PHARMACOLOGY OF ANTIPSYCHOTIC DRUGS (NEUROLEPTICS)

1. PHARMACOLOGY OF ANTIPSYCHOTIC DRUGS (NEUROLEPTICS)

2. psychopharmacological agents or Anti psychotic drugs • “the psychopharmacological agents or psychotropic drugs have primary effects on psyche (mental process) & are used for treatment of psychiatric disorders”.

3. Psychoses • “severe psychiatric illness with serious distortion of thought, behaviour, capacity to recognize reality & of perception (delusions & hallucinations)”. • Cognitive disorders/ Acute and chronic organic brain syndrome(confusion, disorientation, defective memory, disorganisedbehaviour)–delirium & dementia. • Functional disorders (emotion, thought, reasoning, behaviour)–schizophrenia(splitting of perception and interpretation from reality- hallucinations, inability to think coherently), paranoid states (marked persecutory or other kinds of fixed delusions). • Affective disorders (mood)–mania & depression. • Neuroses (less serious; ability to comprehend reality is not lost, though the patient may undergo extreme suffering)- • phobia, anxiety, obsessive compulsive, post traumatic stress disorders, hysterical.

4. Phobia-Fear of the unknown or of some specific objects, person or situations Anxiety- An unpleasant emotional state associated with uneasiness, worry, tension and concern for the future Obsessive-compulsive- Limited abnormality of thought or behaviour; recurrent intrusive thoughts or ritual like behaviours which the patient realizes are abnormal or stupid, but is not able to overcome even on voluntary effort Reactive depression- due to physical illness, loss, blow to self-esteem or bereavement, but is excessive or disproportionate. Post traumatic stress disorder- Varied symptoms following distressing experiences like war, riots, earthquakes,tc Hysterical- Dramatic symptoms resembling serious physical illness, but situational, and always in the presence of others; the patient does not feign but actually undergoes the symptoms, though the basis is only psychic and not physical.

5. Schizophrenia • “Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests as auditory hallucinations, bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social or occupational dysfunction.”

6. Schizophrenia: Clinical Features

7. Anti psychotic drugs • Phenothiazines • Aliphatic side chain –chlorpromazine, triflupromazine. • Piperazine side chain –fluphenazine, trifluoperazine • Piperidine side chain –thioridazine • Butyrophenones –Haloperidol, penfluridol • Thioxanthenes – flupenthixol • Other heterocyclics– loxapine, pimozide • Atypical antipsychotics– clozapine, risperidone, olanzapine, ziprasidone.

8. Dopamine Theory of Schizophrenia Many lines of evidence point to the aberrant increased activity of the dopaminergic system as being critical in the symptomatology of schizophrenia. Drugs which increase DA activity (amphetamines, Ievodopa, bromocriptine) induce or exacerbate schizophrenia, has given rise to the 'Dopamine theory of Schizophrenia‘ stating DA overactivity in limbic area to be responsible for the condition.

9. MOA • Dopamine theory of schizophrenia • D2 blocking • Phenothiazines/thioxanthenes-D1, D2, D3 & D4 blocking. • Blockade of dopaminergic projections to temporal & prefrontal areas (limbic system, emotion, memory) & in mesocortical areas (cognitive control, motivation, and emotion).

10. Initially firing increases-adaptive, later subsides • Clozapine- Blockade of 5-HT2 & α1receptor, D4 • Dopaminergic blockade------in • (basal ganglia)-parkinsonism, • (CTZ)- antiemetic.

