Antiepileptic Drugs

1
Antiepileptic Drugs
Gisvolds book

• Barbiturates
• Hydantoins
• Oxazolidinedienos
• Succinimides
• Phenacemides
• Glutethemides
• Miscellaneous
• Benzodiazepines

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Mechanism of Actions

• Positive allosteric modulation of action of
  g-aminobutyric acid (GABA) at GABAA receptor site
  - benzodiazepines and barbiturates
• Phenobarbital, may also block voltage gated
  Na-channel
• 5,5-dialkylbarbiturates, may also block Ca2
  T-channel
• Oxazolidine-2,4-diones and succinimides appear to
  act via Ca2 T-channel block
• Phenyl-substituted succinimide may also cause
  some Na-channel block
• The major mode of action for phenytoin,
  carbamazepine, oxacarbazepine, valproic acid, and
  felbamate is reported to be voltage-gated
  Na-channel blocker

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Antiepileptic General Structure

• Overall, R1 and R2 should be hydrocarbon
• Lower alkyls tend to be active against absence
  seizures and not active against generalized
  tonic-clonic or partial seizures
• If one of the hydrocarbon substituent is an aryl
  group activity tends to be directed toward
  generalized tonic-clonic and partial seizures and
  not absence seizures

4
Barbiturates

• First synthesized in 1864 by German researcher
  Adolf von Baeyer, the founder of Bayer
  pharmaceuticals company by combining urea with
  malonic acid

• The first pharmacologically active compound
  discovered (1903) was barbital which was very
  effective in putting dogs to sleep
• Barbital was then marketed by Bayer under the
  trade name Veronal (after a peaceful Italian City
  name) and then Phenobarbital, under the trade
  name Luminal, as a sedative-hypnotic
• In the 1950s and 1960s, reports began to be
  published about side effects and dependence
  related to barbiturates
• In 1970 several barbiturates were designated as
  controlled substances with the passage of the
  Controlled Substances Act of 1970

Which are under schedules III and IV?
5
Barbiturate Structures

• The main antiepileptic drug is Phenobarbital
  major metabolite of which is the p-hydroxyl
  and/or the p-hydroxyglucuronide about 25
  excreted unchanged
• Mephobarbital is N dealkylated to phenobarbital
  which many think is the active drug and thus
  mephobarbital is a prodrug
• N1 and N3 are not distinguishable.
• Both drugs being substituted with an aromatic
  ring at R2 are effective against generalized
  tonic-clonic and partial seizures.

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Secobarbital possesses anaesthetic,
anticonvulsant, sedative and hypnotic properties
and sometimes used in physician assisted
suicides. The primary metabolites of secobarbital
are (?-1)-hydroxysecobarbital (36.5) and
dihydroxydihydrosecobarbital (secodiol, 15.7),
both of which are excreted also as glucuronide
conjugates (26.2).
Thiopental is an ultra-short-acting barbiturate
and has been used commonly in the induction phase
of general anesthesia and historically to induce
medical comas. It is also used intravenously for
the purposes of euthanasia. Along with
pancuronium bromide and potassium chloride,
thiopental is used in 34 states of the U.S. to
execute prisoners by lethal injection. Thiopental
is still used in some places as a truth serum
during interrogation. As with all lipid soluble
anaesthetic drugs, the short duration of its
action is almost entirely due to its
redistribution away from central circulation
towards muscle and fat tissue. Once redistributed
the free fraction in the blood is metabolized in
the liver. Sodium thiopental is mainly
metabolized to pentobarbital.
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Barbiturate Relatives

• Primidone is a pyrimidinedione and not a
  barbiturate but is related where C2 oxidation
  leads to conversion into Phenobarbital in vivo
  which is thought to be the active constituent
• Glutethimide is another non barbiturate sedative
  hypnotic used as safe alternative to barbiturates
  to treat insomnia. It is however a schedule II
  drug due to dependency.

