PHARMACOLOGY – Neurology Module
PHARMACOLOGY OF ANTICONVULSANTS
Epilepsy – Introduction
• Epilepsy is one of the commonest chronic neurological conditions, both in adults and children, characterized
by recurrent unprovoked seizures.
• Seizure is a distinct clinical manifestation presumed to result from an abnormal and excessive electrical
discharge of a set of neurons in the cerebral cortex.
• GENERALIZED SEIZURES – Have a diffuse origin involving both hemispheres of the brain; EEG abnormalities are
bilateral.
1. Generalized tonic-clonic seizures (major epilepsy) – The person loses consciousness, falls, stiffens (the
tonic phase), and jerks (clonic phase).
2. Absence seizures – No or only brief episodes of unconsciousness with no warning and immediate
resumption of consciousness; Prevalent in children.
3. Atonic seizures – Brief loss of consciousness with relaxation of all muscles due to excessive inhibitory
discharges. Patient may fall.
4. Myoclonic seizures – Shock-like momentary contraction of muscles of a limb or the whole body; Exhibit
as brief jerks of the limbs.
• FOCAL SEIZURES – The discharge begins locally and often remains localized.
Rational Management of Epilepsy
The rational management of epilepsy includes four therapeutic strategies (combinations of which are often
required),
1) Information and advice – Educating the patient and the family by providing clear, accurate and appropriate
information about the condition including the specific epilepsy syndrome, its diagnosis and treatment
options, and the implications for everyday living.
2) Non–pharmacological treatment – Children with epilepsy should be encouraged to participate in normal
activities with their peers. The requirement of supervision should be individualized taking into account the
type of activity and the seizure history.
o Avoidance of precipitating factors.
o Management of risk and self-care.
o Information to the school (especially on first aid, safety and injury prevention).
o Counseling.
o Ensuring good compliance.
o Training the carers on first-aid management of a convulsing patient.
3) Pharmacological treatment – Anti-epileptic medicines (AEM); Should be individualized according to factors
such as (1) the seizure type; (2) epilepsy syndrome; (3) age and gender of the patient; (4) co-medication
and co-morbidities; (5) the individual’ s lifestyle; and (6) the preferences of the individual, and family etc.
4) Referral
Initiation of Anti-Epileptic Medicines
• Majority of first seizures are provoked by a reversible, and often recognizable, factor (such as infection, drug
toxicity, surgery). Hence, following a single seizure, anticonvulsants are NOT generally prescribed.
• The International League Against Epilepsy (ILAE) recommends that epilepsy be diagnosed when any of the
following exist –
(1). A history of two unprovoked seizures at least 24 hours apart, or,
(2). An unprovoked seizure when the risk for a subsequent seizure is greater than 60% after two
unprovoked seizures over the subsequent 10 years, or,
(3). Seizures that are part of an epilepsy syndrome.
• The information required before initiating AEM include, ◼ Seizure type(s), ◼ Aetiology, ◼ Co-morbidities,
◼ Accurate classification, ◼ Whether provoked or unprovoked, ◼ Precipitating factors, ◼ Whether seizure
pattern fits a specific epilepsy syndrome, ◼ In children – developmental and detail perinatal history.
1 ©AScS – 2019 A/L Batch
, PHARMACOLOGY – Neurology Module
Anti-Epileptic Medicines – Pharmacodynamics
• Anti-epileptic medicines act by inhibiting neuronal discharge or its spread rather than correcting its cause;
Generally act on seizure focus and prevent repetitive discharge by reducing excitability of cell membrane.
• Unlike general anesthetics, AEMs are NOT general CNS depressants (as AEMs are more selective).
• Different modes of action of AEMs are,
o Blocking voltage-dependent sodium channels
o Enhancing inhibitory neurotransmitter Gamma Amino Butyric Acid (GABA).
o Decreasing synaptic vesicle release (by blocking either calcium channels or vesicle recycling).
o Inhibiting the excitatory neurotransmitter (especially Glutamate).
o Blocking excitatory neurotransmitter receptors.
o Potassium channel openers (Eg: Retigabine).
o Multiple mechanisms (Eg: Sodium valproate).
BLOCKING VOLTAGE-DEPENDENT SODIUM CHANNELS – Carbamazepine, Lamotrigine, Phenytoin, Valproate
• They inhibit the action of voltage dependent sodium channels which carry the inward membrane current
necessary for the generation of action potential. Hence, they decrease electrical excitability.
