CENTRAL NERVOUS SYSTEM (CNS)

PHARMACOLOGY (PCL 401)

ANTIEPILEPTIC/ANTICONVULSANTS
DRUGS

ABUBAKAR KABIRU PhD

 Introduction
• A seizure (from the Latin sacire, "to take possession of") is a paroxysmal event due
to abnormal, excessive, hypersynchronous discharges from an aggregate of central
nervous system (CNS) neurons.

• Seizure is a paroxysmal event due to abnormal, excessive, hypersynchronous

discharges from an aggregate of CNS neurons, which can have motor, sensory or
autonomic manifestation.

• Convulsion is the motor manifestation of seizures

• Epilepsy is a very common disorder, characterised by seizures, which take various

forms and result from episodic neuronal discharges, the form of the seizure
depending on the part of the brain affected.
 Introduction
• The characteristic event in epilepsy is the seizure, which is associated with the episodic high-
frequency discharge of impulses by a group of neurons in the brain.

• Epilepsy affects 0.5-1% of the population

• It is estimated to affect almost 70 million people worldwide

• The prevalence of epilepsy in low- and middle-income countries (LMIC) is about twice that of
high-income countries (HIC)

• The estimated median incidence of epilepsy for all studies combined was 50.4/100,000
persons/year

• In Nigeria, prevalence varies from 15 to 37 per 1000

 ETIOLOGY OF EPILEPSY
• Epilepsy can be idiopathic (primary) or symptomatic (secondary),
• 55-60% of all cases of epilepsy reported in Africa are idiopathic while 30% of
cases reported in other parts of the world have an identifiable cause.
• Secondary causes of epilepsy includes;
Genetic
Infection
Metabolic abnormalities
Vascular disorders
Trauma
Genetics: Several studies conducted in recent times showed that inherited forms
of epilepsy account for about 20% of all patients with epilepsy, especially in
children.
 ETIOLOGY OF EPILEPSY
• Infection: At all ages, infections remain a constant cause of symptomatic brain
stress and seizures. The severity is reinforced by malnutrition, poor basic health
and economic conditions.
• Central nervous system infections are the major cause of symptomatic epilepsy
which comprises mainly bacterial and viral meningitis, encephalitis, neurosyphillis,
septicaemia, brain abscess and tuberculosis.
• One of the major causes of seizures in children is severe malaria caused by P.
falciparum
• Metabolic abnormalities: Seizures can be due to lack of energy, intoxication,
impaired neuronal function in storage disorders, disturbances of neurotransmitter
systems with excess of excitation or lack of inhibition
• A great number of metabolic disorders occurring in infancy and childhood have
seizures as one of its commonest symptom, examples include one of the creatinine
deficiency syndromes, guanidinoacetate methyltransferase (GAMT) deficiency,
mitochondrial disorders (26-60%) and hypoglycaemia
 ETIOLOGY OF EPILEPSY
• Vascular disorders: Post ischemic stroke has been reported as very important
causes of recurrent seizures in adult population. Acute ischemia leads to
increased extracellular concentrations of glutamate, an excitatory
neurotransmitter that has been associated with secondary neuronal injury.
• Trauma: Trauma and hypoxia are among the commonest causes of epilepsy in
Nigeria.
• Poor obstetric care and violence at home, work and traffic accidents are the
major contributory factors.
• Birth trauma accounts for 1-2% of symptomatic epilepsies in Africa .
• Neonatal seizures within the first few days of birth occur in about 20 to 35 cases
per 10,000 births and the most common cause of neonatal seizure is Hypoxic
ischemic encephalopathy (HIE) .
 CLASSIFICATION OF SEIZURES
• The clinical classification of epilepsy defines two major seizure categories, namely
partial and generalised, though there is an overlap and many varieties of each. Either
form is classified as simple (if consciousness is not lost) or complex (if consciousness is
lost).
• GENERALIZED SEIZURES
• Generalised tonic-clonic seizures (GTCS, major epilepsy, grand mal): commonest, lasts
1–2 min.
• Absence seizures (minor epilepsy, petit mal): prevalent in children, lasts about 1/2 min.
• Atonic seizures (Akinetic epilepsy): Unconsciousness with relaxation of all muscles due
to excessive inhibitory discharges. Patient may fall.
• Myoclonic seizures: Shock-like momentary contraction of muscles of a limb or the
whole body.
• Infantile spasms (Hypsarrhythmia): Seen in infants. Probably not a form of epilepsy.
Characterized by intermittent muscle spasm and progressive mental deterioration.
 CLASSIFICATION OF SEIZURES
• PARTIAL SEIZURES
• Simple partial seizures (SPS, cortical focal epilepsy): lasts 1/2–1 min. Often
secondary.