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SAR of Barbiturates

• Both hydrogen atoms at C5 must be substituted
• There is a decrease in onset time and a decrease
  in duration as C5 alkyl chain length increases.
• Due to increasing lipid solubility increases rate
  of CNS penetration for shorter onset and
  increases susceptibility to microsomal metabolism
  due to penetration into hepatic cells
• Common metabolic pathway is ? and ?-1 oxidation
• Except for those with very high lipid solubility
  (thiobarbiturates), the barbiturates have short
  duration
• Thiobarbiturates undergo slow metabolism most
  are in the adipose tissue (depot) and not
  available to hepatic enzymes which can be
  converted to corresponding oxybarbiturate by
  desulfuration
• Bulk on C5 (i.e., aromatic ring) is a common
  feature for drugs with activity for generalized
  seizures and also for partial seizures and status
  epilepticus, but not good for absence seizures

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Hydantoins
Hydantoin was first isolated in 1881 by Adolf von
Baeyer in the course of his study of uric acid.
He obtained it by hydrogenation of Allantoin
hence the name

1. Close structural relatives of barbiturates
2. Only lacking the 6-oxo group and are cyclic
   monoacylureas rather than diacylureas
3. As a consequence of losing a carbonyl group
   weaker organic acids than barbiturates and thus
   their sodium salt (e.g., phenytoin sodium)
   generates stronger alkaline solution

SAR of Hydantoins Most of the clinically used
drugs in this class possess bulky aromatic ring
in position C5 that confers usefulness in
generalized seizures, partial seizures and status
epilepticus but not well for absence seizures
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Hydantoin Drugs
Phenytoin is metabolized by p-hydroxylation
followed by conjugation similar to Phenobarbital.
Mephenytoin is the hydantoin analogue of
mephobarbital which is also a prodrug, converted
into the dealkylated derivative. Metabolism is
also by p-hydroxylation and then glucuronidation
Ethotoin is dealkylated to the active drug. In
this case there is free hydrogen at C5, which
explains its very low potency. Metabolism is also
by p-hydroxylation and then glucuronidation
Fosphenytoin is Phosphate ester of phenytoin,
rapidly hydrolyzed to phenytoin in vivo.
Phenytoin sodium must be buffered to an alkaline
pH to maintain solubility, thus is very
irritating when injected. Fosphenytoin is neutral
(pH7) so is less irritating
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Oxazolidinediones
Replacement of the N-H group at position 1 of the
hydantoin with an oxygen atom yields the
oxazolidine-2,4-dione system
Trimethadione is useful for absence seizures.
Note the absence of bulky substituents at the C5
position which are useful in absence seizures. It
is metabolized to 5,5 dimethyl oxazolidine 2,4
dione (dimethadione) which is also active. Both
trimethadione and dimethadione are excreted in
the urine and are very toxic Paramethadione is
also N dealkylated, half life is 12-24 hours.
Some excreted by kidney. The metabolite is active
and probably accounts for most activity the half
life of which is 14 days and is excreted by the
kidney. Also it is fairly toxic
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Succinimides
This group of drugs resulted from a search for a
less toxic version of the oxazolidinediones by
replacing the O with CH2
Ethosuximide is lacking bulky groups attached at
C3 which corresponds to C5 in the other related
structures and thus is good for absence seizures.
Major metabolite is from oxidation of the ethyl
group, hydroxyethyl and conjugated hydroxyethyl,
both are inactive
Methsuximide has a bulky group at C3 which is
good for absence but also picks up some partial
seizures activity. It is N-dealkylated to an
active metabolite. Half life of methsuximide is
1.4 h, the N demethyl has a half life of 38 h. So
most activity are due to metabolite, followed by
p-hydroxylation and conjugation
Phensuximide possesses the bulky group at C3
which is good for absence but also picks up some
generalized tonic-clonic activity. Because of the
free hydrogen at C3, it is much weaker than the
disubstituted compounds. N-dealkylated to an
active metabolite, but the half life is about the
same as the parent (5-12 hr) and the activity is
due to both species. Followed by p-hydroxylation
and conjugation
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Miscellaneous
Dibenzazepines structurally related to the TCAs.
The H2NCO function is referred to as a carbamoyl
or carboxamide. If the N in the ring is included
we have a urea derivative. So it is also a ureide
Oxcarbazepine does not undergo such epoxidation
so is expected to be less toxic
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Valproic Acids

