Phenytoin (Dilantin) PK

Non-linear - With change in dose, t1/2 changes - Induces metabolic enzymes, different time to steady state based on dose t 1/2 15-20 hrs

ASDs Flashcards by Brent Sokola

List the voltage gated Na+ Channel Blockers

Phenytoin, Fosphenytoin
Carbamazepine, Oxcarbazepine
Valproic Acid
Lamotrigine
Topiramate
Zonisamide
Lacosamine

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Which state is are the Na+ channels blocked during

Inactivated state

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Phenytoin (Dilantin)

Indication

Focal seizures

Generalized tonic-clonic seizures

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Phenytoin (Dilantin)

Non-linear

With change in dose, t1/2 changes
Induces metabolic enzymes, different time to steady state based on dose

t 1/2 15-20 hrs

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Phenytoin (Dilantin)

Metabolism

CYP2C9/19

Forms: Arene Oxide Active metabolite with ADRs

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Phenytoin ADRs

Nystagmus
Diplopia
Sedation
Gingival Hyperplasia** 
Hirsutism**

Long term:
Choreoathetosis, peripheral neuropathy

Severe:
Toxic epidermal necrolysis
SJS

**Common

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Phenytoin (Dilantin)

Teratogenicity

Fetal Hydantoin Syndrome

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Phenytoin (Dilantin)

DDIs

-High Plasma Protein Binding (Displacement issues)
-CYP2C9/19 inhibitors
(Cimetidine, Isoniazid, Sulfonamides, Valproic Acid)
-CYP2C9/19 Inducers
(Barbiturates, ChronicEtOH, Carbamazepine, Rifampin)
-Drugs that decrease absorption (Antacids)

-Phenytoin induces CYP3A4, CYP2C, CYP2D

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Carbamazepine (Tegretol, Carbatrol)

MOA

Na+ channel blocker

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Phenytoin (Dilantin)

MOA

Voltage dependent Na+ channel blocker

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Carbamazepine (Tegretol, Carbatrol)

PK: t1/2 and metabolism

t 1/2: 12-30 h (~15 for long term)

Metabolized by CYP3A4 (auto induction), CYP2C9/19

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Carbamazepine (Tegretol, Carbatrol)

Indication

All seizure types except absence seizures

- Temperal lobe epilepsy

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Carbamazepine (Tegretol, Carbatrol)
ADRs

BBW, Dose Related, Dose Unrelated, and Long-term Use

BBW: Leukopenia

Dose related: 
Fatigue, sedation
Nystagmus
Dilopia
Nausea
Ataxia

Dose Unrelated:
Rash & SJS
Teratogenicity

Longterm:
Seizure freq. increased
Aplastic anemia
Hypersensitivity

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Carbamazepine (Tegretol, Carbatrol)

DDIs

-Strong CYP3A4 inducer
Other ASDs, Oral Contraceptives, Warfarin, Corticosteroids.

-CYP3A4 inhibitors
Valproate, Cimetidine, Erythromycin

-CYP3A4 inducers
Phenytoin, Carbamazepine, primidone, phenobarbital, Ethosuximide

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Oxcarbazepine (Trileptal)

MOA and Indication

Same as Carbamazepine

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Oxcarbazepine (Trileptal)
PK
t1/2
t1/2 metabolites
Elimination

Oxcarbazepine : 1-2 h
Active metabolites : 8-12 h

Glucuronide (Urinary)

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Oxcarbazepine (Trileptal)
ADRs
Dose related
Dose un-related

Less common, less severe

Dose related: Somnolence, dilopia, ataxia

Dose-unrelated: Rash, hyponatremia

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Oxcarbazepine (Trileptal)

DDIs

WeakCYP3A4 induction:

Less affected by CYP3A4 modulation

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Valproic Acid (Depakote, Depakene)
MOAs (3)

Na channel blocker
Stimulates GABA synthesis
Inhibits GABA transaminase

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Valproic Acid (Depakote, Depakene)
Indication

Most seizure types INCLUDING absence seizures

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Lamotrigine (Lamictal)

MOA

Na+ Channel Blocker

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Lamotrigine (Lamictal)

Indication

All seizure types

Generalized seizures in children with absence attacks

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Lamotrigine (Lamictal)
PK
t1/2
Elimination

25 h

Glucuronide conjugation

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Lamotrigine (Lamictal)

ADRs

Headache, nausea, vomiting

Rash (SJS)

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Lamotrigine (Lamictal) | DDIs

Hepatic inducers increase glucuronidation (Clearance)

Topiramate (Topamax) | MOAs (3)

- Na+ blocker - Augments GABA at GABAaR - Blockatde of Glutamate receptors (Kainate, AMPA)

Topiramate (Topamax) | Indications

Focal Seizures | Generalized tonic-clonic seizures

Topiramate (Topamax) PK t1/2

20-30 h

Topiramate (Topamax) | ADRs

Sedation, cognitive slowing, confusion | Fetal malformations

Topiramate (Topamax) | DDIs

Carbamazepine, Phenytoin increase topiramate metabolism

Zonisamide (Zonegran) | MOAs (2)

Na+ channel blocker | T-type Ca2+ channel blocker

Zonisamide (Zonegran) | Indication

Focal Seizures

Zonisamide (Zonegran) PK t1/2 metabolism

>60 h | Partially by CYP3A4

Zonisamide (Zonegran) | ADRs

Dizzienes, ataxia Somnolence/Insomnia Cognitive problems Rash (fatal)

Zonisamide (Zonegran) | DDIs

-Phenytoin, Carbamazepine (CYP3A4 inducers) Valproic Acid, Cimetidine, Erythromycin (CYP3A4 inhibitors) Sufonamide hypersensitivity (contraindicated)

Lacosamide (Vimpat) | MOA

Enhances slow inactivation of Na+ channels

Lacosamide (vimpat) | Indication

Adjunctive therapy for focal-onset seizures

Lacosamide (Vimpat) PK t1/2 metabolism

12-16 h | CYP2C19

Lacosamide (Vimpat) | DDIs

N/a? CYP2C19 Inducers? Phenytoin and Carbamazepine?

