Lecture 4 Antipsychotics PDF

Antipsychotic Drugs Learning Objectives Upon completion of this chapter the student should be able to: 1 Discuss the hypotheses and neurotransmitters related to psychotic illnesses. 2 Identify the site and mechanism of action of the following classes of antipsychotic agents: a. phenothiaz...

Antipsychotic Drugs Learning Objectives Upon completion of this chapter the student should be able to: 1 Discuss the hypotheses and neurotransmitters related to psychotic illnesses. 2 Identify the site and mechanism of action of the following classes of antipsychotic agents: a. phenothiazines and thioxanthenes b. butyrophenones c. diarylazepines, benzisoxazole and benzisothiazole 3 List structure–activity relationships (SARs) of drugs of the antipsychotic effect: chlorpromazines, thiothixenes, and butyrophenones. 4.Identify clinically significant physicochemical and pharmacokinetic properties. 5 Discuss, with chemical structures, the clinically significant metabolism of the antipsychotic and and how the metabolism affects their activities. 6 Discuss the clinical application of the antipsychotic agents.  Antipsychotic drugs  The psychoses affect approximately 1% of the population in all cultures.  They are psychogenic mental disorders involving a loss of contact with reality.  The psychotic disorders include schizophrenia, the manic phase of bipolar (manic– depressive) illness, acute idiopathic psychotic illness  The most common is schizophrenia, in which perception, thinking, communication, social functioning, and attention are altered. Schizophrenia is a particular kind of psychosis characterized mainly by a clear sensorium but a marked thinking disturbance. Symptoms are called positive (e.g., delusions, hallucinations) or negative (e.g., flat affect, apathy); cognitive dysfunction may occur.  Dopamine hypothesis (a) drugs that increase dopaminergic neurotransmission, such as levodopa (a DA precursor), amphetamines (a DA releaser), and apomorphine (a DA agonist), induce or exacerbate schizophrenia. (b) DA receptor density is increased in certain brain regions of untreated schizophrenics. (c) Many antipsychotic drugs strongly block postsynaptic D 2 receptors in CNS. (d) Successful treatment of schizophrenic patients has been reported to change the amount of homovanillic acid (HVA), a DA metabolite, in the cerebrospinal fluid, plasma, and urine. Role of dopamine in the development of psychosis The monoamine neurotransmitter dopamine plays a key role in the so-called dopamine hypothesis which argues that the unusual behavior and experiences associated with psychosis can be largely explained by changes in dopamine function in the brain now dopamine has four major pathways by which it affects the brain Dopaminergic pathways  Mesolimbic pathway which is thought to be hyperactive in schizophrenia and to mediate positive symptoms of psychosis such as delusions and hallucinations.  Mesocortical pathway which is thought to be under active in schizophrenia and thus mediate negative psychotic symptoms such as loss of motivation and social withdrawal.  Nigrostriatal pathway which is part of the extrapyramidal nervous system and controls motor function and movement deficiency of dopamine in this pathway can lead to dystonia and parkinsonian symptoms while excess of dopamine can lead to hyperkinetic movements such as tics and dyskinesias.  Tuberoinfundibular pathway which controls prolactin secretion specifically dopamine in this pathway inhibits prolactin release and as a reminder prolactin is a hormone that enables milk production and is also involved in the control of sexual desire and regulation of immune system now within those different pathways dopamine.  Vomiting center block dopamine receptors in vomiting center and act as antiemetic Dopamine receptors  There are five primary types of dopamine receptors known as D1 D2 D3 D4 and D5 out of the five D1 and D2 receptors are found in the highest density in nearly all of the pathways involved in psychotic disorders.  D2 receptors are the most clinically relevant because they are the main targets of antipsychotic drugs.  the antipsychotic action is now thought to be produced (at least in part) by their ability to block DA receptors in the mesolimbic and mesocortical pathways.  Moreover, extrapyramidal side effects of antipsychotic drugs correlate with their D 2 antagonism effect in nigrostriatal pathway.  The hyperprolactinemia that follows treatment with antipsychotics is caused by blockade of DA’s tonic inhibitory effect on prolactin release from the pituitary gland in tuberoinfundibular pathway.  