Lithium is an effective and approved drug for the treatment of bipolar disorder and
acute episodes of mania.1 Unapproved uses for lithium
include augmentation of the action of other antidepressant drugs
and treatment of aggression, post-traumatic stress disorder, and
pediatric conduct disorders. Lithium toxicity most often results
from accidental or intentional overdose or from an alteration in
lithium clearance secondary to impaired renal function.
It has been estimated that up to 75% to 90% of
patients who are treated with lithium over the long term develop
toxicity at some time during their therapy.2 During
2008, the American Association of Poison Control Centers received
reports of 6492 potential toxic exposures to lithium with four reported
Lithium has several known pharmacologic effects, but which ones
are responsible for the therapeutic benefit in treating bipolar
disorder and mania is unknown.4 As would be expected,
lithium competes with other similar cations, including sodium, potassium,
magnesium, and calcium, displacing them from both intracellular
and extracellular sites. Interference with sodium ions at the sodium
channel and the sodium-potassium pump located on the cell membrane
is responsible for the adverse effect that lithium has on myocardial
electrical activity. Lithium inhibits arginine vasopressin, an effect
that is responsible for a common adverse effect seen during lithium
therapy. Some of the toxic effects of lithium may be due to inhibition
of 3-glycogen synthase kinase, which is present in high quantities
in the brain.4
Lithium inhibits inositol monophosphatase and reduces the concentration
of inositol in the cytoplasm.5 Intracellular inositol
depletion is one of the proposed mechanisms for the therapeutic
effect of lithium in bipolar disorders. Lithium inhibits adenylate
cyclase, decreasing intracellular cyclic adenosine monophosphate
and possibly cyclic guanosine monophosphate. Lithium is also thought
to interfere with the release and reuptake of the neurotransmitter
norepinephrine at the nerve terminal site. Lithium may enhance serotonin
release, particularly from the hippocampus, and has been implicated
in serotonin syndrome when combined with other medications that
alter serotonin metabolism.
Risk of lithium toxicity increases when it is combined with other
medications. Most often toxicity involves a drug–drug interaction
with lithium (Table 175-1). Although patients
are routinely cautioned about pharmacologic interactions, they may not understand that nonprescription herbal
diuretics may also potentiate toxicity.6 An
important potential interaction relevant to the emergency physician
is that neuromuscular blocking agents such as succinylcholine, vecuronium,
and pancuronium may result in a prolonged neuromuscular blockade
when given to patients receiving long-term lithium therapy.7
Table 175-1 Drugs
That Interact with Lithium
After oral ingestion of therapeutic doses, lithium is rapidly
and almost completely absorbed, although delayed absorption may
occur with sustained-release products and after ingestion of a large
number of tablets.8 Lithium is not bound to plasma
proteins and has an initial volume of distribution of 0.4 L/kg,
which is similar to that of body water, but over time this can increase
to 0.9 L/kg, as the ion distributes throughout the body.
Lithium distribution into and out of the brain is slower, which
results in neurologic effects that do not correlate with serum levels.
The lithium concentrations in the brain and in the serum may differ
by twofold to threefold.9 Continuation of toxic
effects, even after hemodialysis, can be due to the drug’s
slow movement out of the central nervous system. Therefore, serum
levels do not predict central nervous system levels and do not precisely
correlate with clinical symptoms.
The elimination half-life after one dose of lithium is about
18 to 24 hours in young adults and almost double that in the elderly.8 With
continued therapy of longer than a year, lithium elimination half-life
increases, up to almost 60 hours. Lithium is excreted unchanged,
primarily in the urine, and there is no hepatic metabolism. Like
other ions of similar size, lithium is reabsorbed in the proximal
The presence or development of renal insufficiency is a critical
factor in the development of lithium toxicity. Changes in fluid
and electrolyte status can impact lithium clearance. For example,
sodium and water loss due to heat or exercise may lead to lithium
retention. The elderly are particularly prone to toxicity because
of their decreased volume of distribution and reduced renal clearance.
Elderly patients are at high risk for lithium toxicity when concomitantly
treated with either loop diuretics or angiotensin-converting enzyme
Adverse effects are common with lithium, occurring in 35% to
90% of treated patients.2 The most common
adverse effects are hand tremor, polyuria due to loss of urinary
concentration ability, and rash (Table 175-2).
Hand tremor occurs in up to 65% of patients at some time,
and worsening of a baseline tremor is an important signal of developing
toxicity. Decreasing the intake of caffeine, adding a β-blocker,
or administering vitamin B6
may improve the tremor, but
often a decrease in dosage is necessary. Neurologic side effects
include memory loss, decreased mental concentration, and fatigue.
Ataxia and dysarthria can develop and often improve with cessation of
therapy. Long-term lithium treatment can lead to electroencephalographic
changes, including diffuse slowing, an increase in theta and delta waves,
and a decrease in alpha activity.
Table 175-2 Side Effects
with Long-Term Lithium Therapy
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