You are on page 1of 64

Pharmacology of Antiepileptic

Drugs
Pharmacology of Headaches
Leslie Goldstein, Pharm.D. 2010
Pharmacology of Antiepileptic Drugs
Drug Targets:
| GABAergic or + glutamateric transmission;
or modification of ion conductances
Glutamateric Synapse
(excitatory)
GABAergic Synapse
(inhibitory)
Basic and Clinical Pharmacology Figure 24-1 and 24-2
PHARMACOKINETICS
(general class properties)
Oral; 80-100% bioavailability
Not highly plasma protein bound (except
phenytoin and valproic acid)
Distributed in total body water
(predominantly)
Distributed to CNS
Hepatic metabolism (some active
metabolites)
Half-lives vary
Many of the older agents are
potent inducers of hepatic
microsomal activity.
GOALS OF ANTIEPILEPTIC
THERAPY
Freedom from seizures (if possible)
Treatment of comorbid depression
Minimize side effects
Nonpharmacological treatments:
surgical resection; vagus nerve
stimulation
Pharmacological treatments:
Seizure control achieved in up to
50% of patients
Improvement in another 25%
Goodman and Gilman 11e p507
Cautions
Toxicity potential: The therapeutic index for
most AEDs is low, and toxicity is not uncommon.
Withdrawal: Gradually taper to minimize the
potential of increased seizure frequency.
Suicidal ideations: A consequence of the drug
therapy? or, of the seizure disorder?
Pregnancy: Increased risk of congenital
malformations
Pediatrics: Larger Vd in neonates, infants,
children; neonate has immature metabolic and
elimination capabilities
Geriatrics: Comorbid conditions; physiologic
changes
Drug interactions: Enzyme inducers/inhibitors;
alcohol

Phenobarbital / Primidone bind to GABA
A

receptor
Therapeutic uses:
Partial seizures
Generalized tonic-
clonic seizures
(esp children)
Status epilepticus
(alternative)
Barbiturates bind to allosteric site on both o and |
subunits; prolong duration of the channel openings
permitting Cl
-
influx and hyperpolarization
enhanced GABA-mediated inhibition
Barbiturates may also have GABA-mimetic activity
Phenobarbital
Adverse Effects
Sedation
Depression of
mood
Cognitive
impairment
Hyperactivity
particularly in
children and
patients in acute
pain
Rash
Hepatotoxicity
Bone marrow
toxicity
Intravenous
Respiratory
depression
Hypotension
POTENT INDUCER of CYP enzymes
Positive evidence of human fetal risk
Relationship between serum phenytoin concentration
(steady state) and daily dose in five patients. Saturation points
differ between patients.
Nonlinear: The increase in serum level may not be
proportional to the increase in dose.
Half-life is dependent on plasma concentration
Waldman and Terzic Figure 45-2A
PHENYTOIN exhibits Zero-Order Kinetics
Clinical Correlates
related to phenytoin pharmacokinetics
1. I.V. or oral loading doses are used to rapidly
achieve therapeutic concentrations; monitor (check
blood levels within hours)
2. Cautious adjustment of subsequent doses is
recommended; several weeks may be required to
reliably assess the results of dose changes because
the time to reach steady state increases as the dose
increases (nonlinear kinetics)
3. Maintenance doses, but not loading doses, should
be lower in patients with hepatic failure.
4. Renal failure patients who are hypoalbuminemic
may require lower doses.
Hypoalbuminemia resulting from hepatic failure or
nephrOtic syndrome, or uremia resulting from renal
failure may + protein binding and | free
concentration. Measurement of free phenytoin may
help guide dosing.
p8
Goodman and Gilmans Figure
19-2
Phenytoin (and other AEDs) prolongs inactivated state of VG
Na+ channel stabilizes neuronal membrane in motor cortex
during generation of nerve impulses.
Phenytoin Therapeutic Uses
Partial seizures
(primary and w. secondary generalization)
Status epilepticus
(some experts recommend phenobarbital
1
st
choice in infants-more predictable
kinetics)
Non-seizure application
Sometimes used in the treatment of
ventricular arrhythmias caused by
digitalis intoxication

