(Ch 20) Antiepileptic Drugs Flashcards
(139 cards)
1
Q
What is a seizure?
A
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.
2
Q
How are Seizures Classified
A
They are classified as partial or generalized seizures on the basis of their clinical characteristics and electroencephalographic pattern.
3
Q
Name
five major causes of seizures
A
- Stroke
- Brain Tumors 3. Fever
- Chronic Alcohol 5. Cerebral trauma
Others:
Hypoxia, hypoglycemia, idiopathic, CNS infections,
4
Q
List 2 Main Categories/Classification of seizures.
A
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)
5
Q
List the different classifications of Partial and Generalized Seizure
A
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
6
Q
Partial (Focal) Seizures
Name 3 Classificatins and Characterization
A
–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
7
Q
Generalized Seizures
- Name all classification of Generalized Seizures*
- 6*
A
–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.*
8
Q
“Jacksonian Epilepsy “ or Jacksonian march
A
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.
9
Q
Status Epilepticus Condition
A
Condition in which Patients experience recurrent episodes of Tonic-Clonic seizures without regaining consciousness or normal muscle movement between episodes.
10
Q
Neurobiology of Seizures:
Describe in detail
A
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.
11
Q
What is a partial (focal) seizure?
There are 2 types of partial seizures:
name them
A
A seizure in which abnormal discharges occur from a focal area within the brain.
There are 2 types of partial seizures:
simple and complex.
12
Q
What are the characteristics of a simple partial seizure?
A
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.
13
Q
What happens in a complex partial seizure?
A
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.
14
Q
Where do complex partial seizures originate ?
A
The majority originate in the temporal lobe
15
Q
What part of the brain is involved in a generalized tonic-clonic (grand mal) seizure?
A
The entire cerebral cortex
16
Q
Name and describe:
3** **typical phases** of a **grand mal seizure.
A
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)
17
Q
Can a partial seizure progress into a grand mal seizure?
A
Yes.
This is known as partial seizure with secondary generalization.
18
Q
What is status epilepticus?
A
Continuous seizures not separated by any periods of regained consciousness. This condition is a medical emergency.
19
Q
What are the characteristics of absence (petit mal) seizures?
A
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.
20
Q
What are the characteristics of febrile seizures?
A
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.
21
Q
What are the characteristics of myoclonic seizures?
A
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.
22
Q
Define epilepsy.
A
Epilepsy is a group of chronic syndromes characterized by recurrent seizures with periods of consciousness.
23
Q
Name Drugs used for :
Partial Seizure and Generalized Tonic-Clonic Seizure
6
A
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
24
Q
Name:
Adjunct Drugs for Partial Seizures
5
adjunct agents are primarily used in combination with older drugs for hte treatment of partial seizure.
A
- Clorazepate*
- Felbamate*
- Gabapentin*
- Lamotrigine*
- Topiramate*
25
Name:
*Drugs for* ***Generalized Absence, Myoclonic, or Atonic Seizures:***
***4***
***1. Clonazepam,*** *Diazepam (Benzodiazepines)*
***2. Ethosuximide*** *(Succinimides)*
***3. Lamotrigine***
***4. Valproic Acid*** *(Valproate)*
26
Name:
## Footnote
*Drugs for **Status Epilepticus***
***4***
***1. Diazepam,** Clonazepam (Benzodiazepines)*
***2. Lorazepam***
***3. Phenobarbital,** mephobarbital, primidone (Barbituates)*
***4. Fosphenytoin***
27
*What other mechanisms can be involved in Seizures?*
1. The supression of inhibitory Neurotransmission of *Gamma (y)-aminobutyric acid (GABA)*
2. Increase in *Ca+ influx* via *T-type calcium channels* in *Thalamic Neurons*.
28
* 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.
29
What happens when the ***Action Potential*** reaches the Nerve Terminal?
It evokes the release of a *Neurotransmitter*
30
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.*
31
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.
