Dr.Narmin Hamaamin Hussen Antiepileptic drugs / Medicinal Chemistry III

1. Antiepileptic Drugs
Dr.Narmin Hamaamin Hussen
Medicinal Chemistry III/ 4th stage / 1St semester
College of Pharmacy/ University of Sulaimani
Lecture 3
2021-2022

2. Epilepsy
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▪ Epilepsy is a chronic noncommunicable disease (chronic neurological disorder )of the brain that affects around
50 million people worldwide.
▪ It is characterized by recurrent seizures.
▪ Having two or more seizures at least 24 hours apart that aren't brought on by an identifiable cause is generally
considered to be epilepsy.
▪ The most common cause of seizures is epilepsy.
▪ But not every person who has a seizure has epilepsy ( Febrile seizure)

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▪ Normally, nerve cells in the brain transmit electrical and chemical
signals to other nerve cells, glands, and muscles, which allow the
brain's nerve cells to communicate.
▪ Seizures happen when too many of these nerve cells, or neurons, fire
electrical signals at the same time at a much faster rate than they
normally would. Usually, a seizure lasts a few seconds to several
minutes.
https://www.youtube.com/watch?v=WqtERCawzC4
Why do seizures happen?

4. Causes of Epilepsy
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There are many possible causes of seizures including :
➢ Genetic ( Family history)
➢ Brain tumors or infections,
➢ Head trauma
➢ Neurological diseases
➢ Systemic or metabolic disorders
➢ Alcohol abuse
➢ Drug overdose, or toxicities

5. Classification Of Epileptic Seizures:
➢Investigations:
▪ Seizures are classified, based on their initial signs and symptoms and
the pattern seen on the electroencephalogram (EEG), each of the
epilepsy types is characterized by an abnormal pattern in the EEG.
The EEG indicates sudden, excessive electrical activity in the brain.
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7. Phases of Tonic-Clonic seizure First aid for seizures

8. Mechanisms of action of Antiepileptic Drugs :
Three main mechanisms :
➢ Enhancement of GABA action
➢ Inhibition of sodium channel function
➢ Inhibition of calcium channel function.
Other mechanisms include :
➢ - Inhibition of glutamate release and
➢ - Block of glutamate receptors.
➢ K+ Channel opener
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9. Action on Ion Channels Enhance GABATransmission Inhibit EAA
Transmission
Na+ Channel Blocker :
Phenytoin
Carbamazepine
Lamotrigine
Topiramate
Valproic acid
Zonisamide
For general tonic- clonic and
partial seizures
Benzodiazepines (diazepam,
clonazepam)
Barbiturates (phenobarbital)
Valproic acid
Gabapentin
Vigabatrin
Topiramate
Felbamate
Zonisamide
Most effective in myoclonic but also
in tonic-clonic and partial
Clonazepam: for Absence
Felbamate
Topiramate
Ca2+ Channel Blocker :
Ethosuximide
Valproic acid
For Absence seizures
Classification of Anticonvulsant Drugs
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K+ Channel opener :
Retigabine or Ezogabine

10. Inhibition of sodium channel function
➢ Valproic Acid (Depakene):
▪ 2-propylpentanoic acid (Depakene) has good potency and is used against typical and atypical
absence seizures and absence seizure with generalized tonic-clonic seizure.
▪ It is generally well tolerated, but its use is limited by two rare but significant toxic side effects
(hepatotoxicity and teratogenicity) that can be dose dependent .
▪ VPA is also an important inhibitor of the cytochrome P450 isozymes, mainly of CYP2C9 and
also of uridine diphosphate (UDP)-glucuronyl transferase and epoxide hydrolase.
▪ Valproate causes birth defects; exposure during pregnancy is associated with about three
times as many major abnormalities as usual, mainly spina bifida
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Aliphatic Carboxylic acids:

11. Metabolic pathways of valproic acid
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12. ➢ Alpha fluorovalproic acid:
▪ To prevent the hepatotoxicity of valproic acid
(VPA), a fluorine substituent was introduced at
the alpha-position to eliminate the formation of
putative toxic metabolites through mitochondrial
beta-oxidation.
▪ Recent studies have shown that alpha-
fluorination of a hepatotoxic metabolite of VPA
(Delta(4)-VPA) resulted in a non-hepatotoxic
derivative.
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➢ Divalproex Sodium
▪ Valproate semisodium or divalproex, which contains equal molar quantities of sodium valproate and valproic
acid , is marketed by Sanofi in a formulation called Depakote (gastro-resistant tablets)and by Pfizer Ltd as
Convulex (gastro-resistant capsules).
▪ Depakote is licensed for "treatment of all forms of epilepsy and treatment of manic episode in bipolar disorder
when lithium is contraindicated or not tolerated“
▪ Depakote is an oral drug that has an antiepileptic, antimanic and antimigraine activity.
▪ As an antiepileptic (anticonvulsant) drug, Depakote can be used to control seizures at any age, as well as to
maintain seizure control in children younger than 2 years. As antimigraine or antimanic drug, Depakote should
be prescribed only to patients aged 18 and older.