• Discovered accidentally
• Valproic acid is a liquid and so is used as a
  liquid filled capsule
• Being an organic solvent not soluble in water for
  intravenous use. Valproate sodium was developed
  as a water soluble salt, but too hygroscopic for
  solid oral dosage forms. Also causes GI
  irritation and cannot formulate a liquid into
  sustained release forms
• Divalproex sodium is a stable salt for oral
  tablets and less irritating to the stomach

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Felbamate is a dicarbamate. Carbamates are salts
or esters of the hypothetical carbamic acid
(H2NCOOH), similar to meprobamate. But felbamate
has a phenyl (fel-) instead of the methyl, propyl
groups as in meprobamate
Gabapentin is GABA plus 5 carbons. The idea was
to make GABA more lipid soluble for better CNS
penetration. But works through a non GABA agonist
unknown mechanism. Widely used for neuropathic
pain where it is thought to involve voltage-gated
N-type calcium ion channels. The more potent
successor drug that is also used to treat
neuropathic pain (fibromyalgia) is pregabalin
approved in 2007. Its S-isomer is the active form.
Baclofen modulates mammalian (but not fruit fly)
GABAB receptor. It is used for the treatment of
spastic movement, especially in instances of
spinal cord injury, spastic diplegia, multiple
sclerosis, amyotrophic lateral sclerosis and
trigeminal and glossopharyngeal neuralgias. It
appears to have reduced abuse and dependence
potential. The drug is rapidly absorbed after
oral administration and is widely distributed
throughout the body. Biotransformation is low and
the drug is predominantly excreted in the
unchanged form by the kidneys.
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New Molecular Entity in 2009 Vigabatrin

• ()-4-amino-5-hexenoic acid
• A GABA analog and is dosed as a racemic compound,
  with the S-enantiomer being the pharmacologically
  active form.
• The alkene group forms an irreversible, covalent
  bond with the gamma-aminobutyric acid
  transaminase (GABA-T) and irreversibly inhibits
  it. The enzyme (GABA-T) is responsible for the
  metabolism of the inhibitory neurotransmitter
  GABA its blockade leads to increased levels of
  GABA in the central nervous system.
• Thus, it is an antiepileptic drug indicated as a
  monotherapy for pediatric patients 1 month to 2
  years of age with infantile spasms (IS) and as an
  adjunctive therapy for adult patients with
  refractory complex partial seizures (CPS) who
  have inadequately responded to several
  alternative treatments.
• It is essentially completely orally absorbed and
  widely distributed throughout the body. It is not
  significantly metabolized (80 of a dose is
  recovered as parent drug), although it does
  induce CYP2C9, and it is eliminated primarily
  through renal excretion.

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The Benzodiazepines (sedative-hypnotics)

• 1,4-benzodiazepine-4-oxide

• 1,4-benzodiazepine-2-one

• Annelated benzodiazepines

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BDZ Acid-Base Character

• All are basic most are weakly basic
• N4 is basic (imine) in all except for
  chlordiazepoxide (because the n-electrons are
  utilized in forming the N-oxide). The imine is
  weak because the carbon atom is attached to two
  electron withdrawing aromatic rings (ring A and
  C). e.g., Lorazepam pKa 1.3.
• Some are more basic due to substituents at C2 or
  N1. e.g., chlordizepoxide the nitrogen
  substituent at C2 produces an amidine, pKa 4.76
  flurazepam the N1 substituent is a tertiary
  amine, pKa 8.16.
• Some are more basic due to fused ring D. e.g.,
  midazolam the nitrogens positions 1 an 2 are
  pyridinelike nitrogen, pKa 6.15
• Some are weakly acidic due to the amide (N1C2)
  The nitrogen must be unsubstituted to
  tautomerize. Since amides have a low tendency to
  tautomerize, they have a low tendency to ionize,
  thus are weak acids. e.g., lorazepam pKa 11.5
• Only one is strongly acidic clorazepate is the
  potassium salt of a carboxylic acid, thus is
  highly ionized

