Antiseizure Drugs

Question 1

Epileptic Seizure classification

Answer 1

Partial seizures, ~ 60% of all seizure types; focal origin
o Reflects cortical region affected (ex: motor cortex → convulsive jerking; somatosensory areas → paresthesia, etc.)
o Simple partial: 20-60 sec, consciousness preserved
o Complex partial: 30-120 sec, impaired consciousness
o Partial with secondary generalized tonic-clonic: 1-2 min, simple or complex partial seizure evolves into a tonic-clonic seizure with loss of consciousness and alternating periods of contractions and relaxations

Generalized seizures, ~ 40% of all seizure types; involve both hemispheres from onset
o Absence: < 30 sec; loss of awareness, staring, unresponsiveness
o Myoclonic: ~ 1 sec single or multiple muscle spasms
o Tonic-clonic: 1-3 min; loss of consciousness, muscle rigidity followed by alternating periods of contraction and relaxation
o Status epilepticus: > 5 min of continuous generalized convulsive activity

Question 2

List the Antiseizure drugs

Answer 2

Diazepam 
Pregabalin 
Valproic Acid
Ethosuximide
Topiramate
Phenobarbital
Lamotrigine 
Lorazepam 
Gabapentin
Phenytoin 
Carbamazepine

Question 3

Strategies to inhibit neuronal activity

Answer 3

Inhibit Na+ channels (prolong inactivation → longer refractory period)
• Ex: phenytoin, carbamazepine, lamotrigine

Inhibit Ca++ channels
• Ex: ethosuximide, valproic acid, gabapentin, pregabalin

Potentiate the inhibitory effect of GABA
• Positive modulators of GABAA receptors
• GABA uptake inhibitors
• GABA-Transaminase inhibitors

Inhibit the excitatory effect of glutamate
• NMDA receptor antagonists
• AMPA/KA receptor antagonists

Question 4

Describe the course of treatment for seizures

Answer 4

o Complete control in ~ 50% of patients and another 25% can be improved significantly
o Drug choice is based on diagnosis of seizure class

Once initiated:
• Treatment is typically continued for at least 2 years
• Tapering and discontinuing therapy should be considered if the patient is seizure-free after 2 years

o The risk of recurrent seizures ranges from 12-66%
o Typically, 80% of recurrences will occur within 4 months of discontinuing therapy
o Effective 2009, all manufacturers of antiseizure drugs (used for any indication) are required include a label warning about an increased risk of suicidal ideation

Question 5

List other conditions for which antiseizure drugs are useful.

Answer 5

Inducing anesthesia

Bipolar affective disorders
o Valproic acid, carbamazepine, lamotrigine

Trigeminal neuralgia
o Carbamazepine

Neuropathic pain (ex: postherpetic neuralgia) 
o	Gabapentin, pregabalin 

Migraine
o Gabapentin, phenytoin, topiramate

Question 6

Drug therapies for partial and tonic-clonic seizures

Answer 6

DOC: valproic acid, carbamazepine, phenytoin
Others: phenobarbital, lamotrigine, topiramate
Adjuncts: gabapentin, pregabalin

Question 7

Drug therapies for absence seizures

Answer 7

DOC: ethosuximide, valproic acid
Alternatives: clonazepam

Question 8

Drug therapies for myoclonic seizures

Answer 8

DOC: valproic acid
Alternates: clonazepam, lamotrigine

Question 9

Drug therapies for status epilepticus

Answer 9

DOC: IV lorazepam, IV diazepam
Alternates: phenobarbital, general anesthetics

Question 10

Name the barbiturates

Answer 10

8 available drugs
o 2 (thiopental and phenobarbital) = more commonly used
o Thiopental used IV for anesthesia induction
o Phenobarbital used for seizures

Question 11

Barbiturates: MOA

Answer 11

o Increase the duration of GABA-induced Cl- channel openings
o High concentrations = directly activate the GABAA receptor
o Also bind to the AMPA receptor = depress the actions of glutamate

Question 12

Barbiturates: Other effects

Answer 12

o No significant CV effects except slight ↓ BP
o Additive CNS depression with alcohol and other sedatives and hypnotics
o Can produce surgical anesthesia
o Depress respiratory drive and rhythm
o Are CYP inducers → tolerance, drug interactions

Question 13

Barbiturates: adverse reactions

Answer 13

o Depress REM sleep
o Avoid sudden DC → can get insomnia, anxiety, seizures
o Residual effects: mood distortions, impaired motor skills, poor judgment
o Paradoxical excitement in children and elderly patients
o Can worsen pain perception
o Allergic skin reactions (rash, purpura, dermatitis) in sensitive patients (Especially those with asthma, urticaria, angioedema)
o Most barbiturates are Pregnancy Risk Category D = Avoid use during pregnancy
o Blood dyscrasias, such as megaloblastic anemia or thrombocytopenia, can occur with barbiturates = Regular blood tests should be undertaken if barbiturates are to be used for long-term therapy

Question 14

Describe the general approach to drug therapy of status epilepticus, and a limitation to the use of lorazepam to treat it.

Answer 14

• Goal = terminate attacks and provide long-term control
• DOC: lorazepam, diazepam, fosphenytoin
• Other choices: phenobarbital (especially in children), general anesthetics (severe, refractory cases)
• Lorazepam = a benzodiazepine
o Can cause addictive CNS depression (tolerance, dependence)