Nervous System- Antiepileptic Drugs By Schriefer

Front 1

Nervous System- Antiepileptic Drugs by Schriefer

Back 1

Nervous System- Antiepileptic Drugs by Schriefer

Front 2

Partial Seizures (focal) are in three categories

Back 2

Simple: consciousness preserved, localized EEG spikes, various manifestations of motor or sensory disturbances related to specific cortical area affected

Complex: disturbed consciousness, focal EEG spikes originate from temporal love, confused behavior, automatisms, sensory, emotional distortions

Partial seizures secondarily generalized: spread of epileptic activity to affect both hemisphere, loss of consciousness, motor pattern similar to 'generalized seizures'

Front 3

Absence (petit mal) nonconvulsive type of generalized seizures

Back 3

brief, abrupt loss of consciousness, with or w/o clonic motor activity, generalized 3 per second spike and wave EEG activity

Front 4

Convulsive type: tonic-clonic (Grand mal)

Back 4

major convulsion typified by tonic contraction, clonic jerking and a prolonged post-seizure (postictal) depression of CNS activity.

Front 5

Mechanism of antiepileptic drug action

Back 5

1. Limit sustained repetitive firing of neurons by slowing rate of recovery in Na+ - channels

2. Enhancing GABA-mediated synaptic inhibition

3. Limit activation of Ca++- channels

Front 6

Phenytoin (Dilantin) characteristic, mechanism, disposition

what order elimination is it?

Back 6

A. Characteristic: prevent seizures without producing general CNS depression

B. Mechanism: Produces numerous effects but the major action of phenytoin is to reduce rate at which Na+ channels recover from inactivation, thereby slowing firing.

C. Disposition: Slow, variable oral absorption (3 12 hrs to peak). Rate and extent of absorption varies between manufacturers.

90% plasma protein bound

98% metabolized by liver microsomal enzymes; zero order elimination kinetic at therapeutic concentration; half life 6-24 hrs

- Induces hepatic drug metabolizing enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4)

Front 7

Phenytoin toxicity

Back 7

acute toxicity after rapid IV administration cardiovascular collapse and/or CNS depression. Fosphenytoin ( a soluble prodrug of phenytoin) decreases, but does not eliminate, this problem.

acute toxicity after oral administration ataxia, nystagmus, drowsiness, diplopia

chronic toxicity behavioral changes, *gingival hyperplasia, peripheral neuropathy, *osteomalacia, gi disturbances, megaloblastic anemia (decreased vit. B12), hirsutism, depression of serum folate and vitamin K level.

drug allergies
fetal hydantoin syndrome (Pregnancy Category D)
avoid sudden withdrawal (status epilepticus risk)

Front 8

Phenytoin drug interactions

Back 8

Chloramphenicol, dicumerol, cimetidine, and sulfonamides inhibit metabolism.

*Acutely, phenobarbital and ethanol inhibit metabolism of phenytoin and increase plasma levels; chronically, they stimulate metabolism.

carbamazepine enhances phenytoin metabolism → ↓ plasma level

dicumarol, salicylates, benzodiazepines displace from protein binding plasma level

*Phenytoin may decrease the effectiveness of oral contraceptives.

Front 9

Barbiturates: Phenobarbital (Luminal)

Back 9

1. Characteristics: least toxic, least expensive.

2. Mechanism: Anticonvulsant activity can be achieved at doses lower than those causing sedative hypnotic activity.

a. potentiates GABA inhibitory transmission and decreases glutamate excitation
b. elevation of seizure threshold
c. limit seizure spread

Front 10

Phenobarbital pharmacokinetics

Back 10

oral absorption is slow but complete

40-60% protein bound

10-25% excreted unchanged, rest metabolized by liver microsomal enzymes. Enzyme induction may occur with chronic use (same enzymes as phenytoin).

