Download Chapter 24 Antiseizure Drugs

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)
[email protected]
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
Simultaneous
bilateral
cortical seizure
attack
Cyanosis
Cry
Loss of consciousness,
Fall, crying, and
generalized tonic stiffening
often with bladder incontinence
Clonic phase
Salivary frothing
Jerking of the limbs
Post-ictal phase
Patient feels lethargic and confused after seizures
Often sleeps
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
Generalized
• Topiramate
• Levetiracetam
• Lamotrigine
– Data from randomized
placebo controlled trials
• Lamotrigine
• Gabapentin
• Tiagabine
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
www.boomer.org/c/p4/c21/c2103.html
Oral Dose: about 5 mg / kg
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)
Phenytoin ---Other uses
• 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 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
Phenytoin side effects
Gingival hyperplasia
hirsutism
Mephenytoin:
more severe adverse effects
Ethotoin: Less effective
Carbamazepine
• Blocks Na+ channels and
presynaptically decrease • Safety and Toxicity
–peak effect- diplopia, ataxia
synaptic transmission
–rash 5-10%
• Half life = 8-12 hours
–rare marrow suppression
(steady state)
aplastic anemia and
• Like phenytoin,
agranulocytosis
metabolized by CYP3A
–rare hepatitis
pathway (inducer itself)
–frequent hyponatremia at high
• Effective against partial
dose
and generalized tonic–fetal malformations (class D)
clonic seizures, trigeminal
neuralgia and mania
Carbamazepine
• 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!
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
Initiation of Treatment
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