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

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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

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

11. 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).

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

14. 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.

15. 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.

16. 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

17. 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

18. Mechanism of Action (Relative receptor blocking action)

19. 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

20. 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

21. 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

22. THE END