Thiazide toxicity

A) Quinidine toxicity caused by inhibition of quinidine metabohsm by the thiazide Direct effects of hydrochlorothiazide on the pacemaker of the heart Thiazide toxicity caused by the effects of quinidine on the kidneys Block of calcium current by the combination of quinidine plus thiazide Reduction of serum potassium caused by the diuretic action of hydrochlorothiazide An important therapeutic or toxic effect of loop diuretics is (A) Decreased blood volume Decreased heart rate Increased serum sodium Increased total body potassium Metabolic acidosis... 

Fhtients taking a diuretic and a digitalis glycoside must be monitored closely. Thiazide and loop diuretics (see Chap. 46) may increase the risk and effects of toxicity. 

Calcium is contraindicated in patients with hypercalcemia or ventricular fibrillation and in patients taking digitalis. Calcium is used cautiously in patients with cardiac disease. Hypercalcemia may occur when calcium is administered with the thiazide diuretics. When calcium is administered with atenolol there is a decrease in Hie effect of atenolol, possibly resulting in decreased beta blockade. There is an increased risk of digitalis toxicity when digitalis preparations are administered with calcium. The clinical effect of verapamil may be decreased when the drug is administered with calcium. Concurrent ingestion of spinach or cereal may decrease file absorption of calcium supplements. 

The answer is b. (Hardman, pp 703-704J Low K stores due to the effects of thiazide diuretics such as hydrochlorothiazide increase susceptibility to cardiac glycoside toxicity... 

Most of the lithium is eliminated in the urine, the first phase of the elimination being 6-8 hours after administration, followed by a slower phase which may last for 2 weeks. Sodium-depleting diuretics such as frusemide, ethacrynic acid and the thiazides increase lithium retention and therefore toxicity, while osmotic diuretics as exemplified by mannitol and urea enhance lithium excretion. The principal side effects of lithium are summarized in Table 8.1. 

Lithium is a drug with a narrow therapeutic index and therefore plasma concentrations are regularly monitored. Lithium is used in the prophylaxis and treatment of mania. Concurrent administration of lithium and diuretics, particularly the thiazides, is contraindicated as lithium excretion is reduced, resulting in increased plasma-lithium concentration and hence toxicity. 

Adverse or toxic effects are those associated with effective thiazide-type... 

Lithium intoxication can be precipitated by the use of diuretics, particularly thiazides and metola-zone, and ACE inhibitors. NSAIDs can also precipitate lithium toxicity, mainly due to NSAID inhibition of prostaglandin-dependent renal excretion mechanisms. NSAIDs also impair renal function and cause sodium and water retention, effects which can predispose to interactions. Many case reports describe the antagonistic effects of NSAIDs on diuretics and antihypertensive drugs. The combination of triamterene and indomethacin appears particularly hazardous as it may result in acute renal failure. NSAIDs may also interfere with the beneficial effects of diuretics and ACE inhibitors in heart failure. It is not unusual to see patients whose heart failure has deteriorated in spite of increased doses of frusemide who are also concurrently taking an NSAID. 

Many interactions with lithium have been described. Thiazide and loop diuretics decrease lithium excretion predisposing to serious lithium toxicity. Also non-steroidal anti-inflammatory agents, especially indomethacin can increase the risks for lithium toxicity due to decreased renal excretion. 

Thiazides should be used cautiously in the presence of severe renal and hepatic disease, since azotemia and coma may result. The most important toxic effect associated with this class of diuretics is hypokalemia, which may result in muscular and central nervous system symptoms, as well as cardiac sensitization (see Hypokalemia). Periodic examination of serum electrolytes for possible imbalances is strongly recommended. Appropriate dietary and therapeutic measures for controlling hypokalemia are described later in this chapter. The thiazides also possess some diabetogenic potential, and although pancreatitis during thiazide therapy has been reported in a few cases, the major mechanism contributing to the potential for glucose intolerance is not known. 

Several drug interactions involving amantadine and rimantadine are clinically significant. Anticholinergic drugs can potentiate the toxicity of amantadine. Thiazide-triamterene, trimethoprim-sulfamethoxazole, quinine, and quinidine increase plasma amantadine levels. Cimetidine decreases rimantadine clearance, and aspirin and acetaminophen decrease rimantadine plasma levels. 

In the presence of severe renal and hepatic disease, these drugs may precipitate renal failure or hepatic coma. The most important toxic effect associated with thiazide therapy is hypokalemia and hypochloremic alkalosis. 

Lithium Mechanism of action uncertain suppresses inositol signaling and inhibits glycogen synthase kinase-3 (GSK-3), a multifunctional protein kinase No significant antagonistic actions on autonomic nervous system receptors or specific CNS receptors no sedative effects Bipolar affective disorder-prophylactic use can prevent mood swings between mania and depression Oral absorption, renal elimination half-life 20 h. narrow therapeutic window (monitor blood levels) Toxicity Tremor, edema, hypothyroidism, renal dysfunction, dysrhythmias pregnancy category D Interactions Clearance decreased by thiazides and some NSAIDs... 

Therapy with hydrochlorothiazide, up to 50 mg twice daily, or chlorthalidone, 50-100 mg daily, is recommended. Loop diuretics such as furosemide and ethacrynic acid should not be used because they increase urinary calcium excretion. The major toxicity of thiazide diuretics, besides hypokalemia, hypomagnesemia, and hyperglycemia, is hypercalcemia. This is seldom more than a biochemical observation unless the patient has a disease such as hyperparathyroidism in which bone turnover is accelerated. Accordingly, one should screen patients for such disorders before starting thiazide therapy and monitor serum and urine calcium when therapy has begun. 

Unauthorized use of these diuretics, or the failure to follow label indications for approved use in the cattle, could lead to unacceptable residues in meat and milk destined for human consumption. While there are no official tolerances for these drugs in milk, the Food and Drug Administration (FDA) has established safe levels that range from 7 ppb for trichlormethiazide, to 10 ppb for furosemide, and 67 ppb for the other thiazides (56). Administration of diuretics is associated with potential toxic effects such as bone marrow depression, hyperbilirubinemia. 

The toxic effects of digitalis are frequent and may be fatal. Toxicity may result from overdosage, decreased metabolism and excretion, and hypokalemia stemming from the use of thiazide diuretics, diarrhea, and vomiting. Digitalis toxicity has several manifestations ... 

The special risk is observed in patients with hepatic or renal impairment. It is not advised to use allopurinol in acute attacks of gout, but it is useful in chronic gout. Excretion of allopurinol and its active metabolite oxypurinol is primarily via the kidneys and therefore the dosage should be reduced if renal function is impaired. The adverse effects have been reported in patients receiving allopurinol with thiazide diuretics, particularly in patients with impaired renal function. The metabolism of azathioprine and mercaptopurine is inhibited by allopurinol and their doses should be reduced to one-quarter to one-third of the usual dose when either of them is given with allopurinol to avoid potentially life-threatening toxicity.27-29... 

In an 80-year-old woman a 2-month history of diarrhea, nausea, and abdominal distress attributed to irritable bowel syndrome was ultimately determined to be due to early lithium intoxication (356). Her lithium concentration when she was hospitalized was 1.2 mmol/1, although she had taken no lithium for the previous 10 days. Treatment with a thiazide diuretic contributed to the toxicity. 

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