NEUROPHARMACOLOGY

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ANTI-SEIZURE DRUGS: GENERAL
CONCEPTS

Dr Sindwa Kanyimba
Lecturer, Pharmacology

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INTRODUCTION

A seizure is a particular behaviour produced by an

abnormal high frequency discharge of a group of neurons
starting focally and spreading to affect other parts of the
brain
A seizure is an abnormal, uncontrolled electrical discharge
from neurons due to: (1) Cell membrane disruptions
(permeability) (2) Altered ion distributions (chemical
imbalance) (3) Decreased inhibitory neurotransmitters
(acetylcholine and GABA) (4) Increased excitatory
neurotransmitters (glutamate)

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INTRODUCTION …. CONT’D

Seizures are a symptom of an underlying CNS dysfunction

Seizures may be primary (idiopathic) or secondary
(symptom of a known cause e.g. tumour, CNS infection)
Drugs used in the management of seizure disorders are
referred to as anti-seizure drugs

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LEARNING OBJECTIVES

1. Define the terms “Anti-seizure drug”, “Anti-convulsant

drug” and “Anti-epileptic drug”
2. Classify seizure disorders
3. Describe the pathophysiology of seizures
4. List the clinical indications for anti-seizure drugs
5. Describe the general principles relating to the clinical
use of anti-seizure drugs
6. Describe the mechanisms of action of anti-seizure drugs

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CLASSIFICATION OF SEIZURES

Partial Seizures
Short alterations of consciousness; repetitive unusual
movements (chewing or swallowing); psychologic changes;
confusion
• Simple Partial Seizures: No impaired consciousness; motor
symptoms of face, arm or legs; hallucinations of sight,
hearing, or taste; tingling sensation; autonomic nervous
system changes; personality changes
• Complex Partial Seizures: Impaired consciousness; memory
impairment; behavioral effects; purposeless behaviors; aura,
unreal feelings, bizarre behavior
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CLASSIFICATION OF SEIZURES …. CONT’D

Generalized Seizures
• Temporary lapses in consciousness
• Staring off into space (absence seizure)
• Rhythmic movements of eyes, head, or hands
• Tonic, clonic, myoclonic, atonic, or tonic-clonic seizures
• Brief loss of consciousness without confusion
• Head drop or falling down symptoms

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PARTIAL SEIZURES

Simple partial seizures (no loss of consciousness)

• May have motor symptoms, sensory symptoms or
autonomic symptoms
• Only involve 1 hemisphere
Complex partial (loss of consciousness)
Simple partial seizures followed by loss of consciousness or
impaired at the onset

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GENERALISED SEIZURES

Generalised seizures affect the whole brain with loss of

consciousness)
• Clonic, tonic (1min) or tonic-clonic (2-4min): muscle
spasm (extensors), respiration stops, defecation, salivation,
violent jerks
• Myoclonic: seizures of a muscle or group of muscles
• Absence: Abrupt loss of awareness of surroundings, little
motor disturbance, mostly children
• Atonic: loss of muscle tone/strength

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SOME KEY DEFINITIONS

Convulsion: Involuntary spasmodic contractions of any or

all voluntary muscles throughout the body, including
skeletal and facial muscles. Associated with post-ictal state.
Seizures: Brief episode of abnormal electrical activity in
the neurones of the brain (detected on EEG)
Epilepsy: Chronic, recurrent pattern of seizures. Epilepsy
is a chronic disease in which seizures result from the
abnormal discharge of cerebral neurons

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SOME KEY DEFINITIONS …. CONT’D

Anti-epileptic Drugs: Drugs used in the management of

all types of epilepsy (not just convulsions)
Anti-convulsant Drugs: Drugs used in the management
of convulsions
Anti-seizure Drugs: Drugs used in the management of
seizure disorders. Include anti-epileptic drugs and anti-
convulsant drugs.
Terms overlap and are sometimes used interchangeably

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INDICATIONS FOR ANTI-SEIZURE DRUGS

• Prevention or control of seizure activity

• Long-term maintenance treatment of epilepsy
• Acute treatment of convulsions and status epilepticus
• Prophylactic anti-seizure therapy in brain surgery and
head injuries

