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lithium carbonate (Eskalith, Lithane, Lithobid, Lithonate)

Tradenames: Eskalith, Lithane, Lithobid, Lithonate. Indications: - management of psychotic disorders - bipolar illness - mania - major depression - diminishes risk of dementia in patients with bipolar disorder [14] - diminishes risk of suicide (odds ratio = 0.13) & all-cause mortality (odds ratio = 0.38) in patients with bipolar disease or unipolar depression [18] - cluster headache [19] Contraindications: 1) severe cardiovascular disease 2) severe renal insufficiency Caution: 1) cardiovascular disease 2) thyroid disease 3) severe debilitation 4) patients receiving diuretics, or otherwise predisposed to hyponatremia & dehydration 5) elderly patients may be extremely sensitive to the effects of lithium Dosage: 1) start 300 mg PO BID 2) average effective dose 900-1800 mg/day divided TID-QID 3) average maximum dose: 2.4 g/day divided TID-QID 4) children: 15-60 mg/kg/day divided TID-QID (do NOT exceed adult dosage) 5) take with meals to reduce GI upset 300 mg = 60 mg Li+, 8 meq or mmol Tabs: 150, 300, 600 mg. Slow-release: 300, 450 mg. Syrup: 300 mg/5 mL. Pharmacokinetics: 1) lithium is readily absorbed from the GI tract 2) absorption is increased by food [10] 3) peak serum levels in 0.5-2 hours 4) onset of action is 7-10 days 5) elimination 1/2life is 20-27 hours after a single dose 6) 1/2life may increase to 2.4 days in patients on therapy for 1 year or longer 7) volume of distribution: 0.3-0.4 L/kg (initial) 8) excreted in the urine 9) lithium clearance can be increased or decreased by 30-50% by sodium loading or depletion Monitor: 1) baseline & every six months to annually a) serum creatinine, BUN, urinalysis b) serum TSH c) serum calcium - total serum calcium often elevated - ionized serum calcium is normal [21] d) complete blood count (CBC) e) serum electrolytes [13] r) serum Li+ levels* (more frequently as indicated) 2) pregnancy test - baseline & if suspected (eligible women) 3) during pregnancy, fetal ultrasound at 18-20 weeks; small risk of heart malformation [8] * Lithium toxicity is closely related to serum levels & can occur with therapeutic levels. [21] * Serial serum lithium levels should be monitored during therapy * During pregnancy, monitor monthly & weekly near delivery [8] Therapeutic range: - 0.5-1.4 mmol/L - steady state reached in 5 days - trough levels for acute mania 0.8-1.2 meq/L - trough levels for acute maintenance 0.6-1.0 meq/L - dose increase of 300 mg/day increased trough level by 0.2 meq/L Adverse effects: (may not be dose-related) 1) hypothyroidism 2) renal effects a) renal insufficiency; risk of renal failure is small [15] - increased risk of stage 3 renal failure [21] b) effects on GFR & urinary concentrating ability are small c) nephrogenic diabetes insipidus 1] most common adverse effect 2] occurs in up to 40% of patients [16] 3] amiloride may mitigate [5] d) chronic tubulointerstitial nephritis [24] 1] hyperchloremic metabolic acidosis 2] renal tubular acidosis e) minimal change glomerulonephropathy 3) weight gain 4) aggravation of acne 5) psoriasis/exacerbation of psoriasis 6) hypercalcemia (hyperparathyroidism) 7) tremor (fine, characteristics of essential tremor) - ref [23] refers to as parkinsonian tremor 8) teratogenic a) cardiac anomalies: Ebstein's anomaly, tricuspid atresia b) not teratogenic [15] 9) also see Toxicity: (below) * women at greater risk of renal & thyroid disorders than men * younger women at higher risk than older women * adverse effects generally occur early in treatment [21] Toxicity: - volume depletion (hypovolemia) is a frequent precipitant - diminished glomerular filtration rate & reduced lithium clearance - manifestations: - nausea, vomiting, diarrhea, weakness, fasciculations, twitching, ataxia, tremor, cogwheel rigidity, myoclonus, choreoathetosis, seizures, confusion, agitation, pseudotumor cerebri coma, cardiovascular collapse, renal tubular acidosis, joint pain, rash - laboratory findings: - leukocytosis, hyperglycemia, albuminuria, glycosuria, - ECG changes: AV block, prolonged QT, ventricular arrhythmias - treatment: - GI decontamination if within 2-4 hours of ingestion (charcoal is NOT effective) - Alkaline diuresis for levels > 2-3 mmol/L - Hemodialysis for symptoms or levels > 5 mmol/L. - for patients who must continue lithium, amiloride blocks epithelial sodium channel involved in Li+ uptake by the renal tubules diminishing long-term nephrotoxicity [5] Drug interactions: 1) decreased effect of lithium a) xanthines b) acetazolamide 2) increased toxicity/increased serum [Li+] with: NSAIDs*, haloperidol, phenothiazines (neurotoxicity) neuromuscular blockers, carbamazepine, fluoxetine ACE inhibitors, ARBs [12], tetracycline, spectinomycin, metronidazole, amiloride, Ca+2 channel blockers [9], thiazides, loop diuretics (furosemide, bumetanide), triamterene 3) lithium enhances toxicity of: CNS depressants, alfentanil 4) lithium increases hypothyroid effect of iodide salts 5) phenytoin, methyldopa in combination result in signs of lithium toxicity with therapeutic levels of lithium 6) interactions with other psychotropic agents are unpredicatble 7) sodium intake may affect lithium clearance * aspirin & sulindac OK Laboratory: 1) specimen: a) whole blood, serum, plasma (EDTA, heparin) b) collect sample 5 days after last dose (NEJM) [25] - steady-state levels achieved 5 days after initiation of therapy or after a dose increase [25] c) see Li+ in serum/plasma/blood d) also see pharmaceutical lithium Mechanism of action: 1) competes with other monovalent & divalent cations at cellular sites in body tissues 2) lithium also acts with cAMP 2nd messenger processes 3) inhibits inositol-3-phosphate synthase 4) influences reuptake of serotonin &/or norepinephrine 5) inhibits postsynaptic dopamine D2 receptor supersensitivity Comparative biology: - lithium increases iron in the substantia nigra via pathways that lower beta-amyloid & phosphorylated tau levels & impair iron efflux [23]

