LITHIUM

Group 6:
1. YOLANDA MAYESTIKA W 1511011041
2. ANNISA DEWI FAJAR 1511011042
3. DONY AFRIYANDI 1511011044
4. PRATIWI YANEL P 1511012008
5. NADYA ZAHRA HENNI 1511012009
 INTRODUCTION
• Lithium is an alkali metal that is administered as a monovalent cation
(Li+) for the treatment of bipolar disorder.
• In the United States, orally administered carbonate and citrate salts
of lithium are available.
• While lithium is still used as a primary treatment for bipolar
disorders, valproic acid, lamotrigine, or carbamazepine may be used
for some subsets of the disease.

(Bauer,2008 : 711)
THERAPEUTIC AND TOXIC
CONCENTRATIONS
• Therapeutic range for lithium is 0.6–1.5 mmol/L (0.6–1.5
mEq/L).
• Different therapeutic concentration ranges depending on the
clinical situation of the patient.
• For individuals with acute mania, the usual desired range for
these individuals is 0.8–1 mmol/L.
• If patients with acute mania do not respond to these levels,
use lithium concentrations of 1–1.2 mmol/L and in some
instances concentrations as high as 1.2–1.5 mmol/L are
needed. For long-term maintenance use, the usual desired
range is 0.6–0.8 mmol/L.

(Bauer,2008 : 711)
• If patients do not respond to these levels during maintenance
treatment, use of lithium concentrations equal to 0.9–1
mmol/L and in some cases concentrations as high as 1–1.2
mmol/L are necessary to gain an adequate outcome.
• After oral administration, lithium concentrations follow a
complex concentration/time curve that is best described using
multicompartment models

(Bauer,2008 : 711-712)
(Bauer,2008 : 712)
• Short-term side effects observed when starting lithium or
after a dosage increase include muscle weakness, lethargy,
polydipsia, polyuria, nocturia, headache, impairment memory
orbconcentration, confusion, impaired fine motor
performance, and hand
• Long-term adverse effects include a drug-induced diabetes
insipidus, renal toxicity (glomerulosclerosis, renal tubular
atrophy, interstitial nephritis, urinary casts), hypothyroidism
with or without goiter formation, electrocardiographic
abnormalities, leukocytosis, weight gain, and dermatologic
changes.

(Bauer,2008 : 712)
CLINICAL MONITORING
PARAMETERS
• Generally, onset of action for lithium is 1–2 weeks, and a 4- to
6-week treatment period is required to assess complete
therapeutic response to the drug.
• Lithium serum concentrations
• Complete physical exam,
• General serum chemistry panel (including serum electrolytes
and serum creatinine),
• Complete blood cell count with differential, thyroid function
tests, urinalysis (including osmolality and specific gravity) and
urine toxicology screen for substances of abuse

(Bauer,2008 : 713)
• After patients have been stabilized on a multiple dose per day
regimen, it is possible to consider once daily administration of
lithium for those receiving a total dose of 1800 mg/d or less.
However, the change in dosage interval will alter the 12-hour
lithium concentration, and further dosage titration may be
needed to reestablish desired levels.

(Bauer,2008 : 714)
BASIC CLINICAL PHARMACOKINETIC
PARAMETERS
• Lithium is eliminated almost completely (>95%) unchanged in the
urine.
• Lithium eliminated in the saliva, sweat, and feces accounts for less
than 5% of the administered dose.
• On average, lithium clearance is approximately 20% of the patient’s
creatinine clearance.
• Lithium is administered orally as carbonate or citrate salts. Lithium
carbonate capsules (150, 300, 600 mg) and tablets (rapid release:
300 mg; sustained release: 300, 450 mg) are available.
• There are 8.12 mmol (or 8.12 mEq) of lithium in 300 mg of lithium
carbonate. Lithium citrate syrup (8 mmol or mEq/5 mL) is another
oral dosage form.

(Bauer,2008 : 714)
• Oral bioavailability is good for all lithium salts and dosage
forms and equals 100%.
• The peak lithium concentration occurs 15–30 minutes after a
dose of lithium citrate syrup, 1–3 hours after a dose of rapid-
release lithium carbonate tablets or capsules, and 4–8 hours
after a dose of sustained-release lithium carbonate tablets.
• Lithium ion is not plasma protein bound.
• The typical dose of lithium carbonate is 900–2400 mg/d in
adult patients with normal renal function.

(Bauer,2008 : 714)
EFFECTS OF DISEASE STATES AND CONDITIONS
ON LITHIUM PHARMACOKINETICS

• Adults with normal renal function (creatinine clearance >80

mL/min) have an average elimination half-life of 24 hours,
volume of distribution equal to 0.9 L/kg, and clearance of 20
mL/min for lithium.
• During an acute manic phase, lithium clearance can increase
by as much as 50%, which produces a half-life that is about
1/2 the normal value.
• In children 9–12 years of age, average elimination half-life
equals 18 hours, volume of distribution is 0.9 L/kg, and
clearance equals 40 mL/min for the ion.
• Because glomerular filtration and creatinine clearance
decrease with age, lithium clearance can be decreased in
elderly patients, producing half-lives up to 36 hours.
(Bauer,2008 : 714-
715)
• Because of the circadian rhythm of glomerular filtration,
lithium clearance is about 30% higher during daytime hours
• Because lithium is eliminated almost exclusively by the kidney,
renal dysfunction is the most important disease state that
affects lithium pharmacokinetics.
• Lithium clearance rate decreases in proportion to creatinine
clearance.
• In adults, the lithium clearance/creatinine clearance ratio is
20%, but during a manic phase increases to about 30%.
• This relationship between renal function and lithium clearance
will form the basis for initial dosage computation later in this
chapter.
• Because of the decrease in clearance, the average lithium half-
life is 40–50 hours in renal failure patients.

