Clinical pharmacology: types of epilepsy, treatment strategy, indications, side effects

1. Clinical pharmacology of
antiseizure drugs
Domina Petric, MD

2. Partial seizures
I.

3. Partial seizures
• The attack begins in a specific locus
in the brain.
Types of partial seizures:
• simple partial seizure
• complex partial seizure
• secondarily generalized attack

4. Simple partial seizure
• It is characterized by minimal spread of the
abnormal discharge such that normal
consciousness and awareness are preserved.
• The patient may have a sudden onset of
clonic jerking of an extremity lasting 60-90
seconds.
• Residual weakness may last for 15-30
minutes after the attack.

5. Simple partial seizure
The patient is completely aware of the
attack and can describe it in detail.
The EEG (electroencephalogram) may show
an abnormal discharge highly localized to
the involved portion of the brain.

6. Complex partial seizure
• It has also a localized onset.
• The discharge becomes more widespread
(usually bilateral) and almost always involves
the limbic system.
• Most complex partial seizures arise from one of
the temporal lobes.
• Temporal lobes are susceptible to insults such
as hypoxia or infection.

7. Complex partial seizure
• The patient may have a brief warning
followed by an alteration of consciousness
during which some patients stare and
other stagger or even fall.
• Most attacks demonstrate fragments of
integrated motor behavior: automatisms.
• Patient has no memory for automatisms.

8. Complex partial seizure
• Typical automatisms are lip
smacking, swallowing, fumbling,
scratching and even walking about.
• After 30-120 seconds, the patient
makes a gradual recovery to normal
consciousness, but may feel tired or
ill for several hours after the attack.

9. Secondarily generalized attack
Partial seizure
immediately precedes a
generalized tonic-clonic
(grand mal) seizure.

10. Partial seizures
Complex partial seizure
Disharge is more
widespread and almost
always involves the limbic
system.
Simple partial seizure
Minimal spread of
abnormal discharge.
Secondarily generalized attack
Partial seizure
immediately precedes a
grand mal seizure.
!
Complex
Simple

11. Generalized seizures
II.

12. Generalized seizures
Generalized tonic-clonic (grand mal)
Absence (petit mal) seizure
Myoclonic jerking
Atonic seizures
Infantile spasms

13. Generalized tonic-clonic
• Grand mal seizures are the most dramatic
of all epileptic seizures.
• These seizures are characterized by tonic
rigidity of all extremities, followed in 15-
30 seconds by a tremor.
• Tremor is actually an interruption of the
tonus by relaxation.

14. Generalized tonic-clonic
• As the relaxation phase becomes longer, the
attack enters the clonic phase, with massive
jerking of the body.
• The clonic jerking slows over 60-120
seconds.
• The patient is usually left in a stuporous
state.
• The tongue or cheek may be bitten.
• Urinary incontinence is common.

15. Generalized tonic-clonic
Primary generalized tonic-clonic
seizures begin without evidence of
localized onset.
Secondarily generalized seizures are
preceded by another seizure type,
usually a partial seizure.

17. Absence seizure
• Petit mal seizure is characterized by both
sudden onset and abrupt cessation.
• Its duration is usually less than 10 seconds and
rarely more than 45 seconds.
• Consciousness is altered.
• The attack may also be associated with mild
clonic jerking of the eyelids or extremities, with
postural tone changes, autonomic phenomena
and automatisms.

18. Absence seizure
• Absence attacks begin in
childhood or adolescence and
may occur up to hundreds of
times a day.
• EEG: 2,5-3,5 Hz spike-and-wave
pattern.

19. Epilepsydiagnosis.org

20. Atypical absence
Seizures with more abrupt postural changes.
Such patients are often mentally retarded.
EEG: slower spike-and-wave discharge.
Seizures may be more refractory to therapy.

21. Myoclonic jerking
• It is seen in generalized tonic-clonic, partial
and absence seizures, and infantile spasms.
• Treatment should be directed at the
primary seizure type.
• Some patients have myoclonic jerking and
occasional generalized tonic-clonic seizures
without overt signs of neurologic deficit.

23. Atonic seizures
• The patient has sudden loss of postural tone.
• If standing, the patient falls suddenly to the
floor and may be injured.
• If seated, the head and torso may suddenly
drop forward.
• Most often in children, but not unusual in
adults.
• Many patients wear helmet.

