitors [NE] Increased acetazolamide serum concentrations increase salicylate toxicity due to decreased blood pH. 

Salicylates Interference with renal excretion of drugs that undergo active tubular secretion. Salicylate renal excretion dependent on urinary pH when large doses of salicylate used. Aspirin (but not other salicylates) interferes with platelet function. Large doses of salicylates have intrinsic hypoglycemic activity. Salicylates may displace drugs from plasma protein binding sites. Carbonic anhydrase inhibitors [NE] Increased acetazolamide serum concentrations increased salicylate toxicity due to decreased blood pH. 

Acetazolamide increases lithium renal clearance (650). Furosemide can cause lithium toxicity by inhibiting the tubular excretion of lithium ions (651). 

CARBONIC ANHYDRASE INHIBITORS CARDIAC GLYCOSIDES Risk of digoxin toxicity t by acetazolamide due to hypokalaemia Uncertain Monitor potassium levels closely. Watch for digoxin toxicity and check levels... 

The authors suggested that acetazolamide-induced acidosis increases the concentration of the unionized form of salicylate, which crosses membranes more rapidly, and hence explains the cerebral toxicity associated with low serum concentrations of salicylate. However, an increase in the plasma or erythrocyte concentrations of... 

Sweeney KR, Chapron DJ, Brandt JL, Gomolin IH, Feig PU, Kramer PA. Toxic interaction between acetazolamide and salicylate case reports and a pharmacokinetic explanation. Clin Pharmacol Ther 1986 40(5) 518-24. 

Volume resuscitation is the cornerstone of management of lithium toxicity (Table 3) [124, 125]. Patients with underlying lithium-induced diabetes insipidus may initially present with volume depletion. It must be borne in mind, however, that hypernatremia [125] is a potential complication, especially in those with underlying diabetes insipidus. Forced saline diuresis is expected to increase lithium clearance by decreasing proximal tubular reabsorption. With normal renal function, lithium can be cleared at a rate of 10-40 mL/min [125]. The excretion of lithium can be further increased acutely by using acetazolamide and/or loop diuretics [124,125]. 

Note Acetazolamide is a sulfonamide and can be absorbed systemically. Sulfonamides can produce severe, possibly fatal, reactions such as toxic epidermal necrolysis and Stevens-Johnson syndrome... 

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). 

The effect of urinary pH on the clearance of methadone is an established interaction, but of uncertain importance. Be alert for any evidence of reduced methadone effects in patients whose urine becomes acidic because they are taking large doses of ammonium chloride. Lowering the urinary pH to 5 with ammonium chloride to increase the clearance can also be used to treat toxicity. Theoretically, urinary alkalinisers such as sodium bicarbonate and acetazolamide may increase the effect of methadone. 

A well established and well understood interaction but reports of problems in practice seem rare. The interaction has been exploited to increase the clearance of amfetamines in cases of overdose by acidifying the urine with ammonium chloride. Conversely it can represent an undesirable interaction if therapeutic doses of amfetamines are excreted too rapidly. Care is needed to ensure that amfetamine toxicity does not develop if the urine is made alkaline with sodium bicarbonate or another urinary alkaliniser, acetazolamide. 

Severe osteomalacia and rickets have been seen in a few patients taking phenytoin, phenobarbital, or primidone with acetazola-mide. A marked reduction in serum primidone levels with a loss in seizure controi, rises in serum carbamazepine levels with toxicity, and rises in phenytoin levels have also been described in a veiy small number of patients given acetazolamide. 

A 9-year-old girl and two teenage boys, all of them taking the highest dosages of carbamazepine tolerable (without adverse effects), developed signs of toxicity after taking acetazolamide 250 to 750 mg daily. Their serum carbamazepine levels were found to have increased by about 25 to 50%. In one instance toxicity appeared within 48 hours. ... 

There is some limited evidence to surest that acetazolamide can cause a marked and rapid rise in cielosporin serum levels, possibly accompanied by renal toxicity. 

There is some evidence that the excretion of lithium can be increased by the short-term use of acetazolamide. However, lithium toxicity has been seen in one patient given the combination for a month. 

LiddeU, N. E. and Maren, T. H. (1975) COj retention as a basis for increased toxicity of salicylate with acetazolamide Avoidance of increased toxicity with Benzolamide. J. Pharmacol exp. Ther., 195, 1. 

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