Neuroscience Week 6: Anticonvulsants Flashcards by Jay Sandoval

Objectives

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Classification of seizures

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Classic Anticonvulsant drugs

6 listed

Phenobarbital
Phenytoin
Ethosuximide
Diazepam
Valproic acid
Carbamazepine
*

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Newer Anticonvulsant drugs

8 listed

Lamotrigine
Gabapentin
Topiramate
Tiagabine
Levetiracetam
Oxycarbazepine
Vigabatrin
Fosphenytoin

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Classic Anticonvulsant drugs prototypes

5 listed

Phenytoin
Ethosuximide
Diazepam
Valproic acid
Carbamazepine

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Newer Anticonvulsant drugs prototypes

Lamotrigine
Oxcarbazepine

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The “Treatable Epilepsies”: Simple Partial seizures

~25%

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The “Treatable Epilepsies”:complex partial seizures

40-50%

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The “Treatable Epilepsies”: Tonic clonic seizures

~25%

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The “Treatable Epilepsies”: Absence seizures

<10%

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Simple seizure location

elementary
cortical
focal

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Complex seizures location

Temporal lobe
limbic

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The “Treatable Epilepsies”: overview

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Generalized absence epilepsy: Circuit elements

3 listed

Glutamatergic cortical pyramidal neuron
Glutamatergic ventrobasal thalamo-cortical neuron
GABAergic thalamic reticular neuron

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Generalized absence epilepsy: Circuit

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Identify EEG

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Fill in table

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Ethosuximide: Inhibit T-Type VSCaCs

Yes

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Valproate: Inhibit T-Type VSCaCs

Yes

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Carbamazepine: Inhibit T-Type VSCaCs

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Phenytoin: Inhibit T-Type VSCaCs

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Ethosuximide: Treat Generalized Absence seizures

Yes

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Valproate: Treat Generalized Absence seizures

Yes

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Carbamazepine: Treat Generalized Absence seizures

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Phenytoin: Treat Generalized Absence seizures

Anticonvulsant effects on action potentials vs burst firing

voltage-sensitive Na channels AKA

VSNaCs

Stages of voltage-sensitive Na channels

* Resting * Activated * Inactivated

Fill in table

Ethosuximide: Use-dependent inhibition of VSNaCs

Valproate: Use-dependent inhibition of VSNaCs

Yes

Carbamazepine: Use-dependent inhibition of VSNaCs

Yes

Phenytoin: Use-dependent inhibition of VSNaCs

Yes

Ethosuximide: Treat Simple partial Sz, Complex partial Sz and Generalized Tonic-Clonic

Valproate: Treat Simple partial Sz, Complex partial Sz and Generalized Tonic-Clonic

Yes

Carbamazepine: Treat Simple partial Sz, Complex partial Sz and Generalized Tonic-Clonic

Yes

Phenytoin: Treat Simple partial Sz, Complex partial Sz and Generalized Tonic-Clonic

