Dr. Raushanara Akter, Asst. Professor, Department of Pharmacy Psychotropic Drugs Dr. Raushanara Akter, Asst. Professor, Department of Pharmacy BRAC UNIVERSITY

Psychosis(pl.psychoses): The term “psychosis” denotes a variety of mental disorders: Delusion Hallucination Schizophrenia Mania

Delusion: A false belief (e.g., that one can read the minds of others, send radio messages directly to God or inanimate objects, travel to distant galaxies etc.) brought about without appropriate external stimulation and inconsistent with the individual’s own knowledge and experience is called delusion. The most serious delusions are those that cause patients to harm others or themselves (e.g., fear of being poisoned may cause the patients to refuse food. Delusions may lead to suicide or self-injury. It differs from hallucination, in that the latter involves the false excitation of one or more senses.

Hallucination: A false sense of perception having no relation to reality and not accounted for by any exterior stimulus. It may be visual (esp. in medical illness or drug withdrawal syndromes), and auditory (esp. in psychoses). Auditory hallucination: An imaginaroy perception of sounds, usually voices. Auditory hallucinations are a hallmark of psychotic illness. Visual hallucination: The sensation of seeing objects that are not really there. This is a hallmark of alcohol and drug withdrawal and of other medical illnesses that adversely affect the brain.

Schizophrenia Schizophrenia is a particular kind of psychosis (thought disorder) marked by delusions, hallucinations and disorganized speech and behavior. The common etiology of schizophrenia and related psychoses is the over activity of dopaminergic neuronal system i.e. excessive dopamine activity in the limbic system. Dopamine (stored in the vesicles of nerve ending) is a neurotransmitter which is mainly inhibitory in nature. Treatment: Medicines used to control schizophrenia include antipsychotic drugs that act on dopamine receptors in the brain, such as chlorpromazine, fluphenazine, haloperidol etc.

Mania: Mental disorder characterized by excessive excitement. A form of psycosis characterized by exalted feelings, delusions of grandeur, elevation of mood, psychomotor over activty (excess physical activity) and over production of ideas). Manic: Mood state characterized by excessive energy, poor impulse control, psychosis, agitation, flight of ideas, frenzied movement and decreased sleep. Maniac: Person affected by mania.

The Dopamine Hypothesis: The dopamine hypothesis for schizophrenia is the most fully developed of several hypotheses and is the basis for much of the rationale for drug therapy. Several lines of circumstantial evidence suggest that excessive dopaminergic activity plays a role in the disorder: Most antipsychotic drugs strongly block postsynaptic D2 receptors in the central nervous system, especially in the mesolimbic-frontal system Drugs that increase dopaminergic activity, such as levodopa (a precursor) either aggravate schizophrenia or produce psychosis de novo in some patients.

Dopamine receptor density has been found, post-mortu, to be increased in the brains of schizophrenics who have not been treated with antipsychotic drugs. Positron emission tomography (PET) has shown increased dopamine receptor density in both treated and untreated schizophrenics when compared with such scans of non-schizophrenic persons. Successful treatment of schizophrenic patients has been reported to change the amount of homovanillic acid (HVA), a metabolite of dopamine, in the cerebrospinal fluid, plasma and urine.

Antipsychotic Agents: Antipsychotic agents denote a group of drugs that have been used mainly for treating schizophrenia but are also effective in some other psychoses and agitated states. The terms antipsychotic and neuroleptic are used interchangeably.

Chemical Types(Chemistry) of antipsychotic drugs: A number of chemical structures have been associated with antipsychotic properties. The drugs can be classified into several groups. Phenothiazine derivatives Aliphatic derivatives Piperidine derivatives Piperazine derivatives B. Thioxanthene derivatives C. Butyrophenone (phenylbutylpiperidine) derivatives D. Miscellaneous Structure

Phenothiazine derivatives Phenothiazine has a three-ring structure in which two benzene rings are linked by a sulfur and a nitrogen atom. Three sub-families of phenothiazines, based primarily on the side chain of the molecule, are available. i. Aliphatic derivative (R1 Propyl dialkylamino side chain): e.g. chlorpromazine. General Structure Chlorpromazine

ii. Piperidine derivative (R1 Alkyl piperidyl side chain): e. g ii. Piperidine derivative (R1 Alkyl piperidyl side chain): e.g. thioridazine. iii. Piperazine derivatives (R1 Propyl piperazine side chain): e.g. fluphenazine. Aliphatic derivatives and piperidine derivatives are the least potent. Piperazine derivatives are more potent in the sense that they are effective in lower doses. The piperazine derivatives are also more selective in their pharmacologic effects. Thioridazine Fluphenazine

