Lithium - Anti-Manic Drugs

ANTI-MANIC DRUGS

Lithium

·              Lithium, the lightest of all metals is the drug of choice even today (more than 50 years after its introduction) for the treat-ment of manic-depressive psychosis i.e. bipolar affective disorder. It is also useful as adjunctive therapy for depression, mania in children and young adults, alcoholism, and as a prophylaxis for cluster headaches.

·              Lithium is a naturally occurring alkali metal, present in the earth’s crust at concentrations of 0.005%. Lithium is used in industry as a coolant in nuclear reactor, in alkaline storage batteries, and in the manufacture of alloys. Occupational toxicity is however uncommon. Lithium bromide, lithium chloride, lithium hydroxide, and lithium silicate are synthesised from lithium carbonate which acts as a chemical intermediate.

Toxicokinetics

·              Lithium is rapidly absorbed on oral administration and peak levels are achieved in 2 to 4 hours. Soluble lithium compounds are rapidly and completely absorbed from the gastrointestinal tract, besides subcutaneous, intramuscular, and intraperitoneal areas.

·              The volume of distribution is 0.6 L/kg, and plasma protein binding is to the extent of only 10%. Lithium is evenly distributed among the tissue compartments. Sustained release formulations require 25 to 30 hours for complete distribution.

·              The therapeutic elimination half-life is about 20 to 24 hours, and 95% of the drug is excreted by the kidney of which 80% is reabsorbed, while the remaining 20% appears in the urine unchanged.

Mode of Action

·              The exact mechanism of action is so unclear that there have been innumerable theories propounded to explain the therapeutic efficacy of lithium in bipolar disorders none of which have been conclusively demonstrated to be correct.

·              The main premise is as follows: since lithium crosses cell membranes by various methods including the sodium pump, the sodium leak canal, a lithium-bicarbonate exchange, and the sodium-lithium counter exchange system, it is believed that the chemical exerts its therapeutic effect by substituting for sodium in these transmembranal ion exchanges.

·              A monovalent cation, chemically similar to Na+ and K+, lithium is thought to act by

o     imperfect substitution for other cations in ionic processes and

o     alteration of the critical microenvironment required for humoral or metabolic processes.

·              By these mechanisms in the CNS, lithium affects nerve excitation, synaptic transmission and neuronal metabolism.

Adverse Effects

■■   Thirst, polyuria, tremor (even at rest), acne, hypothy-roidism, impaired concentration, ataxia, and dysarthria.

■■   Less commonly there may be alopecia, psoriasis of finger-nails, and restless legs syndrome.

■■   Sudden cessation of lithium treatment after a prolonged course can sometimes precipitate asthma.

Drug Interactions

·              Diuretics and NSAIDs (except aspirin) reduce lithium excretion. Combination of these drugs increases the steady-state plasma lithium concentration by 39 to 50%. Observation for toxicity and frequent monitoring is recom- mended.

·              Synergistic effect is noted with pancuronium and suxam- ethonium.

·              Combination with neuroleptics may result in encephalitis. The effect of antidepressants in general may be augmented by lithium.

·              Lithium is frequently combined with haloperidol for acute manic episodes during the first and second week of treat- ment. Irreversible neurological toxicity and brain damage have occurred in some of these patients.

·              In a review of lithium drug interactions, treatment of breakthrough depression with tricyclic antidepressants in patients taking lithium was associated with worsening of lithium-induced tremor. There were also case reports of extrapyramidal symptoms and seizures with the combi-nation.

·              ACE inhibitors have been reported to enhance the toxic effects of lithium. They increase the tubular reabsorption of lithium.

·              Thiazide diuretics also, via their action on distal tubules, cause sodium depletion with a subsequent decrease in lithium clearance; lithium toxicity is thus likely to result. 

Clinical (Toxic) Features

·              There are 3 types of lithium poisoning:

o     Acute poisoning in patients not under lithium treatment:mild or moderately severe manifestations.

o     Acute poisoning in patients under lithium treatment: severe manifestations.

o     Chronic poisoning in patients under lithium treatment.

·            Table 19.9 lists the manifestations of lithium toxicity.Nausea and vomiting are common effects. Headache can occur.

·            There are indications that lithium intake during preg-nancy may be associated with cardiovascular and other congenital malformations. Congenital malformations, including cardiac defects have been reported in infants of mothers receiving lithium therapy in the first trimester.

·              Lithium toxicity may be one of the causes of Floppy babysyndrome.

·            In patients treated with lithium chronically, T wave flat-tening is the most common EKG abnormality found in 20 to 100%, occurring within 5 days of starting treatment and disappearing within 3 to 5 days after discontinuing treatment. Sinus node dysfunction is the most frequently reported conduction defect.

·            Hypercalcaemia and hyperkalaemia with cardiac rhythm disturbances have been reported as a side effect of lithium treatment.

·            Neutrophilia is a reported side effect of treatment with lithium, and significant leukocytosis may develop with lithium toxicity.

