Download petit mal

Anxiolytic
used to treat post-traumatic stress disorder, phobias,
panic disorders, obsessive compulsive disorder (OCD). These are
link to many neurotransmitters. But gama-aminobutyric acid (GABA),
norepi, 5HT are consider as having major influence on these disorders.
R
Benzodiazepines
1
9
O
N
8
2
B
A
3
7
X
6
N 4
5
6'
5'
C
2'
3'
4'
Allosteric modulation of the GABA-GABA A receptor interaction
which controls chloride ion channels. (Positive effect)
SAR
A ring
X is electronegative (increase activity)
6,8, and 9 positions should not be substituted.
R
1
9
SAR (Continue)
O
N
8
2
B
A
3
7
X
6
5
N 4
6'
5'
C
2'
3'
B ring
4'
5 position phenyl increase activity
Saturation of 4,5 double bond or shift decrease activity.
Alkyl substitution at the 3- decrease activity (hydroxy does not)
Hydroxyl group (short half-life because glucuronide)
Carbonyl and nitrogen 2 and 1 positions are needed.
R must be a small alkyl
C ring
Electron withdrawing group at orthro (2’) and diorthro (2’,6’) increase activity
4’ substitution decreases activity.
Metabolism of Benzodiazepines
H
N
O
H
N
O
OH
Valium (Diazepam), Centrax (prazepam),
Cl
Paxipam (Halazepam) and Tranxene (clorazepate)
N
Cl
Nordazepam
H
N
Oxazepam
O
Glucuronidation
Librium
Cl
N
N
O
Demoxepam
Benzodiazepines
9
CH3
8
Cl
CF3
1
O
2
N
9
8
3
7
6
6'
5
N4
2'
5'
3'
4'
Valium (Diazepam)
Valium (Diazepam)
Metabolism N-dealkylation,
hydroxylation, glucuronidation
Uses: Anticonvulsant, preop.
Anxiety.
Cl
1
9
O
2
N
8
3
7
6
6'
5
N4
Cl
2'
5'
3'
4'
Centrax (Prazepam)
Centrax (Prazepam)
Metabolism: N-dealkylation,
hydroxylation, glucuronidation.
Uses: Anxiety
1
O
2
N
3
7
6
6'
5
N4
2'
5'
3'
4'
Paxipam (Halazepam)
Paxipam (Halazepam)
Metabolism:
Same as Diazepam
Uses: Anxiety
9
8
Cl
H1
N
7
6
6'
5
O
2
_ +
CO
2 K
3
.
KOH
N4
2'
9
8
Cl
3
6
6'
5
9
O
2
7
N4
8
OH
Cl
5'
H1
N
O
2
7
3
6
6'
2'
5'
3'
4'
Tranxene (Clorazepate)
H1
N
5
OH
N4
2' Cl
5'
3'
4'
Serax (oxazepam)
Tranxene (Clorazepate)
Serax (Oxazepam)
A prodrug
Short half-life
Metabolism: Decarboxylation to
Metabolism: Glucuronidation
Norazepam
Use: Anxiety
Use: Anxiety
3'
4'
Ativan (Lorazepam)
Ativan (Lorazepam)
Metabolism: Glu.
Use: Anxiety
N(CH2CH3)
CF3
9
8
Cl
1
N
7
3
6
6'
5
9
O
2
8
OH
N4
2' Cl
Cl
1
N
7
3
6
6'
5
9
O
2
8
S
N4
3'
4'
Restoril (Temazepam)
O
2
7
3
6
6'
2' F
5
N4
2' F
5'
5'
5'
Cl
1
N
3'
4'
Doral (Quazepam)
3'
4'
Dalmane (Flurazepam)
9
8
O2N
H1
N
O
2
7
9
8
3
6
6'
5
N4
2' Cl
5'
3'
4'
Klonopin (Clonazepam)
Klonopin (Clonazepam)
Nitro group
Metabolism: hydroxylation
glucuronidation
Cl
CH3
1 NH
N
2
7
HCl
3
6
6'
5
N4
2'
O
5'
3'
4'
Librax, Librium and Libritabs (Chlorodiazepoxide HC)l
Librax, Librium and Libritabs (Chlorodiazepoxide)
Metabolism: N-dealkylation, hydroxylsis (lactam)
reduction, hydroxylation and conjugation
CH3
9
8
Cl
CH3
N
N
1
N
7
3
6
6'
5
N4
2'
8
Cl
CH3
N
1
N
3'
4'
Xanax (Alprazolam)
Xanax (Alprazolam)
Triazole ring
Short half-life
Metabolism: hydroxylation
of methyl and conjugation
9
2
7
8
3
6
6'
5
N4
2' Cl
5'
5'
Use: anxiety
9
2
N
3'
4'
Halcion (Triazolam)
Halcion (Triazolam)
Triazole ring
Cl
N
CH
1
N
2
7
3
6
6'
5
N4
2' F
5'
3'
4'
Versed (Midazolam)
Versed (Midazolam)
Imidazole ring
Sleep Aids
N
O
N
CH3
N
O
O
N
CH3
Cl
N
N
N
N CH3
CH3 N
CH3 O
Ambien (Zolpidem)
Lunesta (Eszopiclone)
S-enantiomer in U.S.
