Lithium therapeutic serum concentration

TABLE 36-5. Pharmacokinetics and Therapeutic Serum Concentrations of Lithium and Anticonvulsants Used in the Treatment of Bipolar Disorder... 

Use standard therapeutic serum concentration ranges if clinically indicated if partial response or breakthrough episode, adjust dose to achieve higher serum concentrations without causing intolerable adverse effects valproate is preferred over lithium for mixed episodes and rapid cycling lithium and/or lamotrigine is preferred over valproate for bipolar depression. 

Lithium has a fairly narrow therapeutic range, i.e. the gap between minimum effective serum concentration (0.4 mmoFL-l) and that causing toxicity (1.2 mmoFL-l) is low. It is therefore important to monitor serum lithium regularly. Serum concentrations above 1.2 mmol L-l must be avoided. It should also be remembered that toxicity can occur in a few patients at concentrations below 1.2 mmol-L-l and that toxicity is always a clinical diagnosis. 

Polydipsia and polyuria are common but reversible concomitants of lithium treatment, occurring at therapeutic serum concentrations. The principal physiologic lesion involved is loss of responsiveness to antidiuretic hormone (nephrogenic diabetes insipidus). Lithium-induced diabetes insipidus is resistant to vasopressin but responds to amiloride. 

Difficulty in attaining a therapeutic serum concentration of lithium despite increased doses was attributed to increased renal clearance due to the osmotic effect of glycosuria in a 44-year-old man with poorly controlled diabetes mellitus (682). 

Symptoms suggestive of toxicity at therapeutic serum concentrations also occurred in a 49-year-old man taking lithium (0.7 mmol/1), carbamazepine, and trifluperidol, who developed persistent cerebellar deterioration during a febrile episode of lobar pneumonia (179). 

Another patient who developed cerebellar symptoms consistent with lithium neurotoxicity despite a low therapeutic serum concentration (0.5 mmol/1) was more fortunate, as the symptoms resolved promptly when lithium was withdrawn (180). 

Lithium is used in the management of mania, bipolar disorder (formerly manic depression) and recurrent depressive illnesses. The dosage of lithium is adjusted to give therapeutic serum concentrations of 0.4 to 1 mmol/L, although it should be noted that this is the range used in the UK, and other ranges have been quoted. 

Severe lithium toxicity is associated with seizures. In two cases, seizures were associated with high lithium concentrations (4.86 mmol/1 in a 25-year-old woman and 2.5 mmol/1 in a 48-year-old man) [44 ]. A third case occurred in a 20-year-old man whose lithium concentration was only 0.8 mmol/1 [45 ]. Status epUepticus that lasted 45 minutes occurred in a middle-aged woman undergoing electroconvulsive therapy (ECT) while she had therapeutic serum concentrations of lithium and was also taking agents that reduce the seizure threshold (clomipramine and quetiapine) [46 ]. It has been previously proposed that ECT can cause the intracellular concentration of lithium to rise without a concomitant rise in serum concentration [47 ]. 

Lithium toxicity can occur with serum levels greater than 1.5 mEq/L, but the elderly may have toxic symptoms at therapeutic levels. Severe toxic symptoms may occur with serum concentrations above 2 mEq/L, including vomiting, diarrhea, incontinence, incoordination, impaired cognition, arrhythmias, and seizures. Permanent neurologic impairment and kidney damage may occur as a result of toxicity. 

Indications and Dosages Alert During acute phase, a therapeutic serum lithium concentration of 1-1.4 mEq/L is required. For long-term control, the desired level is 0.5-1.3 mEq/L. Monitor serum drug concentration and clinical response to determine proper dosage. 

Geriatric Considerations - Summary Volume of distribution (Vd), clearance, and half-life are significantly altered in older adults. Lithium toxicity may occur within the usual adult therapeutic range. Older adults are likely to exhibit toxic effects at lower serum concentrations. Significantly lower doses are often efficacious for affective disorders than are used in younger adults. Monitor serum concentrations closely, increased riskof lithium toxicity when a diuretic, NSAID, or ACE Inhibitor is started in a patient already taking lithium. 

