Nonsteroidal anti-inflammatory drugs with diuretics

Lithium toxicity can occur as a result of intentional overdose therefore, care must be taken when administering lithium to potentially suicidal patients with BPAD. Inadvertent lithium toxicity may also occur. For example, diuretics and nonsteroidal anti-inflammatory drugs such as ibuprofen (Advil, Motrin) slow the excretion of lithium and can lead to accidental toxicity. Consequently, the patient should be advised not to take such commonly available medications while treated with lithium. In addition, dehydration resulting from varied causes such as diarrhea, vomiting, and profuse sweating can lead to accidental lithium toxicity. One should advise the patient who takes lithium to be careful to remain well hydrated at all times and to contact his/her physician if any medical condition arises that may cause rapid fluid losses (e.g., stomach virus, high fevers). 

Important drug interactions include those with potassium supplements or potassium-sparing diuretics, which can result in hyperkalemia. Nonsteroidal anti-inflammatory drugs may impair the hypotensive effects of ACE inhibitors by blocking bradykinin-mediated vasodilation, which is at least in part, prostaglandin mediated. 

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. 

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). 

ACE inhibitors are well tolerated in most patients but are not absent of side effects. ACE inhibitors decrease aldosterone and can increase potassium serum concentrations. Usually the increase in potassium is small, but hyperkalemia is possible. It is seen primarily in patients with chronic kidney disease or diabetes mellitus and in those on concomitant ARBs, nonsteroidal anti-inflammatory drugs, potassium supplements, or potassium-sparing diuretics. Judicious monitoring of potassium and serum creatinine values within 4 weeks of starting or increasing the dose of an ACE inhibitor often can identify these abnormalities before they evolve into more serious complications. 

Prostaglandins are important in maintaining glomerular filtration and substrate for diuretic action. When synthesis of prostaglandins is inhibited, as with nonsteroidal anti-inflammatory drugs (Chapter 36), the efficacy of diuretics—especially loop diuretics—decreases. 

Cyclodextrin-based drug delivery systems The hydrophilic cyclodextrins have been extensively )plied to enhance the oral bioavailabilily of steroids, cardiac glycosides, nonsteroidal anti-inflammatory drugs, barbiturates, antiepileptics, benzodiazepines, antidiabetics, vasodilators, etc. Delayed and prolonged release of diltiazem and molsidormine was achieved by their complexation with CD derivatives, modified release of nifedipine can be achieved by its complexation with 2-HP-P-CD fiirosemide and piretanide (loop diuretics) release can be modified after complexation with DM-P-CD. Prednisolone dosage forms can be optimized also by complex-formation with 2-HP-P-CD. 

The role of concomitant medication is not clear due to the lack of good clinical studies [9]. It is recommended to stop nonsteroidal anti-inflammatory drugs, metformin for the risk of lactic acidosis with decreasing renal function, and diuretics. Usually, diuretics used for long-term treatment of hypertension and inhibitors of the renin-angiotensin system should not be discontinued. 

In addition to noncompliance with medication, causes of failure to respond to drug therapy include excessive sodium intake and inadequate diuretic therapy with excessive blood volume, and drugs such as tricyclic antidepressants, nonsteroidal anti-inflammatory... 

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. 

The exact mechanism of the pentamidine-induced hyperkalemia has not yet been defined. Many different mechanisms can impair the renal handling of potassium and thus favor hyperkalemia in patients with AIDS. These include decreased renal function secondary to volume depletion, presence of under-lying renal disease, including tubular dysfunction with the possibility of hyporeninemic hypoaldos-teronism, hypoadrenalism, and the administration of drugs with potential for impairing renal potassium excretion (nonsteroidal anti-inflammatory agents, ACE inhibitors, potassium-sparing diuretics. 

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). 

The most important susceptibility factors are pre-existing chronic kidney disease (CKD eGFR below 60 mVmin) and chronic kidney disease associated with diabetes [15]. Other factors include age over 70 years, the presence of congestive heart failure, nephrotoxic drugs (loop diuretics, metformin, nonsteroidal anti-inflammatory agents), volume depletion, and repeated exposure within short periods of time (under 72 hours). 

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