ANTIEPILEPTICS

Question 1

What is epilepsy?

Answer 1

• Epilepsy is a chronic disorder characterized by
recurrent seizures.
• Seizures are finite episodes of brain dysfunction
resulting from abnormal discharge of cerebral
neurons.
• The pathophysiologic mechanisms underlying
seizure disorders are unknown.
• Seizures are still classified according to their
clinical manifestations rather than their biological
basis.

Question 2

How are seizures classified?

Answer 2

1. PARTIAL SEIZURES
• SIMPLE PARTIAL SEIZURES
• COMPLEX PARTIAL SEIZURES
• PARTIAL WITH SECONDARILY GENERALIZED
TONIC-CLONIC SEIZURES

2. GENERALIZED SEIZURES
   • TONIC-CLONIC SEIZURES
   • ABSENCE SEIZURES

Question 3

Define a simple partial seizure?

Answer 3

• There is no loss of
consciousness.
• Often there is abnormal
activity of a single limb
or muscle group.

Question 4

Define complex partial seizure?

Answer 4

• There is loss of consciousness.
• Motor dysfunction may involve chewing
movements, diarrhea, urination.

Question 5

Define Partial With Secondarily Generalized

Tonic-Clonic Seizure?

Answer 5

• The partial seizure
evolves into a tonic-clonic seizure with loss of
consciousness.

Question 6

Define generalized seizures?

Answer 6

• No evidence of localized
onset.
• They may be convulsive
or nonconvulsive.
• There is immediate loss
of consciousness.

Question 7

Define Absence Seizure (petit mal)

Answer 7

• Brief, abrupt and self-limiting
loss of consciousness.
• The patient stares and
exhibits rapid eye-blinking.
• 3 Hz spike-and-wave
pattern emerges abruptly and ceases after few seconds.

Question 8

Name 6 other generalized seizures?

Answer 8

• ATONIC SEIZURES
• TONIC SEIZURES
• CLONIC SEIZURES
• MYOCLONIC SEIZURES
• FEBRILE SEIZURES
• STATUS EPILEPTICUS

Question 9

Nature and Mechanisms of Seizures, which two neurotransmitters involved?

Answer 9

• A decrease in inhibitory synaptic activity or an increase in excitatory activity might trigger a seizure.
• GABA and glutamate are the main inhibitory and
excitatory neurotransmitters, respectively.

Question 10

Pharmacological evidence for seizures?

Answer 10

• Experimental data shows that:
• Antagonists of the GABAA
receptor trigger
seizures.
• Agonists of glutamate receptors trigger
seizures.
• Drugs that enhance GABAergic transmission
inhibit seizures.
• Glutamate receptor antagonists inhibit seizures.
• Therefore, pharmacological regulation of synaptic function can regulate the propensity
for seizures.

Question 11

Antiepileptic Drugs: MOA

Answer 11

• The principal mechanisms of action of antiseizure
drugs involve:
• Blockade of Voltage-Gated Ion Channels
• Modulation of Synaptic Transmission

Question 12

Drugs that Block Voltage-Gated Ion Channels in which two ways?

Answer 12

1. Drugs that block Voltage-Gated Na+ channels

2. Drugs that block T-type Ca2+ channels

Question 13

Drugs that Block Voltage-Gated Na+ Channels?

Answer 13

• Principal mechanism of action of
• Phenytoin
• Carbamazepine
• Lamotrigine
• Zonisamide
• It may contribute to the effects of
• Phenobarbital
• Valproate
• Topiramate

Question 14

Drugs that Block T-type Ca2+ Channels through which mechanism

Answer 14

• Absence seizures involve oscillatory neuronal
activity between thalamus and cortex.
• The T-type Ca2+ current governs oscillatory
responses in thalamic neurons.
• Ethosuximide and valproate inhibit this
current and are effective in absence seizures.

Question 15

Drugs that Affect Synaptic Transmission in regards to antiepileptics?

