Lithium

Lithium is a monovalent cation used in manic psychosis.

Three salts are available:

1. Lithium carbonate
2. Lithium citrate
3. Lithium chloride

Lithium carbonate is the most commonly used salt in therapeutics, because has less GIT irritation. It prevents mood swings in bipolar disorders.

The exact cause is not known. It is postulated that:

1. Drugs which increase catecholamine activity will aggravate mania.
2. Drugs that decrease catecholamine activity will relieve mania.

In mild cases, lithium carbonate is given alone. Sometimes it is combined with anti psychotics.

Mechanism of Action

The exact mechanism is not known. There are several theories:

1. Shares characteristics with Na, it substitutes Na+ as well as K+ in various cellular transports. Also replaces Na+ in generating action potential in nerve cells.
2. Decreases metabolism of biogenic amines, especially norepinephrine and dopamine.
3. Inhibits conversion of inositol diphosphate (IP2) to inositol monophosphate (IP1), which is further converted into inositol. This leads to depletion of PIP₂, which is a membrane precursor for IP₃ & DAG 2^nd messenger system.
4. Inhibits phospholipase C & adenylyl cyclase, thus interfering with 2^nd messenger system modulating effects on alpha₂ and D₂ receptors.
5. Increases uptake of choline into nerve cells that is utilized in synthesis of Ach.
6. Inhibition of 5HT_1A & 5HT_1B receptors, which are auto regulatory for release of serotonin.
7. With prolonged use, there is reuptake of glutamate into nerve cells.
8. Alters G protein functions causing uncoupling of receptors from G protein.

• Uncoupling of vasopressin leads to polyuria
• Uncoupling of TSH from G protein leads to hypothyroidism

Pharmacokinetics

• Absorption –Absorbed after oral administration.
• PPC –Peak plasma concentration is reached in half an hour.
• Distribution –widely distributed
• T1/2 –20-24 hours
• PPB –none
• Metabolism –none
• Excretion-actively reabsorbed

After administration, filtered by glomerulus and reabsorbed from proximal tubules. There is competition between Na⁺ and lithium for reabsorption. If excess of Na⁺ reabsorbed, more lithium is cleared. Increased lithium reabsorption in cases of Na⁺ depletion can lead to toxicity.

That is why lithium is never given to Na⁺  depleted patients.

• Elimination-biphasic

Around 40% is eliminated in first 10 hours

60% is excreted in about two weeks.

• Serum lithium concentration –done at least 12 hours after last dose
• Steady state concentration –obtained after 5 days.
• Excreted in body secretions; sweat, saliva, tears, milk

Adverse effects

1. GIT

Most common adverse effects are seen in GIT. These include:

• Abdominal discomfort
• Nausea
• Vomiting

2. Neurologic & psychiatric adverse effects

• Motor hyperactivity
• Ataxia
• Aphasia
• Dysarthria
• Choreoathetosis
• Tremors –effectively treated by propranolol, atenolol (beta blockers)
• Confusion

Appearance of new neurologic or psychiatric symptoms are a clear reason to stop lithium administration and perform lithium monitoring.

3. Thyroid functions-reversible

Can decrease thyroid functions, causing thyroid enlargement and hypothyroidism, which is reversible. This is because lithium uncouples G proteins from TSH receptors present on cells of thyroid glands.

4. Nephrogenic Diabetes Inspidus & Renal adverse effects

Can produce:

1. Nephrogenic diabetes inspidus
2. Polyuria
3. Polydipsia
4. Under ADH effect, the ability to conserve water is lost.

This is due to uncoupling of G-proteins from ADH receptors, decreasing the action of ADH on medullary ducts. This decreases the concentrating ability of kidney and increases water excretion. Amiloride can be given.

When given for prolonged periods;

• May produce intestinal nephritis
• Gets deposited in kidneys, impairing functions.

5. Cardiac adverse effects

Depresses sinus node, producing T wave flattening or inversion.

Thus contraindicated in bradytachy syndrome or sick sinus syndrome

6. Pregnancy, lactation

Clearance of lithium is increased. Dose has to be reduced once pregnancy is over.

Can harm the fetus, producing cardiac abnormalities by name of Ebstein abnormality and valvular defects.

If given to lactating mothers, lethargy is seen in suckling infants, hepatomegaly and poor Moro’s reflex.

7. Miscellaneous

• Leukocytosis
• Apneform eruptions
• Weight gain with sodium retention.

Serum lithium concentration

Kept below 0.6-1.4 mEq/l.

If exceeds 2 mEq/l, over dosage and toxicity can occur.

Lab investigations

Serum lithium concentration should be done after every 1 week.

Other lab investigations include:

1. Blood complete picture
2. Urine RE
3. ECG
4. RFTs
5. Thyroid function tests

After every 6 months.

Precautions

1. Formula should not be changed frequently
2. Constant monitoring should be done
3. Taken at fixed times
4. Neurologic symptoms should not appear.

Uses

1. Bipolar affective disorder
2. Acute phase anemia
3. Alcohol abuse
4. SIADH secretion
5. Drug induced leukopenia –due to chemotherapy
6. Hyperthyroidism

Dose

1. Tablets
2. Capsules
3. Syrups –Lithium citrate

Started at a lower dose of 600-900 mg, which is gradually increased to 2400 mg in divided doses.

Contraindications and Drug Interactions

1. Diuretics potentiate lithium toxicity
2. NSAIDs cause lithium retention
3. Neuroleptic drugs (antipsychotics) in a few cases potentiate CNS toxicity. But in severe from of mania, we do combine with antipsychotics.
4. Anticholinergic drugs decrease absorption, therapeutic failure may occur.
5. Digoxin potentiates lithium toxicity
6.  ACE Inhibitors cause lithium retention.