1. Carbamazepine
2. Lamotrigine
3. Phenytoin
4. 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..*
32
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***
33
* Drugs that enhance GABA **_activation_***
* of* **(GABA a)** *receptor-chloride ion channel*
**3**
1. Benzodiazepines (Clonazepam)
2. Barbiturates (Phenobarbital)
3. Topiramate
34
Drugs that ***increase*** **GABA release**
Gabapentin
35
Drugs that ***inhibit***
## Footnote
**GABA degeneration**
Vigabatrin
36
Drugs that **BLOCK**
## Footnote
* Votage-Gated Na+ Channels*
* 4*
1. Carbamazepine
2. Lamotrigine
3. Phenytoin
4. Topiramate
37
Drugs that ***INHIBIT*** *Neurotransmittion*-
## Footnote
*terminates Seizures at an early stage of its development*
***3***
***What mechanism?***
* 1. Felbamate*
* 2. Topiramate*
* 3. Valproate*
***Mechanism:***
Blocks Glycine activation of NMDA receptors (effecting Glutamate synthesis )
*(N-methyl-D-aspartate)*
38
What ***2 drugs*** share *similar MOA* and *clinical effectiveness,*
and
*both **_INDUCE_** **Cytochrome P450** enzymes* and ***increase drug metabolism***
* 1. Carbamazepine*
* 2. Phenytoin*
39
Which Drug ***INHIBITS***
*Cytochrome P450* enzymes
1. Valproate
40
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*
41
Drugs that ***INDUCE***
## Footnote
*Cytochrome P450 enzyme*
1. Carbamazepine
2. Phenytoin
3. Topiramate
4. Valproate
5. Lamotrigine
42
Define
## Footnote
***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,***
43
Indications:
## Footnote
*Carbamazepine*
Treats:
* -Partial Seizures*
* -Generalized Tonic-Colonic seizures*
- Drug of choice for ***Tr******igeminal 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.***
44
***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 C*ytochrome P450 enzymes.*
*Dose dependent kinetics*: lowered dose is eliminated by *First-Order process*;
higher concentrations exibit *Zero-Order kinetics*.
45
***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*
46
***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***
47
***Phenytoin***
*What **induces** the Metabolism of Phanytoin and **decreases** its **serum Levels**?*
*Carbamazepine*
48
**Phenytoin**
What **INHIBITs** the Metabolism of Phenytoin and **increases** its serum Levels?
Cimetidine
49
***Carbamazepine***
***cannot** be used to TX what type of Seizures?*
Absence Seizures (it can worsen them)
50
*Name **2nd-line drugs** for **Partial Seizures** and **generalized Tonic-clonic seizures***
1. Phenobarbital
2. Primidone
51
***Primidone***
*what are its **2 active metabolites***
* 1. phenobarbital*
* 2. phenylethylmalonamide (PEMA)*
***note:*** the parents and its active metabolites contribute to its antiepileptic effects
52
***Phenobarbital***
*MOA:*
*MOA:*
enhances the ***GABA-mediated chloride flux*** (prolong the opening of Cl–ion channels) causes ***membrane hyperpolarization.***
*-Well absorbed in the Gut-*
53
***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*
54
* PHENOBARBITAL (LUMINAL)*
* What is the classification of this drug?*
It is a barbiturate.
55
What are **phenobarbital’s**
* 1. It is the drug of choice for treating **febrile seizures;***
* - used to treat **grand mal seizures** in children.*
* 2. **partia lseizures***
56
How is **phenobarbital**
## Footnote
*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.
57
* State **phenobarbital’s***
* (adverse effects)*
1. Sedation
2. Nystagmus
3. Psychotic reactions
4. Hypersensitivity reactions (rash)
5. Stevens-Johnson syndrome
58
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
59
*When is **Primidone** used?*
*Alternative choice for adults who have **partial seizures** (both **simple** and **complex)***
***and** generalized tonic-clonic seizures.*
60
*How is **Primidone** metabolized?*
*is converted to **phenylethyl- malonamide (PEMA)** and to **phenobarbital** in the **liver.***
61
* What are **Primidone** (Mysoline)*
* adverse effects?*
This drug’s toxic effects are very similar to those of **phenobarbital:**
1. Sedation
2. Ataxia
3. Nausea
4. Vomiting
5. Drowsiness
62
***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)***
63
*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
64
**Valproic acid**
is the most effective agent used in the treatment of WHAT
***absence seizures***
65
***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.***
66
***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.
67
***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.
68
*Does valproic acid **block the metabolism** of other drugs?*
Yes.
It can ***increase the plasma levels*** of other drugs such as ***phenobarbital*** or ***phenytoin***.
69
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-***
70
***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.*
71
*Valproate:*
***Interactions***
- inhibits the metabolism of other drugs
- can *_increase the serum levels_* of
***lamotrigine***, ***phenobarbital, and primidone.***
72
which drugs
*decrease the levels* of
***Valproate***
*Serum levels* of *valproate* are DECREASED by
## Footnote
***carbamazepine***
***phenytoin***
***lamotrigine.***
73
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)*
74
What are the most difficult seizures to control with drug therapy?
***Parial Seizures***
***Complex Partial seizures***
75
Define
## Footnote
***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
76
***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
77
***_F_****elbamate*
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)*
78
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.*
79
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)*
80
***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***
81
***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.
82
***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***.
83
***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***
84
***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.***
85
***Lamotrigine***
***Serum levels*** of ***_lamotrigine_*** are *_DECREASED_* by (***carbamazepine*** and ***phenytoin)***
INCREASED by ***valproate***.
Serum levels of valproate are DECREASED by ***lamotrigine***.
