Download Seizures

2
Epilepsy
A group of chronic CNS disorders
characterized by recurrent seizures.
3
Epilepsy



Seizures are sudden, transitory, and
uncontrolled episodes of brain
dysfunction
resulting from abnormal discharge of
neuronal cells
Associated with motor, sensory or
behavioral changes.
4
Seizures


The causes for seizures can be multiple,
from infection, to neoplasms, to head
injury.
In a few subgroups it is an inherited
disorder.
5
Seizures


Febrile seizures or seizures caused by
meningitis are treated by antiepileptic
drugs
Although they are not considered
epilepsy (unless they develop into
chronic seizures).
6
Seizures

Seizures may also be caused by acute
underlying toxic or metabolic disorders,
7
The EEG in
seizure of Epilepsy
Generalized
Tonic-Clonic
Seizures
Spike wave
Absence
Seizures
3 Hz Paradoxical discharge
Psychomotor
seizures
1.etiology
(1) primary epilepsy: inherited
abnormality.
(2) secondary epilepsy: such as brain
tumors, head injury, hypoglycemia,
meningeal infection, rapid withdrawal
of alcohol from an alcoholic.
2.Pathogenesis
sudden, excessive and abnormal
discharge of cerebral neurons
which diffuses to local or whole
brain in short time
over-excitement.
3. clinic manifestation
regional or whole brain dysfunction:
• motor
• vegetative and mental episodes
• loss of consciousness etc.
Neuronal Substrates of Epilepsy
The Synapse
ions
The Brain
The Ion Channels/Receptors
12
Classification of Epileptic Seizures
I. Partial (focal) Seizures
A.
Simple Partial Seizures
B.
Complex Partial Seizures
II. Generalized Seizures
A.
Generalized Tonic-Clonic Seizures
B.
Absence Seizures
C.
Tonic Seizures
D.
Atonic Seizures
E.
Clonic and Myoclonic Seizures
13
I. Partial (Focal) Seizures
A.
B.
Simple Partial Seizures
Complex Partial Seizures.
14
Scheme of Seizure Spread
Simple (Focal) Partial
Seizures
Contralateral spread
15
I. Partial (Focal) Seizures
A.



Simple Partial Seizures (Jacksonian)
Involves one side of the
brain at onset.
Focal motor, sensory or
speech disturbances.
Confined to a single limb
or muscle group.
16
I. Partial (Focal) Seizures
A.
Simple Partial Seizures (Jacksonian)
Seizure-symptoms don’t
change during seizure.

No alteration of consciousness.
EEG: Excessive synchronized
discharge by a small group of
neurons.
Contralateral discharge.
17
Scheme of Seizure Spread
Complex Partial Seizures
Complex Secondarily
Generalized Partial Seizures
18
B. Complex Partial Seizures (Temporal
lobe epilepsy or Psychomotor
Seizures)



Produces confusion and
inappropriate or dazed behavior.
Motor activity appears as non-reflex
actions.
Automatisms (repetitive coordinated
movements).
19
B. Complex Partial Seizures (Temporal
Lobe epilepsy or Psychomotor
Seizures)


Wide variety of clinical
manifestations.
Consciousness is impaired or lost.
EEG: Bizarre generalized EEG activity
with evidence of anterior temporal
lobe focal abnormalities. Bilateral.
20
II. Generalized Seizures
A.
B.
C.
D.
E.
Generalized Tonic-Clonic
Seizures
Absence Seizures
Tonic Seizures
Atonic Seizures
Clonic and Myoclonic Seizures.
21
In Generalized seizures, both
hemispheres are widely involved
from the outset.
Manifestations of the seizure
are determined by the cortical
site at which the seizure arises.
22
23
A.
Generalized Tonic-Clonic
Seizures
Recruitment of neurons
throughout the cerebrum
Major convulsions, usually with
two phases:
1) Tonic phase
2) Clonic phase
24
Tonic phase:
- Sustained powerful muscle
contraction (involving all body
musculature) which arrests
ventilation.
25
Tonic phase:
EEG: Rythmic high frequency, high
voltage discharges with cortical
neurons undergoing sustained
depolarization, with protracted trains
of action potentials.
26
Clonic phase:
- Alternating contraction and
relaxation.
27
Clonic phase:
EEG: Characterized by groups of
spikes on the EEG and periodic
neuronal depolarizations with
clusters of action potentials.
28
B. Absence Seizures (Petite Mal)

Brief and abrupt loss of
consciousness.

