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Psychopharmacology: Anti-psychotic Medications

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Psychopharmacology: Anti-psychotic Medications Brian Ladds, M.D. Outline Role of dopamine in psychosis Dopamine pathways Dopamine receptors Anti-psychotic medication ... – PowerPoint PPT presentation

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Title: Psychopharmacology: Anti-psychotic Medications


1
Psychopharmacology Anti-psychotic Medications
  • Brian Ladds, M.D.

2
Outline
  • Role of dopamine in psychosis
  • Dopamine pathways
  • Dopamine receptors
  • Anti-psychotic medication
  • Mechanism of action
  • Classification
  • Side effects

3
Schizophrenia The Dopamine Hypothesis
  • Chance discovery
  • Chlorpromazine (Thorazine) reduced psychosis
  • It was found to block the effects of dopamine
  • The dopamine hypothesis posits that the
    development of schizophrenia involves an
    overactive dopamine system in the brain

4
Dopamine
  • One of the key neurotransmitters in the brain,
    together with
  • other monoamine neurotransmitters
  • norepinephrine, serotonin, acetylcholine
  • and the commonest neurotransmitters
  • glutamate, GABA
  • Dopamine is released by a relatively small number
    of neurons, but serves important regulatory
    functions

5
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6
Dopamine Pathways
  • Several different dopamine pathways
  • all originate in the mid-brain
  • 2 of the main clusters of nuclei are
  • Ventral Tegmental Area (VTA)
  • meso-limbic/meso-cortical pathway
  • Substantia nigra
  • nigro-striatal pathway

7
Dopamine Pathways
  • VTA (ventral tegmental area)
  • Mesolimbic mesocortical pathways
  • projects to limbic system and to the pre-frontal
    cortex
  • primary path for production of psychosis
  • target for anti-psychotic medications
  • blockade of the post-synaptic dopamine receptors

8
Dopamine Pathways
  • Substantia nigra
  • Nigro-striatal pathway
  • projects to the striatum (caudate and putamen)
  • anti-psychotic medications block the
    post-synaptic dopamine receptor in the striatum
    causing motoric side effects (e.g., rigidity and
    tremors)

9
Dopamine Pathways
  • Arcuate and peri-ventricular nuclei
  • Tubero-infindibular pathway
  • project to the pituitary
  • inhibits prolactin release
  • some anti-psychotic medications cause increased
    prolactin release (by blocking dopamine) and
    cause galactorrhea

10
Dopamine Receptors
  • D-2 receptors
  • main site of action for the anti-psychotic effect
    of many medications
  • clinical potency for many of the older
    conventional anti-psychotic medications
    correlates with their affinity for the
    post-synaptic D-2 receptor

11
Dopamine Receptors
  • D-3 and D4 receptors
  • May also be involved in the actions of some of
    the newer atypical anti-psychotic medications
  • These receptors are present more in limbic areas
    than in striatum
  • Therefore there are less motoric side effects
    with the newer atypical medications

12
Anti-psychotic Medication Mechanism of Action
  • Anti-psychotic medications all involve blockade
    of the post-synaptic D-2 dopamine receptor
  • The therapeutic actions of the newer atypical
    anti-psychotic medications
  • May also involve blockade of other types of
    dopamine receptors, and,
  • blockade of certain post-synaptic serotonin
    receptors

13
Anti-psychotic Medication Classification
  • Conventional (typical) medications
  • vs. atypical anti-psychotic medications
  • Affinity for the D-2 receptor is related to
    clinical potency (especially for the conventional
    meds)
  • high affinity -gt low dose
  • e.g., haloperidol (Haldol), fluphenazine
    (Prolixen)
  • low affinity -gt high dose
  • e.g., chlorpromazine (Thorazine), thioridazine
    (Mellaril)

14
Side Effects
  • Low potency anti-psychotic medication (e.g.,
    chlorpromazine) cause more of the non-motoric
    side effects
  • sedation (H-1 blockade)
  • hypotension (alpha-adrenergic blockade)
  • anti-cholinergic

15
Anti-cholinergic Side Effects
  • Blurred vision
  • Urinary retention
  • Constipation
  • Dry mouth
  • (Confusion)

16
Side Effects
  • High potency anti-psychotic medication (e.g.,
    haloperidol) cause more of the neurological and
    motoric side effects
  • EPS
  • TD
  • NMS

17
Extra-pyramidal Symptoms
  • Parkinsonian-like symptoms
  • Parkinsons Disease too little dopamine
  • due to degeneration of dopaminergic neurons
  • bradykinesia
  • rigidity
  • shuffling gait
  • tremor

18
EPS cont.
  • Dystonia sudden spasms of head/neck muscles
  • Akathisia restlessness
  • subjective and/or objective

19
EPS Causes and Treatment
  • Nigro-striatal pathway finely regulates
    initiation and coordination of movements
  • DA inhibits acetycholine release in the striatum
  • Anti-psychotic medications block DA in striatum
    causing too much Ach there and thus EPS

20
EPS Treatment
  • Treatment with anti-cholinergic medication
    decreases EPS
  • benztropine (Cogentin)
  • diphenhydramine (Benadryl)

21
Tardive Dyskinesia
  • Involuntary choreo-athetoid movements of mouth,
    tongue, and other muscles
  • generally irreversible
  • after chronic use (gt 3 months) of anti-psychotic
  • 10-20 of patients on conventional AP after 1
    year get TD
  • usually mild, but can be severe
  • elderly and women at highest risk
  • etiology upregulation of striatal D-2 receptor

22
Neuroleptic Malignant Syndrome
  • NMS
  • fever
  • muscular rigidity
  • autonomic instability
  • tachycardia
  • increased blood pressure
  • fluctuating levels of consciousness
  • Rare, but has 20 mortality
  • Males and younger people are at higher risk

23
Atypical Anti-psychotic Meds
  • Clozapine (Clozaril)
  • Risperidone (Risperidal)
  • Olanzapine (Zyprexa)
  • Quetiapine (Seroquel)
  • Ziprasidone (Geodon)

24
Atypical Anti-psychotic Meds
  • Efficacy
  • Generally comparable to conventional meds
  • May have some superior effects
  • Clozapine helps where conventional meds fail
  • They may help more with negative symptoms
  • Side effect profile
  • Superior to conventional meds
  • Little EPS, less TD, less sedation, less
    anti-cholinergic
  • Some may cause EKG changes, weight gain, or
    increase in serum glucose

25
Atypical Anti-psychotic Meds
  • May have different mechanism of action
  • ? more DA blockade in mesolimbic pathway
  • including more D-3 and D-4 ?
  • ? weak D-2 antagonists, esp. in striatum
  • Minimal EPS
  • ?? Increases DA in frontal cortex ??
  • ? Improves negative symptoms

26
Clozapine
  • Clozapine
  • agranulocytosis 1
  • weekly cbc tests
  • approved only for treatment-refractory
    schizophrenia seizure risk 3-5, dose-dependant
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