DRUGS ACTING ON CNS- ANTI PSYCHOTICS

ANTIPSYCHOTICS [TRANQUILIZERS (OR) NEUROLEPTICS]

Antipsychotic drugs are also CNS depressants. Anti psychotic drugs are drugs which are used in the treatment of mental disease that are characteristic of the psychoses which is a behavioral disorder.
These agents have the capacity to sedate or tranquilize the emotional expressions , aggressive and impulsive behavior and influence being free to mind from disturbance and thus calms the mind with out inducing sleep.
Psychosis: The psychoses are inhibition of sharpens or alter the behavioral, mood and emotional responses.
Psychiatric illness can be divided in to neuroses and psychoses.
A neurotic patient usually retains sufficient insight to realize that he is ill. But the psychotic patient have difficulty understanding reality and their own conditions, they lives in a world of his own. They are often hallucinations and delusions (paranoid in nature), thought disorders and with drawel from social contacts and flattering of emotional responses.

The most important types of psychosis are
i) Schizophrenic :
It is neurological as well as psychological disorder. So fundamental and characteristic distortions of thinking and perception.
ii) Affective (mood) disorders :
Disorders in fundamental disturbance is a change in mood to depression associated by a change is the overall activity
iii) Organic psychosis :
Mental disturbances caused by head injuries, alcoholism, or other kind of organic diseases.

Classification :

1. Rauwolfia alkaloids : Reserpine, deserpidine
2. Phenothiazine derivatives : Chlorpromazine hydrochloride, Triflupromazine, Thioridazine hydrochloride, Mesoridazine hydrochloride, Piperacetazine hydrochloride,Prochlorperazine maleate, Trifluoperazine hydrochloride.
3. Ring analogues of phenothiazines :
   i) Thioxanthines – Chlorprothixene, thiothixene
   ii) Dibenzoxazepines – Loxapine succinate
   iii) Dibenzodiazepines – Clozapine
4. Butyrophenones : Haloperidol, Droperidol, Resoperidone
5. Diphenyl methane derivatives : Pipradrol, captodiame, Hydroxyzine, benactyzine
6. beta - Aminoketones : Molindone, Ondansetron
7. Benzamides : Sulperide, Remoxipride.
8. Miscellaneous : Buspirone, Meprobamate, Tybamate

Phenothiazine derivatives :

Synthesis of chlorpromazine:

Synthesis of prochlorperazine:

Ring analogues of phenothiazines :

1. Chlorprothxene

2. Thio thixene

3. Loxapine succinate SAR for Phenothiazine derivatives :

I. Modification in tricyclic systems :

1. Most of the compounds have either a six membered central ring (6-6-6)
   (Example : phenothiazine) classes for good antipsychotic activity.
   
2. Compounds having larger central ring Example : Imipramine (7 membered) and smaller central ring Example : carbazole (5 membered ring) are lack in antipsychotic activities and produce only antidepressant activity.
   
3. Analogues of tricyclic compounds that lock a central ring (Example :Rimozide) generally devoid of antipsychotic activity.

II. Modifications of alkyl side chain at R10 :

1. The maximum potency is obtained when the nitrogen of phenothiazine and basic amino group is connected by a three carbon side chain, because it permits maximum resemblance with that of most preferred conformational form of dopamine.
   
2. Introduction of methyl group at position 1, 2 or 3 of 3 – amines propyl side chain decrease the antipsychotic activity and may result Imipramine like activity.
   
3. If the side chain may be cyclopropane ring decrease neuroleptic activities and produce potent imipramine like activity.
   
4. If oxygen is introduced in to the 1st position of 3 – amino propyl chain results potent anti depressant activities (example : Chlorthiazine).
   
5. Bridging of position 3 of side chain to position 1 of phenothiazine nucleus reduces neuroleptic activity.

III. Modifications of basic amino group :

1. Maximum neuroleptic potency is obtained in amino alkyl substituents having 30 amines group than 20 and 10 amines group containing compounds.
   
2. Alkylation of basic amino group with groups larger than methyl group decreases neuroleptic potency. Example : Diethylamine analogues.
   
3. Replacement of dimethylamine group with Pyrrolidine, morpholine groups decreases the neuroleptic potency.
   
4. The activity is retained or increased if the amino group is replaced with piperidyl or Piperazine groups. Example : Mesoridazine, carphenazine.
   
