TEACHERS' TOPICS Therapeutic Drug Management of Lithium

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American Journal of Pharmaceutical Education 2005; 69 (5) Article 88.

TEACHERS’ TOPICS
Therapeutic Drug Management of Lithium
Marshall E. Cates, PharmD, and Pamela J. Sims, PharmD, PhD
McWhorter School of Pharmacy, Samford University
Submitted February 2, 2005; accepted March 18, 2005.

        Lithium continues to be a mainstay in the treatment of bipolar disorder. Aside from understanding the
        basic pharmacokinetics of lithium and the factors that influence serum lithium concentrations, the
        student should understand the clinical usefulness of serum lithium concentrations, the reasons for
        obtaining them, and how to interpret them. Significant emphasis is placed on the student being able
        to apply the information to clinical scenarios and becoming an inquisitive problem solver. To that end,
        case studies are used to promote a deeper understanding of lecture material.
        Keywords: lithium, pharmacokinetics, therapeutic drug monitoring, bipolar disorder

INTRODUCTION                                                       INSTRUCTIONAL DESIGN
    Therapeutic Drug Management (TDM) is a 2-course                Clinical Use of Lithium
sequence that emphasizes the application of pharmacoki-                 Despite the introduction of many other mood stabil-
netic principles to the individualization of drug regimens.        izers, lithium continues to be considered first-line therapy
The course philosophy is that students should learn to be          for treatment of acute mania and long-term prophylaxis
problem solvers. They should be able to identify the prob-         of bipolar disorder. It is also used in a variety of other
lem, identify and retrieve missing information, apply              conditions, such as schizoaffective disorder, major
appropriate principles, choose realistic solutions, and rec-       depressive disorder (adjunctive therapy), schizophrenia
ommend appropriate follow up. The TDM of lithium ther-             (adjunctive therapy), aggression, premenstrual dyspho-
apy is taught via a traditional 80-minute lecture using            ria, and cluster headaches.1-3
PowerPoint slides. Students then complete case studies
in an independent manner, followed by a 2-hour small-              Basic Pharmacokinetics of Lithium
group work session in which students discuss their find-                Lithium is available in regular-release tablets and
ings with peers and the instructor. After completing the           capsules (as carbonate salt), extended-release tablets (as
course, students should be able to:                                carbonate salt), and syrup (as citrate salt).1-4 The
      1. Describe the basic pharmacokinetic parameters             extended-release tablet has a slower absorption rate, a
         of lithium;                                               lower peak level, and lower bioavailability relative to
      2. Recognize factors that influence serum lithium            the other dosage forms.1,2,5 Patients may prefer capsules
         concentrations;                                           if they cannot tolerate the taste of tablets. Extended-
      3. List the important drug interactions of lithium;          release tablets are more expensive and are usually
      4. State the usual therapeutic range for lithium in          reserved for patients who are experiencing peak-concen-
         the acute and maintenance treatment of mania;             tration related side effects such as tremor, nausea, or pol-
      5. Recognize the various signs/symptoms of lith-             yuria. The syrup is used primarily for patients who refuse
         ium toxicity;                                             to take medication or who have difficulty swallowing
      6. Discuss reasons for obtaining a serum lithium             tablets or capsules.2
         concentration;                                                 Lithium is widely distributed into most body tissues
      7. Interpret serum lithium concentrations that differ        and fluids. However, it is unevenly distributed among
         from expected values; and                                 several tissue compartments, so for instance, the lithium
      8. Describe and apply lithium dosing methods.                concentration is higher in saliva and in the thyroid than in
Corresponding Author: Marshall E. Cates, PharmD.                   serum.1 Lithium initially distributes into an apparent vol-
Address: Department of Pharmacy Practice, Samford                  ume that is about 25%-40% of body weight, and later into
University McWhorter School of Pharmacy, 800 Lakeshore             a volume that is about 50%-100% of body weight. The
Drive, Birmingham, AL 35229. Tel: 205-726-2457.                    apparent volume of distribution at steady state ranges
Fax: 205-726-2669. E-mail: mecates@samford.edu                     from 0.5 L/kg to 1.2 L/kg. Lithium has a smaller volume
                                                               1
American Journal of Pharmaceutical Education 2005; 69 (5) Article 88.

