antipsychotic drugs

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Antipsychotic drugs. Anti-psychotic drugs. The CNS functionally is the most complex part of the body, and understanding drug effects is difficult Understanding the effects of drugs on neurones does not predict the effect on the whole organ - PowerPoint PPT Presentation

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  • Antipsychotic drugs

  • Anti-psychotic drugsThe CNS functionally is the most complex part of the body, and understanding drug effects is difficultUnderstanding the effects of drugs on neurones does not predict the effect on the whole organIn part this is due to complex interactions mediated by different neurotransmitters

  • DopamineImportant neurotransmitterPresent mainly in the nigrostriatal pathwayThere are two main types of dopamine receptor: D1 and D2 . These stimulate and inhibit adenylate cyclase respectively. D2 receptors are mainly responsible for the actions of anti-psychotic drugs

  • Dopamine - functionsMotor control - nigrostriatal system. Deficiency results in rigidity, tremor and difficulty initiating movementBehavioral effects - mesolimbic system. Overactivity in rats leads to abnormal behaviorEndocrine control - tubero-infundibular system. Dopamine and dopamine agonists suppress prolactin release, dopamine antagonists may stimulate it

  • Schizophrenia - Dopamine hypothesisAmphetamine can produce a syndrome similar to the positive features of schizophreniaLevodopa may aggravate the conditionApomorphine and bromocriptine (D2 agonists) produce behavioral abnormalities in animalsD2 receptor antagonists are effective in controlling the positive features of the disorder? Increased D2 receptor binding in the brains of schizophrenic subjects. Evidence of genetic variation in the D4 receptor to which some anti-psychotic drugs have high affinity

  • Anti-psychotic Drugs -5HT (serotonin)Some drugs also act at 5-HT receptors (antagonists of 5HT2)5-HT has a modulatory effect on dopaminergic neuronesLSD which has mixed agonist/antagonist actions produces hallucinations and behavioral disturbance

  • Anti-psychotic Drugs - Modes of ActionAll anti-psychotic drugs have inhibitory effects on the D2 receptorSome have actions against the D4 receptorAll have other effects - to varying degreesSerotonin blockade (may improve negative symptoms)Histamine H1 blockade (drowsiness)Alpha adrenoceptor blockade (postural hypotension)

  • How do we know they work?mostly accidentally for early drugs - designing drugs to reduce anxiety in surgical patientsclinical experience clinical trials - especially more recent drugsPET scanning showing blockade of central D2 receptors

  • Anti-psychotic Drugs - Clinical EffectsControl the positive features of the disease, but little effect on the negative features (clozapine may be superior in this regard)The main side-effects are on the extrapyramidal motor system - leading to rigidity, tremor, and loss of mobility and dyskinesiaTardive dyskinesia is a late onset disorder characterised by repetitive abnormal movements of face and upper limbs. This may be due to proliferation of D2 receptors in the striatum

  • Clinical Effects contNewer atypical anti-psychotic drugs are less inclined to produce these effects - possible due to their greater affinity for the mesolimbic over the striatal areas of the brain

  • Anti-psychotic Drugs - Other Effectssome are effective anti-emeticsanti-muscarinic effects lead to dry mouth, blurred vision, difficulty with micturition a antagonist effects lead to hypotensionantihistamine effects (H1 receptor) lead to drowsinessprolactin stimulation may lead to breast developmentagranulocytosis is fairly common with an atypical drug - clozapineNeuroleptic malignant syndrome is a rare but serious effect leading to autonomic instability and hyperthermia

  • Classification of anti-psychotic drugsclassical/ typicalchlopromazine (gen)haloperidol (gen)fluphenazine (gen)thioridazine (auth)note: classification is based on fewer EPS side-effects,fewer long-term ADRs, efficacy in treatment-resistant groups, negative symptomsatypicalclozapine (sec100)risperidone (auth)olanzapine (auth)quetiapine (auth)

  • newer drugs claims:lower dosesreduced side effectsmore effective (especially negative symptoms)better complianceevidence?trials have been quite small and involved patients previously heavily treated and somewhat resistanttrials have tended to show equivalent efficacy and better side effect profiles with newer drugshead to head trials claimed superiority of olanzapine over risperidone (but company sponsored and controversial); some parallel publicationscostsMuch higher with new drugs (10-40 times higher)

  • Final Slide - summary of the actions of different anti-psychotic drugs at different receptors

    SEE CHAPTER 37 RANG DALE AND RITTER5TH EDITION (NICE OVERVIEW)

    TABLE 37.1

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