Pharmacotherapy of epilepsy

Pharmacotherapy of Epilepsy

Presenter : Dr Swaroop H S

Swaroop: Antiepileptic drugs, 27/12/12

1

Epilepsy: Definition
o Seizures:

oParoxysmal event
oAbnormal excessive or synchronous neuronal
activity in the brain
o

Epilepsy:
o
o

o

Recurrent seizures
Cause: Chronic, underlying condition.

Epidemiological definition:
At least 2 unprovoked seizures

2

Seizure activity


3

History: Christian middle ages
14th century

Epilepsy came from demons, and was thought to be
contagious

4

Christian middle ages
14th century

Falling sickness: praying to virgina
marry for votive tablets

5

History: Renaissance
th TO 17th century
14

Quacks surgery

6

Euthanasia operation T4
'Tiergartenstrasse 4’

Physicians killed thousands of people who were "judged incurably
sick, by critical medical examination"

7

History:1990-1999




It took 12 years for Dr.
K. S. Mani to persuade
Parliament to delete a
clause in the
Indian Marriage Act
that
◦ Disqualified people
with epilepsy from
legally marrying.



The battle was finally
won in December 1999

Dr. K. S. Mani


8

Epilepsy: Classification
Focal
Seizures

Epilepsy

Generalized
Seizures

Focal Seizure without dyscognitive
features
Focal Seizures with dyscognitve
features
Typical
Absence
Seizures
Atypical
Tonic Clonic
Tonic
Atonic
Myoclonic

May be focal, generalized, or unclear epileptic
spasms


9

Epilepsy: Simple focal seizures


10

Epilepsy: Complex focal seizures


11

Generalised tonic clonic seizures



Main seizure type: In ~10% epileptics
Tonic phase:

◦ Stiff, crying out, tongue bite, apnea, cyanosed
◦ Increase heart rate, blood pressure
◦ Fall, labored breathing, salivation



Clonic phase:

◦ Intermittent clonic movements of muscles 
◦ Brief relaxations, involves all limbs 
◦ Incontinence at the end of clonic phase, lasts for few
minutes



Post-ictal period:
Drowsiness, confusion, headache, deep sleep


12

Generalized tonic clonic seizures


13

Absence seizures


14

Mesial Temporal Lobe Epilepsy
Syndrome (MTLE)


Most common syndrome associated with
focal seizures with dyscognitive features



Detection:
◦ High-resolution MRI to identify the
◦ Pathophysiology: Hippocampal sclerosis


15

Causes of Epilepsy



Idiopathic: 72%
Can be determined: 28% case
Determined causes:
 Inherited genetic:
 Acquired :
Trauma, Neuro surgery, Inflammatory,
Metabolic, Infections, Tumor, Toxic
disorders, drugs
 Congenital:
Inborn error of metabolism.
 Withdrawal of drugs:
Alcohol
Barbiturates
Anti-Epileptics
Benzodiazepines

16

Management
 First priorities:
◦ Attention to vital signs
◦ Respiratory and cardiovascular support
◦ Treatment of seizures if they resume
 To be followed by:
Management of life-threatening conditions
CNS infection, metabolic derangement and
drug toxicity
 When the patient is not acutely ill:
Evaluation should initially focus on whether
there is a history of earlier seizures

17

Epilepsy: Treatment algorithm


18

Antiepileptic drug therapy



Mainstay of treatment: Most epileptics
The overall goal:
◦
◦
◦
◦



Completely prevent seizures
Without causing any untoward side effects
Preferably a single medication
Dosing schedule: Easy for the patient to follow

Seizure classification:
An important element in designing the treatment
plan, since some antiepileptic drugs have different
activities against various seizure types

19

Anti Epileptic Drugs (AED):
Classification


Older AEDs:
◦ Phenobarbital, Phenytoin, Primidone
◦ Ethosuximide , Carbamazepine , Valporate



Newer AEDs:
◦
◦
◦
◦

Lamotrigine, Topiramate, Tiagabine
Oxcarbazepine, Zonisamide, Levetiracetam
Vigabatrin, Felbamate, Pregabalin
Rufinamide, Lacosamide, Stiripentol,
Clobazam
◦ Eslicarbazepine, Ezogabine, Perampanel

20

Seizure: Types and Choice of
AEDs


21

Mechanism of action: Older AED’s
Action of phenytoin on
A.

Channel

Na+

Resting State

B.

Na+

Arrival of AP
Na+

Depolarization
Channel opens
Sodium flows in
C.