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Table Log P Values of Selected
BDZs Drug Calc Expt Drug Calc Expt Alprazolam
3.87 2.12 Halazepam 3.73 3.97 Bromazepam 1.93
2.05 Lorazepam 2.41 2.39 Chlordiazepoxide 2.42 2.
44 Medazepam 4.43 4.41 Clonazepam 2.53 2.41 Mid
azolam 4.33
Clorazepate 2.04 Nordazepam 2.87 2.93 Demoxepa
m 1.87 1.49 Oxazepam 3.32 2.24 Diazepam 2.7 2.
82 Prazepam 3.99 3.73 Estazolam 3.32 Quazepa
m 4.3 4.03 Flumazenil 1.03 1.0 Temazepam 2.15 2
.19 Flunitrazepam 1.91 2.06 Triazolam 3.96 2.42
Flurazepam 3.02 from http//esc.syrres.com
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BDZ Metabolism ????

• Currently there are only four drugs available in
  injectable form only one is in pure aqueous
  solution
• The other three utilized organic co-solvents
  which are irritating to tissue
• Two factors are responsible the low water
  solubility and the susceptibility of ring B to
  hydrolysis. Benzodiazepines in solution exist in
  equilibrium with the inactive benzophenone analog
  produced by the opening of the N4-C5 double bond
  (a Shiff base). Low pHs favor the benzophenone
  structure, which also favor aqueous solubility.
  In this form the amide is susceptible to
  hydrolysis. Recall that low pHs catalyze
  hydrolysis. Thus benzodiazepines are unstable in
  acid pHs. Fortunately at blood pH of 7.4
  benzodiazepines exists in the closed ring B form.

