Lithium Dosing Tools
Lithium Dosing Using
Non-Steady State or Steady State Levels, Single Level After Test Dose, Or Multiple Levels After Test
Dose Calculator
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Lithium
Dosing Calculator and Data Fitting for 12-hour post-dose Levels,
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Lithium Pharmacokinetic Dosing Information
Usage: manic episodes of bipolar disorder, bipolar
(manic-depressive) disorder, schizo-affective disorders, major depression,
cluster headaches, ant-suicide, and syndrome of inappropriate antidiuretic hormone.
It has a narrow therapeutic window and predictable pharmacokinetics.
Bioavailability (F):
1 (0.8-1), slow-release formulations may have bioavailable as low as 0.85 or 85%.
Fraction IV:
not available in the USA
Salt: Monovalent cation 1 mmol/L = 1 mEq/L, lithium carbonate 300 mg = 8.12 mEq, lithium
citrate ~ 300 mg = 8 mEq
Route of Administration:
Oral, do not give rectal as it causes painful diarrhea
Absorption:
in the
jejunum and ileum, the extent of absorption is unaffected by food, but
the rate of absorption may be reduced
Peak concentrations:
oral solution 15-45 minutes, immediate release carbonate tablets and capsule
0.5-3 hours, extended-release 4-12 hours
Protein binding: not
protein bound
Metabolism: Not
metabolized
Vd(L/kg): initial compartment 0.25-0.3 L/kg of LBW, final
volume of distribution ~ 0.7 L/kg of lean body weight or fat free mass. Other
references have: Children and adolescents 0.93 l/kg, adults 0.85 l/kg, elderly
(greater than 59 years) 0.53 l/kg.
Cl (L/hour): 0.25 * creatinine clearance (ml/min) * 60 /1000,
renally eliminated, completely filtered by glomerulus with ~ 80% reabsorbed by
proximal renal tubules. Reabsorption is closely linked with sodium reabsorption
and is influenced by the same factors that affect sodium (dehydration,
hypotension). Clearance increases by 50-100% during pregnancy, care monitoring is required,
with downward titration or discontinuation before delivery. Increasing
water intake does not increase excretion.
K (1/hours): 0.25*creatinine clearance (ml/min) *(60/1000) /
(0.7*Fat Free Mass)
Half-life (hours): Distribution half-life is 0.8-1.2 hours,
and post-distribution half-life is 18-30 hours
in normal renal function after multiple dosing. Half-life is dependent of volume of distribution and clearance.
Dosage Forms:
tablets, capsules, oral syrup
Usual Interval: every 6, 8,
12, 24 hours
Usual Oral Dose: Acute Therapy and Maintenance Therapy:
Children
(not FDA approved less than 12 years of age):
6-11 years old: initiation of acute therapy less of 15-20
mg/kg/day or 150 mg twice daily, maintenance 150 mg once daily
12 years and older: initiation of
acute therapy lesser of 15-20 mg/kg/day or 300 mg twice, maintenance 300
mg once daily
Adults: Initiation of acute
therapy 900-1800 mg/day, maintenance 900-1200 mg/day, 15
mg/kg/day
Elderly: Initiation of
therapy 600-900 mg/day, maintenance 600-900 mg/day
Initiation of therapy: Administer doses, 8-8.12 mEq, two
to four times a day depending on age, weight, and renal function.
Therapeutic Levels were established with multiple daily dosing regimens
when levels were drawn 12 hours after the last evening dose of the day.
Serum levels may vary by a factor of 2-3 during a dosage interval therefore a
uniform time for monitoring levels was established at 12 hours post evening
dose. The risk of relapse decreases with higher levels. Relapse is 2.6 times higher
with levels of 0.4-0.6 mEq/L as compared to 0.8-1 mEq/L. Full
therapeutic effect is seen 14-21 days from the start of therapy.
Prophylaxis of mania: 0.6-1 mEq/L
Acute mania: 0.5-1.2 mEq/L
Prophylaxis of depression: 0.4-0.8 mEq/L
Serum Sampling Times and Recommended Monitoring: monitor morning levels 12 hours
after the evening dose, withhold the normally scheduled morning dose if necessary
to obtain the level. Due to the long half-life serial levels every 3 days during
initiation then once weekly are recommended until accumulation is complete. Longer
dosing intervals are associated with higher 12-hour post-dose levels. Once-daily
dosing displays an approximately 40% higher 12-hour post-dose level than the
same total daily dose divided into 2-4 doses a day. Therapeutic ranges were
established with multiple daily doses. No therapeutic range has been established
for once daily dosing. Obtain
a serum creatinine every other day during hospitalization and monitor for drug
interactions and side effects. Monitor lithium concentration every 3-6 months in
stable outpatients.
Pregnant patients: Monitor
levels and creatinine 3-4 weeks unit 34 weeks of pregnancy, then once a week
unit delivery. Consider twice daily dosing to minimize peak levels. Avoid
non-steroidal anti-inflammatory agents. Obtain lithium levels twice weekly for
two weeks postpartum. Adjust the dose as necessary to maintain therapeutic levels.
Pharmacokinetic Model: Lithium may be modeled with 1 or 2-compartment
linear models.