Na+

Refractory State
Inactivation

22

Facilitation of GABA mediated
Chloride channel opening

•
•
•
•
•

Drugs acting
through this
mechanism are
Barbiturate
Benzodiazepine
Vigabatrin
Valproate
Gabapentin


23

Glutaminergic synapse



Type: Excitatory
Permeable to:

Na+
Ca2+

Na+, Ca2+ and K+


Blocked by:
Magnesium ions in
resting state



GLU
GLY

Enhancement:
Glycine (GLY) binding
enhances the ability of
GLU or NMDA to open
the channel



AGONISTS

Mg++

Agonists:
NMDA, AMPA, Kianate

K+

24

Phenobarbitone


Discovery:
1912: First efficacious AED, it raised seizure
threshold as well as limits spread, suppresses kindled
seizures with wide spectrum, one of the safest drugs



Pharmacokinetics:

◦ Slow oral absorption, long plasma t1/2 (80-120
hours), 40-60% bound to plasma proteins
◦ Metabolism: liver , excreted unchanged by kidney



Disadvantage:

◦ Sedation, nystagmus, ataxia, hyperactivity in
children and confusion in the elderly



Dose:
Adult: 60mg OD to tds, children: 3-6mg/kg/day

25

Phenytoin


Synthesis 1908 :
German chemist Sir
Heinrich Blitz



Advantage:
◦ Oldest non-sedative AED

First clinical use 1937 :
Meritt and Putnam


26

Phenytoin


Pharmacokinetics:
◦ Extensively bound (~90%) to serum proteins
◦ Plasma t1/2 : 6 and 24 hours at plasma conc.
10 g/mL but with higher conc.
◦ Metabolism: hepatic CYP2C9/10, CYP2C19
◦ Excretion: Bile and urine

•

Dose:
• Adult: 300mg/day
• Children: 5mg/kg/day

27

Adverse reactions of Phenytoin
•
•
•
•
•

•

Stevens-Johnson
syndrome
Toxic epidermal
necrolysis
Systemic lupus
erythematosus
Fatal hepatic necrosis
Neutropenia
Leukopenia

Gingival hyperplasia
Fetal hydantoin syndrome


28

Fosphenytoin


Type of drug:
Prodrug of phenytoin



Advantage:
Water-soluble



Conversion:
Phosphatases in liver and red blood cells



Pharmacokinetics:

◦ Plasma t1/2 : 8-15 minutes
◦ Extensively bound (95-99%) to human plasma
proteins



Formulations: IV and IM

29

Carbamazepine
•
•
•

Approval: U.S. in1974
Derivative: Iminostilbene with a
carbamyl group at the 5th position
Pharmacokinetics:
• Peak concentrations in plasma usually are
observed 4-8 hours after oral ingestion
• 75% of binds to plasma proteins
• Metabolism: Hepatic CYP3A4


30

Carbamazepine


Adverse reactions: Acute intoxication
◦ Stupor or coma, hyper-irritability, convulsions,
and respiratory depression, drowsiness, vertigo,
ataxia, diplopia, and blurred vision
◦ Aplastic anemia, agranulocytosis



Interactions:
Phenobarbital, phenytoin, and valproate:
induction of CYP3A4 CBZ



Dose:
◦ Adult: 200 to 400mg TDS
◦ Children: 15 to 30mg/kg/day

31

Valproic acid
Spectrum: Broad
 Mechanism of action:


◦ Frequency dependent prolongation of sodium
channel inactivation
◦ Attenuation of calcium mediated T current
◦ Augmentation of release of inhibitory
transmitter GABA by inhibiting its
degradation


32

Valproic acid


Pharmacokinetics:
◦ Plasma protein binding: 90%
◦ Plasma t1/2: 10 -15 hours
◦ Metabolism: Liver Oxidation and glucuronide conj.



Adverse reactions:
◦ Alopecia, Curling of hair, increased blood ammonia,
PCOD, Fulminant hepatitis, neural tube defects
◦ Rashes and thromobocytopenia



Dose:
◦ Adult: 200 – 800mg TDS
◦ Children: 15-30mg/kg/day

33

Fetal Valproate Syndrome

Fetal
Valproate
Syndrome
Child with facial features of FVS: Trigonocephaly which has been surgically
repaired, broad forehead, thin arched eyebrows, flat nasal bridge, infraorbital
grooves, short anteverted nose, long and smooth philtrum and thin upper lip.


34

Ethosuximide
•

Mechanism of action:
• It has an important effect on Ca 2+ currents,
reducing the low-threshold (T-type) current.

