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66 Cards in this Set
- Front
- Back
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What is the overall prevalence of schizophrenia?
In identical twins, if one twin has schizophrenia, what is the chance the other twin will have it? |
1% of general population
50% chance other twin will have it |
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What are the positive symptoms of schizophrenia?
Negative?
Cognitive? |
Positive: - disorganized thought & behavior - delusions - hallucinations
Negative: - affective - flattening - alogia (poverty of speech) - avolition
Cognitive: - impaired attention, memory, and executive function |
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What is alogia? |
poverty of speech |
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What group of symptoms are hardest to treat in schizophrenia? |
cognitive |
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What neurotransmitters play a role in schizophrenia? |
1. Dopamine 2. Seratonin 3. Glutamine |
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T/F Schizophrenia is caused by excessive dopaminergic activity in the brain. |
False.
Dopaminergic activity is "out of tune", not necessarily too much or too little |
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What are the major dopaminergic pathways in schizophrenia?
What is their relative DA activity in schizophrenia?
What classes of symptoms are they responsible for? |
1. Nigrostriatal pathway - involved in movement - DA normal - movement SE in schiz treatment
2. Mesolimbic - DA too high - positive symptoms
3. Mesocortical - DA too low - neg. & cog symptoms
4. Tuberoinfundibular - DA normal - SE of schiz treatment is prolactin secretion |
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What receptors do atypical antipsychotics effect? |
5HT2a > D2 antagonism |
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What is the serotonin hypothesis of schizophrenia? |
LSD & mescaline are 5HT agonist and mimic some symptoms of schizophrenia
- 5HT2a receptors modulate release of DA in cortex, limbic, & striatum
- 5HT2c receptors modulate DA activity |
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How do atypical antipsychotics impact 5HT2a receptors? |
inverse agonists - they act like antagonists |
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What is the evidence of the glutamate hypothesis of schizophrenia?
Do current drugs directly impact glutamate receptors? |
NMDA antagonists (i.e. PCP) are thought to closely mimic aspects of schizophrenia in some of the pos, neg, & cog symptoms → thought that defects of hypofunction of NMDA/GLU receptors might contribute to schizophrenia
- not thought that current drugs affect GLU receptors, but they may have indirect effects |
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What are the three (4) chemical families of typical antipsychotic agents? |
1. Phenothiazine Derivatives
2. Thioxanthene Derivatives
3. Butyrophenone Derivatives
4. Miscellaneous Structures |
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What are the subfamilies (and their example) of Phenothiazine Derivative typical antipsychotics?
Which is most potent?
Which have more side effects? |
1. Aliphatic (chlorpromazine) 2. Piperidine (thioridazine) 3. Piperazine (perphenazine)
most potent: piperizine
more SE: less potent → need higher dose so gen. more SE more potent = more D2 side effects |
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What is the example of a Thioxanthene Derivative typical antipsychotic?
What is its relative potency? |
thiothixene
- high potency |
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What is the example of a Butyrophenone Derivative typical antipsychotic?
How does it compate to phenothiazines?
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haloperidol
- a really good D2 antagonist, but lots of EPS |
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What is the most widely used typical antipsychotic drug? |
haloperidol |
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What are the examples of a Miscellaneous Structure typical antipsychotic?
What Derivative group is it closely related to?
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pimozide, molindone
related to Butyrophenone Derivatives |
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What anti-psychotic is only on label use is for Tourette's?
Why are its uses limited? |
pimozide, and only for refractory
limited by concerns of impact on the heart (QTC) |
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What are the examples of atypical anti-psychotics? |
Lozapine Clozapine Risperidone Quetiapine Olanzapine Ziprasidone Aripiprazole |
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Which atypical anti-psychotic has a metabolite that is a good D2 antagonist so SE profile is similar to typicals? |
Loxapine |
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Which atypical is an active metabolite of another (which?) atypical? |
Paliperidone (9-hydroxyrisperidone) is metabolite of Risperidone |
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What percentage of patients are poor metabolizers of Risperidone? |
10% |
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What is the moa of Aripiprazole? |
D2 partial agonist |
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What are the DA receptor families? |
D1 family - D1 & D2
D2 family - D2, D3, D4 |
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What DA receptor types are involved in cAMP production? |
D1 stimulates cAMP production
D2 inhibits cAMP production |
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What DA receptor types are found both pre- and post- synaptically? |
D2 & D3 |
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What DA receptor types activate PLC-IPS Ca pathway and K channels? |
D2 |
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T/F:
Binding affinity to D2 but not D1 is very strongly correlated with antipsychotic and extrapyramidal potency. |
True
There is no real correlation b/t potency and ability to bind D1 receptors, but there is for D2 receptors ---- this is evidence that although the drugs can have D1 signaling, it's thought that D2 is important for ability to relieve positive symptoms and to cause certain side effects |
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Do D1 selective antagonists act as effective antipsychotics? |
probably not |
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Are actions at D3 or D4 receptors thought to be important for schizophrenia / anti-psychotic actions? |
Though drugs may impact, they are not effective areas of treatment
-- D2 is really the only DA receptor we are concerned with |
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What are the _______ of the Nigrostriatal Tract?
- origin - innervation - function - Dopamine antagonist effect |
Origin: substantia nigra (A9 area)
Innervation: caudate nucleus Putamen
Function: movement, extrapyramidal system
DA antagonist effects: movement disorders |
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What are the _______ of the Mesolimbic Tract?