Rapid onset and short
Duration (6 hours)
Demethylation and oxidation
Metabolites in urine
Imidazopyridine
Weak anticonvulsant
Stronger Sedative effect
Shorten sleep latency and
prolong sleep time (No effect
stages of sleep)
O
O
N
N
O
CH3
O
N
CH3
N
N
F
CH3
O
Romazicon (Flumazenil)
Romazicon (Flumazenil)
Imidazole ring
Competitive benzodiazepine antagonist
Ester hydrolysis and glucuronidation
Use benzodiazepine overdose
N
N3
CH3
O
RO 15-4513
Partial inverse agonist
receptor is frozen
in the inactive state
thus chloride channel
close and conductance
is decrease
Miscellaneous use Selective Serotonin Reuptake Inhibitors (SSRI)
O
N
N
O
OCH3
CF3
CF3
N
N
N
O
N
NHCH3
Prozac (Fluoxetine)
Buspar (Buspirone)
O
NH2
Luvox (Fluvoxamine)
NC
NHCH3
O
O
HCl
(CH2)3N(CH3)2
NH
O
Cl
O
Cl
F
Paxil (Paroxetine)
Zoloft (Sertraline)
F
Lexapro (Escitalopram)
Anticonvulsant and Antiepileptic
Anticonvulsant is drug or agent that blocks seizures.
Antiepileptic is a drug or agent that controls epilepsies.
Types of seizures
Generalized (entire brain)
Unilateral (one side of the brain)
Partial (or focal)
Erratic (new born)
Unclassified (high mortality)
Generalized seizure
tonic-clonic seizure (grand mal)
nonconvulsive seizure or absence (petit mal)
History of Anticonvulsant
First anticonvulsant Potassium Bromide (KBr) 1857
Replaced with phenobarbital 1912 still used to infants
Phenytoin was discovered as anticonvulsant 1937
Approximately 60% patients with seizure are on monotherapy
(Tegretol, Klonopin, diazepam, Zarontin, Dilantin)
20% patients are taking two drug combinations.
Other 20% patients take more than two drugs with little benefits
Cross interaction among anticonvulsant and other drugs.
Increase of dose for children because of metabolism
Anticonvulsant Mechanism of Action
Allosteric modulation of GABAA receptors (Benzodiazepine)
Blocking voltage-gated sodium channel (Phenobarbital, phenyl
succinimide and hydantoins).
Blocking calcium T channel (5,5-dialkyl members of barbiturates,
oxazolidine-2,4-diones and succinimide )
O
H
N
O
N
O2N
Cl
N
N
Cl
Valium (Diazepam)
IV for rapid response
(Status epilepticus)
Klonopin (Clonazepam)
Use for many types of seizure
except grand mal
O
H
N
OH
Cl
O
H
N
O-
K+
N
O
Cl
N
Cl
Cl
Ativan (Lorazepam)
Tranxene (Clorazepate dipotassium)
Rapid response (Status
Prodrug (decarboxylation)
Epilepticus)
Use in combination for partial seizures
IV or IM
Use combination with Dilantin
General SARs for Anticonvulsants
R"
R
R'
O
O
N
R and R’ are hydrocarbon.
If R and R’ are lower alkyl, tendency is to
active against petit mal seizures.
If R or R’ is a phenyl, activity tend to be against
grand mal seizures and partial seizures.
O
Barbiturates
NH
NH
O
CH2
Hydantoin
Oxazolidinediones
Succinimides
Barbiturates (sedative-hypnotic)
O
O
5
4
O
6
3
N
H
5
1 NH
4
2
O
Phenobarbital
Use for grand mal and partial seizures
Less effective than phenytoin and Tegretol
Adminster IV as sodium salt
May be in combination with a benzodiazepine
Metabolism p-hydroxylation followed
by conjugation (glu or sulf).
