Lithium Carbonate

Mechanism

Chemical and Commercial Profile

Common trade names: Plenur, Lithium Carbonate, Litio Carlsbad.
Group: Inorganic monovalent cation (Lithium mineral salt).

Mechanism of Action

The exact cellular mechanism of action remains incompletely delineated, but is attributed to two main pathways of modulation of synaptic plasticity:

1. Inhibition of the Phosphatidylinositol (IP3/DAG) pathway: Lithium non-competitively inhibits the enzymes Inositol Monophosphatase (IMPase) and Inositol Polyphosphate 1-Phosphatase, depressing the recycling of membrane inositol and selectively turning off the hyperactive intracellular signaling of G protein-coupled receptors involved in the mania phases.
2. Direct inhibition of Glycogen Synthase Kinase 3 beta (GSK-3β): Promotes the stabilization of β-catenin and the expression of the neurotrophic factor BDNF, exerting a direct neuroprotective action and reversing the hippocampal atrophy observed in chronic affective disorders.

Pharmacokinetics

Pharmacokinetics

• Absorption: Rapid and complete after oral intake; 100% bioavailability. C_max in 1-2 hours (regular formulas) or 4-6 hours (extended release formulas).
• Distribution: Free cation not bound to plasma proteins. It is distributed slowly throughout the total body water (V_d ≈ 0.7-0.9 L/kg). Cross the BBB slowly.
• Metabolism: Null. It is not metabolized in the liver.
• Excretion: Renal exclusively. Freely filtered by the glomerulus, 80% being reabsorbed in the proximal convoluted tubule due to competitive mimicry with the Sodium ion (Na⁺).
• Half-life (t_1/2): 18 to 24 hours, increasing to >36 hours in the elderly or chronic kidney disease.

Indicators and dose

Indications

• Prevention of the phases of mania and depression in Bipolar Disorder type I and II.
• Treatment of acute manic episode.
• Potentiation of antidepressant treatment in unipolar depression resistant to conventional drugs.
• Demonstrated and direct decrease in suicidal ideation and completed suicidal behavior.

Dosage and Settings

• Acute Manic Phase: 800 mg to 1200 mg/day divided into two doses; look for objective litemia between 0.8-1.2 mEq/L.
• Prophylactic Maintenance: 400 mg to 800 mg/day; look for more conservative maintenance levels between 0.6-0.8 mEq/L.
• Mandatory Laboratory Monitoring: Plasma litemia (every 3-6 months once stable), kidney function (creatinine and GFR at baseline and semi-annual), and thyroid function (TSH and annual free T4).
• Kidney Failure:
  • Cl_Cr [30-60 ml/min]: Reduce the initial dose to 50% and monitor lithemia monthly.
  • Cl_Cr < 30 ml/min: Absolutely contraindicated.

Security

Contraindications

Critical alert · Narrow Therapeutic Margin

The optimal therapeutic range of lithemia is extremely narrow: 0.6 mEq/L to 1.2 mEq/L mandatory measured in the valley (12 hours after the last dose). Plasma levels above 1.5 mEq/L are associated with severe neurological toxicity, and values above 2.5 mEq/L represent a potentially lethal medical emergency that requires the immediate initiation of rescue hemodialysis.

• Moderate to severe chronic renal failure (Cl_Cr < 30 ml/min).
• Severe dehydration, severe sodium depletion or strict low-sodium diet (causes massive lithium reabsorption in the proximal tubule, precipitating toxicity).
• Unstable cardiovascular disease or pre-existing atrioventricular block.

Adverse Effects (ADR)

Clinical Interactions

The dangerous triad that raises lithemia

Three families of commonly used drugs decrease renal clearance of lithium and rapidly and severely increase plasma lithemia, precipitating acute poisoning:

• NSAIDs (especially indomethacin and ibuprofen; they reduce the synthesis of vasodilatory prostaglandins in the renal afferent arteriole, decreasing GFR). Paracetamol and aspirin are safe alternatives.
• Thiazidic diuretics (such as hydrochlorothiazide; induce sodium depletion in the distal tubule, promoting massive compensatory reabsorption of sodium and lithium in the proximal tubule).
• ACEI and ARB (such as enalapril or losartan; they alter renal glomerular hemodynamics).

Pregnancy and Breastfeeding

FDA Category: D. Lithium freely crosses the placental barrier and is classically associated with Ebstein's Anomaly (low implantation of the tricuspid valve in the right ventricle with atrialization of the same; absolute risk of ~1 in every 1000 exposed pregnancies, significantly higher than the baseline incidence). Requires detailed fetal echocardiography in the second trimester if treatment cannot be withdrawn. Breastfeeding: Absolutely contraindicated due to the risk of severe neonatal toxicity (flaccidity, cyanosis, neonatal hypothyroidism).