pharmacology .. treatment of epilepsy

P H R M A C O L O G Y - NOTE 14 - Treatment of Epilepsy

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ANTI-EPILEPTIC DRUGS

Partial seizures & gneralized tonic-clonic

Old Drugs

Phenytoin

Carbamazepine

Valporate

Barbiturates

Newer Drugs

Lamotrigine

Gabapentine

Topiramate

Vigabatrine

Levetriacetam

Felbamate

TiagabineZonisamide

Generalized seizures

Ethosuximide Phensuximide

Trimethadone Oxazolidinediones

Others

Acetazolamide Benzodiazepines

Diazepam

Lorazepam

Clonazepam

Nitrazepam

Clorazepate Dipotassium

Clobazam

Involvement of

Focal Seizures

Generalized Seizures

TREATMENT

• motor area (convulsion)

• hypothalamus (autonomic discharge)

• reticular formation (unconsciousness)

• Repeated seizure activity leads to neurodegeneration due to excitotoxicity

•remains localized

•primary (involve all cortical neurons)

•secondary (spread afterward)

• inhibitory NT.

• excitatory Nt

•alter the permability of membrane to ions (Na, K or Ca)

PA

RTI

AL

SEIZ

UR

ES •simple(consciousness)

•complex (unconsciousness)

•PS secondarily generalized

GEN

ERA

LISE

D

SEIZ

UR

ES •Generalized tonic-clonic (grand mal)

•Absence (petit mal)

•Tonic , Atonic , Clonic & Myoclonicseizures

• Infantile spasm



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Partial seizures & generalized tonic-clonic DRUG PHARMACOKINETIC MECHANISM OF ACTION USES SIDE EFFECT

Old

Dru

gs

Phenytoin It is metabolized in the liver.

plasma conc. <10 mg/L . 1

st order kinetics.

plasma conc. = 10-20 mg/L . zero order kinetics.

The metabolism is inhibited by: o Na valporate. o Cimetidine. o Isoniazide. o Chloramphenicol. o Co-trimoxazole.

It is a inducer of HME.

So, it enhances metabolism of:

Carbamazepine

Warfarin,Steroids.

TCA & OC

Block or alter Na-voltage channels.

At high concentration: Inhibit release of NE & 5-TH. Inhibit MAO activity. Promote uptake of

Dopamine

1) Partial seizures 2) Generalized tonic-clonic seizures. 3) Status epilepticus. 4) Trigeminal neuralgia (2nd

choice). 5) Cardiac arrhythmia.

DOSE DEPENDENT

Acute effect

Nystagmus. Diplopia. Ataxia. Lethargy. Sedation.

Chronic effect:

Gingival hyperplasia, Hirsutism , Acne Nausea ,vomiting ,epigastric pain, anorexia. Megaloblastic anemia. Mild peripheral neuropathy

Osteomalacia. Hemorrhagic diseases of new born. Fetal Hydantoin syndrome.

HYPERSENSITIVITY

Agranulocytosis with fever, rash , SLE & fetal hepatic

necrosis.

Carbamazepine Block Na-voltage channels.

Act pre-synaptically: to synaptic

transmission.

Inhibit uptake & release of NE.

1) Partial seizures 2) Generalized tonic-clonic seizures 3) Trigeminal neuralgia. 4) Mania. 5) Diabetes Insipidus (DI).

DOSE DEPENDENT

CNS: Diplopia, Ataxia ,drowsiness, unsteadiness.

GIT: Vomiting , Diarrhoea.

H2O retention & hyponatremia. IDIOSYNACRATIC BLOOD DYSCRASIS

Aplastic anemia

Agranulocytosis.

Leucopenia.

Hepatic dysfunction. TERATOGENECITY

Fetal malformation ( neural tube defects).

valporate doubles teratogenicity.

Na Valporate NOT used during PREGNANCY .

Inhibite GABA aminotransferase to GABA conc.

Block Na-voltage channels.

1) Partial seizures. 2) Generalized seizures:

a. tonic-clonic. b. absence. c. myoclonic.