• Complex partial seizures (CPS, temporal lobe epilepsy, psychomotor): attacks of

bizarre and confused behaviour and purposeless movements, emotional changes
lasting 1–2 min along with impairment of consciousness. An aura often precedes.
The seizure focus is located in the temporal lobe.

• Simple partial or complex partial seizures secondarily generalized: The partial

seizure occurs first and evolves into generalized tonic-clonic seizures with loss of
consciousness.
The dynamic target of seizure control in the management of epilepsy is achieving balance
between the factors that influence the excitatory postsynaptic potential (EPSP) and those
that influence inhibitory postsynaptic potential (IPSP) (Patrick, 2011).
CLASSIFICATION OF
ANTIEPILEPTICS
• Barbiturates and derivatives
• Benzodiazepines
• Carboxamide derivatives
• Fatty acids derivatives
• Hydantoin derivatives
• Oxazolidine derivatives
• Succinimide derivatives
• Others derivatives
 Major mechanisms of anticonvulsant action

12 08/26/2022
Classification cont’d
• Barbiturate and derivatives
• Metylphenobarbitone
• Primidone
• Phenobarbital
• Metherbital
• Benzodiazepine derivatives
• Clonazepam
• Diazepam
• Carboxamide derivatives (Tricyclics)
• Carbamazepine
• Rufinamide
• Oxcarbazepine
Classification
• Fatty acid derivatives
• Progabide
• Vigabatrin
• Valproic acid
• Tiagabine
• Hydantoin Derivatives
• Fosphenytoin
• Ethotoin
• Mephenytoin
• Phenytoin
 Classification
• Oxazolidine derivatives
• Paramethadione
• Trimethadione
• Succinimide derivatives
• Phensuximide
• Methsuximide
• Ethosuximide
• Other antiepileptics
• Levetiracetam,Lamotrigine, Ezogabine, Perampanel, Zonisamide, Pregabalin
• Phenacemide, Felbamate, Gabapentin, Beclamide
 Mechanism of Action
• Primarily by blocking the initiation or spread of seizures.
• Inhibition of Na+-dependent action potentials in a frequency-dependent manner
(e.g., phenytoin, carbamazepine, lamotrigine, topiramate, zonisamide),
• Inhibition of voltage-gated Ca2+ channels (phenytoin),
• Decrease of glutamate release (lamotrigine), potentiation of GABA receptor
function (benzodiazepines and barbiturates),
• Increase in the availability of GABA (valproic acid, gabapentin, tiagabine), and
• Modulation of release of synaptic vesicles (levetiracetam).
• The two most effective drugs for absence seizures, ethosuximide and valproic acid,
probably act by inhibiting T-type Ca2+ channels in thalamic neurons.
 Pharmacokinetics
• Antiepileptic drugs exhibits similar pharmacokinetic property
• Absorption is 80-100%
• Most are highly protein bound except Phenytoin, Tiagabine, and Valproic acid
• They are cleared by the liver
• Half lives longer than 12 hours
• Many of them are hepatic enzyme inducers
 Phenobarbital
• It is the oldest of the currently available antiseizure drug
• Mainly the drug of choice in infants
• Exact mechanism of action is unknown: ? Similar to phenytoin
• Useful in the treatment of partial and generalised tonic-clonic seizure
• Metabolised in the liver and excreted in urine
Adverse effects
• Neurologic: sedation, ataxia, confusion, dizziness, decreased libido, depression
• Systemic: Rash
• Interaction: Level increased by valproic acid and phenytoin
 Phenytoin
• The oldest non sedative antiseizure drugs
• It alters Na+, K+ Ca2+ conductance, membrane potentials and the concentration of
amino acids and neurotransmitters
• Complete absorption from the GI
• Highly bound to plasma protein
• Excreted in urine
• Half life is 12-36 hours