Answer 15

1. Drugs that enhance GABAergic
neurotransmission
(• Postsynaptically
• Presynaptically)
2. Drugs that reduce glutamatergic
neurotransmission
(• Postsynaptically
• Presynaptically)

Question 16

Drugs that Enhance GABAergic Neurotransmission Postsynaptically?

Answer 16

• Direct action on the GABA receptor
• Benzodiazepines
• Barbiturates
• Topiramate

Question 17

Drugs that Enhance GABAergic Neurotransmission Presynaptically?

Answer 17

• Inhibition of the reuptake of GABA:
Tiagabine.
• Inhibition of degradation of GABA:
Vigabatrin inhibits GABA
aminotransferase.

Question 18

Drugs that Reduce Glutamatergic Neurotransmission Postsynaptically?

Answer 18

• Phenobarbital & topiramate block glutamate receptors.

Question 19

Drugs that Reduce Glutamatergic

Neurotransmission Presynaptically

Answer 19

• Gabapentin and pregabalin decrease
glutamate release by blocking presynaptic
voltage-gated Ca2+ channels.
• Levetiracetam binds to synaptic vesicle glycoprotein 2A (SV2A). This may affect release of glutamate and GABA.

Question 20

Main drugs used for Partial and Secondarily Generalized Tonic-Clonic Seizures

Answer 20

• The main drugs used are:
• Carbamazepine
• Oxcarbazepine
• Levetiracetam
• Zonisamide
• Phenytoin
• Valproate
• Lamotrigine
• Topiramate
• Phenobarbital

Question 21

Main drugs used for tonic-clonic seizures?

Answer 21

• Main drugs used include:
• Carbamazepine
• Oxcarbazepine
• Valproate
• Lamotrigine
• Phenytoin
• Topiramate

Question 22

Drugs used for Absence Seizures?

Answer 22

• Drugs of choice: ethosuximide and valproate.
• If tonic-clonic seizures are present valproate is
the drug of choice.
• Valproate is also preferred for atypical absence seizures.
• Lamotrigine is probably effective.

Question 23

Drugs used for Myoclonic Seizures?

Answer 23

• Valproate is the drug of choice.
• Topiramate is also used.
• Levetiracetam is approved for adjunctive
therapy.

Question 24

Drugs used for atonic seizures?

Answer 24

• Atonic seizures are often refractory to all drugs.

* Valproate and lamotrigine may be beneficial.

Question 25

Guidelines for seizures as Febrile Convulsions?

Answer 25

• If seizures last < 15 minutes treatment is supportive. • Seizures lasting > 15 minutes require pharmacological treatment to prevent brain damage. • Treatment: diazepam given IV or as a rectal solution.

Question 26

Define status epilepticus?

Answer 26

• Status epilepticus is a single seizure lasting more than 5 minutes or two or more seizures without recovery of consciousness between seizures. • It may be convulsive or nonconvulsive. • The most common type, generalized tonic-clonic status epilepticus, is a life-threatening emergency.

Question 27

Status Epilepticus: Management

Answer 27

Initial therapy phase: IM Midazolam Or IV Lorazepam Or IV Diazepam Second therapy phase: IV Fosphenytoin Or IV Valproic acid Or IV Levetiracetam ``` Third therapy phase: Repeat second therapy or IV thiopental, midazolam, pentobarbital, or propofol ```

Question 28

How are drug induced seizures controlled in non-epileptic patients?

Answer 28

• Drug-induced seizures in nonepileptic patients may be controlled with diazepam, lorazepam or phenobarbital.

Question 29

Which antiepileptics induce cytochrome p450?

Answer 29

``` Induce cytochrome P450: • Carbamazepine • Phenobarbital • Phenytoin • Oxcarbazepine is a weak P450 inducer ```

Question 30

Valproate AE?

Answer 30

``` Valproate • Hepatotoxicity. • Inhibits cytochrome P450. • Inhibits metabolism of several drugs. • Inhibits its own metabolism. ```

Question 31

Phenytoin AE?