Phenytoin Adverse
Effects
Metabolic side effects
+ testosterone (sexual
dysfx; gynecomastia);+
vitamin D; + folate
| HDLs may be beneficial
Serious toxicities (rel.rare)
Skin rash; hepatotoxicity;
agranulocytosis
Asian patients with the variant
HLA-B*1502 may be more
susceptible to these effects
I.V.-related
Hypotension;
dysarrhythmia
Extravasation
Purple glove syndrome

Dose-related
Nystagmus; dizziness;
sedation; cognitive
impairment; nausea;
ataxia; tremor, other
movement disorder
Delayed
Peripheral neuropathy
and atrophy of the
cerebellum; folate
deficiency
Long-term
Gingival hyperplasia;
hirsuitism; coarsening
of facial feartures

DRUG INTERACTIONS
Sulfonamides and other highly plasma protein
bound drugs
Phenytoin induction of CYPs
Induction or inhibition of CYPs by other drugs
may affect phenytoin levels (phenytoin is major
substrate of CYP2C9, CYP2C19 and minor
substrate of CYP3A4)
Thyroid function test (bind TBG false +T4)
PREGNANCY
Specific fetal defects that have been associated
with chronic phenytoin use in the pregnant
woman are characterized by intrauterine growth
retardation, including abnormalities of the skull
and facial features, such as cleft palate and
microcephaly, mental retardation, and
underdeveloped nails of the fingers and toes.
Phenytoi
n
Benzodiazepines
Diazepam, Lorazepam, Clonazepam are most commonly
used in the management of seizures
Diazepam exhibits a two-stage distribution process
Diazepam immediate onset; duration 20-30 min;
t
elimination
~40 hours but 3 days active N-
desmethyldiazepam (CYP2C19;3A4)
Lorazepam onset ~5 minutes (I.V.); duration 6-8h;
t
elimination
in adults ~20h or less (hepatic
glucuronidation)
Clonazepam (oral only) onset 20-60 min; duration 6-
8h (children); t
elimination
22-33h (children) (CYP3A4)
Half-life of the initial
phase brain is about
30 minutes (half that
in children and
adolescents)
1) Initial rapid distribution into
CNS
2) Rapid redistribution out of
the brain and into adipose and
other peripheral tissues
Benzodiazepines
Tolerance to the anticonvulsant
effects of BZs develops within weeks
to months, limiting their use (except in
myoclonic seizures).

GABA
A
receptor,
the site of BZ
action
Benzodiazepines
bind to allosteric
site on both o
and | subunits
+
increased
frequency of
the channel
openings
permitting Cl
-

influx and
hyperpolarizatio
n
+
enhanced GABA-
mediated
inhibition

Benzodiazepines in the
Management of Seizures
Acute treatment
Lorazepam preferred for status epilepticus
Diazepam rectal gel for refractory seizures in
patients on stable AED regimen
Chronic treatment
Clonazepam is monotherapy or adjunct in
Lennox-Gastaut syndrome, petit mal variant,
akinetic and myoclonic seizures
Nonseizure applications of BZs
Anxiety; panic disorder; alcohol withdrawal;
muscle relaxant (diazepam); induction of
anesthesia (midazolam)

Benzodiazepine Cautions
ADVERSE EFFECTS
Oral
Sedation; depression;
incoordination with
oral use;
Parenteral
Sedation and
respiratory depression
Gradually titrate to
effect to avoid
respiratory
depression.
DRUG INTERACTIONS
Drugs that induce or
inhibit hepatic
enzymes


PREGNANCY
Demonstrated
teratogenic potential
Benzodiazepines have a tendency to produce
withdrawal seizures upon discontinuation.
Ethosuximide for the treatment of absence
seizures
ADVERSE EFFECTS
GI common
Sedation, headaches fairly
common
Irritability, depression,
psychosis
EPS eported
Blood dyscrasias
Allergic skin reactions,
sometimes severe, can occur.

