Lecture 47 - Pharmacology of Anticonvulsant Drugs

Question 1

Mechanism of action of anticonvulsant drugs:

Answer 1

stabilize and reduce neuronal excitability (reduce E/I balance)
1. Decrease sodium influx, prolong inactivation of Na+ channels (following the opening and subsequent closing of the channel)
2. Reduction of calcium influx (this is critical for absence seizures)
3. Enhance GABA-mediated neuronal inhibition
4. Antagonism of excitatory transmitters (i.e., glutamate)
5. Other targets (i.e., Levetiracetam)

Question 2

Decrease sodium influx, prolong inactivation of Na+ channels examples

Answer 2

carbamazepine oxcarbazepine
phenytoin
lacosamide
lamotrigine
valproate

Question 3

Reduction of calcium influx (this is critical for absence seizures)

Answer 3

ethosuximide
lamotrigine
valproate

Question 4

Enhance GABA-mediated neuronal inhibition

Answer 4

barbiturates (activate the GABAA receptor)

benzodiazepines (activate the GABAA receptor)
valproate (increases GABA levels)
gabapentin (increases GABA release)
vigabatrin (inhibits GABA transaminase)
tiagabine (inhibits GAT-1)

Question 5

Antagonism of excitatory transmitters (i.e., glutamate)

Answer 5

felbamate (antagonist of NMDA receptors)
topiramate (antagonist of kainate/AMPA receptors)

Question 6

Why there are few drugs targeting K channels to treat seizures?

Answer 6

because HERG is also targeted –> heart problems

Question 7

Molecular targets at the excitatory (glutamatergic) synapse

Answer 7

Presynaptic targets
§ Na+ channels
§ Ca2+ channels
Post-synaptic targets
§ NMDA receptors
§ AMPA receptors

Question 8

Molecular targets at the inhibitory (GABAergic) synapse

Answer 8

Presynaptic targets
§ GABA transporter (GAT-1)
§ GABA transaminase (GABA-T)
Post-synaptic targets
§ GABAA receptors
§ GABAB receptors (?)

Question 9

Drugs used to treat focal seizures and generalized tonic-clonic seizures

Answer 9

phenytoin, carbamazepine, oxcarbazapine, lacosamide, phenobarbital, primidone, diazepam, clonazepam, gabapentin, pregabalin, vigabatrin, tiagabine, felbamate, topiramate

Question 10

A number of antiseizure drugs have a common

Answer 10

heterocyclic ring structure.
X group:
-N- hydantoin derivatives (phenytoin)
-C-N- barbiturates (phenobarbital)
-C- succinimides (ethosuximide)

Question 11

Hydantoins

Answer 11

phenytoin (Dilantin)
– oldest non-sedative antiseizure drug (introduced in 1938)
– mechanism of action: binds and stabilizes the inactivated state of Na+ channels (not isoform selective thus can target sodium channels in the brain as well as other parts of the body)
– other drugs in this class with a similar mechanism of action:
* fosphenytoin (Cerebyx): injectable phosphate prodrug
* ethotoin (fewer side effects, but less effective than phenytoin)
* mephenytoin (more toxic than phenytoin)

Question 12

Mechanism of sodium channel activation

Answer 12

Phenytoin and other anticonvulsants (e.g., carbamazepine, valproate) act by binding and stabilizing the inactivated state of Na+ channels.

Question 13

Hydantoins: phenytoin (Dilantin): pharmacokinetics

Answer 13

• Phenytoin elimination kinetics are dose-dependent. This leads to non- linear pharmacokinetics.
• As blood levels of phenytoin increase, the liver enzymes responsible for metabolizing the drug become saturated.
• Small increases in the drug dose can lead to dramatic increases in the drug concentration in the blood.
• Therapeutic plasma level: 7.5-20 μg/mL (a higher level can be toxic).

Question 14

Hydantoins: phenytoin (Dilantin): drug interactions

Answer 14

• Phenytoin can be displaced from plasma proteins by other drugs (e.g., Valproate), leading to an increase in its plasma concentration.
• Phenytoin induces liver cytochrome P450 enzymes, thereby increasing the rate of metabolism of other drugs (e.g., carbamazepine).