5. Bridged piperidine derivatives retains the neuroleptic activities.
   
6. Introduction of hydroxyl , methyl, hydroxy ethyl groups of piperidine and Piperazine moieties increase the potency.
   
7. N4-Piperazine substituents with phenyl ethyl, p – amino phenyl ethyl or estirified long chain fatty acids increases the activity.

IV. Phenothiazine ring substituents at R2 :

1. Substituents at position 2 is optimal for neuroleptic potency, In general, potency increases in the following order of position of ring substitution 1<>
   
2. 2 – substitution is an electron withdrawing group increases the neuroleptic activity, the potency increases in the following order OH <>
   
3. Oxidation of sulfur at 5 – position decrease the neuroleptic activity.


4. 1,2,3,4 – Azo phenothiazines are more effective. 1-Azo phenothiazine is more potent than parent compound. Example: Prothioperdyl.

Butyrophenones :

1. Haloperidol

2. Droperidol 3. Risoperidone

SAR for Butyro phenone derivatives :

1. The 4- fluro phenyl group is necessary for optimal anti psychotic activity.


2. Reduction of carbonyl group and replacement of oxygen, sulphur or sulphone decreases the neuroleptic potency.


3. The bridge between benzoyl and amino group is propyl for good activity. If lengthening, shortening or branching the propylene chain of 4-amino Butyrophenones decreases neuroleptic potency.


4. The amino group is in tertiary form or part of six membered ring like piperidine, Piperazine for good neuroleptic activity.


5. Replacement of six membered ring by larger, smaller or uncyclized diminishes neuroleptic potency.


6. Neuroleptic potency is generally associated with 4,4- disubstituted piperidine. Substitution of 2 or 3 position of piperidine decreases potency

Mechanism of action

1. The neuronal activity in brain is mediated by neuro transmitter. Dopamine is a precursor of adrenaline and nor adrenaline and also function independently as a neurotransmitter. The dopamine have been found in thalamus, hypothalamus and basal ganglia and has depressant action.


2. The control of emotional responses, the hypothalamus is closely associated with reticular and limbic system which incorporates a balanced complex of excitatory(acetyl choline) and inhibitory (dopamine) components.


3. The psychoses associated with the presence of dopamine is greater than the normal level at central synopses in striatum and other brain regions.


4. The anti psychotic drugs act by increasing metabolic rate of dopamine or blocking dopamine (D2) receptors. This results an increasing concentration of excitatory (acetyl choline) and decreasing concentration of inhibitory (dopamine) components.


5. Since anti psychotic drugs shift the balance in favour of acetyl choline. Hence all the anti psychotic drugs are always associated with extra pyramidal effect.


6. The superimposibility of the conformations of dopamine ad phenothiazine derivatives blocks the dopamine receptors, because it possess 3 carbons in side chain separating two nitrogens.

DRUS ACTING ON CNS - Sedatives and Hypnotics

ANXIOLYTICS, SEDATIVES AND HYPNOTICS

These drugs are under the category of CNS depressants.
Sedatives are drugs which decreases activity and excitement of the patients and calm the anxiety by producing mild depression of CNS with out causing drowsiness or sleep.

Hypnotics are drugs which produce drowsiness and induce sleep resembling to natural sleep by depressing CNS.

Anxiolytics are also called as minor tranquillizers which are used in treatment of psychotic disorder by depressing CNS. They are used to treat abnormalities of mental functions.

The various sedatives and hypnotic agents are also employed as :
i) Antianxiety agents in emotional strain and chronic tension ii) Anticonvulsant
iii) Muscle relaxants iv) General anaesthetic v) Potentiation of analgesic drugs
vi) Adjuvants to anesthesia vii) In hyper tension

Classification :

I. Barbiturates:-

1. Long acting barbiturates (More than 8hours) – Barbitone, Barbital sodium,
Phorobarbital, Mephobarbital
2. Intermediate acting barbiturates (4 - 8hours) – Allo barbital, hexobarbitone,
pento hexital sodium
3. Short acting barbiturates (less than 4 hours) – Seco barbitone, hexobarbitone,
Pento barbitone, cyclo barbitone
4. Ultra short acting barbiturates ( I-V anaesthetics) – Thiopental sodium.

