ANTICONVULSANT

Class A
Group 6
A. Phenytoin
• What is Phenytoin ?
Phenytoin is hydantoin compound related to the
barbiturates that are used as antiseizures. Its activity
related to inhibit the repetitive firing of action
potentials in neurons .
At the cellular level, the mechanism of action for
phenytoin appears related to its ability to prolong the
inactivation of voltage-activated sodium ion channels
and reduction of the ability of neurons to fire at high
frequencies.

(Bauer,2008:485)
• Therapeutic and Toxic Concentration
The therapeutic range for phenytoin is 10-20 µ/ml. Since
phenytoin is highly bound (~90%) to albumin, it is prone to
plasma protein binding displacement due to a large variety
of factors
• Suggested therapeutic range for unbound phenytoin (10%)
concentrations is 1–2 μg/mL, which is simply 10% of the
lower and upper bounds for the total concentration range,
respectively.
• In therapeutic range (>15 μg/mL) : minor central nervous
system depression side effects such as drowsiness or fatigue
• > 20 μg/mL : nystagmus
• > 30 μg/mL : ataxia, slurred speech
• > 40 μg/mL : decreased mentation, lethargy
• > 50-60 μg/mL : Drug-induced seizure activity
• Phenytoin _ nonlinear/saturable metabolism -> attain
excessive drug conc
(Bauer,2008:485)
• Clinical Usefulness Of Unbound Phenytoin
Concentrations
Unbound phenytoin serum concentrations should be
measured in patients with factors known to alter
phenytoin plasma protein binding, These factors fall
into three broad categories :
- lack of binding protein where there are insufficient
plasma concentrations of albumin
- displacement of phenytoin from albumin binding sites
by endogenous compounds
- displacement of phenytoin from albumin binding sites
by exogenous compounds

(Bauer,2008:487)
• Basic Clinical Pharmacokinetic Parameters
Phenytoin is primarily eliminated by hepatic metabolism (>95%).
About 5% of a phenytoin dose is recovered in the urine as
unchanged drug.
Phenytoin follows Michaelis-Menten or saturable
pharmacokinetics. This is the type of nonlinear pharmacokinetics
that occurs when the number of drug molecules overwhelms or
saturates the enzyme’s ability to metabolize the drug. When this
occurs, steady-state drug serum concentrations increase in a
disproportionate manner after a dosage increase

(Bauer,2008:491)
1. Michaelis-Menten
The clinical implication of Michaelis-Menten pharmacokinetics
is that the clearance of phenytoin is not a constant as it is with
linear pharmacokinetics, but is concentration- or dose-
dependent. As the dose or concentration of phenytoin
increases, the clearance rate (Cl) decreases as the enzyme
approaches saturable conditions :
Cl= Vmax /(Km + C)
2. Dosage Regimen
Under steady-state conditions the rate of drug administration
equals the rate of drug removal. So, the Michaelis-Menten
equation can be used to compute the maintenance dose (MD in
mg/d) required to achieve a target steady-state phenytoin
serum concentration (Css in μg/mL or mg/L):

MD= Vmax . Css / Km + Css)

(Bauer,2008:491)
When phenytoin steady-state concentrations are far below the
Km value for a patient, this equation simplifies to:
MD = (Vmax/Km)Css
or, since Vmax/Km is a constant, MD = Cl ⋅ Css.
Therefore, when Km>>Css, phenytoin follows linear
pharmacokinetics. When phenytoin steady-state concentrations
are far above the Km value for a patient, the rate of metabolism
becomes a constant equal to Vmax. Under these conditions only a
fixed amount of phenytoin is metabolized per day because the
enzyme system is completely saturated and cannot increase its
metabolic capacity. This situation is also known as zero-order
pharmacokinetics. First-order pharmacokinetics is another name
for linear pharmacokinetics.

