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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)
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
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
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)
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
• halflife : 35 hours
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),
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
• divalproex sodium (a stable coordination compound consisting of a 1:1 ratio of valproic acid
• 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