DRUG INTERACTIONS
Drugs that induce or
inhibit CYP3A4
isoenzymes
PREGNANCY
Teratogenic effects
reported
Blockade of voltage-
gated T-type Ca
2+

channels in the
thalamus,
which have been
strongly implicated in
the pathogenesis of
absence seizures.
Carbamazepine Oxcarbazepine
Oral
CYP3A4 metabolism
Potent inducer of CYPs /
Pgp
Autoinduction
Carbamazepine induces
its own metabolism (as
well as that of other CYP
substrates)
After 3-5 weeks of daily
dosing the half-life
declines from 25-65
hours to 12-17 hours
and the time to peak
plasma levels also
declines; these
parameters then
stabilize.
Oral
Rapid hepatic
conversion to an
active metabolite
(MHD) (not via CYP3A4)
Potent inducer of
CYP3A4
Does not induce own
metabolism
Renal excretion of
unchanged MHD and
metabolites
Carbamazepine / Oxcarbazepine
USES
Carbamazepine: partial
seizures; generalized tonic-
clonic seizures
Oxcarbazepine; partial
seizures
Nonseizure applications
Trigeminal neuralgia; acute
mania associated with
bipolar 1 disorder
Carbamazepine lacks
the cosmetic side
effects of phenytoin;
less sedation; less
effect on cognitive
function
Oxcarbazepine
alternative to
carbamazepine; may
be better tolerated
Blockade of sodium channels
stabilize hyperexcited
neuronal membranes,
inhibiting repetitive firing, and
decreasing the propagation of
synaptic impulses
Carbamazepine / Oxcarbazepine
Adverse Effects
Acute, dose-related: dizziness, somnolence,
ataxia, nystagmus, nausea, and diplopia
Skin rashes; hepatotoxicity; leukopenia (Asian
patients with the variant HLA-B*1502 may be
more susceptible to these effects)
SIADH: Both drugs stimulate the release of
adenine vasopressin (antidiuretic hormone; ADH)
and potentiate its action in promoting
reabsorption of water hyponatremia and water
intoxication can occur (hyponatremia is more
common with oxcarbazepine)
DRUG INTERACTIONS: Numerous
PREGNANCY: Congenital defects reported

Valproic Acid
a broad spectrum antiepileptic drug
1) Enhanced effects of
GABA
Inhibit GABA
transaminase (+
degradation)
Inhibit GABA reuptake
GABA-mimetic at
postsynaptic receptor
2) Inhibition of ion
channels
VG Na
+
channels
T-type Ca
2+
channels

3) Blockade of NMDA
receptor-mediated
excitation
Possible Mechanisms Of Action
Valproic acid is considered first-line for treating
a range of seizure types; it is used as
monotherapy or adjunctive therapy in:
Generalized tonic-clonic seizures
Simple partial seizures and complex partial
seizures (carbamazepine is generally preferred
for partial seizures due to its lesser toxicity
compared to older alternatives)
Absence seizures, simple or complex:
Valproic acid and ethosuximide are first-line agents
Non-seizure applications:
Acute mania associated with bipolar disorder
Migraine prophylaxis in patients 12 years old.

Valproic Acid Adverse Effects
Common: nausea, vomiting, abdominal pain and
heartburn (gradually titrate drug to minimize these
symptoms), sedation, dizziness, ataxia, cognitive
impairment
Weight gain (4-9% of patients), hair loss, and
tremor
Hepatotoxicity
Thrombocytopenia
Hyperammonemia
Acute pancreatitis
Hyperandrogenism in females and polycystic
ovary syndrome
DRUG INTERACTIONS: Inhibitor of CYP
enzymes
PREGNANCY: Teratogenic
Felbamate
MOA:
Block of NMDA
glutamate receptor
Potentiation of
GABA
A
-mediated
inhibition
THERAPEUTIC USE:
Partial seizures
Seizures associated
with Lennox-Gestaut
syndrome
Informed consent
must be obtained
ADVERSE EFFECTS
Unexpectedly high
rates of
aplastic anemia and
severe hepatitis
Contraindicated in
patients with H/O
blood dyscrasias or
liver disease
Common side effects:
Nausea / vomiting,
headache, dizziness,
somnolence, and
insomnia
DRUG INTERACTIONS
CYP-related
Gabapentin / Pregabalin
MOA: Block VG Ca2+
channel on
presynaptic neuron
+ in synaptic release
excitatory
neurotransmitters (eg
Glu; ACh; NE)
Tx of Partial seizures
(adjuncts)
Nonseizure uses:
neuropathic pain
(Pregabalin has other
applications)
ADVERSE EFFECTS
Minor: sedation;
dizziness; weight
gain; peripheral
edema may occur
DRUG INTERACTIONS
No known metabolic
interactions
PREGNANCY
Insufficient clinical
experience to confirm
the safety
Lamotrigine a broad spectrum antiepileptic drug
Possible MOAs:
Inhibition of VG Na
+