3) Bipolar disorder(mania). 4) Migrine prophylaxis.

DOSE DEPENDENT

Nausea, vomiting, abdominal pain.

Weight gain, ↑ appetite.

hair loss, fine tremor. IDIOSYNATRIC REACTION

Hepatotoxicity.

Thrombocytopenia.

Pancreatitis. TERATOGENECITY

Spina bifida,Cardiovascular abnormality.

Orofacial & digital abnormalities.

Bar

bit

ura

tes Penobarbital It is well tolerated, with single dose

Contraindication. o Porphyria (acute attack may occur)

Primidone is used in treatment of Essential Tremor resistant to PROPRANOLOL.

Enahancement of GABAergic pathway.

Reduction of Glutamate action.

Block Na & Ca(L,N) channels.

1) Partial seizures

2) Generalized tonic-clonic seizures.

3) Status epilepticus.

4) Febrile convulsion

Drowsiness , lethargy , depression

Nystagmus, ataxia.

Memory loss, irritability & mental confusion.

Teratogenic & hemorrhagic disease of new born.

Megaloblastic anemia & osteomalacia.

Tolerated with single dose.

Mephbarbital

Metabarbital

Primidone



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Partial seizures & generalized tonic-clonic (cont…) DRUG PHARMACOKINETIC MECHANISM OF ACTION USES SIDE EFFECT

New

er D

rugs

Lamotrigine Block Na-voltage channels, to stabilize pre-synaptic

neuronal membranes.

reduces the release of excitatory amino acids (Glutamate & Aspertate)

adjunctive therapy for refractory: o Partial seizures. o 1

o & 2

o generalized tonic-clonic

seizures.

Dizziness, nausea & headache.

Diplopia.

Somnolence.

Skin rash.

Flu like symptoms.

Gabapentine It is an analogue of GABA .

It crosses blood brain barrier.

GABA synthesis & release.

block L type Ca channels.

Agonize GABAB receptor.

1) Resistant partial seizures. 2) Resistant generalized tonic-clonic. 3) Bipolar disorders. 4) Migraine and neuropathic pain.

Somnolence.

Dizziness & headache.

Ataxia & tremors.

Vigabatrine GABA conc. by irreversible inhibition of

GABA aminotransferase.

1) Partial seizures. 2) 2

o generalized

seizures.

NOT responsible by

other drugs

AT TOXIC DOSE

Dizziness, drowsiness.

Weight gain.

Agitation, confusion & psychosis. LONG USE

Irreversible Visual field defects.

3) Infantile spasms.

Topiramate NOT used during PREGNANCY .

Enahancement of GABAergic pathway.

Block Na-voltage channels.

Block or antagonize Glutamate receptors (weak).

adjunctive therapy for refractory: o Partial seizures. o Generalized tonic-clonic

seizures.

Somnolence, fatigue & Dizziness.

Nervousness & confusion.

Acute myopia ,glaucoma & urolithiasis.

Teratogenic abnormalities.

Tiagabine Treatment by discontinuous doses prevent : Excessive confusion. Somnolence. Ataxia.

prolongs the inhibitory action of synaptically released GABA.

adjunctive therapy for partial seizures.

Nervousness, confusion.

Difficulty in concentration & depression.

Tremor & ataxia.

somnolence & dizziness.

Zonisamide Block Na channels.

Block Ca-voltage channels.

1) Partial seizures. 2) Generalised tonic-clonic seizures. 3) Infantile spasms & myoclonas.

Drowsiness.

cognitive impairment.

Serious skin rashes.

Levetriacetam At brain-specific binding site, it affects: GABA receptors ( sensitivity) Ca-voltage channels (block). K-channels.

adjunctive therapy for partial seizures with or without

generalization.

Asthenia.

Dizziness.

Drowsiness.

Felbamate block NMDA receptor via GLYCINE binding site.

Refractory partial & generalized seizures(3

rd line).

resistant seizures as in Lennox-Gastaur syndrome.

Insomnia.

Dizziness.

Ataxia.

Aplastic anemia.