Yes

Fill in table

Phenytoin: Treat Partial Seizures

Yes ## Footnote **1st line or preferred**

1st line or preferred treatment of partial seizures

Phenytoin

Fosphenytoin: Treat Partial Seizures

Yes

Carbamazepine: Treat Partial Seizures

yes

Oxycarbazepine: Treat Partial Seizures

Yes

Levetiracetam: Treat Partial Seizures

Yes

Topiramate: Treat Partial Seizures

Yes

Phenobarbital: Treat Partial Seizures

Yes

Tigabine: Treat Partial Seizures

Yes

Gabapentin: Treat Partial Seizures

Yes

Valproic acid: Treat Partial Seizures

Yes

Lamotrigine: Treat Partial Seizures

Yes

Ethosuximide: Treat Partial Seizures

Benzodiazepines: Treat Partial Seizures

Diazepam: Treat Partial Seizures

Phenytoin: Treat Generalized Tonic-Clonic Seizures

Yes

Carbamazepine: Treat Generalized Tonic-Clonic Seizures

Yes

Oxycarbazepine: Treat Generalized Tonic-Clonic Seizures

Yes

Levetiracetam: Treat Generalized Tonic-Clonic Seizures

Yes

Topiramate: Treat Generalized Tonic-Clonic Seizures

Yes

Phenobarbital: Treat Generalized Tonic-Clonic Seizures

Yes

Tiagabine: Treat Generalized Tonic-Clonic Seizures

Gabapentin: Treat Generalized Tonic-Clonic Seizures

Valproic acid: Treat Generalized Tonic-Clonic Seizures

Yes

Lamotrigine: Treat Generalized Tonic-Clonic Seizures

Yes

Ethosuximide: Treat Generalized Tonic-Clonic Seizures

Benzodiazepines: Treat Generalized Tonic-Clonic Seizures

Diazepam: Treat Generalized Tonic-Clonic Seizures

Phenytoin: Treat Absence Seizures

Fosphenytoin: Treat Absence Seizures

Carbamazepine: Treat Absence Seizures

Oxcarbazepine: Treat Absence Seizures

Levetiracetam: Treat Absence Seizures

Topiramate: Treat Absence Seizures

Phenobarbital: Treat Absence Seizures

Tiagabine: Treat Absence Seizures

Gabapentin: Treat Absence Seizures

Valproic acid: Treat Absence Seizures

Yes

Lamotrigine: Treat Absence Seizures

Yes

Ethosuximide: Treat Absence Seizures

Yes 1st line or preferred

1st line or preferred treatment of Absence Seizures

Ethosuximide

Benzodiazepines: Treat Absence Seizures

Diazepam: Treat Absence Seizures

Phenytoin: Treat Status Epilepticus

Yes

Fosphenytoin: Treat Status Epilepticus

Yes 1st line or preferred

Carbamazepine: Treat Status Epilepticus

Oxcarbazepine: Treat Status Epilepticus

Levetiracetam: Treat Status Epilepticus

Topiramate: Treat Status Epilepticus

Phenobarbital: Treat Status Epilepticus

Yes

Tiagabine: Treat Status Epilepticus

Gabapentin: Treat Status Epilepticus

Valproic Acid: Treat Status Epilepticus

Lamotrigine: Treat Status Epilepticus

Ethosuximide: Treat Status Epilepticus

Status Epilepticus 1st line or preferred treatment

fosphenytoin

Benzodiazepines: Treat Status Epilepticus

Diazepam: Treat Status Epilepticus

Yes

Phenytoin: blocks VSNaCs

Yes

Forphenytoin: blocks VSNaCs

Yes

Carbamazepine: blocks VSNaCs

Yes

Oxcarbazepine: blocks VSNaCs

Yes

Levetiracetam: blocks VSNaCs

Yes

Topiramate: blocks VSNaCs

Yes

Phenobarbital: blocks VSNaCs

Yes

Tiagabine: blocks VSNaCs

Yes

Gabapentin: blocks VSNaCs

Yes

Valproic acid: blocks VSNaCs

Yes

Lamotrigine: blocks VSNaCs

Yes

Ethosuximide: blocks VSNaCs

Benzodiazepines: blocks VSNaCs

Yes

Diazepam: blocks VSNaCs

Phenytoin: blocks T-type VSCaCss

Fosphenytoin: blocks T-type VSCaCss

Carbamazepine: blocks T-type VSCaCss

Oxcarbazepine: blocks T-type VSCaCss

Levetiracetam: blocks T-type VSCaCss

Topiramate: blocks T-type VSCaCss

Phenobarbital: blocks T-type VSCaCss

Tiagabine: blocks T-type VSCaCss

Gabapentin: blocks T-type VSCaCss

Valproic acid: blocks T-type VSCaCss

Yes

Lamotrigine: blocks T-type VSCaCss

Yes

Ethosuximide: blocks T-type VSCaCss

Yes

Benzodiazepines: blocks T-type VSCaCss

Diazepam: blocks T-type VSCaCss

Phenytoin: Other actions

None

Fosphenytoin: Other actions

None

Carbamazepine: Other actions

Muscarinic antagonist

Oxcarbazepine: Other actions

None

Levetiracetam: Other actions

Modulate Glu & GABA release?

