Antiseizure Drugs

Question 1

Epilepsy is

Answer 1

a group of disorders characterized by excessive neuron stimulation within the CNS. The seizures are initiated by high-frequency discharge from a group of excitable neurons called a focus, caused by: congenital defects, hypoxia at birth, head trauma or brain tumors. The symptoms depend upon location of the focus and how discharge spreads to other portions of brain.

Question 2

Antiseizure drugs act by

Answer 2

suppressing neuronal discharge at the focus and the brain and by inhibition of sodium and calcium influx due to binding of sodium and calcium channels and augmenting GABA responses

Question 3

Therapeutic goal in epilepsy

Answer 3

reduce number and severity of seizures, allowing the patient to live a normal lifeIdeal would be to eliminate seizures, but this may not be possible without causing intolerable side effects. Nowadays it is considered that only 2/3 of the patients will be seizure free after one year of treatment. Also very important is to promote the compliance to antiseizure medication, through education of the patient and family, monitoring plasma drug levels and drawing a seizure frequency chart. Monotherapy is desirable because of fewer side effects and a lower cost. Withdrawal of drugs must be done over an extended period of time (6 weeks to several months). If the patient is receiving two drugs, then they must be withdrawn sequentially not simultaneously.

Question 4

Blockers of sodium channel

Answer 4

carbamazepine, oxcarbazepine, lamotrigine, phenytoin, topiramate, valproic acid, zonisamide

Question 5

calcium channel blockers

Answer 5

Ethosuximide, lamotrigine, valproic acid, zonisamid

Question 6

N methyl D aspartic acid receptor blockers

Answer 6

Felbamate

Question 7

AMPA receptor blockers

Answer 7

topiramate

Question 8

Antiseizure agents influencing GABA, receptor enhancers

Answer 8

Phenobarbital, benzodiazepines

Question 9

Antiseizure agents influencing GABA, reuptake inhibitors

Answer 9

tiagabine

Question 10

Antiseizure agents influencing GABA, degradation inhibitors

Answer 10

vigabatrin, valproic acid

Question 11

Antiseizure agents influencing GABA, influencing vesicle proteins

Answer 11

Levetiracetam

Question 12

Phenytoin mechanism of action

Answer 12

stabilizes neuronal membranes to depolarization by decreasing the flux of sodium ions in neurons in the resting state or during depolarization.

Question 13

Phenytoin pharmakinetics

Answer 13

Absorption: oral absorption of Phenytoin is slow;
Distribution: distribution is rapid and brain concentrations are high; extensively bound to plasma albumin;
Biotransformation and elimination: less than 5% of a given dose is excreted unchanged in the urine; Phenytoin is metabolized in the liver; large genetic variations in the rate of the drug’s metabolism may occur.

Question 14

Phenytoin interactions

Answer 14

inhibition of Phenytoin metabolism is caused by Chloramphenicol, Dicumarol, Cimetidine, sulfonamides and Isoniazid; when used chronically, this drugs increase the concentration of Phenytoin in plasma by preventing its metabolism;
a decrease in the plasma concentration of Phenytoin is caused by Carbamazepine, which enhances Phenytoin metabolism.
increase in metabolism of other drugs by Phenytoin: Phenytoin induces the CYP 450 system, which leads to an increase in the metabolism of other antiepileptics, anticoagulants, oral contraceptives, Quinidine, Doxicicline, Cyclosporine, Mexiletine, Methadone and Levodopa.

Question 15

Phenytoin indications

Answer 15

partial seizures (simple and complex);
tonic-clonic seizures;
status epilepticus;
not effective for absence seizures, which often may worsen after this drug.

Question 16

Phenytoin adverse effects

Answer 16

nystagmus, ataxia;
nausea, vomiting;
gingival hyperplasia, that slowly regresses after termination of drug therapy;
megaloblastic anemia occurs because the drug interferes with vitamin B12 metabolism;
confusion, hallucination, drowsiness;
teratogenic effects: “Fetal hydantoin syndrome” includes cleft lip, cleft palate, congenital heart diseases; half of untreated epileptic women have an increased seizure frequency during pregnancy; these seizures can lead to anoxic episodes, which lead to a higher incidence of congenital birth defects; antiepileptic drugs are given at the lowest possible dose to control seizures.

