Central Nervous System

A selective action of Li+ is inhibition of inositol monophosphatase, thereby interfering with the phosphatidylinositol pathway (Figure 18—1). This effect can decrease cerebral inositol concentrations, possibly interfering with neurotransmission mechanisms by affecting the phosphatidyli-nositol pathway and decreasing the activation of PKC, particularly the a and b isoforms. This effect also is shared by valproic acid (particularly for PKC) but not carbamazepine. A major substrate for cerebral PKC is the myristolated alanine-rich PKC-kinase substrate (MARCKS) protein, which has been implicated in synaptic and neuronal plasticity. The expression of MARCKS protein is reduced by treatment with both Li+ and valproate but not by carbamazepine or antipsychotic, antidepressant, or sedative drugs. Both Li+ and valproate treatment inhibit glycogen synthase kinase-3b, which is involved in neuronal and nuclear regulatory processes, including limiting expression of the regulatory protein b-catenin. Both Li+ and valproic acid affect gene expression, increasing DNA binding of the transcription factor activator protein-1 (AP-1) and altering expression of other transcription factors. Treatment with Li+ and valproate has been associated with increased expression of the regulatory protein B-cell lymphocyte protein-2 (bcl-2), which is associated with protection against apoptotic neuronal degeneration.

ABSORPTION, DISTRIBUTION, AND EXCRETION Li+ is absorbed readily and almost completely from the GI tract. Complete absorption occurs in ~8 hours, with peak plasma concentrations occurring 2-4 hours after an oral dose. Slow-release preparations of lithium carbonate provide a slower rate of absorption and thereby minimize early peaks in Li+ plasma concentrations, but absorption can be variable, lower GI tract symptoms may be increased, and elimination rate is not altered with such preparations. Li+ initially is distributed in the extracellular fluid and then gradually accumulates in various tissues; it does not bind appreciably to plasma proteins. The final volume of distribution (0.7-0.9 L/kg) approaches that of total body water and is much lower than that of most other psychotropic agents, which are lipophilic and protein bound. Passage through the blood-brain barrier is slow, and when a steady state is achieved, the concentration of Li+ in the cerebrospinal fluid and in brain tissue is -40-50% of the concentration in plasma. Approximately 95% of a single dose of Li+ is eliminated in the urine. From one- to two-thirds of an acute dose is excreted during a 6-12-hour initial phase of excretion, followed by slow excretion over the next 10-14 days. The elimination t1/2 averages 20-24 hours. With repeated administration, Li+ excretion increases during the first 5-6 days until a steady state is reached between ingestion and excretion. When Li+ therapy is stopped, there is a rapid phase of renal excretion followed by a slow 10-14-day phase. Since 80% of the filtered Li+ is reabsorbed by the proximal tubule, renal clearance of Li+ is -20% of that for creatinine, ranging between 15 and 30 mL/min. This rate is somewhat lower in elderly patients (10-15 mL/min). Loading with Na+ slightly enhances Li+ excretion, but Na+ depletion promotes a clinically important degree of retention of Li+.

A well-established regimen can be complicated by occasional periods of Na+ loss, as may occur with intercurrent fever, diarrhea, or other medical illness, with losses or restrictions of fluids and electrolytes, or during treatment with a diuretic. Heavy sweating may be an exception due to a preferential secretion of Li+ over Na+ in sweat.

Most of the renal tubular reabsorption of Li+ occurs in the proximal tubule. Nevertheless, Li+ 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 Li+. Some nonsteroidal anti-inflammatory agents can facilitate renal proximal tubular resorption of Li+ 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).

Less than 1% of ingested Li+ leaves the human body in the feces, and 4—5% is secreted in sweat. Li+ is secreted in saliva in concentrations about twice those in plasma, while its concentration in tears is about equal to that in plasma. Since the ion also is secreted in human milk, women receiving Li+ should not breast-feed infants.

Dose; Serum-Level Monitoring The recommended therapeutic concentration usually is attained by doses of 900-1500 mg of lithium carbonate per day in outpatients and 1200-2400 mg/day in hospitalized manic patients. The optimal dose tends to be larger in younger and heavier individuals. Because of its low therapeutic index, periodic determination of serum concentrations of Li+ is crucial. Li+ cannot be used safely in patients who cannot be tested regularly. Concentrations considered to be effective and acceptably safe are between 0.6 and 1.25 mEq/L. The range of 0.9-1.1 mEq/L is favored for treatment of acutely manic or hypomanic patients. Somewhat lower values (0.6-0.75 mEq/L) are considered adequate and are safer for long-term use for prevention of recurrent manic-depressive illness. Some patients may not relapse at concentrations as low as 0.5-0.6 mEq/L, and lower levels usually are better tolerated.

