Drugs Acting on CNS

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Introduction

• Epilepsy is one of the most common disorders of
  the brain, affecting about 50 million individuals
  worldwide. Epilepsy is a chronic and often
  progressive disorder characterized by the
  periodic and unpredictable occurrence of
  epileptic seizures that are caused by abnormal
  discharge of cerebral neurons. Epilepsy is not a
  disease, but a syndrome of different cerebral
  disorders of the CNS.

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Introduction

• This syndrome is characterized by paroxysmal,
  excessive, and hypersynchronous discharges of
  large numbers of neurons. These seizures may be
  identified on the basis of their clinical
  characteristics. These clinical attributes, along
  with their electroencephalographic (EEG) pattern,
  can be used to categorize seizures.

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Introduction

• Seizures are basically divided into two major
  groups
• Partial (focal, local) seizures are those in
  which clinical or EEG evidence exists to indicate
  that the disorder originates from a localized
  origin, usually in a portion of one hemisphere in
  the brain.
• Generalized seizures, the evidence for a local
  origin is lacking.

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Introduction

• The goal of therapy with an anticonvulsant agent
  is to have the patient seizure free without
  interfering with normal brain function. Thus, the
  selection of an anticonvulsant agent is based
  primarily on its efficacy for specific types of
  seizures and epilepsy.
• They are used for the prevention of different
  types of epileptic seizures. They act through
  decreasing the electrical excitability at the
  site of epilepsy or at adjacent neurons.

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Introduction

• They are used for the prevention of different
  types of epileptic seizures. They act through
  decreasing the electrical excitability at the
  site of epilepsy or at adjacent neurons.
• Several classes of compounds belonging to
  different nuclei are used,

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• Al barbiturates are derivatives of barbiturc
  acid.
• Depending on
• The drug structure
• The dose
• The route of administration
• The drug can produce different CNS depression
  such as sedative, hypnotic, anticonvulsant or
  anesthetic.
• They are widely used until the discovery of
  benzodiazepines???

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Mechanism of action

• ?-Aminobutyric acid (GABA) represents the most
  important inhibitory transmitter of the mammalian
  CNS, it act through regulation of chloride
  channel of neuronal membrane.
• Barbiturates act postsynaptically to promote GABA
  binding ? prolong the mean open time of chloride
  channel ? CNS depressant effect.

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Barbituric acid

• It has no CNS depressant activity

Barbiturates

• All barbiturates are 5,5-disubstituted barbituric
  acid.
• Some are with substitution at N1

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Characters

1. They are acid, dissolve in NaOH ? enolate salt.

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Characters

1. They decompose by heating with strong alkali with
   the formation of ammonia and disubstituted acetic
   acid.

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Characters

• They are classified according to the duration of
  action into
• Long acting barbiturates
• intermediate acting barbiturates
• Short acting barbiturates
• Ultra short acting barbiturates

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Generic/Trade name R1 R2 R3
1- Barbital (Veronal) Ethyl Ethyl H
2-Phenobarbital (Luminal) Ethyl Phenyl H
3-Mephobarbital (Meboral) Ethyl Phenyl CH3
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Generic/Trade name R1 R2
1- Amobarbital (Amytol) Ethyl
2-Butabarbital (Butisol) Ethyl
3-Aprobarbital (Alurate) -CH2CHCH2
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Generic/Trade name R1 R2
1- Pentobarbital (Nembutal) Ethyl
2- Secobarbital (Seconal) -CH2CHCH2
3-Cyclobarbital (Phandoran) Ethyl
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Thiopentobarbital, Thiopental sodium(Pentothal
Sod.)
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Thiosecoobarbital, Thiamylal sodium(Surital
Sod.)
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General method for prearation of
5,5-dialkylbarbiturates
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• Substitution of urea with thiourea ?
  2-Thiobarbiturates.
• In case of N1-substitution we use NHR3CONH2.
• It is difficult to introduce aryl group into
  diethyl malonate by alkylation so, in case of
  phenobarbital we use the following method-

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Prearation of phenobarbital
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Structure Activity relationship (SAR)

• Both hydrogen atoms at C5 of barbituric acid must
  be substituted giving 5,5-disubstituted
  barbituric acid. Why??
• A-if only one hydrogen is substituted ?
  toutomerization of the molecule to a highly
  acidic trihydroxypyrimidine derivatives with
  lower lipophilic characters

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Structure Activity relationship (SAR)

• In addition this position(C5) is highly
  susceptible to rapid metabolic attack.
• ? length of the alkyl chain at C5 ? ? lipophilic
  characters ? ?ability of the drug to penetrate
  BBB and ? ? potency of the drug, up to 5-6 C-atom
  (as hydrophilic characters are important for the
  solubility in biological fluids )

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Structure Activity relationship (SAR)

• Branching, unsaturation, replacement of alicyclic
  substituents for alkyl substituents ??lipid
  solubility ? ? duration of action (due to
  increasing the rate of metabolic conversion to
  inactive metabolite )
• Substitution of one nitrogen with short alkyl
  group (ethyl or propyl) ? ? lipophilic characters
  and enhance the anticonvulsant activity.
• But substitution at both nitrogen ? non acidic,
  inactive drugs

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Structure Activity relationship (SAR)

1. Phenyl group at position-5 enhances the
   anticonvulsant activity and prolong duration.
2. Introduction of polar group at position-5 ?
   destroy the CNS depressant activity.
3. Isosteric replacement of O-atom by S-atom at
   position-2? Thiobarbiturates with ultra short
   acting

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• Phenobarbitone and mephobarbitone are the most
  commonly used barbiturates as anticonvulsants

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Introduction

• They are cyclic monoacylureas
• They are weaker organic acids than barbiturates.
• All clinically effective drugs with an aryl
  substitution at 5-position.