• Shows user-dependence – Selectively inhibit the cells which are firing repetitively, without interfering with
the low frequency firing of neurons i.e. higher the frequency of firing, the greater the block produced.
Sodium channels exist in resting, open and inactivated states. When a neuron is repeatedly firing (as in an epileptic
fit), increased frequency of depolarization increases the proportion of sodium channels in the inactivated state. AEMs
preferentially inhibit the sodium channels in the inactivated state preventing them from returning to the resting state,
thus reducing the number of functional sodium channels available to generate subsequent action potentials.
DECREASING SYNAPTIC VESICLE RELEASE
• This can be achieved by either (1) blocking calcium channels or (2) inhibiting vesicle recycling.
o Low voltage T-type calcium channel blockers – Ethosuximide, Sodium valproate.
❖ These low voltage T-type calcium channel blockers are effective in the treatment of absence
seizures, as these calcium channel activity is important in determining the rhythmic
discharge of thalamic neurons associated with absence seizures.
o High voltage L-Type calcium channel blockers (Blocks 𝛼2 𝛿 subunit) – Gabapentin.
o Reducing synaptic vesicle recycling – Levetiracetam.
ENHANCEMENT OF GABA ACTION – Benzodiazepines, Phenobarbital, Vigabatrin, Sodium valproate, Gabapentin
• These drugs enhance the activation of GABAA receptors,
thus facilitating the GABA-mediated opening of chloride
channels, which secondarily reduces cell excitability.
Anti-Epileptic Medicines – Classification
• Principal mode of action
• Therapeutic Spectrum
• Regulatory approval – The currently useful classification.
1 Therapeutic Spectrum
Broad spectrum Narrow spectrum
To treat a broad range of seizures types (both focal and
Primarily for focal seizures
generalized onset)
Levetiracetam, Lamotrigine, Zonisamide, Topiramate, Lacosamide, Pregabalin, Gabapentin, Carbamazepine,
Sodium valproate, Clonazepam, Perampanel, Clobazam, Oxcarbazepine, Ezogabine, Phenytoin, Vigabatrin,
Rufinamide Ethosuximide
2 ©AScS – 2019 A/L Batch
PHARMACOLOGY OF ANTICONVULSANTS
Epilepsy – Introduction
• Epilepsy is one of the commonest chronic neurological conditions, both in adults and children, characterized
by recurrent unprovoked seizures.
• Seizure is a distinct clinical manifestation presumed to result from an abnormal and excessive electrical
discharge of a set of neurons in the cerebral cortex.
• GENERALIZED SEIZURES – Have a diffuse origin involving both hemispheres of the brain; EEG abnormalities are
bilateral.
1. Generalized tonic-clonic seizures (major epilepsy) – The person loses consciousness, falls, stiffens (the
tonic phase), and jerks (clonic phase).
2. Absence seizures – No or only brief episodes of unconsciousness with no warning and immediate
resumption of consciousness; Prevalent in children.
3. Atonic seizures – Brief loss of consciousness with relaxation of all muscles due to excessive inhibitory
discharges. Patient may fall.
4. Myoclonic seizures – Shock-like momentary contraction of muscles of a limb or the whole body; Exhibit
as brief jerks of the limbs.
• FOCAL SEIZURES – The discharge begins locally and often remains localized.
Rational Management of Epilepsy
The rational management of epilepsy includes four therapeutic strategies (combinations of which are often
required),
1) Information and advice – Educating the patient and the family by providing clear, accurate and appropriate
information about the condition including the specific epilepsy syndrome, its diagnosis and treatment
options, and the implications for everyday living.
2) Non–pharmacological treatment – Children with epilepsy should be encouraged to participate in normal
activities with their peers. The requirement of supervision should be individualized taking into account the
type of activity and the seizure history.
o Avoidance of precipitating factors.
o Management of risk and self-care.
o Information to the school (especially on first aid, safety and injury prevention).
o Counseling.
o Ensuring good compliance.
o Training the carers on first-aid management of a convulsing patient.
3) Pharmacological treatment – Anti-epileptic medicines (AEM); Should be individualized according to factors
such as (1) the seizure type; (2) epilepsy syndrome; (3) age and gender of the patient; (4) co-medication
and co-morbidities; (5) the individual’ s lifestyle; and (6) the preferences of the individual, and family etc.
