Kelompok : 12

Anggota :
1. Oktrian Rizky Rosa (1311012015)
2. Cosmas Bafareso Zebua (1311012019)
3. Hani Hazarani (1311012022)
4. Novi Bakri (1311012025)
5. Tri Ayuningtias (1311012029)
 PHENYTOIN
 Phenytoin is a hydantoin compound related to the barbiturates that
are used for the treatment of seizures.
 It is effective anticonvulsant for the chronic treatment of tonic-
clonic (grand mal) or partial seizures and the acute treatment of
generalized status epilepticus.
 Phenytoin is a type 1B antiarrhythmic and is also used in the
treatment of trigeminal neuralgia.
 The usual therapeutic range for total (unbound + bound) phenytoin serum
concentrations when the drug is used in the treatment of seizures is 10–20
μg/mL.
 Phenytoin is highly bound (~90%) to albumin.
 The suggested therapeutic range for unbound phenytoin concentrations is
based on the usual unbound fraction (10%) of phenytoin in individuals with
normal plasma protein binding.
 The generally accepted therapeutic range for unbound phenytoin
concentrations is 1–2 μg/mL,
 the therapeutic range (>15 μg/mL) some patients will experience
minor central nervous system depression side effects (drowsiness
or fatigue)
 Total phenytoin concentrations above 20 μg/mL lateral gaze
 total concentrations exceed 30 μg/mL →ataxia, slurred speech,
and/or incoordination.
 total phenytoin concentrations are above 40 μg/mL →mental
status changes, including decreased mentation, severe confusion or
lethargy, and coma are possible.
 The goal of therapy with anticonvulsants is to reduce seizure frequency and
maximizequality of life with a minimum of adverse drug effects.
 Patients should be monitored for concentration-related side effects
 Phenytoin serum concentrations should be measured in most patients.
Phenytoin serum concentrations are also valuable tools to avoid adverse drug
effects.
 Because phenytoin follows nonlinear or saturable pharmacokinetics, it is fairly
easy to attain toxic concentrations with modest changes in drug dose.
 Phenytoin is primarily eliminated by hepatic metabolism (>95%).
 Hepatic metabolism is mainly via the CYP2C9 enzyme system with a smaller amount metabolized by
CYP2C19.
 Phenytoin follows Michaelis-Menten or saturable pharmacokinetics.
rate of metabolism = (Vmax ⋅ C) / (Km + C)
• Vmax : maximum rate of metabolism (mg/d)

• C : phenytoin concentration (mg/L)

• Km : substrate concentration (mg/L)

• rate of metabolism = Vmax /2.

 Michaelis-Menten clearance of phenytoin is not a constant as it is
with linear pharmacokinetics, but is concentration- or dose-
dependent.
 Dose or concentration of phenytoin increases, the clearance rate
(Cl) decreases as the enzyme approaches saturable conditions
Cl = Vmax / (Km + C)
 This is the reason concentrations increase disproportionately after
a phenytoin dosage increase.
 Phenytoin volume of distribution (V = 0.7 L/kg) is unaffected by saturable
metabolism
V = VB+ (fB/fT)VT
• physiological volume of blood (VB), tissues (VT), the unbound concentration

of drug in the blood (fB) and tissues (fT)

t1/2 = (0.693 ⋅ V)/Cl
 The time to steady-state serum concentrations is approximately 5 days at a
dosage rate of 300 mg/d and 15 days at a dosage rate of 400 mg/d
 Michaelis-Menten equation, to compute the maintenance dose (MD in
mg/d) required to achieve a target steady-state phenytoin serum
concentration Css (μg/mL or mg/L)

 When Km>>Css, phenytoin follows linear pharmacokinetics.

 Liver Dysfunction

 Patients with liver cirrhosis or acute hepatitis have reduced phenytoin clearance
because of destruction of liver parenchyma.
 This loss of functional hepatic cells reduces the amount of CYP2C9 and CYP2C19
available to metabolize the drug and decreases Vmax. The volume of distribution is
larger because of reduced plasma protein binding.
 Protein binding is reduced and unbound fraction is increased due to
hypoalbuminemia and/or hyperbilirubinemia (especially albumin ≤3 g/dL and/or
total bilirubin ≥2 mg/dL)
 However, the effects that liver disease has on phenytoin pharmacokinetics are
highly variable and difficult to accurately predict.
 Trauma/Burns

