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Lithium in General Practice

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Drug interactions

Some drugs can raise serum concentrations of lithium and increase the risk of toxicity (Table 3). These include:

  • Diuretics (mainly thiazides, but frusemide can also interact)
  • NSAIDs, including over-the-counter preparations
  • ACE inhibitors (e.g. cilazapril or quinapril) and ARBs (e.g. candesartan or losartan)

Generally, the interactions with NSAIDs, ACE inhibitors and ARBs are unpredictable and do not occur in all patients so concurrent use is not contraindicated. However, careful monitoring is required as cases of life threatening toxicity have been reported. Increases in lithium concentrations are delayed, taking several days to weeks to manifest, and monitoring should reflect this. Thiazides (e.g. bendrofluazide, hydrochlorothiazide) cause a more rapid (usually within three days) and predictable increase in lithium concentrations. Loop diuretics such as frusemide are much less likely to interact with lithium.

In addition to the above pharmacokinetic interactions, a number of drugs may enhance the adverse or toxic effects of lithium without a change in serum concentration. These include antidepressants, anticonvulsants, antipsychotics and calcium channel blockers. Concurrent use with SSRIs, tricyclic antidepressants and venlafaxine is usually uneventful and lithium is sometimes used to augment antidepressant effects. SSRIs and other drugs with serotonergic activity such as clomipramine, tramadol and venlafaxine have the potential to cause serotonin syndrome when combined with lithium, as lithium also has some serotonergic activity. Patients should be monitored for signs of serotonin syndrome such as confusion, agitation, restlessness, sweating, nausea, diarrhoea, fever, hyperreflexia, tachycardia, myoclonus, lack of coordination, shivering and tremor and should be warned to report these immediately if they occur.

Table 3 Drugs which may alter serum concentrations of lithium (Adapted from Stockley, 2006)

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  Affect on serum lithium concentrations Comments and management
NSAIDs and COXIBs Not always clinically significant.
Usually occurs in the first week after addition of NSAID.
Risk increased in elderly, volume depletion, dehydration, changes in fluid/salt intake.
Avoid concurrent use if possible.
Check lithium concentrations weekly for first month and advise patient to report symptoms of lithium toxicity.
Diuretics Thiazide and related diuretics (e.g. indapamide) can cause a rapid rise in serum lithium concentrations leading to toxicity. Not always clinically significant. Increased lithium concentrations usually occur within 7-10 days.
Frusemide can also interact but this is less common.
Check lithium concentrations for at least two weeks after diuretic is started.
Avoid in high risk patients such as the elderly and those susceptible to dehydration.
Advise patient to report symptoms of lithium toxicity.
ACE inhibitors and ARBs Not always clinically significant but two to four fold increases have been reported. Increase may be delayed by several weeks.
One analysis found an increased relative risk of 7.6 for lithium toxicity requiring hospitalisation in elderly patients newly started on an ACE inhibitor.
Risk increased in elderly, volume depletion, heart failure, dehydration, changes in fluid/salt intake.
Check lithium concentrations weekly for first 4-6 weeks and advise patient to report symptoms of lithium toxicity.
Theophylline Serum lithium concentrations are reduced by 20 to 30% by the concurrent use of theophylline, which may cause patients to relapse.
Caffeine may have a similar effect.
Serum lithium concentrations should be monitored if theophylline is stopped, started or if the dosage is altered. Also monitor if there is a significant change in caffeine intake.
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