pharmcy

1. Antiepileptic Drugs
 The terms anticonvulsant and antiepileptic drug (AED) are used
interchangeably in the literature to describe a diverse group of
medications used clinically to provide seizure control in patients with
epilepsies.
These group includes:
Barbiturates
Hydantoins
Oxazolidinedienos
Succinimides
Phenacemides
Glutethemides
Miscellaneous
Benzodiazepines

2. Hippocrates (an early Greek physician described epilepsy as a disease
of the brain, which should be treated by diet.
Hippocrates provided the first classification of epilepsy, which is still
used.
He distinguished true (idiopathic) epilepsy ( i.e. , a disorder for
which the cause is unknown) from symptomatic (organic) epilepsy (
i.e., a disorder resulting from a physiologic abnormality, e.g., brain
injury, tumor, infection,intoxication or metabolic disturbances).
Epilepsy is an excessive neuronal discharge, may be brought aboutby
a disturbance of physicochemical function and electrical activity of
the brain.
The cause of this abnormality, however , is not clearly understood.

3. The most important property of the nerve cell is its excitability. It
responds to excitation by generating an action potential, which may
lead to repeated discharges.
All normal neurons may become epileptic if subjected to excessive
excitation.
DeRobertis list two possible mechanisms for convulsive disorders:
1- a loss of the normal inhibitory control mechanism, and 2- a chemical
supersensitivity that increases excitability ofneuronal elements.
The origin of the seizures was established as early as the 19th century by
Jackson. According to him, an intense discharge of gray matter in
various regions of the brain initiates the seizures.
They are classified broadly aseither
(i) partial seizures, in which the abnormal firing initially occurs in a
small number of neurons but may spread to adjacent areas,or
(ii)generalized seizures, in which virtually the entire brain is affected
simultaneously.

4. Two major types of generalized seizures are the primarily
generalized tonic–clonic seizures (grand mal) and the absence
(petit mal) seizures.
The typical primarily generalized tonic–clonic seizure is often
followed by a series of bilateral muscular jerks followed by loss of
consciousness, which in
turn is followed by a series of tonic and then clonic spasms.
The typical absence seizure (classic petit mal) consists of a sudden
brief loss of consciousness (10 seconds), sometimes with no motor
activity, although often some minor clonic motor activity exists.
Each of the epilepsy types is characterized by an abnormal pattern
in the EEG.
The EEGindicates sudden, excessive electrical activity in thebrain.
Most of the currently available AEDs work by preventing,
stopping, or lessening this electricalactivity.

5. Mechanism ofActions
These drugs inhibit the neuronal discharge or its
spread, and do so by:
Positive allosteric modulation of action of -
aminobutyric acid (GABA) at GABAA receptor
site - benzodiazepines and barbiturates
 Phenobarbital, may also block voltage gated
Na+-channel
 5,5-dialkylbarbiturates, may also block
T-channel Ca channel ("T" stands for
transient referring to the length of activation)
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
•Decrease of excitatory
(particularly glutamate-
mediated)
neurotransmission in the
brain.

6. Antiepileptic General Structure
The single exception among currently
useful anticonvulsant drugs
Are primidone, valproic acid and carbamazepine
Overall, R and R’ 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
The drugs acting as selective depressant of convulsant activity have in
R''' NH
O
Barbiturates
NH
Hydantoins
O
Oxazolidine diones
CH2
Succinimdes
N
R'
O O
R''
common the structural feature:
R'''
R

7. Barbiturates N
O
R1
R2
R3
O N O
H
Barbituric acid
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 Verona) 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

8. Barbiturate Structures
R2
O
R3
R1
O
O
N
R1 R2
R3
H C2H5 C2H5
H C2H5
CH3 C H
2 5
H
O
O SNa
N
H
N
Barbital
Phenobarbital
Mephobarbital
1
2
3
N
H
5
4
6
Secobarbital
Thiopental sodium
The main antiepileptic drug is Phenobarbital major metabolite of which is
the p-hydroxyl and/or the p-hydroxyglucuronide; about 25% excreted
unchanged (infant and young children)
Mephobarbital is N dealkylated to phenobarbital which many think is the
active drug and thus mephobarbital is a prodrug and its activity depend
upon its conversion in the boday to phenobarbitone.
N1 and N3 are notdistinguishable.
Both drugs being substituted with an aromatic ring at R2 are effective
against generalized tonic-clonic and partial seizures.

9. Secobarbital possesses anaesthetic, anticonvulsant, sedative and
hypnotic properties and sometimes used in physician assisted suicides.
The primary metabolites of secobarbital are 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 (refers to the practice of intentionally ending a life in order
to relieve pain and suffering).
• 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
questioning.
•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.