 Trauma and burn patients have an increased ability to metabolize phenytoin

beginning 3–7 days after their initial injury.
 At this time, these patients become hypermetabolic in order to repair damaged
tissue, and the Vmax for phenytoin increases due to this general increase in
metabolic rate. If caloric needs are not met during this phase of recovery for
trauma patients, many become hypoalbuminemic, and phenytoin plasma protein
binding decreases resulting in an increased unbound fraction.
 Phenytoin dosage requirements are increased while trauma patients are in their
hypermetabolic phase, and unbound concentration monitoring is indicated when
patients have low albumin concentrations (especially for albumin levels ≤3 g/dL).
 Pregnancy
 Pregnant women taking phenytoin have increased dosage
requirements, particularly during the third trimester (>26 weeks)
 several reasons for this change including
• malabsorption of drug resulting in decreased bioavailability

• increased metabolism of phenytoin

• decreased protein binding due to low albumin concentrations

 An additional concern when administering phenytoin to pregnant

patients is the development of fetal hydantoin syndrome by the baby
 Elderly
 Elderly individuals over the age of 65 years have a decreased capacity to
metabolize phenytoin because :
• Decreased amounts of CYP2C9 and CYP2C19
• Hypoalbuminemia
 clinicians tend to prescribe lower initial phenytoin doses for older
patients (~200 mg/d).
Renal Dysfunction
• End-stage renal disease patients with creatinine clearances <10–15 mL/min, these
patients tend to have hypoalbuminemia.
• Unbound phenytoin serum concentration monitoring is very helpful in determining
dosage requirements for renal failure patients
Hypoalbuminemia
Other patients are also prone to hypoalbuminemia, including patients
with the nephrotic syndrome, cystic fibrosis patients, and
malnourished individuals.

Dialysis
Hemodialysis does not remove enough phenytoin that supplemental postdialysis doses
are necessary. The typical sieving coefficient during hemoperfusion for phenytoin is
0.45 so in some cases supplemental phenytoin doses could be needed.
Because of pharmacokinetic variability, check phenytoin concentrations in patients
receiving hemoperfusion.
Hyperalbuminemia

 High bilirubin concentrations can also be found in patients with

biliary tract obstruction or hemolysis. Unbound phenytoin
concentration monitoring should be considered in these patients
especially when albumin concentrations are ≤3 g/dL or total
bilirubin concentrations are ≥2 mg/dL
 Pharmacokinetic Dosing Method
• Phenytoin serum concentration monitoring, including unbound concentration
measurement if altered plasma protein binding is suspected, is an important
component of therapy for this drug.
• Use Child-Pugh parameter.

• MICHAELIS-MENTEN PARAMETER ESTIMATES

• VOLUME OF DISTRIBUTION ESTIMATE

 patients with normal phenytoin plasma protein binding 0.7 L/kg for adults.
Obese individuals 30% or more above their ideal body weight
V = 0.7 L/kg [IBW + 1.33(TBW − IBW)]
• IBW : ideal body weight (kg)

 IBWfemales (kg) = 45 + 2.3(Ht − 60)

 IBWmales (in kg) = 50 + 2.3(Ht − 60)
• Ht : height (inches)

• TBW : total body weight (kg)

LD = Css ⋅ V (loading dose)
• Css : desired total phenytoin concentration (mg/L) mg/L = μg/mL

• V : volume of distribution (L)

 SELECTION OF APPROPRIATE PHARMACOKINETIC MODEL AND EQUATIONS
• Michaelis-Menten pharmacokinetic equation that computes the average
phenytoin steady-state serum concentration (Css in μg/mL = mg/L) is widely
used and allows maintenance dosage calculation :

 S : fraction of the phenytoin salt form that is active phenytoin (0.92 for
phenytoin sodium injection and capsules, 0.92 for fosphenytoin)
 Vmax : maximum rate of metabolism (mg/d)
 MD : maintenance dose of the phenytoin salt (mg/d)
  Css : phenytoin concentration (mg/L = μg/mL)
 Km : substrate concentration (mg/L = μg/mL)
• rate of metabolism = Vmax/2
• LD = (Css ⋅ V)/S
 STEADY-STATE CONCENTRATION SELECTION
• The generally accepted therapeutic ranges for total and unbound phenytoin
concentrations 10–20 μg/mL and 1–2 μg/mL.
fB = Cf/C
 unbound fraction (fB)
 C : total phenytoin concentration (μg/mL)
 Cf : unbound, or “free,” phenytoin concentration (μg/mL)
 CARBAMAZEPINE

