lithium carbonate (Eskalith, Lithane, Lithobid, Lithonate)
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Introduction
Tradenames: Eskalith, Lithane, Lithobid, Lithonate.
Indications
- management of psychotic disorders
- 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
- severe cardiovascular disease
- severe renal insufficiency
Caution:
- cardiovascular disease
- thyroid disease
- severe debilitation
- patients receiving diuretics, or otherwise predisposed to hyponatremia & dehydration
- elderly patients may be extremely sensitive to the effects of lithium
Dosage
- start 300 mg PO BID
- average effective dose 900-1800 mg/day divided TID-QID
- average maximum dose: 2.4 g/day divided TID-QID
- children: 15-60 mg/kg/day divided TID-QID (do NOT exceed adult dosage)
- 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
- lithium is readily absorbed from the GI tract
- absorption is increased by food[10]
- peak serum levels in 0.5-2 hours
- onset of action is 7-10 days
- elimination 1/2life is 20-27 hours after a single dose
- 1/2life may increase to 2.4 days in patients on therapy for 1 year or longer
- volume of distribution: 0.3-0.4 L/kg (initial)
- excreted in the urine
- lithium clearance can be increased or decreased by 30-50% by sodium loading or depletion
elimination via kidney
1/2life = 15-30 hours
protein binding = <5 %
elimination by hemodialysis = -
elimination by hemoperfusion = -
elimination by peritoneal dialysis = -
Monitor
- baseline & every six months to annually
- serum creatinine, BUN, urinalysis
- serum TSH
- serum calcium
- total serum calcium often elevated
- ionized serum calcium is normal[21]
- complete blood count (CBC)
- serum electrolytes[13]
- serum Li+ levels* (more frequently as indicated)
- pregnancy test
- baseline & if suspected (eligible women)
- 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)
- hypothyroidism
- renal effects
- renal insufficiency; risk of renal failure is small[15]
- increased risk of stage 3 renal failure[21]
- effects on GFR & urinary concentrating ability are small
- nephrogenic diabetes insipidus
- most common adverse effect
- occurs in up to 40% of patients[16]
- amiloride may mitigate[5]
- chronic tubulointerstitial nephritis[24]
- minimal change glomerulonephropathy
- renal insufficiency; risk of renal failure is small[15]
- weight gain
- aggravation of acne
- psoriasis/exacerbation of psoriasis
- hypercalcemia (hyperparathyroidism)
- tremor (fine, characteristics of essential tremor)
- ref[23] refers to as parkinsonian tremor
- teratogenic
- cardiac anomalies: Ebstein's anomaly, tricuspid atresia
- not teratogenic[15]
- 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:
- 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
- decreased effect of lithium
- 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
- lithium enhances toxicity of: CNS depressants, alfentanil
- lithium increases hypothyroid effect of iodide salts
- phenytoin, methyldopa in combination result in signs of lithium toxicity with therapeutic levels of lithium
- interactions with other psychotropic agents are unpredicatble
- sodium intake may affect lithium clearance
- drug interaction(s) of lithium carbonate with iodide salts
- drug interaction(s) of lithium carbonate with neuromuscular blockers
- drug interaction(s) of lithium carbonate with CNS depressants
- drug interaction(s) of lithium carbonate with xanthine
- drug interaction(s) of lithium carbonate with fluoxetine
- drug interaction(s) of lithium carbonate with carbamazepine
- drug interaction(s) of lithium carbonate with phenothiazine
- drug interaction(s) of lithium carbonate with haloperidol
- drug interaction(s) of lithium carbonate with NSAIDs
- drug interaction(s) of lithium carbonate with loopt diuretics
- drug interaction(s) of lithium carbonate with thiazide diuretics
- drug interaction(s) of lithium carbonate with ACE inhibitors
Laboratory
- specimen:
- whole blood, serum, plasma (EDTA, heparin)
- 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]
- see Li+ in serum/plasma/blood
- also see pharmaceutical lithium
Mechanism of action
- competes with other monovalent & divalent cations at cellular sites in body tissues
- lithium also acts with cAMP 2nd messenger processes
- inhibits inositol-3-phosphate synthase
- influences reuptake of serotonin &/or norepinephrine
- 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]
More general terms
Additional terms
References
- ↑ The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996.
- ↑ Harrison's Principles of Internal Medicine, 13th ed. Companion Handbook. Isselbacher et al (eds), McGraw-Hill Inc. NY, 1995, pg 134
- ↑ Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
- ↑ Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 714-715
- ↑ 5.0 5.1 5.2 Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 16. American College of Physicians, Philadelphia 1998, 2006, 2012
- ↑ Kaiser Permanente Northern California Regional Drug Formulary, 1998
- ↑ Clinical Guide to Laboratory Tests, 3rd ed. Teitz ed., W.B. Saunders, 1995
- ↑ 8.0 8.1 8.2 Prescriber's Letter 7(11):65 2000
- ↑ 9.0 9.1 Principles of Ambulatory Medicine, 4th edition, Barker et al (eds), Williams & Wilkins, Baltimore, 1995, pg 104
- ↑ 10.0 10.1 Harrison's Principles of Internal Medicine, 14th ed. Fauci et al (eds), McGraw-Hill Inc. NY, 1998, pg 470
- ↑ Harrison's Principles of Internal Medicine, 13th ed. Isselbacher et al (eds), McGraw-Hill Inc. NY, 1994, pg 1039
- ↑ 12.0 12.1 Prescriber's Letter 10(12):70 2003 Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=191211&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 13.0 13.1 deprecated reference
- ↑ 14.0 14.1 Kessing LV et al. Does lithium protect against dementia? Bipolar Disord 2010 Feb; 12:87. PMID: https://www.ncbi.nlm.nih.gov/pubmed/20148870
- ↑ 15.0 15.1 15.2 McKnight RF et al Lithium toxicity profile: a systematic review and meta-analysis Lancet. 2012 Jan 19. [Epub ahead of print] <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/22265699 <Internet> 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] <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/22265701 <Internet> http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2811%2961703-0/fulltext - ↑ 16.0 16.1 Grunfeld JP, Rossier BC. Lithium nephrotoxicity revisited. Nat Rev Nephrol. 2009 May;5(5):270-6 PMID: https://www.ncbi.nlm.nih.gov/pubmed/19384328
- ↑ 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: https://www.ncbi.nlm.nih.gov/pubmed/19940841
- ↑ 18.0 18.1 Cipriani A et al Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis. BMJ 2013;346:f3646 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/23814104 <Internet> http://www.bmj.com/content/346/bmj.f3646
- ↑ 19.0 19.1 Deprecated Reference
- ↑ Geriatric Review Syllabus, 8th edition (GRS8) Durso SC and Sullivan GN (eds) American Geriatrics Society, 2013
- ↑ 21.0 21.1 21.2 21.3 21.4 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: https://www.ncbi.nlm.nih.gov/pubmed/26003379
- ↑ 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: https://www.ncbi.nlm.nih.gov/pubmed/15086664
- ↑ 23.0 23.1 23.2 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: https://www.ncbi.nlm.nih.gov/pubmed/27400857 - ↑ 24.0 24.1 Pawar AS, Kattah AG Lithium-Induced Nephropathy N Engl J Med 2018; 378:1042. March 15, 2018 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/29539276 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMicm1709438
- ↑ 25.0 25.1 25.2 NEJM Knowledge+ Psychiatry