Pharmacology & Therapeutics

Lithium toxicity

Lithium is cleared by the kidney alongside sodium, so volume depletion, renal impairment or a drug that blocks its elimination turns an unchanged dose into rising concentrations and neurotoxicity.

In a nutshell

Lithium toxicity is accumulation from reduced renal clearance, usually after dehydration, vomiting, diarrhoea, acute kidney injury or an interacting NSAID, angiotensin converting enzyme (ACE) inhibitor or thiazide. Stop lithium, give intravenous sodium chloride 0.9%, and record the time of the last dose: monitoring levels are drawn 12 hours post dose.

Classic presentation

A woman on long-term lithium has two days of vomiting and diarrhoea, and now has a coarse tremor, ataxia, slurred speech and confusion.

Key points

Lithium is prescribed by brand and formulation. Priadel prolonged-release is the usual UK choice, and any switch needs the same monitoring as starting lithium.
Chronic toxicity is dangerous at a lower number than acute: the brain is already loaded, so neurotoxicity appears while the serum concentration still looks unremarkable.
Thiazides can raise the level fast. Theophylline, acetazolamide and sodium bicarbonate products lower it, as do sodium-glucose co-transporter 2 (SGLT-2) inhibitors.
Antipsychotics, verapamil, diltiazem, carbamazepine, selective serotonin reuptake inhibitors (SSRIs) and triptans raise neurotoxicity risk without necessarily raising the level.
Dehydration and low-sodium diets are BNF contra-indications to lithium, not merely cautions.
Persistent deficits are called SILENT, the syndrome of irreversible lithium-effectuated neurotoxicity. A 2024 review of 117 cases found cerebellar dysfunction in 77%.
Lithium causes hypothyroidism, hypercalcaemia through the parathyroid glands, and nephrogenic diabetes insipidus that may not reverse after stopping.
NICE CG185 governs lithium prescribing and monitoring. TOXBASE governs toxicity management, and it needs a professional login.

First-line investigation

Urgent serum lithium with the time of the last dose recorded, alongside U&E, creatinine and eGFR, calcium, thyroid function, glucose and an ECG.

Management

Stop lithium and stabilise

Withhold lithium immediately, assess A to E (airway, breathing, circulation, disability, exposure), and phone the National Poisons Information Service (NPIS) on 0344 892 0111.^10,3,7
Send an urgent serum lithium and write the time of the last dose on the form, with U&E, creatinine and eGFR, calcium, thyroid function, glucose and an ECG.^1,2

Read the level against the clock

Monitoring levels are taken 12 hours post dose; in twice-daily dosing the morning dose is withheld until the sample is drawn. In toxicity, take it now and repeat.^1,2
NHS Lanarkshire defines toxicity as any level above 1.2 mmol/L; Royal Cornwall expects toxic effects above 1.5 mmol/L. Both say toxicity occurs within the normal range.^3,2
Usual targets: 0.6 to 0.8 mmol/L in bipolar disorder, and 0.4 to 0.6 mmol/L in recurrent major depressive disorder and initially at 65 years and over.^1,8
Peak effects can be delayed up to 24 hours, especially in someone not on regular lithium, so one falling result does not end observation.^2,4

Restore clearance, and what does not work

Give sodium chloride 0.9% IV even if euvolaemic. If hypovolaemic without overload risk, give 500 mL isotonic crystalloid over under 15 minutes, then reassess; otherwise NPIS sets the replacement plan.^4,2,11,10
There is no antidote, and activated charcoal does not adsorb lithium, a small inorganic cation with nothing for charcoal to bind.^5,2,4
Recurrent or prolonged seizures: lorazepam 4 mg by slow intravenous injection into a large vein, repeated once after 5 to 10 minutes if needed. Do not use phenytoin.^12,5

Haemodialysis, and the numbers behind it

Extracorporeal Treatments in Poisoning (EXTRIP) recommends dialysis if kidney function is impaired and lithium exceeds 4.0 mmol/L, or for reduced consciousness, seizures or life-threatening dysrhythmia at any level.^6,4
It suggests dialysis above 5.0 mmol/L, for confusion, or when the predicted time to reach below 1.0 mmol/L with optimal management exceeds 36 hours.⁶
Intermittent haemodialysis is preferred. Stop below 1.0 mmol/L or on clear clinical improvement, or after at least 6 hours if no level is available.⁶
Take serial levels over the 12 hours after stopping: lithium redistributing out of tissue can push the level back up and need another session.⁶

The monitoring schedule, which is your job

Level 1 week after starting lithium and 1 week after every dose or formulation change, then weekly until stable.^1,13
Once stable, every 3 months for the first year, then every 6 months. Stay 3-monthly at 65 or over, on interacting drugs, or if the last level was 0.8 mmol/L or higher.^1,8
Weight or BMI, renal and thyroid function, and U&E including calcium at least every 6 months. Extra levels for intercurrent illness, sodium or fluid changes, or toxicity signs.^1,4
Sick-day rule: vomiting, diarrhoea, fever or heavy sweating means urgent medical advice and a level. Issue the lithium treatment pack: booklet, alert card and record book.^1,7
Do not restart lithium after toxicity without specialist review. Stopping for good needs a taper over at least 4 weeks, preferably up to 3 months, then relapse monitoring for 3 months.^1,5

Exam traps

A lithium level without a sampling time is uninterpretable. Ask when the last dose was taken before you interpret any number.
Fine tremor is a therapeutic adverse effect. Coarse tremor, ataxia, dysarthria and myoclonus are toxicity.
Activated charcoal is the reflex answer in overdose and the wrong one here: lithium is an inorganic ion with nothing for charcoal to bind.
Severe neurotoxicity, seizure or life-threatening dysrhythmia is an indication for dialysis whatever the concentration. Do not wait for a number above 4.0 mmol/L.
A falling level after dialysis is not the end. Lithium redistributes out of tissue, so levels are repeated over the next 12 hours.
The UK severity bands are symptom bands, not concentration bands, and UK sources do not even agree on where toxicity begins.
Do not add a thiazide, NSAID or ACE inhibitor for a patient on lithium without planning a level. They raise it by reducing renal elimination.

Illustrations

Proximal tubular handling of lithium and sodiumDiagram showing renal sodium and lithium handling and how dehydration, renal impairment and interacting medicines reduce lithium clearance.PassFinals · original

Dose-response spectrum of lithium neurotoxicityGraphic progressing from gastrointestinal symptoms and worsening tremor to ataxia, dysarthria, confusion, seizures and coma, with a warning that serum levels correlate imperfectly with clinical severity.PassFinals · original

Key sources

This page is exam revision material, not medical advice, and must not be used for patient care. Always check drug doses against the BNF and current guidance. Full disclaimer.