Month: June 2020

Metals: Lithium

Pictures, stories, and facts about the element Lithium in the ...

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Lithium (named from “lithos”, Greek word for stone) is a chargeless metal and the simplest xenobiotic. Lithium is a soft, silvery-white alkali metal while also highly reactive and flammable. Lithium is widely distributed on Earth but does not naturally occur in its elemental form due to its high reactivity. Trace amounts of lithium are found in virtually all rocks.

Additionally, trace amounts of lithium have been found in plants, plankton, and invertebrate tissues. Industrial applications include lithium-ion batteries, metal additives, and grease lubricants. Lithium has a limited therapeutic index and has long been used in the treatment of bipolar disease (mania and depression) (1).

Toxicokinetics (1, 2, 4)

  • Bioavailability: rapidly absorbed (~100%)
    • Lithium exerts its effects once it has moved to intracellular compartment
    • Patients with elevated serum levels tend to be asymptomatic
  • Serum Levels: reflect extracellular lithium concentrations
  • Distribution:
    • Widely in total body water and does not bind to serum proteins
    • Tissue distribution follows multiple compartment model
      • Delayed diffusion from the extracellular to the intracellular compartment
  • Absorption/Accumulation:
    • Rapidly taken up by liver, kidney, thyroid, and bone
    • Brain and kidney show highest levels
      • Delayed diffusion in CSF (24 hrs)
      • 80% of lithium that is filtered by kidneys is reabsorbed
    • Overdose: prolonged gastric absorption and clumping from insoluble aggregates may occur (4)
  • Metabolism: Lithium is neither metabolized nor protein-bound.
  • Excretion: 
    • 95% excreted in kidneys
    • ~5% removed via sweat and feces
  • Elimination:
    • Serum elimination half-life can vary 12 to 27 hours
    • Patients with chronic intoxication: half-life up to 48 hours
    • Elderly patients: half-life up to 58 hours
  • Renal Clearance: 
    • Usually 10 to 40 mL/min
    • May be decreased to 15 mL/min
  • Fetal Distribution:
    • Freely crosses placenta and is excreted in breast milk
      • Labeled pregnancy Class D
      • Implicated in increased congenital cardiac defects
      • Reported signs of cyanosis, hypotonia and lethargy in infants of mothers taking lithium

Mechanism of Action (1-3)

The precise mechanism of action of Li+ is currently unknown. An increasing number of scientists have concluded that the excitatory neurotransmitter glutamate is the key factor in understanding how lithium works. Let’s take a look:

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There are several proposed and confirmed mechanisms of actions for lithium including that noted above. Other mechanisms include:

  • Disrupting glutamate receptors (GluR3) resulting in a decrease (depression) or increase (mania)
  • Non-competitive inhibition of enzyme, inositol monophosphatase (IP) by inhibiting glycogen synthase-3
  • Enhanced deactivation of GSK-3B enzyme resulting in circadian rhythm disruptions and DNA damage
  • Reducing neuronal responsiveness to neurotransmitters due to inhibitory effects of adenylate cyclase and G proteins vital for ion channel opening
  • Stimulating serotonin release from hippocampus

Signs and Symptoms of toxicity (2)

The severity of lithium toxicity is often divided into the following three grades: mild, moderate, and severe.

  • Mild symptoms: nausea, vomiting, lethargy, tremor, and fatigue
  • Moderate intoxication: confusion, agitation, delirium, tachycardia, and hypertonia
  • Severe intoxication: Coma, seizures, hyperthermia, and hypotension

Infographic by Oluwatobi via Canva

Biomarkers/Diagnostic Testing (1)

Once the patient presents to the emergency room, a lithium concentration should be determined, and serial measurements should be performed. Lithium concentration serves as a marker for exposure. 

Infographic by Oluwatobi via Canva

Unique Exposures: Drinking Water (6)

Harari et al., concluded that elevated lithium exposure through drinking water during pregnancy may impair calcium homeostasis, particularly vitamin D. This implication is of a huge public health concern because vitamin D deficiencies have been associated with impaired maternal and fetal health!

In summary, check out this 1-minute video!

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References:

(1) A. Greller H. Lithium. In: Nelson LS, Howland M, Lewin NA, Smith SW, Goldfrank LR, Hoffman RS. eds. Goldfrank’s Toxicologic Emergencies, 11e. McGraw-Hill; Accessed June 14, 2020. https://accesspharmacy-mhmedical-com.proxy.lib.ohio-state.edu/content.aspx?bookid=2569&sectionid=210274851

(2) Hedya SA, Avula A, Swoboda HD. Lithium Toxicity. [Updated 2019 Nov 13]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK499992/

(3) Lithium cation. https://www.drugbank.ca/drugs/DB01356. Updated 2007. Accessed June 14, 2020.

(4) Decker BS, Goldfarb DS, Dargan PI, et al. Extracorporeal Treatment for Lithium Poisoning: Systematic Review and Recommendations from the EXTRIP Workgroup. Clin J Am Soc Nephrol. 2015;10(5):875‐887. doi:10.2215/CJN.10021014

(5) Pérez-Granados, Ana & Vaquero, MP. (2002). Silicon, aluminium, arsenic and lithium: Essentiality and human health implications. The journal of nutrition, health & aging. 6. 154-62.

(6) Harari F, Åkesson A, Casimiro E, Lu Y, Vahter M. Exposure to lithium through drinking water and calcium homeostasis during pregnancy: A longitudinal study. Environmental Research. 2016;147:1-7. http://www.sciencedirect.com/science/article/pii/S0013935116300305. doi: https://doi.org/10.1016/j.envres.2016.01.031.