Pharmacology – II PHL-322 Lecture: 02 ANTI-PSYCHOTICS / NEUROLEPTICS By Majid Ahmad Ganaie M. Pharm., Ph.D. Assistant Professor Department of Pharmacology E mail: majidsays@gmail.com

Definition Neurosis Psychosis Depressant Abnormal behavior characterized by increased anxiety, tension and emotionalism Psychosis Severe psychiatric illness with distortion of thought and behaviors, capacity to recognized reality and of perception Depression Depressant Mental state characterized by depressed mood with feelings of frustration and hopelessness

Psychotic disorders 1.) Psychoses 2.) Neuroses (a) Schizophenia (split mind) splitting of perception and interpretation from reality inability of thinking coherently (b) Mania Elation, hyperactivity, uncontrollable thought and speech maybe associated with violet behaviour (c) Depression Sadness, guilt, physical and mental slowing self-destructive ideation 2.) Neuroses (less seriousness) (a) Anxiety An unpleasant emotional state associated with uneasiness and concern for the future (b) Obsessive / Compulsive limited abnormality of talk or behaviour

Schizophrenia One of the psychotic disorders Major disturbances in: Thought Emotion Behavior Disordered thinking Faulty perception and attention Inappropriate or flat emotions Bizarre motor activity Disrupted interpersonal relationships

Schizophrenia Disorder impacts families & friends Difficult to live with someone who experiences delusions, hallucinations, and paranoia. Social skills deficits common Isolation, few social contacts Symptoms impact employability Often lead to unemployment & homelessness Substance abuse & suicide rates high

Schizophrenia Lifetime prevalence ~1% Occurs equally in men and women Onset typically late adolescence or early adulthood Men diagnosed at a slightly earlier age Diagnosed more frequently in African Americans May reflect diagnostician bias

Positive Symptoms: Behavioral excesses Delusions Firmly held beliefs Contrary to reality Resistant to disconfirming evidence Persecutory delusions common “The CIA has planted a listening device in my head” Hallucinations Sensory experiences in the absence of sensory stimulation Types of hallucinations Audible thoughts Voices commenting Voices arguing Increased levels of activity in Broca’s area during hallucinations Broca’s area: area of brain linked to speech production

Negative Symptoms: Behavioral deficits Avolition Lack of interest and drive Alogia Poverty of speech Poverty of content Anhendonia Inability to experience pleasure Flat affect Exhibits little or no affect in face or voice Asociality Inability to form close personal relationships

Other Symptoms Catatonia Catatonic immobility Waxy flexibility Motor abnormalities Repetitive, complex gestures Usually of the fingers or hands Excitable, wild flailing of limbs Catatonic immobility Maintain unusual posture for long periods of time e.g., stand on one leg Waxy flexibility Limbs can be manipulated and posed by another person Inappropriate affect Emotional responses inconsistent with situation e.g., laugh uncontrollably at a funeral

NEUROLEPTIC DRUGS Mechanism of Action Dopamine receptor blocking activity in the brain Serotonin receptor blocking activity in the brain.

Dopamine receptor blocking activity in the brain All neuroleptic drugs block dopamine receptors in the brain and the periphery. Five types of dopamine receptors  D1,D2,D3,D4,D5. D1 and D5  activate adenylyl cyclase D2,D3,D4  inhibit adenylyl cyclase Adenylyl cyclase  an enzyme that initiates the conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP).

Dopamine Theory of Schizophrenia BioMedical Science_nEurOphaRm XanEeFi - FiFi Faridz Dopamine Theory of Schizophrenia

Serotonin receptor blocking activity in the brain. Newer agents atypical agents appear to exert part of their unique actions. Through inhibition of serotonin receptors (5-HT). Example of drug clozapine: Has high affinity for D1, D2, D4, D5, 5 HT2, muscarinic and alpha adrenergic receptors. Example of drug Risperidone: blocks 5-HT2 receptors more than D2 receptors.

Outcome Antipsychotic actions. Reduces hallucinations and delusions associated with schizophrenia by blocking dopamine receptors in the mesolimbic system of the brain. Causes parkinson like symptoms.

Drug suitable for treating Schizopherenia Has antipsychotic actions Reduce hallucination Reduce delusions Suitable in treating negative symptoms of schizophrenia such as withdrawal, blunted emotions and reduced ability to relate to other people

CLASSIFICATION OF ANTIPSYCHOTIC DRUGS 1. TYPICAL ANTIPSYCHOTICS a. Phenothiazine derivatives Aliphatic Derivative: CHLORPROMAZINE Piperidine Derivative: THIORIDAZINE Piperazine Derivative: FLUPENAZINE, PERPHENAZINE, TRIFLUOPERAZINE b. Thioxanthene Derivative: THIOTHIXENE c. Butyrophenone: HALOPERIDOL 2. ATYPICAL ANTIPSYCHOTICS CLOZAPINE LOXAPINE OLANZAPINE QUETIAPINE RISPERIDONE MOLINDONE ZIPRASIDONE SERTINDOLE ARIPIPRAZOLE PIMOZIDE

Mechanism of Action (Relative receptor blocking action)

Desirable Effects Reduction of positive symptoms Hyperactivity, bizarre ideation, hallucinations, delusions Typicals and atypicals reduce positive symptoms Improve negative symptoms Emotional blunting, social withdrawal Atypicals Also reduces psychotic symptoms in schizoaffective disorder, Tourette’s syndrome, toxic psychoses Except thioridazine phenothiazines have antiemetic properties via H1 blocking

Adverse Effects Reversible parkinsonism, akathisias, and dystonias Treatment is to decrease antipsychotic dose or use muscarinic blocking agents Less common with atypicals Tardive dyskinesias Develop within 6 months to several years of therapy Antimuscarinics increase TD severity May be caused by dopamine receptor sensitization because increasing antipsychotic doses temporarily attenuates symptoms May be irreversible No pharmacological treatment Autonomic effects (tolerance may develop with continued therapy) Muscarinic blockade – dry mouth, constipation, urinary retention, visual problems Alpha adrenergic receptor blockade – postural hypotension, failure to ejaculate

Miscellaneous toxicities Endocrine and metabolic effects Hyperprolactinemia, amenorrhea, galactorrhea, infertility, weight gain, gynecomastia Neuroleptic Malignant Syndrome Muscle rigidity, impairment of sweating, hyperpyrexia, autonomic instability May be life threatening Treat with dantrolene and possibly dopamine agonists Sedation More marked with phenothiazines Except for sertindole, all atypicals block histamine receptors Miscellaneous toxicities Thioridazine – retinal deposits causing visual impairments, high doses leads to fatal ventricular arrhythmias Sertindole – prolonged QT segment leading to arrhythmias Clozapine – 1-2% incidence of agranulocytosis, seizures at high doses Overdose toxicity Other than thioridazine (cardiotoxicity), overdoses are usually not fatal Lowers seizure threshold Hypotension responds to fluid replacement

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