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Lectures > Anti-psychotics > Flashcards

Anti-psychotics Flashcards

1
Q

Typical anti-psychotics

A

Chlorpromazine
Fluphenazine
Perphenazine
Haloperidol

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2
Q

Atypical anti-psychotics

A 
Amisulpride
Aripiprazole
Clozapine
Olanzapine
Quetiapine
Risperidone
Ziprasidone
Zotepine
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3
Q

Typicals - pharmacokinetics and side effects

A
  • well absorbed after parenteral or oral administration
  • metabolized in the liver
  • main differences are potency and adverse effect profile

Common adverse effects

  • anticholinergic –> dry mouth, blurred vision, urinary retention, constipation
  • sedation
  • orthostatic hypotension
  • tachycardia
  • extrapyramidal symptoms

Less expensive

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4
Q

Atypicals - pharmacokinetics and side effects

A
  • well absorbed after parenteral or oral administration
  • metabolized in liver
  • less adverse side effects (supposedly)

Common adverse side effects

  • less likely to have extrapyramidal symptoms
  • associated with weight gain, hyperglycemia, and diabetes
  • agranulocytosis (clozapine)
  • less worrisome = nausea, dizziness ,headache, hypotension

More expensive

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5
Q

Good and bad qualities of antipsychotics

A

Good

  • improve symptoms, help medical cost containment
  • hard to OD on
  • shallow dose response curve –> plasma level not that critical
  • no abuse by patients

Bad

  • not a cure, delayed effectiveness, common side effects
  • heterogeneity of diseases being treated
  • greatly variably bioavailability
  • compliance poor –> subjectively unpleasant
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6
Q

Mechanisms of antipsychotics - general

A

All current antipsychotic meds block dopamine receptors –> especially D2

4 major dopamine pathways

  1. nigrostrial –> movement pathway
  2. mesolimbic –> target for positive symptoms
    - –> increased DA = increased psychosis
    - –> decreased DA = decreased psychosis
  3. mesocortical –> related mood, source of negative symptoms
  4. tuberoinfundibular –> regulates prolactin secretion from the pituitary
  • Traditional antipsychotics block DA receptors
  • Atypicals block both DA and 5HT receptors –> are less “sticky” at the receptor
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7
Q

Mechanism of typicals

A

Typicals mimic dopamine = DA receptor antagonists
- effective at reducing positive symptoms due to blockade of D2 receptors specifically in the mesolimbic pathway

Patient responses

  • hallucinations, delusions, etc (positive symptoms) decline over 3-6 weeks
  • benefit 60-80% of patients

In addition to blocking D2, they block many other receptors –> different affinities for the various receptors leads to different efficacies and side efcects

  • block D2
  • block M1
  • block alpha1
  • block H1
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8
Q

Antipsychotics

  • efficacy
  • potency
A

Efficacy

  • all antipsychotics are considered equally effective –> rationale for determining which med to use is based on side effect profile
  • primary mechanism of action = post-synaptic blockade of the D2 receptor

Potency –> variable
- potency determines the predictable side effects of the antipsychotics

Low potency medications

  • sedation
  • anti-cholinergic
  • orthostatic htn

High potency
- extra-pyramidal symptoms (haloperidol has highest most specific potency for D2)

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9
Q

Side effects of H1 blockade

A
  • sedation
  • weight gain
  • hypotension

Potency for H1:
chlorpromazine>thioridazine>fluphenazine

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10
Q

Side effects of alpha 1 blockade

A
  • postural hypotension
  • reflex tachycardia
  • dizziness

Potency for alpha1:
chlorperazine>thioridazine>fluphenazine

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11
Q

Side effects of muscarinic blockade

A
  • blurred vision
  • dry mouth
  • tachycardia
  • constipation
  • urinary retention
  • memory dysfunction

Potency for muscarcinic receptors:
thioridazine>chlorpromazine

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12
Q

Haloperidol

A
  • high potency
  • lacks H1 and M1 block –> reduced side effects except for those caused by block of DA action in the other DA pathways
  • negative effects in tuberoinfundibular, mesocortical and nigrostriatal pathways
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13
Q

Tuberoinfundibular pathway

A

Controls prolactin secretion

  • blockade of D2 receptor = increased prolaction
  • hyperproactinemia
  • –> breast secretions
  • –> amenorrhea
  • –> infertility
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14
Q

Mesocortical pathway

A

Mediates negative and cognitive symptoms –> current thought is that negative symptoms are due to a deficit in DA in the mesocortical pathway, so D2 blockade ecxacerbates negative symptoms

Blockade of mesocortical pathways

  • emotional blunting
  • cognitive problems
  • mimic negative symptoms
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15
Q

Nigrostriatal pathway

A

Projects from the substantia nigra to the basal ganglia –> D2 blockade in this system responsible for EPS

  • component of extrapyrimadal nervous system
  • movement disorders referred to as extrapyramidal symptoms
  • blockade of post synaptic D2 receptors produces parkinsonian like movement disorders
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16
Q

Extrapyramidal symptoms

- DA vs. ach

A
  • dystonias (muscle cramps)
  • tremor - course parkinson like
  • akinisia - decreased movement
  • akathisia - motor restlessness, constant urge to move
  • tardive dyskinesia - may be permanent

