Bannon: Anti-seizure Drugs Flashcards
Seizure
Definition:
Definition: finite episodes of brain dysfunction resulting from abnormal discharge of cerebral neurons
Types: (6)
Partial Seizures (Simple) Partial Seizures (Complex) Tonic-Clonic Seizures (Generalized) Absence Seizures (Generalized) Monoclonic Seizures Status Epilepticus
Partial Seizures (Simple)
Consciousness:
Various manifestations: (4)
Consciousness preserved (simple)
Various manifestations:
- Convulsive jerking
- Paresthesias
- Psychic symptoms (altered sensory perceptions, illusions, hallucinations, affect changes)
- Autonomic dysfunction
Partial Seizures (Complex) Consciousness:
Partial Seizures (Complex): o Impaired consciousness (complex) that is preceded, accompanied, or followed by psychologic symptoms
Tonic-Clonic Seizures (Generalized):
Tonic phase involves abrupt LOC, muscle rigidity and respiration arrest (less than 1 minute)
Clonic phase involves jerking of body muscles, with lip or tongue biting, and fecal and urinary incontinence (2-3 minutes)
Formerly called grand mal seizures
Absence Seizures (Generalized):
Impaired consciousness (often sudden onset and brief)
Sometimes accompanied by automatisms, loss of postural tone, or enuresis
Begin in childhood and usually cease by age 20
Formerly known as petit mal seizures
Myoclonic Seizures:
Single or multiple myoclonic jerks
Status Epilepticus:
A series of seizures (usually tonic-clonic) without recovery of consciousness between attacks
Life-threatening emergency
Risk Factors
Children:
Adults:
Elderly:
Children: fever, mental retardation, cerebral palsy, genetics
Adults: trauma, tumors
Alzheimer’s Disease, Stroke
First Generation Drugs
Use:
Effective for the treatment of: (2)
Use: effective for the treatment of generalized tonic-clonic and partial seizures
- Many rate-dependently prolong inactivation of voltage-gated Na channels (similar to lidocaine)
- Others potentiate GABA by several mechanism
Use: effective against generalized (absence) seizures
- Thought to block T-type Ca channel-mediated current in thalamic neurons
Newer Drugs
Newer Phenotypic Models:
Targeting of Defined Biochemical Mechanisms:
Novel AD Targets:
Newer Phenotypic Models: mutant mice, models of kindling or neuropathic pain
Targeting of Defined Biochemical Mechanisms: GABA uptake, metabolism, receptor effects
Novel AD Targets: glutamate receptors (NMDA), K+ channels (open to hyperpolarize) or Ca++ channels
Drugs with Broad Spectrum of Action:
May be due to multiple mechanisms of action and/or novel mechanisms of action
Drugs for Partial and Generalized Tonic-Clonic Seizures
Drugs of Choice: (3)
o Phenytoin (Dilantin)
o Carbamazepine
o Valproic Acid
Phenytoin (Dilantin)
History:
MOA:
History: oldest nonsedative antiseizure drug
MOA: blockade of Na channels is the strongest effect (but not the only effect) at therapeutic concentrations
Phenytoin (Dilantin)
Absorption:
Elimination:
Absorption: highly dependent on the formulation
o Fosphenytoin: soluble prodrug that allows for IM or IV administration
Elimination: via the liver; dose-dependent and need to titrate dose slowly
Phenytoin (Dilantin)
Toxicity/Side Effects: (4)
Nystagmus early
Diplopia and ataxia are dose-limiting effects
Gingival hyperplasia and hirsutism are common long-term
Idiosyncratic reactions are rare
Drugs for Partial and Generalized Tonic-Clonic Seizures
Phenytoin (Dilantin)
Use:
Use: considered a 2nd line drug by some, but still one of the most widely used drugs in the world
Carbamazepine
Structure:
Other Uses (Besides Seizures): (3)
Structure: tricyclic compound related to some antidepressants
Other Uses (Besides Seizures):
- Treatment of BPD
- Treatment of trigeminal neuralgia
- Drug abuse (?)
