Antiepileptic drugs

Question 1

What causes a seizure? What is a seizure?

Answer 1

1) Abnormal, excessive, hyper-synchronous discharge of population of cortical neurons.
2) Massive disruption of electrical communication between neurons in the brain.

This is promoted by:
A) Increased excitatory synaptic neurotransmission
B) Decreased inhibitory synaptic neurotransmission
C) Alterations in voltage-gated ion channels to favor depolarization.

Question 2

What are the goals of antiepileptic drugs?

Answer 2

A) Decreased excitatory synaptic neurotransmission (decreased glutamate)
B) Increased inhibitory synaptic neurotransmission (increased GABA)
C) Alterations in voltage-gated ion channels to favor polarization (alterations in sodium and calcium channels).

Question 3

Voltage-gated sodium channel binders

Answer 3

Carbamazepine, phenytoin, lamotrigine

Question 4

Neuronal voltage-gated calcium channel binders

Answer 4

Ethosuximide

Question 5

GABA agonists

Answer 5

Phenobarbital

Question 6

Drugs with multiple mechanisms

Answer 6

Valproate (sodium and calcium channels, GABA); topiarmate (sodium channels, glutamate, GABA)

Question 7

Drugs with unknown mechanisms

Answer 7

Gabapentin, pregabalin, levetiracetam

Question 8

Side effects of ALL antiepileptic drugs

Answer 8

Dose-related sedation
Cognitive impairment
Dizziness
Potential for long-term bone demineralization
Teratogenicity
Stevens-Johnson syndrome

Question 9

What is Stevens-Johnson syndrome?

Answer 9

Stevens-Johnson syndrome begins with flu-like symptoms, followed by a painful red or purplish rash that spreads and blisters. Then the top layer of the affected skin dies and sheds.

Stevens-Johnson syndrome is a medical emergency that usually requires hospitalization. Treatment focuses on eliminating the underlying cause, controlling symptoms and minimizing complications.

Question 10

Side effects of many antiepileptic drugs (but not all)?

Answer 10

Bone marrow suppression and hepatotoxicity

Question 11

Carbamazepine: MOA

Answer 11

Binds to VG Na channels extending the inactivated phase.

Question 12

Phenytoin: MOA

Answer 12

Binds VG Na channels, prolongs inactivated phase, but also affects resting membrane potential, synaptic transmission, second messenger systems.

Question 13

Lamotrigine: MOA

Answer 13

Not understood. Binds to and inactivates neuronal VG Na channels. May selectively influence neurons that synthesize excitatory nts such as glutamate.

Question 14

Carbamazepine: Indications

Answer 14

Epilepsy, trigeminal neuralgia, mood stabilization in Type I bipolar disorder

Question 15

Carbamazepine: Side effects

Answer 15

Decreased consciousness, N/V, double vision, ataxia.
Leukopenia (anemia and pancytopenia).
Hyponatremia.

Question 16

Neuronal voltage-gated sodium channel binders.

Answer 16

Metabolized

in the liver

Question 17

Which drugs are p450 inducers?

Answer 17

Carbamazepine and phenytoin

Question 18

Which drug does not affect p450 BUT is influenced by p450 inducers/inhibitors?

Answer 18

Lamotrigine

Note: Most important interactions are with estrogens (OCPs and ERT) and with other AEDS because of their affects on p450 system.

Question 19

Phenytoin: Indication

Answer 19

Epilepsy

Question 20

Phenytoin: Side Effects

Answer 20

At toxic levels – decreased
consciousness, N/V, double
vision, ataxia.
PHT infamous for LT bone
demineralization. Specific to PHT –
gingival hyperplasia. IV PHT
associated with significant
hypotension, cardiac arrhythmias,
venous irritation and tissue
necrosis (fosphenytoin used
instead when IV indicated to reduce
these problems).

Question 21

Lamotrigine: Indications

Answer 21

Epilepsy, mood
stabilization in
bipolar disorder.

Question 22

Lamotrigine: Side effects

Answer 22

At toxic levels – dizziness,
somnolence.
LTG is especially famous for terrible
problems with life-threatening
rash, initially occurring in up to 10%.
This risk has been attenuated by
very slow dosage titration. This
slow titration is especially
important when LTG is
administered with VPA, which is a
liver enzyme inhibitor. VPA
increases the plasma concentration
of LTG and thus increases the risk
of life-threatening rash. Unlike many
AEDs, bone marrow suppression
and hepatotoxicity are uncommon.
Specific to LTG – antidepressant
effect.

Question 23

Ethosuximide: MOA

Answer 23

It affects the alpha
subunit of neuronal
voltage-gated calcium
channels heavily
expressed in some
thalamic neuron
populations (T-type
calcium channels).

Question 24

Ethosuximide: Indications

Answer 24

It is the first-line
agent in
absence
epilepsy.