T1/2: 3-4 days

Front 11

Phenobarbital side effects, toxicity, drug interactions

Back 11

Side effects and toxicity:

sedation, ataxia, hyperactivity (children), skin rash, megaloblastic anemia, confusion in elderly patients, decreased cognitive ability

*precipitate acute intermittent porphyria

causes tolerance and dependence; sudden withdrawal may precipitate status epilepticus

-potentially teratogenic (Pregnancy Category D)

Drug interactions:

a. interaction with phenytoin may produce variable results.
-competition for microsomal enzymes
-*induction of enzyme for metabolism
-displacement from plasma protein binding

b. ↓ plasma level of anticoagulants

c. additive effect with CNS depressants

Front 12

Barbiturates: Primidone (Mysoline)

Back 12

just like phenobarbital but less potent. probably will never use this.

Front 13

Carbamazepine (Tegretol)

character, mechanism, pharmacokinetics

Back 13

A. Characteristic: structurally related to tricyclic antidepressants

B. Mechanism: anticonvulsant effects resemble phenytoin (slows recovery of voltage-sensitive Na+ channels).

C. Pharmacokinetics:
oral absorption rapid
70% protein bound
T1/2 :13 17 hours (36 hours initially)
- Induce hepatic drug metabolizing enzymes (same as phenytoin)
- Extended release forms (Carbatrol, Tegretol-XR) available

Front 14

Carbamazepine (Tegretol)

adverse effects (liver toxicity?)

what can I, a man of Asian descent, get because of my usage of carbamazepine?

Back 14

Adverse effects diplopia, blurred vision, drowsiness, dizziness, nausea, vomiting, ataxia, *liver toxicity, weight gain

*blood dyscrasias (aplastic anemia, agranulocytosis)--> can be fatal, do bloodwork first, make sure there's no sore throat that doesn't go away.

- skin reactions, Stevens-Johnson Syndrome

- Hypersensitivity reactions (Stevens-Johnson) in Asians with HLA-B* 1502 gene. FDA recommends genetic testing before starting therapy. Some risk with phenytoin, too.

Front 15

Carbamazepine drug interaction

Back 15

metabolism may be increased by phenytoin and phenobarbital

it may increase the metabolism of phenytoin, primidone, valproic acid

Front 16

Oxcarbazepine (Trileptal)

Back 16

- a new drug which is chemically similar to carbamazepine except it is less likely to cause severe skin reactions and hematologic toxicity.

Front 17

Ethosuximide (Zarontin) character, mechanism, pharmacokinetics

What type of seizures?

Back 17

A. Characteristic: Commonly used to treat ABSENCE seizure

B. Mechanism
Increases neuronal refractory period by decreasing conductance in Ca++ channels (T current). T currents in thalamic neurons important in generation of absence seizures.

C. Pharmacokinetics:
-well absorbed following oral administration
-metabolized by hepatic microsomal enzymes (80%)
-T1/2: 30 hours in children, 60 hours in adult

Front 18

Toxicity, drug interaction

Back 18

D. Toxicity:
Nausea, vomiting and drowsiness are dose related, Parkinsonism, blood dyscrasias, urticaria, Stevens-Johnson syndrome

E. Drug interaction:
- metabolism may be delayed by valproic acid

Front 19

Valproic acid (Depakene, Stavzor, Depakote)

Back 19

A. Characteristic: approved for absence and complex partial seizures in U.S. May also be useful in treatment of grand mal, myoclonic and febrile seizures. Also used in patients who don't respond to any drug, regardless of seizure type.

B. Mechanism: Acts via several mechanisms. Blocks recovery in Na+ channels, hyperpolarizes cell via an action on K+ channels and perhaps an action on GABA systems.

C. Pharmacokinetics

-rapid and complete absorption (Depakene and Stavzor; slower with enteric coated preparation; Depakote)
-80 95% protein bound
-metabolized by liver
-T1/2  15 hours
- inhibits drug metabolizing enzymes (CYP2C9?)
- iv form (Depacon)

Front 20

side effects, toxicity, drug interactions

Back 20

D. Side effects and toxicity

Low degree of toxicity

- GI most common, some sedation, ataxia. May rarely cause pancreatitis in children.

