Lithium is an alkalai metal and mood stabilizer used in the treatment of all phases (manic, maintenance, and depressive) of bipolar I disorder. It is the gold standard treatment for bipolar I disorder and mania.
Absorption | Lithium is rapidly absorbed from the GI tract, with Tmax= 1-3 hours (adults). With extended-release tablets (Lithmax SR), absorption is delayed, with Tmax=4-12 hours (adults). Food or antacids do not appear to influence absorption. |
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Distribution | Lithium is not protein bound, and distributes freely throughout body water, both intra- and extracellularly |
Metabolism | Lithium is not metabolized, rather, it is excreted almost entirely by the kidneys (95%). |
Elimination | Lithium is excreted almost exclusively excreted by the kidneys; most lithium is reabsorbed at the proximal convoluted tubules via sodium channels. |
Half-life | 18-36 hours |
Substrate of (Metabolized by) | Not applicable |
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Induces | - |
Inhibits | - |
Most risk factors for developing lithium toxicity involve changes in sodium levels or the way the patient's body handles sodium. For example low salt diets, dehydration, drug-drug interactions (see below) and illnesses like Addison’s disease can lead to toxicity. Patients should be well-informed of these risk factors when starting treatment. Also, always remember to treat the patient and not the number! Serum lithium concentrations do not always reliably correlate with the clinical severity of toxicity.[2]
Level (mmol/L) | Symptoms |
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>1.5 | • GI symptoms (anorexia, nausea and diarrhea) • CNS symptoms (muscle weakness, drowsiness, ataxia, coarse tremor and muscle twitching). |
>2.0 | • Blurred vision, confusion, slurred speech, unsteady gait. • Increased disorientation and seizures usually occur, which can progress to coma, and ultimately death. • Osmotic or alkaline diuresis can be used (not thiazide or loop diuretics, which would worsen symptoms!) |
>3.0 | • Severe toxicity, coma, cardiovascular collapse, death. • Peritoneal or hemodialysis is often used for emergency management. |
Starting | • Outpatient: 300 mg PO daily for the first week • Inpatient: 600 mg PO daily for the first week and generally titrated more aggressively |
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Titration | Increments of 300 to 600 mg each week during the titration phase |
Maximum | Typically does not exceed 2400 mg per day (though the lithium level is most important) |
Taper | See below |
Level (mmol/L) | |
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Maintenance/prophylaxis | 0.6 to 1.0 |
Acute bipolar mania/depression (<65 years) | 0.8 to 1.2* |
Acute bipolar mania/depression (>65 years) | 0.4 to 0.8 |
Toxic levels | > 1.5 mmol/L |
Stage of treatment | Everyone | High Risk/Geriatric |
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Pre-treatment | Cr (eGFR), BUN, TSH, total calcium, albumin, weight, height, blood pressure | ECG (cardiovascular risks or dysfunction), fasting glucose, lipid panel |
Starting | • Plasma lithium level 7 days after starting treatment (you are measuring the trough level, i.e. - 12 hours after last dose, [though there is some debate on this[5][6][7]] • Measure plasma lithium after another 7 days, and titrate dose as needed. • This q1-2 weekly monitoring should continue until you have 2 consecutive levels within the therapeutic range (0.8 to 1.2) for the same dosage | Start with a lower dose of lithium, with similar monitoring |
Ongoing | • Plasma lithium level, electrolytes, Cr (eGFR), TSH, BUN, q6-12 months. • Serum calcium, albumin, q1 year • Parathyroid hormone levels should be measured in patients with elevated calcium levels | Elderly, those with drug-drug interactions, existing renal impairment, or other illnesses should be monitored more closely. |
Stopping | Dose needs to be reduced slowly over the course of 1 month. Reductions in plasma level should not be > 0.2mmol/L each time you reduce the dose. |
Drug | Examples | Interaction |
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ACE Inhibitors | Captopril, cilazapril enalapril, fosinopril, imidapril, lisinopril, moexipril, perindopril, quinapril, ramipril and trandolapril | Reduces thirst which can lead to mild dehydration. Increases renal sodium loss leading to increased sodium re‐absorption by the kidney, resulting in an increase in lithium plasma levels. In the elderly, ACE inhibitors increase seven‐fold the risk of hospitalisation due to lithium toxicity. ACE inhibitors can also precipitate renal failure so, if co‐prescribed with lithium, more frequent monitoring of e‐GFR and plasma lithium is required. |
Angiotensin II Receptor Antagonists (ARBs) | Candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan and valsartan | Similar drug-drug interactions as with ACE inhibitors. |
Thiazide and Loop Diuretics | Thiazide diuretics: bendroflumethiazide, chlortalidone, cyclopenthiazide, indapamide, metolazone and xipamide Loop diuretics: bumetanide, furosemide and torasemide | Diuretics reduces the renal clearance of lithium. Thiazide diuretics have a much larger effect compared to loop diuretics. Lithium levels usually rise within 10 days of a thiazide diuretic being prescribed; the magnitude of the rise is unpredictable and can vary from an increase of 25% to 400%. Although there are case reports of lithium toxicity induced by loop diuretics, many patients can recieve this combination of drugs without apparent problems. |
NSAIDs / COX-2 Inhibitors | Aceclofenac, acemetacin, celecoxib, dexibuprofen, dexketofrofen, diclofenac, diflunisal, etodolac, etoricoxib, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indometacin, ketoprofen, lumiracoxib, mefenamic acid, meloxicam, nabumetone, naproxen, piroxicam, sulindac, tenoxicam and tiaprofenic acid | NSAIDs inhibit the synthesis of renal prostaglandins, reducing renal blood flow, which increases renal re‐absorption of sodium and therefore lithium. The magnitude of the rise is unpredictable for any given patient; case reports vary from increases of around 10% to over 400%. |
LMNOP
can be used to remember important side effects and adverse events related to lithium:L
- LithiumM
- Movement (tremor)N
- Nephrology (kidney injury) and nephrogenic diabetes insipidus (thirst and urination)O
- HypO
thyroidismP
- Pregnancy (Ebstein's anomaly)