Anti-Seizure Drugs

Question 1

Drugs for Partial Seizures

Answer 1

• Phenytoin
• Carbamazepine
• Valproate

Question 2

Drugs for Generalized Tonic-Clonic (grand mal) Seizures

Answer 2

• Phenytoin
• Carbamazepine
• Valproate
• Phenobarbital

Question 3

Drugs for Absence (petit mal) Seizures

Answer 3

• Ethosuximide**

- Valproate

Question 4

Drugs for Myoclonic Seizures

Answer 4

• Phenobarbital

- Valproate (especially for Juvenile Myoclonic)

Question 5

Status Epilepticus

Answer 5

• Phenobarbital
• home use and prn use of diazepam
• ambulance use of lorazepam

Question 6

Major mechanisms of anti-seizure drugs

Answer 6

1. Diminution of glutamatergic excitatory transmission
2. Enhancement of GABA-mediated synaptic inhibition, either by a presynaptic or postsynaptic action
3. Modification of ionic conductances
   - inhibition of sustained and repetitive firing of neurons by promoting the inactivated state of voltage-activated sodium channels
   - inhibition of voltage-activated calcium channels

Question 7

Molecular Targets for Anti-seizure Drugs at the Excitatory (glutamatergic) Synapse

Answer 7

1. Voltage-gated Sodium Channels (Phenytoin, Carbamazepine)
2. Voltage-gated Calcium Channels (Ethosuximide)
3. Potassium Channels (Retigabine)
4. SV2A synaptic vesicle proteins (Levetiracetam)
5. CRMP-2, collapsin-response mediator protein-2 (Lacosamide)
6. AMPA Receptors (blocked by Phenobarbital)
7. NMDA Receptors (blocked by Felbamate)

Question 8

Anti-Seizure Drugs Targeting GABA-mediated Synaptic Inhibition

Answer 8

1. GABA transporters inhibits reuptake of GABA (especially Tiagabine)
2. GABA-transaminase inhibitor (Vigabatrin)
3. GABAa receptors (Benzodiazepines)
   - inhibits the postsynaptic cell by increasing the inflow of Cl- ions into the cell
   - hyperpolarization
   - clinically relevant concentrations of both benzodiazepines and barbituates enhance GABAa receptor-mediated inhibition through distinct actions on GABAa receptor
4. GABAb receptors

Question 9

Anti-seizure drug-enhanced Na+ channel inactivaton

Answer 9

1. Selective inhibition of depolarizaiton and fire action potentials at high frequencies would be expected to reduce seizures
2. Thought to be mediated by reducing the ability of Na+ channels to recover from inactivation
3. Prolong the inactivation of the Na+ channels
4. Inactivated channel is blocked by the inactivation gate

Question 10

Inhibiton of voltage-gated Ca++ channels

Answer 10

1. Inhibition of the T-type calcium channels
2. These type of anti-seizure drugs reduce the flow of Ca++ channels thus reducing the pacemaker current that underlies the thalamic rhythm in spikes and waves seen in generalized absence seizures
3. Generalized absence seizures (thalamus and neocortex pacemaker action)

Question 11

Phenytoin

Answer 11

• Oldest non-sedative anti-seizure drug
• Since non-sedative it is more uncomfortable, but is still given today
• Fosphenytoin is a prodrug of “this drug” designed for parenteral use
• Alters Na+, K+, and Ca++ conductance, membrane potentials
• Decreases synaptic release of glutamate and enhances the release of GABA

Question 12

Pharmacokinetics of Phenytoin

Answer 12

• rapid release and extended-release forms (once-daily dosing)
• time to peak = 3-12 hours
• Fosphenytoin well absorbed after IV and IM admin.
• highly-bound to plasma proteins
• metabolized to inactive metabolites in liver and excreted in urine
• at low blood levels, metabolism follows 1st order kinetics
• at therapeutic range and higher, non-linear relationship of dosage and plasma concentration occurs
• half-life = 12-36 hrs
• at low blood levels, 5-7 days to reach steady-state blood levels after every dosage change
• at high blood levels, it takes 4-6 weeks to reach steady-state blood levels after dosage change