Sometimes with no motor
manifestations.
29
B. Absence Seizures (Petite Mal)

Typical 2.5 – 3.5 Hz spike-and-wave
discharge.

Usually of short duration (5-10 sec),
but may occur dozens of times a day.
30
C.


Tonic Seizures
Opisthotonus, loss of
consciousness.
Marked autonomic manifestations
D. Atonic Seizures (atypical)

Loss of postural tone, with sagging
of the head or falling.

May loose consciousness.
31
Neuronal Substrates of Epilepsy
The Synapse
ions
The Brain
The Ion Channels/Receptors
32
Pharmacotherapy of
Seizures
Goals:



Block repetitive neuronal firing.
Block synchronization of neuronal
discharges.
Block propagation of seizure.
33
Pharmacotherapy of Seizures
Goals:

Minimize side effects with the
simplest drug regimen.
MONOTHERAPY IS RECOMMENDED
IN MOST CASES
34
Strategies of
treatment



Modification of ion conductances.
Increase inhibitory (GABAergic)
transmission.
Decrease excitatory (glutamatergic)
activity.
35
Pharmacokinetics of antielpileptics
Most classical antiepileptic
drugs exhibit similar
pharmacokinetic properties.
 Good absorption (although
most are sparingly soluble).

36
Pharmacokinetics of antielpileptics


Low plasma protein binding
(except for phenytoin, BDZs,
valproate, and tiagabine).
Conversion to active metabolites
37
Pharmacokinetics of
antielpileptics

Cleared by the liver but with low extraction
ratios.

Distributed in total body water.

Plasma clearance is slow.

At high concentrations phenytoin exhibits
zero order kinetics.
38
Pharmacokinetic Parameters
39
I
Stabilize membrane and
prevent depolarization by
action on ion channels
40
PHENYTOIN
(Dilantin)
41
Phenytoin
【pharmacokinetics】
• high concentrations in brain,
• high plasma albumin binding,
• half-life: 24 hours.
Actions of Phenytoin on Na+
Channels
Na+
A.
B.
C.
Resting State
Arrival of action
potential causes
depolarization and
channel opens
allowing sodium to
flow in.
Na+
Refractory State,
Sustain channel
Inactivation
Na+
in this
conformation
43
Phenytoin
【mechanism of action】
to decrease Na+ conductance in
neurons
to stabilize nervous cellular
membranes.
Phenytoin
【mechanism of action】
to reduce the influx of calcium
ions during depolarization
suppresses high-frequency
repetitive firing
halts seizure
activity.
【Pharmacologic effects】
1.antiepileptic effect
effective for tonic-clonic and partial
seizures
2. Anti-peripheral neuralgia
3. antiarrhythmia
【therapeutic uses】
1. epilepsy.
• highly effective for all partial
seizures, tonic-clonic seizures
and status epilepticus(First line).
• not effective for absence seizure.
【therapeutic uses】
2. peripheroneural pain.
Trigeminal neuralgia,
glossopharyngeal neuralgia and
sciatic neuralgia etc..
3. arrhythmia
Phenytoin
【Adverse
effects】
Digestive
system
 Gingival
hyperplasia
 Nervous system
 Hematological

Skeletal
system
 Allergic
response
 Others

Phenytoin
【Adverse effects】

Digestive system: anorexia,
nausea, vomiting and abdominal
pain
(recommend to take it after meal).

It may cause phlebitis after IV.

