anti psychotic drugs-02

8/6/2019 Anti Psychotic Drugs-02

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Anti Psychotic Drugs( Neuroleptic Drugs)


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Nature of schizophreniaNature of schizophrenia

Positive symptoms - Delusions,Hallucinations,

Thought disorder.

Negative symptoms - Social withdrawal,Flattening of emotions,

Dementia.

Acute episodes (Mainly positive symptoms) Chroniccases (Mostly negative symptoms)


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Pathophysiology ofPathophysiology of

schizophreniaschizophrenia

Unopposed dopamine activity or

dopamine overactivity at D2 receptorsin limbic system & neocortex - positive

symptoms.

5HT overactivity at 5HT2A receptors in

limbic system - negative symptoms.


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Mechanism of AntipsychoticMechanism of Antipsychotic

DrugsDrugs Mejority block D2 receptors in limbic

system & neocortex.

Risperidone, Clozapine, Olanzapine,Quetiapine, Sertindole & Amisulpride block

both D2/ D2 like & 5HT2A receptors.

(D2 like receptors: D3 , D4)


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Classification of Antipsychotic agentsClassification of Antipsychotic agentsPhenothiazines:

Aliphatic: Chlorpromazine, Triflupromazine. Piperidine: Thioridazine, Mesoridazine.

Piperazine: Trifluperazine, Fluphenazine,

Thioxanthines: Chlorprothixene, Thiothixene, Flupenthixol.

Butyrophenones: Haloperidol, Droperidol.

Dibenzodiazepines: Clozapine, Olanzapine, Quetiapine

Benzisoxazole: Risperidone

Benzamides: Amisulpride, Remoxipride, Sulpiride,

Flurophenylindone: Sertindole

Miscellaneous agents:

Dibenzoxazepines: Loxapine.

Diphenylbutylpiperidines:Pimozide, Penfluridol.

Dihydroindolones: Molindone, Oxypertine, Ziprasidone


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Pharmacological ActionsPharmacological Actions

Actions due toActions due to dopamineantagonismdopamineantagonism

Blocks both pre & post synoptic D2 receptors .

Dopeminergic systems in CNS:

Mesolimbic-mesocortical pathway:SN - LS & NC Nigrostriatal pathway: SN - Corpus striatum,

CTZ of medulla,

Tuberoinfundibular pathway,

Medullary-periventricular pathway

*So antipsychotics have Selective CNS effects.


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Sites of action of antipsychoticsSites of action of antipsychotics


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Behavioral effectsBehavioral effectsAre due to blockade of D2receptors in LS & NC

Produce Tranquility without clouding ofconsciousness -- detached serenity

Initially there may be some slowness in responseto external stimuli & drowsiness - but subjects are

easily aroused, can answer direct questions Retain intact intellectual functions

Ataxia, incoordination, dysarthria do not occur

Psychotic patients:

Soon become less agitated withdrawn patientsbecome more responsive & communicative.

Aggressive & impulsive behavior diminishes.

Gradually hallucinations, delusions, disorganized

incoherent thinking tend to disappear.


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Extrapyramidal motorExtrapyramidal motor

disturbancesdisturbancesAre due to blockade of D2receptors in

corpus striatum.

Early reactions: Dystonia,Parkinsonism,

Akathisia

Treatment: Centrally acting anticholinergicslike benztropine.


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Extrapyramidal motorExtrapyramidal motor

disturbancesdisturbances Late reactionsi) Tardive dyskinesia is due to

supersensitivity of dopamine receptors.

No effective treatment.

Prevention: Prescribe at lowest doses possible.

Observe drug free holidays.

Avoid prescribing anticholinergics.

ii) Neuroleptic malignant syndrome

Treatment: Stop drug, administer dantrolene &

Dopamine agonists like bromocriptine.


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Why atypical antipsychotics doWhy atypical antipsychotics do

not cause extrapyramidal motornot cause extrapyramidal motordisturbancesdisturbances

Combined D2 /D2 like & 5HT2A blockadeproduces antipsychotic response with

reduced incidence of extrapyramidal effects

The serotonin system inhibits dopaminesystem in the nigrostriatal circuit. (nigro-

striatal circuit is under inhibition fromendogenous 5 HT & the administered D2blocking antipsychotics)


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Other actions due toOther actions due to

dopamine blockadedopamine blockadeAnti-emetic activity: is due to blockade of

Dopamine receptors in CTZ.

Endocrine effects: Hyper prolactinemia due toblockade of D

2receptors in anteriorpituitary

- Dopamine is an hypothalamic hormone, which

inhibits prolactin secretion.

Inhibit secretion of gondotropins, growth

hormone.Effect on eating behavior: Increased

appetite and weight gain are due to inhibitory

effect on medullary-periventricularpath way.


