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ANTIPSYCHOTICS

Dr. RAGHU PRASADA M SMBBS,MDASSISTANT PROFESSOR DEPT. OF PHARMACOLOGYSSIMS & RC.

Types of psychosis

The most important types of psychosis are: Schizophrenia Affective disorders (e.g. depression, mania) Organic psychoses (mental disturbances caused by

head injury, alcoholism, or other kinds of organic disease).

The dopamine hypothesis

PET studies Post-mortem studies Drugs increasing central dopamine activity- L-dopa,

amphetamines Excessive dopaminergic activity plays a role in the

disorder. The enhancement of function of 5-HT2

Pharmacologically, they are characterized as dopamine receptor antagonists, though many of them also act on other targets, particularly 5-HT receptors, which may contribute to their clinical efficacy.

5-HT hypothesis (Serotonin)

LSD- 5HT2 agonist – Visual hallucinations 5-HT has a modulatory effect on dopaminergic

neurones

Glutamate hypothesisPhencyclidine, ketamineGlutamate-NMDA antagonists –can produce psychotic

symptoms

Dopaminergic Systems

The nigrostriatal pathway (coordination of voluntary movement

Mesolimbic- mesocortical ( behavior ) Tuberoinfundibular- pituitary system (endocrine) The medulla oblongata (vomit) Medullary - periventricular pathway ( eating

behavior)

Nature of psychosis /schizophrenia

Positive Symptoms-mesolimbic. Hallucinations, delusions, paranoia, ideas of

reference.

Negative Symptoms-mesocortical Apathy, social withdrawal, anhedonia, emotional

blunting, cognitive deficits, extreme inattentiveness or lack of motivation to interact with the environment.

These symptoms are progressive and non-responsive to medication.

Dopamine System

DOPAMINE RECEPTORS There are at least 5 subtypes of receptors:

D1 and D5: mostly involved in postsynaptic inhibition.

D2, D3, and D4: involved in both pre-and postsynaptic inhibition.

D2: the predominant subtype in the brain:regulates mood, emotional stability in the limbic system and movement control in the basal ganglia.

Antipsychotics/Neuroleptics

Presynaptic EffectsBlockade of D2 receptors

Compensatory Effects

Ý Firing rate and activity of nigrostriatal and mesolimbic DA neurons.

Ý DA synthesis, DA metabolism, DA release.

Postsynaptic EffectsDepolarization Blockade

Inactivation of nigrostriatal and mesolimbic DA

neurons.

Receptor SupersensitivityProlonged use-feedback

inhibition of dopamine releasedecreased dopamine turnover

Classification of Antipsychotic drugs

Typical Antipsychotics Phenothiazines –Aliphatic tertiary amine side chain:Chlorpromazine, Piperazine moiety: Perphenazine, Fluphenazine,Piperidine moiety: Thioridazine Thioxanthenes -Flupenthixol, Thiothixene Butyrophenones -Haloperidol, Droperidol,

Benperidol, Domperidone

Antipsychotic drugs

Miscellaneous –Pimozide, Pepenfluridol, Molindone, Loxapine, Sulpride,

Atypical Antipsychotics - Clozapine, Quitiapine, Risperidone, Sulpiride, Olanzapine

Phenothiazines: Chlorpromazine

Pharmacologic effects and mechanism: CNS: A. Neuroleptic Effect-Antipsychotic drugs probably

owe their therapeutic effects mainly to blockade of D2-receptors (lies in midbrain-cortex and midbrain-limbic system ) Mesolimbic,mesocortical D2

More effective for treating positive symptomB. Antiemetic Effect--- inhibit chemoreceptor trigger zone or

directly depress the medullary vomiting center. C. Temperature-regulating Effect--- produce hypothermia

Phenothiazines- Chlorpromazine

Pharmacologic effects:

(2) Autonomic Nervous System: block α-adrenergic and M-Cholinergic receptors and result in hypotension, dry mouth, constipation and blurred vision.

(3) Endocrine system: increase the release of prolactin and decrease corticotropin release and secretion of pituitary growth hormone.

Thioxanthenes- Flupenthixol, Thiothixene

Chlorprothixene: mild antipsychotic action, and antianxiety and antidepressant action.

Butyrophenones

Haloperidol: control psychomotor excitement potent antipsychotic, longer t1/2- 24hrs

lesser incidence of autonomic S/E than CPZDOC- Gilles de la tourette’s syndrome, huntington’s

chorea Adverse effects: severe extrapyramidal symptoms.

[Drug dose]

Eff

ect

Phenothiazine

Thioxanthene

Butyrophenone

Antipsychotic/Neuroleptics

Atypical antipsychotics

Unique receptor affinityClozapine: D4 = 1>5-HT2 = M>D2 = D1 = 2;H1, low incidence of

EPS, low sedation, no gynacomastia

Quetiapine: 5-HT2 = D2 = 1 = 2; H1drowsiness and postural

hypotension

Risperidone: 5-HT2 >>1 >H1 >D2 >2>>D1

Aripiprazole-partial agonist at D2 and 5-HT1A 5HT2A agonist- called as DA:5HT stabiliser in CNS Has long t1/2 of 3 days

Atypical antipsychotics

Sertindole –long plasma T1/2 Asenapine –sub lingually Effective negetive > positive symptoms Effective in patients refractory to typical neuroleptics Less liability to cause EPS low affinity for D1 and D2

receptors Antagonists at 1, m, H1, D2

Pharmacokinetics

Most antipsychotics are readily but incompletely absorbed.

Significant first-pass metabolism. Bioavailability is 25-65%. Most are highly lipid soluble. Most are highly protein bound (92-98%). High volumes of distribution (>7 L/Kg). Slow elimination. Duration of action longer than expected, metabolites

are present and relapse occurs, weeks after discontinuation of drug.

Therapeutic uses

Treatment of psychotic disorders: schizophrenia, Schizo affective disorders -mania, paranoid states,

alcoholic hallucinosis. Drug induced psychosis Anesthesia in hypothermia and artificial hibernation

(used with pethidine and promethazine). Nausea , Vomiting-CPZ Tourettes syndrome Huntingtons disease Preanaesthetic medication Intractable hiccups -CPZ

Adverse effects

Behavioural Effects (pseudodepression, akinesia, confusion)

Neurological Effects (Parkinsonism, Akathisia, Dystonia, Tardive Dyskinesia)-

Tardive dyskinesia comprises mainly involuntary movements of face and tongue, but also of trunk and limbs, appearing after months or years of antipsychotic treatment. It may be associated with proliferation of dopamine receptors (possibly presynaptic) in corpus striatum.

Adverse effects

c) Autonomic Effects (orthostatic hypotension, impaired ejaculation)

d) Metabolic and Endocrine Effects (weight gain, hyperprolactinemia, loss of libedo, impotence)

e) Toxic or allergic effects (agranulocytosis, choleostatic jaundice- clozapine)

Adverse effects

f) Ocular complications (thioridazine only)

g) Cardiac toxicity (Thioridazine T wave abnormality)

h) Neuroleptic Malignant Syndrome (life threatening, marked muscle rigidity, sweating, fever, autonomic instability, blood pressure, heart rate, muscle breakdown, CV collapse, arrhythmias mortality

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