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1- Diphenyl Hydantoin (Epanutin, Phenytoin)

• It is one of the most effective and widely used
  epileptics

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Synthesis
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2- Ethotoin (Peganone)
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1- trimethadione (Tridione)
Synthesis
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2- Paramethadione (Paradione)
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1- Phensuximide

• Metabolized by N-demethylation ? N-demethylated
  (Active metabolite)
• Phensuximide and its active metabolite are
  inactivated via p-hydroxylation.

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2- Methsuximide and Ethosuximide
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• They are the drugs of choice for treatment of
  anxiety.
• They are used as
• sedative-hypnotics
• Muscle relaxant
• Anticonvulsant
• They are characterized by-
• Higher activity.
• Wide therapeutic range (Safe).
• No respiratory depression as in case of
  barbiturate

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Mechanism of action

• They bind and stimulate specific benzodiazepine
  receptors (BZ1 BZ2) which are adjacent to GABAA
  receptors.
• These GABAA receptors are involved in the
  regulation of the chloride channel.
• As a result, they increase the binding of GABA
  with GABAA receptors and so the intensity of the
  action of GABA resulting in opening of chloride
  channel and the influx of Cl- ions into neuron
  leading to neuronal inhibition.

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1-Chlorodiazepoxde (Librium)
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Discovery

• It was prepared by chance. How??
• During the synthesis of 6-chloro-2-methylaminometh
  yl-4-phenylquinazolin-3-oxide where the ring
  expansion occur ? Chlorodiazepoxde

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Metabolism
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2- Diazepam (Valium)

• Used mainly as anxiolytic, sedative-hypnotic,
  muscle relaxant and anticonvulsant.
• It is one of the most widely used benzodiazepin.

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Metabolism
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3- Oxazepam (Serax)

• The prototype for 3-hydroxy compounds.
• It Possesses short duration of action.

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4- Lorazepam (Ativan)

• The presence of 2-chloro substitution ? ?
  increase CNS depressant activity

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5- Clorazepate dipotassium (Tranxene)

• It is a prodrug. In vivo it is decarboxylate
  ?nordiazepam, which has a long-half life and
  undergoes hepatic conversion to oxazepam.

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6- Alprazolam (Xanax)

• With sedative-hypnotic and antianxiety
  activities.
• duration of action is short. Why?? .

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• It is rapidly metabolized by hydroxylation of
  triazolomethyl group.
• This metabolite is active but it is rapidly
  conjugated.

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7- Bromazepam (Calmepam)

• Used mainly as anxiolytic.

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SAR

• Position 1- N- atom is essential for activity
• N-substitution must be small alkyl group.
• Position 2- the carbonyl group is essential for
  the interaction with B2 receptors

• Position 3- the OH or COO- is optimal, The
  presence of alkyl ?? activity.

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• Position 4, 5-
• Saturation of 4,5-double bond or its shift to
  3,4-position ??activity.
• A phenyl at position 5 ??activity.
• Ortho or diortho substitution of the phenyl group
  with electron withdrawing group ??activity, but
  p-substitution ??activity.
• Annelation of the 1,2-bond of the diazepine ring
  with triazole or imidazole ring afforded active
  compounds with higher affinity for B2 receptors
  and short duration.
• Isosteric substitution of the henyl group with
  other heterocyclic structure ?active compounds.

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• Position 7-
• The presence of electron withdrawing group
  ??activity.
• Position 6,8,9-
• must be remained unsubstituted.
• The benzene ring of the benzodiazepine structure
  could be substituted with other heterocyclic ring
  ?active compounds
• Substitution of 1,4-benzodiazepin with
  1,5-benzodiazepine ?active compounds.

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• Examples of benzodiazepines that are used in
  mainly as anticonvulsants
• 1- Diazepam
• 2-Lorazepam
• 3-Clonazepam
• 4-Clorazepate dipotassium
• 5-Midazolam
• All exert their activity through enhancing the
  effect of GABA at GABA A receptors.

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1)Carbamezepine (Tegretol)

• One of the most saftest and effective agent.
• It is equal in efficacy to phenytoin in
  controlling seizure.
• Act by blocking Na-channels ?prolong the
  inactivation of Na-channels ?? Na-influx
  ??depolarization and neuronal conductance
  ??spreding of seizures.

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2) Valproic acid (Depakin)

• It has a satisfactory margin of safty and good
  potency.
• Act by potentiate the inhibitory effect of GABA
  and by blocking Na-channels

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