Antipsychotic drugs—previously known as neuroleptic drugs are used in the First-generation 'typical' antipsychotics  Block D2 receptors in almost all areas of the brain this has positive as well as negative consequences  Blockade dopamine receptors in the mesolimbic pathway reduces positive symptoms such as delusions and hallucinations which is beneficial.  blockade of dopamine receptors in the mesocortical pathway that is already underactive in schizophrenia may cause worsening of negative symptoms and thus lead to lack of motivation and social disengagement.  blockade of dopamine receptors in the nigrostriatal pathway may lead to extrapyramidal and Parkinson's-like symptoms such as tremors muscle rigidity and difficulty in starting and stopping movements.  blockade of dopamine receptors in the tuberoinfundibular pathway may cause hyperprolactinemia which lead to gynecomastia and sexual dysfunction.  typical antipsychotics are subclassified into  high potency agents produce strong antipsychotic effect and tend to cause more extrapyramidal side effects and greater increase in prolactin levels.  low potency agents do not bind to D2 receptor as tightly as the high potency agents and generally affect a range of other receptors. for example, blockade of alpha-adrenergic receptors can lead to orthostatic hypotension blockade of muscarinic receptors can lead to anticholinergic symptoms such as dry mouth blurred vision difficulty urinating. blockade of H1-histamine receptors can lead to sedation and some weight gain. Second-generation 'atypical' antipsychotics  block both D2 receptors as well as serotonin receptors subtype 2A because serotonin inhibits dopamine release  agents that block serotonin receptors may increase dopamine levels in brain areas that need it.  Atypicals occupy D2 receptors transiently and dissociate quickly allowing for relatively normal dopamine neurotransmission  this modest D2 receptor blockade in combination with serotonin receptor blockade is thought to significantly lower the incidence of extrapyramidal side effects as well as decrease negative symptoms and improve cognition compared to typical agents  now in addition to dopamine and serotonin 2A receptor blockade atypical antipsychotics also bind to many other targets including other subtypes of serotonin receptors as well as histamine alpha- adrenergic and muscarinic receptors.  side-effects of second-generation agents can vary depending on the drug's receptor binding profile for example Atypical antipsychotics that have strong affinity for serotonin receptors subtype 2C may cause metabolic side effects including weight gain hyperglycemia and dyslipidemia agents that have strong affinity for H1 receptors may cause sedation and may also contribute to weight gain agents that have significant affinity for alpha-1-adrenergic receptors may cause orthostatic hypotension in addition all second-generation agents Risperidone seems to have the strongest Typical antipsychotics [i] Phenothiazines  Several dozen phenothiazine antipsychotic drugs are chemically related agents.  Others are marketed primarily for their antiemetic, antihistaminic, or anticholinergic effect.  They have a tricyclic structure (6-6-6 system) in which two benzene rings are linked by a sulfur and a nitrogen atom. ☼ SAR:  S ☼ SAR: 7 6 5 4 3 8 2 activity 9 10 1 R2 = EWGs e.g. Cl 2 N R    R Amine is always tertiary N R group can be in a ring R3 R 3- atom chain between 2 Ns is optimal S S S.2HCl S S S S S.HCl N CF3.HCl.HCl.HCl N Cl N Cl N Cl N N CF3 N SCH3 N SCH3.2C4H4O4 O N N N N N N N N N N N OH OH Fluphenazine Chlorpromazine Promazine Triflupromazine Prochlorperazine Perphenazine hydrochloride hydrochloride Thioridazine hydrochloride Mesoridazine Maleate hydrochloride hydrochloride Phenothiazine ring substituents  The best position for substitution is the 2- position. Activity increases as electron-withdrawing ability of the 2-substituent increases.  Potency increases in the following order of position of ring substituents 1< 4 < 3 < 2.  The significance of these substituent effects is that the hydrogen atom of the protonated amino group of the sidechain H-bonds with an electron pair of an atom of the 2-substituent to develop a DA- like arrangement.  x-ray crystallography, proposed that the chlorine-substituted ring of chlorpromazine base is superimposed on the aromatic ring of DA base, with the sulfur atom aligned with the p-hydroxyl group of DA and the aliphatic amino groups of the two compounds also aligned.  The effect of the substituent at the 1-position might be to interfere  Alkyl side chain  The three-carbon chain between position 10 and the aliphatic amino nitrogen is critical for neuroleptic activity. Shortening or lengthening the chain at this position drastically decreases the activity.  