Seizure Disorders.pptx

1. Seizure Disorders

2. • Sezures are sudden abnormal electrical
discharges from the brain

3. PATHOPHYSIOLOGY

4. CLASSIFICATION OF SEIZURES
• PARTIAL/FOCAL SEIZURES
• GENERALIZED SEIZURES
• SECONDARY GENERALIZED

5. CLASSIFICATION OF SEIZURES
PARTIAL SEIZURES
TYPE CHARACTERISTICS
COMPLEXPARTIAL SEIZURES IMPAIRED LEVEL OF
CONCIOUSNESS
-AUTOMATISM(lip smacking,
chewing, fidgeting, walking
and other repetitive
involuntary but coordinated
movements)
SIMPLE PARTIAL SEIZURES WITHOUT LOSS OF
CONCIOUSNESS
a) Jerking, muscle rigidity,
spasms, head turning
b) Unusual sensation
affecting either vision,
hearing, smell taste, touch
c) Memory or emotional
disturbance

6. CLASSIFICATION OF SEIZURES
GENERALIZED SEIZURES
TYPE CHARACTERISTICS
ABSENCE SEIZURES (PETIT
MAL)
BRIEF disconnection from
sorounding stimuli, the patient
appear absent and stares off
vacantly for a few seconds
TONIC CLONIC SEIZURES
(GRAND MAL)
UNCONCIOUSNESS,
CONVULSIONS, MUSCLE
RIGIDITY

7. CLASSIFICATION OF SEIZURES
• GENERALISED SEIZURES
TYPE CHARACTERISTIC
MYOCLONIC SEIZURES SPORADIC JERKS
(usually both sides of the
body)
ATONIC SEIZURES SUDDEN AND GENERAL LOSS
OF MUSCLE TONE,
PARTICULARY IN THE ARMS &
LEGS WHICH OFTEN RESULTS
IN A FALL

8. CLASSIFICATION OF SEIZURES
GENERALISED SEIZURES
TYPE CHARACTERISTICS
TONIC SEIZURES MUSCLE STIFFNESS & RIGIDITY
CLONIC SEIZURES REPITITIVE , RHYTHMIC JERKS
THAT INVOLVE BOTH SIDES OF
THE BODY AT THE SAME TIME

9. CLASSIFIACTION OF SEIZURES
• The classification of epilepsies is more
complex, since cases can involve more than
one seizure type.
• The newly recommended approach is to refer
to epilepsies in regard to etiology; genetic,
structural, metabolic, idiopathic, age of onset,
EEG findings, neurologic examination Berg et
al.2010

10. STATUS EPILEPTICUS
• A single seizure lasting more than five minutes
or two or,
• more seizures within a five minute period
without the person returning to normal
between them.

11. FEBRILE SEIZURES
• A convulsion in a child that is caused by a
fever.
• The fever is often from an infection

12. ANTIEPILEPTIC DRUGS
• Antiepileptic drugs can be grouped according
to their major mechanisms of action
• Some antiepileptic drugs work by acting on
combination of channel or through some
unknown mechanisms

13. SODIUM CHANNEL BLOCKERS
The firing of an action potential by an axon is
accomplished through sodium channels
• Resting state: channel allows passage of
sodium into the cell
• Active state: during an action potential
channel allows increased influx of sodium into
the cell
• Inactive state: channel does not allow passage
of sodium into the cell

14. MOA:
• AEDs that target the sodium channels prevent
the return of these channels to the active
state by stabilizing them in the inactive state.
Hence prevent the repetitive firing of the
axons
• Stabilize the inactive configuration of sodium
channel, preventing high frequency neuronal
firing

15. CARBAMAZEPINE
• Block sodium channels during rapid,
repetitive, sustained neuronal firing and
prevent posttetanic potentiation.
• Crystaline, insoluble in water, limited to oral
admnistration
• Unstable, hot and humid conditions decrease
its bioavailability by 50%

16. CBZ
• Approximately 75-85% is protein bound
• CSF levels range from 13-31%
• Metabolized extensively by the liver (CYP3A4)
and induces its own metabolism
• Hence induces the metabolism of tricyclic
antidepressants, oral contraceptives,
cyclosporin A, warfarin