Serum concentrations of Li+ have been found to follow a clear dose-effect relationship between 0.4 and 0.9 mEq/L, with a corresponding dose-dependent rise in polyuria and tremor as indices of adverse effects, and little gain in benefit at levels above 0.75 mEq/L. This pattern indicates the need for individualization of serum levels to obtain a favorable risk-benefit relationship. The concentration of Li+ in blood usually is measured at a trough of the daily oscillations that result from repetitive administration (i.e., from samples obtained 10-12 hours after the last oral dose of the day). Peaks can be two or three times higher at a steady state. When the peaks are reached, intoxication may result, even when concentrations in morning samples of plasma at the daily nadir are in the acceptable range of 0.6-1 mEq/L. Because of the low margin of safety of Li+ and because of its short t1/2 during initial distribution, divided daily doses are usually indicated even with slow-release formulations.

TOXIC REACTIONS AND SIDE EFFECTS Toxicity is related to the serum concentration of Li+ and its rate of rise following administration. Acute intoxication is characterized by vomiting, profuse diarrhea, coarse tremor, ataxia, coma, and convulsions. Symptoms of milder toxicity are most likely to occur at the absorptive peak of Li+ and include nausea, vomiting, abdominal pain, diarrhea, sedation, and fine tremor. The more serious effects involve the nervous system and include mental confusion, hyperreflexia, gross tremor, dysarthria, seizures, and cranial nerve and focal neurological signs, progressing to coma and death. Sometimes both cognitive and motor neurological damage may be irreversible. Other toxic effects are cardiac arrhythmias, hypotension, and albuminuria. Adverse effects common even in therapeutic dose ranges include nausea, diarrhea, daytime drowsiness, polyuria, polydipsia, weight gain, fine hand tremor, and dermatological reactions, including acne.

A small number of patients treated with Li+ develop diffuse thyroid enlargement; patients usually remain euthyroid, and overt hypothyroidism is rare. In patients who do develop goiter, discontinuation of Li+ or treatment with thyroid hormone results in shrinkage of the gland.

The kidneys' ability to concentrate urine decreases during Li+ therapy. Polydipsia and polyuria occur in patients treated with Li+, occasionally to a disturbing degree. Acquired nephro-genic diabetes insipidus can occur in patients maintained at therapeutic plasma concentrations (see Chapter 29). Typically, mild polyuria appears early in treatment and then disappears. Late-developing polyuria is an indication to evaluate renal function, lower the dose of Li+, or consider adding a potassium-sparing agent such as amiloride to counteract the polyuria. Polyuria disappears with cessation of Li+ therapy. Since progressive, clinically significant impairment of renal function is rare, many experts consider these to be incidental findings. Nevertheless, plasma creatinine and urine volume should be monitored during long-term use of Li+.

Li+ routinely causes EEG changes characterized by diffuse slowing, widened frequency spectrum, and potentiation with disorganization of background rhythm. Seizures have been reported in nonepileptic patients with therapeutic plasma concentrations of Li+. Myasthenia gravis may worsen during treatment with Li+. A benign, sustained increase in circulating polymorphonuclear leukocytes occurs during the chronic use of Li+, which reverses within a week after termination of treatment. Allergic reactions such as dermatitis and vasculitis can occur with Li+ administration. Worsening of acne vulgaris is a common problem, and some patients may experience mild alopecia.

In pregnancy, Li+ may exacerbate maternal polyuria. Concomitant use of lithium with natri-uretics and a low-Na+ diet during pregnancy can contribute to maternal and neonatal Li+ intoxication. During postpartum diuresis, one can anticipate potentially toxic retention of Li+ by the mother. Lithium freely crosses the placenta, and fetal or neonatal lithium toxicity may develop when maternal blood levels are within the therapeutic range. Lithium also is secreted in breast milk of nursing mothers. The use of Li+ in pregnancy has been associated with neonatal goiter, CNS depression, hypotonia ("floppy baby" syndrome), and cardiac murmur. All of these conditions reverse with time, and no long-term neurobehavioral sequelae have been observed.

The use of Li+ in early pregnancy may be associated with an increase in the incidence of cardiovascular anomalies of the newborn, especially Ebstein's malformation. The antimanic anti-convulsants valproic acid and probably carbamazepine have an associated risk of irreversible spina bifida that may exceed 1/100, and so do not represent a rational alternative for pregnant women. In balancing the risk versus benefit of using Li+ in pregnancy, it is important to evaluate the risk of untreated manic-depressive disorder and to consider conservative measures, such as deferring intervention until symptoms arise or using a safer treatment, such as a neuroleptic or ECT.

TREATMENT OF LITHIUM INTOXICATION There is no specific antidote for Li+ intoxication, and treatment is supportive. Vomiting induced by rapidly rising plasma Li+ may tend to limit absorption, but fatalities have occurred. Care must be taken to assure that the patient is not Na+- and water-depleted. Dialysis is the most effective means of removing the ion from the body and is necessary in severe poisonings, i.e., in patients exhibiting symptoms of toxicity or patients with serum Li+ concentrations >4 mEq/L in acute overdoses or >1.5 mEq/L in chronic overdoses.

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