Epilepsy Drugs I

WVSOM Neuro: Shcriefer 3/14/11

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Epilepsy Drugs I by Mind Map: Epilepsy Drugs I

1. Epilepsy in General

1.1. Types

1.1.1. Partial (focal)

1.1.1.1. Simple partial

1.1.1.1.1. Consciousness: preserved

1.1.1.1.2. EEG: localized spikes

1.1.1.1.3. Sx: Motor and sensory disturbance related to specific cortical area affected

1.1.1.2. Complex partial

1.1.1.2.1. Consciousness: disturbed

1.1.1.2.2. EEG: focal spike originating in temporal lobe

1.1.1.2.3. Sx: confused behavior, automatisms, sensory/emotional distortions

1.1.1.3. Partial seizures secondarily generalized

1.1.1.3.1. Consciousness: lost

1.1.1.3.2. Origin: spread of epileptic activity from focal to both hemispheres

1.1.1.3.3. Sx: motor pattern similar to "generalized seizures

1.1.2. Generalized

1.1.2.1. Usually from a metabolic or idiopathic cause

1.1.2.2. Nonconvulsive type

1.1.2.2.1. Absence (Petit Mal)

1.1.2.2.2. Atypical absense

1.1.2.3. Convulsive type

1.1.2.3.1. Tonic-clonic (Grand Mal)

1.1.2.3.2. Tonic, clonic, myoclonic (sudden, forceful contraction), atonic

1.1.2.3.3. Infantile spams ("jack knife" convulsion)

1.1.2.3.4. Status epilepticus

1.2. Can be either primary or secondary

1.3. M&M d/t anoxia during seizures

1.3.1. Also danger of excitotoxicity (repeated seizures lower the threshold)

2. General drug MOA

2.1. Antiepileptic drugs work by 3 mechanisms

2.1.1. Limiting firing of neurons by slowing rate of recovery in Na channels

2.1.2. Enhancing GABA-mediated synaptic inhibition

2.1.2.1. Note: GABA is the primary inhibitory NT in the brain

2.1.3. Limit activation of Ca++ channels

2.1.3.1. Slows synaptic transmission

3. Phenytoin (Dilantin)

3.1. Prevents seizures w/o producing general CNS depression

3.2. MOA

3.2.1. Reduces rate at which Na channels recover from inactivation

3.2.1.1. slows firing

3.3. Use

3.3.1. All seizure types except absence

3.3.2. Tonic-clonic in adults and older children

3.3.3. Used in status epilepticus

3.3.4. Wound healing

3.4. Admin/PK

3.4.1. Slow, variable oral absorption (3-12 hr to peak)

3.4.2. 90% plasma protein bound

3.4.2.1. Therefore small changes in % free drug -> large changes in effective drug

3.4.3. 98% metabolized by liver NZ

3.4.3.1. Metabolism can be saturated (loses linear increase)

3.4.3.1.1. 1st order at sub-Tx doses

3.4.3.1.2. zero-order elimination at Tx doses

3.4.4. t1/2 = 6-24 hrs

3.4.5. Induces a lot of hepatic drug-metabolizing NZs

3.4.5.1. CYP3A4, along w/ several others

3.4.5.1.1. This is a big deal!

3.5. SE

3.5.1. Acute toxicity after rapid IV admin

3.5.1.1. CV collapse

3.5.1.2. CNS depression

3.5.1.3. Use soluble prodrug fosphenytoin to decrease this effect

3.5.1.4. Don't use phenytoin for a fast effect

3.5.2. Acute tox after oral admin

3.5.2.1. ataxia, nystagmus, drowsiness, diplopia

3.5.3. Chronic tox

3.5.3.1. Epilepsy is a life-long Dz

3.5.3.2. Behavioral changes, gingival changes, peripheral neuropathy, hirsutism

3.5.3.3. GI disturbances and malabsorption

3.5.3.3.1. Osteomalacia d/t decreased Vit D

3.5.3.3.2. Decreased Vit B12 -> megaloblastic anemia

3.5.3.3.3. Depression of serum folate and Vit K levels

3.5.4. Drug allergies

3.5.5. Fetal hydantoin syndroms (Category D)

3.5.6. Avoid sudden withdrawal

3.5.6.1. Causes rapid increase in neuronal activity -> seizures (esp. status epilepticus)

3.6. DD interaxns

3.6.1. Drugs that inhibit metabolism

3.6.1.1. Chloramphenical, dicumerol, cimetidine, sulfonamides

3.6.2. Drugs that enhance metab

3.6.2.1. carbamazepine

3.6.2.1.1. decrease plasma levels

3.6.3. Phenobarbital and ethanol

3.6.3.1. Acutely: inhibit metab

3.6.3.1.1. Increase plasma levels

3.6.3.2. Chroincally: stimulate metab

3.6.3.2.1. Decrease plasma levels

3.6.4. Dicumerol, salicylates, BZDs

3.6.4.1. Displace phenytoin from binding sites

3.6.4.1.1. Rapid increase in plasma levels!

3.6.5. Phenytoin decreases effectiveness of OC!

4. Phenobarbital

4.1. MOA

4.1.1. Potentiates GABA inhibitory transmission

4.1.1.1. Both of these elevate seizure threshold and limit spread

4.1.2. Decreases glutamate excitation

4.2. Use

4.2.1. Alternative to phenytoin

4.2.1.1. Stronger SE than DOC

4.3. Admin/PK

4.3.1. Oral absorption slow, but complete

4.3.2. 40-60% protein bound

4.3.3. Chronic use may induce hepatic NZ, but much less so than phenytoin

