(Ch 20) Antiepileptic Drugs Flashcards
What is a seizure?
Episodes of abnormal, synchronized electrical depolarization of particula group of neurons in the Cerebral Cortex which cause involuntary movements, sensations, or thoughts.
(Potential involvement of excessve excitatory neurotransmission mediated by glutamate)
- Most seizures are self-limited - last from about 10 seconds to 5 minutes.
- Some seizures are preceded by an aura, which is a sensation or mood that may help identify the anatomic location of the seizure focus.
How are Seizures Classified
They are classified as partial or generalized seizures on the basis of their clinical characteristics and electroencephalographic pattern.
Name
five major causes of seizures
- Stroke
- Brain Tumors 3. Fever
- Chronic Alcohol 5. Cerebral trauma
Others:
Hypoxia, hypoglycemia, idiopathic, CNS infections,
List 2 Main Categories/Classification of seizures.
1. Partial (focal) seizures —(originates in one cerebral hemisphere) (60%)
2. Generalized Seizures —(arises in both cerebral hemishperes and involves loss of consciousness)
Seizures are accompanied by charracteristic chages in the electroencephalogram (EEG)
List the different classifications of Partial and Generalized Seizure
1. Partial (Focal) Seizures:
(Simple Partial Seizure —-Complex Partial Seizure—Secondary generalized seizure)
2. Generalized:
- (Tonic-Clonic (grand-mal) seizure) –Tonic seizure—Colonic seizure—Febrile Myocolonic seizure–Atonic Seizure—Absence (petit mal) seizure)*
3. Status epilepticus
Partial (Focal) Seizures
Name 3 Classificatins and Characterization
–Arise in one cerebral hemisphere–
1. Simple Partial seizure:
No alteration of consciousness
2. Complex Partial seizure:
Altered consciuousness, automatisms (repetitive behaviors), and behavioral changes, originate in Temporal lobe (Tempral lobe Epilepsy or Psychomorot Epilepsy)
3. Secondarily generalized seizure:
Focal seizure becomes generalized and is accompanied by loss of consciousness
Generalized Seizures
- Name all classification of Generalized Seizures*
- 6*
–Arise in both cerebral hemispheres and are accompanied by loss of consciusness–
1. Tonic-Clonic (Grand mal) seizure:
Increased muscle tone followied by spasms of muscle contraction and relaxation
2. Tonic Seizure:
Increased muscle tone
3. Clonic Seizure:
Spasms of muscle contractions and relaxation
4. Myoclonic Seizure:
Thythmic, jerking spasms
5. Atonic Seizure:
Sudden loss of all muscle tone
6. Absence (petit mal) Seizure:
- Brief loss of consciousness with minor muscle twitching and eye blinking.*
- Characterized by abrupt loss of consciousness and decreased muscle tone.*
- -synchronous 3-Hz (3 cycles per second), spike- and-dome pattern that usually lasts 10 -15 sec.*
“Jacksonian Epilepsy “ or Jacksonian march
Some Partial seizures progess along anatomical lines as the electrical discharges spread across the cortex…
Ex: seizure may first involve the fingers, then the hand and finally the entire arm.
Status Epilepticus Condition
Condition in which Patients experience recurrent episodes of Tonic-Clonic seizures without regaining consciousness or normal muscle movement between episodes.
Neurobiology of Seizures:
Describe in detail
Potential involvement of excessive excitatory neruotransmisson mediated by glutamate.
Excessive activation by gluamate of N-methyl-D-aspartate (NMDA) receptora displaces Mg+2 ions from the NMDA receptor-calcium ion channel and thereby faciliates calcium entry into neurons.
Ca+** contributes to the long-term potentiation of excitatory glutamage neruotransmission by activating the syntheis of **Nitric Oxide.
Nitric Oxide** is gas that can diffuce backward to the presynaptic neuron, where it facilitates **glutamate release** via stimulationof a **G Protein** that actiate the syntesis of **Cyclic Guanosine Moniphosphate.
Note: These actions further increase NMDA receptor activation and calcium influx which are believed to contribute to the Depolarization Shift obsereved in seizure foci.
What is a partial (focal) seizure?
There are 2 types of partial seizures:
name them
A seizure in which abnormal discharges occur from a focal area within the brain.
There are 2 types of partial seizures:
simple and complex.
What are the characteristics of a simple partial seizure?
A simple partial seizure involves a focal neurological symptom that can be sensory (for example, auditory or visual hallucinations), motor, or psychomotor. Consciousness is always retained.
What happens in a complex partial seizure?
The initial focus of abnormal discharge spreads, so that the patient experiences loss of consciousness and postictal (postseizure) confusion.
Symptoms can include coordinated motor activity, mental distortion, and sensory hallucinations.
Where do complex partial seizures originate ?
The majority originate in the temporal lobe
What part of the brain is involved in a generalized tonic-clonic (grand mal) seizure?
The entire cerebral cortex
Name and describe:
3** **typical phases** of a **grand mal seizure.