17. CBZ
• Inducers of CYP3A4 eg phenobarbital,
phenytoin, felbamate, primidone, grapefruit
juice, st john’s wort decrease CBZ levels.
• Inhibitors of CYP3A4 eg macrolide antibiotics,
isoniazid, chloramphenicol, CCB, cimetidine
raise CBZ levels

18. CBZ
• Highly effective for partial onset seizures
including cryptogenic and symptomatic partial
seizures
• Good efficacy in treatment of generalised
tonic clonic seizures
• Potential dose related adverse effects
dizziness, diplopia, nausea, ataxia, blurred
vision. (transiet at the initiation of therapy)

19. CBZ
• Idiosyncratic adverse effects include aplastic
anemia, agranulocytosis, thrombocytopenia,
SJS
• Asymptomatic elevation of liver enzymes is
observed commonly during the course of
treatment , rarely severe hepatotoxic effects
occur.

20. OXCARBAZEPINE
• Recently developed analogue of CBZ.
• Developed in attempt to maintain the benefits
of CBZ while avoiding its autoinduction and
drug interaction properties.
• Does not produce epoxide metabolite
• Interacts with oral contraceptives hence
reduce efficacy

21. OXC
• Approved monotheray or adjunctive therapy
in patients with partial and secondary
generalised seizures.
• Somnolence, headache, dizziness, rash,
hyponatremia, weight gain, gastrointestinal
disturbances and alopecia are the most
comon side effets

22. PHENYTOIN
• Blocks the movement of ions through sodium
channels during the propagation of the action
potential and thus block and prevent the
posttetanic potentiation , limits development of
maximal seizure activity and reduce the spread of
seizures.
• Inhibitting effect on calcium channels and the
sequestration of calcium ions in nerve terminals
thereby inhibiting voltage dependent
neurotransmission at the level of the synapse

23. PHT
• The antiepilepic effect on calmodulin and
other secondary messenger systems is unclear
• Lipid soluble crystalline powder, weak acid pka
8.3-9.2, hence soluble in alkaline solutions.
• Not absorbed in the stomach ,absorbed slowly
in the small intestine (higher ph)
• Oral bioavailability 95%
• 70-95% bound to plama protein

24. PHT
• Plasma brain ratio 1- 2
• Metabolised in the liver by the CYP 450 mixed
oxidase system and follows zero order kinetics
• Strong inducer of hepatic enzymes alters
levels of other drugs
• Decreases levels of furosemide, cyclosporin,
folate, praziquantel,
• Excretion is through kidneys

25. PHT
• Commonly used first line or adjunctive
treatment for partial and generalised seizures,
Lennox-Gastaut syndrome, status epilepticus
and childhood epileptic syndromes.
• Contraindicated in myoclonus and absence
seizures.
• And in pregnancy ( cleft palate, cleft lip,
congenital heart disease, mental deficiency,
slowed growth rate)

26. PHT
• PHT causes CNS and Systemic adverse effects.
• Affects the vestibular-cerebellum resulting
into ataxia and nystagmus
• PHT is not a generalised CNS depressant,
however some degree of drowsiness and
lethargy is present without progression to
hypnosis

27. PHT
• Nausea, vomitting, rash, blood dyscrasias,
headaches, vitamin k and folate deficiencies,
loss of libido, hormonal disfunction and bone
marrow hypoplasia
• Long term use has been associated with
osteoporosis

28. LAMOTRIGINE
• Oral bioavailability close to 100%
• Protein binding 55%, half life 24 to 41 hrs
• Metabolised by liver, excreted through kidneys
• Produces autoinduction at higher doses and has
no active metabolites
• Does not induce or inhibit hepatic enzymes
• LTG levels increase with concomitant use of
Valproate to 70hrs, hence enhanced epileptic
effect ( increase chances of developing allergic
skin reactions)

29. LTG
• Effective in partial onset and secondary
generalised tonic clonic seizures, primary
generalised seizures, atypical absence
seizures, tonic/atonic seizures and Lennox
Gastaut syndrome.
• Preffered treatment during pregnancy and for
the elderly

30. LTG
• Adverse drug effects include headacche,
diplopia, ataxia, tremors, psychosis,
somnolence, insomnia, blood dyscrasias, GI
disturbances.
• Rash is the main concern associated with this
drug, especially when combined with
Valproate.
• Severe rash may develop and lead to Stevens
Johnson syndrome.