• Adverse Effects: Neurologic: dizziness, diplopia, ataxia, incoordination, confusion.

• Systemic: gum hyperplasia, lymphadenopathy, hirsutism, osteomalacia, facial
coarsening, skin rash
Interaction
• Level increased by isoniazid, sulfonamides, fluoxetine
• Level decreased by enzyme-inducing drug
• Altered folate metabolism

• Clinically used in partial and generalised tonic-clonic seizures

 Carbamazepine
• A derivative of tricyclic antidepressants

• Used also in trigeminal neuralgia and bipolar depression Exerts a lithium-like therapeutic effect in mania and bipolar
mood disorder. It also has antidiuretic action, probably by enhancing ADH action on renal tubules.

• Similar mechanism of action to phenytoin

• Now first line antiepileptic drug.

• Absorption varies among patients

• ≈ 70% protein bound

• Half life is 8-36 hours

• Available only in oral form

• metabolized in liver by oxidation to an active metabolite (10-11 epoxy carbamazepine) as well as by hydroxylation and
conjugation to inactive ones. It is a substrate as well as inducer of CYP3A4 and CYP2C9.
Carbamazepine
• Neurologic: ataxia, dizziness, diplopia, vertigo
• Systemic: aplastic anaemia, leukopenia, gastrointestinal irritation,
hepatotoxicity, hyponatremia
INTERACTION
• Level decreased by enzyme-inducing drugs
• Level increased by erythromycin, propoxyphene, isoniazid, cimetidine,
fluoxetine
 Valproate
• A member of series of fatty acids with antiseizure property
• Chemically unrelated to other antiepileptic drugs
• Mechanism of action not clear; weak inhibition of GABA transaminase; some
effect on sodium channels
• Effective against absence seizure, tonic-clonic attacks, myoclonus, atonic
attacks and partial seizures
• Valproate (unlike most antiepileptic drugs) is effective against both.
• Also in Bipolar disorders and migraine prophylaxis
• Well absorbed after an oral dose
• Food may delay absorption
• 90% bound to plasma
 Valproate
• Neurologic: ataxia, sedation, tremor

• Systemic: hepatotoxicity, thrombocytopenia, gastrointestinal irritation, weight gain,

transient alopecia, hyperammonemia

• Valproate is teratogenic, causing spina bifida and other neural tube defects so should
not be given to pregnant women.

INTERACTION
• Level decreased by enzyme-inducing drugs
• Valproate displaces phenytoin from plasma protein
• It inhibits the metabolism of several drugs like phenorbarbital, phenytoin, and
carbemazepine
 Ethosuximide
• Introduced as ‘pure petit mal’ drug
• It reduces the low-threshold T-type Calcium current
• Complete GI absoption
• It is not protein bound
• Completely metabolised by hydroxylation to inactive metabolite
• Low body clearance≈ ½ life of 40 hours

• Adverse Effects: Neurologic: Ataxia, lethargy, headache

• Systemic: gastrointestinal irritation, skin rash, bone marrow suppression

Interaction Valproate reduces the clearance of ethosuxamide

Clonazepam
• A long acting benzodiazepine
• One of the most potent antiseizure drug
• Sedation is prominent
• Metabolised in the liver
• Excreted in urine
• Neurologic adverse effects: ataxia, sedation, lethargy
• Systemic effect: anorexia
• Interaction: Level decreased by enzyme-inducing drugs
 NEW DRUGS
• Vigabatrin:
• acts by inhibiting GABA transaminase (GABA-metabolising enzyme): Vigabatrin
is extremely specific for this enzyme and works by forming an irreversible
covalent bond
• effective in patients unresponsive to conventional drugs
• main side-effects: drowsiness, behavioural and mood changes.