 Carbamazepine is an iminostilbene derivative related to the

tricyclic antidepressants, 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 accepted therapeutic range for carbamazepine : 4–12 μg/mL
(for the treatment of seizures)
 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 proteins, plasma protein
binding is 75–80% resulting in a free fraction of drug of 20–25%.
 AGP is classified as an acute phase reactant protein that is present in lower
amounts in all individuals, but is secreted in large amounts in response to
certain stresses and disease states (trauma, heart failure, and myocardial
infarction)
 In patients with these disease states, carbamazepine binding to AGP can be even
larger resulting in an unbound fraction as low as 10–15%.
 Carbamazepine-10, 11-epoxide is an active metabolite of carbamazepine that
contributes to both the therapeutic and toxic effects of the drug, and can be
measured in serum samples at a limited number of epilepsy centers.
 Epoxide concentrations tend to be higher in patients taking enzyme inducers and
lower in patients taking enzyme inhibitors.
 The therapeutic range of carbamazepine-10, 11-epoxide is not known
although a suggested range of 0.4–4 μg/mL is used by several
research centers.
 In the upper end of the therapeutic range (>8 μg/mL) some patients
will begin to experience the concentration-related adverse effects of
carbamazepine treatment.
 Because carbamazepine induces its own hepatic metabolism, these
adverse effects can also be seen early during dosage titration
periods soon after dosage increases are made.
 The goal of therapy is reduce seizure frequency and maximize quality

of life with a minimum of adverse drug effects.

 Patients should be monitored for concentration-related side effects.
 Because carbamazepine has antidiuretic effects associated with
reduced levels of antidiuretic hormone, some patients may develop
hyponatremia during chronic therapy with carbamazepine, and
serum sodium concentrations can be periodically measured.
 Hematologic adverse effects can be divided into two types.
• Leukopenia

• Thrombocytopenia, leukopenia (trend downward in white blood cell

count with <2500 cells/mm2 or absolute neutrophil count <1000

cells/mm2), or anemia are in this category
 Other idiosyncratic side effects include skin rash, Stevens-Johnson
syndrome, and systemic lupus-like reactions.
 Carbamazepine serum concentrations are also valuable tools to
avoid adverse drug effects.
 Carbamazepine is primarily eliminated by hepatic metabolism (>99%)
mainly via the CYP3A4 enzyme system.
 Carbamazepine is a potent inducer of hepatic drug metabolizing enzymes,
and induces its own metabolism, a process known as autoinduction.
 At first, patients are started on 1/4–1/3 of the desired maintenance dose
(This exposes hepatic drug metabolizing enzymes to carbamazepine and
begins the induction process.)
 The dose is increased by a similar amount every 2–3 weeks until the total
desired daily dose is ultimately given.
 Therapeutic effect and steady-state carbamazepine serum
concentrations can be assessed 2–3 weeks after the final dosage
increase.
 An injectable form of carbamazepine is not available.
 For oral use, the drug is available as :
• immediate-release tablets (chewable: 100 mg, regular: 100 mg, 200 mg, 300
mg)
• sustained-release tablets (100 mg, 200 mg, 400 mg)

• sustained-release capsules (100, 200,300 mg)

• suspension (100 mg/5 mL).

 Based on the best estimates available, carbamazepine bioavailability is good and
averages about 85–90%.
 The relative bioavailability of other dosage forms (chewable tablet, suspension,
sustained-release tablets and sustainedrelease capsules) compared to the
immediate-release tablet approaches 100%.
 Usual initial maintenance doses :
• 10–20 mg/kg/d (children under 6 years)
• 200 mg/d (children 6–12 years old)
• 400 mg/d for adults
 single loading doses of 8 mg/kg have been given to adults as suspension or
immediate-release tablets to achieve therapeutic concentrations within 2–4
hours after administration.
 After single doses of carbamazepine (adults)
• the oral clearance (Cl/F) : 11–26 mL/h/kg

• halflife : 35 hours

 During multiple dosing after maximal autoinduction has taken place

• oral clearance : 50–100 mg/h/kg

• half-life equals 5–27 hours

 Children 6–12 years old (during chronic dosing)

• oral clearance : 50–200 mL/h/kg

• half-life : 3–15 hours

 Clearance rates can be higher and half-lives shorter in patients
receiving other hepatic drug metabolizing enzyme inducers
(phenytoin, phenobarbital, rifampin)
 Carbamazepine volume of distribution using immediaterelease
tablets (V/F) is 1–2 L/kg.
Liver Dysfunction