of distribution in elderly patients. Lithium is not bound to        inhibition.6,7 Distal tubule diuretics, such as hydrochlor-
plasma proteins.1,2,5                                               othiazide, have been reported to increase serum lithium
     Lithium is not metabolized. It is filtered by the glo-         concentrations by approximately 25%.6 The purported
meruli and eliminated renally as the free ion. Although             mechanism of this interaction is the induction of natriu-
small amounts are eliminated via sweat, saliva, and feces,          resis, which leads to a compensatory increase in the reab-
lithium is excreted almost entirely in the urine. Its clear-        sorption of sodium (and thus lithium) in the proximal
ance is directly proportional to a patient’s glomerular             tubule.6,7 Angiotensin-converting enzyme (ACE) inhibi-
filtration rate and renal blood flow. About 80% of lithium          tors, such as captopril, enalapril, and lisinopril, can in-
filtered by the glomeruli is reabsorbed in the proximal             crease serum lithium concentrations through volume
tubules (in parallel with sodium); thus, clearance of lith-         depletion and reduction in glomerular filtration rate or a
ium is about 20% of the patient’s glomerular filtration             decrease in aldosterone levels that leads to sodium deple-
rate. Renal clearance of lithium is affected by several             tion and subsequent lithium retention. The onset of this
factors, including circadian rhythms (day . night), affec-          interaction appears to be delayed (3-5 weeks), and elderly
tive phase (manic . nonmanic), age (younger . elderly),             patients may be predisposed.6
and pregnancy (pregnant . nonpregnant).1,2,5 The approx-                 Drugs that have been reported to decrease serum lith-
imate half-life of lithium is 24 hours in adults, 36 hours in       ium concentrations include carbonic anhydrase inhibitors
elderly patients, and 40-50 hours in patients with impaired         (eg, acetazolamide), osmotic diuretics (eg, mannitol, urea),
renal function.4                                                    methylxanthines (eg, caffeine, theophylline), and sodium
                                                                    bicarbonate.6 Drugs that have minor, variable effects
Serum Lithium Concentration                                         on serum lithium concentrations include loop diuretics
     Important considerations in how the body handles               (eg, furosemide) and potassium-sparing diuretics (eg,
lithium are three-fold: water balance, sodium balance,              amiloride).5
and renal function.2,5 A decreased water balance would
be expected to result in increased serum lithium concen-            Usefulness of Serum Lithium Concentrations
trations, whereas an increased water balance would be                    Because lithium concentrations vary widely during
expected to result in decreased serum lithium concentra-            a dosing interval, a representative single time point for
tions. Because of the manner in which the body handles              serum lithium concentration monitoring was established
lithium renally, a decreased sodium balance would be                for standardization. Although somewhat arbitrary, the 12-
expected to result in increased serum lithium concentra-            hour post-dose time point was selected for this purpose
tions, whereas an increased sodium balance would be                 because it avoids the highly variable absorption and dis-
expected to result in decreased serum lithium concentra-            tribution phases. The usual practice is to obtain the sample
tions. Renal function plays an obvious role in influencing          in the morning before the first lithium dose and 12 hours
serum lithium concentrations, as almost all lithium is              after the previous evening dose.1,5,7
excreted renally. Through these mechanisms, many dif-                    Acute mania typically presents with a combination of
ferent factors can affect serum lithium concentrations.             mood (eg, euphoria, elation, lability, irritability), hyper-
Examples include such things as alterations in diet (eg,            active (eg, decreased need for sleep, rapid speech, psy-
low salt diet, slimming diets) or physical activity (eg,            chomotor agitation, racing thoughts), and behavioral (eg,
excessive sweating), drug-drug interactions (eg, nonster-           intrusiveness, challenging, hypersexual) symptoms, and
oidal anti-inflammatory drugs [NSAIDs], diuretics),                 occasionally psychotic (eg, hallucinations, delusions)
medical illnesses (eg, renal dysfunction, diarrhea or vom-          symptoms. Most clinicians advocate a serum concentra-
iting), and pregnancy and delivery.                                 tion of 0.8-1.2 mEq/L during initial treatment of acute
                                                                    mania.1,8 On the other hand, during long-term mainte-
Drug Interactions With Lithium                                      nance treatment, serum concentrations of 0.6-1.0 mEq/L
     Some of the most clinically relevant drug interactions         are usually adequate to prevent the recurrence of a manic
