Pharmacology and chemistry of Antipsychotic (Neuroleptics) drugs: Notes for GPAT

Neuroleptics or antipsychotics come under the class of drugs which are mainly employed for the treatment of schizophrenia. For a common man schizophrenia is a disorder of thoughts in which a person can comprehend with the reality. Generally, there are two types of sy,ptoms of schizophrenia:

a) Positive symptoms of schizophrenia- It includes hallucinations usually auditory (patients often listen commands from the sky to perform his deeds).

b) Negative symptoms of schizophrenia- It includes losing interest in society including society. This is possibly results from the atrophy of the brain.

Classification of antipsychotic/neuroleptic drugs:

Phenothiazines

Antipsychotic drugs are classified in the following classes as given below-

a) Phenothiazines- Phenothiazines are further classified in following three parts-

i) Phenothiazine containing aliphatic side chain: Chloropromazine, Triflupromazine

ii) Piperazine containing phenothiazine:Trifluperazine, Fluphenazine

iii) Phenothiazine with piperidine:Thioridazone

b) Thioxanthenes- Flupenthixol, Thiothixene

c) Butyrophenones- Haloperidol, Trifluperidol, Penfluperidol

d) Other heterocyclics- Pimozide, Loxapine

 e) Atypical neuroleptics- Reserpine, Olanazipine, Quatipine

Structural activity relationship (SAR) studies of antipsychotics

a) Phenothiazines: SAR of phenothiazines can be broken into following three parts for easy understanding:

SAR of phenothiazines

i) Alkyl side chain-

·         Phenothiazines show maximum potency when N of phenothiazine is connected by 3 carbons with the N of other alkyl chain.

·         Branching at β position of the chain decreases the activity

·         Introduction of CH3 group at 2 or 3 of the 3-aminopropyl side chain has only minor or no effect.

ii) Basic amino groups-

·         Maximum neuroleptic activity is obtained with tertiary amino group.

·         Alkylation with larger than basic methyl group decreases the antipsychotic activity.

·         Piperidinyl and pyrolidinyl derivatives are somewhat less potent.

iii) Phenothiazine ring substitution-

·         Potency of phenothiazines increases in the following order of substitution: 1<4<3<2

·         2-substituents of the phenothiazines increases potency in the following order: OH<CH₃<nC₃H₇CO<C₂H₅CO<CH₃COCl<SCH₃<CF₃

·         Oxidation of 5 Sulfur decreases the activity of the phenothiazines.

b) Butyrophenones- SAR study of the butyrophenones can be studied by considering the following points below:

Butyrophenones

     

i) All potent butyrophenones contains 4-flurophenyl group; only exception is amiroperidone

ii) Reduction of the CO group to CHOH or replacement by Sulfur decreases the potency of the butyrophenone.

iii) As a rule, lengthening, shortening or branching of alkyl chain decreases the activity of butyrophenones.

Mechanism of action of Antipsychotics/Neuroleptics

There are four dopaminergic pathways in the human brain-

a) Mesolimbic pathway (from midbrain to limbic system)

b) Nigro-striatal pathway (from midbrain to frontal cortex)

c) Mesocortical pathway (substantia nigra to basal ganglia)

d) Tuber-infundibular pathway (from tuber cinerium of hypothalamus to anterior pituatory)

All neuroleptics act by by antagonizing the DA₂ receptors of mesolimbic-mesofrontal pathways. As they are dopamine antagonists so they frequently produce drug induced Parkinsonism. Also dopamine is responsible for the reduced lactation hence neuroleptics cause hyperlactinemia. As dopamine produces emesis so these drugs are strong anti-emetics.

Only antipsychotic drug which do not act by this mechanism is Clozapine. Clozapine is the antagonist of Nor-adrenaline and serotonin.

Major drug interactions of the antipsychotic drugs

Antipsychotic drugs have following major interactions with other class of drugs:

a) Antisychotics show synergism with sedatives, alcohol and antihistamines hence increase the action of these classes of drugs.

b) When administered with pethidine it increases the respiratory depression.

Side effects of Antipsychotic drugs:

1. Akathisia (Agitaion in the body)

2. Parkinsonism

3. Dystomia (Painful spasm)

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