Antipsychotic drugs

1. Antipsychotic Drugs

2. Psychopharmacological agents /
psychotropic drugs
 Agents which have primary effects on psyche
(mental processes) and are used for treatment
of psychiatric disorders.
 Categories
 Anti-psychotics
 Anti-manic and mood stabilizing
drugs
 Antidepressant drugs
 Antianxiety drugs
2

3. Psychiatric (Mental) illness
 Divided into two categories
 Psychoses
 Distortion of
 thoughts,
 behavior,
 capacity to recognize reality and
 Perception (delusions and hallucinations).
 Neuroses (anxiety, phobia, depression,
OCD)
 These are less serious; ability to comprehend
reality is not lost.
3

4. Psychoses types
1. Acute and chronic organic (physiologic)
brain syndromes
 Cognitive disorder + psychotic symptoms
2. Functional disorders
 Schizophrenia (Split mind)
 Paranoid state
 Mood affective disorder (Unipolar and
bipolar)
 Mania
 Depression
4
Functional disorders (Memory
intact, but emotion, thought,
reasoning and behavior are
seriously altered)

5. Topics
 Psychosis
 Pathogenesis
 Classification of antipsychotics
 Mechanism of action
 Adverse effects
 Drug interactions
 Uses
5

6. Manifestations
 Positive symptoms (present in people with
schizophrenia, but not experienced in normal
individuals)
 Delusion
 Illusions
 Auditory hallucinations
 Thought disorders
 Negative symptoms
 Introvert behavior
 Poor socialization
 Emotional blunting
 Lack of motivation and cognitive deficits
6

7. Pathogenesis of schizophrenia
1. Genetic predisposition
2. Dopamine (DA) theory (DA overactivity)
3. 5-HT theory (Serotonin overactivity, 5-HT2A)
4. Glutamate theory (NMDA-R underactivity)
7

8. Antipsychotic (neuroleptic) drugs
 These are drugs having a valuable therapeutic
effect in psychoses.
 Pathogenesis of schizophrenia
1. Genetic predisposition
2. Dopamine (DA) theory (DA overactivity)
 DA-R blockers are useful
 But, psychotomimetic agents such as
 d-lysergic acid (LSD), is a potent serotonin 5-
HT2 receptor agonist
 Phencyclidine and ketamine, are antagonists
of the N-methyl-D-aspartate (NMDA)
glutamate receptor
 Therefore, along with DA, 5-HT and
glutamate pathways are also involved
8

9. Pathogenesis of schizophrenia
 Three major dopaminergic projections
 Behaviour
1. Mesolimbic –mesocortical –mesofrontal
 Movements
2. Nigrostriatal pathway
 Endocrinal response
3. Tubero - infundibular
9

10. Classification of drugs
1. Phenothiazines
 Aliphatic side chain:
 Chlorpromazine, Triflupromazine
 Piperidine side chain:
 Thioridazine
 Piperazine side chain:
 Trifluoperazine, Fluphenazine
2. Butyrophenones:Haloperidol, Trifluperidol, Penfluridol
3. Thioxanthenes: Flupenthixol, thiothixene
4. Other heterocyclics: Pimozide, Loxapine
5. Atypical antipsychotics:
Clozapine, Aripiprazole, Risperidone, Ziprasidone,
Olanzapine, Amisulpiride, Quetiapine, Zotepine
10

11. Mechanism of actions
11

12. 12
Mechanism of actions

13. 13

14. Mechanism of antipsychotics
 Dopamine theory:
 reduction of dopaminergic neurotransmission is the
major mechanism of antipsychotic action.
 All antipsychotics (except clozapine-like atypical
ones) have potent dopamine D2 receptor blocking
action.
 Blockade of dopaminergic projections in mesolimbic
and mesocortical pathways is responsible for
antipsychotic action.
 Blockade of DA receptors in basal ganglia produces
the parkinsonian adverse effects.
 Atypical neuroleptics such as clozapine
 5-HT2A , and D4 blocking action
 Also, through alpha-1, M1, H1, and mild D2 receptor
blockade
14