(Bauer,2008:493)
B. Carbamazepine
• What is Carbamazepine ?
Carbamazepine is iminostilbene derivative related to
the tricyclic antidepressants that is used in the
treatment of tonic-clonic (grand mal), partial or
secondarily generalized seizures. Its ability to decrease
transmission in the nucleus ventralis anterior section of
the thalamus. It may prevent increases in cyclic
adenosine monophosphate (cAMP).

(Bauer,2008:548)
• Therapeutic and Toxic Concentration
Therapeutic range for carbamazepine is 4-12 µ/ml. The 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%
In patients with these disease states, carbamazepine binding to AGP
can be even larger resulting in an unbound fraction as low as 10–15%.

(Bauer,2008:548)
• Clinical Monitoring Parameters
The goal of therapy with anticonvulsants is to reduce seizure
frequency and maximize quality of life with a minimum of adverse
drug effects
• Basic Clinical Pharmakokinetic Parameters
Carbamazepine is primarily eliminated by hepatic metabolism
(>99%) mainly via the CYP3A4 enzyme system.

(Bauer,2008:550)
• Drug Interactions
Carbamazepine is a potent inducer of hepatic drug metabolizing
enzyme systems and P-glycoprotein. Carbamazepine can increase
the Cl rates and decrease the Css of several drug such as
felbamate, lamotrigine, phenytoin, primidone, tiagabine,
topiramate, and valproic acid.
It also happen with many other drugs including oral
contraceptives, calcium channel blockers, tricyclic antidepressants,
cyclosporin, tacrolimus, theophylline, and warfarin

(Bauer,2008:554)
• Initial Dosage Determination Methods
The original computation of these doses were based on the
pharmacokinetic dosing methods, and subsequently modified
based on clinical experience.
In general, the expected carbamazepine steady-state serum
concentrations used to compute these doses was 6–8 μg/mL.

(Bauer,2008:554)
If the 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.

(Bauer,2008:555)
Estimate carbamazepine dose according to disease
states and conditions present in the patient
Usual initial maintenance doses are 10–20 mg/kg/d for
children under 6 years of age, 200 mg/d for children 6–
12 years old and 400 mg/d for adults. 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.
Most adults will require 800–1200 mg/d of
carbamazepine while older children will require 400–
800 mg/d.
A steady-state trough total carbamazepine serum
concentration should be measured after steady state is
achieved in 2–3 weeks at the highest dosage rate attained

(Bauer,2008:555)
• Pseudolinear Pharmacokinetics Method
A simple, easy way to approximate new total serum
concentrations after a dosage adjustment with
carbamazepine is to temporarily assume linear
pharmacokinetics, then subtract 10–20% for a dosage
increase or add 10–20% for a dosage decrease to
account for autoinduction pharmacokinetics:
Cssnew= Dss,new/Dss,old) Cssold

(Bauer,2008:556)
This method is only intended to provide a rough
approximation of the resulting carbamazepine steady-state
concentration after an appropriate dosage adjustment, such
as 100–200 mg/d, has been made
 C. VALPROIC ACID
• isan agent that is chemically related to free
fatty acids and is used in the treatment of
generalized, partial, and absence (petit mal)
seizures.
• widest spectrum, antiepileptic drugs
• Drug form intravenous
• Can be used for the acute treatment and
chronic prophylaxis of seizures.
• Also auseful agent for the treatment of bipolar
affective disorders and the prevention of
migraine headaches.

Bauer, 2008 : 563

THERAPEUTIC AND TOXIC CONCENTRATIONS
• Css valproic acid is 50–100 μg/mL,
• Although some clinicians suggest drug
concentrations as high as 175 μg/mL with
appropriate monitoring of serum concentrations
and possible adverse effects.
• Valproic acid is highly protein bound to albumin
with typical values of 90–95%.7,8

Bauer, 2008 : 563

BASIC CLINICAL PHARMACOKINETIC
PARAMETERS
• Valproic
acid is primarily eliminated by
hepatic metabolism (>95%)
• Theoral bioavailability of valproic acid is
very good for all dosage forms and ranges
from 90% for the sustained-release tablets
to 100% for the other oral dosage forms.
• maintenance dose for valproic acid is 15
mg/kg/d resulting in 1000 mg or 500 mg
twice daily for most adult patients.

