‫بسم هللا الرحمن الرحيم‬

Sudan University for Science & Technology

Faculty of Pharmacy
Fourth year- sem 7
Pharmacology 3
Lecture 3: 28.12.2023
Drugs Acting on theCentral Nervous System
Antiepileptic drugs (Anti-seizure drugs) –I
Drugs used in partial seizures and generalized tonic-clonic seizures
Mohammed Taj Eldin Abdalla
B. Pharm., M. Pharm., Clinical Pharmacology
Email: Mohammedtaj654@gmail.com
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 ❖ Intended Learning Outcomes (ILOs)
❖At the end of this lecture students should be able to:
▪Differentiate Between Convulsion, Seizure & Epilepsy.
▪Identify The Potential Causes and types of Seizures.
▪Classify antiepileptic drugs.
▪Discuss PKs and PDs of antiepileptic Drugs.

M.TAJ 2
❖ Antiepileptic drugs (Anti-seizure drugs)
• Epilepsy is a very common disorder, affecting 0.5 - 1% of the population.
• Epilepsy is a disorder that characterized by periodic recurrence of seizure with or
without convulsion.
• Seizure: is a brief, temporary disturbance in the electrical activity of the brain.
• Convulsion: is an involuntary contraction of voluntary muscles
• Epileptic seizures often cause transient impairment of consciousness, leaving the
individual at risk of bodily harm and often interfering with education and
employment.

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• Therapy is symptomatic in that available drugs inhibit seizures, but
neither effective prophylaxis nor cure is available.
• Anti-seizure drugs are available, however compliance with medication is a
major problem because of the need for long-term therapy together with
unwanted effects of many drugs.
• Compliance with medication is a major problem because of the need for
long-term therapy together with unwanted effects of many drugs.

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• Usually there is no recognizable cause of epilepsy called idiopathic epilepsy, in
which the genetic component is the main factor for its etiology.
• Also epilepsy may develops after brain damage, such as trauma, infection or
tumor growth, or other kinds of neurologic disease. Which defined as
Cryptogenic epilepsies.
• 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, what starts as a local abnormal discharge may then spread to other areas
of the brain.
• The site of the primary discharge and the extent of its spread determines
the symptoms that are produced.

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• The particular symptoms produced depend on the function of the region
of the brain that is affected:
• Involvement of the motor cortex causes convulsions.
• Involvement of the hypothalamus causes peripheral autonomic discharge.
• Involvement of the reticular formation in the upper brainstem leads to loss of
consciousness.
• Abnormal electrical activity during a seizure can be detected by
electroencephalograph (EEG) recording from electrodes distributed over the
surface of the scalp. Therefore it is the main diagnostic step to determine
even the kind of epilepsy.

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Types of epilepsy:
• Seizures are divided into two groups:
1. Partial seizure.
2. Generalized seizure.
1- Partial Seizures:
• Partial seizures are those in which the discharge
begins locally, and often remains localized.
• There are three types of partial seizure determined to
some extent by the degree of brain involvement by
the abnormal discharge:
I. Simple partial seizure
II. The complex partial seizure
III. Secondarily generalized attack
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2- Generalized seizures:
Generalized seizures involve the whole brain,
including the reticular system, thus producing
Abnormal electrical activity throughout both
hemispheres
Immediate loss of consciousness is characteristic of
generalized seizures.
• The main categories of generalized seizures are:
I. Generalized tonic-colnic (grand mal) seizures
II. The absence (petit mal) seizure
III. Myoclonic jerking
IV. Atonic seizures
V. Infantile spasms
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• In EEG, doctors attach electrodes to your scalp with a paste-like
substance, the electrodes record the electrical activity of your brain.

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❖General Approach for the treatment of Epilepsy:
➢Antiepileptic drugs are fully effective in controlling seizures in 50-80% of
patients, although unwanted effects are common.
➢Patients with epilepsy usually need to take drugs continuously for many
years, so avoidance of side effects is particularly important.
➢The treatment of choice depends on the type of epilepsy and on drug-
specific adverse effects and patient preferences.
➢Regimen with monotherapy; about 50% to 70% of patients can be
maintained on one antiepileptic drug (AED), but all are not seizure-free.

