CASE 1: A 7 year old girl was brought to the ER after losing consciousness while

playing with neighbors several minutes prior to consult. As encountered by the

owner of a nearby store, the childs body suddenly stiffened which was followed by
jerking movements of both upper and lower extremities. The patient looked
confused and couldnt remember what happened. The mother claimed similar
attack occurred once the previous month. The doctor in a nearby clinic who saw the
child advised them to observe the child closely for any repeated episode and to
bring her to the nearest hospital in case of another attack.
Guide Questions:
1. What is your diagnosis? If an EEG was requested, what would be the
expected finding?
Diagnosis: Generalized tonic-clonic seizure
EEG finding: 2-3 Hz spike-and-wave discharges on electroencephalogram.
2. Describe the mechanism/s in the development of such attacks and
identify possible targets for drug therapy.
Epilepsy is a heterogeneous symptom complex-a chronic disorder
characterized by recurrent seizures. Seizures are finite episodes of brain
dysfunction resulting from abnormal discharge of cerebral neurons.
New antiseizure drugs are being sought to act by one of the three
mechanism:
a. Enhancement of GABAergic (inhibitory) transmission
b. Diminution of excitatory (usually glutamatergic) transmission
c. Modification of ionic conductances
Neuronal targets for current and potential antiseizure drugs include both
excitatory and inhibitory synapses:
a. Molecular targets for antiseizure drugs at the excitatory, glutamatergic
synapse. Presynaptic targets diminishing glutamate release include
voltage-gated Na channel, voltage-gated calcium channel, potassium
channels, synaptic vesicle proteins, CRMP-2 (collapsing-response mediator
protein-2). Postsynaptic target includes AMPA receptors and NMDA
receptors.
b. Molecular targets for antiseizure drugs at the inhibitory, GABAergic
synapse. These include specific targets: GABA transporters, GABAtransaminase, GABA A receptors, GABA B receptors and synaptic vesicular
proteins. Effects may also be mediated by nonspecific targets such as by
voltage-gated ion channels and synaptic proteins.

3. What drugs can be used for the case? Differentiate their mechanisms
of action and common and serious adverse effects associated.
Antiseizures
Cyclic Ureides
1. Phenytoin
(and
congeners)

2. Primidone
3. Phenobarbit
al
Tricyclics
4. Carbamazep
ine

GABA
derivatives
5. Gabapentin

Others
6. Valproate

Mechanism of action

Side effects/ Toxicities

- At therapeutic
concentrations, the major
action of phenytoin is to block
sodium channels and inhibit
the generation of rapidly
repetitive action potentials.
- Also alters sodium,
potassium and calcium
conductance, membrane
potentials, and the
concentrations of amino acids
and the neurotransmitters
norepinephrine, acetylcholine,
and GABA.

- Nystagmus occurs early, as

does loss of extraocular
pursuit movements. Diplopia
and ataxia are the most
common dose related
adverse effects. Gingival
hyperplasia and hirsutism
occur to some degree in
most patients. Coarsening of
facial features and with mild
peripheral neuropathy.
Abnormalities of vitamin D
metabolism which results to
osteomalacia. Idiosyncratic
reactions are relatively rare.
- Seadation, cognitive
issues, atxia, hyperactivity.
- Sedation, cognitive issues,
ataxia, hyperactivity

- Similar to phenytoin but

converted to phenobarbital.
- Ebhances phasic GABA A
receptor responses. Reduces
excitatory synaptic responses.
- Carbamazepine like
phenytoin, blocks Na channels
at therapeutic concentrations
and inhibits high-frequency
repetitive firing in neurons in
culture.It also acts
presynaptically to decrease
synaptic transmission.
Potentiation of voltage-gated
K current has also been
described.

- Diplopia and ataxia, mild

GIT upset, unsteadiness and
in much higher doses,
drowsiness. Hyponatremia
and water intoxication .
Idiosyncratic blood
dyscrasias including
aplapstic anemia and
agranulocytosis.

- Decreases excitatory
transmission by acting on VG
calcium channels
presynaptically

- Somnolence, dizziness,
ataxia

Blocks high-frequency firing of

Nausea, tremor, weight

7. Lamotrigine

8. Levetiraceta
m
9. Topiramate

10.Zonisamide

11.Lacosamide

neurons, modifies amino acid

metabolism.
- Prolong inactivation of VG Na
channels. Acts presynaptically
on VG Ca channels,
decreasing glutamate release.
- Action on synaptic protein
- Multiple actions on synaptic
function, probably
phosphorylation
- Blocks high frequency firing
via action on VG Na channels
- Enhance slow inactivation of
Na channels. Blocks action of
neurotrophins (via CRMP-2)

gain, hair loss, teratogenic,

hepatotoxic
- Dizziness, headache,
diplopia, rash

Nervousness, dizziness,
depression, seizures
Somnolence, cognitive
slowing, confusion,
paresthesias
- Drowsiness, cognitive
impairement, confusion,
poor concentration
- Dizziness, headache,
nausea

4. Which among them have clinically significant drug-drug interaction?

Antiseizure Drugs
1. Phenytoin

2. Phenobarbital

3. Primidone
4. Carbamazepine

5. Valproate
6. Lamotrigine
7. Topiramate

Drug-drug interactions
- primarily related to protein binding or to metabolism.
Since phenytoin is 90% bound to plasma proteins, other
highly bound drugs like phenylbutazone and
sulphonamides can displsce phenytoin from its binding
site.
- Interactions: Phenobarbital, carbamazepine, isoniazid,
felbamate, oxcarbazepine, topiramate, quinidine,
cyclosporine, steroids, oral contraceptives
- Interactions: Valproate, carbamazepine, felbamate,
phenytoin, cyclosporine, felodipine, lamotrigine,
nifedipine, steroids, theophylline, verapamil
Similar to phenobarbital
- Interactions: Phenytoin, carbamazepine, valproate,
fluoxetine, verapamil, macrolide, antibiotics, isoniazid,
propoxyphene, danazol, phenobarbital, primidone
- Interactions: Phenobarbital, phenytoin, carbamazepine,
lamotrigine, felbamate, rifampin, primidone
- Interactions: Valproate, carbamazepine, oxcarbazepine,
phenytoin, phenobarbital, primidone, topiramate
- Interactions: Phenytoin, carbamazepine, oral
contraceptives, lamotrigine

Reference: Katzung B., Basic and Clinical Pharmacology, 12 th edition,

Chapter 24 pp 404-426.