14. ➢ Phenytoin (Dilantin) and Fosphenytoin (Cerebyx):
▪ Phenytoin is very effective against all seizure types except absence; however, the drug may be incompletely or
erratically absorbed from sites of administration because of its very low water solubility(limited water solubility
– not given by i.m).
▪ For this reason, fosphenytoin, a prodrug of phenytoin, was developed and marketed to avoid complications such
as vein irritation, tissue damage, and muscle necrosis associated with parenteral phenytoin administration.
▪ Fosphenytoin is rapidly absorbed either by intravenous or intramuscular administration. It is converted into
phenytoin through phosphatase catalyzed hydrolysis of the phosphate ester.
▪ Phenytoin is absolutely contraindicated in pregnancy .
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Hydantoin Derivatives:

15. Biotransformation of fosphenytoin to phenytoin.
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16. Metabolism Of Phenytoin
▪ The principal metabolic pathway of phenytoin
in humans is aromatic hydroxylation,
catalyzed by the cytochrome P450 isozymes
(CYP2C9 and CYP2C19).
▪ The major metabolites of phenytoin are the5-
(4-hydroxyphenyl)-5-phenyl hydantoins
(pHPPH) and dihydrodiol. Both of these
inactive metabolites are excreted as the
corresponding O-glucuronides.
▪ Oxidation of p-HPPH leads to a catechol
metabolite, which appears in the urine as a
methyl conjugate by the action of catechol-
Omethyltransferase (COMT).
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17. ➢ Carbamazepine (Tegretol) , Oxcarbazepine (Trileptal) , Eslicarbazepine acetate
and licarbazepine :
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N,N-diacylureas:
Eslicarbazepine acetate
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▪ Carbamazepine is useful in generalized tonic–clonic and partial seizures.
▪ The two phenyls substituted on the urea nitrogen fit the pattern of antigeneralized tonic activity.
▪ The drug has the potential for serious hematological toxicity, and it is used with caution.
▪ Effects on the body's production of red blood cells, white blood cells, and platelets: rarely, there are major effects of
aplastic anemia and agranulocytosis reported and more commonly, there are minor changes such as decreased white blood
cell or platelet counts, but these do not progress to more serious problems.
▪ Risks to the fetus in women who are pregnant, specifically congenital malformations like spina bifida
▪ Oxcarbazepine is a newer AED with a similar mechanism of action to CBZ except for its metabolic inactivation pathway
. It is also not a liver enzyme inducer like CBZ and phenytoin.
▪ Licarbazepine is an active metabolite of oxcarbazepine. In addition, an enantiomer of licarbazepine, eslicarbazepine, is an
active metabolite of eslicarbazepine acetate.
▪ Eslicarbazepine acetate is converted to the active metabolite eslicarbazepine which carries out its anticonvulsant
activity.
▪ Eslicarbazepine had a moderate inhibitory effect on CYP2C19 and a mild activation of UGT1A1-mediated glucuronidation
when studied in human hepatic microsomes. It has been shown to induce CYP3A4 enzymes in vivo.

19. Metabolism of carbamazepine , oxcarbazepine and eslicarbazepine acetate 19
▪ The major metabolic pathway of CBZ is the formation of a stable metabolite, 10, 11-CBZ epoxide by cytochrome P450
isozyme CYP3A4.This reactive metabolite is further deactivated by the action of epoxide hydrolase to give inactive 10, 11-
CBZ-diol that is excreted as the corresponding glucuronides.
▪ With the presence of a carbonyl function at the C-10 carbon, OXC is reduced to the corresponding CBZ-10-ol by the action
of alcohol dehydrogenase that is excreted as its O-glucuronide or can be further oxidized to the 10, 11-CBZdiol as an inactive
metabolite
epoxide hydrolase