15. Typical (Classical) Neuroleptics
 Pharmacological actions of
Chlorpromazine (CPZ), Haloperidol
etc.
 1. On CNS:
 Antipsychotic action
 Inhibit positive symptoms (by inhibition of
dopaminergic neurotransmission in
mesocortical and mesolimbic pathway)
 Parkinsonian-like (extrapyramidal) effects
 DA inhibition in nigrostriatal pathway
 Hyperprolactinemia
 DA inhibition in tubero-infundibular pathway
 DA blockade in CTZ – Antiemetic action
15

16. CNS action continued..
 Effects differ in normal and psychotic
individuals.
 In normal subjects:
 CPZ produces indifference to surroundings, paucity of
thought, psychomotor slowing, emotional quietening,
reduction in initiative and tendency to go off to sleep.
 In a psychotic (- positive symptoms)
 CPZ reduces irrational behaviour, agitation and
aggressiveness and controls psychotic
symptomatology.
 CPZ lowers seizure threshold and can precipitate fits in
untreated epileptics.
16

17. Other actions
 2. Local anaesthetic
 Chlorpromazine is as potent a local anesthetic as procaine.
However, it is not used for this purpose because of its
irritant action.
 3. CVS:
 Postural hypotension
 High doses: Arrhythmia (QT prolongation)
 4. Endocrine:
 Neuroleptics consistently increase prolactin release by
blocking the inhibitory action of DA on pituitary lactotropes.
 reduce gonadotropin, ACTH, GH, ADH secretion
 Glucose tolerance, increase triglycerides, obesity
17

18. ATYPICAL (Second generation) ANTIPSYCHOTICS
 Distinction between classical and
atypical antipsychotics
1. Unique receptor affinity profile
2. More effectiveness against the negative
than the positive symptoms
For example: cognitive functions
3. Effective in refractory cases
4. Lesser liability to cause EPS
18

19. Clozapine
 First atypical antipsychotic
 Both positive and negative symptoms of
schizophrenia are improved
 Clozapine is the most effective drug in refractory
schizophrenia, i.e. patients not responding to typical
neuroleptics may respond to it.
 Produces few/no extrapyramidal symptoms; tardive
dyskinesia is rare and prolactin level does not rise
 Example of other important atypical antipsychotics
 Olanzapine, Risperidone, Ziprasidone, Aripiprazole,
Paliperidone, Quetiapine (new short-acting)
19

20. Adverse effects
 I. Based on pharmacological actions (dose
related)
 Drowsiness, lethargy, mental confusion
 Tolerance develops to sedative effects
 aggravation of seizures in epileptics
 Postural hypotension, arrhythmia
 Dry mouth, blurring of vision, constipation,
 Hyperprolactinemia
20

21. Adverse effects
 EPS:
 Parkinsonism,
 Perioral tremors ‘rabbit syndrome’,
 Acute muscular dystonias
 Akathisia
 Malignant neuroleptic syndrome: The patient
develops marked rigidity, immobility, tremor,
hyperthermia, semiconsciousness, fluctuating BP
and heart rate, +++ creatine kinase,
 Tardive dyskinesia
 purposeless involuntary facial and limb
movements like constant chewing.
21

22. Adverse effects
 II. Hypersensitivity reactions
 Cholestatic jaundice
 Skin rashes, urticaria, contact
dermatitis, photosensitivity
22

23. Drug interactions
1. Neuroleptics potentiate all CNS depressants
…hypnotics, anxiolytics, alcohol
2. Neuroleptics block the actions of levodopa and
direct DA agonists in parkinsonism
3. Antihypertensive action of clonidine and
methyldopa is reduced,
…probably due to central α2 adrenergic blockade.
4. Phenothiazines and others are poor enzyme
inducers—no significant pharmacokinetic
interactions occur.
5. Enzyme inducers (barbiturates,
anticonvulsants) can reduce blood levels of
neuroleptics.
23

24. Assignment
1. With suitable examples, classify
antipsychotic drugs. (4Marks)
2. Explain the mechanism of action of
antipsychotic drugs (4 marks)
3. Discuss the major pharmacological actions
of haloperidol/chlorpromazine (8 marks)
4. Write a short note on atypical
antipsychotics (4 marks)
5. Write four major drug interactions due to
antipsychotic therapy. (4 marks)
6. What are the major adverse effects of
typical antipsychotics? (4 marks)
24