·            Tremor, hyperreflexia, ataxia, slurred speech, lethargy, confusion, and cogwheel rigidity occur with mild to moderate intoxications. Agitation is common. Seizures and coma may develop with severe poisoning. Fine tremor of the hands is usually seen in 45 to 50% of patients starting lithium therapy. Less than 10% of patients experience tremor after one year of therapy.

·              Severe neurologic effects are much more common in patients with chronic poisoning than in those with acute overdose. Since lithium clears from the plasma much faster than from the brain, patients with chronic lithium toxicity may still have neurological toxicity when lithium levels have fallen into or below the therapeutic range.

·            Dehydration is a common finding in patients with chronic lithium intoxication. Dehydration may precipi-tate chronic lithium toxicity secondary to increased renal tubular resorption of lithium ion, and lithium toxicity may cause dehydration secondary to nausea and vomiting, polyuria and decreased water drinking from mental status changes.

·            Long-term lithium therapy has been shown to result in decreased renal glomerular function. Nephrogenic diabetes insipidus and resulting hypernatraemia may develop, particularly with chronic overdose. Acute over-dose can lead to renal failure.

·            Only 1% of lithium therapy patients experience derma-tologic effects. Acne, folliculitis, psoriasis, alopecia, cutaneous ulcers, xerosis cutis, anaesthesia of the skin, and exfoliate dermatitis can all occur, which usually resolve when therapy is discontinued.

·            Hypothyroidism has been associated with chronic lithium intoxication. In systematic studies, the incidence has been consistently elevated (10.4% of cases), espe-cially in females (14%) and in older individuals. There is a substantially increased risk of hypothyroidism in female patients age greater than 60, and in patients with a family history of thyroid disease. The symptoms of Graves’ disease may be masked by lithium therapy.

Diagnosis

·      Blood lithium level (BLL): Toxicity is associated with levels over 2 mEq/L. Death is likely if the BLL crosses 5 mEq/L. Therapeutic levels generally range from 0.6 to 1.2 mEq/L. However, serum levels do not necessarily correlate with toxicity after acute ingestion.

·      Evidence of hypernatraemia, hypocalcaemia, and hypopar-athyroidism.

·              Perform urinalysis and determine serum creatinine to rule out impaired renal function.

Treatment

·      Stabilisation: Maintenance of airway, breathing, andcirculation. Cardiac monitoring is desirable. In the case of hypotension, infuse 10 to 20 ml/kg of isotonic fluid and place in Trendelenburg position. If hypotension persists, administer dopamine or noradrenaline. Consider central venous pressure monitoring to guide further fluid therapy. For mild/moderate asymptomatic hypertension, pharmacologic intervention is seldom necessary and 4 to 6 hours of observation is usually adequate. For severe hypertension, use nitroprusside or esmolol.

·      Decontamination : Activated charcoal is ineffective.Stomach wash may help if the patient is seen early. Whole-bowel irrigation with a balanced polyethylene-electrolyte solution (PEG-ELS) is said to be quite beneficial. The recommended rates of administration are 2 L/hr (adult), and 500 ml/hr (child). Bentonite has been shown to reduce lithium absorption in vitro. In one study, bentonite reduced the lithium concentration by 20.5% in deionised water (pH and by 48.1% in simulated gastric fluid (pH 1.2) at a bentonite lithium ratio of 30.1 (p value 0.0001).

·      Elimination enhancement: Haemodialysis is indicated inthe following situations—

·              Severe intoxication with coma, convulsions, or respiratory failure.

Ø   Grade 3 coma.

·              Progressive deterioration.

·              Rising serum concentration.

Ø   4 mEq/L of serum concentration.

On an average, 4 hours of haemodialysis will reduce plasma lithium concentration by 1.0 mEq/L, and a total dialysis time of 10 to 12 hours may be required. Lithium clearance during haemodialysis is approximately 100–120 ml/min; thus four hours of haemodialysis is equivalent to 24-hour clearance of 16–20 ml/min. Renal lithium clearance is 20 to 30% of creati-nine clearance; thus those with renal impairment (calculated creatinine clearance less than 60 ml/min) are generally good candidates for haemodialysis. Serum lithium levels should not be considered a major criterion in acute intoxications. The deci-sion to institute dialysis in acute intoxications should be based on a combination of clinical toxicity, the duration of exposure, and a serial profile of serum lithium levels.

However, patients who have been dialysed sometimes develop a “rebound” lithium level after treatment because of subsequent leakage of intracellular lithium into the plasma. Hence a repeat level should always be performed 6 hours post-dialysis, and if this is high, a second round of dialysis may be needed.

·              If haemodialysis cannot be done, some investigators suggest that sodium polystyrene sulfonate can be administered which is beneficial in decreasing lithium absorption. It can however cause sodium overload and hypokalaemia.

·              Recent studies indicate that continuous arteriovenous haemodiafiltration (CAVH) can be very effective in lithium poisoning. Successful use of veno- venous filtration has also been reported in some isolated case reports.