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CLINICAL ADVICE IN THE USE OF ANTI-SEIZURE
DRUGS

• It is essential to have an accurate and comprehensive

diagnosis
• Must treat underlying causes e.g. electrolyte imbalances,
hypoglycemia, infection and tumor
• Diagnosis: Adequate description of symptoms both from
patient and eye witness
• Electro-encephalogram (EEG) is supportive of diagnosis of a
seizure disorder
• EEG should not be an indication for confirming a seizure
disorder nor to stop treatment for seizure free patients (not all
patients with a positive recording with EEG have a seizure
disorder)
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PRINCIPLES OF DRUG THERAPY WITH ANTI-
SEIZURE DRUGS

• Up to 80% of patients can expect partial or complete

control of seizures with appropriate treatment
• Anti-seizure drugs suppress but do not cure seizures
• Anti-seizure drugs are indicated when there is two or
more seizures occurring in short interval (6months to 1
year)
• An initial therapeutic aim is to use only one drug
(monotherapy)

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PRINCIPLES OF DRUG THERAPY WITH
ANTI-SEIZURE DRUGS …. CONT’D

Advantage of monotherapy:
• Fewer unwanted effects, decreased drug-drug
interactions, better compliance, lower costs
• Addition of a second drug is likely to result in significant
improvement in only approximately 10% of patients

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PRINCIPLES OF DRUG THERAPY WITH ANTI-
SEIZURE DRUGS …. CONT’D

Dosage recommendations
• Gradual dose increments
• Dose individualization
• Plasma concentration monitoring (necessary for some
drugs e.g. phenytoin)

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PRINCIPLES OF DRUG THERAPY WITH ANTI-
SEIZURE DRUGS …. CONT’D

Withdrawal of anti-seizure treatment

• The sudden withdrawal of drugs should be avoided
• Withdrawal may be considered after seizure-free period
of 2-3 or more years
• Relapse rate when anti-seizure drugs are withdrawn is
20-40 %

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PRINCIPLES OF SEIZURE DISORDER
MANAGEMENT …. CONT’D

When to withdraw treatment

• Normal neurological examination
• Normal IQ
• Normal EEG prior to withdrawal
• Seizure-free for 2-5 years or longer
• The seizure disorder should not be juvenile myoclonic
epilepsy

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TREATMENT FAILURE OF ANTI-SEIZURE
DRUGS

Common causes of treatment failure of anti-seizure drugs

include:
• Improper diagnosis of the type of seizures
• Incorrect choice of drug
• Inadequate or excessive dosage
• Poor compliance

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COMMON ADVERSE EFFECTS OF ANTI-
SEIZURE DRUGS

• CNS reactions (mostly dose related)

• Haematological reactions
• Hepatic toxicity

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MECHANISMS OF ACTION OF ANTI-SEIZURE
DRUGS

Inhibition of ion channels involved in neuronal

excitability
• Sodium channel inhibition: carbamazepine, phenytoin,
lamotrigine, valproate, topiramate
• Calcium channel inhibition: ethosuximide, gabapentin,
valproate
Inhibition of excitatory transmission
• Inhibition of glutamate release e.g. lamotrigine
• Blockade of glutamate receptors e.g. topiramate,
felbamate
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MECHANISMS OF ACTION OF ANTI-SEIZURE
DRUGS …. CONT’D

Enhancement of GABA-mediated inhibition

• Drugs that enhance GABA action: benzodiazepines
(midazolam, lorazepam, diazepam & clonazepam),
barbiturates (phenobarbital, thiopental), topiramate
• Drugs that inhibit GABA degradation: vigabatrin,
valproate, gabapentin
• Drugs that inhibit reuptake of GABA: tiagabine
• Drugs that increase the synthesis of GABA: valproate

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COMMONLY USED ANTI-SEIZURE
DRUGS

Dr Sindwa Kanyimba
Lecturer, Pharmacology

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INTRODUCTION

There are many drugs available for treatment of seizure

disorders
Drug selection should be based on diagnosis of the seizure
type, age of patient, concurrent diseases and concurrent
drug therapy
During therapy with anti-seizure drugs the patient should
be monitored closely for drug adverse effects. Precautions
should be taken in patients with factors likely to increase
the incidence and severity of the adverse effects.