Question 13

Therapeutic Levels & Dosage of Phenytoin

Answer 13

• loading dose can be given either orally or IV (Fosphenytoin)
• IV injection of Fosphenytoin preferred method for status epilepticus!!!
• because of dose-dependent kinetics, some toxicity may occur with only small increments in dosage
• ample time should be allowed for the new steady state to be achieved before further increasing the dosage
• only slow-release extended-action formulation can be given in a single daily dosage

Question 14

Drug Interactions & Interference of Phenytoin

Answer 14

• 90% bound to plasma proteins
• increased proportions of free (active) drug are observed in newborn, in patients with hypoalbuminemia, and in uremic patients
• other drugs (e.g. valproate) can compete for protein binding sites and inhibits phenytoin metabolism, resulting in marked and sustained increases in free phenytoin
• phenytoin has been shown to induce microsomal enzymes responsible for the metabolism of a number of drugs (e.g. oral contraceptives)

Question 15

Toxicity of Phenytoin

Answer 15

• general toxicity includes diplopia, ataxia, gingival hyperplasia, hirsutism, neuropathy
• nystagmus occurs early, as does loss of smooth extraocular pursuit movements
• diplopia and ataxia are the most common dose-related adverse effects requiring dosage adjustment
• sedation usually occurs only at considerably higher levels
• gingival hyperplasia and hirsutism occurs to some degree in most patients

Question 16

Toxicity of Phenytoin in long-term use

Answer 16

• in some patients with coarsening of facial features and with mild peripheral neuropathy, usually manifested by diminished deep tendon reflexes in the LEs
• serum folic acid, thyroxine and vit. K concentrations may decrease with long-term therapy
• abnormalities of vit. D metabolism may result in osteomalacia
• low folate levels and megaloblastic anemia have been reported, but the clinical importance of these observations is unknown

Question 17

Carbamazepine

Answer 17

• now considered to be a primary drug for the treatment of partial and tonic-clonic seizures
• used for benign occipital
• related chemically to the TCAs
• limits the repetitive firing of action potentials evoked by a sustained depolarization
• mediated by a slowing of the rate of recovery of voltage-gated Na+ channels from inactivation

Question 18

Pharmacokinetics of Carbamazepine

Answer 18

• complex
• influenced by its limited aqueous solubility and the ability of many anti-seizure drugs, including carbamazepine itself, to increase their conversion to active metabolites by hepatic oxidative enzymes
• absorbed slowly and erratically after PO admin.
• metabolite, 10,11-epoxide, is as active as the parent compound
• induces CYP2C, CYP3A, and UGT, thus enhancing the metabolism of drugs (e.g. oral contraceptives) degraded by these enzymes

Question 19

Drug Interactions of Carbamazepine

Answer 19

• phenobarbital, phenytoin, and valproate may increase the metabolism of carbamazepine by inducing CYP3A4
• carbamazepine may enhance the biotransformation of phenytoin
• concurrent administration of carbamazepine may lower concentrations of other anti-seizure drugs such as valproate

Question 20

Adverse Effects of Carbamazepine

Answer 20

• Drowsiness, blurred vision, diplopia, headache, -dizziness, ataxia, nausea, and vomiting
• cognitive effects can interfere with learning
• mild leukopenia and hyponatremia are fairly common
• with high doses of the drug, thrombocytopenia can occur
• rash, particularly with high starting doses or rapid dose escalation
• FDA recently recommended that Asian patients, who have a ten-fold higher incidence of carbamazepine-induced Stevens-Johnson syndrome (SJS), be tested for susceptibility to SJS before starting the drug