31. CALCIUM CHANNEL BLOCKERS
• Exist in 3 known forms in the human brain L, N
and T
• Low voltage calcium currents, T type are
responsible for the rythmic thalamocortical
spike and wave patterns of generalised
absence seizures

32. MOA
• AEDs that inhibit these channels, lock these
channels, inhibiting underlyng slow
depolarizations necessary to generate spike
wave bursts.
• Eg Valproate, Ethosuximide

33. GABA ENHANCERS
• Gamma aminobutyric acid has 2 types of
receptors, A and B.
• When GABA binds to GABA A receptors the
passage of chloride into the cells is facilitated
via chloride channels.
• The influx increase the negativity of the cell
• hence hyperpolarization and inhibition

34. MOA
1. Modulate the enzyme glutamic acid
decarboxylase (GAD) that mediate the
decarboxylation of glutamate to produce
GABA. e.g. gabapentine, valproate
2. Function as agonists to chloride conductance
e.g. barbiturates, benzodiazepines,
progesterone, ganaloxone

35. MOA
3. Blocking the presynaptic uptake of GABA e.g.
tiagabine
4. Inhibitting the metabolism of GABA by GABA
transaminase e.g. vigabatrin
Resulting in increased accumulation of GABA at
the post synaptic receptors.

36. 1. GABA Receptor Agonists
GABA A receptors have multiple binding sites for
benzodiazepines, barbiturates, and other
substances eg picrotoxins, bicuculline,
neurosteroids (progesterone)
Clinical implications of each receptor site are not
well understood

37. BENZODIAZEPINES
• Eg lorazepam, diazepam, midazola,
clonazepam, clobazam
• The first 2 are used mainly for emergency
treatment of seizures because of their quick
onset of action, availability of IV forms and
strong anticonvulsant effect
• Their use for longterm treatment is limited
because of -TOLERANCE

38. BARBITURATES
• Eg Phenobarbital, primidone
• They bind to the barbiturate binding site of
the benzodiazepine receptor to affect the
duration of chloride channel opening
• Very potent anticonvulsants, with significant
adverse effects
• Currently widely used as second line drugs for
the treatment of chronic seizures

39. PHENOBARBITAL
• Free acid, insoluble in water
• Apart from acting on GABA receptors, it also
reduces sodium and potassium conductance
and calcium influx and depress glutamate
excitability
• Oral and IM bioavailabity of 80 to 100%, oral
bioavailabity reduced in patients with poor GI
motility
• Absorbed mainly in the small intestine

40. PHB
• Plasma protein binding 40 to 60 %
• Brain penetration is faster during status
epilepticus because of increased blood flow
and acidosis
• Half life 75 to 140hrs, up to 400hrs in infants
• Metabolized by the liver
• Metabolism is inhibited by phenytoin,
valproate, felbamate and dextropropoxyphene

41. PHB
• Enzyme inducers such as rifampin decrease
PHB levels.
• PHB is a potent inducer of hepatic enzymes
hence increases the metabolism of estrogen,
steroids, warfarin, carbamazepine, diazepam,
clonazepam
• Its effect on phenytoin is unpredictable

42. PHB
• First line treatment of status epilepticus
• Second line agent in the treatment of partial
onset and secondary generalised tonic clonic
seizures
• Widely used because of low cost
• Adverse effect include cognitive and behavioural
alterations
• Sedation, psychomotor slowing, poor
concentration, irritability, ataxia, decreased libido

43. PHB
• Longterm use: coarsening of facial features,
osteomalacia, dupuytren contractures, folate
deficiency, megaloblastic anameia,
idiosyncratic skin reaction are rare and
hepatitis has been reported secondary to an
immune mediated process

44. PRIMIDONE
• Metabolised to PHB and
phenylethylmalonamide (PEMA).
• Its main action is through the derived PHB
• Oral bioavailability is close to 100%
• Halflife 5 to 18hrs
• Metabolised by Cytochrome oxidase system,
hence affected by enzyme inducers including
PHB.

