The document discusses therapeutic drug monitoring of lithium, which is used to treat acute mania and bipolar disorder. It outlines the optimal plasma concentration ranges for treatment of mania and prophylaxis based on 12-hour standardized lithium levels. Both dose-dependent and independent side effects are described. Factors that can impact lithium clearance like renal function and concomitant medications are also discussed. The document emphasizes the importance of therapeutic drug monitoring to ensure therapeutic concentrations are achieved while avoiding toxicity.

1. TDM OF DRUGS USED
IN PSYCHIATRIC
CONDITION
DR. RAMESH BHANDARI
ASST. PROFESSOR
DEPARTMENT OF PHARMACY PRACTICE
KLE COLLEGE OF PHARMACY, BELAGAVI

2. Dr.RameshBhandari
TDM OF LITHIUM
 Lithium is used in the treatment of acute mania and in the
prophylaxis of manic depression.
The mechanism of action is not fully understood, but it is thought
that it may substitute for sodium or potassium in the CNS.
Lithium is toxic producing dose-dependent and dose-independent
side effects.
Hence, TDM of lithium is essential in assisting in management of
the dosage.

3. Dr.RameshBhandari
Dose dependent effects
The plasma concentration-response relationship derived on the basis of the
12-hour standardised lithium level:
 <0.4 mmol/L: little therapeutic effect
 0.4-1.0 mmol/L: optimum range for prophylaxis
 0.8-1.2 mmol/L: Optimum range for acute mania
 1.2-1.5 mmol/L: Causes renal impairment
 1.5-3.0 mmol/L: Causes renal impairment, ataxia, weakness, drowsiness,
thirst, diarrhoea
 >3.0 mmol/L: Causes confusion, spasticity, dehydration, convulsions, coma,
death (>3.5 mmol/L: Medical emergency)

4. Dr.RameshBhandari
Dose Independent effects
It includes tremor, hypothyroidism, nephrogenic
diabetes insipidus, GI upset, loss in bone density,
weight gain and lethargy.

5. Dr.RameshBhandari
General pharmacokinetics of LITHIUM
Distribution: Unevenly distributed through out the
body, with a Vd of 0.7L/Kg. It follows 2
compartmental model with a distribution time of 8
hours.
Elimination: Excreted unchanged by Kidney.
Lithium clearance is approx. 25% of CrCl due to
reabsorption in the renal tubules.

6. Dr.RameshBhandari
General pharmacokinetics of LITHIUM
Elimination:
Changes in renal function, dehydration, diuretics,
ACEI and NSAIDs all decreases lithium clearance.
Aminophylline and sodium loading increase
lithium clearance.
Lithium half life: 8-35 hours (18 hours)
Lithium clearance shows diurnal variation.

7. Dr.RameshBhandari
INDICATION FOR TDM OF LITHIUM
Confirmation of toxicity
Assessing the effect of factors altering
pharmacokinetics
Therapeutic efficacy
Medication Compliance

8. Dr.RameshBhandari
Appropriate Sampling Time
 Blood samples should be drawn 12 hours after the evening dose, because this
will allow for distribution and represent the slowest excretion rate.
In general, lithium concentration should be determined 3-7 days after therapy
has started.
In acute mania, initial 12 hour lithium concentration is monitored once or
twice weekly until the desired therapeutic concentration achieved.

9. Dr.RameshBhandari
PHARMACODYNAMIC MONITORING
 Manic Symptoms:
1–3 weeks
Decrease in pressured speech
Decreases in hostile or assaultive behaviors
2–3 weeks
Improved thought pattern disturbances
2–4 weeks
Increased attention to appearance or hygiene
1–2 months
Less grandiosity Less irritability
Depressive Symptoms:
2–4 weeks
Improved motor and mental activities Improved sleep pattern
Decrease in any psychotic features
1–2 months Improved mood

10. Dr.RameshBhandari
CONCENTRATION RELATED TOXICITY
 Toxicity occurs with 12-hour trough concentration >1.5 mEq/L.
Whereas side effects may occurs at therapeutic concentration.
 Mild and transient effects such as fine tremor, nausea, diarrhea, muscle
weakness, polyuria, and polydipsia can be seen at concentrations of less
than or equal to 1.5 mEq/L.
 Moderate toxicity usually occurs at concentrations of 1.5 to 2.5 mEq/L.
 severe toxicities observed at trough concentrations greater than 2.5
mEq/L.
 Concentrations above 3–3.5 mEq/L are usually considered life
threatening.

11. Dr.RameshBhandari
DRUG-DRUG INTERACTION
 A number of lithium drug–drug interactions are associated with effects on fluid
and/or sodium balance, thus, GFR and sodium excretion are of particular importance.
 Drugs causing a decrease in GFR or a compensatory increase in sodium
reabsorption result in reduced lithium clearance and elevated lithium concentrations.
DRUG AFFECTED PARAMETER ADJUSTMENT FACTOR
Thiazide Diuretics Renal Clearance 0.32-0.74
Theophylline Renal Clearance 1.21
Sodium containing IV Fluids Renal Clearance 1.2
NSAIDs Renal Clearance 0.33-1
ACEI Renal Clearance 0.87 (<50 yrs) 0.69 (>50 yrs)

12. Dr.RameshBhandari
DOSING STRATEGIES FOR LITHIUM
 Dosage prediction using the traditional Pharmacokinetic method:
D = CL x t x CSSav / S x F
Where, D = dose (mEq)
CL= clearance of lithium (L/hour)
t = dosing interval (hour)
CSSav = average steady state concentration (mEq/L)
F = fraction absorbed (90%)
S= Salt form (1)
Then dose is converted to mEq to mg.
Dosage prediction by lithium clearance estimation:
ClLi = 0.235 x CrCl

13. Dr.RameshBhandari
Treatment Initiation and Monitoring for
Patients Receiving Lithium
Follow-up 12 hour lithium concentration and clinical response
Good response adequate concentration
Response questionable or toxicity or lack of
response
Select lithium dose, dosage form, and interval for target concentration
Estimate lithium clearance
Calculate creatinine clearance
Continue to monitor periodically Adjust lithium dose proportionately