Phenytoin
【Adverse effects】


Gingival hyperplasia: occurs in
children and teenagers after long
term use, the incidence rate is
about 20%.
Generally, this effect can
resolve after drug withdraw 3 to
52
Phenytoin
【Adverse effects】
 Nervous system: nystagmus,
diplopia, vertigo, ataxia
(usually only at very high
concentration).

Severe patient occurs language
disorder, mental confusion and
Phenytoin
【Adverse effects】
inhibit the
absorption of folinic acid
and
accelerate
its
metabolism.
 inhibit folic cid reductase.

Hematological system:
Phenytoin
【Adverse effects】
 Hematological system:

cause
megaloblastic
anemia
after long-term use (recommend
to pretreat with folinic acid).
Phenytoin
【Adverse effects】
 Skeletal system:


enhance vitamin D metabolism
so Phenytoin may increase
the risk of hypocalcemia,
rickets after long-term
treatment(pretreat with
Phenytoin
【Adverse effects】
 Allergic response:
 rash, thrombocytopenia

Others: lymphadenectasis.
Fosphenytoin


A Prodrug of phenytoin, more
soluble, for parenteral use. rapidly
converted to in the body.
Avoids local complications
associated with phenytoin: vein
irritation, tissue damage,et al.
58
Fosphenytoin
Can be injected with both saline
and glucose
While phenytoin cannot be injected
with glucose
59
CARBAMAZEPINE
(Tegretol)
60
Carbamazepine
1.The actions and mechanism
are similar to those of
phenytoin.
• highly effective for all partial
seizure as first-choice drug(for
complex partial seizures)
Carbamazepine
• highly effective for tonic-clonic
seizures,
• effective for trigeminal neuralgia
etc..
Carbamzepine
【Adverse effects】



CNS: somnolence, disequilibrium
Gastrointestinal tract: nausea,
vomiting and anorexia.
Rash and hepatic lesion.
OXCARBAZEPINE
(Trileptal)




Structure & mechanism Closely
related to carbamazepine
With improved toxicity profile
Less potent than carbamazepine
Active metabolite
64
OXCARBAZEPINE (Trileptal)

Use in partial and
generalized seizures as
adjunct therapy.
Toxicity:
•Hyponatremia
 May aggravate
•Less hyper-sensitivity and induction
myoclonic and
of hepatic enzymes
than with
absence
seizures.
carbamazepine
65
LAMOTRIGINE
(Lamictal)


like phenytoin, block
repetitive firing involving Na+
channels
Effective in myoclonic &
generalized seizures in
childhood and absence attacks.
66
LAMOTRIGINE (Lamictal)

Add-on therapy with valproic acid
Toxicity:
•Dizziness
 Almost completely absorbed
•Headache
•Nausea
 T1/2 = 24 hrs
•Somnolence
•Life
threatening
rash “Stevens-Johnson”
 Low
plasma protein
binding
67
II
Inhibitors of Calcium
Channels
68
ETHOSUXIMIDE (Zarontin)

Mechanism
reducing low-threshold Ca2+
channel current (T-type channel)
in thalamus
69
At high
+
+
 Inhibits Na /K ATPase.

Depresses cerebral metabolic rate.

Inhibits GABA aminotransferase.
At high

Choice for absence seizures.

High efficacy and safety.

Not plasma protein or fat binding
Ethosuximide
1.effective for absence seizure(First
-choice),
no effective for other seizures.
Ethosuximide
2.more adverse effects:
Gastrointestinal intolerance
Tiredness
Mood change
III
Increase GABAergic
transmission
74
CLONAZEPAM
(Klonopin)



A benzodiazepine.
(+) frequency of Cl- channel
opening.
One of the most potent antiepileptic
agents known.
75
CLONAZEPAM (Klonopin)


Long acting drug with efficacy for
absence seizures.
Also effective in some cases of
myoclonic seizures.
76
CLONAZEPAM (Klonopin)


Has been tried in infantile spasms.
Doses should start small.
77




Toxicity:
Sedation is prominent.
Ataxia.
Behavior disorders.
PHENOBARBITAL
(Luminal)
The oldest antiepileptic drug
except for the bromides
 A safest drugs, it has sedative
effects.
 Prolongs opening of Cl- channels.