86
What are the Side effects of
***lamotrigine***?
1. Dizziness
2. Blurred vision
3. 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)
87
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.*
88
***(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.***
89
***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.***
90
***Topiramate***
*approved for adjunct use in TX of ?*
*Partial Seizures*
91
***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***.
92
***Topiramate***
Which drugs may *induce the metabolism* of *Topiramate* and DECREASE its *serum leve*l ?
***-Carbamazepine***
***-phenytoin***
93
***Topiramate***
***SE:***
***Category?***
* ataxia*
* dizziness*
* drowsiness*
* nystagmus*
* paresthesia*
* psychomotor impairment*
***Category D** (increase incidence if **Cleft palate**)*
94
***Perampanel***
Define:
*recently approved **antiseizure medication** that acts as a antagonist* of
the ***ionotropic AMPA glutamate receptor*** *on Postsynaptic Neurons*
95
***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.*
96
***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*
97
***Vagabartin***
Actions:
***Decrease*** *GABA degradatio*n and drugs with muyltiple mechanisms
98
***Valproate***
***Actions:***
***INCREASE*** **GABA** turnover**,**
**DECREASE** Na+ channels,
***DECREASE*** NMDA receptors
99
***Topiramate***
Actions:
***DECREASE*** Na+ channels
***DECREASE** AMPA / Kainate receptors*
***INCREASE** GABA A receptors*
100
***Felbamate***
ACTIONS:
***DECREASE** Na+ channels*
***INCREASE*** GABA A receptors
***DECREASE*** NMDA receptors
101
***Levetiracetam***
*and*
***Brivaracetam***
drug binds to a **synaptic vesicle protein (SV2A)**, *reducing vesicular packaging of* **GABA** and impeding *neurotransmission across synapses*.
## Footnote
*This leads to a decrease in neuronal burst firing present in seizure disorders.*
102
***Zonisamide***
When would this drug be prescribed?
As an adjustment drug in the therapy of partial seizures and generalized seizures.
103
***Zonisamide***
MOA:
***1.*** acts at ***sodium channels*** and ***voltage-dependent,*** transient inward currents of calcium channels ***(low-threshold, T-type Ca2+ currents)***
## Footnote
***2. blocks Na+ channels in the inactivated state and reduces the ion flow in Ca2+ channel proteins.***
104
***Zoni******sande***
*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.*
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***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*
106
***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***.
107
***Vigabatrin***
MOA:
- an ***irreversible inhibito***r 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.***
108
***Lacosamide***
MOA:
***-selectively enhances inactivation*** *o*f ***voltage-gated sodium channels***,
* resulting in stabilization of hyperexcitable neuronal membranes* and
* inhibition of repetitive neuronal firing*
109
***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.***
110
***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) .
111
Rufinamide
MOA
***modulates the activity of sodium channels***
and
particularly ***prolongs the inactive state of the channel.***
112
***Clobazam***
MOA:
a ***benzodiazepine*** that ***increases the inhibition*** by ***GABA at GABAA receptors***,
as do all the other benzodiazepines.
113
***Clobazam***
* Class:*
* USE:*
***benzodiazepine***
USE: approved solely for the adjunct treatment of seizures in children and adults with LGS.
114
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
115
***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.***
116
***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 )
117
***Ethosuximide***
***AE:***
little toxicity
can cause dizziness
drowsiness
gastric distress
nausea
118
***ethosuximide***
What drug
* inhibits Ethousuximide?*
* Resulting in serum levels?*
***Valproate***
*Increases its serum Levels*
119
***ethosuximide***
*What drug can alter the seizure pattern in patiens treated with Ethousuximide?*
* Haloperidol*
* (high potency antipsychotic drug)*
120
***Ethosuximide***
***Most effective in what type of Seizures?***
***Does it work on Adults?***
1. safe and highly effective in the treatment of ***generalized absence seizures*** in ***children***
2. 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.
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***Clonazepam***
* Name Class:*
* Treats what type of conditions:*
***1. benzodiazepine***
***2.*** treats:
***absence***
***myoclonic***
**atonic seizures**
122
***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*.
123
***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.
124
***Status epilepticus***
Drug
***diazepam*** or ***lorazepam***
125
***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***
126
127
***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***
128
***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*** c*an be used to control the seizures.*
129
***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***
130
***Secod-Line Drugs***
used for
***partial seizures*** and ***generalized tonic-clonic*** seizures
NAME:
* phenobarbital*
* primidone*
131
***First line of Drugs*** for
## Footnote
***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*
132
First line of Drugs for
***generalized absence seizures***
in
***ADULTS***
***Valproate***
133
***Valproate***
* Used to TX:*
* WHOM?*
* What conditions?*
- treating ***adults***
- ***absence seizures*** and ***multiple types of seizures***
- ***generalized myoclonic*** and ***atonic seizures***
134
*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*
135
1. 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.
136
2. 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.
137
3. 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.
138
4. 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.
139
5. 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.
