Lithium gastrointestinal effects

Patients at increased risk of NSAID-induced gastrointestinal adverse effects (e.g., dyspepsia, peptic ulcer formation, and bleeding) include the elderly, those with peptic ulcer disease, coagulopathy, and patients receiving high doses of concurrent corticosteroids. Nephrotoxicity is more common in the elderly, patients with creatinine clearance values less than 50 mL/minute, and those with volume depletion or on diuretic therapy. NSAIDs should be used with caution in patients with reduced cardiac output due to sodium retention and in patients receiving antihypertensives, warfarin, and lithium. 

Lithium salts, generally in the form of the carbonate or bicarbonate, are rapidly absorbed from the gastrointestinal tract and reach a peak plasma concentration after 2- hours. Extreme fluctuations in blood lithium levels, which are associated with side effects such as nausea, diarrhoea and abdominal cramp, are reduced by using sustained release preparations. Lithium is not protein bound and therefore is widely distributed throughout the body water, which accounts for the adverse effects it has on most organ systems should it reach toxic levels. To avoid toxicity, and ensure optimal... 

Lithium carbonate is completely absorbed by the gastrointestinal tract and reaches peak plasma levels in 1-2 hours. The elimination half-life is approximately 24 hours. Steady-state lithium levels are achieved in approximately 5 days. Therapeutic plasma levels range from 0.5 to 1.2 mEq/L. Lower plasma levels are associated with less troubling side effects, but levels of at least 0.8 mEq/L are often required in the treatment of acute manic episodes. Therefore, when intolerable side effects have not intervened, treatment of acute mania with lithium should not be considered a failure until plasma levels of 1.0-1.2 mEq/L have been reached and have been maintained for 2 weeks. As discussed at the end of this chapter (see Treatment of Mania or Mixed Episodes ), more severely ill patients may require combination treatment. 

Nausea and diarrhea are common early side effects. Gastrointestinal symptoms may improve with dose reduction or with ingestion of lithium at meals. Slow-release formulations are more often associated with nausea, whereas sustained-release preparations are more commonly associated with diarrhea. 

Acetylsalicylic acid is usually given by oral administration (0.5-8 g/day) for pain and inflammation and for antiplatelet therapy (75-100 mg/day). It is also available in rectal and topical formulations and as a soluble lysine derivative for intravenous or intramuscular application. Acetylsalicylic acid is often used in multi-drug preparations. The main side-effects are gastrointestinal disorders. Use in children is limited due to the risk of Reye s syndrome (Waldmann et al., 1982). The lithium, magnesium, calcium, and aluminium salts of acetylsalicylic acid are used in some special preparations. 

Lithium not only treats acute episodes of mania and hypomania but was the first psychotropic agent shown to prevent recurrent episodes of illness. Lithium may also be effective in treating and preventing episodes of depression in patients with bipolar disorder. It is least effective for rapid cycling or mixed episodes. Overall, lithium is effective in only 40 to 50% of patients. Furthermore, many patients are unable to tolerate it because of numerous side effects, including gastrointestinal symptoms... 

Initially, when the maintenance dose of lithium is being established, the patient may experience gastrointestinal discomforts such as nausea, vomiting, diarrhea, stomach pain, muscular weakness, unusual thirst, frequent urination, a slight feeling of being dazed, tiredness, and sleepiness. These early side effects disappear once the patient is stabilized. 

Etodolac This drug has effects similar to those of the other NSAIDs. Gastrointestinal problems may be less common. However, other adverse effects such as fluid retention and abnormal kidney and liver function have been reported. Etodolac may increase the serum levels and thus raise the risk of adverse reactions caused by digoxin, lithium, methotrexate, and enhance the nephrotoxicity of cyclosporine. 

To determine the safety of using lithium chloride dilution to measure cardiac output, the pharmacokinetic and toxic effects of intravenous lithium chloride have been studied in six conscious healthy Standardbred horses (527). The mean peak serum concentration was 0.56 mmol/1. There were neither toxic effects nor significant changes in laboratory studies, electrocardiograms, or gastrointestinal motility. Three horses had increased urine output. 

Whether elderly patients taking lithium received proper monitoring was questioned in a case note audit of 91 patients, over 40% of whom had deviations from practice standards. These included absence of pretreatment laboratory tests, infrequent monitoring of serum lithium concentrations, lack of adequate adverse effects documentation, and the use of risky concomitant drugs (403). In a placebo-controlled study, there was poor tolerance of hthium augmentation of antidepressants in 76% (13/17) of elderly (mean age 70 years) patients at a mean serum concentration of 0.63 mmol/1, due to tremor and muscle twitches, cognitive disturbance, tiredness and sedation, and gastrointestinal upsets (404). 

Lithium augmentation of antidepressants is a well-established treatment for resistant depression and is usually well tolerated with all classes of antidepressants, although there have been a few reports of the serotonin syndrome with SSRIs (474). It is possible that shared adverse effects could be magnified by combining lithium with various antidepressants (for example tremor, weight gain, gastrointestinal upset). Hyponatremia secondary to the SIADH has been linked to SSRIs and tricyclic antidepressants, especially in elderly patients, and could predispose to lithium toxicity. 

As might be expected, the presence of food in the gastrointestinal tract has been shown to affect lithium absorption and a diurnal variation in renal lithium clearance has been reported 183, 184). In our experiments, diurnal and other factors appeared to influence lithium pharmacokinetics to a greater degree than did formulation differences 182). We conclude that the practice of administering an early evening dose after a meal may delay the lithium peak sufficiently to reduce the possible discomfort of any transient side effects and may improve patient compliance. This is more important than the choice of preparation to be given. 

D. Enhancement of Elimination Enhancement of elimination is possible for a number of toxins, including manipulation of urine pH to accelerate renal excretion of weak acids and bases. For example, alkaline diuresis is effective in toxicity due to fluoride, isoniazid, fluoroquinolones, phenobarbital, and salicylates. Urinary acidiflcation may be useful in toxicity due to weak bases, including amphetamines, nicotine, and phencyclidine, but care must be taken to avoid acidosis and renal failure in rhabdomyolysis. Hemodialysis or hemoperfusion enhances the elimination of many toxic compounds, including acetaminophen, ethylene glycol, formaldehyde, lithium, methanol, procainamide, quinidine, salicylates, and theophylline. Cathartics such as sorbitol (70%) may decrease absorption and hasten removal of toxins from the gastrointestinal tract. 

In contrast, 13 healthy subjects taking lithium carbonate 450 mg twice daily or 900 mg once daily had a small reduction in serum-lithium levels (from 0.51 to 0.47 mmol/L) when they were given tetracycline 500 mg twice daily for 7 days. The incidence of adverse reactions remained largely unchanged, except for a slight increase in CNS and gastrointestinal adverse effects. 

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