11. AII antipsychotics (except clozapine-like atypical) have potent dopamine D2 receptor blocking action; antipsychotic drugs bind to D2 receptor. Phenothiazines and thioxanthenes also block D1, D2, D3 & D4receptors, but there is no correlation with antipsychotic potency. Blockade of dopaminergic projections to the temporal and prefrontal areas constituting the 'limbic system' and in mesocortical areas is probably responsible for the antipsychotic action. As an adaptive change to blockade of D2 receptors, the firing of DA neurones and DA turnover increases initially. But over a period of time this subsides and shows diminished activity. Tolerance to DA turnover enhancing effect of antipsychotics is not prominent in the limbic area-may account for the continued antipsychotic effect. The antipsychotic activity of clozapine and other atypical antipsychotics have weak D2 blocking action, but they have significant 5-HT, and α1blocking action, and some are relatively selective for D4 receptors which is the basis for their action . Dopaminergic blockade in the basal ganglia appears to cause the extrapyramidal symptoms while that in CTZ is responsible for antiemetic action.

12. Pharmacological actions • 1. CNS: • Normal – indifference to surroundings, paucity of thought, psychomotor slowing, emotional quietening, reduction in initiative & tendency to go off to sleep. • In a psychotic –reduces irrational behaviour, agitation & aggressiveness & controls psychotic symptamatology. • Disturbed thought & behaviour are gradually normalized, anxiety is relieved. • Hyperactivity, hallucinations & delusions are suppressed. • Performance & intelligence are relatively unaffected. • Antiemetic action through CTZ.

13. 2. ANS: -α adrenergic blocking activity • CPZ = triflupromazine > thioridazine > clozapine > fluphenazine > haloperidol > trifluoperazine > pimozide • Anticholinergic (M) property • thioridazine > CPZ > triflupromazine> trifluoperazine = haloperidol • 3. Local anaesthetic –potent LA but has irritant action. • 4. CVS –postural hypotension-not prominent in psychotic patients- reflex tachycardia accompanies • High dose- Depress heart---ECG changes. • antiarrhythmic action but cause arrhythmia at higher dose. • 5. Skeletal muscle – reduces spasticity.

14. 6. Endocrine – • ↑ prolactin release by blocking inhibitory action of DA (may cause galactorrhoea & gynaecomastia). • ↓gonadotropin secretion, ACTH & GH. • ↓ ADH

15. Therapeutic uses • Schizophrenia • Their antipsychotic effects, including • decreasing the positive symptoms: symptoms of thought disorders, restlessness, anxiety, aggression, paranoid features, delusions, hallucinations • to a lesser degree decreasing the negative symptoms (apathy, poverty of speech, social withdrawal). • Other selected therapeutic uses: • Mania: CPZ, haloperidol; (lithium/valproate are first prefered) • Anxiety : not first choice • Antiemetic : drug/disease induced vomiting • Potentiate analgesics, anesthetics, hypnotics • intractable hiccough • Tetanus, alcoholic hallucinosis, Huntington’s disease.

16. Adverse effects

17. Akathisia: State of extreme motor restlessness & drive to move. • Acute dystonia: Spasms involving head, neck, trunk & extremities. • Tardive dyskinesia (TD): Stereotyped, repetitive, involuntary movements of the mouth, lips, tongue & choreiform movements of the limbs & body.

18. Drug Interactions • Additive effects with sedatives. • Additive effects with anticholinergics. • Additive effects with antihistaminergics. • Additive effects with -AR blocking drugs. • Additive effects with drugs with quinidine-like action (mainly thioridazine). (antiarrhythmic effect)

19. Salient features of atypical antipsychotics • Clozapine: • weak D2 blockade, potent 5-HT2 antagonistic activity, alpha bloackade • It is D4 selective (less in basal ganglia) • Sedation, anticholiergic; but paradoxically induce hypersalivation. • Significant H1 blocking. • minimum extrapyramidal symptoms, rarely tardivedyskinesia, no prolactine rise. • Supress both positive & negative symptoms • improve impaired cognitive function

20. Limitation: agranulocytosis, blood dyscrasias, sedation, unstable BP, tachycardia, urinary incontinence, weight gain and precipitation of diabetes • Few cases of myocarditis • Highdose- can induce seizure

21. Obsessive Compulsive Disorders • Repetitive unwanted obsessions or compulsive acts • Obsession is recurrent and intrusive thought, feeling, idea, image or impulses • Usually distressing • Extreme need for orderliness • Persistent doubts