involving lithium are those that result in increased serum          episode.1,8 Some patients may require serum lithium con-
lithium concentrations. Some NSAIDs, such as indome-                centrations outside the usual ranges. For instance, elderly
thacin and ibuprofen, can increase serum lithium concen-            patients may require lower levels.1
trations by approximately 40%, but aspirin and sulindac                  Unfortunately, lithium possesses a narrow therapeu-
have only minimal effects.6 Possible mechanisms of this             tic index.9 Toxic effects of lithium become more likely
interaction include decreased renal blood flow secondary            as serum concentrations rise, and most patients will expe-
to prostaglandin inhibition and enhanced reabsorption of            rience some toxic effects with concentrations above
sodium (and thus lithium) secondary to prostaglandin                1.5 mEq/L.9 Symptoms of mild toxicity include such
                                                                2
American Journal of Pharmaceutical Education 2005; 69 (5) Article 88.

things as nausea, diarrhea, tremors, muscle weakness,               12-hour serum lithium concentration by about 0.2 mEq/L
and fatigue. Symptoms of moderate toxicity include                  relative to twice-daily or thrice-daily dosing regimens.2,7
such things as sedation, confusion, lethargy, ataxia,               Recommendations for therapeutic concentrations (as noted
coarse tremors, dysarthria, nystagmus, and increased                above) are based on multiple daily dosing regimens.
deep tendon reflexes. Severe toxicity (.2.5 mEq/L) may              Finally, the accuracy and reliability of the laboratory can
result in permanent neurological impairment, seizures,              certainly impact the interpretability of serum lithium con-
coma, and death. The severity of lithium toxicity is related        centration determinations. Therefore, guidelines for ensur-
to both serum concentrations and the duration at which              ing the accuracy and reliability of standardized 12-hour
concentrations have remained high.1,3,4,9                           serum lithium concentrations include: optimal compli-
                                                                    ance; sample obtained 12 6 1/2 hours after the last evening
                                                                    dose; sample obtained after at least 4-5 days at a given
Reasons for Monitoring Serum
                                                                    dose; twice-daily or thrice-daily dosing schedule; and appro-
Lithium Concentrations
                                                                    priate precision of laboratory analyses.1
     There are many clinical reasons to obtain serum lith-
                                                                         When interpreting unexpected serum lithium concen-
ium concentration measurements. When lithium therapy
                                                                    tration values, the clinician must consider various explan-
is initiated, or anytime that the lithium dosage is changed,
                                                                    ations. Perhaps the serum concentration measurement
serum concentrations are helpful in determining optimal
                                                                    reveals a ‘‘true’’ concentration, so the clinician should look
dosing.4 During maintenance therapy for prophylaxis of
                                                                    for those factors that alter serum lithium concentrations,
bipolar disorder, most clinicians obtain serum concentra-
                                                                    such as changes in water balance, sodium balance, and
tion measurements every 3-6 months.4 Signs/symptoms
                                                                    renal function. On the other hand, the clinician should
of either manic or depressive symptoms, or symptoms of
                                                                    consider whether the measurement is actually inaccurate
possible lithium toxicity, necessitate serum lithium con-
                                                                    or unreliable, and thus may be due to a missed or extra
centration determinations. When situations arise that may
                                                                    dose, improper timing, non–steady-state, dosing sched-
alter steady-state serum concentrations, such as develop-
                                                                    ule, or laboratory error. Regardless, the clinician should
ment of medical disease (eg, diarrhea), significant increases
                                                                    not make hasty decisions based on aberrant values, rather
in sweating, initiation/dosage alteration/discontinuation
                                                                    he or she should consider obtaining another measurement
of drugs that may interact with lithium, and change in salt
                                                                    for verification.