- Weight Gain

Low incidence of hepatotoxicity, but is a problem. Risk greatest for children under 2 and those taking multiple drugs. Careful monitoring at start. Most deaths within 4 months.
-Low incidence of thrombocytopenia

-Increased risk of spina bifida (Category D)

E. Drug interactions

1. valproate displaces phenytoin from plasma protein binding sites
2. valproate INHIBITS metabolism of phenobarbital, carbamazepine, phenytoin, and ethosuximide

Front 21

Benzodiazepines: diazepam (Valium), clonazepam (Klonopin), lorazepam (Ativan), chlorazepate (Tranxene)

character, mechanism, side effects, drug interactions

Back 21

A. Characteristic: relatively safe; transient effect due to development of tolerance

B. Mechanism:
1. Suppression of seizure spread in the cortex, thalamus and limbic structures.
2. **May facilitate GABA mediated pre and post synaptic inhibition

C. Side effects
1. iv diazepam cardiovascular, respiratory depression
2. clonazepam drowsiness, ataxia, paradoxical aggression behavior, hyperkinesia may also occur.
3. abrupt withdrawal may lead to status epilepticus.

D. Drug interaction: Potentiation of CNS depressant effects of antipsychotics, tricyclic antidepressants, sedative hypnotics, alcohol.

Front 22

felbamate (Felbatol)

what's its only use?

Back 22

approved for use in adults with partial seizures and in children with seizures associated with Lennox-Gastaut Syndrome. Mechanism of action may involve blockade of sodium channels. Important interactions with other antiepileptic drugs. Use limited due to surprisingly high incidence of aplastic anemia, and liver failure.

Front 23

vigabatrin (Saybril)

Back 23

1. mechanism – inhibits GABA degradation and reuptake

2. adverse reactions – vision loss in 30% of patients

3. use – last resort for infantile spasms.

Front 24

Rufinamide (Benzel)

Back 24

1. mechanism – thought to act on sodium channels

2. Adverse reactions – somnolence, vomiting

3. use – Lennox-Gastant Syndrome

Front 25

Lamotrigene: how does it work?

Back 25

Lamotrigene acts by slowing recovery in Na+ channels, inhibiting voltage gated calcium channels and by inhibiting glutamate release.

Front 26

Gabapentin and pregabalin

Back 26

Gabapentin and pregabalin act at voltage-gated calcium channels to decrease depolarization-induced calcium influx. This decrease release of excitatory neurotransmitters (glutamate).

Front 27

topiramate

Back 27

Difficulty concentrating, drowsiness, dizziness, ataxia, weight loss. Slight increase in incidence of *kidney stones - may require discontinuation. Inhibits carbonic anhydrase (Measure serum bicarb); metabolic acidosis may result.

Front 28

Status epilepticus

Back 28

A state of continuous seizure activity without recovery of consciousness. Generalized tonic clonic type is life threatening (10% fatal).

Some causes: Sudden withdrawal of CNS depressants or antiepileptic agents, or drug poisoning.

Treatment:

1. Supportive care to correct fluid electrolyte imbalance, cardiac arrhythmias, shock, maintain an open airway

2. Drug therapy: iv diazepam or lorazepam followed by maintenance therapy of slow iv infusion of phenytoin or phenobarbital

Front 29

DOC for Primary Generalized Tonic-Clonic (Grand Mal)

Back 29

Valproate
Carbamazepine
Pheytoin

Front 30

DOC Partial , including secondarily generalized

Back 30

Carbamazepine
Phenytoin
Valproate

Front 31

DOC Absence (Petit Mal)

Back 31

Ethosuximide (only absensce)
Valproate (basically any seizure)

(when i doubt, chose valproate!)

Front 32

DOC atypical Absence, myoclonic, atonic

Back 32

valproate