Diuretics, interaction with lithium

Diuretics, interaction with lithium, 36 65-66 Divalent cations hydration shell, 34 211 structure, 34 210-212... 

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. 

Drug interactions with lithium have been reviewed (569-573) another review focused on interactions in the elderly (573). A review of drug interactions with lithium considered both pharmacokinetic interactions [for example diuretics, nonsteroidal anti-inflammatory drugs (NSAIDs)] and pharmacodynamic interactions (for example antipsychotic drugs, SSRIs) and summarized the most important ones in tabular form (569). 

Although amiloride may reduce the renal clearance of lithium, it appears to be free of the troublesome interaction with lithium that complicates the use of thiazides and loop diuretics. 

The most potentially serious drug interactions include the concomitant use of NSAIDs with lithium, warfarin, oral hypoglycemics, high-dose methotrexate, antihypertensives, angiotensin-converting enzyme inhibitors, fi-blockers, and diuretics. 

As noted earlier, lithium is contraindicated in patients with unstable congestive heart failure or the sick sinus node syndrome ( 307, 328). In older patients or those with prior cardiac histories, a pretreatment ECG should be obtained. Except for the potential adverse interactions with diuretics, the concomitant use of other cardiac drugs is generally safe. Because verapamil may lower serum levels of lithium, however, more careful monitoring may be required to assure continued therapeutic effects (329). Some data also indicate that verapamil may predispose to lithium neurotoxicity. Conversely, increased lithium levels leading to toxicity has occurred with methyidopa and enalapril. When antihypertensive therapy is necessary, b-blockers are a reasonable choice when lithium is coadministered. 

Renal clearance of lithium is reduced about 25% by diuretics (eg, thiazides), and doses may need to be reduced by a similar amount. A similar reduction in lithium clearance has been noted with several of the newer nonsteroidal anti-inflammatory drugs that block synthesis of prostaglandins. This interaction has not been reported for either aspirin or acetaminophen. All neuroleptics tested to date, with the possible exception of clozapine and the newer atypical antipsychotics, may produce more severe extrapyramidal syndromes when combined with lithium. 

The loop diuretics increase the renal excretion of lithium after single-dose intravenous administration in both animals (711) and man (712). Furosemide has been used to treat lithium intoxication (713). The effect of etacrynic acid is larger than those of furosemide and bumetanide (712). However, long-term treatment with furosemide and bumetanide can cause lithium intoxication in some patients (714,715), perhaps by causing sodium depletion and a secondary increase in lithium reabsorption. An adverse interaction of lithium during long-term therapy with etacrynic acid is therefore theoretically likely. 

Interactions. Several types of drug interfere with lithium excretion by the renal tubules, causing the plasma concentration to rise. These include diuretics (thiazides more than loop type), ACE inhibitors and angiotensin-11 antagonists, and nonsteroidal anti-inflammatory analgesics. Theophylline and sodium-containing antacids reduce plasma lithium concentration. The effects can be important because lithium has such a low therapeutic ratio. Diltiazem, verapamil, carbamazepine and pheny-toin may cause neurotoxicity without affecting the plasma lithium. Concomitant use of thioridazine should be avoided as ventricular arrhythmias may result. 

Edema associated with lithium is uncommon (249,250). It is usually restricted to the legs, and is usually transient or intermittent. If treatment is necessary, the intermittent and cautious use of a loop diuretic may be helpful (but see drug-drug interactions). 

Lithium is also known to interact in a variety of ways with different classes of diuretic drugs. Thiazide diuretics increase serum lithium concentration by increasing reabsorption of lithium, along with that of sodium, in the proximal tubule. With potassium-sparing diuretics, conflicting results have been reported. Increased serum lithium concentrations may be seen after amiloride. However, the loop diuretic furosemide safely can be combined with lithium with no reduction in renal lithium clearance or consequent increase in serum lithium concentration (191, 192). Other diuretics, for example, carbonic anhydrase inhibitor and xanthine derivatives, decrease serum... 

Clinically important, potentially hazardous interactions with albuterol, alcohol, clonidine, corticosteroids, danazol, diuretics, epinephrine, estrogens, isoniazid, lithium, oral contraceptives, pentamidine, phenothiazines, propranolol, somatropin, terbutaline, thyroid... 

Clinically important, potentially hazardous interactions with allopurinol, amiloride, cimetidine, corticosteroids, cyclosporine, insulin, lithium, potassium sparing diuretics, potassium supplements, procainamide, spironolactone, triamterene... 

Clinically important, potentially hazardous interactions with alcohol, amiodarone, anticholinergics, antihistamines, barbituates, cisapride, dofetilide, doxazosin, erythromycin, guanethidine, hydralazine, levodopa, lithium, methyldopa, metoclopramide, moxifloxacin, piperazine, quinidine, sibutramine, sotalol, thiazide diuretics, thioridazine... 

Diuretics can be used safely with most other agents. However, concurrent administration with lithium may result in increased lithium serum concentrations. This interaction can predispose patients to lithium toxicity. 

One of the best-known lithium interactions is the clinically relevant reduction of renal lithium clearance by combined administration of the drug with diuretics. Special caution is advised when long-term thiazides are combined with lithium. The potassium-sparing diuretics such as spironolactone can also increase plasma... 

No interaction study has been done with lithium and eplerenone. Serum lithium should be monitored frequently if eplerenone is given with lithium, although, in the UK, the manufacturers advise avoidance of the combination. This is because lithium toxicity has occurred with lithium and ACE inhibitors , (p. 1112) or diuretics , (p. 1122). 

No significant interactions have been reported when tiie expectorants are used as directed. The exception is iodine products. Lithium and other antithyroid drug may potentiate the hypotliyroid effects of these drug if used concurrently with iodine products. When potassium-containing medications and potassium-sparing diuretics are administered with iodine products, the patient may experience hypokalemia, cardiac arrhythmias, or cardiac arrest. Thyroid function tests may also be altered by iodine... 

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. 

While theoretically it is possible that botanicals with diuretic effects can increase drug excretion, most botanical diuretics are not as potent as furo-semide and are unlikely to result in significant interactions. Most botanicals also do not affect urinary pH significantly, and hence are unlikely to affect renal tubular reabsorption of drugs. Nevertheless, lithium toxicity was thought to be related to the use of a botanical diuretic mixture in a patient. If the toxicity indeed is related to the use of the botanical diuretic, the mechanism of action or the responsible constituent(s) is not known (48). 

Interactions. Hyperkalaemia can result from use with potassium-sparing diuretics. Renal clearance of lithium is reduced and toxic concentrations of plasma lithium may follow. Severe hypotension can occur with diuretics (above), and with chlorpro-mazine, and possibly other phenothiazines. 

Most of the renal tubular reabsorption ofU occurs in the proximal tubule. Nevertheless, Id retention can be increased by any diuretic that leads to depletion of Na, particularly the thiazides (see Chapter 28). Renal excretion can be increased by administration of osmotic diuretics, aceta-zolamide or aminophylline, and triamterene. Spironolactone does not increase the excretion of LiL Some nonsteroidal anti-inflammatory agents can facilitate renal proximal tubular resorption of Id and thereby increase concentrations in plasma to toxic levels. This interaction appears to be particularly prominent with indomethacin, but also may occur with ibuprofen, naproxen, and COX-2 inhibitors, and possibly less so with sulindac and aspirin. A potential drug interaction can occur with angiotensin-converting enzyme inhibitors, causing lithium retention (see Chapter 29). 

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