Thioxanthene Derivative General Structure B. Thioxanthene derivatives: If the nitrogen at position 10 of phenothiazine is replaced by a carbon atom with a double bond to the side chain, the compound is thioxanthine. In general, these compounds are slightly less potent than their phenothiazine analogs. The thioxanthenes also have Aliphatic substituents (e.g. chlorprothixene) and Piperazine substituents (e.g. thiothixene). Thioxanthene Derivative General Structure Thiothixene Chlorprothixene

General Structure of Butyrophenone derivatives C. Butyrophenone (phenylbutylpiperidine) derivatives: This group (of which haloperidol is the most widely used) has a very different structure from those of the two preceding groups. Diphenylbutylpiperidines are closely related compounds. These agents tend to be more potent and to have fewer autonomic side effects such as hypotension. General Structure of Butyrophenone derivatives Haloperidol

D. Miscellaneous structures: The newer drugs have a variety of structures and include molindone, pimozide, loxapine, clozapine, olanzapine, quetiapine, risperidone, ziprasidone and aripiprazole etc.

Structure Activity Relationship of Phenothiazine Antipsychotic Drugs The phenothiazine may be presented by the following general structure: Basic ring modification: Phenothiazine has a three-ring structure in which two benzene rings are linked by a sulfur and a nitrogen atom. If the nitrogen at position 10 is replaced by a carbon atom with a double bond to the side chain, the compound is thioxanthine which is also active. In general, these compounds are slightly less potent than their phenothiazine analogs. Thioxanthene

Structure Activity Relationship of Phenothiazine Antipsychotic Drugs 2. Substitution at different positions: a. The best position for substitution is the 2-position. Substitution at position 2 by an electron-withdrawing group increases the efficacy of phenothiazines. E.g. Chlorpromazine vs. promazine. Chlorpromazine Promazine b. Substitution at the 3-position can improve activity over nonsubstituted compounds, but not as significantly as substitution at the 2-position. c. Substitution at 1-position has a deleterious effect on antipsychotic activity. d. A substitution at position 4 might interfere with receptor binding by the sulfur atom.

Structure Activity Relationship of Phenothiazine Antipsychotic Drugs 3. The nature of the substitution at position 10 influences pharmacological activity: a. Those with an aliphatic side chain are relatively low in potency (but not in clinical efficacy). E.g. chlorpromazine, triflupromazine. Decreases in size from a dimethylamino group, as in going to a monomethylamino, greatly decreases activity, as do effective size increases, such as he one that occurs with N, N-diethylaimino. b. Those with a piperidine ring in the side chain show lower incidence of extrapyramidal side effects (e.g. parkinsonism) possibly due to increased central antimuscarinic activity. E.g. thioridazine. Chlorpromazine Triflupromazine Thioridazine.

c. Those with a piperazine ring in the side chain are potent antipsychotic compounds. e.g. Fluphenazine, trifluoperazine etc. These compounds have relatively weak anticholinergic activity, entails a greater risk of inducing extrapyramidal effects but less tendency to produce sedation and autonomc side effects such as hypotension. d. The three carbon-atom chain between position 10 of the central ring and the amino nitrogen is required. Shortening or lengthening the chain at this position drastically decreases activity. Fluphenazine

Butyrophenones (phenylbutylpiperidine) derivatives General features of butyrophenones are expressed in the following structure: Optimal activity is seen when AR1 is an aromatic system. A p-fluoro substituent aids activity. E.g. haloperidol. When X= C=O, optimal activity is seen, although other groups, C(H)OH and C(H)aryl, also give good activity. When n=3, activity is optimal; longer or shorter chains decrease activity. The aliphatic amino nitrogen is required, and highest activity is seen when it is incorporated into a cyclic form. AR2 is an aromatic ring and is needed. It should be attached directly to the 4-position or occasionally separated from it by one intervening atom. E.g. droperidol. The Y-group can vary and assists activity. An example is the hydroxyl group of haloperidol. General Structure of Butyrophenone derivatives Haloperidol Droperidol