intake or diet, then the clinician is wise to obtain serum
lithium concentration measurements.1,4 Finally, sus-
                                                                    Lithium Dosing Methods
pected noncompliance with prescribed lithium regimens
                                                                         The lithium dosage must be individualized according
frequently dictates the need for serum lithium concentra-
                                                                    to serum lithium concentrations, clinical response, and
tion measurements.1
                                                                    adverse effects. Various prospective dosing methods exist
                                                                    in order to minimize the number of serum lithium con-
Interpreting Serum Lithium Concentrations                           centration determinations and decrease the amount of
    There are various factors that can affect the accuracy          time required to achieve a therapeutic dose. However,
and reliability of serum lithium concentration measure-             there is no empirical evidence that these strategies
ments. Certainly patient compliance with the lithium reg-           actually result in a more rapid clinical response.8 In the
imen, especially the doses immediately prior to the serum           Cooper method,11,12 a 600-mg test dose is given and the
concentration determination, can affect the accuracy of             serum lithium concentration is determined 24 hours later.
the results.7 Because the standard concentration is con-            Depending upon that concentration, a chart reveals the
sidered a 12-hour post-dose determination, samples                  predicted daily dose to yield a steady-state concentration
obtained before that timeframe result in falsely increased          of 0.6-1.2 mEq/L. Another example is the Perry
concentrations, while samples obtained after that time-             method,13,14 which utilizes a 1200-mg test dose, with
frame result in falsely decreased concentrations. Due to            subsequent serum lithium measurement 24 hours later.
the approximate 24-hour half-life in most patients,                 The clinician then plots the 24-hour concentration against
steady-state concentrations are obtained in about 4-5               a desired steady-state concentration on a nomogram,
days.10 Thus, samples obtained prior to that timeframe              revealing the approximate daily dose needed for that
after increasing or decreasing the lithium dosage will              patient. Despite the availability of such prospective meth-
result in falsely decreased or increased steady-state con-          ods, the traditional (‘‘retrospective’’) method is almost
centrations, respectively. The dosing interval can also             always used by clinicians because of its ease and familiar-
affect the interpretation of lithium concentrations. Once-          ity, as well as the fact that it minimizes initial adverse
daily (ie, bedtime) dosing of lithium typically increases the       effects, which may increase the likelihood of long-term
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American Journal of Pharmaceutical Education 2005; 69 (5) Article 88.

compliance. In this method, lithium therapy is usually              improved tolerability of therapy. Since CS is acutely
initiated at 300-mg given 2 or 3 times daily, and the dos-          manic, the most appropriate serum lithium concentration
age is adjusted utilizing serum concentration determinations        range is 0.8-1.2 mEq/L. First-order linear kinetics mean
once or twice a week until the desired serum concentration is       that the patient’s dosage should be increased to 1500 mg/
obtained. Since lithium follows first-order linear kinetics,        day. Assuming no other reasons for more frequent mon-
as the dose is changed, the steady-state serum lithium              itoring, serum lithium concentration measurements
concentration changes proportionately.1,2,9,10                      should be made every 3-6 months, with a desired concen-
                                                                    tration of 0.6-1.0 mEq/L.