channels
Inhibits release of
glutamate
(mechanism not
understood)
Weak inhibitory effect
on the 5-HT
3
receptor
(relevance unknown)
Inhibits dihydrofolate
reductase in vitro

THERAPEUTIC USES
Partial seizures
Primary generalized
seizures
Generalized seizures
of Lennox-Gestaut
syndrome
May be effective in
absence and
myoclonic seizures in
children
Nonseizure uses
Bipolar disorder
(maintenance)
Lamotrigine Adverse Effects
Common: Nausea, dizziness, ataxia, anxiety,
insomnia, worsening of migraine headaches, and
other CNS effects
Lamotrigine does not cause sedation or cognitive
side effects.
Serious:
Skin rash: most are nonserious; rarely, deaths
have occurred from SJS and toxic epidermal
necrolysis; usu w/in 2-3 mon
Clinical correlate: To reduce the risk of rash, the
drug should be slowly titrated over 6 to 8 weeks.
Monitor for S/S of asceptic meningitis;
hypersensitivity reactions; accumulation in
melanin-rich tissues (clinical significance
unknown)
Lamotrigine
Drug Interactions / Use in Pregnancy
DRUG INTERACTIONS
Phenytoin, carbamazepine, and phenobarbital
induce metabolism of lamotrigine (~50%
decrease in t)
Valproic acid inhibits lamotrigines metabolism
(~2-3x increase in t)
Use dosing guidelines when drugs are co-
administered
Folate inhibitors: the prescriber should keep in
mind that lamotrigine inhibits dihydrofolate
reductase in vitro

PREGNANCY Data is limited
Topiramate
Possible MOA
Block VG Na+
channels (modest
effect)
Depresses the
excitatory action of
AMPA/kainite subtype
of the glutamate
receptor
Acts on GABA
A
R
enhances inhibitory
effect of GABA
Carbonic anhydrase
inhibition (clinical
relevance unknown)
THERAPEUTIC USES
Adjunctive treatment of:
Partial onset seizures
Primary generalized
tonic-clonic seizures
Seizures of Lennox-
Gastaut symdrome,
infantile spasm, and
absence seizures
Non-seizure
applications:
Prophylaxis of
migraine (approved)
Off-label uses are
accumulating

Topiramate Adverse Effects
Most common: Somnolence, fatigue, dizziness,
cognitive slowing, paresthesias, nervousness, and
confusion; weight loss reported
Carbonic anhydrase inhibition: effects include,
Acute myopia with 2angle-closure glaucoma
Metabolic acidosis: + serum HCO
3
-
(due to |renal
HCO
3
-
loss)
Renal calculus: | increase the risk of kidney stones
Oligohydrosis / Hyperthermia: normal heat-related
perspiration becomes severely impaired
DRUG INTERACTIONS
Concurrent use of topiramate and valproic acid may
increase the risk of hyperammonemia and associated
encephalopathy
PREGNANCY: Teratogenic in animal models;
hypospadias reported in human male infants
Levetiracetam
Possible MOA
Binds synaptic
vesicular protein SV
2
A
it might modify the
synaptic release of
glutamate and GABA
through an action on
vesicular function
Inhibits VG N-type
Ca
2+
channels in the
hippocampus
May displace negative
modulators to
facilitate GABA-ergic
inhibitory transmission
THERAPEUTIC USES
Adjunctive use
Partial seizures
Primary generalized
tonic-clonic seizures
Myoclonic seizures
AE: fatigue and
irritability; weakness,
dizziness, and
somnolence;
psychosis
Low potential for
metabolic drug
interactions (can
increase phenytoin
serum levels)