 Patients with liver cirrhosis/acute hepatitis →reduced carbamazepine clearance

because of destruction of liver parenchyma.
 This loss of functional hepatic cells reduces the amount of CYP3A4 available to
metabolize the drug and decreases clearance.
 volume of distribution may be larger because of reduced plasma protein binding.
 Protein binding may be reduced and unbound fraction maybe increased due to
hypoalbuminemia or hyperbilirubinemia (especially albumin ≤3 g/dL and/or total
bilirubin ≥2 mg/dL)
 An index of liver dysfunction can be gained by applying the Child-Pugh clinical
classification system.
Other Disease and Conditions

 Elderly patients have lower carbamazepine oral clearance rates than

younger adults so lower initial doses (100 mg/d) may be used in older
individuals.
 During the third trimester of pregnancy, oral clearance of carbamazepine
may decrease and require dosage adjustment.
 Doses of carbamazepine do not require adjustment for patients with renal
failure, and the drug is not removed by dialysis.
 Breast milk concentrations of carbamazepine are about 60% of
concurrent serum concentrations.
 Carbamazepine is a potent inducer of hepatic drug metabolizing enzyme systems and P-
glycoprotein.
 The CYP1A2, CYP2C9, and CYP3A4 enzyme systems are all induced by carbamazepine, and
drug substrates for other enzyme systems also have known drug interactions with
carbamazepine
 Other antiepileptic drugs that have their clearance rates increased and steady-state
concentrations decreased by carbamazepine-related enzyme induction include felbamate,
lamotrigine, phenytoin, primidone, tiagabine, topiramate, and valproic acid.
 Carbamazepine is a substrate for CYP3A4, and other drugs can affect carbamazepine
clearance and steady-state serum concentrations.
 Phenytoin, phenobarbital → carbamazepine clr ↑ and Css ↓
 Cimetidine, macrolide antibiotics, azole antifungals, fluoxetine,
fluvoxamine, nefazodone, cyclosporine, diltiazem, verapamil,
indinavir, ritonavir → carbamazepine clr ↓and Css ↑
 The original computation of these doses were based on the pharmacokinetic dosing methods,
and modified based on clinical experience
 In general, the expected carbamazepine Css used to compute these doses was 6–8 μg/mL.
 Twice daily dosing is initially used until autoinduction takes place.
 Dosage increases to allow for autoinduction are made every 2–3 weeks depending on response
and adverse effects
• 800–1200 mg/d (adults)

• 400–800 mg/d (children)

 patient has significant hepatic dysfunction (Child-Pugh score ≥8), maintenance doses prescribed
using this method should be decreased by 25–50% depending on how aggressive therapy is
required to be for the individual.
 Valproic Acid
 Valproic Acid is agent that is chemically related to free fatty acids and is used in the treatment of
generalized, partial, and absence (petit mal) seizures.
 It has thewidest spectrum of activity compared to the other currently available antiepileptic
drugs.
 Now available in intravenous, as well as oral, form, valproic acid can be used for the acute
treatment and chronic prophylaxis of seizures.
 Also a useful agent for the treatment of bipolar affective disorders and the prevention of migraine
headaches.
 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,

• to exert a direct effect on cellular membranes.

 The generally accepted therapeutic range for total valproic acid Css : 50–100
μg/mL.
 some clinicians suggest drug concentrations as high as 175 μg/mL with
appropriate monitoring of serum concentrations and possible adverse
effects.
 highly protein bound to albumin with typical values of 90–95%.
 Plasma protein binding of valproic acid is saturable within the therapeutic
range, which results in less protein binding and higher unbound fraction of
drug at higher concentrations.
 The concentration-dependent protein binding of valproic acid causes
the drug to follow nonlinear pharmacokinetics (fundamentally
different from phenytoin)
 In the case of valproic acid, when the dose ↑total drug steady-state
concentration ↑ less than expected, but unbound steady-state drug
concentration ↑ in a proportional fashion.
 unbound steady-state concentration therapeutic range for valproic acid of 2.5–
10.
 As is the case with phenytoin, measurement of unbound valproic acid serum
concentrations should be considered in patients with factors known to alter
valproic acid plasma protein binding.
 These factors fall into three broad categories :
• lack of binding protein where there are insufficient plasma concentrations of
albumin
• displacement of valproic acid from albumin binding sites by endogenous compounds

• displacement of valproic acid from albumin binding sites by exogenous compounds

 The goal of therapy with anticonvulsants → 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 (local
irritation of gastric mucosa)
 Valproic acid serum concentrations should be measured in most patients.
 Valproic acid serum concentrations are also valuable tools to avoid adverse
drug effects. Patients are more likely to accept drug therapy if adverse
reactions are held to the absolute minimum.
 Valproic acid is primarily eliminated by hepatic metabolism (>95%).
 Hepatic metabolism is via glucuronidation, β-oxidation, and α-hydroxylation.
 Over 10 metabolites have been identified for valproic acid, and the 4-en-
valproic acid metabolite may be associated with the drug’s propensity to
cause hepatotoxicity.
 About 1–5% of a valproic acid dose is recovered in the urine as unchanged
drug.
 Valproic acid is eliminated almost completely by hepatic metabolism, and it is
a low hepatic extraction ratio drug.
 This is the reason total steady-state concentrations increase
disproportionately after a valproic acid dosage increase.