Gabapentin (Neurontin, Gralise) | MOAs(2)

Ca2+ Channel Blocker --> Decrease glutamate release GABAergic --> Increases release of GABA

Gabapentin (Neurontin, Gralise) | Indication

Focal Seizures

``` Gabapentin (Neurontin, Gralise) PK t1/2 PPB Metabolism ```

~6 h 0% hardly metabolized

Gabapentin (Neurontin, Gralise) | ADRs

Sedation, Somnolence, Dizziness, Fatigue Nystagmus Ataxia

Gabapentin (Neurontin, Gralise) | DDIs

None (Based on PK)

Pregabalin (Lyica) | MOA

Ca++ channel blocker --> decreased Glu release

Pregabalin (Lyrica) | Indication

Focal seizures

``` Pregabalin (Lyrica) PK t1/2 PPB Metabolism ```

~6 h 0% hardly metabolized

Pregabalin (Lyrica)

``` SEDATION, somnolence, dizziness Headache WEIGHT GAIN Dry mouth Blurred vision ```

Pregabalin (Lyrica) | DDIs

N/a

Tiagabine (Gabitril) | MOA

GABA reuptake inhibitor

Tiagabine (Gabitril) | Indication

``` Focal seizures (Mainly Ad on, no longer 1st line) ```

Tiagabine (Gabitril) PK t1/2 metabolism

7h | CYP3A

Tiagabine (Gabitril) | ADRs

Sedation, dizzines, somnolence Difficulty with concentration abdominal Pain **Can actually induce status epilepticus!! (rare)

Tiagabine (Gabitril) | DDIs

CYP3A inducers/inhibitors

Vigabatrin (Sabril) | MOA

GABA Transaminase Inhibitor Transaminase converts GABA to glutamate (in the synaptic cleft) which then is converted to glutamine in the glia to be recycled to glutamate in glutaminergic neurons

Vigabatrin (Sabril) | Indication

Adjunct for infantile spasms, Frefractory complex focal seizures, West Syndrome

``` Vigabatriin (Sabril) PK t1/2 PPB Elimination ```

5-7 h 0% Renal

Vigabatrin (Sabril) | ADRs

Sedation, fatigue - Depresion, psychotic disurbances - WHITE MATTTER LESIONS (30%) - PROGRESSIVE PERMANENT BILATERAL VISION LOSS (30-50%!!!!!) --> Only available through "SHARE"

Vigabatrin (Sabril) | DDIs

Decreases phenytoinn Cp by 20-30% Minimal due to PK

Phenobarbital (Luminal) | MOA

GABAa Receptor agonist

Phenobarbital (Luminal) | Indication

All seizure types except absence seizures

``` Phenobarbital (Luminal) PK t1/2 PPB Elimination ```

>60 h 40-60% Renal excretion of non-metabolized drug *Strong induction of CYP2C and CYP3A (DDIs)

Phenobarbital (Luminal) | ADRs

Sedation, tolerance develops Nystagmus, Ataxia Learning Difficulties (Don't give to children)

Phenobarbital (Luminal) | DDIs

Induces CYP2C and CYP3A, induces metabolism of other drugs

Benzodiazepines | Drugs

Diazepam (Valium, Diastat) Clonazepam (Klonopin) Lorazepam (Ativan) Clobazam (Onfi)

Benzodiazepines | MOA

GABAa Receptor

Benzodiazepines | Indications (Drugs specific)

``` Diazepam - Status Epilepticus Clonazepam - Long-term (also absence) Lorazepam - Status Epilepticus Clorazepate - Long term Clobazam Lennox-Gastaut Syndrome (Adjunct) ```

Benzodiazepines PK t1/2 PPB

20-50 h | 85-99%

Benzodiazepines | ADRs

Tolerance (50%, 1-6 months)!! CNS depression, STRONG Sedation, Lethargy Aggressiveness (25%) Withdrawal Syndrom

Benzodiazepines | DDIs

GABAa Acting substances

ASDs for for focal seizures and generalized tonic-clonic seizures

Carbamazepine Phenytoin Valproic Acid Phenobarbital Lamotrigine, Oxcarbazepine, Felbamate, Gabapentin, Pregabalin, Vigabatrin, Lacosamide, Levitiracetam, Tiagabine, Topiramate

ASDs for Gernalized absence, myclonic, or atonic seizures

Valproic Acid Ethosuximide Clonazepam Lamotrigene

ASDs for status epilepticus

Diazepam | Lorazepam

ASDs with weight gain

``` Valproate (common) Carbamazepine Gabapentin Pregabalin Perampanel ```

ASDs with weight los

Topiramate Felbamate Zonisamide

ASDs that are weight neutral

Phenytoin Lamotrigine Lacosamide Levetiraetam

Hormonal contraception DDIs | CYP3A4

``` Carbamazepine Oxcarbazepine Felbamate Topiramate Phenytoin Phenobarbital ```

ASDs with Teratogenic effects

Phenytoin Phenobarbital Valproic Acid Carbamazepine

Which ASD probably transfers to breast milk

Levetiracetam

ASDs Flashcards

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