7/23/2019 Antipsicóticos - Resumo

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Antipsychotics (neuroleptics)

The dopamine hypothesis of psychosis:•   Psychotic symptoms result from ! dopamine neurotransmission• Dopamine receptors:

o D1-like:! D1 and D5

! Are post-synaptic! Stimulate adenylate cyclase and ! cAMP

o   D2-like:! D2, D3 and D4

! Are both pre- and post-synaptic!   Inhibit adenylate cyclase and " cAMP

• Dopaminergic pathways:o   Mesolimbic / mesocortical:

! Concerned with mood and emotional stability! Ventral tegmental area:

• Ventral striatum and the frontal cortexo Nigrostriatal:

! Concerned with movement! Substantia nigra and the dorsal striatum

• Neuroleptics block D2 receptors:o Explains why they cause movement disorders as a side effect

Clinical classification of neuroleptics:• Typical:

o Produce extrapyramidal symptoms (EPS)• Atypical:

o So-called because they have a low incidence of EPSo However, all apart from clozapine can cause EPS at high doses

Chemical classification of neuroleptics:• Typical:

o   Phenothiazines:! Propylamines (chlorpromazine):

• Sedation ++• Anticholinergic ++• EPS ++

! Piperidines (thioridazine):• Sedation ++• Anticholinergic ++• EPS +• Can cause torsade de pointes

! Piperazines (fluphenazine):• Sedation +• Anticholinergic +• EPS +++

o   Thioxanthines (flupenthixole):! Sedation +

 

! Anticholinergic +! EPS ++

o   Butyrophenones (haloperidol):! Sedation -! Anticholinergic -! EPS +++

• Atypical:o  “True”:

!   Clozapine:• Sedation ++• Anticholinergic +• EPS -

o  “Apparent”:!   Sulpiride:

• Sedation +• Anticholinergic –• EPS +

!   Risperidone:• Sedation ++• Anticholinergic +• EPS +

General effects of the neuroleptics:• Early (hours):

o   Desired:! Sedation (histamine / #-receptor blockade)! Tranquilisation (dopamine blockade)

o   Unwanted:! Acute dystonic reactions

• Medium (days–weeks):o   Desired:

! Suppression of:• Delusions• Disordered thinking• Hallucinations

o   Unwanted:! Akathisia! Parkinsonism

• Late (months–years):o   Desired:

! Prevention of relapseo   Unwanted:

!  Tardive dyskinesia• Any time:

o   Neuroleptic malignant syndromeChlorpromazine:

• Indications:o   Psychotic disorders (e.g. schizophrenia / mania)o Labyrinthine disorders / vertigo

 

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o Nausea / vomitingo   Chronic hiccups

• Adverse effects:o   Common:

!   Sedation!   Anticholinergic effects:

• Blurred vision• Dry mouth• Postural hypotension• Constipation• Urinary retention

!   Extrapyramidal effects:• Acute dystonia• Akathisia• Parkinsonism• Tardive dyskinesia

!   Hyperprolactinaemia:• Amenorrhoea• Galactorrhoea• Impotence

o Uncommon:! Neuroleptic malignant syndrome! Agranulocytosis!   Cholestatic  jaundice

•

Interactions:o ACE inhibitors:

! Can cause severe hypotension

Haloperidol:• Indications:

o   Psychosiso   Motor tics

• Adverse effects:o Common:

!   Extrapyramidal effects:• Acute dystonia• Akathisia• Parkinsonism

!   Postural hypotensiono Uncommon:

! Convulsions! Neuroleptic malignant syndrome! Tardive dyskinesia! Weight loss

• Interactions:o Amiodarone:

!   ! risk of ventricular arrhythmiaso Carbamazepine:

!   " plasma levels of haloperidol (metabolism accelerated)

 

o Fluoxetine:!   ! plasma levels of haloperidol

Clozapine:• Regarded by many as the only “true” atypical neuroleptic:

o   EPS is not evident even at high doseso   Effective in patients refractory to other neurolepticso Can treat the negative symptoms of schizophrenia

• Mechanism of action:o   Blocks D4 and 5-HT2 receptorso Weak blockade of striatal D2 receptors

• Adverse effects:o   Agranulocytosis (requires regular blood monitoring)o Myocarditis / cardiomyopathyo Ileus

• Contraindications:o Severe cardiac disorderso History of neutropenia / agranulocytosis

• Interactions:o Avoid concomitant use with drugs that have a high risk of

causing agranulocytosis (e.g. carbimazole)