Pharmacology of Headaches
The causes and mechanisms of
primary headaches are still poorly
understood and controversial.
The pathogenesis of headaches
involves complex interactions taking
place in the sensory neuronal
network, with many
neurotransmitters involved.
Some migraine and other primary
headaches have a genetic
component.
Both vascular and neural influences cause
migraines
Stress triggers
changes in the brain
The changes cause
serotonin to be
released
Blood vessels
constrict and dilate
Chemicals irritate
nerves and blood
vessels and cause
neurogenic
inflammation and
pain

BK, bradykinin; CGRP, calcitonin gene-
related peptide; NKA, neurokinin A; NO, nitric
oxide; SP, substance P.
Waldman and Terzic FIGURE 48-2 (From Bianchi A, Caraci
F, Salomone S. The pain in primary headache. In Capasso A
[ed]: Recent Developments in Pain Research. Trivandrum,
India: Research Signpost, 2005, pp 343-357.)
Direction of spread (arrows) and maximal extent (colored region) of depressed
cerebral blood flow (CBF) in migraine with and without aura. These processes
may be initiated by the trigeminovascular sensory system input from meningeal
vessels, which projects through the nucleus caudalis to the periaqueductal gray,
sensory thalamus, and sensory cortex.
Figure 2-10
Goals of therapy
Abort the head pain at the onset of the
attack
Prevent future episodes
Triggers should be avoided or limited.
Response is variable among and within
individual patients.
Migraine therapy must be
individualized.

Triptans
Class Pharmacokinetic Properties
Structurally similar to serotonin
Oral; subcutaneous; nasal administration
Onset of action varies according to the drug
Extensive hepatic metabolism by CYP3A4,
CYP2D6, CYP1A2, or MAO-A
Some renal excretion of unchanged drug
Elimination half-life varies 2-6 hours, except
frovatriptan (26h)
T
max
1 to 3 hours (almotriptan; eletriptan;
rizatriptan), 2-2.5 hours (sumatriptan;
zolmitriptan), 2-4 hours (frovatriptan; naratriptan);
sumatriptan subcutaneously T
max
~12 minutes

Serotonin
Triptans Proposed Mechanism of Action
Restores blood flow to
the brain and inhibits
the release of
proinflammatory
neuropeptides
Vasoconstriction
Triptans bind 5-HT
1D/1B

receptors in cranial
vessels
Thus aborting migraine
headache
Stimulates vasoconstriction
in the basilar artery and
blood vessels in the dura
mater
Inhibits the release of
vasodilating peptides
Activation of 5-HT
1D/1B

receptors on presynaptic
trigeminal nerve endings
Triptans Therapeutic Uses
Migraine: Triptans acutely abort migraine
Triptans are not intended for headache
prophylaxis
Cluster headaches:
Subcutaneous (sumatriptan)
Nasal sprays (sumatriptan and zolmitriptan)
Oral triptan is not effective

The safety of treating more than 4 migraines
in a 30-day period with triptans has not been
established.
Efficacy of Triptans
Most of the triptans have similar efficacy.
Clinical efficacy appears to be related more to
time to the peak plasma level (T
max
) than to the
potency, bioavailability, or half-life.
The triptans have a duration of effect that is often
shorter than the duration of the headache, which
may necessitate additional doses during a
prolonged migraine attack.
Naratriptan and frovatriptan have slower onset of
effect but are better tolerated.
Triptans are not effective in migraine with aura
unless given after the aura is completed and the
headache initiated
Triptans are not effective in tension headache