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ActionsActions unrelatedtodopamineunrelatedtodopamine

antagonismantagonism Phenothiazines and to a variable extent,other

antipsychotics, block the actions ofAcetylcholine (muscarinic), Histamine (H1),

Noradrenaline (alpha) and 5HT(5HT2A ).a) Antimuscarinic effects:

More common with Piperidine group ofphenothiazines.

Less potent antipsychotics have moreantimuscarinic effects --As antimuscariniceffect increases, extrapyramidal side effectsdecreases.


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antagonismantagonism

b) Antiadrenergic effects: As antipsychotic potency decreases, intensity

of antiadrenergic effects increases.

Orthostatic hypotensive and sedative effectsare more with less potent antipsychotics

c) Antihistamine effects

Commonly seen with phenothiazines.

Contributes sedative and anti-emetic property.d) Anti 5HT effects: Clozapine and Risperidone

5HT2A antagonism, controls negativesymptoms of schizophrenia.


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antagonismantagonism

e) Poikilothermic effects:

Phenothiazines

Depends on dose and environment.

f) Seizure threshold: Decreased by lowpotency drugs.


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Adverse effectsAdverse effects

Acute toxicity is not a problem, doses up to100 times the therapeutic dose are non-fatal.

Therapeutic-index is >100.

Most of the unwanted effects are extensions

of their pharmacological actions.a) Behavioral effects: Pseudodepression,

Sedation,Toxic-confusional states.

b) Extrapyramidal reactions: Parkinsonism,

Dystonia, Akathisia,

Perioral tremor, Tardive dyskinesia,

Neuroleptic malignant syndrome.


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Adverse effectsAdverse effectsc) Autonomic effects:

Anti adrenergic effects: Postural hypotension,Inhibition of ejaculation.

Anti muscarinic effects: Blurring of vision, drynessof mouth, constipation, urinary retention etc.

d) Allergic & Idiosyncratic effects:Cholestatic jaundice, Photosensitivity reactions

e) Neuroendocrine effects: Hyperprolactinemia,

Galactorrhea, Breast engorgement, Sexual

dysfunction, Weight gain & Increased appetite.

f) Agranulocytosis. g) Seizures.

h) Pigmentary keratopathy. i) Cardiac toxicity,

j) Drug interactions:


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PharmacokineticsPharmacokinetics Readily but incompletely absorbed.

Undergo significant first-pass metabolism.

Large volume of distribution >500L becausethey are sequestrated in body lipids.

Highly lipid-soluble & protein-bound(92-99%). Almost all completely metabolized.

The less potent drugs weakly induce theirown metabolism.

Plasma half-lives vary from 10 to 24 hours. Biological half- life persist for at least 24

hours. Usually given as a single dose.

Repository preparations absorbed and

eliminated more slowly.


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Clinical potency of antipsychoticsClinical potency of antipsychotics

Low potency drugs Chlorpromazine, 100 mg

Triflupromazine,

Thioridazine etc.

Quetiapine (150 mg)

Clozapine (50 mg )Medium potency drugs Piperacetazine, 10 mg

Loxapine, Molindone.

Medium-High potency drugs Olanzapine 5 mg

Trifluperazine Risperidone

Sertindole (4 mg )

High potency drugs Fluphenazine, 2 mg

Haloperidol, Thiothixene.


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As the potency increases:As the potency increases: Sedative action, Toxic confusional states,

Autonomic adverse effects, tendency to

produce seizures, Allergic & Idiosyncraticeffects and Agranulocytosis will decrease.

Extrapyramidal toxicity and

hyperprolactinemia will increase.

Elderly people can tolerate better


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Repository preparationsR

epository preparations Fluphenazine decanoate,

Fluphenazine enanthate,

Haloperidol decanoate.

Absorbed and eliminated more slowly. Can be given once in 2-4 weeks.


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Therapeutic usesTherapeutic uses

Psychiatric indications:Psychiatric indications: Schizophrenia,

Mania,

Schizoaffective disorders,

The paranoia's,

Delirium with agitation,

Disturbed behavior in senile dementia,

Tourette`s syndrome,

Huntington`s disease Dysmorphophobias and monosymptamatic

hypochondriacal psychosis

Alcoholic hallucinations.


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T

herapeutic usesT

herapeutic usesNonpsychiatric indicationsNonpsychiatric indications::

Nausea and Vomiting Intractable hiccups,

Neuroleptanalgesia,

Pruritus.


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Chlorpromazine ( CPZ )Chlorpromazine ( CPZ )

less potent antipsychotic,

has effects on various receptors,

sedation, autonomic adverse effects are more,

extrapyramidal adverse effects are less, may impairs glucose tolerance,

poikilothermic effect is more predominant,

not preferred in elderly and in the treatment ofdelirium and dementia.


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Haloperidal

Haloperidal

More potent antipsychotic (50 times more

potent than CPZ ),

sedation and autonomic adverse effects are

less, extrapyramidal adverse effects are more,

no poikilothermic effect,

Preferred in elderly and in the treatment ofdelirium and dementia.


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anti psychotic drugs-02

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