Therapeutic drug monitoring (TDM) of drugs used in seizure disorders- Phenytoin, Valproic acid, Carbamazepine are major drugs used in epilepsy disorders. These drug need TDM to ensure their proper usage.

1. THERAPEUTIC DRUG MONITORING OF
DRUGS USED FOR SEIZURE DISORDER
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2. PHENYTOIN
 Phenytoin is antiepileptic drug is used in the
management of generalized tonic-clonic and
complex partial seizure.
 It may also be used in the prevention of seizures
following head trauma, and in ventricular
arrhythmias.
2

3. NEED FOR TDM
 Large inter individual differences are explained,
in large part, by capacity limited metabolism.
 Large individual variability in steady state
plasma concentration.
 Capacity limited metabolism results in a
relatively narrow dosage range for each patient.
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4. CLINICAL PHARMACOKINETICS
 Absorbed slowly from intestine and the rate of
absorption varies among dosage forms.
 The time at which the concentration peaks is 3-
12 hours after a single oral dose of a capsule or
tablet.
 This slow absorption and relatively slow
elimination of the drug have led to the
recommendation of once daily administration
4

5.  BIOAVAILABILITY
 Bioavailability of phenytoin is difficult to determine
by conventional methods.(bioavailabiliy:85%)
 Bioavailability of phenytoin may be reduced in
gastrointestinal diseases particularly those associated
with increased intestinal motility.
 The absorption of phenytoin is impaired when given
concurrently to patients receiving continuous
nasogastric feedings . The steady state plasma
concentration is drastically reduced.
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6. • t max :3-12hrs
• t1/2 :6-24hrs(increases with dose)
• Vd :0.65 L/Kg (0.6-0.8)in patients with normal
renal function and with plasma albumin concentration.
Phenytoin binds primarily to albumin in plasma, being
the bound fraction 0.9%under the normal conditions.
6

7. • Elimination of phenytoin occurs primarily by
biotransformation to several inactive hydroxylated
metabolites.
• Some of this metabolites, notably 5-(p- hydroxyphenyl)-5-
phenylhydantoin (p-HPPH) are further metabolized by
conjugation with glucoronic acid.
• The urinary recovery of p-HPPH and its glucoronide
accounts for 60% to 90% of an oral dose of phenytoin.
• Phenytoin shows capacity limited metabolism or shows
saturability.
METABOLISM
7

8. •The usually accepted therapeutic range for plasma
phenytoin concentration is 10 to 20 mcg/ml.
• These concentrations are usually effective in controlling
both seizure disorders and cardiac arrhythmias.
•Clinical evaluation of the patient should accompany
monitoring of plasma concentration.
PHARMACODYNAMICS
8

9. THERAPEUTIC RANGE
Adult and children:10-20mcg/ml
ADVERSE EFFECTS
Related to plasma concentration
Plasma level symptoms
20-30 mcg/L Nystagmus
30-40mcg/L Ataxia
>40mcg/L Mental changes
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10. LONG TERM EFFECTS:
• Gingival hyperplasia
• acne
• Hirsutism
• Cognitive impairement
• Folate and vit D defficiency
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11. SAMPLING TIME
•The timing of the plasma sampling for phenytoin is not
critical,because the fluctuation in its plasma
concentration is relatively small,even when the dosage
is once daily.
•Thats why individual sample is usually drawn at steady
state and the end of the dosage interval.
•one or two weeks may required for steady state to be
Achieved.
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12. FACTORS AFFECTING PHENYTOIN PLASMA
CONC:
• Liver disease(acute hepatitis).
• Hypoalbuminaemia(chronic liver
disease,nephrotic syndrom,Pregnancy which results
hypoalbuminaemia which increase the Free phenytoin
fraction and results in an increased rate of its
metabolism.)
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13. CARBAMAZEPINE
•Carbamazepine is an iminostilbene derivative related to the
tricyclic antidepressants.
•It used in the treatment of tonic-clonic (grand mal), partial or
secondarily generalized seizures
•Carbamazepine is also a useful agent to treat trigeminal
neuralgia and bipolar affective disorders.
• The drug is used primarily as a prophylactic agent in the
chronic therapy of epilepsy
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14. Need of TDM
The accepted therapeutic range for carbamazepine
is 4–12 μg/mL when the drug is used for the
treatment of seizures.
1) Carbamazepine plasma protein binding is quite
variable among individuals because it is bound to
both albumin and α1-acid glycoprotein (AGP).
In patients with normal concentrations of
these proteins, plasma protein binding is 75–80%
resulting in a free fraction of drug of 20–25%. AGP
secreted in large amount in diseases like trauma,
heart failure, myocardial infarction.
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15. 2) Carbamazepine induces its own hepatic
metabolism, ie. Carbamazepine-10, 11-epoxide.
Epoxide concentrations tend to be higher in
patients taking enzyme inducers and lower in patients
taking enzyme inhibitors.The ADR (nausea, vomiting,
lethargy, dizziness, drowsiness, headache, blurred
vision, diplopia, unsteadiness, ataxia, incoordination.)
can also be seen early during dosage titration periods
soon after dosage increases are made.
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16. CLINICAL MONITORING PARAMETERS
1) Carbamazepine has antidiuretic effects associated
with reduced levels of antidiuretic hormone, some
patients may develop hyponatremia during chronic
therapy.
2) Hematologic adverse effects: Thrombocytopenia,
leukopenia (trend downward in white blood cell count
with <2500 cells/mm2 or absolute neutrophil count
<1000 cells/mm2), or anemia are common while
patient is on Carbamazepine treatment. 16