Reversible electrocardiographic (EKG) T-wave depression occurs frequently with therapeutic serum lithium concentrations. Arrhythmias have occurred rarely. The cardiac effects of lithium may result partly from displacement of potassium from intracellular myocardial sites by lithium, resulting in a slow, partial depletion of intracellular potassium (Kawata, 1979). 

Lithium. For most psychiatrists, lithium testing is the area of laboratory testing with which they are most familiar. Lithium has a well-defined, narrow serum concentration range (49). For acute mania, therapeutic lithium levels range between 0.5 mEq/L at the low end and about 1.5 mEq/L at the high end. Individual patients, however, may have idiosyncratic responses outside this range. Samples for blood levels should be drawn about four to five half-lives (i.e., 4 to 6 days) after an adjustment in dose, or more frequently if unexpected reactions occur. Blood samples should be collected 10 to 12 hour after the last dose. 

Lithium is toxic in rats at the same serum concentrations as in humans (Schou, 1976). In a rat study by Smith and Smith (1973), lithium was administered in the low therapeutic range for a period of only 1 week. The authors summarized, The most consistent effect of lithium was to decrease the voluntary activity of the rats. ... 

Lithium is easily, inexpensively, and accurately measurable in the serum, and serum concentration determination is a useful adjunct to monitoring its therapeutic efficacy and avoiding toxicity (54). 

Reports of overdose-related neurological symptoms abound (150-160). Among these reports, are cases of neurotoxicity at therapeutic serum lithium concentrations (150,158,160) and neurotoxicity associated with noncon-vulsive status epilepticus (154,156). 

A 56-year-old man with normal renal function and therapeutic lithium concentrations became toxic (serum concentration 2.53 mmol/1 24 hours after the last dose) with renal impairment (serum creatinine 141 gmol/l 1.6 mg/ dl) within days of starting levofloxacin. Both symptoms and laboratory abnormalities resolved with withdrawal of both lithium and levofloxacin (615). 

The recommended guidelines for baseline and routine laboratory testing for lithium are listed in Table 68-12. The 12-hour postdose lithium serum concentration may be 12% to 33% higher with extended-release preparations and lower with regular-release tablets with divided dosage schedules. The dose should be adjusted based on the steady-state serum concentration drawn 12 hours ( 30 minutes) after the last dose. A therapeutic trial (lithium serum concentrations of 0.6 to 1.2 mEq/L) should last a minimum of 4 to 6 weeks. Acutely manic patients may require serum concentrations of 1 to 1.2 mEq/L, and some need up to 1.5 mEq/L to achieve a therapeutic response. Although serum concentrations less than 0.6 mEq/L are associated with higher rates of relapse, some patients may do well at 0.4 to 0.7 mEq/L. For bipolar prophylaxis in elderly patients, serum concentrations of 0.4 to 0.6 mEq/L are recommended because of increased sensitivity to adverse effects. ... 

B. F. Rocks, R. A. Sherwood, and C. Riley, Direct Determination of Therapeutic Concentrations of Lithium in Serum by Flow Injection Analysis with Atomic Absorption Spectroscopy Detection. Clin. Chem., 28 (1982) 440. 

Lithium is given under close supervision with regular monitoring of serum concentrations because there is a narrow margin between therapeutic concentrations and those that are toxic. Initially weekly monitoring is advised, dropping to every 3 months for those on stable regimens. It is usual to take serum-lithium samples about 10 to 12 hours afterthe last oral dose. 

Similarly, lithium-7 MRS has been used to examine the pharmacokinetics of lithium, a drug that is widely used in the treatment of a number of psychiatric disorders. Initial studies showed that there was a slow accumulation of lithium in the brain, which may be responsible for the delay in therapeutic response that is often seen following the initiation of therapy. Subsequent studies showed that lithium levels in the brain and muscle were lower than the average serum concentration. From the ratio of these in vivo measurements, the authors hypothesized that the minimal effective concentration of brain lithium level for maintenance treatment... 

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