Neuroscience Week 6: Anticonvulsants Flashcards
Objectives
Classification of seizures
Classic Anticonvulsant drugs
6 listed
- Phenobarbital
- Phenytoin
- Ethosuximide
- Diazepam
- Valproic acid
- Carbamazepine
*
Newer Anticonvulsant drugs
8 listed
- Lamotrigine
- Gabapentin
- Topiramate
- Tiagabine
- Levetiracetam
- Oxycarbazepine
- Vigabatrin
- Fosphenytoin
Classic Anticonvulsant drugs prototypes
5 listed
- Phenytoin
- Ethosuximide
- Diazepam
- Valproic acid
- Carbamazepine
Newer Anticonvulsant drugs prototypes
- Lamotrigine
- Oxcarbazepine
The “Treatable Epilepsies”: Simple Partial seizures
~25%
The “Treatable Epilepsies”:complex partial seizures
40-50%
The “Treatable Epilepsies”: Tonic clonic seizures
~25%
The “Treatable Epilepsies”: Absence seizures
<10%
Simple seizure location
- elementary
- cortical
- focal
Complex seizures location
- Temporal lobe
- limbic
The “Treatable Epilepsies”: overview
Generalized absence epilepsy: Circuit elements
3 listed
- Glutamatergic cortical pyramidal neuron
- Glutamatergic ventrobasal thalamo-cortical neuron
- GABAergic thalamic reticular neuron
Generalized absence epilepsy: Circuit
Identify EEG
Fill in table
Ethosuximide: Inhibit T-Type VSCaCs
Yes
Valproate: Inhibit T-Type VSCaCs
Yes
Carbamazepine: Inhibit T-Type VSCaCs
No
Phenytoin: Inhibit T-Type VSCaCs
No
Ethosuximide: Treat Generalized Absence seizures
Yes
Valproate: Treat Generalized Absence seizures
Yes
Carbamazepine: Treat Generalized Absence seizures
No
Phenytoin: Treat Generalized Absence seizures
No
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
No
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
No
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
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
No
Benzodiazepines: Treat Partial Seizures
No
Diazepam: Treat Partial Seizures
No
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
No
Gabapentin: Treat Generalized Tonic-Clonic Seizures
No
Valproic acid: Treat Generalized Tonic-Clonic Seizures
Yes
Lamotrigine: Treat Generalized Tonic-Clonic Seizures
Yes
Ethosuximide: Treat Generalized Tonic-Clonic Seizures
No
Benzodiazepines: Treat Generalized Tonic-Clonic Seizures
No
Diazepam: Treat Generalized Tonic-Clonic Seizures
No
Phenytoin: Treat Absence Seizures
No
Fosphenytoin: Treat Absence Seizures
No
Carbamazepine: Treat Absence Seizures
No
Oxcarbazepine: Treat Absence Seizures
No
Levetiracetam: Treat Absence Seizures
No
Topiramate: Treat Absence Seizures
No
Phenobarbital: Treat Absence Seizures
No
Tiagabine: Treat Absence Seizures
No
Gabapentin: Treat Absence Seizures
No
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
No
Diazepam: Treat Absence Seizures
No
Phenytoin: Treat Status Epilepticus
Yes
Fosphenytoin: Treat Status Epilepticus
Yes
1st line or preferred
Carbamazepine: Treat Status Epilepticus
No
Oxcarbazepine: Treat Status Epilepticus
No
Levetiracetam: Treat Status Epilepticus
No
Topiramate: Treat Status Epilepticus
No
Phenobarbital: Treat Status Epilepticus
Yes
Tiagabine: Treat Status Epilepticus
no
Gabapentin: Treat Status Epilepticus
No
Valproic Acid: Treat Status Epilepticus
No
Lamotrigine: Treat Status Epilepticus
No
Ethosuximide: Treat Status Epilepticus
No
Status Epilepticus 1st line or preferred treatment
fosphenytoin
Benzodiazepines: Treat Status Epilepticus
No
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
No
Benzodiazepines: blocks VSNaCs
Yes
Diazepam: blocks VSNaCs
No
Phenytoin: blocks T-type VSCaCss
No
Fosphenytoin: blocks T-type VSCaCss
No
Carbamazepine: blocks T-type VSCaCss
No
Oxcarbazepine: blocks T-type VSCaCss
No
Levetiracetam: blocks T-type VSCaCss
No
Topiramate: blocks T-type VSCaCss
No
Phenobarbital: blocks T-type VSCaCss
No
Tiagabine: blocks T-type VSCaCss
No
Gabapentin: blocks T-type VSCaCss
No
Valproic acid: blocks T-type VSCaCss
Yes
Lamotrigine: blocks T-type VSCaCss
Yes
Ethosuximide: blocks T-type VSCaCss
Yes
Benzodiazepines: blocks T-type VSCaCss
No
Diazepam: blocks T-type VSCaCss
No
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
Status epilepticus concerns
Neurological emergency!
- Seizures lasting more than 5 minutes
- Neurological damage at ~ 30 minutes
Status epilepticus Treatment
- Diazepam, Lorazepam and Fos-Phenytoin IV (efficacious in 2/3 of patients)
- Inhalation Anesthetics
Other uses of anticonvulsants
4 listed
- Bipolar disorder
- Trigeminal Neuralgia
- Neuropathic pain / Diabetic neuropathy
- Migraine
Anticonvulsants for bipolar disorder
- Carbamazepine
- Valproate
- Lamotrigine
- Oxcarbazepine
Anticonvulsants for Trigeminal Neuralgia
- Carbamazepine
- Oxcarbazepine
Anticonvulsants for Neuropathic pain
- Gabapentin
- Pregabalin
Anticonvulsants for Diabetic Neuropathy
- Gabapentin
- Pregablin
Anticonvulsants for Migraine
- Valproate
- Topiramate
status epilepticus drugs are
3 listed
fosphenytoin, phenobarbital, diazepam
