Antiepiletpic Drugs (AEDs)

-----Epilepsy is a chronic disorder characterized by recurrent seizures, which are finite episodes of brain dysfunction resulting from abnormal discharge of cerebral neurons

Dept of Pharmacology

Shi-Hong Zhang (张世红 )

shzhang713@zju.edu.cn

International Classification of Epileptic Seizures:

Partial Onset Seizures

– Simple Partial

– Complex Partial (consciousness is affected)

– Partial Seizures with secondary generalization

Source of seizure

International Classification of Epileptic Seizures: Primary Generalized Seizures

–Absence (Petit Mal)–Generalized

Tonic+Clonic (Grand Mal)

–Tonic–Atonic–Clonic and myoclonic

Stereotypical complex partial seizures

Tonic phase

Clonic phase

CyanosisCry

Salivary frothing

Jerking of the limbs

Post-ictal phase

Patient feels lethargic and confused after seizuresOften sleeps

Loss of consciousness, Fall, crying, and generalized tonic stiffeningoften with bladder incontinence

Simultaneous bilateral cortical seizure attack

AEDs Effective as Monotherapy (Single Agent)

Partial (Localization

Related)

• Phenytoin• Carbamazepine• Valproate• Oxcarbazepine• Lamotrigine• Topiramate• Gabapentin

Generalized

• Phenytoin• Carbamazepine • Valproate

– (GTC and absence)

• Ethosuximide - (absence)• Topiramate

– (GTC)

• Lamotrigine – (absence)

Bold= new generation AED

New AEDs effective as adjunctive treatment for refractory epilepsy

Partial

• Topiramate• Levetiracetam• Pregabalin • Zonisamide • Oxcarbazepine

• Lamotrigine• Gabapentin• Tiagabine

Generalized

• Topiramate• Levetiracetam• Lamotrigine

– Data from randomized placebo controlled trials

Drugs in red are generally considered high potency

Effects of three antiseizure drugs on sustained high-frequency firing of action potentials by

cultured neurons.

Mechanisms of AEDs

• Modification of ionic conductance.

- Na+

- K+

- Ca2+

• Enhancement of GABAergic (inhibitory) transmission

• Diminution of excitatory transmission

Drugs which act on Na+ channel

• Phenytoin• Carbamazepine• Oxcarbazepine• Lamotrigine

Phenytoin

• Effective against partial seizures and generalized tonic-clonic seizures

• Non-linear kinetics• Therapeutic range = 10-20

ug/ml–Levels above 20 cause ataxia and nystagmus (眼球震颤 )

• Half life = 12-24 hours, slow effect

• Hepatic metabolism–CYP3A enzyme pathway

Oral Dose: about 5 mg / kg

www.boomer.org/c/p4/c21/c2103.html

Phenytoin -----Mechanisms of action

• Binding to and hence prolonging the status of inactivated state of Na+ channels (main mechanism)

• Blocking L- and N- type Ca2+ channels (inhibits release of transmitters, stabilizes membrane)

• Chronic neuropathic pain: trigeminal

neuralgia (三叉神经痛 ), sciatica (坐骨神经痛 ), glossopharyngeal neuralgia (

舌咽神经痛 )

• Arrhythmia--b anti-arrhythmia drug

Phenytoin ---Other uses

Phenytoin side effects

• CNS: nystagmus, diplopia, ataxia, depression

• Local irritating: gingival hyperplasia, GI upset, phlebitis• Hematologic complications - Megaloblastic anemia: folic acid loss

- Agranulocytosis• Idiosyncratic or allergic reactions

- Rash, up to 10%, can be very serious - stop drug- Fever- Hepatitis

• Skeleton: osteomalacia (骨软化 , Vit D degradation↑)

• Others: birth defects (fetal malformations, class D), hirsutism

hirsutismGingival hyperplasia

Phenytoin side effects

Mephenytoin: more severe adverse effects

Ethotoin: Less effective

Carbamazepine

• Blocks Na+ channels and presynaptically decrease synaptic transmission

• Half life = 8-12 hours (steady state)

• Like phenytoin, metabolized by CYP3A pathway (inducer itself)

• Effective against partial and generalized tonic-clonic seizures, trigeminal neuralgia and mania

• Safety and Toxicity–peak effect- diplopia, ataxia–rash 5-10%–rare marrow suppression

aplastic anemia and

agranulocytosis–rare hepatitis–frequent hyponatremia at high dose–fetal malformations (class D)

• Mechanisms: blockade of Na+ and Ca2+ channels, potentiation of GABA transmission

• Dose in Adults– 200 mg once a day – After several days, 200

mg twice a day– Slowly titrate to 10 mg/kg

• Therapeutic = 6 -12 ug/ml

Watch for Rash!