Metho hexital sodium

II. Benzodiazepines -

Diazepam, Chlordiazepoxide, oxazepam, chlorazepate dipotassium, prazepam,

Lorazepam, Halazepam, Flurazepam, Alprazolam, Triazolam

III. Amides and Imides –

Glutethimide, methyprylon, methaqualone

IV. Aldehydes and their derivatives –

Chloral hydrate, Paraldehyde, Triclofos sodium

V. Alcohol and their carbamate derivatives –

Ethinamate, Meprobamate

VI. Miscellaneous –

Antihistamines, KBr, Morphine, Pethidine

I.Barbiturates

Barbiturates are cyclic diurides which are the derivative of barbituric acid( 2,4,6 tri oxo hexahydro pyrimidine). As such barbituric acid has no CNS depressant activities. But substitution at 5th position by alkyl or aryl groups confers sedative and Hypnotic activity.
barbituric acid or barbiturates are prepared from malonic acid or its esters.

1.Barbital (Barbitone sodium)

2.Pheno barbitone

Structure-activity relationship of barbiturates (SAR):

1. Barbituric acid itself does not possess any sedative and hypnotic activity. The sedative
   or hypnotic activity is produced when the two active hydrogen atoms at position 5,5
   have appropriate substituents by alkyl or aryl groups.
2. The total number of carbon atoms present in two groups at 5th position must not be less
   than 4 and more than 10 for their optiomal activity.
3. Only one of the substituents may be a closed chain for good activity
   (Example : Hexobarbital, Cyclobarbital, Phenobarbital)
4. The branched chain isomer exhibits greater activity and shorter duration. The drug
   having greater branching is more potent (Example : Pento barbital, amobarbital).
5. Double bonds are present in alkyl substituents groups produce compounds more
   readily to tissue oxidation. Hence they are short acting (Example : Seco barbital) .
6. Stereo isomers have appropriately same potencies.
7. Aromatic or alicyclic substituted analogues are more potent than the corresponding
   aliphatic analogues having same number of carbon atoms.
8. Short chain at carbon 5 resists oxidation and hence long acting .Long chains are readily
   oxidized and thus produce short acting (Example : Barbital, Pentobarbital, Seco barbital)
9. Introduction of halogen atom is to 5 – alkyl substituents increases potency
10. Introduction of polar groups (OH, NH2, COOH, SO3H, CO, RNH) is to 5 – alkyl or
    aryl substituents decrease lipid solubility and Potency.
11. Alkylation at 1 or 3 position enhances onset and reduce duration of action
    (Example : Hexobarbital).
12. Replacement of oxygen by sulphur at 2 – carbon (thio barbiturates) shortens on set and duration of action due to increased lipid solubility. But more sulphur at C4SC6 decrease the activity (Example: Thio pental)

Mechanism of action

1. Barbiturates either have a Gam amino butyric acid (GABA) like action or enhance the effect of GABA, an inhibitory transmitter.
2. The effects of barbiturates on synaptic transmission are caused by an alteration of post synaptic sensitivity of the neurons to excitatory and inhibitory transmitters.
3. When GABA receptors are activated, chloride channels are open and chloride enters the cell, hyper polarizes it and produces decreased excitation.
4. Barbiturates bind to picrotoxin site of GABA receptor and decrease chloride ion flux and produce an increased chloride ion concentration.
   They may interfere with the passage of impulses from centers in hypothalamus to the cortex.

Benzo diazepines:

Bendiazepines and their derivatives are mainly used for sedative, hypnotic, tranquillizer, muscle relaxant and anti convulsant.
1. Diazepam

Synthesis of Diazepam

2.Chlor Diazepoxide

Synthesis of Chlor Diazepoxide

3. Oxazepam

4. Chlorazepate Dipotassium 5. Lorazepam

6.Halazepam

7.Flurazepam
8. Alprazolam

Structure-Activity Relationship Of Benzo Diazepines

1. All Benzodiazepines are used as CNS depressant are usually substituted with a 5-aryl or 5- cyclo hexenyl groups .
2. The substituents present in position 1 to 3 does not affect the activity.
3. The N(4) usually substituted with a low electron density group.
4. The electron with drawing group present in the position 7 is required for hypnotic activity. Position 6,8 & 9 should not be substituted.
5. A phenyl group at 5th position promotes the activity. An electron withdrawing group in ortho or di ortho position increase the activity. (Eg. Lorazepam, Flurazepam)
6. If 4,5 double bond is saturated or shift to 3,4th position decrease the activity.
7. Alkyl substitution at 3rd position decrease the activity.