Shortening the chain to two carbons increase the antihistaminic and anticholinergic activities.  α- carbon substitution reduce the activity.  β- substitution can tolerate methyl group increasing or decreasing the activity.  γ- substitution with methyl group decrease dopaminergic activity and increase anticholinergic activity which help in reducing extrapyramidal side effect.  Activity can be enhanced with increasing chain length, as in N2- Amino group  For maximum activity, the amino function must be tertiary in nature.  Primary and secondary amino groups are less potent  Alkylation of the amino group with groups larger than methyl decrease antipsychotic activity.  Phenothiazines Alkyl side chain derivatives 1. Chlorpromazine Hydrochloride: (Thorazine) S The first phenothiazine compound introduced into therapy. It is still useful as an antipsychotic..HCl Other uses are in nausea, vomiting, and hiccough. Oral bioavailability between 25% to 35% N Cl because of significant first-pass metabolism. In contrast, bioavailability increases up to 10-fold with injections, but the clinical dose usually is decreased by only threefold to fourfold. The drug N has significant sedative and hypotensive properties, reflecting central histaminergic and Chlorpromazine hydrochloride peripheral α1-noradrenergic blocking activity, respectively. Also, with a peripheral anticholinergic activity. S 2. Promazine: (Sparine).HCl N It was introduced into antipsychotic therapy after its 2-chloro-substituted relative. The 2H- substituent vis-à-vis the 2Cl substituent gives a milligram potency decrease as an antipsychotic. N Tendency to EPS is also lessened. Promazine hydrochloride  S 3. Triflupromazine Hydrochloride: (Vesprin).HCl N CF3 N Triflupromazine hydrochloride It has a greater milligram potency as an antipsychotic, higher EPS, but lower sedative and hypotensive effects than chlorpromazine. Overall, the drug has uses analogous to those of chlorpromazine.  Phenothiazines pieridine derivatives 1. Thioridazine Hydrochloride: (Mellaril) S It is a member of the piperidine subgroup of the phenothiazines. The drug has a relatively.HCl N SCH3 low tendency to produce EPS. The drug has high anticholinergic activity, and this activity in the striatum, counterbalancing a striatal DA block, may be responsible for the N low EPS. It also has been suggested that there may be increased DA receptor selectivity, which may be responsible. The drug has sedative and hypotensive activity in common Thioridazine hydrochloride with chlorpromazine and less antiemetic activity. At high doses, pigmentary retinopathy has been observed. Thioridazine is converted to the active metabolite mesoridazine, which probably contributes to the antipsychotic activity of thioridazine. S N SCH 3 2. Mesoridazine Besylate: (Serentil) O It shares many properties with thioridazine. However, NO pigmentary retinopathy has N been reported. Mesoridazine  Phenothiazines piperazine derivatives S N Cl 1. Prochlorperazine Maleate: (Compazine).2C4H4O4 It is in the piperazine subgroup of the phenothiazines, characterized by high-milligram N antipsychotic potency, a high prevalence of EPS, and low sedative and autonomic N Prochlorperazine effects. Because of the high prevalence of EPS, however, it is used mainly for its Maleate antiemetic effect, NOT for its antipsychotic effect. S N Cl 2. Perphenazine: (Trilafon) It is an effective antipsychotic and antiemetic. N N OH Perphenazine 3. Fluphenazine Hydrochloride: (Permitil, Prolixin) S.2HCl N CF3 The most potent antipsychotic phenothiazine on a milligram basis. It is also available as two lipid-soluble esters for depot intramuscular injection, the N enanthate (heptanoic acid ester) and the decanoate ester. These long-acting N OH preparations have use in treating psychotic patients who do not take their Fluphenazine hydrochloride medication or are subject to frequent relapse.  [ii] Thioxanthenes Thiothixene: (Navane) The thioxanthene system differs from the phenothiazine system by replacement of the N-H moiety with a carbon atom doubly bonded to the propylidene side chain. With the substituent in the 2-position, Z and E-isomers are produced. In accordance with the concept that the presently useful antipsychotics can be superimposed on DA, the Z-isomers are the more active antipsychotic isomers. The compounds of the group are very similar in pharmacological properties to the corresponding phenothiazines. Thus, thiothixene displays properties similar to those of the piperazine subgroup of the phenothiazines. S SO2N N N Thiothixene  Thank You