Answer 31

``` Phenytoin • Diplopia, ataxia. • Gingival hyperplasia. • Coarsening of facial features in children. • Hirsutism. • Rash. Stevens-Johnson Syndrome. • Zero order kinetics of elimination. ```

Question 32

Carbamazepine AE?

Answer 32

* Aplastic anemia, agranulocytosis. | * Rash. Stevens-Johnson syndrome

Question 33

Which antiepileptics induce Rash & Stevens-Johnson Syndrome High risk: Which has a black box warning?

Answer 33

``` High risk: • Phenytoin • Lamotrigine • Carbamazepine • Phenobarbital ``` Lamotrigine has a black box warning: “Lamotrigine should ordinarily be discontinued at the first sign of rash.”

Question 34

AE of phenobarbital and primidone?

Answer 34

``` Phenobarbital • Sedation, drowsiness. • Rash. Stevens-Johnson syndrome. • Tolerance, dependence. • Cognitive impairment, hyperactivity. • P450 inducer. Primidone • The adverse effects of primidone are similar to those of its metabolite, phenobarbital. ```

Question 35

AE of Vigabatrin?

Answer 35

Vigabatrin | • Visual field loss.

Question 36

AE of Felbamate?

Answer 36

Felbamate • Aplastic anemia • Hepatotoxicity • For refractory epilepsy

Question 37

Guidelines for Discontinuing Antiepileptic Therapy

Answer 37

• If a patient is seizure-free for 3-5 years discontinuation is warranted. • Discontinuation should be slow. • Benzodiazepines and barbiturates should be discontinued very gradually to avoid withdrawal seizures. • If the patient is on combination therapy, drugs should be withdrawn one at a time.

Question 38

Consequence of overdose on antiepileptics?

Answer 38

• Antiepileptic drugs are commonly taken in intentional drug overdoses. • Antiseizure drugs are rarely lethal. • The most dangerous effect after large overdoses is respiratory depression. • Treatment is supportive. • Stimulants should not be used.

Question 39

Are antiepileptics teratogenic, which one specifically?

Answer 39

• There is an increased risk of congenital malformations in infants born of women taking antiseizure drugs. • Valproate causes a significantly higher rate of fetal malformations compared to other antiepileptic drugs. • Prophylactic folic acid decreases incidence of neural tube defects.

Question 40

What is Newborn Hemorrhagic Disease in regards to antiepileptics?

Answer 40

• Enzyme-inducing antiepileptic drugs may increase degradation of vitamin K in the fetus. • This can cause bleeding in the newborn infant. • Vitamin K supplementation is recommended for the mother in the final month of pregnancy and for the newborn.

Question 41

Other Uses of Antiseizure Drugs?

Answer 41

``` • Carbamazepine: Neuropathic pain; bipolar disorder. • Gabapentin: Neuropathic pain. • Lamotrigine: Bipolar Disorder. • Pregabalin: Neuropathic pain. • Topiramate: Migraine. • Valproate: Bipolar disorder; migraine. • Primidone: First line for essential tremor (propranolol is also first line). ```

Question 42

Nonpharmacologic Approaches part 1 to antiepileptics?

Answer 42

• About 1/3 of patients with epilepsy continue to have seizures on medication. Surgery • For most patients whose seizures originate from a local area of abnormal brain, function improves markedly when the epileptic focus is resected.

Question 43

Non-pharmacological approaches to antiepileptic management?

Answer 43

The Ketogenic Diet • Four parts fat to one part protein and carbohydrate. • The high fat content and extremely low carbohydrate content produce ketosis, which appears to have a direct anti seizure effect. • How the ketogenic diet suppresses seizures remains unclear. Vagus Nerve Stimulation • Intermittent electrical stimulation of the left vagus nerve with an implanted pacemaker-like device. • The patient can activate the device when they sense a seizure is imminent.