Carbamazepine

Oxcarbazepine --- less effective --- improved toxicity profile (fewer hypersensitivity reactions less hepatic enzyme induction)

Lamotrigine• Na+ channel blocker• Ca2+ channel blocker• Moderate effective against both

partial and generalized epilepsy (absence/myoclonic) as add-on or monotherapy

• Hepatic metabolism, significant drug interactions with valproate (CYP inhibitor) leads to twofold increase in half-life time (level and side-effects increase)

• Linear clearance• Half life -24 hours• Start 25 mg/day, titrate slowly to

300-500 mg/day

• 10% risk of rash• Dizziness,

headache, diplopia, nausea, somnolence

• Class C in pregnancy, but significantly lower than other

Drugs acting at the chloride channel

• Benzodiazepines–Binds to BZD specific receptors

• Phenobarbital –Binds to barbiturate specific receptors

• Gabapentin– GABA analogue, alters GABA metabolism, release

and reuptake, effective as an adjunct against partial seizures and generalized tonic-clonic seizures

• Valproate –Decreases GABA degradation in presynaptic terminal

Valproate • Broad spectrum: - absence: ethosuximide

first choice - generalized tonic-clonic - partial• Blocks Na+ channels and

NMDA receptors• Increases GABA levels

– Facilitates GAD– Inhibits GAT-1– Inhibits degradation of

GABA• dose = 15-20 mg/kg to start

using a TID schedule

• GI side effects(abdominal pain and heartburn)

• Obesity + Metabolic syndrome (weight gain, increased appetite, and hair loss)

• Hepatotoxicity, elevates ammonia (liver function monitoring required)

• Fine tremor

• Serious neural tube (spina bifida, split spine) and cardiac defects in fetus in 1% (Pregnancy Category D)

During and After Valproate Therapy

It should be noted that valproate is an effective and popular antiseizure drug and that only a very small number of patients have had severe toxic effects from its use.

Drugs which primarily affect potassium channel

• Levetiracetam– Blocks voltage gated K+

channels in hippocampus neurons

– Blocks kainate receptors – Affects GABA receptors– Blocks action potentials,

and paroxysmal depolarizing shifts

Madeja et al Neuropharamacology 2003

Drugs which primarily affect potassium channel

Levetiracetam• Effective for partial

epilepsy• High Potency-----75% reduction in

seizures in over 20% of refractory patients

• Few side effects except: – Somnolence, asthenia,

and dizziness– Pregnancy category C

Drugs which affect Kainate and AMPA receptors

• Topiramate• Zonisamide

Topiramate

• Mechanisms -Multiple– Blocks AMPA+kainate

receptors– Blocks Na+ and Ca2+

channels– Potentiates GABA

transmission• Effective against both

partial and generalized epilepsy

• Excreted primarily in urine• Start at 25 mg/day, titrate

to 300-500/day

• Behavioral /Cognitive problems common (somnolence, fatigue, dizziness, cognitive slowing, paresthesias, nervousness, and confusion)

• Low risk of rash• Causes weight loss• Relatively safe, Class C? in

pregnancy• High Potency

----75% reductions in over 20% of refractory patients

Drugs which affect calcium channels

Ethosuximide

• Mechanism– Blocks T-Ca2+ channels in thalamic neurons (T-type

calcium currents are thought to provide a pacemaker current in thalamic neurons responsible for generating the rhythmic cortical discharge of an absence attack)

• Effective against absence seizures• Long half life time 40~50h• Effective dose range 750–1500 mg/d• Adverse effects: gastric distress (stomachache, nausea,

vomiting), CNS response (fatigue, dizziness, headache, euphoria, sleepiness, hiccup)

Teratogenicity• All AEDs cause fetal

malformations in at least 6% of infants, such as neural tube defects, mouth malformation, cardiopathy.

• Highest risk with phenytoin, valproate, phenobarbital, and carbamazepine (Class D drugs)

• Folate supplementation prevents neural tube defects (split spine, 脊柱裂 ).

When to initiate treatment?

Case Study: Initiation of Treatment

• A 22 year old female sustains a head injury with loss of consciousness

• Two years later she develops a single secondarily generalized tonic-clonic seizure

• MRI and EEG are normal

• You should

1. Instruct her not to drive. Report the event to the department of public health or DMV

2. Wait until a second seizure, and then initiate an AED

3. Initiate a pregnancy class C AED now.

4. Initiate, phenytoin, valproic acid, phenobarbital, or carbamazepine now

Initiation of Treatment

• Consider all the facts. – After a first seizure, the risk of subsequent

epilepsy is 35% within 1-2 years– After a second seizure, the risk is over 90%

• It depends on the level of risk and the patient’s situation

Initiation of Treatment

Increased risk• Known symptomatic cause• Partial seizures• Family history of epilepsy• Abnormal electroencephalogram (particularly generalized spike-and-slow wave)• Abnormal findings on neurologic examination• Abnormal imaging findings

Decreased risk• Idiopathic cause• Generalized seizure• No family history of epilepsy• Normal electroencephalogram• Normal findings on neurologic examination

Initiation of Treatment

• the risk-benefit ratio of the anticonvulsant treatment must be carefully assessed in patients after a single seizure

• Avoid valproic acid in a woman of childbearing potential. Answer 4 is clearly a poor choice.

Initiation of Treatment

Initiation of Treatment