CASE STUDIES                                                             Case Study #2. The outpatient psychiatrist in the
     Case Study #1. CS is a 45-year-old woman who was               mood disorders clinic has called you for consultation con-
brought to the state psychiatric facility by the police. She        cerning one of his patients, LS, a 46-year-old black male
was causing a disturbance at a local television station by          patient with a long history of bipolar disorder. He is rather
insisting on addressing the city during a news broadcast.           well-known for being compliant with therapy overall, yet
She is euphoric and grandiose. She exhibits rapid speech            very absent-minded; for instance, he always shows up for
and psychomotor agitation. She admits to racing thoughts            his clinic appointments but is frequently very early or very
and decreased need for sleep. CS denies that she has a              late because he cannot remember when the appointment
mental illness and states that she does not need any med-           is. You have known LS for quite some time, and recall that
ication. CS is diagnosed with bipolar disorder, manic epi-          he was receiving lithium, 600 mg twice daily, and nifedi-
sode. Her only medical illness is hepatitis C.                      pine, 30 mg three times daily, the last time you checked
      1. The psychiatrist is considering lithium or val-            his profile several months ago.
         proate to treat CS’s mania. Why might lithium                   The reason the psychiatrist has called you is because
         be the best choice for CS?                                 of LS’s serum lithium concentration. LS generally has a
      2. Lithium is available in several different dosage           serum lithium concentration of approximately 0.9 mEq/L.
         forms. What would be your advice to the psy-               A routine level was drawn this morning and was just
         chiatrist concerning choice(s) of dosage forms             reported as 1.6 mEq/L. The psychiatrist states that
         and why?                                                   although he has made some recent adjustments to LS’s
      3. Describe the various dosing techniques that                lithium therapy, he has not altered the daily dose for many
         could be utilized to treat CS’s manic episode.             years. He also states that LS appears as usual, except that
         Which would you prefer and why?                            he complains of ‘‘not feeling good lately,’’ which LS
      4. What is the most appropriate serum lithium con-            attributes to either a ‘‘stomach virus caught from my
         centration range to treat CS’s condition?                  nephew’’ or ‘‘side effects from that new pill they gave
      5. CS is started on 300 mg of lithium 3 times daily           me in hypertension clinic.’’
         and has a steady-state lithium concentration of                 Based upon the information above:
         0.6 mEq/L. If the desired lithium concentration                  1. What are the possible factors, which may, individ-
         is 1.0 mEq/L, what should the dosage be                             ually or collectively, explain why LS’s serum lith-
         adjusted to?                                                        ium concentration is so much higher than usual?
      6. Describe the maintenance treatment of CS with                    2. What information would you need to gather from
         lithium, including desired steady-state serum                       various sources (eg, patient, psychiatrist, labora-
         concentrations and frequency of serum concen-                       tory studies, medication profile) in order to either
         tration monitoring.                                                 rule out or further substantiate each of the afore-
     Comments: The student should recognize that lithium                     mentioned factors as the etiology for the high
would be preferred over valproate in a patient with active                   level?
liver disease, as lithium is not metabolized and is renally              Comments: The student should consider that the
excreted. The syrup formulation should be used, at least            serum lithium concentration may or may not be accurate
initially, owing to the patient’s lack of insight into the          and reliable. The patient may, in fact, be lithium toxic, as
need for medication and consequent likelihood of non-               he describes gastrointestinal distress. It is important to
compliance. Although prospective dosing methods would               note that symptoms such as diarrhea and vomiting may
yield quicker therapeutic serum concentrations, and thus            be the cause or effect of lithium toxicity. So perhaps he
possibly a quicker response, the increased likelihood of            really does have a stomach virus that has indirectly caused
adverse effects, with resultant effects on compliance, is           the serum lithium concentration to increase. It is also
a major drawback. The retrospective dosing method                   important to rule out a drug interaction as the cause of
is slower, but conventional and easy and allows for                 an elevated lithium concentration, which may be the case
                                                                4
American Journal of Pharmaceutical Education 2005; 69 (5) Article 88.