•

Pharmacokinetics:
• t1/2 : 40 hours
• Metabolism: Hydroxylation

•

inactive products

Adverse reactions:
• Gastric distress including pain, nausea, and
vomiting

•

Dose: 20-30mg/kg/day

35

Levitracetam


◦ It inhibits partial and secondarily generalized
tonic-clonic seizures in the kindling model
◦ Inhibits synaptic vesicle protein (SV2A)



Pharmacokinetics:
◦ Oral absorption: Nearly complete, rapid and
unaffected by food
◦ Plasma half-life: 6–8 hours
◦ Two thirds of the drug is excreted unchanged
in the urine

36

Levitracetam
Advantage: Well tolerated.
 Adverse drug reactions:


◦ Somnolence, asthenia, and dizziness
◦ Behavioral problems, Psychosis and
depression


Dose: Adult: 500-3000mg/day


37

Oxcarbazepine





It is a prodrug of carbamazepine
Mechanism of action: Similar to that of
carbamazepine.
Half-life: 1–2 hours
Advantage:
◦ Less potent enzyme inducer than carbamazepine



Most common AE: Hyponatremia,
Dizziness, nausea, vomiting, abdominal pain,
headache, somnolence, diplopia, fatigue,
imbalance and tremor

38

Esclicarbazepine
Type of drug: Prodrug
 Advantage: Once daily dosing
 Half-life: 9-11 hours
 Approved in Europe as adjunctive therapy
in adults with partial-onset seizures, with
or without secondary generalization
 Dose: 400–1200 mg/d



39

Lacosamide


Functionalized amino acid




◦ Lacosamide facilitates slow inactivation of
voltage gated sodium ion channels
◦ Binds to a collapsin response mediator
protein-2
◦ This protein performs important roles like
cytoskeletal, vesicle, and synaptic functions in
the developing brain


40

Lacosamide


Pharmakokinetics:

◦ Metabolism: CYP2C19 by demethylation
◦ No significant induction/inhibition or interaction



Adverse drug reactions:
Dizziness, headache, nausea, and diplopia



Use:
Adjunctive therapy in the treatment of partial-onset
seizures



Dose:

◦ Adult: 50 mg twice daily; may be increased at weekly
intervals by 100 mg/day
◦ Maintenance dose: 200-400 mg/day

41

Rufinamide
•

It slows sodium ion channel recovery from the
inactivated state & limits repetitive neuronal
firing

•

Plasma half life: 6-10 hours
• Most common AE:
Dizziness, fatigue, somnolence, nausea, headache
•

Use:
In the treatment of generalized seizures of
Lennox-Gastaut syndrome (LGS)

42

Vigabatrin


It irreversibly inhibits the major degradative enzyme
for GABA



Use:
◦ Adjunctive treatment for infantile spasms and adult
refractory complex partial seizure
◦ Good 1st choice for infantile spasms from tuberous
sclerosis (TS)



Reserve drug:
Due to progressive and permanent bilateral vision
loss, must be reserved for patients who have failed
several alternative therapies

43

Perampanel
•
•

•

Targets the AMPA component
Pharmacokinetics:
95% bound to plasma proteins
Metabolized by CYP3A4

Adverse reactions:
Dizziness, Somnolence, fatigue and headache

•

Use:
Approved for refractory partial onset seizures in Oct
2012

44

Ezogabine
•

Approved in 2011
• Mechanism of action:
K+ opener
•

Adverse reactions:
• Dizziness, somnolence, fatigue, urinary retention,
ataxia, blurred vision.

•

Use:
• For refractory partial onset seizures for patients ≥
18years, with Seizure ≥ 4 /month
• In clinical trial, Ezogabine reduced seizure frequency
by 44.3% vs 17.5% for placebo

45

References








Goodman and Gilman‟s: The Pharmacological basis of Therapeutics
12th edition, Laurence L Bruton, 2010, USA
Katzung „s “ Basic and Clinical Pharmacology”: 12th edition,
Bertram G Katzung.
Antiepileptic drugs by Martha I. Dávila-García, Ph.D. Howard
University, available on www.medscape.com accessed on
21/12/2012
Essentials of Medical pharmacology by KD Tripathi 6th edition,
2008, Jaypee brothers, New Dehli.
Text book of Internal Medicine by Harrisons 16th edition.
Magiorkinis E, Sidiropoulou K and Diamantis A. Hallmarks in the
history of epilepsy: from antiquity till the twentieth century.
Available from: http://cdn.intechopen.com/pdfs/21744/InTechHallmarks_in_the_history_of_epilepsy_from_antiquity_till_the_twe
ntieth_century.pdf, accessed on 25th October, 2012.

46

Thank You


47

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