(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*
How is phenobarbital
absorbed and metabolized?
- The drug is well absorbed orally;
- 75% of it is metabolized in the liver.
- It is a potent inducer of the cytochrome P-450 system.
The metabolic by-products are excreted in the urine.
- State phenobarbital’s*
- (adverse effects)*
- Sedation
- Nystagmus
- Psychotic reactions
- Hypersensitivity reactions (rash)
- Stevens-Johnson syndrome
What drug is primidone
structurally related to?
It is related to phenobarbital and it works the same way as phenobarbital.
-Shorter 1/2 life (then Phenobarbital) reaching steady-state levels more rapidly
When is Primidone used?
Alternative choice for adults who have partial seizures (both simple and complex)
and generalized tonic-clonic seizures.
How is Primidone metabolized?
is converted to phenylethyl- malonamide (PEMA) and to phenobarbital in the liver.
- What are Primidone (Mysoline)*
- adverse effects?*
This drug’s toxic effects are very similar to those of phenobarbital:
- Sedation
- Ataxia
- Nausea
- Vomiting
- Drowsiness
Valproate
- Pharmacokinetics:*
- Several valproate formulations are available*
- Provide EX*
Free acid form (valproic acid)
- -the sodium salt of valproic acid (valproate sodium), and*
- a 1 : 1 mixture of valproic acid and valproate sodium =*
(divalproex sodium)
Divalproex sodium
What is it?
Divalproex sodium is a:
1 : 1 mixture of valproic acid and valproate sodium
- is absorbed more slowly than the other formulations,*
- and*
it usually causes fewer adverse gastrointestinal and CNS side effects
Valproic acid
is the most effective agent used in the treatment of WHAT
absence seizures
Valproate
MOA:
- It prolongs the inactivated state of Na+ channels and inhibits voltage-sensitive T-type calcium channels
- It increase GABA concentrations (synthesis) and decreases GABA degeneration in the brain
- it decrease glutamate synthesis.*
- By these actions, valproate inhibits the repetitive firing of neurons and the spread of epileptic seizures.*
Valproate
What is the route of administration?
Valproic acid is well absorbed orally.
Once absorbed, approximately 90% of the drug is bound to plasma proteins.
Valproate
How is it metabolized?
The drug is extensively metabolized in the liver by the cytochrome P-450 system.
However, it does not induce the enzymes of this system, as do carbamazepine and phenytoin. Approximately 3% of the drug is excreted unchanged.
Does valproic acid block the metabolism of other drugs?
Yes.
It can increase the plasma levels of other drugs such as phenobarbital or phenytoin.
VALPROATE
What side effects should you watch for when administering valproic acid?
Hepatotoxicity
This drug may cause a fulminant hepatitis, which can be fatal. Therefore liver enzymes should be monitored.
GI distress; nausea and vomiting Sedation
Tremor
-Children under 2 years of age are at the greatest risk of liver failure-
Valproate
Birth Defects in offsprings:
-increased incidence of spina bifida
epidemiologic studies showed:
impaired cognitive development in the offspring of women who took valproate during pregnancy
Note:
salicylates can increase the serum levels of valproate.
Valproate:
Interactions
- inhibits the metabolism of other drugs
- can increase the serum levels of
lamotrigine, phenobarbital, and primidone.
which drugs
decrease the levels of
Valproate
Serum levels of valproate are DECREASED by
carbamazepine
phenytoin
lamotrigine.
Valproate
Indications:
- effective in the TX of partial seizures and* all forms of generalized seizures
- -can be given in combination with other drugs when a single drug does not adequately control seizures*
also used as an alternative to lithium to treat the manic phase of bipolar disorder and for the prophylaxis of migraines
(see Chapter 22)
What are the most difficult seizures to control with drug therapy?
Parial Seizures
Complex Partial seizures
Define
Prodrug
Ex:
A prodrug is a medication or compound that, after administration, is metabolized
(i.e., converted within the body) into a pharmacologically active drug.
Ex:
Clorazepate is a prodrug that is converted to an active metobolite of Diazepam in the liver
Clorazepam is a prodrug
that is converted to what in the Liver?