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➢Up to 60% of patients with epilepsy are noncompliant, and this is the
most common reason for treatment failure.
➢Drug therapy may not be indicated in patients who have had only one
seizure or those whose seizures have minimal impact on their lives.
➢Patients who have had two or more seizures should generally be
started on AEDs
➢Factors favoring successful withdrawal of AEDs include a seizure free
period of 2 to 4 years, complete seizure control within 1 year of onset
of seizures after age 2 and before age 35 years, and a normal EEG

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➢Poor prognostic factors include a history of a high frequency of seizures,
repeated episodes of status epilepticus, a combination of seizure types, and
development of abnormal, and mental functioning.
➢Patient knowledge of epilepsy and treatment correlates with an improved
quality of life.

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❖ Anti-seizure drugs (Antiepileptic drugs):
➢ Mechanisms of action:
A. Enhancement of GABA action "mediated inhibition": Include:
• Direct action on the GABA receptor chloride channel "benzodiazepines,
barbiturates".
• Drugs act on the or metabolism of GABA: "gabapentin, tiagabine, and vigabatrin".
B. Reduction of excitatory glutamatergic neuron transmission:
• AMPA Receptor blockade propably contribute to the effect of phenobarbital and
topiramate, and NMDA receptor blockade probably contributes to the effect of
remacemide "an investigational drug".

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C. Inhibition of sodium channel function:
• Voltage-dependent Na+ channels enter an inactive state following each
action potential. Prolongation of this inactive state with a concomitant
prolongation of refractoriness is thought to be the principal mechanism of
action of: phenytoin, carbamazepine, and lamotrigine; it also contribute
into effects of phenobarbital, valporate, and topiramate.
D. Inhibition of voltage-activated Ca2+channel:
E.g: ethosuximide, dimethadione "used for absence seizures".

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I. Drugs used in partial seizures and generalized tonic-clonic
seizures:
▪ The major drugs for partial and generalized tonic-clonic seizures are:
Phenytoin, carbamazepine, valproate, and the barbiturates, and the newer
drugs: lamotrigine, gabapentin, oxcarbazepine, topiramate and vigabatrin.
1. Phenytoin:
• Phenytoin is the oldest non-sedative anti-seizure drug, introduced in 1938
• Phenytoin (diphenyl hydantoin) is the most important member of the hydnation
group of compounds, which are structurally related to the barbiturates.
Phenytoin analogs:
• Many analogues of phenytoin have been synthesized
mephenytoin, ethotoin and phenacemide e.g.

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❖Mechanism of action:
• At therapeutic concentrations, the major action of phenytoin is
to block sodium channels and inhibit the generation of
repetitive action potential (high frequency repetitive firing).
• These anti-epileptic drugs bind preferentially to Na+ channels
in the inactivated state, preventing them from returning to the
resting state, and thus reducing the number of functional
channels available to generate action potentials.
❖ Clinical use:
1- Phenytoin is one of the most effective drugs against partial seizures and
generalized tonic-clonic seizures.
• * "The drug is not effective against absence seizures, which may even get
worse".
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❖ Pharmacokinetics:
• Phenytoin is well absorbed when given orally.
• The time to peak may range from 3 hours to 12 hours.
• Phenytoin is highly bound to plasma protein (about 80-90% of the plasma
content is bound to albumin).
• Phenytoin is metabolized by the hepatic mixed function oxidase system and
excreted mainly as glucuronide.
• The metabolites are clinically inactive and are excreted in the urine.
• It causes induction, and thus increases the rate of metabolism of other
drugs (e.g. oral anticoagulants).

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❖ Drug interactions:
• Drug interactions involving phenytoin are primarily related to protein
binding or to metabolism.
• Phenytoin is 90% bound to plasma protein, other highly bound drugs, such
as phenylbutazone, salicylates, valporate and sulfonamides, can displace
phenytoin from its binding site. "this many cause a transient increase in free
drug".
• Phenobarbital and carbamazepine cause decreases in phenytoin steady-
state concentrations through induction of hepatic microsomal enzymes.
• Isoniazide inhibits the metabolism of phenytoin, resulting in increased
steady-state concentrations when the two drugs are given together.