Carbamazepine
MOA:
MOA: blockade of Na channels is the primary effect
Carbamazepine
Metabolism:
Metabolism: significant microsomal induction and may have to adjust dose of this and other drugs over time (ie. induces its own metabolism)
Carbamazepine
Toxicity/Side Effects: (3)
Side effects may be decreased with:
- Diplopia and ataxia (dose-related)
- Idiosyncratic blood dyscrasia in the elderly
- Stevens-Johnson Syndrom (rare but serious skin reaction)
o Genetic risk determined by presence of a specific HLA allele (testing recommended by FDA)
o 10x higher risk in Asians
Side effects may be decreased with ER formulation
Carbamazepine
Important:
Important: may exacerbate myoclonic and absence seizures (do not use for these)
Valproic Acid
Use in Seizures: (6)
- Partial seizures
- Generalized tonic-clonic
- Myotonic seizures
- Atonic seizures
- Generalized (absence) seizures
- Combination seizures
Valproic Acid Other Uses (Besides Seizures):
Treatment of BPD
Treatment of migraine (Divalproex sodium ER)
Valproic Acid
MOA:
- Blockade of:
- GABA
- Histone deacetylation inhibition
- Ca++ channels
MOA: unclear; broad spectrum of action most likely due to multiple MOA
- Blockade of Na channels possible
- GABA effects may also be relevant
- Histone deacetylation inhibition to INCREASE gene expression (potentiation of Sp transcription factor family –> turns on a bunch of genes)
- May also have effects on Ca++ channels (due to efficacy against absence seizures)
Valproic Acid
Side Effects:
Side Effects: serious effects are rare, but may not be first line due to these rare events
- Severe idiosyncratic hepatotoxicity (requires monitoring of liver function)
Valproic Acid
Formulations:
Divalproex Sodium ER: used once daily
- Complex partial seizures
- Absence seizures
- Migraine
Alternative Drugs for Treatment of Seizures: (5)
Phenobarbital Lamotrigine Levetiracetam Gabapentin and Pregabalin (Lyrica) Topiramate (Topamax)
Phenobarbital
MOA:
Use:
Side Effects:
MOA: potentiate GABA effects
Use: rapid effects, safety profile and low cost can make it a DOC
Side Effects: sedative effects can be limiting
Lamotrigine
MOA:
Use:
Side Effects:
MOA: blockade of Na channels; may have additional MOAs due to broad spectrum of activity
Use: shown to be as effective as the DOCs (may now be considered one)
Side Effects: rare but life-threatening dermatitis possible in infants
Levetiracetam
MOA:
Use:
Side Effects:
MOA: binds SV2A to interfere with release of NT
Use: very good for refractory seizures in adults and children (another possible DOC)
Side Effects: well tolerated
Gabapentin and Pregabalin (Lyrica)
MOA: Other Uses (Besides Seizures): (4)
MOA: binds voltage gated Ca channel subunit (not related to GABA)
Other Uses (Besides Seizures):
- Neuropathic pain
- Migraine
- Anxiety
- Surgical analgesia
Topiramate (Topamax)
MOA:
Use:
Side Effects:
MOA: broad spectrum drug, probably with multiple MOAs
Use: hot drug for off-label use
- Refractory migraine
- BPD
- Many other disorders
Side Effects: typical CNS side effects and memory problems
Drugs for Generalized (Absence) Seizures
Drugs of Choice: (3)
Ethosuximide
Valproic Acid
Clonazepam
Ethosuximide
Use:
MOA:
Use: A first line drug for absence seizures ONLY (no other types)
MOA: blocks T-type Ca++ channel
Ethosuximide
Absorption:
Metabolism:
Toxicity:
Pharmacokinetics:
- Absorption: good
- Metabolism: complete
Toxicity: well tolerated
- Dose-related gastric distress
- More rare instances of rashes and psychosis
Clonazepam
Use: (4)
- Absence seizures (may be less effective that ethosuximide or valproic acid)
- Myoclonic seizures
- Atonic seizures
- Infantile spasms
Clonazepam
Side Effects: (3)
Side Effects: typical benzo side effects that limit use
- Sedation
- Development of tolerance
- Withdrawal syndrome
Treatment of Status Epilepticus
Treatment:
Important Point:
Treatment:
o IV diazepam or lorazepam
o Followed by IV fosphenytoin or phenobarbitol
Important Point: watch for synergistic CNS depression when combining these drugs!