20. ➢ Lamotrigine (Lamictal):
▪ Lamotrigine, an AED of the phenyl triazine class, has been found effective
against refractory partial seizures. Like phenytoin and CBZ, its main
mechanism of action appears to be blockade of sodium channels that is
both voltage- and use dependent.
▪ For antiepileptic drugs by the Commission on Human Medicines has
confirmed that lamotrigine (Lamictal) and levetiracetam (Keppra) are the
safer of the medicines reviewed during pregnancy.
▪ Lamotrigine is metabolized predominantly by glucuronidation. The major
inactive urinary metabolites isolated are 2-N-glucuronide (76%) and 5-N-
glucuronide (10%) because the aromatic ring is somewhat deactivated by
the presence of chlorine atoms toward arene oxide formation.
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Phenyltriazine Class:

21. ➢ Topiramate (Topamax):
▪ TPM is a sulphamate-substituted monosaccharide, a derivative of the naturally occurring sugar D-
fructose that exhibits broad and potent AED actions at both glutamate and GABA receptors.
▪ It has good oral bioavailability of 85% to 95%, most likely resulting from its structural similarity to D-
glucose. Thus, it may be actively transported into the brain by the D-glucose transporter. Only about
20% of the drug is eliminated by hepatic metabolism (CYP2C19), the remaining drug is excreted
unchanged by the kidneys.
▪ The sulphamate ester is hydrolyzed by sulfatases to the corresponding primary alcohol, which is
further oxidized to the corresponding carboxylic acid.
▪ TPM is said to have a weak carbonic anhydrase inhibitory activity because of the presence of the
sulphamate moiety. Thus, concomitant use of TPM with other carbonic anhydrase inhibitors should be
avoided.
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Sulphamate type:

22. ➢ Zonisamide (Zonegran):
▪ Zonisamide, a sulfonamide-type anticonvulsant was recently approved for adjunctive therapy in the
treatment of partial seizures in adults with epilepsy.
▪ Zonisamide is primarily metabolized by reductive ring cleavage of the 1,2-benzisoxazole ring to 2-
sulfamoyl-acetyl-phenol .This biotransformation is mainly carried out by the intestinal bacteria rather
than the mammalian cytosolic aldehyde oxidase.
▪ Because of the presence of a sulfonamide moiety in zonisamide molecule, precaution should be given
to patients who have a history of hypersensitivity reactions toward sulfonamide drugs and
concomitant use of zonisamide with other carbonic anhydrase inhibitors should also be avoided.
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Sulfonamide-type:

23. ▪ The GABAA receptor is one of two ligand-gated ion channels responsible for mediating the effects of
GABA, the major inhibitory neurotransmitter in the brain. Activation of the GABAA/benzodiazepine
(BZD) receptors/chloride channel complex allows increased chloride conductance, thereby preventing the
spread of neuronal excitations. The potential targets for AED’s action on the GABAergic inhibitory
synapses include:
a) drugs that enhance the biosynthesis of GABA (gabapentin, pregabalin, andVPA)
b) drugs that inhibit GABA degradation (vigabatrin)
c) drugs that inhibit the reuptake of GABA (tiagabine)
d) drugs that bind to an allosteric site on the postsynaptic GABAA receptor complex that increase chloride
conductance (barbiturates, BZDs, neurosteroids, FBM,TPM).
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GABAA Receptors asTargets for Anticonvulsants:

24. Biosynthesis and metabolism of GABA
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25. ▪ Gabapentin and its closely related analog pregabalin, (S)-3-isobutyl-GABA, are broad spectrum anticonvulsants with
multiple mechanisms of action. In addition to modulating calcium influx and stimulate GABA biosynthesis, they also
compete for the biosynthesis of L-glutamic acid because of their structural similarity to L-leucine.
▪ Gabapentin and pregabalin have very little liability for causing metabolic based drug– drug interactions, particularly
when used in combination with other AEDs because they are not metabolized in humans.
▪ More than 95% of the drug is excreted unchanged through the kidneys. However, there are some differences in their
bioavailability.
▪ Unlike gabapentin, which exhibits 60% bioavailability when given in low doses because of intestinal uptake by a
saturable small neutral L-amino acid transporter, the absorption of pregabalin is almost complete (98%) .
▪ This high bioavailability of pregabalin can be attributed to its closer structure similarity to the essential amino acid, L-
leucine.
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➢ Gabapentin (Neurontin) and Pregabalin (Lyrica):

26. ➢ Felbamate (Felbatol) and Flurofelbamate:
▪ FBM, is a carbamate ester of 2-phenyl-1, 3-propanediol. The carbamate ester is stable to esterases and
therefore provides good oral bioavailability.
▪ However, the FBM therapy was found to be associated with rare but severe side effects such as aplastic anemia
and hepatic failures within 6 months of its market introduction.
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27. Metabolic biotransformation of felbamate.
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2- phenyl-1, 3- propandiol monocarbamate 3-carbamoyl-2- phenylpropionic acid (CPPA).
3-carbamoyl-2-phenylpropionaldehyde