Depression Depression is one of several mood disorders marked by loss of interest or pleasure in living. Depression is considered as the disease of the end of the twentieth century. It accompanies many physical, mental and emotional disorders. Characteristics symptoms of the depressive disorders include- Persistent sadness Hopelessness or tearfulness Loss of energy (or persistent fatigue) Persistent feelings of guilt or self-criticism A sense of worthlessness

Inability to concentrate Decreased interest in daily activities Depression (contd.) Irritability Inability to concentrate Decreased interest in daily activities Changes in appetite or body weight Insomnia or excessive sleep. Recurrent thoughts of death or suicide. These symptoms cause pervasive deficits in social functioning.

Mania: Manic depression: Mania is a mood disorder characterized by excessive excitement or a form of psychosis characterized by exalted feelings, delusions of grandeur, elevation of mood, psychomotor over activity and over production of ideas. Manic depression: A mental illness causing somebody to change quickly from being extremely happy to being extremely depressed. In 1980, the American Psychiatric Association supported the division of depressive illness into two classes, bipolar and unipolar. In bipolar/affective disorder, patients suffer episodes of both mania and depression. In unipolar, they undergo one or more major depressive episodes but without any manic episodes.

The affective disorders were classified as: Bipolar disorder (manic-depressive disorder, or mixed type). Uni-polar depression (“major depression with melancholia”) formerly known as endogenous depression. Cyclothymic disorder (Depression in association with mania).

Dysthymic (minor) depression: Dysthymic disorder is a chronically depressed mood that is present in more than 50% of the time for at least 2 years in adults or 1 year for children or adolescents. Affected persons describe themselves as being chronically sad. The symptoms include poor appetite or overeating, insomnia or hypersomnia, low energy or fatigue, low self-esteem, poor concentration or difficulty in making decisions, and feelings of hopelessness.

Affected disorder: A group of disorders marked by a disturbance of mood accompanied by a full or partial manic or depressive syndrome that is not caused by any other physical or mental disorder. Pathogenesis of affective disorders: Various theories have been advanced to explain the biochemical causes of affective disorders. Most of them ascribe a fundamental role to neurotransmitter amines, such as norepinephrine, and serotonin (5-hydroxytryptamine). Thus, according to the biogenic amine hypothesis, affective disorders result from deficiencies in the functional activity of these neurotransmitters.

Antidepressants: Antidepressants are those agents used to restore mentally depressed patients to an improved mental status. They are useful especially in depression and in depressive symptoms and, to a certain extent, in the treatment of depressive phases of certain types of schizophrenia. They decrease the intensity of the patient’s symptoms, reduce his tendency to suicide, accelerate the rate of his improvement, and promote his mental well-being.

Chemistry of Antidepressants A variety of different chemical structures have been found to have antidepressant activity. Tricyclic antidepressants (TCAs): Tricyclic antidepressants-so called because of the characteristic three-ring nucleus. They closely resemble the phenothiazines chemically and to a lesser extent, pharmacologically. R1 : - (CH2)3N(CH3)2 R2 : H Imipramine R1 : =CH(CH2)2N(CH3)2 Amitriptyline  R1: =CH(CH2)2NHCH3 Nortriptyline

Chemistry of Antidepressants B. Heterocyclics; second and third generation drugs: Between 1980 and 1996, a number of heterocyclic agents denoted as second generation and third generation or heterocyclic antidepressants were introduced. Second generation agents: Amoxapine, maprotiline, trazodone, bupropion etc. Amoxapine and maprotiline resemble the structure of the tricyclic agents, while trazodone and bupropion are distinctive. Third generation agents: Venlafaxine, mirtazapine etc. Trazodone Bupropion Venlafaxine

Chemistry of Antidepressants C. Selective serotonin reuptake inhibitors (SSRIs): SSRIs are effective and more selective antidepressants (selective serotonin reuptake inhibitors) with minimal autonomic toxicity. All are structurally distinct from the tricyclic molecules. E.g. Fluoxetine, Sertraline, citalopram etc. Fluoxetine Phenelzine

D. Monoamine oxidase (MAO inhibitors): MAO inhibitors may be classified as hydrazides, exemplified by the C-N-N moiety, as in the case with phenelzine or nonhydrazides, which lack such a moiety, as with tranylcypromine. Tranylcypromine

Chemistry of Antidepressants E. Lithium and strontium salts: Inorganic lithium salts (acetate, carbonate, citrate etc) and strontium carbonate are a recent acquisition of anti-depressive therapy. They are effective primarily for control of mood in patients with manic-depressive psychoses. They are not recommended for other psychiatric disorders. Patients treated with these salts should be maintained under close medical observation, because of the toxic effects these salts produce.