• F : valproic acid bioavailability

• D : valproic acid dose

• τ : the dosage interval

• ClH : hepatic clearance

 However, since unbound steady-state concentrations are only
influenced by intrinsic clearance, unbound concentrations increase
in a proportional amount to dose
 Valproic acid volume of distribution (V = 0.15 − 0.2 L/kg) is also
affected by
• concentration-dependent plasma protein binding and is determined by

the physiologic volume of blood (VB) and tissues (VT)

• the unbound fraction of drug in the blood (fB) and tissues (fT)

 As valproic acid concentrations↑, unbound fraction of drug in the

blood↑which causes an ↑in the volume of distribution for the drug
 t1/2 is related to clearance and volume of distribution using the same equation as for linear
pharmacokinetics

 On average, valproic acid half-life is 12–18 hours in adult patients with total concentrations
within the therapeutic range.
 Valproic acid is available as three different entities (all of them are prescribed as valproic acid
equivalents)
• valproic acid

• sodium valproate (the sodium salt of valproic acid)

• divalproex sodium (a stable coordination compound consisting of a 1:1 ratio of valproic acid

and sodium valproate)

 For valproic acid, oral clearance :
• (Cl/F) is 7–12 mL/h/kg and half-life is 12–18 hours for adults

• In children 6–12 years old, oral clearance and half-life equal 10–20 mL/h/kg and 6–8 hours

 Clearance rates can be higher and half-lives shorter in patients receiving other hepatic drug–
metabolizing enzyme inducers
 For adults receiving other antiepileptic drugs that are enzyme inducers, valproic acid clearance
• adults is 15–18 mL/h/kg and half-lives range from 4 to 12 hours

• Children is 20–30 mL/h/kg and half-life is 4–6 h

 Valproic acid volume of distribution (V/F) is 0.15–0.2 L/kg

 Valproic acid is a potent inhibitor of hepatic drug metabolizing enzyme systems and
glucuronidation
 antiepileptic drugs that have their clearance rates ↓ and Css ↑by valproic acid-related enzyme
inhibition (clonazepam, carbamazepine, phenytoin, primidone, lamotrigine, and ethosuximide)
 Valproic acid therapy also ↓ the clearance and ↑ Css of other drugs (zidovudine, amitriptyline,
and nortriptyline)
 Phenytoin, lamotrigine, rifampin, and carbamazepine can ↑ valproic acid clr and ↓valproic acid
steady-state serum concentrations
 Cimetidine, chlorpromazine, and felbamate are examples of drugs that ↓valproic acid clearance
and ↑valproic acid steady-state concentrations.
 Aspirin, warfarin, and phenytoin all have plasma protein binding drug
interactions with valproic acid, and these drugs have higher unbound
fractions when given concurrently with valproic acid.
 The drug interaction between valproic acid and phenytoin deserves
special examination because of its complexity and because these two
agents are regularly used together for the treatment of seizures
 Pharmacokinetic dosing method
• CLEARANCE ESTIMATE
• VOLUME OF DISTRIBUTION ESTIMATE
• HALF-LIFE AND ELIMINATION RATE CONSTANT ESTIMATE
• SELECTION OF APPROPRIATE PHARMACOKINETIC MODEL AND EQUATIONS
 Literature-Based Recommended Dosing
 USE OF VALPROIC ACID SERUM CONCENTRATIONS TO ALTER DOSES
• Pseudolinear Pharmacokinetics Method
• Pharmacokinetic Parameter Method
 BAYESIAN PHARMACOKINETIC COMPUTER PROGRAMS
 Phenytoin, Carbamazepine, Valproic Acid have narrow therapeutic
window so the range between MIC and MTC is very little so the dose
must be given correctly
 For the patients with renal failure and liver disease the elimination
and metabolism of drug is abnormal so we mush calculate the
appropriate dose.
Bauer, Larry A.2008. Applied Clinical Pharmacokinetics Second Edition. Washington
: MacGrawHill Medical

Bauer, Larry A. 2006. Clinical Pharmacokinetics Handbook. Washington :

MacGrawHill Medical