45. primidone
• Indicated for the treatment of partial onset
seizures and secondary generalised seizures
• Mostly used as a second line
• Adverse effects include intense sedation,
diziness, nausea at the onset of treatment
• Effects usually clear aftr a week
• A very low dose is recommended at the start

46. 2. GABA Reuptake Inhibitors
• Reuptake of GABA is facilitated by atleast 4
specific GABA transporting compounds, these
carry GABA from the synaptic space into
neurones and glial cells where it is metabolised.
• Nipecotic acid and tiagabine are inhibitors of
these transporters, hence increased amounts of
GABA in the synaptic cleft and prolongation of
inhibitory postsynaptic potentials.

47. TIAGABINE
• Derivative of nipecotic acid
• Inhibits GABA transporter 1(reversible)
• Lipid soluble thus cross BBB
• Oral bioavailability approximately 96%
• Food decrease absorption by 2 to 3 fold
• halflife 4.5 to 8.1
• Metabolised in the liver
• Use is limited to adjunctive therapy in refractory
partial epilepsy

48. • It can worsen seizure and cause status
epilepticus
• Adverse effects include diziness, asthenia,
nervousness, tremor, depressed mood,
emotional lability.
• Diarhea, somnolence, headaches, abnormal
thinking, abdominal pain, pharyngitis, ataxia,
confusion and skin rash

49. 3. GABA Transaminase Inhibitors
• GABA is metabolised by transamination in the
extracellular compartment by GABA
transaminase (GABA T).
• Inhibition of GABA T leads to an increase in
extracellular concentration of GABA.
• Vigabatrin inhibits GABA T.

50. 4. GAD Modulators
• Glutamic acid decarboxylase converts
glutamate (GAD) into GABA.
• Some AEDs are known to have effect on GAD
and thereby enhance the synthesis of GABA,
in addition to other potential mechanisms of
action.
• Eg Gabapentin, Pregabalin, Valproate

51. GABAPENTIN
• Oral Bioavailability of less than 60% reduced
by antiacids
• Halflife 5 to 9 hrs
• Not bound to plamsa proteins
• Not metabolised
• Excreted entirely in unchanged form

52. GBP
• Useful in treatment of partial and secondary
generalised tonic clonic seizures
• Effective in treatment of epileptic patients
with coexistent neuropathic pain and/or
migraine
• Useful in patients with renal or hepatic
disease
• Relatively well tolerated, effects in high doses
and are usually minor (neutropenia, rash)

53. VALPROATE
• Oral bioavailability almost 100%
• 85 to 95% plasma bound
• Metabolized in the liver
• Potent inhibitor of both oxidation and
glucurodination
• Drug of choice in the treatment of primary
generalised epilepsies and approved for
partial seizures

54. VPA
• Should be avoided in pregnancy and women
of reproductive age
• Adverse effects include insulin resistance,
change is sex hormones (anovulatory cycles,
amenorrjea, PCOS), bone marrow suprression,
allergic rashes,acute pancreatitis,
hepatotoxicity

55. GLUTAMATE BLOCKERS
• Glutamate receptors bind glutamate an
excitatory amino acid neurotransmitter.
• Upon binding ,the flow of sodium and calcium
ions into the cell is facilitated, while potassium
ions flow out of the cell, resulting in
excitation.
• Glutamate receptor has 5 potential binding
sites AMPA, kainate , NMDA, glycine and
metabotropic site

56. Glutamate blockers
• Some AEDs modify these receptors are
antagonistic to glutamate, reponses differ
depending on the binding site affected.
• Eg felbamate, Topiramate, Perampanel,

57. CARBONIC ANHYDRASE INHIBITORS
• Inhibition of enzyme carbonic anhydrase
increase the concentration of hydrogen ions
intracellulary and decrease the ph.
• The potassium ions shift to the extracellular
compartment to buffer the acid base status
hence hyperpolarization and an increase in
seizure threshold of the cells

58. CAI
• Acetazolamide has been used as adjunctive
therapy in the refractory seizures with
catamenial pattern
• Topiramate and Zonisamide are also weak
inhibitors of CA, though this is not believed to
be their main mechanism of action

59. NEURONAL POTASSIUM CHANNEL
OPENERS
• Ezogabine