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BDZ SARs
IC50 1.8
IC50 350
1) Applicable to 4-oxides only a) nitrogen at
position 2 is not essential (does increase basic
character) b) increasing size of 2 substituent
beyond methyl decreases potency. This group can
not bind with Site 2 and may introduce steric
hindrance. c) the N-oxide is not essential and
decreases potency. Since it is a polar group it
has a repulsive interaction with site 4. 2) Ring
A SARs a) Small e/w substituents at C7 increase
potency NO2 gt CF3 gt Br gt Cl gt H gt phenyl b)
Substituents on other ring A positions decrease
potency. e/w groups make ring A slightly electron
deficient. This increase the London interaction
with Site 1. Groups at other positions have the
same electronic effects. c) Large groups or
electron donors decrease potency. These introduce
steric factors. Clonazepam with a 7-nitro has an
IC50 of 1.8.
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3) Ring B SARs
a) Removal of phenyl at C5 decreases potency b)
Replacement of phenyl with isostere at C5 is
allowed. Ring C provides a London interaction
with Site 5. Loss activity if this interaction
decreases binding with the receptor c) Isosteric
replacement of O by S at C2 decreases potency.
Generally this isosteric replacement results in
an increase in potency. However, since the
benzodiazepeines are so lipid soluble, the
increase in lipid solubility makes the log P too
high d) Saturation of atoms at 4 and 5 form sp2
hybridized to sp3. This changes the shape of ring
B. Further studies have shown that the shape of
ring B is the most important factor determining
binding. Dihydrodiazepam has an IC50 greater than
1000 vs 8.1 for diazepam.
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IC50 of 8.4 (8.1 for diazepam)
IC50 of 92 (14.8 for flurazepam)
IC50 of 18 (14.8 for flurazepam)
e) A methyl is the best substituent at N1. 1) By
removing the methyl the interaction with Site 1
is lost. (nordiazepam) 2) Increasing the size of
the alkyl introduces steric factor, however
linear substituents retain sufficient potency to
be useful clinically, but bulky groups like
t-butyl produce very weak agents. f) A hydroxyl
at C3 decreases potency as polar group
interacting with the lipophilic Site 3, decrease
half-life, as it is susceptible to rapid
glucuronidation. The decrease in toxicity is due
to the ease of metabolism (oxazepam). g)
Annulation with triazole or imidazole markedly
increases potency. The ring increases LWPC and
increases receptor affinity. Annelated
benzodiazepines are more potent than
corresponding 2-one derivatives.
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IC50 3.5 18 for oxazepam
4) Ring C SARs a) Halogenation only at 2'
enhances potency, other positions decrease
potency Cl gt F gt Br gt NO2 gt CF3 gt H. Electron
withdrawing groups have similar electronic
effects as discussed for ring A, thus promote
binding with site 5. (Lorazepam) 5) 1,2-Annelated
SARs a) Introduction of 1methyl shortens
duration of action. The 1-methyl is very
susceptible to oxidation, thus easily
hydroxylated. The hydroxy metabolite retains
potency but may be quickly conjugated and
excreted.
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BDZ Mechanism of Action
As with the barbs, the GABAA receptor complex is
implicated as the site of action. The GABAA
receptor is a ligand gated ion channel composed
of different combinations of a, b, g, r
subunits. a16, ß13, ?13,, ?13. Different
combinations result in affinity for different
drugs and producing different activities Major
subtype (60 ) a1ß2?2 Sedative, amnestic,
anticonvulsant Minor subtype (15 ) a2ß3?2
Anxiolytic Minor subtype (10 ) a3ßn?2 To date
three BDZ receptors have been identified. The BDZ
receptors are also known as omega1, omega2 and
omega3. The BDZ1 receptors are located in areas
of the brain that are involved in sedation, and
the BDZ2 receptors are highly concentrated in
areas responsible for cognition, memory, and
psychomotor functioning. The BDZ3 receptors are
located in peripheral tissues and not involved in
hypnotic efficacy. The BDZs bind to all three
receptor subtypes. This lack of selectivity
allows the benzodiazepines to be used as
anticonvulsants, sedatives, hypnotics,
anxiolytics muscle relaxants and general
anesthetics, the activity is determined by the
dose and the desires of the company.
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Other Benzodiazepine Receptor Ligands Type 1
selective agents should have less central adverse
effects on cognition, memory, and psychomotor
function. Compared to benzodiazepine, these
agents have little effect on the normal stages of
sleep, and few if any anxiolytic, anticonvulsant,
muscle relaxant properties or amnesia. Zolpidem,
Zaleplon and Eszopiclone selectively bind to
BDZ1 receptors. Hypnotic efficacy may not differ
between benzodiazepine and the newer selective
agents. Zaleplon has a half-life of 1 hour. This
allows dosing up to four hours before a patient
needs to be awake. However, it may lead to
awakening during the night. Eszopiclone has the
advantage of being the only hypnotic approved by
the FDA for continual use.
Benzodiazepine Receptor Antagonists Benzodiazepine
antagonists are useful in treating overdoses and
in terminating benzodiazepine induced anesthesia.
Flumazenil binds the receptor with high affinity
(IC50 2.5) but the lack of ring C and the
modifications of ring B prevent activation of the
receptor. Activity is terminated by hydrolysis
to the inactive acid.
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Study Guide

• The mode of action of all antiepileptic drugs
• Critically analyze the differences in structural
  changes of all the classes. How the bulkiness of
  groups R1 and R2 affect the activity of the drugs
  against generalized seizures, partial seizures or
  absence seizures?
• Structures of most important drugs in these
  classes in the way that you can recognize them
• Metabolic pathways and pharmacokinetics of the
  drugs indicated
• SAR in general and also for the individual drugs
• SAR of BDZs. What is truth serum? Which drugs are
  used to cause physician assisted suicide or
  execute the criminals?
• Know all about vegabatrin
• Which antiepileptic class of drugs are most
  toxic?
• Which receptor(s) are modulated by BDZs?
• Which ones are Type-1 selective agents? What are
  their advantages? What are benzodiazepine
  receptor antagonists?

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Case Study
Case 1. JB, a 34-year-old woman, was the recent
victim of car accident in which she sustained a
severe head injury. She has come to emergency
room after suffering a severe, generalized
tonic-clonic convulsive episode. She is
hospitalized and, within the next few days, two
more generalized seizures are experienced. It is
decided to initiate chronic anticonvulsant
therapy, and your advice is solicited.

1. Which of the anticonvulsant structures (1-5)
   should be administered to JB?
2. What structural features of your drug of choice
   are responsible for your answer?