Published: 7 September 2017

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Drug Interactions with Lithium and Therapeutic Drug Monitoring

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Prescriber Update 38(3): 36-38
September 2017

NZ Case Report

A 72-year-old woman with impaired renal function was prescribed lithium and cilazapril (as well as other medicines). She was stable until a non-steroidal anti-inflammatory drug (NSAID) was added, leading to fatal lithium toxicity. It was suspected that the NSAID triggered lithium toxicity due to a pharmacokinetic interaction. The patient’s lithium levels had only been sporadically monitored.

Drug Interactions with Lithium

Lithium is not metabolised and is almost entirely eliminated by the kidneys¹. As a result, serum lithium levels are sensitive to physiological factors that affect renal function, including age, dehydration, sodium balance and haemodynamics¹. In addition, lithium has a narrow therapeutic index and minor changes in plasma concentrations can have significant clinical consequences¹.

Drug interactions with lithium mostly occur through the direct effect of other medicines on renal function, notably glomerular filtration rate and sodium absorption¹.

Medicines that interact with lithium are summarised in Table 1. Regular monitoring of serum lithium and assessment for signs of lithium toxicity (see below) should be performed for patients requiring concomitant treatment with lithium and interacting medicines^2–4. The dose of lithium may require adjustment. In some cases, the concomitant treatment may need to be stopped^2–4.

Table 1: Medicines that may interact with lithium (adapted from data sheets)^2–4

Interactions that may increase lithium concentrations
Selective serotonin re-uptake inhibitors (SSRIs)
Non-steroidal anti-inflammatory drugs (NSAIDs)
Angiotensin-converting enzyme (ACE) inhibitors
Angiotensin-II receptor antagonists
Diuretics: thiazides, spironolactone, furosemide
Other: metronidazole, tetracyclines, topiramate, medicines that affect electrolyte balance
Interactions that may decrease lithium concentrations
Xanthines: theophylline, caffeine
Sodium bicarbonate and sodium chloride containing products
Other: psyllium or ispaghula husk, urea, mannitol, acetazolamide
Interactions that may cause or aggravate neurotoxicity
Antipsychotics: haloperidol, risperidone, clozapine, phenothiazines	In rare cases: confusion, disorientation, lethargy, tremor, extrapyramidal symptoms, myoclonus.
SSRIs, sumatriptan, tricyclic antidepressants	Associated with episodes of neurotoxicity and may precipitate serotonin syndrome. Either presentation justifies immediate discontinuation of treatment.
Calcium channel blockers	May lead to ataxia, confusion and somnolence, reversible after discontinuation of the medicine. Lithium concentrations may be increased or decreased.
Carbamazepine, phenytoin	May lead to dizziness, somnolence, confusion, cerebellar symptoms.
Methyldopa
Other interactions
Neuromuscular blocking agents	Lithium may prolong the effects of these agents.
Iodine	May act synergistically with lithium to produce hypothyroidism.
Other: baclofen, cotrimoxazole, aciclovir, prostaglandin-synthetase inhibitors	Case reports of interactions with lithium. Clinical significance uncertain.

Lithium Toxicity

Patients and family members should be warned of the signs and symptoms of impending lithium toxicity such as:

• gastrointestinal: progressive anorexia, diarrhoea and vomiting.
• central nervous system: muscle weakness, lack of coordination, drowsiness or lethargy (these may progress to dizziness, ataxia, tinnitus, blurred vision, dysarthria, coarse tremor, and muscle twitching)^2-4.

If signs of toxicity appear, patients should be instructed to stop taking lithium immediately and seek medical attention^2-4.

Monitoring Requirements for Patients Taking Lithium

Routine monitoring of serum lithium levels should be performed weekly after initiation until levels are stable^2-4. Once stabilised, levels should be monitored at least every three months^2-4.

Additional monitoring should occur if signs of lithium toxicity occur, following dose changes, development of intercurrent disease, signs of manic or depressive relapse, dehydration or other significant change in sodium intake or fluid balance^2-4. Patients travelling to the tropics and/or experiencing gastroenteritis are at particular risk and should be appropriately advised.

It is also important to monitor renal function regularly to ensure early detection and management of renal impairment. Further information on renal monitoring is available in a previous edition of Prescriber Update (www.medsafe.govt.nz/profs/PUArticles/RenalDanagersSept10.htm).

Case Reports from New Zealand

The Centre for Adverse Reactions Monitoring (CARM) has received a total of nine case reports that identify a drug interaction with lithium. The interacting medicines identified by the reporter include venlafaxine, furosemide and a calcium channel blocker (two reports each).

References

1. Finley PR. 2016. Drug Interactions with Lithium: An Update. Clinical Pharmacokinetics 55(8): 925-41.
2. Mylan New Zealand Ltd. 2014. Lithicarb FC Data Sheet. 9 June 2014. URL: medsafe.govt.nz/profs/Datasheet/l/LithicarbFCtab.pdf (accessed 27 June 2017).
3. Douglas Pharmaceuticals Ltd. 2017. Lithium Carbonate Data Sheet. 18 April 2017. URL: medsafe.govt.nz/profs/Datasheet/l/Lithiumcarbonatecap.pdf (accessed 27 June 2017).
4. WM Bamford & Co Ltd. 2014. Priadel Data Sheet. 20 May 2014. URL: medsafe.govt.nz/profs/Datasheet/p/priadeltab.pdf (accessed 27 June 2017).