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 child’s body suddenly stiffened which was followed by jerking movements of both upper and lower extremities. The patient looked confused and couldn’t 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 seizureEEG 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) transmissionc. 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, GABA-transaminase, 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 Mechanism of action Side effects/ ToxicitiesCyclic Ureides

1. Phenytoin (and congeners)

- 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.

2. Primidone - Similar to phenytoin but converted to phenobarbital.

- Seadation, cognitive issues, atxia, hyperactivity.

3. Phenobarbital - Ebhances phasic GABA A receptor responses. Reduces excitatory synaptic responses.

- Sedation, cognitive issues, ataxia, hyperactivity

Tricyclics4. Carbamazepine - 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.

GABA derivatives5. Gabapentin - Decreases excitatory transmission

by acting on VG calcium channels presynaptically

- Somnolence, dizziness, ataxia

Others6. Valproate Blocks high-frequency firing of

neurons, modifies amino acid metabolism.

Nausea, tremor, weight gain, hair loss, teratogenic, hepatotoxic

7. Lamotrigine - Prolong inactivation of VG Na channels. Acts presynaptically on VG Ca channels, decreasing glutamate release.

- Dizziness, headache, diplopia, rash

8. Levetiracetam - Action on synaptic protein Nervousness, dizziness, depression, seizures

9. Topiramate - Multiple actions on synaptic Somnolence, cognitive slowing,

function, probably phosphorylation confusion, paresthesias10. Zonisamide - Blocks high frequency firing via

action on VG Na channels- Drowsiness, cognitive impairement, confusion, poor concentration

11. Lacosamide - Enhance slow inactivation of Na channels. Blocks action of neurotrophins (via CRMP-2)

- Dizziness, headache, nausea

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

Antiseizure Drugs Drug-drug interactions1. Phenytoin - 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

2. Phenobarbital - Interactions: Valproate, carbamazepine, felbamate, phenytoin, cyclosporine, felodipine, lamotrigine, nifedipine, steroids, theophylline, verapamil

3. Primidone Similar to phenobarbital4. Carbamazepine - Interactions: Phenytoin, carbamazepine, valproate, fluoxetine,

verapamil, macrolide, antibiotics, isoniazid, propoxyphene, danazol, phenobarbital, primidone

5. Valproate - Interactions: Phenobarbital, phenytoin, carbamazepine, lamotrigine, felbamate, rifampin, primidone

6. Lamotrigine - Interactions: Valproate, carbamazepine, oxcarbazepine, phenytoin, phenobarbital, primidone, topiramate

7. Topiramate - Interactions: Phenytoin, carbamazepine, oral contraceptives, lamotrigine

Reference: Katzung B., Basic and Clinical Pharmacology, 12th edition, Chapter 24 pp 404-426.