Bauer, 2008 : 567

EFFECTS OF DISEASE STATES AND
CONDITIONS ON PHARMACOKINETICS
AND DOSING
• Valproic
acid, oral clearance (Cl/F) is 7–12
mL/h/kg and half-life is 12–18 h for adults
• Inchildren 6–12 years old, oral clearance
and half-life equal 10–20 mL/h/kg and 6–8
h,
• Valproicacid clearance in patients with liver
disease is 3–4 mL/h/kg.
• Average half-life for valproic acid in patients
with liver disease is 25 hours.
Bauer, 2008 : 569
Bauer, 2008 : 569
DRUG INTERACTIONS
• Decreases the clearance of VA and increases
Css with drugs zidovudine, amitriptyline,
and nortriptyline.

INITIAL DOSAGE DETERMINATION

METHODS
A. Pharmacokinetic Dosing Method
1. Clearance Estimate
2. Volume Of Distribution Estimate
V = 0.15 L/kg. BB (kg)

Bauer, 2008 : 571

3. Half-life And Elimination Rate Constant
Estimate
ke = Cl/V.
t1/2 = 0.693/ke
4. Selection Of Appropriate Pharmacokinetic
Model And Equations
Css = (D/τ) / Cl or D = Css ⋅ Cl ⋅ τ

B. Literature-Based Recommended Dosing

Bauer, 2008 : 573

C. Pseudolinear Pharmacokinetics Method
Dnew = (Cssnew/Cssold) Dold

• Cssnew is the expected steady-state

concentration from the new valproic acid
dose (μg/mL)
• Cssold is the measured steady-state
concentration from the old valproic acid
dose (μg/mL)
• Dnew is the new valproic acid dose to be
prescribed in mg/d
• Dold is the currently prescribed valproic acid
dose in mg/d.
Bauer, 2008 : 578
D. Phenobarbital/Primidone
• Phenobarbital is a barbiturate and primidone is a
deoxybarbiturate that are effective in the treatment of
generalized tonic-clonic and partial seizures
• Phenobarbital is available as a separate agent, but is also an
active metabolite produced via hepatic metabolism during
primidone treatment
• Because of this, and because they share a similar antiseizure
spectrum, these two drugs are considered together in this
chapter
• The probable mechanism of action for phenobarbital is elevation
of seizure threshold by interacting with γ-aminobutyric acidA
(GABAA) postsynaptic receptors which potentiates synaptic
inhibition.3,4 While the exact mechanism of action is not known
for the antiepileptic effect of primidone, a portion of its
antiseizure activity is produced by the active metabolites
phenobarbital and phenylethylmalonamide (PEMA)

Bauer, 2008 : 599

International Classification of
Epileptic Seizures with
Treatment Recommendations

Bauer, 2008 : 6o0

CLINICAL MONITORING
PARAMETERS
• The goal of therapy with anticonvulsants is to reduce
seizure frequency and maximize quality of life with a
minimum of adverse drug effects
• Phenobarbital serum concentrations, or primidone plus
phenobarbital serum concentrations for those patients
receiving primidone therapy, should be measured in
most patients. Because epilepsy is an episodic disease
state, patients do not experience seizures on a
continuous basis

Bauer, 2008 : 601

BASIC CLINICAL
PHARMACOKINETIC
PARAMETER
• Phenobarbital is eliminated primarily by hepatic
metabolism (65–70%) to inactive metabolites.7 About
30–35% of a phenobarbital dose is recovered as
unchanged drug in the urine
• Phenobarbital is about 50% bound to plasma
proteins.The absolute bioavailability of oral
phenobarbital in humans approaches 100%.