• Lamotrigine:
• acts by inhibiting sodium channels
• broad therapeutic profile
• main side-effects are hypersensitivity reactions (especially skin rashes).
• Felbamate:
• mechanisms of action unknown
• broad therapeutic profile
• use limited to intractable disease because of the risk of severe
hypersensitivity reactions
• Gabapentin: Gabapentin was designed as a simple analogue of GABA that
would be sufficiently lipid soluble to penetrate the blood-brain barrier
• mechanism of action not known
• It exhibit saturable absorption (increasing the dose does not
proportionately increase the amount absorbed); therefore, it is safe in
overdose
• relatively free of side-effects
• Tiagabine:
• Tiagabine, an analogue of GABA that is able to penetrate the blood-brain barrier
• Acts by inhibiting the reuptake of GABA by neurons and glia
• It enhances the extracellular GABA concentration
• And also potentiates and prolongs GABA-mediated synaptic responses in the brain.
• It has a short plasma half-life, and its main side-effects are drowsiness and confusion.
• The clinical usefulness of tiagabine has not yet been fully assessed.
• Topiramate:
• complex actions, not fully understood
• similar to phenytoin with fewer side-effects and simpler pharmacokinetics
• it is teratogenic in animals, so it should not be used in women of child-bearing age.
• Currently, it is recommended for use as add-on therapy in refractory cases of epilepsy.
 STATUS EPILEPTICUS
• A seizure that lasts longer than 5 minutes, or having more than 1 seizure
within a 5 minutes period, without returning to a normal level of consciousness
between episodes is called status epilepticus. This is a medical emergency that
may lead to permanent brain damage or death.
.
•  the various systems characterize status epilepticus according to where the
seizures arise—
• from a localized region of the cortex (partial onset) or
• from both hemispheres of the brain (generalized onset).
• The other major categorization hinges on the clinical observation of overt
convulsions; thus, status epilepticus may be convulsive or non-convulsive in
nature.
Systemic Pathophysiology
Failure of cerebral autoregulation* Cardiac/respiratory

Vomiting Hypoxia

Incontinence Arrhythmia

Renal: High output failure*

Acute renal failure from

Pneumonia
rhabdomyolysis*
Myoglobinuria*
 Treatment of Status epilepticus
• Once the diagnosis of status epilepticus is made, however, treatment should be
initiated immediately. Necessary interventions include maintaining oxygenation
and circulation, assessing the etiology and laboratory evaluations, obtaining
intravenous access, and initiating drug therapy
• Pharmacologic Management
• Rapid treatment of status epilepticus is crucial to prevent neurologic and
systemic pathology.
• The goal of treatment always should be immediate diagnosis and termination of
seizures.
• For an anti-seizure drug to be effective in status epilepticus, the drug must be
administered intravenously to provide quick access to the brain without the risk
of serious systemic and neurologic adverse effects.
• Multiple drugs are available, each with advantages and disadvantages.
 Treatment of SE cont’d
• Choice of Antiepileptic Drug
• Although there is no ideal drug for treatment of status epilepticus, a number of
considerations influence the choice of antiepileptic drug for this condition. 
• consensus has emerged concerning initial medications. Most authors agree that
lorazepam or diazepam should be initiated, followed by phenytoin. 
• BENZODIAZEPINES
• The benzodiazepines are some of the most effective drugs in the treatment of
acute seizures and status epilepticus. The benzodiazepines most commonly
used to treat SE are diazepam (Valium)  5 to 10 mg per minute, lorazepam
(Ativan), and midazolam (Versed). All three compounds work by enhancing the
inhibition of γ-aminobutyric acid (GABA).
• Other drugs: Phenytoin, Fosphenytoin, valproate and phenobarbital