Question 17

Carbamazepine mechanism of action

Answer 17

Carbamazepine reduces the propagation of abnormal impulses in the brain by blocking sodium channels, thereby inhibiting the generation of repetitive action potentials in the epileptic focus.

Question 18

Carbamazepine indications

Answer 18

partial seizures;

in manic-depressive patients to ameliorate the symptoms.

Question 19

Carbamazepine pharmacokinetics

Answer 19

Absorption: it is absorbed slowly following oral administration;
Distribution: it enters the brain rapidly because of its high lipid solubility;
Biotransformation: Carbamazepine induces the drug metabolizing enzymes in the liver, and its t1/2 therefore decreases with chronic administration; the enhanced hepatic CYP 450 system activity also increases the metabolism of other antiepileptic drugs.

Question 20

Carbamazepine adverse effects

Answer 20

stupor, coma;
respiratory depression;
drowsiness, vertigo, ataxia, blurred vision;
nausea, vomiting;
liver toxicity (frequent liver function tests!).

Question 21

Phenobarbital action

Answer 21

after binding to the barbiturate site of GABA receptors, it potentiates the inhibitory effect of GABA-mediated neurons.

Question 22

Phenobarbital pharmacokinetics

Answer 22

Absorption: it is well absorbed orally;
Distribution: the drug freely penetrates the brain;
Biotransformation and elimination: approximately 75% of the drug is inactivated by the hepatic microsomal system; the remaining drug is excreted unchanged by the kidney; Phenobarbital is a potent inducer of the CYP 450 system, and when given chronically, it enhances the metabolism of other agents.

Question 23

Phenobarbital indications

Answer 23

simple partial seizure;
febrile seizures in children;
recurrent tonic-clonic seizures, in patients who do not respond to Diazepam plus Phenytoin;
anxiety, nervous tension, insomnia.

Question 24

Phenobarbital adverse effects

Answer 24

sedation, ataxia, nystagmus, vertigo, agitation, confusion;
acute psychotic reactions;
nausea, vomiting.

Question 25

Valproic acid mechanism of action

Answer 25

it reduces the propagation of abnormal electrical discharge in the brain, by blocking sodium and calcium channels;
it inhibits the enzyme GABA-transaminase, responsible of GABA degradation to succinic semialdehyde (SSA).

Question 26

Valproic acid pharmacokinetics

Answer 26

Absorption: the drug is effective orally and rapidly absorbed;
Distribution: about 90% is bound to plasma proteins;
Biotransformation and elimination: 3% is excreted unchanged, the rest is converted to active metabolites by the liver.

Question 27

Valproic acid indications

Answer 27

myoclonic seizures (the most effective agent);
absence seizures;
tonic-clonic seizures.

Question 28

Valproic acid adverse effects

Answer 28

nausea, vomiting;
sedation, ataxia, tremor;
hepatic toxicity;
rash;
alopecia;
bleeding.

Question 29

Benzodiazepines indications

Answer 29

absence and myoclonic seizures (Clonazepam);
partial seizures (Clorazepate in conjunction with other drugs);
acute treatment of status epilepticus (Diazepam)

Question 30

Benzodiazepines adverse effects

Answer 30

drowsiness, somnolence, fatigue;
ataxia, dizziness, behavior changes;
respiratory and cardiac depression (after IV administration in acute situations).

Question 31

Gabapentine and Lamotrigine action

Answer 31

Gabapentin is an analogue of GABA, but its exact mechanism is not known;
Lamotrigine inhibits glutamate release, blocks sodium and calcium channels and prevents repetitive firing.

Question 32

Gabapentin and lamotrigine pharmacokinetics

Answer 32

Distribution: Gabapentin does not bind to plasma proteins;
Biotransformation and elimination: Gabapentin is excreted unchanged through the kidneys, minimizing the likelihood of drug interactions; Lamotrigine is metabolized in the liver; its t1/2 is decreased by enzyme-inducing drugs (Carbamazepine, Phenytoin) and is increased by Valproic acid.

Question 33

Gabapentin and Lamotrigine indications and adverse effects

Answer 33

Indications
simple or complex partial seizures;
generalized tonic-clonic seizures.
Adverse effects
mild CNS effects;
rash.