Clorazepate
is a prodrug that is converted to an active metobolite of Diazepam in the liver
Felbamate
Was a promising drug until WHAT CASES were reported ?
Limited to WHAT type of Tx?
f**atal **aplastic anemia
and
acute hepatic failure
Limited:
partial seizures that are refractory to other drugs
(does not respond to or is resistant to)
GABAPENTIN (NEURONTIN)
State the therapeutic use of this drug
used to treat partial seizures with and without secondary generalization.
This drug is used in adults in combination with other antiseizure drugs.
Gabapentin has also been found useful for the
TX of neuropathic pain.
GABAPENTIN (NEURONTIN)
What is the mechanism of action?
is a GABA analog that appears to act by increasing the release of GABA from central neurons.
It has no direct effect on the GABAA receptor–chloride ion channel itself.
Gabapentin also inhibits the L-type Ca+2 channel like pregabalin
(Analog-similar substance-not identical)
Gabapentin
What is the metabolism of this drug?
- It is excreted unchanged in the urine.
- Because the drug has a relatively short half-life, it must be given several times a day.
- Effective when used in combination with other drugs to treat all forms of partial seizures
Gabapentin
AE:
- its adverse effects are minimal at usual therapeutic doses
- can cause ataxia, dizziness, drowsiness, nystagmus, and tremor
- An extended-release form of gabapentin (Gralise) was recently approved for the TX of postherpetic neuralgia;
- an additional prodrug formulation, gabapentin enacarbil (Horizant), was approved for restless legs syndrome.
Lamotrigine
What is the therapeutic role ?
It is used to treat
partial seizures
generalized tonic-clonic seizures
absence seizures
-TX of LGS (Lennox-Gastaut Syndrome) , a syndrome characterized by multiple types of seizures in patients with mental retardation and other neurologic abnormalities
-TX of the manic phase of bipolar disorder.
Lamotrigine
What is its MOA?
Lamotrigine blocks sustained repetitive firing by blocking voltage-dependent Na+ channels thereby interferes with neuronal membrane conduction and the release of excitatory neurotransmitters such as glutamate
Lamotrigine
Name the site of metabolism.
- This drug is metabolized in the liver.
- It is mostly conjugated with glucuronate in the liver and excreted by the kidneys.
Lamotrigine
Serum levels of lamotrigine are DECREASED by (carbamazepine and phenytoin)
INCREASED by valproate.
Serum levels of valproate are DECREASED by lamotrigine.
What are the Side effects of
lamotrigine?
- Dizziness
- Blurred vision
- Asceptic meningitis
- cerebellar dysfunction, drowsiness, rash (can progress to SJS)
- Rarely life-threatening skin disorders such
as (SJS) Stevens-Johnson syndrome
(potentially fatal syndrome, a severe form of erythema multiforme, is characterized by mucocutaneous and systemic lesions-toxic epidermal necrolysis)
What are the toxic effects of
lamotrigine in Children taken concurrently what other Drug?
-much higher incidence of serious dermatologic toxicity in children who are concurrently taking valproate
-lamotrigine should be started at much lower doses in these patients.
(SJS) Stevens-Johnson syndrome
Define:
- -potentially fatal syndrome,*
- -a severe form of erythema multiforme, is characterized by mucocutaneous and systemic lesions-toxic epidermal necrolysis*
The syndrome is more common in patients who are being TX with the combination of lamotrigine and valproate
Note: possibly because valproate INCREASES the serum level of lamotrigine.
Topiramate
MOA
- monosaccharide derivative
1. including blockade of voltage-sensitive sodium channels
2. augmentation of GABA activation of GABAA receptors
3. blockade of 2 types of excitatory glutamate receptors
Ex: kainate receptors and amino- 3-hydroxy-5-methyl-4-isoxazole propionate acid (AMPA) receptors.
Topiramate
approved for adjunct use in TX of ?
Partial Seizures
Topiramate
Name the site of metabolism
Topiramate is adequately absorbed from the gut,
- partly metabolized before excretion in the urine,
- has a half-life of about 21 hours.