Mechanism of action

1. The mid brain reticular activating system which is responsible for the maintenance of a wakefulness is depressed by benzodiazepines.
2. The anti anxiety activity of benzodiazepines may be attributed to the depressant action of these drugs on the mechanism which evoke anxiety and aggression.
3. Like GABA, the benzodiazepines cause either pre synoptic or post synoptic inhibition in poly synaptic neuronal pathways in CNS, affecting the various turnover of various neurotransmitters in the brain, therefore interfere the transmission process.
   

Trichlofos sodium

DRUGS ACTING CNS-General anesthetics

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DRUGS ACTING ON CENTRAL NERVOUS SYSTEM

GENERAL ANESTHETICS

The term Anesthesia means loss of sensation. General anesthetic is a class of CNS depressant drugs which produce total loss of sense of pain with controlled and reversible loss of consciousness.
General anesthetics bring about descending depression of the CNS starting with cerebral cortex, basal ganglia, cerebellum and finally the spinalcord. General anesthetics are mainly used in surgical operations for relaxation of muscles of patients. These agents are non specific with receptors and used at high concentration to access to all areas of the body.
CLASSIFICATION :
Based on the method of administration, these may divided in to three groups.
1. Inhalation Anesthetics
i) Hydro Carbons – Cyclo propane, Ethylene
ii) Halogenated Hydro carbon – Halothane, Chloroform, Ethyl chloride
iii) Ethers – Di ethyl ether, Vinyl ether, Enflurane, Methoxy flurane, Iso flurane, Desflurane, Sevoflurane.
iv) Alcohols – Trichloro ethanol
v) Miscellaneous – Nitrous oxide

2. Intravenous anesthetics
i) Ultra short acting Barbiturates – Metho hexitol sodium, Thio amylol sodium, Thio pentol sodium
ii) Benzo diazepines – diazepam, Midazolam
iii) Miscellaneous – Ketamine, Etomidate, Propofol, Alphaxalone

3. Basal Anesthetics
Fentanyl citrate, Tribromo ethanol, paraldehyde

Inhalation Anesthetics

These are volatile liquid or Gases and they are administered through inhalation process.

1. Di ethyl ether or Anesthetic ether

C2H5 – O - C2H5
Synthesis

C2H5 OH + H2SO4 C2H5 HSO4 C2H5 – O - C2H5

C2H5 ONa + C2H5Br C2H5 – O - C2H5

2. Vinyl Ether
CH2 CH– O - CH CH2

Synthesis
Cl CH2 CH2OH Cl ----- CH2 CH2O CH2 CH2 Cl ---------CH2 -- CH– O - CH --CH2

3.Halothane

4. Methoxy flurane

5. Enflurane( 2-Chloro- 1,1,2 –tri fluoro ethyl methyl ether )

CHF2 – O - CF2CHFCl

6. Sevo flurane

FCH2 – O – CH(CF3)2

7. Nitrous oxide (Laughing Gas) N2O

8. Cyclo propane
CH2
CH2 CH2

9. Tri chloro ethylene

CCl2 CHCl

II. Intravenous anesthetics

These are administered through intravenously and cause unconsciousness. These are mainly sodium salt of barbiturates. They are ultra short acting barbiturates which duration of action is less than 30 minutes.

1. Metho hexitol sodium

2.Thiamylal sodium

3. Thio pental sodium

Ketamine Hydro chloride


Mechanism of action

General anesthetics are non specific in action because they do not act on specific receptor site.
When General anesthetics are dissolved in lipid layer and membranes , they cause dis ordering or increased fluidity of the membrane. This may inactive the protein essential functioning of CNS or ion channel, which would remain open resulting in chloride ion influx leading to synoptic hyper polarization, which inhibits neuronal function.
Volatile General anesthetics are rapidly evaporates and cooled immediately and skin gets anesthetized.
Barbiturates mainly depress the CNS and decrease specific functional activities in brain. They increase the GABA ergic inhibitory response by influencing conductance at the chloride channel. They are also uncoupling of the oxidative phosphorylation, prevent the electron transport system and inhibit the cerebral carbonic anhydrase activity.

Introduction

In this web blog I have regularly posted notes on Pharmaceutical Chemistry for B.Pharm, Pharm.D and M.pharm students.

I request all the viewers to comment on my posts to enhance the utility of this web blog. This is a simplified notes which is useful for the students. This notes was taken from various book references, journals and from the web sources.