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❖ Unwanted effects (toxicity):
• The milder side-effects include: vertigo, ataxia, headache and nystagmus. At
higher plasma concentrations, marked confusion with intellectual deterioration
occurs; these effects occur acutely and are quickly reversible.
• Hyperplasia of the gums often develops gradually (Gingival hyperplasia).
• Hirsutism (probably results from increased androgen secretion).
• Long-term chronic use is associated mild peripheral neuropathy.
• Chronic use, abnormalities of vitamin D metabolism, leading to osteomalacia.

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• Megaloblastic anemia, associated with a disorder of folate metabolism,
some times occurs, and can be corrected by giving folic acid.
• Hypersensitivity reactions, mainly rashes, are quite common.
• Phenytoin Has implicated as a cause of the increased incidence of foetal
malformations in children, particularly the occurrence of cleft palate.
• Severe idiosyncratic reactions, including hepatitis and skin reactions.

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2. Carbamazepine:
• It is chemically derived from the tricyclic antidepressant.
• It was initially marketed for the treatment of trigeminal neuralgia but has
proved useful for epilepsy as well.
• Pharmacologically and clinically its actions resemble those of phenytoin, though
it appears to be particularly effective in treating complex partial seizures.
❖ Mechanism of action:
• Mechanism of action of carbamazepine similar to that of phenytoin.
• Carbamazepine blocks sodium channels at therapeutic concentrations and
inhibits high-frequency repetitive firing in neurons.

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❖ Clinical use:
1. Carbamazepine is considered the drug of choice for partial seizures, and
many physicans also use it first for generalized tonic-clonic seizures.
2. It can be used with phenytoin in many patients who are difficult to
control.
1. The drug is also very effective in some patients with trigeminal neuralgia.
2. The drug is also useful in some patients with mania (bipolar disorder) as a
mood stabilizer

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❖ Pharmacokinetics:
• Carbamazepine is well absorbed, peak levels are usually achieved 6-8
hours after administration.
• The drug is only 70% bound to plasma proteins; no displacement of
other drugs from protein binding sites has been observed.
• The drug has a notable ability to induce microsomal enzymes.
• A slow-release preparation is used for patients who experience dose-
related side effects.

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❖ Unwanted effects (toxicity):
• Other dose-related compliants include mild gastrointestinal upsets, drowsiness.
• The most common dose-related adverse effects of Carbamazepine are diplopia
and ataxia. The diplopia often occurs first and may last less than an hour during
a particular time of day.
• It can also cause water retension and a variety of cardiovascular side-effects.
• Severe bone marrow depression, causing neutropenia, and other severe
forms of hypersensitivity reaction have occurred, but are very rare.
• The most common idiosyncratic reaction is an erythematous skin rash; other
responses such as hepatic dysfunction are unusual.
3. Oxcarbazepine:
• Oxcarbazepine is closely related to carbamazepine and useful in the same
seizure types, but it may have an improved toxicity profile.
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❖ Drug interactions:
• Almost exclusively related to the drug's enzyme-inducing properties.
• The increased metabolic capacity of the hepatic enzymes may cause a
reduction in steady-state carbamazepine concentrations (pharmacokinetic
tolerance) and an increased rate of metabolism of primidone, phenytoin,
ethosuximide, valporic acid, and clonazepam.
• Drugs such as cimetidine, and valproic acid may inhibit carbamazepine
clearance and increase steady state carbamazepine blood levels.
• Anticonvulsants such as phenytoin and phenobarbital, may decrease steady-
state concentrations of carbamazepine through enzyme induction.
• No clinically significant protein-binding interactions have been reported.

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4. Phenobarbital:
• Phenobarbital is the oldest of the currently available antiseizure drugs.
• The four derivatives of barbituric acid clinically useful as antiseizure
drugs are phenobarbital, mephobarbital, metharbital, and primidone.
• It is (like phenytoin) ineffective in treating absence seizures.

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❖Mechanism of action:
▪The exact mecahnism of action of phenobarbital is unknown, but enhancement
of inhibitory process and diminution of excitatory transmission probably
contribute importantly.
▪Like phenytoin, phenobarbital suppresses high-frequency repetitive firing in
neurons in culture through action on Na+ conductance, but only at high
concentrations.
▪Also at high concentrations, barbiturates block some Ca2+ currents.
▪Both the enhancement of GABA-mediated inhibition and the reduction of
glutamate-mediated excitation are seen with therapeutically relevant
concentrations of phenobarbital.
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❖ Pharmacokinetics:
• It is well absorbed and about 50% of the drug in the blood is bound to
plasma albumin. It is eliminated slowly from the plasma (t1/2 50-120
hours).
• About 25% is excreted unchanged.
• It is a weak acid and renal elimination is increased if urine is alkalinized.
• The remaining 75% is metabolized, by oxidation and conjugation, by
hepatic microsomal enzymes.
• Phenobarbitone is a particularly effective inducer, and by this mechanism,
it lowers the plasma concentration of several other drugs.