Question 25

Phenobarbital: MOA

Answer 25

``` Phenobarbital binds to the GABA receptor, augmenting the effect of GABA by extending the duration of GABA-mediated chloride channel openings. The net effect is neuronal hyperpolarization. ```

Question 26

Phenobarbital: Indications

Answer 26

``` Epilepsy, tremor (a closely related compound called primidone is still used for treatment of essential tremor) ```

Question 27

Phenobarbital: Side Effects

Answer 27

``` At toxic levels – decreased consciousness, nausea/vomiting, double vision, ataxia. Dose-related sedation and cognitive impairment are especially severe with phenobarbital and greatly limits its use except in status epilepticus, neonatal seizures, and refractory epilepsies. Specific to PBT – hyperactivity, addiction. ```

Question 28

Phenobarbital: Metabolism

Answer 28

Metabolized in liver

Question 29

Phenobarbital: Drug Interactions

Answer 29

p450 inducer

Question 30

Valproate: MOA

Answer 30

``` VPA blocks VG sodium channels (but at a site different from that of phenytoin and carbamazepine), increases brain GABA concentrations by an unknown mechanism, and acts against T-type calcium channels. ```

Question 31

Valproate: Indications

Answer 31

``` Epilepsy, mood stabilization in bipolar disorder, migraine prophylaxis ```

Question 32

Valproate: Side Effects

Answer 32

``` At toxic levels – decreased consciousness, nausea/vomiting, ataxia. Nausea/vomiting especially awful in the uncoated form [brand Depakene], thus usually given in a coated form [brand Depakote]. Teratogenicity (while all AEDs pose some increased risk of fetal malformation, the risk is highest for VPA; specifically associated with neural tube defects, the incidence of which can be reduced by folate supplementation). Bone marrow suppression (thrombocytopenia is most common, anemia and pancytopenia also occur); hepatotoxicity (VPA rarely used in children under 10). Specific to VPA – low-amplitude, highfrequency tremor, weight gain, hair thinning (all common); pancreatitis (infrequent). Rarely can cause hyperammonemia with nml LFTs, leading to lethargy, increased seizures, or death. ```

Question 33

Valproate: Metabolism

Answer 33

Metabolized in liver

Question 34

Valproate: Drug Interactions

Answer 34

p450 inhibitor

Question 35

Topiramate: MOA

Answer 35

``` TPM blocks VG sodium channels, enhances the action of GABA at a nonbenzodiazepine site on GABA-alpha, and antagonizes the NMDA glutamate receptor. ```

Question 36

Topiramate: Indications

Answer 36

Epilepsy, migraine prophylaxis

Question 37

Topiramate: Side Effects

Answer 37

Cognitive impairment is a common complaint with TPM when compared to the other second-generation AEDs. Unlike many AEDs, bone marrow suppression and hepatotoxicity are very uncommon. Specific to TPM – weight loss, increased risk of kidney stones, decreased sweating, paresthesias, mood disturbances, metabolic acidosis (rare).

Question 38

Topiramate: Metabolism

Answer 38

``` 70% excreted unchanged by the kidney, 30% metabolized in the liver ```

Question 39

Gabapentin: MOA

Answer 39

``` Binds to auxiliary alpha-2-delta subunit of a neuronal VG calcium channel, which may inhibit inward Ca currents and stop NT release. ```

Question 40

Gabapentin: Indications

Answer 40

``` Epilepsy, chronic pain, neuropathic pain (not FDA approved for this but is frequently used off-label). ```

Question 41

Gabapentin: Side Effects

Answer 41

At toxic levels – decreased consciousness, ataxia. Unlike many AEDs, not associated with hepatotoxicity or bone marrow suppression. Specific to GBP – peripheral edema and weight gain.

Question 42

Gabapentin: Metabolism

Answer 42

``` 100% excreted unchanged in the urine (requires dose adjustment for kidney dz). ```

Question 43

Gabapentin: Drug Interactions

Answer 43

Must be taken at least two hours after use of antacids (which impair bioavailability)

Question 44

Pregabalin: MOA

Answer 44

``` Binds to auxiliary alpha-2-delta subunit of a neuronal voltagedependent calcium channel. ```

Question 45

Pregabalin: Indications

Answer 45

Epilepsy, neuropathic pain, fibromyalgia.

Question 46

Pregabalin: Side Effects

Answer 46

At toxic levels – decreased consciousness, ataxia. Unlike many AEDs, not associated with hepatotoxicity or bone marrow suppression. Specific to PGB – peripheral edema and weight gain.

Question 47

Which drugs are secreted 100% unchanged in urine?

Answer 47

Gabapentin, pregabalin, levetiracetam (drugs with unknown mechanisms).

Question 48

Pregabalin: Side Effects

Answer 48

``` Must be taken at least two hours after the use of antacids (which impair its bioavailability) ```

Question 49

Levetiracetam: MOA

Answer 49

``` Not well-understood; available data show that it binds to SV2A, a protein in pre-synaptic neurotransmitter vesicles, and likely modulates neuronal calcium channels ```

Question 50

Levetiracetam: Indications

Answer 50

Epilepsy

Question 51

Levetiracetam: Side Effects

Answer 51

Unlike many AEDs, not associated with hepatotoxicity or bone marrow suppression LEV has very few serious side effects. Irritability/other significant psychiatric problems can occur in 10-15% of patients

Question 52

Levetiracetam: Drug Interactions

Answer 52

No significant drug interactions!

Question 53

Levetiracetam is an attractive AED because?

Answer 53

Very few pharmacokinetic interactions with other drugs (like other AEDs or OCPs). Can be used in patients with hepatic failure because it's excreted 100% renally. LEV does not require a titration period, and it appears to have a very rapid onset of action. * The drug is relatively well tolerated and effective (74% of people are still taking it at one year). * An intravenous formulation of LEV has been approved for use in clinical situations when patients are temporarily unable to take oral medication. * An extended-release formulation of LEV is available (once-a-day dosing of AEDs is associated with increased compliance).