DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

450 Li + intoxication. Li + freely crosses the placenta, and fetal or neonatal
Li + toxicity may develop when maternal blood levels are within
the therapeutic range. Fetal Li + exposure is associated with neonatal
goiter, CNS depression, hypotonia (“floppy baby” syndrome),
and cardiac murmur. Most recommend withholding lithium therapy
for 24-48 hours before delivery, and this is considered standard practice
to avoid the potentially toxic increases in maternal and fetal
serum Li + levels associated with postpartum diuresis. This brief
period of discontinuation results in a mean decrease of 0.28 mEq/L
in maternal Li + concentrations (Newport et al., 2005). The physical
and CNS sequelae of late-term neonatal Li + exposure are reversible
once Li + exposure has ceased, and no long-term neurobehavioral
consequences are observed (Viguera et al., 2007).
Other Effects. A benign, sustained increase in circulating polymorphonuclear
leukocytes (12,000-15,000 cells/mm 3 ) occurs during the
chronic use of Li + and is reversed within a week after termination
of treatment. Some patients complain of a metallic taste, making
food less palatable. Myasthenia gravis may worsen during treatment
with Li + .
Acute Toxicity and Overdose. The occurrence of toxicity is related to
the serum concentration of Li + and its rate of rise following administration.
Acute intoxication is characterized by vomiting, profuse diarrhea,
coarse tremor, ataxia, coma, and convulsions. Symptoms of
milder toxicity are most likely to occur at the absorptive peak of Li + and
include nausea, vomiting, abdominal pain, diarrhea, sedation, and fine
tremor. The more serious effects involve the nervous system and
include mental confusion, hyperreflexia, gross tremor, dysarthria,
seizures, and cranial nerve and focal neurological signs, progressing to
coma and death. Sometimes both cognitive and motor neurological
damage may be irreversible, with persistent cerebellar tremor being the
most common (El-Mallakh, 1986). Other toxic effects are cardiac
arrhythmias, hypotension, and albuminuria.
Treatment of Lithium Intoxication. There is no specific antidote for
Li + intoxication, and treatment is supportive, including intubation if
indicated, and continuous cardiac monitoring. Levels > 1.5 mEq/L are
considered toxic, but inpatient medical admission is usually not indicated
(in the absence of symptoms) until levels exceed 2 mEq/L.
Care must be taken to assure that the patient is not Na + and water
depleted. Dialysis is the most effective means of removing Li + and
is necessary in severe poisonings, that is, in patients exhibiting
symptoms of toxicity or patients with serum Li + concentrations
≥ 3 mEq/L in acute overdoses. A review of 213 case reports of acute
Li + toxicity between 1948 and 1984, found that complete recovery
occurred with an average maximal level of 2.5 mEq/L, permanent
neurological symptoms with mean levels of 3.2 mEq/L, and death
with mean maximal levels of 4.2 mEq/L (El-Mallakh, 1986). The
most common neurological sequelae are due to cerebellar damage,
and manifest clinically as ataxia, tremor, dysarthria, and dysmetria
(Mangano et al., 1997).
SECTION II
NEUROPHARMACOLOGY
Use in Pediatric and Geriatric Populations
Pediatric Use. The anticonvulsants all have pediatric indications for
epilepsy, but only Li + has FDA approval for child/adolescent bipolar
disorder for ages ≥ 12 years (Tueth et al., 1998). Recently, aripiprazole
and risperidone were FDA-approved for acute mania in
children and adolescents ages 10-17. Children and adolescents have
higher volumes of body water and higher GFR than adults. The
resulting shorter t 1/2
of Li + demands dosing increases on a mg/kg
basis, and multiple daily dosing is often required. In children ages
6-12 years, a dose of 30 mg/kg/day given in three divided doses will
produce a Li + concentration of 0.6-1.2 mEq/L in 5 days (Danielyan
and Kowatch, 2005), although ongoing dosing is always guided by
serum levels and clinical response. Use in children under 12 represents
an off-label use for Li + and care givers should be alert to evidence
of the development of toxicity. As with adults, ongoing
monitoring of renal and thyroid function is important, along with
clinical inquiry into extent of polyuria.
A limited number of controlled studies suggest that valproate
has efficacy comparable to that of Li + for mania in children or adolescents
(Danielyan and Kowatch, 2005). As with Li + , weight gain
and tremor can be problematic; moreover, there are reports of hyperammonemia
in children with urea-cycle disorders. Ongoing monitoring
of platelets and liver function tests, in addition to serum drug
levels, is recommended. There have been no controlled studies of
carbamazepine for the treatment of children and adolescents with
mania, although there is substantial safety data for epilepsy indications
in this age group.
Geriatric Use. The majority of older patients on Li + therapy are those
maintained for years on the medication. Less than 10% of individuals
with bipolar disorder experience their first manic episode at
age 50 or above. Elderly patients frequently take numerous medications
for other illnesses and the potential for contraindications or
drug-drug interactions is substantial. For patients naïve to Li + , these
issues can be addressed relatively easily prior to commencement of
Li + treatment. The more difficult clinical decision revolves around
switching treatment in stable patients who have taken Li + for years
or decades with excellent clinical response. In addition, age-related
reductions in total body water and creatinine clearance reduce the
safety margin for Li + treatment in older patients. Targeting lower
maintenance serum levels (0.6-0.8 mEq/L) may reduce the risk of
toxicity. As GFR drops below 60 mL/min, strong consideration must
be given to a search for alternative agents, despite lithium’s therapeutic
advantages (Morriss and Benjamin, 2008). Li + toxicity occurs
more frequently in elderly patients, in part as the result of concurrent
use of loop diuretics and angiotensin-converting enzyme inhibitors
(Juurlink et al., 2004). Anticonvulsants, especially extended-release
divalproex, are a reasonable alternative to Li + . Elderly patients who
are drug-naïve may be more sensitive to CNS adverse effects of all
types of medications used for acute mania, especially parkinsonism
and tardive dyskinesia from D 2
antagonism, confusion from antipsychotic
medications with antimuscarinic properties, and ataxia or
sedation from Li + or anticonvulsants.
Major Drugs Available in the Class
Formulations. Most Li + preparations currently used in
the U.S. are tablets or capsules of lithium carbonate in
strengths of 150, 300, and 600 mg. Slow-release preparations
of lithium carbonate also are available in
strengths of 300 and 450 mg, as is lithium citrate syrup
(with 8 mEq of Li + /5 mL citrate liquid, equivalent to
300 mg of lithium carbonate). Salts other than the carbonate
have been used, but the carbonate salt is favored
for tablets and capsules because it is relatively less