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❖ Clinical use:
• Phenobarbital is useful in the treatment of partial seizures and generalized tonc-
clonic seizures.
• Phenobarbital may worsen patients with absence seizures, atonic attacks, or
infantile spasms.

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❖ Unwanted effects:
• The main unwanted effect is sedation, which often occurs at theraleutic
plasma concentrations.
• Other unwanted effects that may occur with clinical dosage include
megaloblastic anaemia (similar to that caused by phenytoin), mild
hypersensitivity reactions and osteomalacia.
• Like other barbiturates it must not be given to patients with porphyria.
• In overdose, It produces coma and respiratory and circulatory failure, as
do all barbiturates.

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5- Primidone:
• Primidone was first marketed in early 1950s.
• It was later reported that primidone was metabolized to phenobarbital and
phenylethyl malonamide. All three compounds are active anticonvulsants.
❖ Mechanism of action:
• Although primidone is converted to phenobarbital, the mechanism of action of
primidone itself may be more like that of phenytoin.
❖ Clinical use:
• Primidone, like its metabolites, is effective against partial seizures and
generalized tonic-clonic seizures and may be more effective than
phenobarbital.

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6. Vigabatrin:
• Vigabatrin is a γ-vinyl-GABA designed as an inhibitor of the GABA
metabolizing enzymes "GABA-transaminase".
❖ Mechanism of action:
• Vigabatrin is an irreversible inhibitor of GABA aminotransferase (GABA-T),
the enzyme responsible for the degradation of GABA.
• It apparently acts by increasing the amount of GABA released at synaptic
sites, there by enhancing inhibitory effects.
• Vigabatrin may also potentiate GABA by inhibiting the GABA transporter.

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❖ Clinical use:
• Vigabatrin is useful in the treatment of partial seizures and West's
syndrome.
❖ Side effects:
• Typical toxicities include: drowsiness, dizziness, and weight gain.
• Less common adverse reactions: agitation, confusion, and psychosis.
• More recently, long-term therapy with vigabatrin has been associated
with development of visual field defects in up to one-third of patents.

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7. Lamotrigine:
❖ Mechanism of action:
• Lamotrigine's principal mechanism of action, like that of phenytion, the
drug suppresses sustained rapid firing of neurons and produces a voltage-
and use- dependent inactivation of sodium channels.
• It appears likely that lamotrigine has another mechanism of action to
account for its efficacy in primary generalized seizures in childhood,
including absence attacks, this mechanism may involve action on voltage-
activated Ca+2 channels.

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❖ Clinical use:
• Most controlled studies have evaluated lamotrigine as add-on therapy; some
also suggest that the drug is effective as monotherapy for partial seizures.
• The drug also active against absence and myoclonic seizures in
children.
• Mood stabilizer (treatment of bipolar disorder).
❖ Adverse effects:
• Dizziness, headache, diplopia, nausea, somnolence, and skin rash.

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8. Gabapentin:
• Gabapentin is an aminoacid, an analog of GABA.
• Originally planned as a spasmolytic, it was found to be more effective as
an antiseizure drug.
❖ Mechanism of action:
• In spite of its close structural relationship to GABA, gabapentin appears
not to act on GABA receptors.
• It may alter GABA metabolism, its non-synaptic release, or its reuptake
by GABA transporters.
• Its mechanism of action is as yet poorly understood and appears
to be different from that of any other anti-seizure drug.
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❖ Clinical use:
1. Gabapentin is effective as an adjunct against partial seizure
and generalized tonic-clonic seizures.
2. Gabapentin has also been found effective in the treatment
of neuropathic pain.
❖ Side effects:
• The side effects of gabapentin (mainly sedation and ataxia) are less
severe than with many antiepileptic drugs.

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 THANKS

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