Other Aspects of Antiseizure Drug Therapy
Teratogenicity
Difficult to assess:
Teratogenicity: Difficult to assess due to seizures and heterogeneity of these medications
- Most pregnant patients on these drugs deliver normal infants
- Apparent overall 2X increase in risk of congenital malformations when on the drugs (no increased risk if off the drugs during pregnancy)
- If you choose to keep them an a drug (which is typically done), use the lowest effective dose of monotherapy
Other Aspects of Antiseizure Drug Therapy
Teratogenicity
Specific Known Risks: (2)
Phenytoin: fetal hydantoin syndrome (?)
Valproic Acid: risk of spina bifida (1-2%) and possible effect on IQ
Other Aspects of Antiseizure Drug Therapy
Drug Withdrawal:
Most difficult for people on benzodiazepines and barbiturates
~70% of people with epilepsy enter remission while on medications (>5 years seizure free)
~75% of these patients can be successfully and gradually withdrawn from their medications
Other Aspects of Antiseizure Drug Therapy
Other:
Increased suicide risk (2X)
Decreased bone density (chronic use)
Future of Pharmacotherapy for Seizures:
Large number of candidate drugs being identified through high-throughput screening
Some have novel MOAs and should be useful/improve the treatment of refractory epilepsy
Improved understanding of genetic and cellular basis for epilepsy will lead to more precisely targeted therapeutics and new strategies to delay/prevent epileptogenesis
Ketogenic Diet
History:
Description:
Use:
History:
o Fasting formerly used to treat epilepsy
o Lost favor because of practical difficulties and antiquated medical theories
Use:
o Treatment of refractory seizures in children (ie. Lennox-Gastaut Syndrome)
Ketogenic Diet
Description:
Description:
o Low calorie diet with 4 grams of fat per gram of protein or carbs
o Diet creates ketones by fat metabolism (mimics fasting) and ketones replace glucose as fuel
o Not entirely clear what the MOA of this diet is with regard to seizure treatment
o Strict adherence is required (children need to initially be hospitalized to ensure adherence)
Anterior Temporal Lobectomy
Use:
Results:
Use: very effective for refractory and harmful cases of the most common partial seizure of adults
Results: most patients seizure free for 5 years (enter remission)
Corpus Callostomy
Use:
Lennox-Gastaut Syndrome (difficult to treat childhood onset form of epilepsy characterized by frequent and different types of seizures)
Hemispherectomy
Use: (2)
Use: other severe forms of childhood epilepsy
- Ramussen Syndrome (rare chronic inflammatory neurological disorder)
- Sturge Weber Syndrome (rare congenital neurological and skin disorder)
Vagus Nerve Stimulation (NeuroCybernetic)
Use: (4)
- Refractory complex partial and generalized seizures
- Poor surgical candidates
- Now being tested in children
- Also used in depression, anxiety and other disorders
Vagus Nerve Stimulation (NeuroCybernetic)
Response:
Response: MOA is unclear but clearly effective
- Good response (seizure reduction in 30-75% of patients)
Therapeutic Principles for the Management of Epilepsy
Pre-Therapy:
Pre-Therapy:
- Determine cause of seizures if possible
- For children, wait and see before treating after a single, unprovoked seizure
Therapy
Partial Seizures and Generalized Tonic-Clonic: (3)
Possibly: (3)
Partial Seizures and Generalized Tonic-Clonic: phenytoin, carbamazepine, valproic acid
Possibly: phenobarbital, lamotrigine, levetiracetam
Therapeutic index and toxicity:
Need to ensure:
Therapeutic index and toxicity not uncommon with most antiseizure drugs, so need to ensure adequate trial of a single drug AND monitor plasma levels closely
Cases of Treatment Failure:
Occurs in as many as ½ of patients- first try monotherapy with another first line drug
If total pharmacological failure (20-30% of patients), consider surgery or vagal nerve stimulation