Interactions

drug interactions drug adverse effects of psychotropic agents

Related

Li+ in serum/plasma/blood lithium citrate lithium orotate (Serenity)

General

pharmaceutical lithium salt

Properties

MISC-INFO: elimination route KIDNEY 1/2life 15-30 HOURS therapeutic-range 0.6-1.2 MEQ/L toxic-range >2.0 MEQ/L protein-binding <5% elimination by hemodialysis - hemoperfusion - peritoneal dialysis - pregnancy-category D safety in lactation -

Database Correlations

PUBCHEM correlations

References

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  2. Harrison's Principles of Internal Medicine, 13th ed. Companion Handbook. Isselbacher et al (eds), McGraw-Hill Inc. NY, 1995, pg 134
  3. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
  4. Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 714-715
  5. Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 16. American College of Physicians, Philadelphia 1998, 2006, 2012
  6. Kaiser Permanente Northern California Regional Drug Formulary, 1998
  7. Clinical Guide to Laboratory Tests, 3rd ed. Teitz ed., W.B. Saunders, 1995
  8. Prescriber's Letter 7(11):65 2000
  9. Principles of Ambulatory Medicine, 4th edition, Barker et al (eds), Williams & Wilkins, Baltimore, 1995, pg 104
  10. Harrison's Principles of Internal Medicine, 14th ed. Fauci et al (eds), McGraw-Hill Inc. NY, 1998, pg 470
  11. Harrison's Principles of Internal Medicine, 13th ed. Isselbacher et al (eds), McGraw-Hill Inc. NY, 1994, pg 1039
  12. Prescriber's Letter 10(12):70 2003 Detail-Document#: 191211 (subscription needed) http://www.prescribersletter.com
  13. deprecated reference
  14. Kessing LV et al. Does lithium protect against dementia? Bipolar Disord 2010 Feb; 12:87. PMID: 20148870
  15. McKnight RF et al Lithium toxicity profile: a systematic review and meta-analysis Lancet. 2012 Jan 19. [Epub ahead of print] PMID: 22265699 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61516-X/abstract - Malhi GS and Berk M Is the safety of lithium no longer in the balance? Lancet. 2012 Jan 19. [Epub ahead of print] PMID: 22265701 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2811%2961703-0/fulltext
  16. Grunfeld JP, Rossier BC. Lithium nephrotoxicity revisited. Nat Rev Nephrol. 2009 May;5(5):270-6 PMID: 19384328
  17. Bendz H, Schon S, Attman PO et al Renal failure occurs in chronic lithium treatment but is uncommon. Kidney Int. 2010 Feb;77(3):219-24. PMID: 19940841
  18. Cipriani A et al Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis. BMJ 2013;346:f3646 PMID: 23814104 http://www.bmj.com/content/346/bmj.f3646
  19. Deprecated Reference
  20. Geriatric Review Syllabus, 8th edition (GRS8) Durso SC and Sullivan GN (eds) American Geriatrics Society, 2013
  21. Shine B, McKnight RF, Leaver L, Geddes JR Long-term effects of lithium on renal, thyroid, and parathyroid function: a retrospective analysis of laboratory data. Lancet. 2015 May 20. pii: S0140-6736(14)61842-0 PMID: 26003379
  22. Juurlink DN, Mamdani MM, Kopp A et al Drug-induced lithium toxicity in the elderly: a population- based study. J Am Geriatr Soc. 2004 May;52(5):794-8. PMID: 15086664
  23. Geller B A Likely Cause of Lithium-Associated Parkinsonian Tremor. NEJM Journal Watch. July 25 2016 Massachusetts Medical Society (subscription needed) http://www.jwatch.org - Lei P et al. Lithium suppression of tau induces brain iron accumulation and neurodegeneration. Mol Psychiatry 2016 Jul 12; PMID: 27400857
  24. Pawar AS, Kattah AG Lithium-Induced Nephropathy N Engl J Med 2018; 378:1042. March 15, 2018 PMID: 29539276 http://www.nejm.org/doi/full/10.1056/NEJMicm1709438
  25. NEJM Knowledge+ Psychiatry