AntiEpiletic Drugs

Question 1

What is Epilepsy? What are seizures?

Answer 1

Epilepsy: heterogenous symptom complex: a chronic disorder characterized by recurrent seizures
Seizure: finite episodes of brain dysfunction resulting from abnormal discharge of cerebral neurons arising from the cerebral cortex

Question 2

Lets talk about the different types of seizures. First up are the partial seizures, what are the different types of partial seizures?

Answer 2

Simple Partial Seizures
Complex Partial Seizures
Partial with Secondarily Generalized Tonic Clonic Seizures

Question 3

First up, simple partial seizures, what are these?

Answer 3

NO LOC

• -abnormal activity of a single limb or muscle group
• -duration 20-60 seconds

Question 4

Second up, complex partial seizures, what are these?

Answer 4

Complex sensory hallucinations, mental distortion and LOC

• -originate from the temporal lobe
• -duration: 30-120 seconds

Question 5

Third up, partial with secondarily generalized tonic clonic seizures, what are these?

Answer 5

Simple or complex partial seizure evolves into a tonic clonic seizure with LOC
–lasting 1-2 minutes

Question 6

Next are the generalized seizures. What are the different types?

Answer 6

May be convulsive or nonconvulsive 
--patient has immediate LOC
Tonic Clonic Seizures ( grand mal)
Absence Seizures (petit mal) 
Atypical Absence seizures

Question 7

First up are the tonic clonic seizures (grand mal), what are these?

Answer 7

Most commonly encountered

• -LOC, followed by tonic, then clonic phases
• -followed by period of confusion and exhaustion

Question 8

Second up are the absence seizures (petit mal), what are these?

Answer 8

Brief, abrupt and self limiting LOC

• -onset occurs at ages 3-5 y/o and lasts until puberty.
• -patient stares and exhibits rapid eye blinking
• -EEG shows 3 Hz spike and wave pattern that emerges abruptly

Question 9

Third up, are the atypical absence seizures. what are these?

Answer 9

More intense muscle involvement and a longer recovery time

–respond poorly to treatment and are often associated with severe neurologic treatment

Question 10

What are the various other types of generalized seizures ?

Answer 10

Atonic: sudden loss of postural tone
Tonic: muscles contract and consciousness is altered for about 10 seconds
Clonic: very rare. young children
Myoclonic: short episodes of muscle contractions that may reoccur for several minutes
Febrile: high fever in young children
Status Epileptics: repeated seizure or a seizure prolonged for at least 30 minutes. – generalized tonic clonic epilepticus is a life threatening emergency requiring immediate cardiovascular, resp and metabolic management.

Question 11

What is the general mechanism for seizures?

Answer 11

Defective synaptic function might lead to seizure

–a decrease in inhibitory synaptic activity or an increase in excitatory activity

Question 12

What neurotransmitters mediate the bulk of synaptic transmission in brain?

Answer 12

GABA: main inhibitory
Glutamate: main excitatory
–therefore antagonist of the GABAa receptor or agonist of the glutamate receptor subtypes (NMDA or AMPA) trigger seizures
Therefore pharmacological regulation of synaptic function can regulate the propensity for seizures

Question 13

Moving on the drugs and their MOA. What drugs block voltage gated Na channels?

Answer 13

Phenytoin 
Carbamazepine
Oxcarbazepine 
Lamotrigine
Zonisamide 
may also contribute to effects of Phenobarb, valproate and topiramate

Question 14

What drugs block T type Ca2+ channels?

Answer 14

Absence seizure involve neuronal activity between thalamus and cortex
–a low threshold calcium current ( t type Ca2+ current) governs oscillatory responses in thalamic neurons
Reduction of this current by Ethosuximide and Valproate i

Question 15

Now there are drugs that affect synaptic transmission. What drugs enhance GABAergic neurotransmission?

Answer 15

Postsynaptically
–direct action on the GABAa receptor: benzos, barbiturates and topiramate
Presynaptically:
–inhibition of reuptake of GABA: Tiagabine
–Inhibition of degradation of GABA: Vigabatrin is an irreversible inhibitor of GABA aminotransferase, the enzyme responsible for degradation of GABA

Question 16

What drugs reduce glutamatergic neurotransmission?

Answer 16

Postsynaptically:
–Phenobarbital and Topiramate: inhibit excitatory responses induced by glutamate
Presynaptically:
–Gabapentin and Pregablin: decrease glutamate release; this effect is a consequence of blockage of presynpatic voltage gated Ca2+ channels.
–Levetiracetam: binds to synaptic vesicle glycoprotein 2A (SC2A)

Question 17

The aim of therapy is total seizure freedom within clinically significant adverse effects. What are some general principles to consider when starting antiepileptic treatment?

Answer 17

1. Tx should be started with a single drug
2. Dosage should be gradually titrated to that which is maximally tolerated and/or produces optimal seizure control
3. Tx should be monitored regularly
4. Combo therapy should be attempted only if at least two adequate sequential trials of single agents have failed

Question 18

Moving on to choice of drug, this depends on the type of seizure experienced by the patient. First up, partial and secondarily generalized tonic clonic seizures. what drugs are used?