Topiramate
Which drugs may induce the metabolism of Topiramate and DECREASE its serum level ?
-Carbamazepine
-phenytoin
Topiramate
SE:
Category?
- ataxia*
- dizziness*
- drowsiness*
- nystagmus*
- paresthesia*
- psychomotor impairment*
Category D (increase incidence if Cleft palate)
Perampanel
Define:
recently approved antiseizure medication that acts as a antagonist of
the ionotropic AMPA glutamate receptor on Postsynaptic Neurons
Tiagabine
Define
binds to recognition sites associated with the GABA reuptake transport protein.
By this action, tiagabine blocks GABA reuptake into presynaptic neurons, permitting greater levels of GABA in the synapse.
Increasing GABA at the neuronal synapse inhibits the generation of the action potential of the neuron, thereby making it less likely to excite nearby neurons.
SV2A
Define:
Synaptic vesicle glycoprotein 2A (SV2A) is a membrane protein specifically expressed in synaptic vesicles and it modulates action potential-dependent neurotransmitter release in the brain
Vagabartin
Actions:
Decrease GABA degradation and drugs with muyltiple mechanisms
Valproate
Actions:
INCREASE GABA turnover,
DECREASE Na+ channels,
DECREASE NMDA receptors
Topiramate
Actions:
DECREASE Na+ channels
DECREASE AMPA / Kainate receptors
INCREASE GABA A receptors
Felbamate
ACTIONS:
DECREASE Na+ channels
INCREASE GABA A receptors
DECREASE NMDA receptors
Levetiracetam
and
Brivaracetam
drug binds to a synaptic vesicle protein (SV2A), reducing vesicular packaging of GABA and impeding neurotransmission across synapses.
This leads to a decrease in neuronal burst firing present in seizure disorders.
Zonisamide
When would this drug be prescribed?
As an adjustment drug in the therapy of partial seizures and generalized seizures.
Zonisamide
MOA:
1. acts at sodium channels and voltage-dependent, transient inward currents of calcium channels (low-threshold, T-type Ca2+ currents)
2. blocks Na+ channels in the inactivated state and reduces the ion flow in Ca2+ channel proteins.
Zonisande
What are its toxic adverse effects?
- somnolence, ataxia, and headache.
- Rarely can cause renal stones.
- recent data suggest an increased risk of metabolic acidosis, especially in younger patients.
- REOMMENDED TO : obtain serum bicarbonate levels before and during treatment, even in the absence of symptoms.
Pregabalin
MOA:
binds to the alpha (α)2-delta site on an auxiliary subunit of voltage-gated calcium channels and REDUCES the calcium current
NOTE: All alpha2delta subunits increase the density at the plasma membrane of Ca(2+) channels activated by high voltage
Additionally: This action may be responsible for its antiseizure effects, as well as analgesic effects
Pregabalin
Additional Indications:
indicated for:
1. neuropathic pain associated with diabetes and postherpetic neuralgia
2.first drug approved specifically for fibromyalgia
3. approved for the treatment of neuropathic pain after spinal cord injury.
Vigabatrin
MOA:
- an irreversible inhibitor of GABA transaminase (GABA-T), the enzyme responsible for the breakdown of GABA in the brain.
- The inhibition of the GABA-T enzyme leads to increased levels of the inhibitory neurotransmitter GABA.
Lacosamide
MOA:
-selectively enhances inactivation of voltage-gated sodium channels,
- resulting in stabilization of hyperexcitable neuronal membranes* and
- inhibition of repetitive neuronal firing*
Ezogabine
MOA:
unique MOA among antiepileptic agents:
- that it acts at potassium channels to increase K+ ion flow.
In this way, ezogabine hyperpolarizes neurons and decreases their firing potential.
It has also been shown to enhance GABA-mediated chloride ion currents.
Rufinamide
USE:
antiepileptic agent approved SOLELY for the adjunct treatment of seizures in children and adults with LGS
(syndrome characterized by multiple types of seizures in patients with mental retardation and other neurologic abnormalities) .