A linear one-compartment open model is adequate for dosage
predictions, but levels should be drawn 12 hours after post-dose to ensure the
level is in drawn in the post-distributive phase. Levels drawn in the
distributive phase will be elevated and should not be used for dosing
adjustments. When levels are at steady state doses can be adjusted proportional
for the desired concentration.
Side effects:
Common side effects on initiation are nausea, polyuria, polydipsia, and diarrhea.
Divided doses with meals helps to minimize nausea and vomiting. Hypothyroidism,
fine intentional tremor, weight gain, acne, worsening psoriasis, and
nephrotoxicity may develop with long term therapy
Toxicity: usually occurs with 12-hour post-dose levels > 1.5 mEq/L. Levels above 3-3.5 mEq/L are considered life-threatening. Whole bowel
irrigation is used to prevent the absorption of unabsorbed lithium. HD may be used,
it removes lithium from the central compartment; but is ineffective in removal
from deep compartments. Repeat levels should be drawn 6-8 hours post-dialysis
due to redistribution with a goal of lithium levels less than 1 mEq/L. Pregnancy Category D, avoid
use in the first trimester. Use in second and third trimester has not been
associated with fetal risk. Breast milk concentrations are 50% of maternal
concentrations. Lithium crosses the placenta with
concentrations similar in fetal and maternal serum.
Common Drug interactions:
with clearance adjustment factors
Decrease clearance: non-thiazide, thiazide diuretics 0.5 and loop
diuretics; NSAIDs, ACEI
Increased clearance: cisplatin
(1.6), caffeine (1.2), theophylline (1.21), and sodium containing IV fluids (1.2)
Disease state or physiologic condition interactions:
Decrease
clearance: acute mania clearance 60% of usual, renal dysfunction,
cirrhosis of liver, dehydration, sodium loss, low salt diet
clearance 80% of usual. Renal excretion has not been shown to increase with
increasing water intake or acidification of urine.
Increase clearance:
pregnancy clearance increases by 50-100%, increase starts in the first
trimester, peaks mid-pregnancy, and returns to non-pregnancy value immediately
postpartum, strenuous exercise 20% increase in clearance
Dosage Calculations: There are multiple published dosage methods including
Pepin, Jermain, Zetin and Winter to determine the initial dose. The method
of Winter is shown below. Due to the long half life serum level monitoring is
the key to preventing toxic levels.
BMI: Actual Body Weight
/ (Height in meters)^2
Body Weight Calculations:
Ideal Body Weight
IBW(kg) (Devine Formula)
Adult Males (18 years and older) in kg: 50 kg + 2.3*(Height in inches greater
than 60 inches)
IBW(kg) (Devine Formula) Adult Female (18 years and older): 45.5 + 2.3*(Height in
inches greater than 60 inches)
Fat Free Mass (Janmahasatian Formula):
FFM(kg) Adult Males = 9270 * Actual Body Weight(kg) / (668 + (216* BMI))
FFM(kg) Adult Females = 9270 * Actual Body Weight(kg) / (8780 / (244*(BMI))
Body Surface Area in Meters Squared = ((Weight in kg)^0.425)*((Height
in centimeters)^0.725)*(71.84/10000)
Dosing Weight(kg) =
Fat-Free Mass for Vd, and Creatinine Clearance
Calculation
Creatinine Clearance(ml/min):
Adult
Males: Creatinine Clearance (mL/min)= (140-age(years))*(Fat
Free Mass(kg)) / (serum creatinine(mg/dl)*72)
Adult
Females: Creatinine Clearance (mL/min) = 0.85 *( (140-age(years))*(Fat
Free Mass(kg)) / (serum creatinine(mg/dl)*72))
Serum creatinine
is rounded up to 0.7 mg/dL for all adult patients at my institution without
paralysis or malnutrition. FFM is recommended to be used in the creatinine
clearance equations, including obese patients, as dosing predictions are
improved. The calculations below use the lower of FFM or actual body weight in
the calculation of creatinine clearance and
volume of distribution.
Clearance(L/hr)
Males = 0.25 * (140-age) * FFM *60/1000 / (72*Serum Creatinine(mg/dL))
Female
= 0.25 * 0.85 * (140-age) * FFM * 60/1000 / (72 * Serum Creatinine(mg/dL))
Volume of Distribution(L)
= 0.7 * Fat Free Mass(kg)
K(1/hours) = Clearance / Vd
Vd(L) = 0.7*Dosing weight(kg)
Maintenance Dose(mEq) =
Cpaverage(mEq/L or mmol/L) * Tau(Hours) * Clearance(L/hr) / Fraction
Cpaverage(mEq/L)
= Fraction * Dose(mEq) / (Clearance(L) * Tau)
Cpmaximum(mEq/L) = Fraction *
Dose(mEq) / (Vd(L) * (1-exp(-K*Tau)))
Cp 12 hours post-dose(mEq/L) = Cpmaximum(mEq/L) * exp(-K*12)
Cpminimum(mEq/L) = Cpmaximum(mEq/L) * exp(-K*Tau)
Lithium Dosing Using
Non-Steady State or Steady State Levels, Single Level After Test Dose, Or Multiple Levels After Test
Dose Calculator
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Comparison of dosing weight equations
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