A.

definition
Lihtium is an alkali metal that is administered as a
monovalent cation (Li+) for 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 disoders, its use
as the primary agent is being challenged by valproic
acid and carbarnazepine for some subsets of the
disease. (Bauer, 2006:401).
B. Therapeutic and Toxic
Concentrations
The general therapeutic range for lithium is 0,6 1,5 mmol/L.
Because lithium is a monovalent cation, the therapeutic range
expressed in mEq/L is identical to these values (i.e 0,6 1,5
mEq/L)

most clinicians apply different therapeutic concentration ranges
depending on the clinical situation of the patient.
For individual with acute mania, a minimum lithium
concentration of 0,8 mmol/L is usually recomended. The
usual desired range for these individuals is 0,8-1 mmol/L
and in some instances concentrations as high as 1,2-1,5
mmol/L.
For long-term maintenance use, the usual desired range is
0,6-0,8 mmol/L. If patient do not respond to these levels
during maintenance treatment, use of lithium concentration
of 0,9-1 mmol/L may be required, and in some cases
concentration as high as 1-1,2 mmol/L are necessary to
gain an adequate outcame. (Bauer, 2006:401).
The therapeutic ranges are based on steady-state lithium
serum concentration obtained 12 hours after a dose.
After oral administraion, lithium concentration follow a
complex concentration/time curve that is bet described using
multicompartment models. (figure 17-1). (Bauer, 2006:401).

Figure 17-1 Lithium ion
serum concentraion/
time curve after a single
900-mg oral dose of
lithium carbonate (24.4
mmol or mEq of lithium
ion) rapid-release
capsules. Maximum
serum concentration is
achieved, the distribution
phase lasts for 6-10
hours. (Bauer,
2006:402).
Short term side effects observed when
starting lithium or after a dosage.increase
include muscle weakness, lethargy,
polydipsia, polyuria, nocturia, headache,
impairment of memory or concenttatio,
confusion, impaired,fine motor performace
and hand tremors.many of these adverse
effects diminish with continued dosing of
lithium. (Bauer, 2006:402).

Long term adverse affects of lithium therapy
include a drug induced diabetes insipidus ,renal
toxicity (gromelorulosclerosis, renal tubular atropy,
interstitial nephritis, urinary casts) hypothyroidism
with or without goiter formation,
electrocardiographic abnormalities, leukocytosis,
weight gain, and dermatological changes.
At lithium serum concentration near the upper and of
therapeutic range (1.2-1.5 mmol/L) the following adverse
effects may be noted in patiens decreased memory and
concentration,drowsiness,fine hand tremor,weakness,lack
off coordination,nausea,diarrhea,vomiting,or fatigue.
At concentration just above the therapeutic range (1.5-3
mmol/L), confusion, giddiness, aiation , blackouts , and
muscle fasciculations may occur in patients.
If concentration exceed 3 mmol/L, severe toxicity occurs,
with choreoathetosis,stupor, coma, and death.
(Bauer, 2006:402).
Clinical Monitoring
Parameter
Her regular bipolar illness suffered by the patient.
(Bauer, 2006:403).

Depresi
Mania
The signs and symtoms of bipolar
disease include those of both
depression and mania.
Generally, onset of action for lithium is
1-2 weeks, and a 4-6 week treatment
period is required to asses complete
therapeutic response to the drug.
(Bauer, 2006:403).


Basic Clinical Pharmacokinetic
Parameters
Lithium is eliminated almost completly (>95%) unchanged in
the urine. The ion is filtered freely at the glomelurus, and
subsequently 60-80% of the amount filtered is reabsorbed by
the proximal tubule of the nephron.
Lithium eliminated in saliva, sweat, and feces accounts for
less than 5% of the adminitered dose
Lithium is administered orally as carbonate or citrate salts.
Oral bioavailability is good for all lithium salts and dosage
forms and equals 100%.
The peak lithium concentration occurs 15-30 minute aftr a
dose of lithium citrate syrup, 1-3 hours after a dose of rapid-
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 eith normal renal function. (Bauer, 2006:404).
Adults with normal renal function (creatinine clearance >80
ml/min) have an average elimination half life of 24 hours,volume
of distribution of 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 half the
normal value. (Bauer, 2006:404).
In children 9-12 years of age ,average elimination half life is 18
hours volume distribution is 0.9 L/kg and clearance is 40 ml/min
for the ion.
Because glomeruler filtration and creatinine cratine decrease
with age, lithium clearance can be decreased in elderly
patients, producing half lives of up to hours.
Because of the circadian rhythm of glomerular filtration, lithium
clearance is about 30% higher during daytime hours. (Bauer,
2006:405).
Effects of drugs on renal disorder
patients
Because lithium is eliminated almost exclusively by the
kidney,renal dysfunction is the most important disease state
that effects lithium pharmacokineties.lithium clearance rate
decreases in proportion to creatinin clearance.
In adults,the lithium clearance/creatinine clearance ratio
is 20%,but during a manic phase it increases to about
30%
The relationship between renal functin and lithium
clearance forms the basis for the initial dosage
computations lterin the chapter.bacause of the decrease
in clearance,the average lithium half life is 40-50 hours in
renal failure patients. (Bauer, 2006:405).







Acute mania
During periods of acute mania,lithium
clearance can be increased by as much
as much as 50 %. (Bauer, 2006:405).
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.lthium reabsorption increases
and lithium clearance decreases by 40-
50 % during treatment with thiazide
diuretics. (Bauer, 2006:406).
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 similiar
interaction,there are also reports of no
drug interaction between lithium and
these agents. (Bauer, 2006:406).
Recommended dose
For the treatment of acute mania,initial doses are
usually 900-1200 mg/d of lihium carbonate.
renal dysfunction is the major condition that alters
lithium pharmacokinetics and dosage
If creatine clearance is 10-50 ml/min,the prescribed initial
dose is 50-75% of the recommended for patiens with
normal renal function.
For creatine clearance volues below 10 ml/min,the
prescribed dose should be 25-50% of the usually dose in
patiens with good renal function. (Bauer, 2006:411).
Example
Mj is a 50-year old, 70 kg (heigth = 510) mae with bipolar disease. He
is not currently experiencing an episode of acute maniaHis . serum
creatine is 0,9 mg/dl/ recomend an oral lithium dose for this patient for
maintenance theraphy.
1. Estimete creatine clearance.




CrLs = 97 ml/min

2. Choose a lithium dose based on diease states and conditions
present in the patient. The patient requaires prophylacticnlithium
therapy for bipolar disiase, and he has good renal funtion. A lithium
carbonate dose of 600 mg/d, given as 300 mg every 12 hours, is
recomeded as the initial dose. The doasag rate will be increased
300-600 mg/d every 2-3 das as needed to provide adequate
therapeutic effets, and produce therapeutic lthium steady-state
concetration. (Bauer, 2006:412).
Dosing strategies (Bauer,
2006:242).
Tabel of dosing strategies
Dosing Approach /
philosophy
Initial dosing Use fo serum
concentration to
alter doses
Pharmacokinetic
parameters/equations
Pharmacokinetic
dosing methode
Pharmacokinetic
parameter methode
Literature-based /
concept
Litherature-based
recommended dosing
Linear pharmcokiteic
methode
computerized Bayesian computer
program
Bayesian computer
program

references
Bauer, L.A (2006).lithium on Clinical
Pharmacokinetics Handbook Newyork

attachments
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