(Bauer,2008 : 715)
DRUG INTERACTIONS
• Thiazide diuretics cause sodium and water depletion, which leads to
increased sodium reabsorption in the proximal tubule of the kidney
as a compensatory mechanism.
• Since lithium is reabsorbed by the same mechanisms as sodium,
lithium reabsorption increases and lithium clearance decreases by
40–50% during treatment with thiazide diuretics.
• Other diuretics that work at the site of the distal tubule of the
kidney may cause a similar interaction with lithium (chlorthalidone,
metolazone).
• Although there are case reports of loop diuretics causing a similar
interaction, there are also reports of no drug interaction between
lithium and these agents.
• Because of this, many clinicians favor the use of a loop diuretic, with
careful monitoring of adverse effects and lithium serum
concentrations, in patients taking lithium.
• Amiloride has also been reported to have minimal effects on lithium
clearance.
(Bauer,2008 : 715-716)
• Nonsteroidal antiinflammatory agents (NSAIDs) also decrease
lithium clearance and increase lithium concentrations.
• The probable mechanism is a NSAID-induced decrease in renal
blood flow via inhibition of prostaglandins. Of these agents, sulindac
and aspirin appear to have little or no drug interaction with lithium.
• Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin
receptor blockers (ARBs) have been reported to inhibit the
elimination of lithium by an undefined mechanism.
• Of the two classes of drugs, more documentation exists for the
ACEIs where lithium serum concentrations have increased by as
much as 200–300% from pretreatment levels. Some serotonin-
specific reuptake inhibitors (SSRIs) have been reported to cause a
serotonergic hyperarousal syndrome when taken in conjunction with
lithium.

(Bauer,2008 : 711)
• Case reports of this problem are currently available for
fluoxetine, sertraline, and fluvoxamine.
• In addition to elevated lithium concentrations, patients have
developed stiffness of arms and legs, course tremors,
dizziness, ataxia, dysarthric speech, and seizures when taking
these SSRI agents with lithium.
• Although there are also literature reports of these
combinations used safely, caution should be exercised when
concurrent treatment with SSRIs and lithium is indicated.
• Theophylline increases the lithium clearance/creatinine
clearance ratio by as much as 58% resulting in an average
decrease of 21% in steady-state lithium concentrations.
• A rare, but severe, drug interaction between lithium and
antipsychotic drugs has been reported where patients are
more susceptible to the development of extrapyramidal
symptoms or irreversible brain damage.
• Again, although there are reports of using antipsychotic
agents and lithium together successfully, patients requiring
this combination therapy should be closely monitored for
adverse drug reactions.

(Bauer,2008 : 716)
INITIAL DOSAGE
DETERMINATION METHODS
1. Pharmacokinetic Dosing Method
• The goal of initial dosing of lithium is to compute the best
dose possible for the patient given their set of disease states
and conditions that influence lithium pharmacokinetics and
the type and severity of their bipolar disease.
2. CLEARANCE ESTIMATE
3. SELECTION OF APPROPRIATE PHARMACOKINETIC MODEL
AND EQUATION
• When given orally, lithium follows a two-compartment model
• Maintenance dosage calculation:
Css = [F(D/τ)] / Cl or D/τ = (Css ⋅ Cl) / F
4. STEADY-STATE CONCENTRATION SELECTION
(Bauer,2008 : 716-718)
5. Literature-Based Recommended Dosing
• For the treatment of acute mania, initial doses are usually 900–1200
mg/d of lithium carbonate. If the drug is being used for bipolar
disease prophylaxis, an initial dose of 600 mg/d lithium carbonate is
recommended. In both cases, the total daily dose is given in 2–3
divided daily doses.
• To avoid adverse side effects, lithium doses are slowly increased by
300–600 mg/d every 2–3 days according to clinical response and
lithium serum concentrations.
1. Estimate creatinine clearance.
2. Choose lithium dose based on disease states and conditions
present in the patient.

(Bauer,2008 : 720-721)
Test Dose Methods to Assess Initial
Lithium Dosage Requirements
• COOPER NOMOGRAM
• PERRY METHOD
• REPEATED ONE-POINT OR RITSCHEL METHOD

(Bauer,2008 : 722)
(Bauer,2008 : 723-724)
USE OF LITHIUM SERUM
CONCENTRATIONS TO ALTER DOSAGES
• Linear Pharmacokinetics Method
• Because lithium follows linear, dose-proportional
pharmacokinetics, steady-state serum concentrations change
in proportion to dose according to the following equation:

Dnew/Cssnew = Dold/Cssold or
Dnew = (Cssnew/Cssold)Dold

(Bauer,2008 : 711)
BAYESIAN PHARMACOKINETIC
COMPUTER PROGRAMS
• Computer programs are available that can assist in the
computation of pharmacokinetic parameters for patients.
• The most reliable computer programs use a nonlinear
regression algorithm that incorporates components of Bayes’
theorem.

(Bauer,2008 : 711)
DOSING STRATEGIES
• Initial dose and dosage adjustment techniques using serum
concentrations can be used in any combination as long as the
limitations of each method are observed.
• Some dosing schemes link together logically when considered
according to their basic approaches or philosophies.
• Dosage strategies that follow similar pathways are given in
Table 17-2.

(Bauer,2008 : 711)
DAFTAR PUSTAKA
• Bauer, Larry A. 2008. Applied Clinical Pharmacokinetics Second
Edition. Washington : MacGrawHill Medical.