Lith

Uses

Treatment and prophylaxis of mania, bipolar disorder and recurrent depression.

Lith is also used to associated treatment for these conditions: Bipolar Disorder (BD), Acute Manic episode

How Lith works

Lithium's mechanism of action is still unknown. However, the “inositol depletion theory” suggests 3 main potential targets. These targets are inositol monophosphatase, inositol polyphosphatase, and glycogen synthase kinase 3(GSK-3).

The “Inositol depletion theory” suggests lithium behaves as an uncompetitive inhibitor of inositol monophosphatase in a manner inversely proportional to the degree of stimulus. This inhibition lowers levels of inositol triphosphate. However, stronger inhibitors of inositol monophosphatase are not as clinically effective and low levels of inositol triphosphate are associated with memory impairment.

Lithium acts on inositol polyphosphatase as an uncompetitive inhibitor. This inhibition is thought to have multiple downstream effects that have yet to be clarified.

Lithium regulates phosphorylation of GSK-3 which regulates other enzymes through phosphorylation. Lithium can also inhibit GSK-3 through interfering with the magnesium ion in the active site.

Dosage

Lith dosage

Adult and child over 12 years: initially 1 gm to 1.5 gm daily; prophylaxis, initially 300-400 mg daily. Should be taken with food.

Side Effects

Tiredness, loss of appetite, nausea, vomiting, diarrhoea, hands shaking, memory problems, increased thirst and consequently passing urine more often by day, and perhaps also by night.

Toxicity

In rats, the oral LD50 is 525mg/kg and the inhalation LC50 is >2.17mg/L over 4 hours.

There is insufficient data regarding the carcinogenicity, mutagenicity, or fertility impairment of lithium carbonate. However, studies in rats and mice have shown repeated daily dosing of lithium carbonate result in adverse effects on male reproductive organs, spermatogenesis, and testosterone levels.

There is conflicting evidence regarding the incidence of cardiovascular abnormalities in first trimester administration of lithium. Animal studies have shown adverse effects on the fetus and fertility overall. The risk and benefit of lithium use in pregnancy must be weighed and should lithium treatment continue in pregnancy, serum lithium concentrations should be regularly monitored, dosages should be adjusted, and lithium should be decreased or stopped 2 or 3 days before delivery to avoid maternal and/or neonatal toxicity.

Breastfeeding is not recommended with maternal lithium use but if it is continued, the infant should be monitored for thyroid function and symptoms of lithium toxicity such as hypertonia, hypothermia, cyanosis, and ECG changes.

Safety in effectiveness in patients under 12 years has not been established, however dosing for patients 12 years and older is similar to that of adult patients.

Safety in geriatric patients has not been established, however caution is advised when using lithium as this population is more likely to have impaired renal function.

Patients with creatinine clearance between 30mL/min and 89mL/min should be started at a lower dose and slowly titrated to the correct dose while monitoring serum lithium levels. Patients with a creatinine clearance less than 30mL/min should not take lithium, especially in the case of a low sodium diet.

Precaution

Decreased tolerance to lithium has been reported to ensue from protracted sweating or diarrhoea and, if such occur, supplemental fluid and salt should be administered under careful medical supervision and lithium intake reduced or suspended until the condition is resolved.

Interaction

Reduced serum levels with carbonic anhydrase inhibitors, chlorpromazine, sodium-containing preparations, theophylline, urea. Enhanced hypothyroid effects with iodine salts. Enhanced effects of neuromuscular-blocking agents. Reduced pressor response to sympathomimetics.

Food Interaction

• Avoid alcohol. Alcohol increased peak serum concentrations of lithium.
• Avoid iodine-containing foods and supplements. Iodine and lithium may synergistically produce hypothyroidism.
• Limit caffeine intake. Caffeine may decrease lithium concentrations.
• Take with food. Food reduces gastrointestinal upset.

Volume of Distribution

Apparent volume of distribution is 0.7 to 1.0L/kg.

Elimination Route

Lithium absorption is rapid and oral bioavailability is close to 100%.

Half Life

The half life of lithium carbonate is 18 to 36 hours. Other sources say it may be 7 to 20 hours.

Clearance

Clearance is generally between 10 and 40mL/min but may be as low as 15mL/min in elderly patients and those with renal impairment.

Elimination Route

Lithium is primarily eliminated through the kidneys and elimination in the feces is insignificant.

Pregnancy & Breastfeeding use

Pregnancy Category D. An increased incidence of cardiovascular abnormality has been noted in infants of women given lithium during the first 3 months of pregnancy, such use should be avoided unless essential. Breast feeding is not advised unless the benefits of lithium use outweigh the advantages.

Contraindication

Renal insufficiency, cardiovascular insufficiency, Addison's disease and untreated hypothyroidism are all contraindications to lithium therapy.

Special Warning

Renal Impairment: CrCl 10-50: 50-75% of normal dose.

Acute Overdose

In the event of accumulation, lithium should be stopped and serum estimations should be carried out every six hours.Under no circumstances should a diuretic be used. Osmotic diuresis (mannitol or urea infusion) or alkalinisation of the urine (sodium lactate or sodium bicarbonate infusion) should be initiated. If the serum lithium level is over 4.0 mmol/L, or if there is a deterioration in the patient's condition, or if the serum lithium concentration is not falling at a rate corresponding to a half-life of under 30 hours, peritoneal or haemodialysis should be instituted promptly. This should be continued until there is no lithium in the serum or dialysis fluid. Serum lithium levels should be monitored for at least a further week to take account of any possible rebound in serum lithium levels as a result of delayed diffusion from body tissues.

Storage Condition

Store at 25° C

Innovators Monograph

You find simplified version here Lith