Question 15

Hydantoins: phenytoin (Dilantin): toxicity

Answer 15

• arrhythmia
• visual: nystagmus (involuntary eye movements), diplopia (blurred vision)
• ataxia
• GI symptoms
• sedation (only at high doses)
• gingival hyperplasia, hirsutism (growth of facial hair)
• hypersensitivity reactions (skin rash)

Question 16

Iminostilbenes

Answer 16

carbamazepine (Tegretol) and oxcarbazepine (Trileptal)

Question 17

Carbamazepine

Answer 17

– structure: tricyclic compound (used to treat bipolar depression)
– 3D structure is very similar to that of phenytoin
– mechanism of action: binds and stabilizes the inactivated state of Na+ channels
– drug interactions: induces liver cytochrome P450 enzymes, thereby increasing the rate of metabolism of itself and other drugs (e.g., phenytoin, ethosuximide, valproate, clonazepam)
– toxicity: blurred vision, ataxia, GI disturbances; sedation at high doses, serious skin rash (Stevens-Johnson Syndrome/toxic epidermal necrolysis); Drug reaction with eosinophilia and systemic symptoms (DRESS) hypersensitivity reaction

Question 18

Oxcarbazepine

Answer 18

– reduced toxicity compared to carbamazepine

Question 19

Lacosamide (Vimpat)

Answer 19

– mechanism of action: enhances inactivation of voltage-gated Na+ channels
– toxicity: dermatological reactions, cardiac risks (PR interval prolongation), visual disturbances

Question 20

Barbiturates and benzodiazepines bind

Answer 20

an allosteric regulatory site on the GABAA receptor.

Question 21

Barbiturates

Answer 21

phenobarbital (Luminal) and primidone (Mysoline)

Question 22

Phenobarbital

Answer 22

drug of choice in infants up to 2 months of age
– structure: 3D structure similar to that of phenytoin
– oldest anti-seizure drug other than the bromides
– mechanisms of action:
* binds to an allosteric regulatory site on the GABAA receptor, increases duration of Cl- channel-opening events (and thus enhances GABA inhibitory signaling).
– drug interactions: induces liver cytochrome P450 enzymes
– toxicity: sedation, physical dependence (potential of abuse)

Question 23

Primidone

Answer 23

– mechanism of action: may be more similar to that of phenytoin than phenobarbital

Question 24

Benzodiazepines

Answer 24

diazepam (Valium) and clonazepam (Klonopin)

Question 25

Diazepam

Answer 25

especially useful for tonic-clonic status epilepticus; often administered as a rectal gel for acute control of seizure activity
– mechanisms of action:
* binds to an allosteric regulatory site on the GABAA receptor, increases frequency of Cl- channel-opening events (and thus enhances GABA inhibitory signaling).
– toxicity: sedation, physical dependence (tolerance); therefore, not useful for chronic treatment.

Question 26

Clonazepam

Answer 26

useful for acute treatment of epilepsy and absence seizures
– similar properties as for diazepam

Question 27

Gabapentin

Answer 27

used as an adjunct anti-seizure therapy (also used for neuropathic pain and migraine)
– structure: analog of GABA
– mechanisms of action:
* increases GABA release
* decreases presynaptic Ca2+ influx, thereby reducing glutamate release
– toxicity: sedation, ataxia, behavioral changes

Question 28

Pregabalin

Answer 28

– similar properties as for gabapentin

Question 29

Vigabatrin

Answer 29

used as an adjunct therapy for refractory patients
– structure: analog of GABA (γ-vinyl-GABA)
– mechanism of action:
* irreversible inhibitor of GABA transaminase (GABA-T), the enzyme responsible for degrading GABA
– toxicity: sedation, weight gain, agitation, psychosis, depression, visual field defects

Question 30

Tiagabine

Answer 30

also used as an adjunct therapy
– mechanism of action: inhibits GABA transporter (GAT-1)
– toxicity: nervousness, depression, tremor, sedation, ataxia

Question 31

Drugs targets at the inhibitory (GABAergic) synapse

Answer 31

Presynaptic targets
§ GABA transporter (GAT-1) (tiagabine)
§ GABA transaminase (GABA-T) (vigabatrin)
Post-synaptic targets
§ GABAA receptors (phenobarbital, benzodiazepines)

Question 32

Molecular targets at the excitatory, glutamatergic synapse

Answer 32

NMDA and AMPA (and kainate) receptors

Question 33

NMDA receptor

Answer 33

glutamate binding triggers an influx of Na+ and Ca2+ and an efflux of K+.