4.4. SE

4.4.1. Sedation, ataxin, skin rash, megaloblastic anemia

4.4.2. Decreased cognitive ability, hyperactivity (kids), confusion (elderly)

4.4.2.1. Most SE worse in young and old pts

4.4.3. acute intermittent porphyria

4.4.4. Causes tolerance and dependence

4.4.4.1. Sudden withdrawal -> status ep.

4.4.5. Potentailly teratogenic

4.5. DD interaxns

4.5.1. Variable results when in combo w/ phenytoin

4.5.2. Decreases plasma level of anticoagulants

4.5.3. Additive effect w/ CNS depressants

5. Primidone

5.1. MOA

5.1.1. Structurally similar to phenobarbital

5.1.1.1. similar pharmacology, but less potent

5.2. Use

5.2.1. Alternative Tx

5.2.2. Useful in Tx of myoclonic seizures in young children

5.3. Admin/PK

5.3.1. Metabolized to phenobarbital and PEMA

5.4. Tox

5.4.1. similar to PBB

5.4.2. Greater incidence of drowsiness, dizziness, megaloblastic anemia

5.4.3. Pregnancy Cat. D

6. Carbamazepine

6.1. MOA

6.1.1. Structurally similar to tricyclic antidepressants

6.1.2. Slows recovery of Na channels

6.1.2.1. Like phenytoin

6.2. Use

6.2.1. Tonic-clonic and partial seizures

6.2.2. Neuropathic pain

6.2.3. bipolar disorder

6.3. Admin/PK

6.3.1. rapid oral absorp

6.3.2. 70% protein bound

6.3.3. t1/2 = 13-17 hrs

6.3.3.1. Available in extended release forms

6.3.3.1.1. Carbatrol, tegretol-XR

6.4. SE

6.4.1. Diplopia, blurred vision, drowsiness, dizziness, NV, ataxia, liver tox, wt gain

6.4.2. Blood dyscracias

6.4.2.1. Aplastic anemai, agranulocytosis

6.4.3. Skin rxns

6.4.3.1. Steven-Johnson Syndrome

6.4.4. Hypersensitivity rxns in Asians w/ HLA-B1502

6.4.4.1. Do genetic testing on Asian pts prior to starting Tx

6.5. DDI

6.5.1. Metab increased by phenytoin and phenobarbital

6.5.2. It increases metab of phenytoin, primidone, valproic acid

6.6. Oxcarbazepine

6.6.1. New drug same as carbamazepine, w/ fewer skin rxns and hematologic toxicity

7. Ethosuximide

7.1. Use

7.1.1. Absence seizure

7.2. MOA

7.2.1. Decreases conductance in Ca channels in T current

7.2.1.1. Increases neuronal refractory peroid

7.2.1.2. T currents important in generation of absence seizures

7.3. Admin/PK

7.3.1. long 1/2 life

7.4. Tox

7.4.1. NV and drowsiness - both dose-related

7.4.2. Parkinsonism, blood dyscrasias, utricaria, S-J syndrome

7.5. DDI

7.5.1. Metab delayed by valproic acid

8. Valproic Acid

8.1. Use

8.1.1. absence and complex partial seizures

8.1.2. Maybe also grand mal, myoclonic, and febrile seizures

8.1.3. If pt doesn't respond to any drug, use this one

8.2. MOA

8.2.1. Block recovery of Na channels

8.2.2. Uses K channels to hyperpolarize

8.2.3. Some action on GABA-mediated inhibition

8.2.3.1. Wide variety of mechanisms -> why it works on so many diff kinds of seizure

8.3. Admin/PK

8.3.1. Rapid and complete absorption

8.3.1.1. Slower w/ enteric coated prep (Depakote)

8.3.2. 80-95% protein bound - high!

8.3.3. Inhibits CYP2C9

8.3.4. Oral or IV form

8.4. Tox

8.4.1. Low degree of tox

8.4.2. GI, sedation, ataxia, wt gain, prolonged bleeding, alopecia

8.4.3. Rare: pancreatitis in kids

8.4.4. Rare: hepatotox

8.4.4.1. Most common in kids < 2 yo or those on multiple drugs

8.4.4.1.1. Risk greatest early in 1st 4 months of Tx

8.5. DDI

8.5.1. It displaces phenytoin from protein binding sites

8.5.2. Inhibits metab of PBB, carbamazepine, phenytoin, ethosuximide

9. Benzodiazepines

9.1. Diazepam

9.1.1. IV used for status ep.

9.1.2. Can -> CV & resp depression

9.2. Lorazepam

9.2.1. status ep.

9.3. Clonazepam

9.3.1. akinetic, myoclonic, & absence

9.3.2. Unusual seizures

9.4. Chlorazepate

9.4.1. Adjunct Tx for CPS

9.5. Use

9.5.1. Relatively safe, but transient effect d/t quick tolerance

9.5.1.1. Rarely used for chronic Tx

9.5.2. New node

9.6. MOA

9.6.1. Suppresses seizure spread in the cortex, thalamus, and limbic structures

9.6.2. Facilitates GABA-mediated pre- and post-synaptic inhibition

9.7. SE

9.7.1. IV diazepam

9.7.1.1. CV & resp depression

9.7.2. Clonazepam

9.7.2.1. Drowsiness, ataxia, paradoxical agression behavior, hyperkinesia

9.7.2.1.1. Most likely in kids and pts that are very emotionally controlled (the drug lowers inhibitions!)

9.7.3. Abrupt withdrawal -> Status ep.

9.8. DDI

9.8.1. Potentiates CNS depressant effects of antipyschotics, TC antidepressants, sedative hypnotics, and alcohol