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INTRODUCTION …. CONT’D

Monitoring of therapy for some anti-seizure drugs requires

measurement of plasma levels for dosage optimization
Some anti-seizure drugs induce cytochrome P-450
enzymes (e.g. carbamazepine) and some inhibit
cytochrome P-450 enzymes (e.g. valproate). This should be
taken into consideration when planning to introduce a
second anti-seizure drug or if the patient is on concurrent
therapy for another disease

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LEARNING OBJECTIVES

1. List the drugs commonly used in the management of

seizure disorders and indicate the seizure disorders for
which each drug is effective
2. Recommend the first line drug therapy and
alternative/adjunct drugs for the various seizure
disorders
3. Describe the major adverse effects associated with anti-
seizure drugs
4. Describe the precautions that need to be taken with the
use of the commonly used anti-seizure drugs

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COMMONLY USED ANTI-SEIZURE DRUGS AND
THEIR INDICATIONS

Drug Indications

Carbamazepine Partial seizures, complex partial seizures, generalised

tonic-clonic seizures, mixed seizures (but not absence
or myoclonic seizures)
Clonazepam Absence seizures, akinetic and myoclonic seizures

Ethosuximide Absence seizures

Gabapentin Partial seizures (simple and complex partial seizures),

generalised tonic-clonic seizures (as adjunct therapy)
Vigabatrin

Lamotrigine Simple partial seizures, complex partial seizures,

generalised tonic-clonic seizures, generalised seizures
in Lennox-Gastaut syndrome
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COMMONLY USED ANTI-SEIZURE DRUGS AND
THEIR INDICATIONS …. CONT’D

Drug Indications
Phenobarbital Partial seizures, generalised tonic-clonic seizures, status
epilepticus
Phenytoin Simple partial seizures, generalised tonic-clonic seizures,
complex partial seizures, prevention of seizures
secondary to neurosurgery or head trauma, status
epilepticus
Tiagabine Partial seizures (adjunct therapy)
Topiramate Simple partial seizures, complex partial seizures,
generalised tonic-clonic seizures

Felbamate Partial and generalized seizures resistant to other drugs,

partial and generalised seizures in Lennox-Gastaut
syndrome
Valproate All types of seizures
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CHOICE OF ANTI-SEIZURE DRUGS

Seizure type Drugs of choice Alternative and adjunct

drugs

Simple partial seizures Valproate Phenytoin

Generalised tonic- Carbamazepine Vigabatrin (adjunct)
clonic seizures Gabapentin (adjunct)
Complex partial Lamotrigine
seizures
Phenobarbital
Topiramate
Tiagabine (adjunct in
simple partial seizures)
Absence seizures Ethosuximide Clonazepam
Valproate

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CHOICE OF ANTI-SEIZURE DRUGS …. CONT’D

Seizure type Drugs of Alternative and adjunct

choice drugs

Myoclonic seizures Clonazepam Valproate

Status epilepticus Lorazepam Diazepam

Clonazepam
Phenytoin
Phenobarbital
Chlormethiazole
Midazolam
Thiopentone

Febrile convulsions Diazepam Phenobarbital

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ADVERSE EFFECTS OF THE ANTI-SEIZURE DRUGS

Drug Adverse effects Other information

Phenytoin Dose related: ataxia, blurred vision, Induces cytochrome P450

nystagmus, sedation, mental confusion, enzymes
paradoxical seizures Teratogenic
Non-dosage related: gum hypertrophy, Narrow therapeutic index
coarsening of facial features, rash, There is need for monitoring
hepatitis, lymphadenopathy, plasma drug concentrations
megaloblastic anaemia [phenytoin
causes folic acid deficiency], hirsutism
Valproate GI upset, hepatotoxicity, weight gain, Avoid in liver disease
alopecia, idiosyncratic Inhibits cytochrome P450
hyperammonemic encephalopathy enzymes
Teratogenic
Carbamazepine Ataxia, nystagmus, dysarthria, vertigo, Induces cytochrome P450
sedation, behavioural abnormalities, enzymes
leucopenia Avoid in children
Ethosuximide GI upset, drowsiness, mood swings, skin
rashes
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ADVERSE EFFECTS OF THE ANTI-SEIZURE
DRUGS …. CONT’D

Drug Adverse effects Other information

Lamotrigine Rashes, fever, malaise, drowsiness,

rarely hepatic dysfunction

Vigabatrin Depression, visual hallucinations, Avoid in patients with

drowsiness, dizziness history of psychosis

Gabapentin Somnolence, dizziness, ataxia, fatigue

Felbamate Aplastic anaemia, liver failure Inhibits cytochrome

P450 enzymes

Phenobarbital Sedation, respiratory depression, Induces cytochrome

paradoxical hyperactivity in children, P450 enzymes
nystagmus, ataxia, learning Avoid in children and
difficulties, idiosyncratic anaemia and elderly people
rash