Block sodium channels and GABAA receptors
O
6
3
N
H
1N
2
O
Mephobarbital
Use for grand mal and partial seizures
Metabolism N-demethylation
(active metabolite), also p-hydroxylation
follow by conjugation
Same mechanism of action
O
5
6
1 NH
4 3 2
CH2
O
N
H
Mysoline (Primidone)
2-deoxy of barbiturates
Use for all types of seizure
except petit mal
Less effective than Dilantin
Associated with sedation
Overall safe
Hydantoins
Relatives of barbiturates but lack 6-oxo group.
Weaker acid than barbiturates therefore forms strong basic salts.
Phenyl ring indicates active against grand mal seizure
CH2OPO3
NH
O
2Na+
N
O
N
H
-2
O
O
N
H
Dilantin (Phenytoin and Phenytoin sodium)
Cerebyx (Fosphenytoin)
Block Sodium channel
Disodium phospate ester prodrug of Dilantin
(decrease presynaptic
IV or IM (phenytoin sodium has poor water
glutamic acid release)
solubility
Activity against all seizures except
Indication same as Dilantin
petit mal.
Side effect include severe bradycardia
Metabolism involves p-hydroxylation
and conjugation.
Oxazolidinediones
NH
O
O
N
Replacement of NH of hydantoin to
oxygen yields oxazolidine-2,4dione. Oldest drugs used to treat
Petit mal seizures (1940s)
Peganone (Ethotoin)
Use grand mal and complex
Partial seizures
Less active than Dilantin and
More sedating
Use in combination therapy
5
4
O
3
1O
2
O
N
Tridione (Trimethadione)
Prodrug undergoes N-demethylation
To active metabolite (water soluble)
Use Petit mal
Blocks Calcium T-channel
Succinimides
Due to toxicity of oxazolidinediones,
these drugs were develop for
treatment of petit mal seizure (1950s).
CH2 replaces the O of
oxazolidine-2,4-dione
5
4
O
CH2
3
5
4
O
1
2
3
1CH2
2
O
N
O
N
H
Zarontin (Ethosuximide)
Use for petit mal seizure
(worsen grand mal seizure)
Block calcium T channel
Toxicity involves skin and
blood. Metabolism oxidation
(hydroxyl) of ethyl group
Milontin (Phensuximide)
Primarily use for petit mal seizure
Phenyl group indicates some activity
against grand mal seizure
N-demethylation to yield active
metabolite which is deactivated
by p-hydroxylation and conjugation
Turn urine to pink or red color
Less active than Zarontin
5
4
O
3
1CH2
2
O
N
Celontin (Methsuximide)
Use for petit mal and
complex partial seizures
(does not worsen grand mal
seizure)
Metabolism in p-hydroxylation
and conjugation
Ureas and Monoacylureas
O
N
N
O
NH2
O
NH2
Tegretol (CBZ, Carbamazepine)
Block sodium channel
Use for grand mal and partial seizures
Hematological toxicity ( rare aplastic anemia)
Metabolism involve epoxidation at
double bond convert to Trans diol
It is one of the safest and effective anticonvulsant alone with Dilantin.
Tricyclic structure similar imipramine
Trileptal (Oxcarbazepine)
Block sodium channel
Use partial seizures
Metabolism involve reduction of
ketone to active metabolite.
Miscellaneous Agents
CH
CO2H
N
Cl
N
Cl
H2N
Depakene (Valproic Acid)
Block sodium channel and increase GABA
Active as anion available as sodium salts (IV)
Metabolism involves conjugation of
carboxylic acid
and oxidation of hydrocarbon chains.
Side effects are mild, but potentially
fatal fulminate hepatitis.
N
NH2
Lamictal (Lamotrigine)
Blocks sodium channels and
release of glutamate
Use for refractory partial seizures
Clinical trial for amyotrophic
lateral sclerosis (ALS)
H
CO2H
N
O
H2 N
OH
Neurotin (Gabapentin)
Design to mimetic GABA
May alter metabolism or release
of GABA
Bind to calcium channels?
Use grand mal, partial seizures
as single drug therapy
S
S
Gabitril (Tiagabine)
Pipiderine 3-carboxylic acid
Know to inhibit GABA uptake
Binding GABA transporter GAT1
Blocks GABA reuptake
Use partial seizures
O
NH2
O
N
H2 N
Keppra (S-(-)Levetiracetam)
Use partial, grand mal and
Myoclonic seizures.
O
O
O
NH2
O
Felbatol (Felbamate)
Dicarbamate
Blocks NMDA receptor
Blocks sodium channel.
Interact with GABAA receptor
Side effects aplastic anemia.
O
S
H2NO2S
N
NHCOCH3
N
Diamox (Acetazolamide)
Carbonic acid anhydrase
inhibitor
N O
S NH2
O
Zonergan (Zonisamide)
Blockage of sodium
channels
Blockage of voltage-gate
calcium channels