10. Barbiturate Relatives
H3C
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
O H
O H
Primidone
Glutethimide is another non barbiturate sedative hypnotic used as
safe alternative to barbiturates to treat insomnia.
N
2
N
H3C
O
O
N
H
Glutethimide

11. SAR ofBarbiturates
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 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
O
NH
O N O
H

12. Hydantoins
NH
O
O
R2
R1
1
5
4 3
2
N
R3
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
Close structural relatives of barbiturates
Only lacking the 6-oxo group and are cyclic
monoacylureas rather than diacylureas
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
Unlike barbiturates, anticonvulsant with little or no
sedative effect.
SAR of Hydantoins:
• Most of the clinically used drugs in this class possess bulky aromatic
ring in position C5 which enhance the binding to voltage gated Na
channel at the inactivation site, that gives usefulness in generalized
seizures, partial seizures and status epilepticus but not well for
absence seizures.

13. Hydantoin Drugs
H
N
O
N
H
O
Phenytoin
H3C
CH3
H
O
O
N
N
Mephenytoin
CH3
H
O
H O
N
N
Ethotoin
P ONa
ONa
O
O
O
O
N
H
N
Fosphenytoin
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.
Phenytoin the most active used for adult and older
children.
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
(pH~7) so is less irritating

15. R
R'
O
KCN
N
H
NH
O
O
R' R
(NH4)CO3
Synthesis of Hydantoins:
Hydantoins can be synthesised directly by the Bucherer reaction
which involves treatment of a ketone or aldehydes with ammonium
carbonate and KCN
The reaction can be rationalized by assuming that the 1st step consists
of the formation of cyanohydrin and then α-aminonitrile by addition of
ammonia

16. R
R'
C
NH2
C NH2
NH
R
R'
C O
2
KCN / H O R
C
C N
R' OH
cyanohdrin
NH3
O C O
N
H
O
O
R' R
NH
Alkylation of the NH at position 3 will give the N3-alkyl hydantoin (ethotoin,
mephentoin)
α-aminonitrile
R
R'
C
NH2
C N
NH3
- H2O

17. Oxazolidinediones
O
O
R2
O
R1
5 1
4 3
2
N
R3
Oxazolidinedione
CH3
H3C O
O
O
N
Trimethadione
CH3
H3C
H3C
O
O
O
N
Trimethadione is useful for absence seizures. Note the absence H3C
of bulky substituents at the C5 position which are useful in absence
seizures (petit mal seizure). 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 (nephrosis aplastic amaemia, bone
marrow depression, skin eruption) now replaced by Valproic
acid.
Paramethadione
Replacement of the N-H group at
Paramethadione is also N dealkylated, half life is 12-24 hours.
Some excreted by kidney. The metabolite is active and probably
accounts for most of activity, the half life of which is 14 days
and is excreted by the kidney. Also it is fairly toxic
N
O
oxazole
N
H
position 1 of the hydantoin with an
oxygen atom yields the oxazolidine-
2,4-dione system
O
oxazolidine
R'
R
O O
R''
R'''

18. Succinimides
2
N
O
O
R
R1
2
CH
2
1
3 4
5
HO
O
OH
O
Succinic acid
Ethosuximide is
R3
Succinimides
lacking bulky groups H
H3C
H3C
O
O
N
Ethosuccimide
CH3
H3C
O
O
N
Methsuccimide
CH3
O
H O
N
Phensuccimide
attached at C3 which
This group of drugs resulted from a search
version
replacing
of the
the “O”
for a less toxic
oxazolidinediones by
with CH2
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 C which is good for
3
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

19. Miscellaneous
N
O NH2
Carbamazepine
O NH2
Oxacarbazepine
anticonvulsantthat doesn’t contain the generalfeature
O
N
related to the
Dibenzazepines structurally
TCAs(Tricyclic antidepressant). 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

20. Valproic Acids
CH3
OH
O
CH3
Valproic acid
H3C
ONa
O
H3C
Valproate sodium
H3C
H3C
O
CH3
CH3
HO
ONa O
Divalproex sodium
Discovered accidentally when was used as solvent in testing
potential new AED, was found effective and with margin of safety.
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 be formulated as a liquid into sustained release forms
Divalproex sodium is a stable salt for oral tablets and less irritating
to the stomach

22. 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
meprobamate . Felbamate is bind
the methyl, propyl groups as in
to the
excitatory Glutamate-Mediated Receptors as
Target for its anticonvulsants activity
O
O
N H 2
O
N H 2
F e l b a m a t e O
NH2
NH2
H3C O
O
O
H3C
Meprobamate O
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.
NH2
O
Gabapentin OH
Pregabalin OH
H
NH2
O

23. NH2
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.
COOH
Cl
Baclofen

24. OH
H N
H2C
2
VIGABATRIN O
Sabril
(±)-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.
New Molecular Entity in 2009: Vigabatrin