1. Feels a sense of strong déjà vu, lightheadedness and/or dizziness, unusual, altered vision and hearing
2. Tonic phase—Falls unconscious, muscles tense up, extremities are pulled toward or rigidly pushed away from the body, rigidity, loss of bowel and bladder control
3. Clonic phase—Muscles contract and relax, causing convulsions (movements of the entire body)
Can a partial seizure progress into a grand mal seizure?
Yes.
This is known as partial seizure with secondary generalization.
What is status epilepticus?
Continuous seizures not separated by any periods of regained consciousness. This condition is a medical emergency.
What are the characteristics of absence (petit mal) seizures?
They are characterized by a very brief few seconds loss of consciousness.
The child will stop whatever he or she is doing and stare or have some facial twitching.
Following the attack, the child immediately becomes alert and is seldom even aware that it has occurred.
What are the characteristics of febrile seizures?
They occur in children.
They usually last less than 10 min.
The child has a fever, but there is no apparent infection or other defined cause for the seizure.
What are the characteristics of myoclonic seizures?
They are sudden, short episodes of either local or generalized muscle contractions.
They can occur at any age.
They are associated with a variety of rare hereditary neurodegenerative disorders.
Define epilepsy.
Epilepsy is a group of chronic syndromes characterized by recurrent seizures with periods of consciousness.
Name Drugs used for :
Partial Seizure and Generalized Tonic-Clonic Seizure
6
1. Phenytoin, Mephenytoin, Ethotoin (Hydantoins)
Treat tonic-clonic and psychomotor seizures
2. Carbamazepine
Treats tonic-clonic and psychomotor seizures
- Oxcarbazepine
-
Phenobarbital, Mephobarbital, Primidone (Barbituates)
* Treat grand mal and acute episodes or status epilepticus, meningitis, toxic rations, and eclampsia* -
Primidone (Barbituates)
* Treat grand mal and acute episodes or status epilepticus, meningitis, toxic rations, and eclampsia*
6. Valproic acid (Valproate)
Treats absence and tonic-clonic seizures
Name:
Adjunct Drugs for Partial Seizures
5
adjunct agents are primarily used in combination with older drugs for hte treatment of partial seizure.
- Clorazepate*
- Felbamate*
- Gabapentin*
- Lamotrigine*
- Topiramate*
Name:
Drugs for Generalized Absence, Myoclonic, or Atonic Seizures:
4
1. Clonazepam, Diazepam (Benzodiazepines)
2. Ethosuximide (Succinimides)
3. Lamotrigine
4. Valproic Acid (Valproate)
Name:
Drugs for Status Epilepticus
4
1. Diazepam, Clonazepam (Benzodiazepines)
2. Lorazepam
3. Phenobarbital, mephobarbital, primidone (Barbituates)
4. Fosphenytoin
What other mechanisms can be involved in Seizures?
- The supression of inhibitory Neurotransmission of Gamma (y)-aminobutyric acid (GABA)
- Increase in Ca+ influx via T-type calcium channels in Thalamic Neurons.
- Functions of anticonvulsant medication:*
- Name:*
1. Suppresses sodium influx by binding to the sodium channel, prolonging the sodium channel’s inactivation, and preventing neurons from firing
2. Suppresses calcium influx, preventing stimulation of the T-calcium channel (responsible for neuronal depolarization)
3. Increases the action of the GABA, inhibiting the excitatory glutamate neurotransmittion and resulting in suppression seizure activity.
What happens when the Action Potential reaches the Nerve Terminal?
It evokes the release of a Neurotransmitter
Describe the Neuronal Mechanism underlying seizures.
4
1. Seizure is caused by the synchronous discharge of a group of Nurons (Focus) in the Cortex.
2. Activation of N-methyl-D-asparate (NMDA) receptors increases Calcium influx and Nitric Oxide sythesis
3. Nitric Oxide then diffuses to the presynaptic neuron and increases the release of Glutamate via formation of Cyclic Guanisone Monophosphate.
4. Increased excitatory Glutamate neurotransmisson leads to long-term potentiation.
Note: Long-term potentiation is believed to facilitate a deporarization shift, characterized by prolonged depolarizations with spikelets.
The depolarization shifts can cause adjacent neurons to discharge synchronously and thereby precipitate a seizure.
Name the group of AED’s (Antiepileptic drugs) which suppress the formation or spread of abnormal electrical discharges in the brain.
4
Also exibit ____ _____ preventing spread of abnormal discharges in a seizure focus to another neurons.
- Carbamazepine
- Lamotrigine
- Phenytoin
- Topiramate
* Exibit* : use-dependent blockade
AEd’s that prolong time that the Na+ channels inactivaton gate remains closed, this delays the formation of the next action potential..
Name 2 drugs that Block T-type (Low Threshold) Calcium Channels located in the ____ _____ & participate in the initiation of generalized Absence Seizures.
