Anticonvulsants 1.2

Question 1

Phenytoin (Dilantin)**: Mechanism of Action

Answer 1

• Inhibition of seizure spread
– Blockade of Ca2+ influx
– Enhancement of Cl- mediated inhibitory post synaptic
potentials (IPSPs)

• Suppression of epileptic focus
– Enhanced affinity for inactivated Na+ channels at more
depolarized membrane potentials
– Enhancement of the inhibitory surround via stimulation
of Cl- mediated IPSPs

Question 2

Phenytoin (Dilantin)**: Uses

Answer 2

• Initial drug of choice in all types of epilepsy
except absence epilepsy and atonic seizures
• Highly effective in the treatment of generalized
tonic-clonic seizures, partial and status
epilepticus

Question 3

Phenytoin (Dilantin)**: Pharmacokinetics/Chemistry

Answer 3

• Oral administration (I.V. for Status Epilepticus)
• Intramuscular injection results in crystallization
and possible muscle necrosis at injection site
• Highly protein bound in plasma (~90%)
• Phenytoin metabolism is rate limited and the
enzyme system involved is saturable within the
therapeutic range of plasma concentrations

Question 4

Phenytoin (Dilantin)**: Side effects

Answer 4

Gingivial Hyperplaysia
Common in children ~20%

Hirsuitism

Note can also occur with:
• Cyclosporine
• Nifedepine, diltazem, verapamil

CNS
• Nystagmus, ataxia, vertigo, diplopia, slurred speech

Other
• Hyperglycemia, osteomalacia, lymphadenopathy,
• Rashes (Stevens-Johnson syndrome (erythema
multiforme bullosum)),
• Hematological reactions (leukopenia, megaloblastic
anemia, thrombocytopenia, agranulocytosis, aplastic
anemia).
These allergic reactions require cessation of therapy

Question 5

Phenytoin (Dilantin)**: Side Effects / Tox

Answer 5

Fetal Abnormalities
• Pregnancy Category D
• cleft lip, cleft palate, and heart malformations
Cardiovascular Collapse
• Only with i.v. phenytoin
– If too large a bolus administerd

Question 6

Phenytoin (Dilantin)**: Drug Interactions

Answer 6

• Metabolism of phenytoin can be enhanced
(Carbamazepine)/decreased via microsomal
enzymes.
• Phenytoin induces CYP3A4
– May reduce levels of Digoxin, steroids, vitamin K.
– Patients should be treated with vitamin K supplements
to prevent hypoprothrombinemia and bleeding.

Question 7

Fosphenytoin (Cerebryx)

Answer 7

• Prodrug of Phenytoin
• Highly water soluble
• Can be administered IM
• Side effect profile improved compared to
parenteral phenytoin

Question 8

Carbamazepine (Tegretol)**: MoA and Uses

Answer 8

Mechanism of Action:
• Unknown, but seems similar to phenytoin (decrease
Na+ conductance)

Uses:
• Generalized tonic-clonic seizures
• Complex partial seizures
• Trigeminal neuralgia
• Ineffective in absence seizures
• Not well tolerated in elderly
• May Make Myoclonic Seizures Worse

Question 9

Carbamazepine (Tegretol)**: Pharmacokinetics/Chemistry

Answer 9

• Almost completely metabolized to the 10,11-
epoxide, which is pharmacologically active
• Autoinduction of metabolism
– CYP 1A2 / 2C / 3A
– Rate of metabolism increases in first 4-6 weeks
• Naïve patient t 1/2 = 30 hr
• After a few weeks t½ = 10-20 hr
• Process stabilizes after about a month

Question 10

Carbamazepine (Tegretol)**: Side Effects

Answer 10

• G.I. upset
• Vertigo, diplopia, blurred vision, ataxia
• Hematological disorders – aplastic anemia (rare),
thrombocytopenia, hyponatremia,
agranulocytosis, leucopenia
• Hepatotoxicity
– Routine liver panels

Question 11

Phenobarbital (Luminol)*: Mechanism of action:

Answer 11

Mechanism of action:
• Enhances the GABA-mediated Cl- flux that causes
membrane hyperpolarization.
• Increases threshold for firing and inhibits spread of
activity from focus

Question 12

Phenobarbital (Luminol)*: Uses:

Answer 12

Uses:
• Generalized tonic-clonic epilepsy
• Partial seizures
• Prophylaxis or treatment of febrile convulsions
• Now typically only used in neonates

Question 13

Phenobarbital (Luminol)*: Side effects

Answer 13

• Sedation – tolerance develops
• Interference with cognitive function
• In children may cause motor hyperactivity,
irritability, decreased attention and mental
slowing
• Concerns about addiction
• Potential for withdrawal seizures
• Rashes in 1-2% - scarlatiniform or morbilliform.
Symptomatic of allergic reaction.
• Ataxia, nystagmus at excessive doses

Question 14

Phenobarbital (Luminol)*: Drug Interactions

Answer 14

• Induces various CYPs
• Additive with other CNS depressants
• Valproic acid increases Phenobarbital blood
levels

Question 15

Primidone (Mysoline): Mechanism of Action

Answer 15

Mechanism of Action
• Blockade of sodium channels and preventing
membrane depolarization
• May potentiate GABA via formation of Phenobarbital

Uses
• Complex partial seizures – more effective than
Phenobarbital
• Generalized tonic-clonic seizures
• Simple Partial seizures
• Frequently combined with phenytoin
• Generally only used in essential tremor now.

Question 16

Primidone (Mysoline): Uses

Answer 16

Uses
• Complex partial seizures – more effective than
Phenobarbital
• Generalized tonic-clonic seizures
• Simple Partial seizures
• Frequently combined with phenytoin
• Generally only used in essential tremor now.

Question 17

Primidone (Mysoline): Pharmacokinetics/Chemistry

Answer 17

• Metabolized in liver to phenobarbital and
phenylethylmalonamide
– Parent and metabolites have anticonvulsant activity

Question 18

Primidone (Mysoline): Side Effects, Drug Interactions:

Answer 18

• Rashes, leukopenia, thrombocytopenia, systemic lupus
erythematosus
• CNS depression
• Ataxia, dizziness, drowsiness, cognitive impairment
• Depression of respiration at excessive doses

Drug Interactions:
• Same as phenobarbital

Question 19

Valproic acid / Divalproex (Depakote)**: Mechanism of Action:

Answer 19

• Interacts with GABAergic neurons-potentiating
inhibitory effects
• Induces blockage of both Na+ and K+ channels.
• Inhibits T-type calcium channels
Effects on GABA + Blockade of Na+ channels gives
a BROAD spectrum of action

Question 20

Valproic acid / Divalproex (Depakote)**: Uses

Answer 20

• Absence seizures refractory to ethosuximide
– Often used as first choice
• Myoclonic seizures
• Reflex epilepsies (especially photosensitive)
• Generalized tonic clonic seizures-used as combination
therapy
• Complex partial seizures-used as combination therapy
• Bipolar disorder

Question 21

Valproic acid / Divalproex (Depakote)**: Pharmacokinetics/Chemistry

Answer 21

• Low molecular weight fatty acid
• Well absorbed from gut and is metabolized to
active metabolites and inactive conjugates before
excretion
• Multiple formulations including oral, extended
release, “sprinkles”

Question 22

Valproic acid / Divalproex (Depakote)**: Side Effects

Answer 22

• Alopecia (5%)
• Transient GI effects (16%); nausea and vomiting
• CNS-mild behavioral effects, ataxia, tremor, not a CNS
depressant
• Hepatic failure (rare); elevated liver enzymes (dose
dependent)
– Patients under 2 years of age are at the greatest risk of liver
failure.
• Possible decrease in platelet and clotting function
– avoid in patients with bleeding disorders

Question 23

Valproic acid / Divalproex (Depakote)**: Drug Interactions

Answer 23

• Increases lamotrigine, phenobarbital and primidone
levels by increasing t1/2 of elimination
– Inhibits P450s
• Displaces Phenytoin from Plasma Proteins
• Decreases Elimination of Phenytoin

Question 24

Valproic acid / Divalproex (Depakote)**: Pregnancy

Answer 24

• Potential for birth defects, not recommended for
women of child bearing age
– Spina bifida
– Atrial septal defect (a hole in the heart)
– Cleft palate
– Hypospadias (an abnormality in the opening of the
urethra in boys)
– Polydactyly (extra fingers or toes)
– Craniosynostosis (one or more sutures on a baby’s
skull close prematurely)