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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 ... – PowerPoint PPT presentation

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Title: Antipsychotic drugs


1
Antipsychotic drugs
2
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
  • In part this is due to complex interactions
    mediated by different neurotransmitters

3
Dopamine
  • Important neurotransmitter
  • Present mainly in the nigrostriatal pathway
  • There 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

4
Dopamine - functions
  • Motor control - nigrostriatal system. Deficiency
    results in rigidity, tremor and difficulty
    initiating movement
  • Behavioral effects - mesolimbic system.
    Overactivity in rats leads to abnormal behavior
  • Endocrine control - tubero-infundibular system.
    Dopamine and dopamine agonists suppress prolactin
    release, dopamine antagonists may stimulate it

5
Schizophrenia - Dopamine hypothesis
  • Amphetamine can produce a syndrome similar to the
    positive features of schizophrenia
  • Levodopa may aggravate the condition
  • Apomorphine and bromocriptine (D2 agonists)
    produce behavioral abnormalities in animals
  • D2 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

6
Anti-psychotic Drugs -5HT (serotonin)
  • Some drugs also act at 5-HT receptors
    (antagonists of 5HT2)
  • 5-HT has a modulatory effect on dopaminergic
    neurones
  • LSD which has mixed agonist/antagonist actions
    produces hallucinations and behavioral
    disturbance

7
Anti-psychotic Drugs - Modes of Action
  • All anti-psychotic drugs have inhibitory effects
    on the D2 receptor
  • Some have actions against the D4 receptor
  • All have other effects - to varying degrees
  • Serotonin blockade (may improve negative
    symptoms)
  • Histamine H1 blockade (drowsiness)
  • Alpha adrenoceptor blockade (postural hypotension)

8
How do we know they work?
  • mostly accidentally for early drugs - designing
    drugs to reduce anxiety in surgical patients
  • clinical experience
  • clinical trials - especially more recent drugs
  • PET scanning showing blockade of central D2
    receptors

9
Anti-psychotic Drugs - Clinical Effects
  • Control 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 dyskinesia
  • Tardive 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

10
Clinical Effects cont
  • Newer 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

11
Anti-psychotic Drugs - Other Effects
  • some are effective anti-emetics
  • anti-muscarinic effects lead to dry mouth,
    blurred vision, difficulty with micturition
  • a antagonist effects lead to hypotension
  • antihistamine effects (H1 receptor) lead to
    drowsiness
  • prolactin stimulation may lead to breast
    development
  • agranulocytosis is fairly common with an
    atypical drug - clozapine
  • Neuroleptic malignant syndrome is a rare but
    serious effect leading to autonomic instability
    and hyperthermia

12
Classification of anti-psychotic drugs
  • classical/ typical
  • chlopromazine (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 symptoms
  • atypical
  • clozapine (sec100)
  • risperidone (auth)
  • olanzapine (auth)
  • quetiapine (auth)

13
newer drugs
  • claims
  • lower doses
  • reduced side effects
  • more effective (especially negative symptoms)
  • better compliance
  • evidence?
  • trials have been quite small and involved
    patients previously heavily treated and somewhat
    resistant
  • trials have tended to show equivalent efficacy
    and better side effect profiles with newer drugs
  • head to head trials claimed superiority of
    olanzapine over risperidone (but company
    sponsored and controversial) some parallel
    publications
  • costs
  • Much higher with new drugs (10-40 times higher)

14
Final Slide - summary of the actions of
different anti-psychotic drugs at different
receptors SEE CHAPTER 37 RANG DALE AND
RITTER 5TH EDITION (NICE OVERVIEW) TABLE 37.1
15
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