Rufinamide
MOA
modulates the activity of sodium channels
and
particularly prolongs the inactive state of the channel.
Clobazam
MOA:
a benzodiazepine that increases the inhibition by GABA at GABAA receptors,
as do all the other benzodiazepines.
Clobazam
- Class:*
- USE:*
benzodiazepine
USE: approved solely for the adjunct treatment of seizures in children and adults with LGS.
Drugs for Generalized Absence, Myoclonic, or Atonic Seizures;
What Drug is considered to be the most effective and least toxic of the several succinimide derivatives that have been used to treat epilepsy over the past 50 years
Ethosuximide
is the most effective and least toxic of the several succinimide derivatives that have been used to treat epilepsy over the past 50 years
Ethosuximide
Absorbtion / Metabolism:
Half life:
- well absorbed from the gut
- widely distributed to tissues
- metabolized to inactive compounds before it is excreted in the urine
- long half-life of about 30 hours in children and 55 hours in adults.
Ethosuximide
MOA:
-inhibits T-type calcium channels in thalamic neurons.
(These low-threshold channels are believed to be responsible for the pacemaker current that generates the synchronous 3-Hz (three cycles per second) spike-and-dome depolarizations observed on the EEG during absence seizures )
Ethosuximide
AE:
little toxicity
can cause dizziness
drowsiness
gastric distress
nausea
ethosuximide
What drug
- inhibits Ethousuximide?*
- Resulting in serum levels?*
Valproate
Increases its serum Levels
ethosuximide
What drug can alter the seizure pattern in patiens treated with Ethousuximide?
- Haloperidol*
- (high potency antipsychotic drug)*
Ethosuximide
Most effective in what type of Seizures?
Does it work on Adults?
- safe and highly effective in the treatment of generalized absence seizures in children
- Ethosuximide is not very effective, in the treatment of adults with absence seizures or other type of seizures
valproate (discussed earlier) is often used instead.
Clonazepam
- Name Class:*
- Treats what type of conditions:*
1. benzodiazepine
2. treats:
absence
myoclonic
atonic seizures
Status epilepticus
Define:
- life-threatening emergency
- Patients with this condition have recurrent episodes of tonic-clonic seizures without regaining consciousness or normal muscle movement between episodes
-If their seizures are not controlled, prolonged hypoxia can lead to severe brain damage.
Status epilepticus
- Immedicat attention to WHAT:*
- Sezures must be controled within what time period:*
- Immediate attention must be given to cardiopulmonary support
- seizures must be controlled within 60 minutes of the onset of an episode in order for a favorable prognosis to be achieved.
Status epilepticus
Drug
diazepam or lorazepam
diazepam
or
lorazepam
- What condition are these drugs used for?*
- How are they administered?*
(Chp 19-20)
Either drug
-**administered as a **slow intravenous injection** given **every 10 to 15 minutes until seizures are controlled** or a **maximal dose has been administered
diazepam or lorazepam
- What is often administerd following the injections of either drug mentioned above?*
- and what condition?*
Condition:
Status Epilepticus
phenytoin (or the newer form, fosphenytoin) is often administered intravenously to provide a longer duration of seizure control
than is provided by a benzodiazepine
Status Epilepticus
What 2 options
may be effective if a benzodiazepine or phenytoin fails to control the seizures
1. Large doses of Phenobarbital
or
2. general anesthesia can be used to control the seizures.
First-Line Drugs
- used for
- partial seizures** and generalized tonic-clonic seizures
NAME:
1. carbamazepine (fewer AE then #2)
2. phenytoin (slightly less sedating than #1 at equally effective doses)
3. valproate
Secod-Line Drugs
used for
partial seizures and generalized tonic-clonic seizures
NAME:
- phenobarbital*
- primidone*
First line of Drugs for
generalized absence seizures
in
CHILDREN
ethosuximide
first choice in treating children with this condition, which usually has its onset during childhood and often remits during adolescence
First line of Drugs for
generalized absence seizures
in
ADULTS
Valproate
Valproate
- Used to TX:*
- WHOM?*
- What conditions?*
- treating adults
- absence seizures and multiple types of seizures
- generalized myoclonic and atonic seizures
Principales of Drug use:
attempt should be made to control seizures with WHAT TYPE OF THERAPY?