EPS - DA vs. ach

  • in the basal ganglia, DA and Ach are in a delicate balance –> DA suppresses Ach activity
  • when DA is blocked, this system goes out of balance –> increased Ach release and activity –> increase in Ach is associated with EPS
  • blocking Ach with drugs that have anticholinergic side effects puts the system back in balance –> anticholinergic properties of typical antipsychotics help to overcome excess ach activity and thus reduce EPS –> does NOT relieve risk for tardive dyskinesia

Benefits of anti-muscarinic action

  • varying degrees of muscarinic blockade –> may explain why some typical antipsychotics have a greater propensity to produce EPS
  • drugs with a lower affinity for the muscarinic receptors will produce more EPS due to higher levels of Ach being present
17
Q

Nigrostriatal pathway

- tardive dyskinesia

A

Chronic blockade of D2 receptors in the nigrostriatal pathway results in a tardive dyskinesia = hyperkinetic movement disorder

  • characterized by repetitive, involuntary, purposeless movement
  • facial and tongue movements
  • quick, jerky choreiform limb movements

Chronic blockade of D2 receptors in the nigrostrial pathway causes an up regulation that may be irreversible

  • about 5% of patients maintained on typical antipsychotics will develop tardive dyskinesia every year
  • if blockade is removed early enough, may be reversed
18
Q

Dilemma of blocking D2

A

Ideally we want to…

  • decrease DA in the mesolimbic system (responsible for positive symptoms)
  • increase DA in the mesocortical pathway (responsible for negative symptoms)
  • leave DA along in the nigrostriatal pathway and tuberoinfundibular pathway
19
Q

Atypical antipsychotics

  • pharmacology
  • clinical perspective
A

Heterogeneous group of compounds with large differences in chemical structure

Pharmacology

  • serotonin and DA antagonists
  • occupy and block fewer D2 receptors –> 40-60% vs. >70-80% (typicals)
  • block a higher number (70-90%) of 5HT2a receptors

Clinical perspective

  • low EPS
  • effective for negative symptoms

In general, 5HT inhibits DA release from dopaminergic terminals, but degree of control differs from one pathway to the other

Nigrostriatal pathway and low EPS

  • in the nigrostriatal pathway, serotonin normally acts on 5HT2a receptors to inhibit DA release –> blocking the 5HT2a receptors results in an increase in endogenous DA release and activity
  • even though the drugs also bind to post synaptic D2 receptors, increased levels of endogenous DA released due to 5HT2a antagonism enable DA to overcome this block and act on their receptors = decreased EPS

Mesocortical pathway and improved negative symptoms

  • high density of 5HT2a in cerebral cortex –> antagonizing these receptors leads increase in endogenous DA release
  • increased endogenous DA out competes D2 antagonists
  • increased DA in this system = decreased negative symptoms
20
Q

Clozapine

A
  • first atypical
  • very few EPS
  • does not cause tardive dyskinesia
  • does not increase prolactin
  • patients report an “awakening”
  • may work when typical agents fail (30-40% of the time)
  • greatest efficacy but most side effects
21
Q

Clozapine - side effects

A
  • agranulocytosis –> occurs in .5-2% of patients = life threatening; mechanisms remain unclear
  • M1 anticholinergic –> dry mouth, constipation, blurred vision, drowsiness, memory impairment
  • alpha adrenergic –> low bp, dizziness
  • H1 antihistamine –> drowsiness, weight gain
  • 5HT2C blockers –> weight gain
22
Q

Risperidone

A
  • Positive and negative efficacy
  • mood stabilizer
  • decreased TD

Side effects

  • does related EPS
  • less is better
  • prolactin elevation
  • WEIGHT GAIN
23
Q

Olanzapine

A
  • positive and negative efficacy
  • mood stabilizer
  • decreased TD

Side effects

  • higher dose related EPS
  • slight prolactin elevation
  • big weight gain
  • diabetes
  • sedation
24
Q

Quetiapine

A
  • More is better
  • very low EPS
  • very low TD risk
  • some weight gain
  • sedating
  • dose titration to decrease dizziness
  • low dose may be useful in borderline disorder
25
Q

Ziprasidone

A
  • Newer antipsychotic
  • dose related EPS
  • NO WEIGHT GAIN!
  • very low DB risk!
  • higher dose often better than low
  • antidepressant activity
  • nausea, sleep disturbance
26
Q

Aripiprazole

A
  • D2 partial agonist
  • 5HT2A antagonist
  • appears to cause little or not weight gain, little EPS, little sedation, and little effect on heart function
27
Q

Zotepine

A
  • antagonist activity at DA and 5HT receptors
  • high affinity for the D1 and D2 receptors
  • affects the 5HT2a receptor
  • ALSO –> inhibits NE reuptake –> thought to underlie high efficacy for the negative symptoms of schizophrenia

side effects

  • weight gain
  • somnolence
  • constipation, asthenia, dry mouth, akathisia
28
Q

Neuroleptic malignant syndrome

A

An idiosyncratic, life threatening illness associated with anti-psychotic therapy
- usually within 30 days of new medication or dose increase

Clinical manifestations

  • hyperthermia/fever
  • autonomic instability –> increased HR, labile BP, rapid breathing, shortness of breath, sweating
  • muscle rigidity
  • tremor, myoclonus
  • confusion, stupor

Treatment

  • immediate discontinuation of anti-psychotic
  • hydration
  • maintain vital functions
  • prescribe bromocriptine and dantrolene

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