Question 34

AMPA receptor

Answer 34

glutamate binding triggers an influx of Na+ and an efflux of K+. This is also true of a 3rd type of ionotropic glutamate receptor, the kainate receptor.

Question 35

Felbamate

Answer 35

used as a 3rd line drug for refractory cases (especially for focal seizures)
– mechanism of action:
* NMDA receptor antagonist
– toxicity: severe hepatitis (which is why it’s a 3rd line drug)

Question 36

Topiramate

Answer 36

used as a monotherapy or an adjunct therapy
– structure: substituted monosaccharide (unique structure compared
to that of other anticonvulsants)
– mechanism of action:
* AMPA and kainate receptor antagonist
– toxicity: nervousness, confusion, cognitive dysfunction, sedation, vision loss

Question 37

Drugs used to treat absence seizures

Answer 37

ethosuximide

Question 38

Succinimides

Answer 38

ethosuximide (Zarontin)
– introduced in 1960 as a ‘pure petit-mal’ drug
– mechanism of action: blocks T-type Ca2+ channels (low-threshold
current) in thalamic neurons
– T-type Ca2+ channels are thought to be involved in generating the rhythmic discharge of an absence attack. (Remember from Lecture 47 that generalization involves thalamocortical signaling).
– Toxicity: GI distress, sedation, psychiatric disturbances

Question 39

T/F Gabapentin increases Cl- influx in postsynaptic neurons

Answer 39

True

Question 40

Drugs used to treat focal seizures, generalized tonic-clonic seizures, and absence seizures

Answer 40

clonazepam, lamotrigine, valproate, levetiracetam,

Question 41

Lamotrigine (Lamictal)

Answer 41

– uses: primary or adjunct therapy for focal and primary generalized seizures, including absence; also used for bipolar disorder
– structure: phenyltriazine
– mechanisms of action:
* inhibits Na+ and voltage-gated Ca2+ channels
* disrupts synaptic glutamate release
– toxicity: sedation, ataxia, serious skin rash (Stevens-Johnson Syndrome/toxic epidermal necrolysis)

Question 42

Valproate (Depaken)

Answer 42

– uses: focal and generalized seizures, including absence; bipolar disorder, migraine headache
– structure: fatty acid (note: ionized at physiological pH)
– mechanisms of action:
* inhibits Na+ and Ca2+ channels
* increases GABA levels (by stimulating glutamic acid decarboxylase or inhibiting GAT-1 or GABA-T)
– drug interactions:
* displaces phenytoin from plasma proteins
* inhibits the metabolism of phenytoin, carbamazepine, phenobarbital, lamotrigine
– toxicity: GI distress, hyperammonemia, hepatotoxicity (can be fatal – careful monitoring necessary), sedation, weight gain; tremor (at high doses)

Question 43

Levetiracetam (Keppra)

Answer 43

– uses: focal and generalized seizures, myoclonic seizures, status epilepticus
– mechanisms of action:
* binds the synaptic vesicular protein SV2A, and thus interferes with synaptic vesicle release and neurotransmission.
* also appears to interfere with calcium entry through Ca2+ channels and with intraneuronal calcium signaling.
* because of its unique mechanism of action, it is a candidate for treatment of status epilepticus cases that are refractory to other therapies.

Question 44

Brivaracetam (briviact)

Answer 44

analog of levetiracetam that acts via a similar mechanism, but with a higher affinity for SV2A.

Question 45

Drug targets at excitatory (glutamatergic) synapse

Answer 45

Presynaptic targets:
Na+ channels (phenytoin, carbamazepine, lacosamide, lamotrigine, valproate)
Ca2+ channels (ehtosuximide, lamotrigine, levetiracetam, valproate)
Post-synaptic targets:
NMDA receptors (felbamate)
AMPA receptors (topiramate)