Question 21

Valproic Acid

Answer 21

• main drug used for myoclonic seizures (along with Levetiracetam)
• 1st line for tonic-clonic seizures
• inhibits tonic hind limb extension in maximal electroshock seizures and kindled seizures at non-toxic doses
• effective in absence as well as partial and generalized tonic-clonic seizures in humans
• inhibits sustained repetitive firing induced by depolarization by a prolonged recovery of voltage-activated Na+ channels from inactivation
• in neurons isolated from the nodose ganglion, this drug produces small reductions of T-type Ca++ currents
• drug increases the amount of GABA that can be recovered from the brain after the drug is administered to animal studies
• can stimulate the activity of the GABA synthetic enzyme, glutamic acid decarboxylase, and inhibit GABA degradative enzymes, GABA transaminase and succinic semialdehyde dehydrogenase

Question 22

Pharmacokinetics of Valproic acid

Answer 22

• absorbed rapidly and completely after PO admin.
• peak concentration = 1-4 hrs
• 90% plasma protein binding, but fraction is reduced as the total concentration of valproate is increased through the therapeutic range
• although concentrations of valproate in CSF suggest equilibrium with free drug in the blood, there is evidence for carrier-mediated transport of valproate both into and out of the CSF
• vast majority of valproate (95%) undergoes hepatic metabolism
• hepatic metabolism occurs mainly by UGT enzymes and beta-oxidation
• half-life = ~15 hrs, but is reduced in patients taking other anti-epileptic drugs

Question 23

Drug Interactions of Valproic Acid

Answer 23

• transient GI symptoms, including anorexia, nausea, and vomiting
• effects on CNS include sedation, ataxia, and tremor
• rash, alopecia, and stimulation of appetite have been observed occasionally and WEIGHT GAIN has been seen with chronic valproic acid treatment in some pts
• dose-related tremor, transient hair thinning and loss, decreased platelet fxn, and thrombocytopenia
• several effects on hepatic fxn (elevation of hepatic transaminases in plasma)
• rare complication is fulminant hepatitis that is frequently fatal
• acute pancreatitis and hyperammonemia
• children below 2 y.o. with other medical conditions who were given anti-seizure agents were especially likely to suffer fatal hepatic injury
• valproic acid can also produce teratogenic effects such as neural tube defects!!!

Question 24

Ethosuximide

Answer 24

• main drug specifically used for absence seizures
• has an important effect on Ca++ currents, reducing the low-threshold (T-type) current
• the T-type calcium currents are thought to provide a pacemaker current in thalamic neurons responsible for generating the rhythmic cortical discharge of an absence attack

Question 25

Drug Interactions of Ethosuximide

Answer 25

-valproic acid can decrease ethosuximide clearance and higher steady-state concentrations owing to inhibition of metabolism

Question 26

Toxicity of Ethosuximide

Answer 26

- most common is gastric distress, including pain, N/V - transient lethargy or fatigue - much less commonly headache, dizziness, hiccup, euphoria - urticaria and other skin reactions, including SJS, as well as systemic lupus erythematosus, eosinophilia, leukopenia, thrombocytopenia, pancytopenia, and aplastic anemia also have been attributed to the drug

Question 27

Phenobarbital

Answer 27

- oldest of the currently available anti-seizure drugs, for virtually every seizure type, especially when attacks are difficult to control - many consider the barbituates the drugs of choice for seizures only in infants - relatively low toxicity, and low cost - exact mechanism unknown, but enhancement of inhibitory process and diminution of excitatory transmission probably contribute significantly - at high concentration, drug can suppress high-frequency repetitive firing in neurons through an action on Na+ conductance - also blocks some Ca++ currents - binds to an allosteric regulatory site on GABAa receptor, and it enhances the GABA receptor-mediated current by prolonging the openings of the Cl- channels - can also decrease excitatory responses such as glutamate release