24. Atonic seizures
Momentary increased
tone may be observed
in some patients: tonic-
atonic seizure.

26. Infantile spasms
• Epileptic syndrome.
• The attack is most often bilateral.
• Infantile spasms are most often characterized
clinically by brief, recurrent myoclonic jerks of
the body with sudden flexion or extension of
the body and limbs.
• 90% of affected patients have their first attack
before the age of 1 year.
• Most patients are intellectually delayed.

27. Generalized seizures
Myoclonic jerking
Treatment is directed at the
primary seizure type.
Atonic seizures
Patients often wear
helmet.
Petit mal
Start in childhood or
adolescence
Grand mal
Generalized tonic-clonic
seizures
Grand
mal
Atonic
seizures
Myoclonic
jerking
Absence
Infantile spasms: epileptic syndrome.

28. Therapeutic strategy
III.

29. Therapeutic strategy
• The use of a single drug is preferred,
especially in patients who are not
severely affected and who can benefit
from the advantage of fewer adverse
effects.
• For patients with hard-to-control seizures,
multiple drugs are usually utilized
simultaneously.

30. Therapeutic strategy
• The therapeutic index for most
antiseizure drugs is low.
• Toxicity is not uncommon.
• Effective treatment of seizures often requires
an awareness of the therapeutic levels and
pharmacokinetic properties as well as the
characteristic toxicities of each agent.

31. Therapeutic strategy
Measurements of antiseizure
drug plasma levels can be
very useful when combined
with clinical observations and
pharmacokinetic data.

32. Management of epilepsy
IV.

33. Partial and tonic-clonic generalized
seizures
Phenytoin Carbamazepine Barbiturates
Benzodiazepines
Newer:
lamotrigine,
levetiracetam…

34. Generalized seizures
Ethosuximide Valproate Clonazepam
Lamotrigine Topiramate

35. Generalized seizures
• Specific myoclonic syndromes are usually
treated with valproate.
• Zonisamide, levetiracetam, clonazepam,
nitrazepam may be useful.
• Juvenile myoclonic epilepsy can be aggravated
by phenytoin or carbamazepine: VALPROATE is
drug of choice, followed by lamotrigine and
topiramate.

36. Generalized seizures
Atonic seizures are often refractory to all
available medications.
Valproate, lamotrigine, benzodiazepines and
felbamate may be helpful is some patients.
The ketogenic diet may also be useful.

37. Infantile spasms
• The treatment is limited to improvement of
control of the seizures.
• Most patients receive a course of im.
corticotropin.
• Prednisone may be equally effective and can be
given orally.
• Other drugs: clonazepam, nitrazepam,
vigabatrin.

38. Status epilepticus
• Diazepam is the most effective drug in
most patients.
• It is given iv. 10 mg bolus up to 20-30 mg
in adults.
• It may depress respiration and, less
frequently, cardiovascular function.
• Lorazepam has longer duration of action.

39. Generalized seizures
• Fosphenytoin iv.
• Phenobarbital 100-200 mg iv. to a
total of 400-800 mg.
• Lidocaine iv.
• Benzodiazepines or iv. valproate
for absence status.

40. Toxicology of antiseizure drugs
V.

41. Teratogenicity
• Children born to mothers taking
antiseizure drugs have an increased risk
of congenital malformations.
• Phenytoin can cause fetal hydantoin
syndrome.
• Pregnant woman taking valproic acid or
sodium valproate has a 1-2% risk of
having a child with spina bifida.

42. Withdrawal
• Withdrawal of antiseizure drugs can cause
increased seizure frequency and severity.
• Withdrawal of anti-absence drugs is
easier than withdrawal of drugs needed
for partial or generalized tonic-clonic
seizures.
• Barbiturates and benzodiazepines are the
most difficult to discontinue.

43. Overdose
• The most dangerous effect of
antiseizure drugs after large
overdoses is respiratory depression,
which may be potentiated by other
agents (for example, alcohol).
• Treatment is supportive.

44. Toxicology of antiseizure drugs
Specific agent
Barbiturates,
benzodiazepines
Respiratory
depression
0,37% of
patients
Side effects
Teratogenicity
Withdrawal
Overdose
Suicidality
Phenytoin,
valproate

45. Literature
• Katzung, Masters, Trevor.
Basic and clinical
pharmacology.
• A.D.A.M. pictures
• Epilepsydiagnosis.org