Triptans Adverse Effects
Common: Tingling or warm sensations, dizziness,
muscle weakness, neck pain
Injection site reactions (sumatriptan)
Chest discomfort occurs in 1-5% of patients
Cardiac effects (rare but serious) occurring
predominantly in patients with risk factors for
coronary artery disease
Chest pain (coronary vasospasm)
Atrial and ventricular arrhythmias
Myocardial infarction
Chest pain after the use of a triptan requires
evaluation.
Triptans Contraindications
Ischemic heart disease
Cerebrovascular syndromes
Peripheral vascular disease
Uncontrolled hypertension
Hepatic or renal impairment (nara-, ele-,
rizatriptan)
Peripheral vascular syndromes (nara-, ele-,
frovatriptan)
Wolff-Parkinson-White syndrome (zolmatriptan)
Triptans Drug Interactions
Ergot derivatives / other 5HT1 agonists
Drugs with serotonergic effects

Serotonin Syndrome: Excess synaptic serotonin
causes a serious, potentially fatal syndrome that
is diagnosed on the basis of a history of
administration of a serotonergic drug and physical
findings.
Severe increases in heart rate and blood pressure
that may lead to shock, and temperatures over
106F (41.1C) with metabolic acidosis,
rhabdomyolysis, seizures, renal failure, and
disseminated intravascular coagulation
Ergot Alkaloids
Ergotamine tartate / Dihydroergotamine
MOA: 5-HT
1D/1B
agonists
Other actions: partial agonists or antagonists at -
adrenergic, dopaminergic, and serotonergic
receptors
TU: alternative to other measures for the acute
treatment of migraine pt established on ergot;
long attacks (>48h); frequent headache
recurrence
AE: peripheral vasoconstriction; emetic effects;
oxytocic activity (pregnant pt)
Chronic ergotism can cause itching and edema,
and gangrene especially in patients with PVD
Nontriptan Drugs For Headache Abortive
Therapy
NSAIDs
Aspirin-acetaminophen-caffeine
Acetaminophen-isometheptene-
dichloralphenazone
Butalbital-acetaminophen or aspirin-caffeine
codeine
Opioids
Butorphanol nasal spray

Adjunctive therapy
Antiemetics: metoclopramide; prochlorperazine
Prophylaxis of Migraine
Evidence of efficacy with:
-adrenergic blockers
Tricyclic antidepressants
Valproate
Topiramate
Review and Clicker Quiz
In selecting concomitant medication for a patient taking
and AED for the management of partial seizures, the
family doctor keeps in mind that the antiseizure
medication is a potent inducer of CYP isoenzymes. The
drug is most likely:

C
a
r
b
a
m
a
z
e
p
i
n
e

C
l
o
n
a
z
e
p
i
n
e

E
t
h
o
s
u
x
i
m
i
d
e

L
a
m
o
t
r
i
g
i
n
e

V
a
l
p
r
o
a
t
e
20% 20% 20% 20% 20%
1. Carbamazepine
2. Clonazepine
3. Ethosuximide
4. Lamotrigine
5. Valproate
The neurologist adjusts a patients AED dose to increase
the blood levels by an additional 50%. As the drug exhibits
zero order kinetics, the dose is increased in small
increments:

C
a
r
b
a
m
a
z
e
p
i
n
e

P
h
e
n
o
b
a
r
b
i
t
a
l

P
h
e
n
y
t
o
i
n

P
r
i
m
i
d
o
n
e

V
a
l
p
r
o
a
t
e
20% 20% 20% 20% 20%
1. Carbamazepine
2. Phenobarbital
3. Phenytoin
4. Primidone
5. Valproate
A patient suffers from both absence seizures and
generalized tonic-clonic seizures. Which one of the
following is effective in the treatment of both types of
seizures?