Sever hepatitis.

LENNOX-GASTAURE SYNDROM

It consiste of:

multiple seizure types.

mental retardation.

refractoriness to anti-seizure drugs.



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Note

Generalized tonic-clonic DRUG PHARMACOKINETIC MECHANISM OF ACTION USES SIDE EFFECT

Ethosuximide Therapeutic levels & Dosage– 60-100 mg/ml achieved with 750-1500mg/day.

It depresses the cerebral MR.

The clearance is reduced by Valporic Acid.

Inhibits: T type Ca-channels in thalamas. Na/K ATPase. GABA aminotransferase enzymes

It depresses the cerebral MR.

Absence seizures GIT: Pain, nausea & vomiting.

CNS: Headache, dizziness, euphoria

Blood: Eosinophilia. Pancytopenia (Thrombocytopenia, leucopenia)

Transient lethargy or fatigue.

Skin rash.

Steven Johnson syndrome.

SLE.

Trimethadone NOT used during pregnancy.

Act actively against Pentyleneterazole that induce seizures.

Petit mal epilepsy ( drug of choice). Sedation.

HEMERALOPIA(reversible impaired visual adaptation)

Others DRUG PHARMACOKINETIC MECHANISM OF ACTION USES SIDE EFFECT

Ben

zod

iaze

pin

es

Diazepam

used I.V. or rectally They act as anti-epileptic by:

GABAergic activity.

CLORAZEPATE DIPOTASSIUM---Used as an. are common adverse effects.

CLOBAZAM—

ADVERSE effects of Benzodiazepins ------

.

Generalized tonic-clonic (grand-mal).

Status epilacticus

Sedation.

Tolerance.

paradoxical hyperactivity(in children).

Ataxia, hypotonia , dysarthria.

Salivation.

↑respiratory secretions.

WITHDRAWAL SYMPTOMS Exacerbation of seizures if

the drug is stopped suddenly.

Lorazepam longer acting than diazepam. More effective in status epilepticus.

Clonazepam Absence (petit mal) siezures.

Myoclonic seizures.

infantile spasms.

Nitrazepam Less potent than Clonazepam.

Clorazepate Dipotassium

adjunct to treatment of complex partial seizures.

Drowsiness.

Lethargy.

Clobazam

Commonly not used due to quick & high tolerance

less sedative.

High TOLERANCE

Acetazolamide

It is a carbonic anhydrase inhibitor Exerts its anti- seizure activity by: Mild acidosis in the brain.

Epilepsy during menses (as it discontinuously administrated, NO rolerance)

Tolerance (quick develop).

Sulthium It is a carbonic anhydrase inhibitor

TYPE DRUG OF CHOICE ALTERNATIVE DRUG G

ENER

ALI

ZED

SE

IZU

RES

ALT

ERN

ATI

VE

DR

UG

Lam

otr

igin

e

Lam

otr

igin

e

Ph

eno

bar

bit

on

Ph

en

yto

in

Clo

naz

ep

am

Ph

en

ob

arb

ito

ne

La

mo

trig

ine

Top

iram

ate

Clo

naz

ep

am

Eth

osu

xim

ide

Vig

abat

rin

e

Clo

baz

am

Gab

apen

tin

e

Felb

am

ate

Top

iram

ate

Tiag

abin

e

SIM

PLE

SEIZ

UR

Es

Simple partial Phenytoin Gabapentine

Complex partial Phenobarbitone Felbamate

Partial with secondarily generalised

valporate Topiramate

Lamotrigine Tiagabine

Phenytoin Gabapentine

DR

UG

OF

CH

OIC

E

Clo

naz

ep

am

Eth

osu

xim

ide

Val

po

rate

Val

po

rate

Val

po

rate

Clo

naz

ep

am

Car

bam

aze

pi

ne

P

he

no

bar

bit

on

e

Ph

en

yto

in

Pri

mid

on

e

Val

po

rate

Lam

otr

igin

e

Type Absence Atonic Myoclonic Grand mal/tonic/clonic

pharmacology .. treatment of epilepsy

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