17. 3) Drug induced hepatitis due to carbamazepine
therapy has also been reported.
The severe hematologic and hepatic adverse
effects tend to occur early in treatment because of this,
many clinicians measure a complete blood cell count
and liver function tests monthly for the first 3–6 months
after a patient first begins carbamazepine treatment,
and repeat these tests every 3–6 months
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18. CLINICAL PHARMACOKINETICS
• Absorption of carbamazepine from regular tablets is
generally slow and irregular.
•Time to peak concentration vary from 4-8 hours or
longer because of very low water solubility of this drug
.
•It is dissolution rate limited absorption.
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19. •Carbamazepine has relatively large volume of
distribution.
•It is found in cerebro spinal fluid, aminiotic fluid and
breast milk.
• Salivary concentration reflect unbound plasma
concentration and measurement of Carbamazepine
in saliva can become a useful tool in therapeutic
monitoring.
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20. •The distribution characteristics of the 10,11–epoxide
metabolite of Carbamazepine is important because of its
anticonvulsant properties (therapeutic and toxic) .
•The epoxide metabolite is less bound than Carbamazepine ,
and its free fraction in plasma is twice that of parent drug.
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21. •Carbamazepine is primarily eliminated by hepatic
metabolism (>99%) mainly via the CYP3A4 enzyme
system.
•The epoxide metabolite is active and probably
contributes to both the therapeutic and toxic side
effects observed during therapy.
• Carbamazepine is a potent inducer of hepatic drug
metabolizing enzymes, and induces its own
metabolism, a process known as autoinduction .
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22. •As a result, patients cannot initially be placed on the
dose of carbamazepine that will ultimately result in a
safe and effective outcome.
• The gradual exposure of carbamazepine allows liver
enzyme induction and carbamazepine clearance increases to
occur over a 6- to 12-week time period.
•Therapeutic effect and steady-state carbamazepine serum
concentrations can be assessed 2–3 weeks after the final
dosage increase.
•Auto - induction continues to occur in patients who are
stabilized on a carbamazepine dose but require a dosage
increase.
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23. SAMPLE TIMING.
•A total of 6-8 weeks may be required to reach the steady
state conc.
•If carbamazepine administered at every 6-8 hrs serum levels
during dosing interval fairly flat at and all levels will be
representative of trough conc.
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24. DRUG SUBSTRATE INTERACTION
Phenytoin
Phenobarbital
Carbamazepine Increased clearance
Decreased serum
concentration
Cimitidine
Macrolide antibiotic
Azol antifungal
Diltiazam
Verapamil
Fluvoxamide
Carbamazepine Decreased clearance
Increased serum
concentration
Grape fruit juice Carbamazepine Increased clearance
DRUG INTERACTION
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25. •Valproic acid is an agent that is chemically related to free
fatty acids and is used in the treatment of generalized, partial,
and absence (petit mal) seizure.
•Its antiepileptic effect is thought to result from its ability to
increase concentrations of the neuroinhibitor γ-aminobutyric
acid (GABA), to potentiate the postsynaptic response to
GABA or to exert a direct effect on cellular membranes
VALPROIC ACID
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26. Therapeutic Range: 50-100 μg/mL
Possible toxic levels: >100 μg/mL
Generalized seizure: 30 – 60 μg/mL
Partial seizure: 55-100 μg/mL
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27. •Absorption and Bioavailability
Rapidly and completely absorbed (f = 1)
Oral (fasting)  Peak: 1-3 hours
Meal (food)  peak late 6-8 hours
Enteric coated  absorbed delayed 3-5 hrs (lag time 2-4
hrs)
Distribution and Protein binding
Vd = 0.15 L/Kg (0.1 – 0.5 L/Kg)
Protein (Albumin) binding get saturated at a
concentration >50 μg/mL
Pharmacokinetic Parameters
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28. >95% hepatic metabolism
1-3% renal excretion
Oral clearance (Cl/F) is 7–12 mL/h/kg for adults.
In children 6–12 years old, oral clearance10–20 mL/h/kg
Half-life is 12–18 hours in adults.
Half-life for children 6-12year old is 6–8 hours.
•Metabolism and elimination
•Half-Life (t1/2)
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29. ADVERSE EFFECT
Related to plasma drug conc
Plasma level symptoms
>75mcg/L Ataxia,sedation,lethargy.
>100mcg/L tremor
>175 mcg/L coma,stuper
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30. SAMPLING TIME
•3-5 days may be required to reach the steady state
concentration.
•Trough samples are taken,but sometimes both
trough and peak samples are withdrawn
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31. •The goal of therapy with anticonvulsants is to reduce seizure
frequency and maximize quality of life with a minimum of
adverse drug effects.
•Patients should be monitored for concentration-related side
effects (ataxia, sedation, lethargy, tiredness, tremor, stupor,
coma, and thrombocytopenia) as well as gastrointestinal upset
associated with local irritation of gastric mucosa (nausea,
vomiting, and anorexia).
CLINICAL MONITORING PARAMETERS
31

32. •Elevated liver function tests, increased serum ammonia,
alopecia, and weight gain have been reported during chronic
Valproic acid treatment.
•Serious, but rare, idiosyncratic side effects include
hepatotoxicity, pancreatitis, pitting edema, systemic lupus-
like reactions, and leucopenia with bone marrow changes.
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33. •Phenytoin, lamotrigine, rifampin, and carbamazepine can
increase valproic acid clearance and decrease valproic acid
steady-state serum concentrations.
•Cimetidine, chlorpromazine, and felbamate are examples
of drugs that decrease valproic acid clearance and increase
valproic acid steady-state concentrations.
Drug interactions:
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34. 34
REFERENCE
• Anti epilepic drug –best practice giudelines of
therapeutic drug monitoring by patsalas etal.
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