Provide reason:
- control seizures with single-drug therapy (monotherapy),
- REASON:
- minimize side effects*
- reduce cost*
- increase patient compliance*
- The molecular mechanism underlying the antiepileptic effects of carbamazepine and phenytoin is best described by which one of the following statements?
(A) inhibiting low-threshold Ca2+ ion channels
(B) prolonging the inactivation of the Na+ ion channel
(C) potentiating the release of GABA by inhibiting
GABA reuptake
(D) increasing the release of GABA by vesicular fusion
(E) blocking glutamate receptor excitation
prolonging the inactivation of the Na+ ion channel. Both these agents bind to the Na+ channel protein and prolong the state of inactivation. This leads to a decrease of repetitively firing neurons. Answer A, inhibiting low-threshold Ca2+ ion channels, is the mecha- nism of action of ethosuximide and valproic acid, par- ticularly useful in controlling absence seizures. Answer C, potentiating the release of GABA by inhibiting GABA reuptake, is the mechanism of action of tiagabine. Answer D, increasing the release of GABA by vesicular fusion, is the action of gabapentin, although the precise mecha- nisms are unknown. Answer E, blocking glutamate receptor excitation, is part of the mechanism of action of topiramate.
- Which antiepileptic agent gained wider therapeutic use also to treat trigeminal neuralgia and the manic phase of bipolar disorder?
(A) ethosuximide
(B) zonisamide
(C) levetiracetam
(D) carbamazepine
(E) phenytoin
carbamazepine. This agent has also gained approval for the use as an antimanic agent or mood stabilizer, for treatment of bipolar disorder and for trigeminal neuralgia. Answer A, ethosuximide, is the drug of choice for treating absence seizures in children. Answers B, zonisamide, and C, levetiracetam, are approved only for adjunct treatment of partial seizures. Answer E, phenytoin, has gained some acclaim as a mood stabilizer but has not been mentioned for use in trigeminal neuralgia.
- Which one of the following agents is considered the drug of choice for initial treatment of generalized absence seizure (petit mal) in children?
(A) ethosuximide
(B) zonisamide
(C) levetiracetam
(D) carbamazepine
(E) phenytoin
ethosuximide. Ethosuximide acts by inhibiting the low-threshold Ca2+ channels thought to be active during absence seizures. Answers B, zonisamide, and C, levetiracetam, are newer agents for the treatment of partial seizures. Answers D, carbamazepine, and E, phenytoin, are classic drugs used to treat partial seizures and generalized tonic-clonic seizures.
- Topiramate has which set of three mechanisms of action?
(A) increases Na+ channel inactivation, increases GABA, blocks glutamate
(B) decreases Na+ channel inactivation, decreases GABA, blocks glutamate
(C) increases Ca2+ channel inactivation, increases GABA, blocks glutamate
(D) decreases Ca2+ channel inactivation, increases GABA, blocks glutamate
(E) decreases Ca2+ channel flow, increases GABA, blocks glutamate
A: increases Na+ channel inactivation, increases GABA, blocks glutamate. Topiramate is a newer agent with three known mechanisms of action. The other answers, B through E, contain at least one mechanism of action that would produce greater excitation of neurons or is not a mechanism of topiramate.
- Gabapentin has which mechanism of action?
(A) inhibits monoamine oxidase
(B) has an agonist effect at dopamine receptors
(C) increases Na+ channel inactivation
(D) blocks reuptake of neurotransmitters
(E) increases release of neurotransmitters
E: increases release of neurotransmitters. Gabapentin is an analogue of GABA and is known to cause greater release of GABA from neurons, but the precise mechanism is unknown. Answer A, inhibits monoamine oxidase, is an action of certain types of antidepressant drugs. Answer B, agonist effect at dopamine receptors, is an action of some antiparkinsonism agents. Answer C, increases Na+ channel inactivation, and answer D, blocks reuptake of neurotransmitters, describe the action of the newer antiepileptic agent tiagabine.