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ADVERSE EFFECTS OF THE ANTI-SEIZURE
DRUGS ….. CONT’D

Adverse effects Drugs

Hepatotoxicity Phenytoin, valproate, lamotrigine,
felbamate
Neurological Phenytoin, carbamazepine, ethosuximide,
phenobarbitone, gabapentin, vigabatrin
Psychiatric (mental confusion, Carbamazepine, phenobarbitone,
hallucinations, behavioural vigabatrin, phenytoin
abnormalities)
Blood dyscrasias Phenytoin, carbamazepine, felbamate,
phenobarbitone
Cytochrome P450 enzyme inhibition Valproate, felbamate
Cytochrome P450 enzyme induction Carbamazepine, phenytoin,
phenobarbitone
Teratogenic Phenytoin, valproate

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MANAGEMENT OF SEIZURES IN
SPECIAL CIRCUMSTANCES

Dr Sindwa Kanyimba
Lecturer, Pharmacology

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INTRODUCTION

Status epilepticus and occurrence of seizures in pre-

eclampsia/eclampsia are emergencies that require
administration of rapidly acting drugs that can be
administered parenterally, preferably intravenously
Management of seizure disorders in pregnancy requires
caution as most of the anti-seizure drugs have potential to
cause harm to the fetus. However, poor control of seizures
during pregnancy can be detrimental to development of
the fetus.
Anti-seizure drugs do not pose any additional risk to full-
term infants and ant-seizure therapy should not be contra-
indicated in lactation

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LEARNING OBJECTIVES

1. Describe the relevant clinical pharmacology of

magnesium sulphate as an anti-seizure drug
2. Outline the drug therapy of status epilepticus
3. State the precautions that need to be taken in the drug
management of seizure disorders in pregnancy and
lactation

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MAGNESIUM SULPHATE

• Magnesium sulphate is the drug of choice for the

management of seizures associated with severe pre-
eclampsia and eclampsia
• Mechanism of action: Alters calcium metabolism
(physiological antagonist to calcium)
• Given IM or IV
• Adverse effects: Nausea, vomiting, thirst, hypotension,
drowsiness, muscle weakness, loss of tendon reflexes,
respiratory depression and coma

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STATUS EPILEPTICUS

• Status epilepticus is a seizure lasting more than five

minutes or more than one seizure within a five minute
period without the person returning to normal between
them
• It is a life-threatening emergency characterized by tonic-
clonic convulsions that occur in succession. There is loss
of consciousness, hypotension, hypoxia, cardiac
dysrhythmias; brain damage and death may quickly
result.
• Status epilepticus may occur in those with a history of
epilepsy as well as those with an underlying problem of
the brain, such as trauma, infections, or strokes
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MANAGEMENT OF STATUS EPILEPTICUS

First line treatment

Intravenous lorazepam (intravenous diazepam if intravenous
lorazepam is unavailable, or buccal midazolam if unable to
secure immediate intravenous access)
Second line treatment
If seizures continue, administer intravenous phenobarbital
or phenytoin

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STATUS EPILEPTICUS …. CONT’D

Refractory convulsive status epilepticus

• Adults: intravenous midazolam, propofol or thiopental
sodium in adults
• Children and adolescents: intravenous midazolam or
thiopental sodium

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MANAGEMENT OF SEIZURE DISORDERS IN
PREGNANCY AND LACTATION

• No anti-seizure drug is completely safe to use in

pregnancy as the risk of foetal abnormality is increased
• Valproate and phenytoin are contraindicated because of
the risk of major malformations
• Ideally a plan for managing the woman's epilepsy during
pregnancy should be prepared before conception

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MANAGEMENT OF SEIZURE DISORDERS IN
PREGNANCY AND LACTATION …. CONT’D

• The occurrence of an unexpected pregnancy should not

trigger sudden cessation or alteration of anti-seizure
drug treatment without medical advice
• The smallest effective dose of a drug with a low risk of
teratogenicity should be used. Doses may need
adjustment as the pharmacokinetics of some drugs
change during pregnancy.
• Data are limited, but most anti-seizure drugs seem to
have little effect on full-term breastfed babies

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 END
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