4) Referral
Initiation of Anti-Epileptic Medicines
• Majority of first seizures are provoked by a reversible, and often recognizable, factor (such as infection, drug
toxicity, surgery). Hence, following a single seizure, anticonvulsants are NOT generally prescribed.
• The International League Against Epilepsy (ILAE) recommends that epilepsy be diagnosed when any of the
following exist –
(1). A history of two unprovoked seizures at least 24 hours apart, or,
(2). An unprovoked seizure when the risk for a subsequent seizure is greater than 60% after two
unprovoked seizures over the subsequent 10 years, or,
(3). Seizures that are part of an epilepsy syndrome.
• The information required before initiating AEM include, ◼ Seizure type(s), ◼ Aetiology, ◼ Co-morbidities,
◼ Accurate classification, ◼ Whether provoked or unprovoked, ◼ Precipitating factors, ◼ Whether seizure
pattern fits a specific epilepsy syndrome, ◼ In children – developmental and detail perinatal history.
1 ©AScS – 2019 A/L Batch
, PHARMACOLOGY – Neurology Module
Anti-Epileptic Medicines – Pharmacodynamics
• Anti-epileptic medicines act by inhibiting neuronal discharge or its spread rather than correcting its cause;
Generally act on seizure focus and prevent repetitive discharge by reducing excitability of cell membrane.
• Unlike general anesthetics, AEMs are NOT general CNS depressants (as AEMs are more selective).
• Different modes of action of AEMs are,
o Blocking voltage-dependent sodium channels
o Enhancing inhibitory neurotransmitter Gamma Amino Butyric Acid (GABA).
o Decreasing synaptic vesicle release (by blocking either calcium channels or vesicle recycling).
o Inhibiting the excitatory neurotransmitter (especially Glutamate).
o Blocking excitatory neurotransmitter receptors.
o Potassium channel openers (Eg: Retigabine).
o Multiple mechanisms (Eg: Sodium valproate).
BLOCKING VOLTAGE-DEPENDENT SODIUM CHANNELS – Carbamazepine, Lamotrigine, Phenytoin, Valproate
• They inhibit the action of voltage dependent sodium channels which carry the inward membrane current
necessary for the generation of action potential. Hence, they decrease electrical excitability.
• Shows user-dependence – Selectively inhibit the cells which are firing repetitively, without interfering with
the low frequency firing of neurons i.e. higher the frequency of firing, the greater the block produced.
Sodium channels exist in resting, open and inactivated states. When a neuron is repeatedly firing (as in an epileptic
fit), increased frequency of depolarization increases the proportion of sodium channels in the inactivated state. AEMs
preferentially inhibit the sodium channels in the inactivated state preventing them from returning to the resting state,
thus reducing the number of functional sodium channels available to generate subsequent action potentials.
DECREASING SYNAPTIC VESICLE RELEASE
• This can be achieved by either (1) blocking calcium channels or (2) inhibiting vesicle recycling.
o Low voltage T-type calcium channel blockers – Ethosuximide, Sodium valproate.
❖ These low voltage T-type calcium channel blockers are effective in the treatment of absence
seizures, as these calcium channel activity is important in determining the rhythmic
discharge of thalamic neurons associated with absence seizures.
o High voltage L-Type calcium channel blockers (Blocks 𝛼2 𝛿 subunit) – Gabapentin.
o Reducing synaptic vesicle recycling – Levetiracetam.
ENHANCEMENT OF GABA ACTION – Benzodiazepines, Phenobarbital, Vigabatrin, Sodium valproate, Gabapentin
• These drugs enhance the activation of GABAA receptors,
thus facilitating the GABA-mediated opening of chloride
channels, which secondarily reduces cell excitability.
Anti-Epileptic Medicines – Classification
• Principal mode of action
• Therapeutic Spectrum
• Regulatory approval – The currently useful classification.
1 Therapeutic Spectrum
Broad spectrum Narrow spectrum
To treat a broad range of seizures types (both focal and
Primarily for focal seizures
generalized onset)
Levetiracetam, Lamotrigine, Zonisamide, Topiramate, Lacosamide, Pregabalin, Gabapentin, Carbamazepine,
Sodium valproate, Clonazepam, Perampanel, Clobazam, Oxcarbazepine, Ezogabine, Phenytoin, Vigabatrin,
Rufinamide Ethosuximide
2 ©AScS – 2019 A/L Batch
