Drugs Acting on CNS

CNS Depressants

Antiepileptic Agents

 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.

 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.

 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.

 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.

 Several classes of compounds belonging to different nuclei are used,

(Barbituric acid derivatives) 1. Barbiturates

 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???

 γ-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.

 It has no CNS depressant activity Barbiturates All barbiturates are 5,5- disubstituted barbituric acid. Some are with substitution at N 1

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

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

3. They are classified according to the duration of action into 1) Long acting barbiturates 2) intermediate acting barbiturates 3) Short acting barbiturates 4) Ultra short acting barbiturates

Duration: 6 hours or moreOnset: minutes Long acting barbiturates

Generic/Trade nameR1R1 R2R2 R3R3 1- Barbital (Veronal ® )Ethyl H 2-Phenobarbital (Luminal ® ) EthylPhenylH 3-Mephobarbital (Meboral®) EthylPhenylCH 3

Duration: 3-6 hoursOnset: minutes Intermediate acting barbiturates

Generic/Trade name R1R1 R2R2 1- Amobarbital (Amytol ® ) Ethyl 2-Butabarbital (Butisol ® ) Ethyl 3-Aprobarbital (Alurate®) -CH 2 CH=CH 2

Duration: 1-3 hoursOnset: minutes Short acting barbiturates

Generic/Trade name R1R1 R2R2 1- Pentobarbital (Nembutal ® ) Ethyl 2- Secobarbital (Seconal ® ) -CH 2 CH=CH 2 3-Cyclobarbital (Phandoran®) Ethyl

Duration: minutesOnset: few seconds after IV Ultra short acting barbiturates

 Substitution of urea with thiourea → 2-Thiobarbiturates.  In case of N 1 -substitution we use NHR 3 CONH 2.  It is difficult to introduce aryl group into diethyl malonate by alkylation so, in case of phenobarbital we use the following method:-

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

b) In addition this position(C 5 ) is highly susceptible to rapid metabolic attack. 2. ↑ length of the alkyl chain at C 5 → ↑ 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 )

3. 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 ) 4. 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

5. Phenyl group at position-5 enhances the anticonvulsant activity and prolong duration. 6. Introduction of polar group at position-5 → destroy the CNS depressant activity. 7. Isosteric replacement of O-atom by S-atom at position-2→ Thiobarbiturates with ultra short acting

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

2- Hydantoins

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

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

3- Oxazolidindiones

Synthesis

4- Succinimides

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

5-Benzodiazepines

 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

 They bind and stimulate specific benzodiazepine receptors (BZ 1 & BZ 2 ) which are adjacent to GABA A receptors.  These GABA A receptors are involved in the regulation of the chloride channel.  As a result, they increase the binding of GABA with GABA A 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.

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

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

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

 The presence of 2-chloro substitution → ↑ increase CNS depressant activity

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

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

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

 Used mainly as anxiolytic.

 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 B 2 receptors Position 3:- the OH or COO - is optimal, The presence of alkyl →↓ activity.

 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 B 2 receptors and short duration. Isosteric substitution of the henyl group with other heterocyclic structure →active compounds.

 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.

 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.

6-Miscellaneous Anticonvulsants

 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.

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

With best wishes