Answer 18

Carbamazepine 
Oxcarbazepine 
Levetiracetam
Zonisamide 
Phenytoin
Valproate 
Lamotrigine 
Topiramate 
Phenobarbital

Question 19

What drugs are used for tonic clonic seizures?

Answer 19

Carbamazepine
Oxcarbazepine
Valproate 
Lamotrigine 
Phenytoin 
Topiramate

Question 20

What drugs are used for Absence Seizures?

Answer 20

DOC: ethosuximide and valproate
-if tonic clonic seizures emerge during therapy valproate is the drug of choice
Valproate is preferred for atypical absence seizures

Question 21

What drugs are used for Myoclonic Seizures?

Answer 21

Valproate: DOC
Topiramate can be used
Levetiracetam: adjunctive therapy

Question 22

What drugs are used for Atonic Seizures?

Answer 22

Refractory to all available meds

–valproate and lamotrigine may be helpful

Question 23

Lets talk alittle about febrile convulsions. What are these?

Answer 23

Seizures associated with an elevated temp greater than 38C in a child younger than 6 years of age
–with no CNS infection or inflammation or metabolic abnormality
Tx is supportive if seizures last less than 15 minutes
More than 15 minutes diazepam IV or rectally

Question 24

Status epilepticus, what is the management?

Answer 24

Most common: generalized tonic clonic

• -life threatening emergency
• -goal of tx is rapid termination of seizure activity
• -drugs given IV
• -give a benzo like Lorazepam IV (much longer duration of antiepileptic action than diazepam)

Question 25

If seizures continue in status epilepticus what is done?

Answer 25

IV phenytoin or fosphenytoin --if benzos and phenytoin fail then IV phenobarb is given but respiratory complication is a common complication And if all this fails the seizure is refractory --general anesthesia should be instituted

Question 26

What are other types of convulsive emergencies?

Answer 26

Drug overdose or poisoning | --controlled via diazepam, lorazepam or phenobarb all given IV

Question 27

What are breakthrough seizures? And how are they managed?

Answer 27

Seizures experienced by epileptic patients who are on antiepileptic therapy --diazepam rectal gel is used

Question 28

Next are side effects. Just listed here are the bolded high yield side effects, however look at the chart in the notes for other side effects.

Answer 28

1. Carbamazepine: aplastic anemia, agranulocytosis 2. Phenytoin: gingival hyperplasia 3. Benzodiazepine: sedation, tolerance, dependence 4. Phenobarb: sedation, ataxia, drowsiness. Tolerance, dependence. Cognitive impairment and Hyperactivity 5. Valproic Acid: Hepatotoxicity 6. Felbamate: Aplastic Anemia, hepatotoxicity. For refractory epilepsy 7. Gabapentin: sedation and drowsiness 8. Lamotrigine: Rash, stevens-johnson syndrome. should be discontinued at the first sign of rash 9. Vigabatrin: Visual field loss

Question 29

Antiepileptic drugs are often associated with skin rashes: which are they?

Answer 29

Phenytoin Lamotrigine (Black box warning about life threatening skin reactions.. should be discontinued if rash noticed) Phenobarb Carbamazepine

Question 30

Finally what is discontinuing antiepileptic therapy?

Answer 30

If a patient is seizure free for 3-5 years, gradual discontinuation of antiepileptic drugs is warranted --should be done slowly

Question 31

Antiepileptic drugs are common agents taken in intentional drug overdoses. What happens?

Answer 31

CNS depressants: but rarely lethal Most dangerous effect is respiratory depression --tx is supportive, stimulants should not be used

Question 32

There is good evidence of an increased risk of congenital malformations in infants born of women taking antiseizure drugs. Most pregnant patients exposed to antiepileptic drugs deliver normal infants. However, fetal exposure to which drugs are teratogenic?

Answer 32

Valproate (spina bifida) Phenobarb (cardiac defects and oral clefts) --congenital malformations with developmental delay Seizure drugs should be monotherapy Phenytoin: fetal hydantoin syndrome Topiramate: risk of oral cleft Lower risk drugs: Lamotrigine, Levetiracetam, and Gabapentin

Question 33

Why is vitamin K supplementation recommended for the mother in the final month of pregnancy and for the newborn?

Answer 33

Phenytoin, Phenobarb, Primidone and Carbamazepine | --cross the placenta and may increase the rate of oxidative degradation of vitamin K in the fetus

Question 34

Finally go through the seizure drugs and list other uses of antiseizure drugs

Answer 34

1. Carbamazepine: trigeminal neuralgia and bipolar disorder 2. Gabapentin: postherpetic neuralgia 3. Lamotrigine: bipolar disorder 4. Pregabalin: diabetic periperal neuropathy, postherpetic neuralgia and fibromyalgia 5. Topiramate: migraine prophylaxis 6. Valproate: bipolar disorder; migraine prophylaxis 7. Primidone: first line for essential tremor