25. The Benzodiazepines (sedative-hypnotics)
O
N
5-Phenyl-1,4-benzodiazepine
A
1
2
5
B 3
N 4
8
9
7
1'
C
4'
2'
3'
6
6'
5'
N
A B
1
N 5
X 3
4
8
9
6
1'
C
4'
2'
3'
7
6'
5'
10
2
N
D
Annelated benzodiazepine
Cl
OH
Cl
O
N
H
N
Lorazepam
Cl N
N
O
F
CH3
CH3
N
Flurazepam
O
Cl N
N CH3
1,4-benzodiazepine-4-oxide
H
N
Chlordiazepoxide
Cl N
CH3 O
N
Diazepam
1,4-benzodiazepine-2-one
N
Cl
Alprazolam
Cl
N N
Annelated benzodiazepines
H3C N H3C N
N N
N
Cl
Triazolam

26. OK
COOK
Cl N
N
Cl
O
H
N
COOK
N KOH
Clorazepate dipotassium
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 pyridine–like nitrogen, pKa 6.15
Some are weakly acidic due to the amide (N1–C2): 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
BDZ Acid-Base Character

27. Cl
O
O2N N
H
N
Clonazepam
N
Br
O
N
H
N
Bromazepam
Cl
O
N
N
CF3
Halazepam
O
Cl N
H
N
O
Demoxepam
Cl N
CH3
N
Medazepam
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 Midazolam 4.33 —
Clorazepate 2.04 — Nordazepam 2.87 2.93
Demoxepam 1.87 1.49 Oxazepam 3.32 2.24
Diazepam 2.7 2.82 Prazepam 3.99 3.73
Estazolam 3.32 — Quazepam 4.3 4.03
Flumazenil 1.03 1.0 Temazepam 2.15 2.19
Flunitrazepam 1.91 2.06 Triazolam 3.9 2.42
Flurazepam 3.02 —
from http://esc.syrres.com

28. 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.
BDZ Metabolism ????
N
Cl
CH3 O
N
Cl
CH3 O
N
O NH2
N
Cl
CH3
O
H
NH2
O
HO
Diazepam
Cl N
N
N
F
Cl
N
N
CH3 CH3
O NH2
F
Midazolam

29. lipophilic
site
lipophilic
site
N
N
1
Cl
lipophilic
pocket
5
CH 2
3
O
Diazepam
2
33
4
Chlordiazepoxide
N
N
H
N
Cl
O
CH3
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 > CF3 > Br > Cl > H >
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.
Cl
O
O2N N
H
N
Clonazepam

30. 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.
N
O
Cl
H
N
OH
N
N
Cl
CF3
O
N
O
Cl
H
N
Nordazepam Halazepam Oxazepam
1
lipophilic
site
lipophilic
site
N
N
Cl
lipophilic
pocket
5
CH 2
3
O
Diazepam
2
33
4

31. 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)Annulations with triazole or imidazole markedly increases potency. The
ring increases lipid/water partition coefficient (LWPC) and increases
receptor affinity. Annelated benzodiazepines are more potent than
corresponding 2-one derivatives.
N
O
Cl
H
N
OH
N
N
Cl
CF3
O
N
O
Cl
H
N
Nordazepam
IC50 of 8.4
(8.1 for diazepam)
Halazepam Oxazepam
(14.8 for flurazepam)
(14.8 for flurazepam)
Cl N
N
O
F
CH3
3
N CH
Flurazepam

32. 4) Ring C SARs
a) Halogenation only at 2' enhances potency, other positions
decrease potency: Cl > F > Br > NO2 > CF3 > 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 1–methyl 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.
Cl
OH
Cl
O
N
H
N
Lorazepam
18 for oxazepam
N
H3C N
N
N
Cl
Alprazolam
Cl
N
H3C N
N
N
Cl
Triazolam

33. BDZ Mechanism of Action
As withthe 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
, , ,  subunits.
α1–6, β1–3, γ1–3,, ρ1–3. Different combinations result in affinity fordifferentdrugs and
producing differentactivities
Major subtype (60% ):α1β2γ2: Sedative, amnestic,anticonvulsant
Minor subtype (15% ):α2β3γ2:Anxiolytic
Minor subtype (10% ): α3βnγ2
T
o date three BDZ receptors have been identified. The BDZ receptors are also known
as omega–1, omega–2 and omega–3. The BDZ–1 receptors are located in areas of
the brain that are involved in sedation, and the BDZ–2 receptors are highly
concentrated in areas responsible for cognition, memory, and psychomotor
functioning. The BDZ—3 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 bythe dose and the desires of thecompany.

34. 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 oramnesia.
Zolpidem, Zaleplon and Eszopiclone selectively bind to BDZ–1 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 onlyhypnotic approved bythe FDAforcontinualuse.
O
CH3
O
F
O
N
N
N
Flumazenil
CH3
Benzodiazepine ReceptorAntagonists
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.
O
CH3
CH3
N
3
H C
CH3
N
N
Zolpedem O
CH3
CH3
N
C
N
N
N
N
Zaleplon
Cl
O
N
O
N CH3
O
N
N
N
N
Eszopiclone

35. 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?

36. 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 requested.
CH3
H3C
H3C O
O
O
N
1
H
N
O
N
H
O
2
H
H3C
H3C
O
O
N
3
H3C
CH3
O
O
N
H
N
4
O
H3C
O H
N
N
O H
5
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?