Thalamic Neurons
1. Ethosuximide
2. Valproate
- Drugs that enhance GABA activation*
- of* (GABA a) receptor-chloride ion channel
3
- Benzodiazepines (Clonazepam)
- Barbiturates (Phenobarbital)
- Topiramate
Drugs that increase GABA release
Gabapentin
Drugs that inhibit
GABA degeneration
Vigabatrin
Drugs that BLOCK
- Votage-Gated Na+ Channels*
- 4*
- Carbamazepine
- Lamotrigine
- Phenytoin
- Topiramate
Drugs that INHIBIT Neurotransmittion-
terminates Seizures at an early stage of its development
3
What mechanism?
- Felbamate*
- Topiramate*
- Valproate*
Mechanism:
Blocks Glycine activation of NMDA receptors (effecting Glutamate synthesis )
(N-methyl-D-aspartate)
What 2 drugs share similar MOA and clinical effectiveness,
and
both _INDUCE_ Cytochrome P450 enzymes and increase drug metabolism
- Carbamazepine*
- Phenytoin*
Which Drug INHIBITS
Cytochrome P450 enzymes
- Valproate
Additional MOA of Carbamazepine
SE
Blocks adenosine receptors which leads to up-regulation of these receptors and it blocks Norepinephrine reuptake
(ex: same way that Tricyclic antidepressants block it)
SE: drowsiness, ataxia, depression, GI reactions
less SE than Phenytoin
Drugs that INDUCE
Cytochrome P450 enzyme
- Carbamazepine
- Phenytoin
- Topiramate
- Valproate
- Lamotrigine
Define
Cytochrome P450 enzyme
- enzyme mainly found in the liver and in the intestine.
- It oxidizes small foreign organic molecules (xenobiotics), such as toxinsor drugs, so that they can be removed from the body.
-involved in drug metabolism,
Indications:
Carbamazepine
Treats:
- -Partial Seizures*
- -Generalized Tonic-Colonic seizures*
- Drug of choice for Trigeminal Neuralgia
(condition that can cause Chronic and intense pain on one or both sides of the Face)
-Alternative to Lithium in the TX of Bipolar Disease.
Phenytoin
Pharmacokinetics
New formulatin: Fosphenytoin (parenteral admin) more water soluble-prevents precipitation of the drug after IM or IV admin
Phenytoin is converted to an inactive Hydroxylated metabolite by Cytochrome P450 enzymes.
Dose dependent kinetics: lowered dose is eliminated by First-Order process;
higher concentrations exibit Zero-Order kinetics.
Phenytoin
MOA:
SE:
MOA: Blocks Voltage-sensitive Sodium channels by prolonging the inactivation state of these channels.
Inhibiting the repetitive firing of neurons in a sizure focus.
SE: inteferes with Folate metabolism leading to Megaloblastic anemia
- Birth defects Ex: Fetal hydantoin syndrome (characterized by cardiac defects; malformation of ears; lips; mouth; nasal bridge; mental retardation and microcephaly*
- Additional: impaires cerebellar function, can cause Ataxia, diplopia, nystagmus, slurred speech.*
- Interfears with Vit D metabolism, decreases calcium absorption form the gut (osteomalacia)*
- -Gingival hyperplasia (gums extend over the teeth)*
- -Excessive hair growth (hirsutism)*
- -Stevens-Johnsosn syndrome*
- -Toxic epidermal necrosis*
Phenytoin
Interactions:
Induces the CYP3A4 isozyme and accelerates the metabolism
(CYP3A4 is a member of the cytochrome P450 family of oxidizing enzymes.)
Reduces levels of Digoxin, Steroids, Vitamin K
When using the Drug:** use **Vitamin K** supplements to prevent **Hypoprothrombinemia** and **bleeding
Phenytoin
What induces the Metabolism of Phanytoin and decreases its serum Levels?
Carbamazepine
Phenytoin
What INHIBITs the Metabolism of Phenytoin and increases its serum Levels?
Cimetidine
Carbamazepine
cannot be used to TX what type of Seizures?
Absence Seizures (it can worsen them)
Name 2nd-line drugs for Partial Seizures and generalized Tonic-clonic seizures
- Phenobarbital
- Primidone
Primidone
what are its 2 active metabolites
- phenobarbital*
- phenylethylmalonamide (PEMA)*
note: the parents and its active metabolites contribute to its antiepileptic effects
Phenobarbital
MOA:
MOA:
enhances the GABA-mediated chloride flux (prolong the opening of Cl–ion channels) causes membrane hyperpolarization.
-Well absorbed in the Gut-
Primidone
- MOA:*
- SE:*
MOA:
- Blocks sodium channels* and preventing membrane depolarization. It can also potentiate GABA via formation of phenobarbital.
- -Well absorbed in the Gut-*
- -Shorter 1/2 life (then Phenobarbital) reaching steady-state levels more rapidly*
- SE:*
Ataxia, dizziness, drowsiness and congitive impairment.
Excessive doses: can depress respiration
- PHENOBARBITAL (LUMINAL)*
- What is the classification of this drug?*
It is a barbiturate.
What are phenobarbital’s
- It is the drug of choice for treating febrile seizures;*
- used to treat grand mal seizures in children.*
- partia lseizures*
Perampanel
Define:
recently approved antiseizure medication that acts as a antagonist of
the ionotropic AMPA glutamate receptor on Postsynaptic Neurons