Question 28

Pharmacokinetics of Phenobarbital

Answer 28

- oral absorption is complete but somewhat slow - peak concentrations in plasma = several hours after single dose - 40-60% bound to plasma proteins and bound to a similar extent in tissues, including the brain - up to 25% dose is eliminated by pH-dependent renal excretion of the unchanged drug - inactivated by hepatic microsomal enzymes, principally CYP2C9, with minor metabolism by CYP2C19 and CYP2E1 - induces UGT enzymes as well as the CYP2C and CYP3A subfamilies - drugs metabolized by these enzymes (e.g. oral contraceptives) can be more rapidly degraded when co-administered with phenobarbital

Question 29

Toxicity of Phenobarbital

Answer 29

- sedation, but tolerance develops with chronic use - nystagmus and ataxia occur at excessive dosage - can produce irritability and hyperactivity in children, and agitation and confusion in the elderly - scarlatiniform or morbilliform rash, possibly with other manifestations of drug allergy, occurs in 1-2% of pts - hypoprothrombinemia with hemorrhage has been observed in the newborns of mothers who have received phenobarbital during pregnancy - megaloblastic anemia that responds to folate and osteomalacia that responds to high doses of vitamin D occur during chronic phenobarbital therapy

Question 30

Toxicity of Gabapentin (new antiseizure drug)

Answer 30

- very high dosages are needed to achieve improvement in seizure control - somnolence, dizziness, ataxia, headache, and tremor

Question 31

Toxicity of Felbamate (new antiseizure drug)

Answer 31

-causes aplastic anemia and severe hepatitis (and acute hepatic failure) at unexpectedly high rates and has been relegated to the status of a third-line drug for refractory cases

Question 32

Toxicity of Lamotrigine (new antiseizure drug)

Answer 32

- dizziness, headache, diplopia, nausea, somnolence, and skin rash - can cause toxic epidermal necrolysis and SJS - pediatric pts are at high risk of rash, some studies suggest that a potentially life-threatening dermatitis will develop in 1-2% of pediatric pts

Question 33

Toxicity of Topiramate (new antiseizure drug)

Answer 33

- somnolence, fatigue, dizziness, cognitive slowing, paresthesias, nervousness, and confusion - acute myopia and glaucoma may require prompt drug withdrawal - urolithiasis has also been reported - hypospadias have been reported in male infants exposed in utero (however, no causal relationship could be established)

Question 34

Considerations of Chronic Therapy With Anti-Seizure Drugs

Answer 34

- drug resistance - poor absorption or rapid metabolism, resulting in low blood levels - inhibit drug metabolism - long-term use of phenytoin is associated in some pts with coarsening of facial features and with mild peripheral neuropathy, usually manifested by diminished deep tendon reflexes in the LEs - long-term use of phenytoin may also result in abnormalities of fitamin D metaboism, leading to osteomalacia - long-term treatment of phenytoin may cause teratogenicity

Question 35

Adverse Effects of Long-Term Therapy with Carbamazepine

Answer 35

- diplopia, cognitive dysfunction, drowsiness, ataxia - rare occurance of severe blood dyscrasias and SJS - teratogenic potential

Question 36

Adverse Effects of Long-Term Therapy with Felbamate

Answer 36

- aplastic anemia | - hepatic failure

Question 37

Adverse Effects of Long-Term Therapy with Gabapentin

Answer 37

dizziness, sedation, ataxia, nystagmus

Question 38

Adverse Effects of Long-Term Therapy with Lamotrigine

Answer 38

dizziness, ataxia, nausea, rash, rare SJS

Question 39

Adverse Effects of Long-Term Therapy with Phenytoin

Answer 39

-nystagmus, diplopia, sedation, gingival hyperplasia, hirsutism, anemias, peripheral neuropathy, osteoporosis, induction of hepatic drug metabolism

Question 40

Adverse Effects of Long-Term Therapy with Valproic Acid

Answer 40

drowsiness, nausea, tremor, hair loss, weight gain, hepatotoxicity (infants), inhibition of hepatic drug metabolism

Question 41

BZs Lorazepam and Diazepam

Answer 41

Used for status epilepticus