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➢ Flurofelbamate
▪ Fluorofelbamate -a very potent anticonvulsant
▪ Still under phase 2 clinical trials
▪ A product of placement of fluorine atom at the C-2 position of FBM

29. Benzodiazepines Class : Clonazepam (Klonopin) and Diazepam(valium) :
▪ Clonazepam is useful in absence seizures and in myoclonic seizures. Tolerance to the anticonvulsant effect of
the clonazepam often developed rather quickly, and it is a common problem with the BZDs. Metabolism
involves hydroxylation of the C-3 position, followed by glucuronidation and nitro group reduction, followed by
acetylation.
▪ Diazepam is given orally (Valium) or rectally (Diastat) as an adjunctive treatment in patients with generalized
tonic–clonic status epilepticus (i.e., an acute and potentially fatal seizure) or in patients with refractory
epilepsy in combination with other AEDs and febrile seizures.

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➢ Barbiturates:
▪ Phenobarbital and mephobarbital display enough anticonvulsant selectivity for use as antiepileptics.
▪ The metabolism of phenobarbital involves p-hydroxylation, followed by conjugation.
▪ Mephobarbital is extensively N-demethylated in vivo and is thought to owe most of its activity to the
metabolite phenobarbital. In keeping with their structures, both agents are effective against generalized
tonic-clonic and partial seizures.
Mephobarbital

31. ➢ Tiagabine (Gabitril)
▪ Itis blocks GABA reuptake as a major mode of its anticonvulsant activity. Its use is against partial
seizures. Inhibitors of GABA transporter-1(GAT-1 inhibitors) increase extracellular GABA
concentration.
▪ Nipecotic acid is a potent inhibitor of GABA reuptake into synaptosomal membranes, neurons,
and glial cells. However, nipecotic acid fails to cross the blood-brain barrier following systemic
administration because of its high degree of ionization.
▪ Over 90% of tiagabine is metabolized by CYP3A4 isozymes.The primary site of metabolic attack
is the oxidation of the thiophen rings leading to 5-oxo-tiagabine that lacks anticonvulsant activity
and the glucuronidation via the carboxylic function.
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32. Succinimides Derivatives :
➢ Ethosuximide (Zarontin) and Methsuximide (Celontin):
▪ Ethosuximide is considered the prototypical anticonvulsant needed for treating patients with absence
seizures.
▪ Ethosuximide and the N-dealkylated active metabolite of methsuximide work by blocking the low
threshold T-type calcium channels, thereby reducing the hyperexcitability of thalamic neurons that is
specifically associated with absence seizure.
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Inhibition of Ca2+ Channel function:

33. Newer Drugs
➢ Rufinamide:
▪ Rufinamide is an anticonvulsant medication. It is used in combination with other
medication and therapy to treat Lennox–Gastaut syndrome and various other seizure
disorders. Rufinamide, a triazole derivative.
➢ Lacosamide:
▪ Lacosamide is an anticonvulsant compound approved for the adjunctive treatment, as
well as, conversion to monotherapy and monotherapy treatment of partial-onset
seizures and neuropathic pain.
➢ Vigabatrin:
▪ Vigabatrin, brand name Sabril, is a medication used to treat epilepsy.
▪ It works by inhibiting the breakdown of γ-aminobutyric acid (GABA).
▪ It is also known as γ-vinyl-GABA, and is a structural analogue of GABA, but does not
bind to GABA receptors
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34. ➢ Retigabine or Ezogabine:
▪ It's an anticonvulsant used as an adjunctive treatment for partial epilepsies in treatment
experienced adult patients.
▪ Retigabine works primarily as a potassium channel opener—that is, by activating a certain
family of voltage-gated potassium channels in the brain.
➢ Perampanel:
▪ It's an antiepileptic drug developed by Eisai Co. that is used in addition to other drugs to
treat partial seizures and generalized tonic-clonic seizures for people older than 12 years.
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➢ Levetiracetam
▪ Levetiracetam is an antiepileptic drug marketed since 2000. Its novel mechanism of
action is modulation of synaptic neurotransmitter release through binding to the
synaptic vesicle protein SV2A in the brain.
▪ Levetiracetam is used alone and along with other medications to control partial-onset
seizures (seizures that involve only one part of the brain) in adults, children, and infants 1
month of age or older

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END