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) Simple partial Consciousness: preserved EEG: localized spikes Sx: Motor and sensory disturbance related to specific cortical area affected Complex partial Consciousness: disturbed EEG: focal spike originating in temporal lobe Sx: confused behavior, automatisms, sensory/emotional distortions Partial seizures secondarily generalized Consciousness: lost Origin: spread of epileptic activity from focal to both hemispheres Sx: motor pattern similar to "generalized seizures

1.1.2. Generalized Usually from a metabolic or idiopathic cause Nonconvulsive type Absence (Petit Mal) Atypical absense Convulsive type Tonic-clonic (Grand Mal) Tonic, clonic, myoclonic (sudden, forceful contraction), atonic Infantile spams ("jack knife" convulsion) 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 Note: GABA is the primary inhibitory NT in the brain

2.1.3. Limit activation of Ca++ channels 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 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 Therefore small changes in % free drug -> large changes in effective drug

3.4.3. 98% metabolized by liver NZ Metabolism can be saturated (loses linear increase) 1st order at sub-Tx doses 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 CYP3A4, along w/ several others This is a big deal!

3.5. SE

3.5.1. Acute toxicity after rapid IV admin CV collapse CNS depression Use soluble prodrug fosphenytoin to decrease this effect Don't use phenytoin for a fast effect

3.5.2. Acute tox after oral admin ataxia, nystagmus, drowsiness, diplopia

3.5.3. Chronic tox Epilepsy is a life-long Dz Behavioral changes, gingival changes, peripheral neuropathy, hirsutism GI disturbances and malabsorption Osteomalacia d/t decreased Vit D Decreased Vit B12 -> megaloblastic anemia 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 Causes rapid increase in neuronal activity -> seizures (esp. status epilepticus)

3.6. DD interaxns

3.6.1. Drugs that inhibit metabolism Chloramphenical, dicumerol, cimetidine, sulfonamides

3.6.2. Drugs that enhance metab carbamazepine decrease plasma levels

3.6.3. Phenobarbital and ethanol Acutely: inhibit metab Increase plasma levels Chroincally: stimulate metab Decrease plasma levels

3.6.4. Dicumerol, salicylates, BZDs Displace phenytoin from binding sites 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 Both of these elevate seizure threshold and limit spread

4.1.2. Decreases glutamate excitation

4.2. Use

4.2.1. Alternative to phenytoin 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) Most SE worse in young and old pts

4.4.3. acute intermittent porphyria

4.4.4. Causes tolerance and dependence 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 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 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 Available in extended release forms 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 Aplastic anemai, agranulocytosis

6.4.3. Skin rxns Steven-Johnson Syndrome

6.4.4. Hypersensitivity rxns in Asians w/ HLA-B1502 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 Increases neuronal refractory peroid 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 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 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 Most common in kids < 2 yo or those on multiple drugs 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 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 CV & resp depression

9.7.2. Clonazepam Drowsiness, ataxia, paradoxical agression behavior, hyperkinesia 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