Mechanism of Action: The exact mechanism of action of antidepressants is not known. Several theories have been advanced to explain it. Most antidepressants (except MAO inhibitors) raise primarily the levels of norepinephrine or of serotonin, or of both, in the central nervous system by inhibiting the reuptake of either one of these biogenic amines or both at nerve terminals.

R-CH2-NH2 + O2 + H2O R-CHO + NH3 + H2O2 MAO inhibitors: Amine oxidase more commonly called monoamine oxidase and for short, MAO, plays the physiological role of oxidatively deaminating primary and secondary amines to aldehydes, ammonia and hydrogen peroxide: R-CH2-NH2 + O2 + H2O R-CHO + NH3 + H2O2 It deaminates the neurotransmitter amines (dopamine, epinephrine, norepinephrine, serotonin), potentially toxic amines found in food stuffs (tyramine, for example) and a wide variety of other amines (benzylamine, for example).

MAO inhibitors: The structure of MAO varies according to organs, tissues, and species from which it is extracted. It follows that it is not a single enzyme, but a group of enzymes, divided into two classes, A and B, and differing in substrate specificities and in response to drugs. Thus neurotransmitter amines are deaminated primarily by type A MAO, benzylamine by type B MAO and tyramine by both type A and B MAO.

MAO inhibitors: MAO inhibitors block a major degradative pathway (oxidative deamination) of the amine neurotransmitters, which permits more amines to accumulate in presynaptic stores and more to be released. In this way they increase the concentration of these central excitatory amines in the body, including that of serotonin and norepinephrine in the brain.

MAO inhibitors: A dangerous pharmacodynamics interaction may occur when fluoxetine or one of the newer selective serotonin reuptake inhibitors is used in the presence of a monoamine oxidase inhibitor. The combination of increased stores of the monoamine plus inhibition of reuptake after release is thought to result in marked increases of serotonin in the synapses, leading to a serotonin syndrome. This sometimes fatal syndrome includes hyperthermia, muscle rigidity, myoclonus (muscle spasm) and rapid changes in mental status. Hyperthermia: An unusually high fever. Myoclonus: Twitching (sudden) or clonic (successive) spasm of a muscle or group of muscles. Clonic: Alternatively contracting and relaxing the muscles.

Uses of antidepressants: Tricyclic antidepressants: Tricyclic compounds are the most widely used drugs for the treatment of depressed patients, being more effective and less dangerous than MAO inhibitors. They are useful in patients with major depression, because they elevate mood, increase physical activity an mental alertness and improve appetite and sleep patterns. They are also useful in treating mild forms of depression associated with anxiety, because of their sedative effects.

Uses of antidepressants: Selective serotonin reuptake inhibitors: While the SSRIs have not been shown to be more effective overall than prior drugs, they lack many of the toxicities of the tricyclic and heterocyclic antidepressants. Thus, patient acceptance has been high despite adverse effects such as nausea, decreased libido, and even decreased sexual function.

Uses of Antidepressants: MAO inhibitors: The main therapeutic value of MAO inhibitors is in patients with neurotic (atypical-block 5-HT2A receptors) depressive illness, for which the tricyclic antidepressants are not so useful. As a group these drugs are less effective and produce more serious adverse reactions than the tricyclic antidepressants. For these reasons they are drugs of second choice and should be used only in patients who were already treated with them or with those in whom tricyclic compounds have been not effective. Lithium carbonate: It is a drug of choice for severe acute mania; it is used in the prophylaxis and treatment of bipolar manic-depressive disorder.

Synthesis of Antipsychotic Agents

Synthesis of Chlorpromazine:

Synthesis of Fluphenazine

Synthesis of Amitriptyline

Synthesis of Phenelzine

Thank you..