79
PHENOBARBITAL
(Luminal)
Many consider them the drugs
of choice for seizures only in
infants.
 Useful for partial, generalized
tonic-clonic seizures, and febrile
seizures

80
PHENOBARBITAL
(Luminal)
Toxicity:
 Sedation.
 Cognitive impairment.
 Behavioral changes.
 Induction of liver enzymes.
 May worsen absence and
atonic seizures.
81
VALPROATE (Depakene)
Mechanism similar to phenytoin.
 (+) levels of GABA in brain.
 Facilitates glutamic acid
decarboxylase
 Inhibits the GABA-transporter in
neurons and glia (GAT).

82
VALPROATE (Depakene)


Fully ionized at body pH, thus
active form is valproate ion.
One of a series of carboxylic acids
with antiepileptic activity.
83
VALPROATE (Depakene)
Toxicity:
•Elevated liver enzymes including
own.
•Nausea and vomiting.
•Abdominal pain and heartburn.
Hepatotoxicity.
84
TOPIRAMATE
(Topamax)



Mechanism
(-)voltage-dependent sodium
channels
(+) inhibition of GABA (acting at a
site different from BDZs and
BARBs).
85
DIAZEPAM (Valium) AND
ClORAZEPAM (Ativan)

Toxicity
•Sedation
•Children
may manifest
a paradoxical
hyperactivity.
•Tolerance




Benzodiazepines.
Given I.V.
Lorazepam may be
longer acting.
for treating status
epilepticus
Have muscle
relaxant activity.
86
Benzodiazepines
Intravenous diazepam is
used for epilepticism in
adults( First-choice ).
Clonazepam is used for
absence
and
myoclonic
seizure in children.
PRIMARY GENERALIZED TONIC-CLONIC
SEIZURES (Grand Mal)
Drugs of choice: Carbamazepine
Phenytoin
Valproate*
*Not approved except if absence
seizure is involved
88
GENERALIZED ABSENCE SEIZURES
Drugs of choice: Ethosuximide
Valproate*
* First
choice if primary generalized
tonic-clonic seizure is also present.
89
ATYPICAL ABSENCE, MYOCLONIC, ATONIC*
SEIZURES
Drugs of choice:
Valproate
Clonazepam
Lamotrigine**
* Often refractory to medications.
**Not FDA approved for this indication. May worsen
myoclonus.
90
INTERACTIONS BETWEEN ANTISEIZURE DRUGS
With other antiepileptic Drugs:
Carbamazepine with
phenytoin
Increased metabolism of carbamazepine
phenobarbital
Increased metabolism of epoxide.
Phenytoin with
primidone
Increased conversion to phenobarbital.
Valproic acid with
clonazepam
May precipitate nonconvulsive status
epilepticus
phenobarbital
Decrease metabolism, increase toxicity.
phenytoin
Displacement from binding, increase
toxicity.
91
Drug choice for The Therapy of Epilepsy
1. Accurate evaluation.
2. The drug choice for initial treatment of seizures
.
(1) grad mal and simple partial seizures
Carbamazepine, phenytoin
phenobarbital, primidone and valproic acid as
alternative.
Therapy for Epilepsy
(2)Absence seizure
ethosuxide, valproic acid, clonazepam.
(3)Complex partial seizures
Carbamazepine, phenytoin,
primidone, valproic acid.
Therapy for Epilepsy
(4) Status epilepticus
Diazepam iv, or plus lorazepam.
or clonazepam, phenytoin and phenobarbital.
(5)Tonic seizure: valproic acid
(6)Myoclonic seizure
Glucocorticoids, clonazepam.
Therapy for Epilepsy
3. Duration of therapy: 2-3 years.
4. Change drug or add a second drug
and/or combination ----gradually.
5. Withdrawn or discontinue
----gradually (half year).
6. Monitoring the serum drug level.
Summary for this chapter
1. Choice of drugs for different
patterns of epilepsies
2. Effects and uses of phenytoin