Topiramate: Other actions

↑ GABA action

Phenobarbital: Other actions

↑ GABA-A action (weak)

Tiagabine: Other actions

GABA reuptake inhibitor

Gabapentin: Other actions

↓ "high voltage-gated" Ca²⁺ channels

Valproic acid: Other actions

GABA transaminase inhibitor

Lamotrigine: Other actions

Inhibits glutamate release

Ethosuximide: Other actions

None

Benzodiazepines: Other actions

GABA-A positive allostermeric modulator

Diazepine: Other actions

None

Putative sites of anticonvulsant action 2 listed

* T-type Voltage-sensitive Ca2+ channel inhibition (VSCACs) * "use-dependent" inhibition of voltage sensitive Na+ channels (VSNaCs)

Abosorption of anticonvulsants

Variable absorption among patients

Anticonvulsants plasma binding and exception

High degree of plasma protein binding (75-95%) except Ethosuximide and more variable with newer drugs

Anticonvulsants drug interactions

interfere with metabolism of other drugs

Anticonvulsants metabolism

Induction of self-metabolism & other drug metabolisms (Most notably with phenytoin, carbamazepine and phenobarbital)

Anticonvulsants Non-linear dose

Plasma concentration curves (most notable for phenytoin and phenobarbital)

Consequences of anticonvulsant overdose

* Most serious effect is respiratory depression * Management of overdose is largely by supportive measures to sustain cardiovascular and respiratory function * Rarely fatal, unless another CNS depressant is present (ethanol or benzodiazepines) * Becoming a growing concern with increased use for other indications

Most common side effects of anticonvulsants

* GI distress, nausea and vomiting * sedation, dizziness, ataxia and diplopia * Cognitive slowing / impairments (dose-dependent) * There is a variable degree of expression of side effects in patients * Some tolerance may develop with repeated administration

More serious side effects of anticonvulsants categories 3 listed

* Hematologic * Hepatic * Dermatologic

More serious side effects of anticonvulsants: Hematologic

* aplastic anemia * Thrombocytopenia * Lupus-like syndrome * Agranulocytosis

More serious side effects of anticonvulsants: Hepatic

Hepatic Failure Fulminating necrosis (pediatric & elderly patients)

More serious side effects of anticonvulsants: Dermatologic

* Steven-Johnson Syndrome * Toxic Epidermal Necrolysis

Fill in table

Ethosuximide Side Effects: GI

* Distress * Nausea * Vomiting

Ethosuximide Side Effects: Neurologic

* Headache * Fatigue

Ethosuximide Side Effects: Dermatologic

* Itching * Steven-Johnson syndrome

Valproate Side Effects: GI

* Distress * Nausea * Vomiting

Valproate Side Effects: Neurologic

Tremor

Valproate Side Effects: Metabolic

Weight gain Pancreatitis Hepatotoxicity (rare but serious)