if the new medication prescribed in the hypertension                2. Perry PJ, Alexander B, Liskow BI. Psychotropic Drug
clinic is hydrochlorothiazide or an ACE inhibitor. On               Handbook. 7th ed. Washington, DC: American Psychiatric Press,
                                                                    Inc.; 1997:221-56.
the other hand, the concentration may be falsely elevated
                                                                    3. Bezchlibnyk-Butler KZ, Jeffries JJ. Clinical Handbook of
due to the forgetfulness of the patient (eg, may have taken         Psychotropic Drugs. 12th ed. Seattle, Wash: Hogrefe & Huber
a dose in the morning), a change to bedtime dosing by the           Publishers; 2002:133-9.
psychiatrist, or simply laboratory error. Regardless, the           4. Fankhauser MP. Bipolar Disorder. In: DiPiro JT, Talbert RL, Yee
psychiatrist should confirm this particular serum lithium           GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A
concentration measurement by obtaining another meas-                Pathophysiologic Approach. 5th ed. New York, NY: McGraw-Hill;
                                                                    2002:1273-83.
urement.                                                            5. Carson SW. Lithium. In: Evans WE, Schentag JJ, Jusko WJ, eds.
                                                                    Applied Pharmacokinetics: Principles of Therapeutic Drug
SUMMARY                                                             Monitoring. 3rd ed. Vancouver, WA: Applied Therapeutics, Inc.;
     Major principles of the therapeutic drug management            1992:34-1-34-26.
of lithium are consistently highlighted through the learn-          6. Finley PR, Warner MD, Peabody CA. Clinical relevance
                                                                    of drug interactions with lithium. Clin Pharmacokinet. 1995;29:
ing objectives, lecture content, case studies, and test ques-       172-91.
tions. Aside from understanding information specific to             7. Mitchell PB. Therapeutic drug monitoring of psychotropic
lithium, students must use their information retrieval              medications. Br J Clin Pharmacol. 2000;49:303-12.
skills to obtain information regarding other drug therapy.          8. Eilers R. Therapeutic drug monitoring for the treatment of
The students must then apply their understanding of phar-           psychiatric disorders: clinical use and cost effectiveness. Clin
                                                                    Pharmacokinet. 1995;29:442-50.
macology to determine whether the drugs’ mechanisms of
                                                                    9. Practice guideline for the treatment of patients with bipolar
actions may impact lithium therapy. Students must under-            disorder (revision). Am J Psychiatry. 2002;159(4 suppl):1-50.
stand the usual drug therapy for certain medical diagnoses          10. Preskorn SH, Burke MJ, Fast GA. Therapeutic drug monitoring:
and predict when potentially prescribed drugs might                 principles and practice. Psychiatr Clin North Am. 1993;16:
impact lithium therapy. Students must evaluate the many             611-45.
possible explanations for the patient’s symptoms and deter-         11. Cooper TB, Bergner PE, Simpson GM. The 24-hour serum
                                                                    lithium level as a prognosticator of dosage requirements. Am J
mine the probability of those that are important. Signifi-          Psychiatry. 1973;130:601-3.
cant emphasis is placed on students being able to apply the         12. Cooper TB, Simpson GM. The 24-hour lithium level as a
information to clinical scenarios and becoming inquisi-             prognosticator of dosage requirements: a 2-year follow-up study.
tive problem solvers.                                               Am J Psychiatry. 1976;133:440-3.
                                                                    13. Perry PJ, Prince RA, Alexander B, Dunner FJ. Prediction of
                                                                    lithium maintenance doses using a single point prediction protocol.
REFERENCES                                                          J Clin Psychopharmacol. 1983;3:13-7.
1. Vertrees JE, Ereshefsky L. Lithium. In: Schumacher GE, ed.       14. Perry PJ, Alexander B, Prince RA, Dunner FJ. The utility of a
Therapeutic Drug Monitoring. Norwalk, CT: Appleton & Lange;         single-point dosing protocol for predicting steady-state lithium
1995:493-526.                                                       levels. Br J Psychiatry. 1986;148:401-5.

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