Bauer, 2008 : 601

EFFECTS OF DISEASE STATES
AND CONDITIONS ON
PHARMACOKINETICS AND
DOSING
• Phenobarbital clearance rate (Cl) for older children (≥12
years old) and adults is 4 mL/h/kg,and for younger
children is 8 mL/h/kg.6,8,11 Phenobarbital volume of
distribution (V) equals 0.7 L/kg, and its half life averages
120 hours in neonates (0–4 weeks old), 60 hours in
children (≥2 months old) and 100 hours in adults.
Although only limited studies in patients with hepatic
disease are available, a 50% increase in half-life is seen
in adults with liver cirrhosis or acute viral hepatitis

Bauer, 2008 : 603

Continue
• Based on this information, patients with liver cirrhosis or
acute hepatitis may have reduced phenobarbital
clearance because of destruction of liver parenchyma.
This loss of functional hepatic cells reduces the amount
of enzymes available to metabolize the drug and
decreases clearance

Bauer, 2008 : 603

DRUG INTERACTIONS
• Phenobarbital is a potent inducer of hepatic drug
metabolism for the CYP1A2, CYP2C9, and CYP3A4
enzyme systems
• Because phenobarbital is also a metabolite produced
during primidone therapy, primidone has similar drug
interaction potential. Because phenobarbital is such a
broad-based hepatic enzyme inducer, patients should be
monitored closely for drug interactions whenever either
of these agents is added to their therapeutic regimen

Bauer, 2008 : 604

Continue
• Other anticonvulsants that decrease the metabolism and
clearance of phenobarbital are felbamate and valproic
acid. Phenytoin may also exhibit an interaction with
phenobarbital where both agents change the
metabolism and clearance of each other. The net result
of this drug interaction is quite variable and can result in
an increase, decrease, or no change in the steady-state
concentration of both drugs. Primidone metabolism and
clearance are increased by carbamazepine and
phenytoin treatment while valproic acid therapy
decreases primidone metabolism and clearance

Bauer, 2008 : 604

INITIAL DOSAGE
DETERMINATION METHODS
EXAMPLE
• GO is a 50-year-old, 75-kg (5 ft 10 in) male with tonic-
clonic seizures who requires therapy with oral
phenobarbital. He has normal liver and renal function.
Suggest an initial phenobarbital dosage regimen
designed to achieve a steady-state concentration equal
to 20 μg/Ml

Bauer, 2008 : 605

Continue
1. Estimate clearance and volume of distribution according to
disease states and conditions present in the patient.
• The clearance rate for an older patient is 4 mL/h/kg. Using
this value, the estimated clearance would equal 0.3 L/h: Cl =
75 kg ⋅ 4 mL/h/kg = 300 mL/h or 0.3 L/h. The estimated
volume of distribution would be 53 L: 75 kg ⋅ 0.7 L/kg = 53 L.

Bauer, 2008 : 605

Continue
2. Estimate half-life and elimination rate constant.
Once the correct clearance and volume of distribution
estimates are identified for the patient, they can be
converted into the phenobarbital half-life (t1/2) and
elimination rate constant (k) estimates using the following
equations: t1/2 = (0.693 ⋅ V)/Cl = (0.693 ⋅ 53 L)/0.3 L/h =
122 h, k = Cl/V = 0.3 L/h / 53 L= 0.0057 h−

Bauer, 2008 : 606

Continue
• 3. Compute dosage regimen.
Oral phenobarbital tablets will be prescribed to this
patient (F = 1). (Note: μg/mL = mg/L and this
concentration unit was substituted for Css in the
calculations so that unnecessary unit conversion was not
required.) The dosage equation for oral phenobarbital is D
= (Css Cl ⋅ τ) / F = (20 mg/L⋅ 0.3 L/h ⋅ 24 h) / 1 = 144 mg,
rounded to 120 every 24 hours.