C
a
r
b
a
m
a
z
e
p
i
n
e

E
t
h
o
s
u
x
i
m
i
d
e

P
h
e
n
o
b
a
r
b
i
t
a
l

P
h
e
n
y
t
o
i
n

V
a
l
p
r
o
a
t
e
20% 20% 20% 20% 20%
1. Carbamazepine
2. Ethosuximide
3. Phenobarbital
4. Phenytoin
5. Valproate
A patient on AED treatment over time develops gingival
hyperplasia, hirsuitism, and coarsening of facial
features. The mechanism of action of the AED is thought
to be inhibition of:

C
a
r
b
o
n
i
c

a
n
h
y
d
r
a
s
e

G
A
B
A
A

r
e
c
e
p
t
o
r

G
A
T
-
1

G
A
B
A

t
r
a
n
s
p
o
r
t
e
r

T
-
t
y
p
e

C
a
2
+

c
h
a
n
n
e
l
s

V
G

N
a
+

c
h
a
n
n
e
l
s
20% 20% 20% 20% 20%
1. Carbonic
anhydrase
2. GABA
A
receptor
3. GAT-1 GABA
transporter
4. T-type Ca
2+

channels
5. VG Na
+
channels
A patient who suffers from generalized tonic clonic seizures
is to be started on adjunctive therapy with lamotrigine. The
drug is slowly titrated over 6-8 weeks to reduce the risk of:

A
p
l
a
s
t
i
c

a
n
e
m
i
.
.
.

H
e
p
a
t
i
t
i
s

M
e
t
a
b
o
l
i
c

a
c
i
d
.
.
.

N
e
u
r
o
p
a
t
h
i
c

p
a
.
.
.

R
a
s
h

V
e
n
t
r
i
c
u
l
a
r

a
r
.
.
.
17% 17% 17% 17% 17% 17% 1. Aplastic anemia
2. Hepatitis
3. Metabolic acidosis
4. Neuropathic pain
5. Rash
6. Ventricular
arrhythmias
A patient suffers from a severe seizure disorder that is not
controlled with several of the first-line AEDs. The neurologist
receives informed consent and prescribes a drug that is
associated with unexpectedly high rates of aplastic anemia and
hepatitis:

C
a
r
b
a
m
a
z
e
p
i
n
e

F
e
l
b
a
m
a
t
e

L
a
m
o
t
r
i
g
i
n
e

T
o
p
i
r
a
m
a
t
e

V
i
g
a
b
a
t
r
i
n
20% 20% 20% 20% 20%
1. Carbamazepine
2. Felbamate
3. Lamotrigine
4. Topiramate
5. Vigabatrin
A woman with a seizure disorder tells her neurologist that is
planning on becoming pregnant. Which of the following is
absolutely contraindicated in her case (U.S. Boxed
Warning)?

B
e
n
z
o
d
i
a
z
e
p
i
n
e
.
.
.

C
a
r
b
a
m
a
z
e
p
i
n
e

F
e
l
b
a
m
a
t
e

L
a
m
o
t
r
i
g
i
n
e

P
h
e
n
o
b
a
r
b
i
t
a
l

P
h
e
n
y
t
o
i
n

T
o
p
i
r
a
m
a
t
e

V
a
l
p
r
o
a
t
e

V
i
g
a
b
a
t
r
i
n
11% 11% 11% 11% 11% 11% 11% 11% 11%
1. Benzodiazepin
es
2. Carbamazepin
e
3. Felbamate
4. Lamotrigine
5. Phenobarbital
6. Phenytoin
7. Topiramate
8. Valproate
9. Vigabatrin
A patient managed on an AED is found to have
hyponatremia. Included in the differential is a drug-
induced cause by:


B
e
n
z
o
d
i
a
z
e
p
i
n
e
s

C
a
r
b
a
m
a
z
e
p
i
n
e

F
e
l
b
a
m
a
t
e

L
a
m
o
t
r
i
g
i
n
e

P
h
e
n
o
b
a
r
b
i
t
a
l

P
h
e
n
y
t
o
i
n

T
o
p
i
r
a
m
a
t
e

V
a
l
p
r
o
a
t
e

V
i
g
a
b
a
t
r
i
n
11% 11% 11% 11% 11% 11% 11% 11% 11%
1.
Benzodiazepin
es
2. Carbamazepin
e
3. Felbamate
4. Lamotrigine
5. Phenobarbital
6. Phenytoin
7. Topiramate
8. Valproate
9. Vigabatrin
The neurologist decides on adjunctive therapy for the
management of partial seizures. She considers an oral drug
with low hepatic metabolism and 100% bioavailability, low
plasma protein binding, renal excretion and two times daily
dosing:

C
a
r
b
a
m
a
z
e
p
i
n
e

L
a
m
o
t
r
i
g
i
n
e

L
e
v
e
t
i
r
a
c
e
t
a
m

P
h
e
n
o
b
a
r
b
i
t
a
l

P
h
e
n
y
t
o
i
n
20% 20% 20% 20% 20%
1. Carbamazepine
2. Lamotrigine
3. Levetiracetam
4. Phenobarbital
5. Phenytoin
A child with a seizure disorder presents to the ED with S/S of
hyperthermia. The AED the child is taking could cause this
adverse effect by its action on:

C
a
r
b
o
n
i
c

a
n
h
y
d
.
.
.

G
A
B
A
A

r
e
c
e
p
t
o
r


G
A
T
-
1

G
A
B
A

t
r
.
.
.

T
-
t
y
p
e

C
a
2
+

c
h
.
.
.

V
G

N
a
+

c
h
a
n
n
e
l
.
.
.
20% 20% 20% 20% 20%
Impaired normal heat-related perspiration
1. Carbonic
anhydrase
2. GABAA receptor
3. GAT-1 GABA
transporter
4. T-type Ca2+
channels
5. VG Na+ channels
A 23-year-old woman presents to the office for
consultation regarding her antiseizure
medications. Seven years ago, this otherwise
healthy young woman had a generalized tonic-
clonic seizure (GCTS) at home. She was rushed
to the emergency department, at which time she
was alert but complained of headache. A
consulting neurologist placed her on
levetiracetam, 500 mg bid. Four days later, EEG
showed rare right temporal sharp waves. MRI
was normal. One year after this episode, a repeat
EEG was unchanged, and levetiracetam was
gradually increased to 1000 mg bid. The patient
had no significant adverse effects from this
dosage.
At age 21, she had a second GTCS while in
college; further discussion with her roommate at
that time revealed a history of two recent
episodes of 1-2 minutes of altered consciousness
with lip smacking (complex partial seizures). A
repeat EEG showed occasional right temporal
spikes. Lamotrigine was gradually added to the
regimen to a dosage of 200 mg bid. Since then,
the patient has been seizure-free for 2 years but
now comes to the office for a medication review.
Gradual discontinuation of levetiracetam is
planned if the patient continues to do well for
another year, although risk of recurrent seizures
is always present when medications are
withdrawn.
Waldman and Terzic Figure 45-3 Drug Choice Algorithm
A 20-year-old woman who suffers from migraines takes a
subcutaneous injection of a drug at the onset of the
headache. The drug is effective in aborting the migraine. It s
site of action is thought to be:

5
-
H
T
1
B
/
1
D

5
-
H
T
2

5
-
H
T
3

G
A
B
A

t
r
a
n
s
p
o
r
t
.
.
.

G
l
u
t
a
m
a
t
e

t
r
a
n
.
.
.

N
a
+

c
h
a
n
n
e
l
s

T

t
y
p
e

C
a
2
+

c
h
.
.
.
14% 14% 14% 14% 14% 14% 14%
1. 5-HT
1B/1D
2. 5-HT2
3. 5-HT3
4. GABA transporter
5. Glutamate
transporter
6. Na+ channels
7. T type Ca2+
channels
References
Katzung Basic and Clinical Pharmacology 11e
McGraw-Hill 2009: Chapter 24; p282-288
Waldman and Terzic Pharmacology and
Therapeutics Principles to Practice Saunders
Elsevier 2009: Chapter45; 48
Goodman and Gilmans Pharmacological Basis of
Therapeutics 11e McGraw-Hill 2006: Chapter 19;
p306-313
Harrisons Principles of Internal Medicine 17e
2008
Thomsan Reuters Micromedex Healthcare Series
January 2011
Lexicomp Online January 2011