Valproate side effect that is rare but can be serious

Hepatotoxicity

Valproate Side Effects: reproductive

Teratogenic potential

Phenytoin Side Effects: GI

* Distress * Nausea * Vomiting

Phenytoin Side Effects: Neurologic

* Nystagmus * diplopia * ataxia * sedation * peripheral neuropathy

Phenytoin Side Effects: Dermatologic

* Hirsutism * gingival hyperplasia * Steven-Johnson Syndrome

Phenytoin Side Effects: Hematologic

Megaloblastic anemia

Phenytoin Side Effects: Reproductive

Teratogenic potential

Phenytoin Side Effects: Musculoskeletal

* Osteopenia * Lupus-like Syndrome

Carbamazepine Side Effects: GI

* Distress * nausea * vomiting

Carbamazepine Side Effects: Neurologic

* diplopia * ataxia

Carbamazepine Side Effects: Dermatologic

Steven-Johnson Syndrome

Carbamazepine Side Effects: Hematologic

* Agranulocytosis * aplastic anemia

Carbamazepine Side Effects: Reproductive

Teratogenic potential

Carbamazepine Side Effects: Cardiovascular

* Tachycardia * arrhythmias

Teratogenic consequences of anticonvulsants

* Fetal Hydantoin Syndrome (Phenytoin, Phenobarbital and Carbamazepine) * Spina bifida (valproate) * 2 fold increased risk of congenital malformations * 3 fold increased risk of autism with valproate * Risk increases with combinations of anticonvulsants * Consensus is to minimize exposure to anticonvulsants while not allowing maternal seizures to go unchecked

Fetal Hydantoin Syndrome similar phenotype to?

Fetal Alcohol Syndrome (FAS)

Fetal Hydantoin Syndrome phenotype

* Small eyes * smooth philtrum * thin upper lip * Wide flat nasal bridge * smaller head circumference

Spina Bifida Phenotype

Incomplete closure of the neural tube

Anticonvulsants that can lead to Fetal Hydantoin Syndrome

* Phenytoin * Phenobarbital * Carbamazepine

Anticonvulsants that can lead to Spina Bifida

Valproate

Anticonvulsants that can lead to autism

3 fold increased risk with valproate

Therapeutic goals for newer anticonvulsant drugs

Oxcarbazepine similar structure to?

Carbamazepine

Oxcarbazepine Action

VSNaCs

Oxcarbazepine Plasma protein binding

40%

Oxcarbazepine Advantages

↓ Incidence of drug interactions ↓ affinity as muscarinic antagonist

Oxcarbazepine concerns

Other side effects similar to carbamazepine

Oxcarbazepine Clinical uses

Monotherapy for: * Partial seizures * generalized tonic-clonic

Carbamazepine and Oxcarbazepine metabolism

Oxcarbazepine Overview

Lamotrigine Structure

similar to Phenytoin

Lamotrigine action

VSNaCs & VSCaCs (presynaptic)

Lamotrigine plasma protein binding

55%

Lamotrigine advantages

* ↓ cognitive side effects * Less teratogenic potential

Lamotrigine concerns

* Other Phenytoin-like side effects * Dermatologic syndromes * Hepatotoxicity

Lamotrigine Clinical uses

Monotherapy for: * Partial seizures * Generalized Tonic-Clonic seizures * some efficacy for General Absence seizures

Lamotrigine Overview

Levetiracetam Structure

Piracetam analog

Levetiracetam action

VSNaCs & VSCaCs (presynaptic)

Levetiracetam Plasma protein binding

\< 10%

Levetiracetam Concerns

* Somnolence * dizziness * ataxia * irritability * aggression * anxiety

Levetiracetam advantages

minimal drug interactions?

Levetiracetam Clinical uses

Monotherapy or combination therapy for: * Partial seizures * Generalized Tonic-clonic

Principles of Anticonvulsant therapy I

Principles of Anticonvulsant therapy II

Relative degree of successful response to anticonvulsant therapy: Absence seizures

Good

Relative degree of successful response to anticonvulsant therapy: Tonic-clonic

adequate

Relative degree of successful response to anticonvulsant therapy: Simple partial

Adequate

Relative degree of successful response to anticonvulsant therapy: Complex partial

Fair-Poor

Relative degree of successful response to anticonvulsant therapy: Others (newborn, infancy, early childhood)

Poor

Refractory to anticonvulsants Surgical treatments for seizures 2 listed

* surgical resection * Vagus nerve stimulator

Refractory to anticonvulsants Surgical treatments for seizures: Surgical Resection

* Often temporal lobe in origin * Efforts to limit resection area by EEG / MEG & MRI * Postoperative anticonvulsant medication required

Refractory to anticonvulsants Surgical treatments for seizures: Vagus Nerve Stimulator

* Adjunct treatment for focal seizures * Seizure repression mechanism uncertain * Patient activated at onset of seizure * Efficacy appears to increase over time