- origin - innervation - function - Dopamine antagonist effect |
Origin: Midbrain ventral tegmentum (A10 area)
Innervation: Limbic areas
Function: arousal, memory, motivation
DA antagonist effects: relief of psychosis (pos. symptoms) |
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What are the _______ of the Mesocortical Tract?
- origin - innervation - function - Dopamine antagonist effect |
Origin: Midbrain ventral tegmentum (A10 area)
Innervation: Frontal and prefrontal lobe cortex
Function: cognition, communication, social fx, stress response
DA antagonist effects: aggrevates neg & cog symptoms |
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What are the _______ of the Tuberoinfundibular Tract?
- origin - innervation - function - Dopamine antagonist effect |
Origin: Hypothalamus
Innervation: Pituitary gland
Function: Regulates prolactin release
DA antagonist effects: Increased prolactin concentrations |
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In summary, what are the D2 antagonist effects on:
- nigrostriatal pathway?
- mesolumbic pathway?
- mesocortical pathway?
- tuberoinfundibular tract? |
- nigrostriatal = EPS
- mesolumbic = relief of psychosis (pos symptoms)
- mesocortical = ↑ in negative symptoms
- tuberoinfundibular = ↑ prolactin levels |
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Explain how % occupancy of D2 receptors relates to treatment and side effects
How is aripiprazole different? |
> 78% occupancy runs risk for EPS
Typicals must achieve 60-75% occupancy to treat - atypicals may be on low end of that range
Aripiprazole has high occupancy of D2 receptors, but as a partial-agonist, does not cause EPS and 5HT2a antagonist, 5HT1a partial-agonist reduces SE profile |
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How does the addition of Aripiprazole affect the DA response curve of DA antagonists? |
As a partial agonist, aripiprazole maxes at about 20% of max response. When administered with a D2 antagonist, it blocks part of the response to the full antagonist. |
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Do 5HT impacts in the mesolimbic seem to be stronger or less strong than in other tracts? |
5HT impacts in the mesolimbic seem to be less strong than in other tracts |
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What is the function of DA in the tuberoinfundibular pathway?
What is the effect of a D2 antagonist? |
Function of DA is to block prolactin release
D2 antagonist will block DA binding and raise prolactin levels → hyperprolactemia |
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What is the function of 5HT in the tuberoinfundibular pathway?
What is the effect of a 5HT2a antagonist?
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5HT binding to the 5HT2a receptor promotes prolactin production and release
5HT2a antagonist will prevent the increase in prolactin
****This is why it is thought that atypicals treat positive symptoms w/o causing EPS & hyperprolactemia |
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What is the moa and results of anti-psychotics in the Autonomic nervous system? (2) |
Muscarinic cholinoceptor blockade → loss of accommodation, dry mouth, difficulty urinating, constipation
α-Adrenergic blockade → orthostatic hypotension, impotence, failure to ejaculate
Most prominaent with low-potency phenothiazines (chlorpromazine), clozapine
Esp. concerning for elderly (poss. due to exacerbation of low Ach activity) |
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What is the moa and results of anti-psychotics in the Central nervous system? (4) |
Dopamine-receptor blockade → Parkinson's syndrome, dystonias
Supersensitivity of DA receptors → Tardive Dyskinesia
Muscarinic Blockade → toxic- confusional state
Unknown → Akathisia (restlessness) |
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What is the moa and results of anti-psychotics in the Endocrine system?
What agents have the lowest risk?
Highest? |
D2-receptor blockade in pituitary → hyperprolactemia amenorrhea-galactorrhea, infertility, impotence, gynecomastia
Most atypicals have low risk, EXCEPT risperidone & paliperidone
High potency typicals (haliperidole) are highest risk |
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What is the result of anti-psychotic combined blockade of H1 and 5HT2c?
What AP's are associated with highest risk? |
weight gain - may be 1° due to increase in appetite
Highest Risk: clozapine, olanzapine, low potency typicals |
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What is Acute Dystonia?
What is the time of maximal risk?
What is the proposed mechanism? |
Spasm of muscles of the face, neck, tongue, & back May mimic seizures Is not hysteria
1-5 days; young, naive pt at greatest risk
moa: acute DA antagonism |
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What is Akathisia?
What is the time of maximal risk?
What is the proposed mechanism? |
Motor restlessness Not anxiety or agitation
5-60 days
moa: unknown; it is seen w/ typicals & atypicals
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What is Parknisonism?
What is the time of maximal risk?
What is the proposed mechanism? |
Bradykinesia, rigidity, tremor, mask facies, shuffling gait
5-30 days; elderly at greatest risk
moa: DA antagonism (D2 in nigrostriatal) |
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What is Neuroleptic malignant syndrome?
What is the time of maximal risk?
What is the proposed mechanism? |
Severe form of EPS: Catatonia, stupor, fever, unstable BP, myoglobinemia Can be fatal
weeks-months; can persist days after stopping drug
moa: poss. antagonism of DA |
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What is Perioral Tremor?
What is the time of maximal risk?
What is the proposed mechanism? |
"rabbit syndrome"
months-years
moa: unknown |
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What is Tardive Dyskinesia?
What is the time of maximal risk?
What is the proposed mechanism? |
Oral-facial dyskinesia, choreoathetosis / dystonia
months-years, esp. on withdrawal, elderly at greatest risk
moa: supersensitivity or upregulation of DA receptors |
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What is often considered the most important anti-psychotic side effect and why?
What % of patients get it?
Which drugs are highest risk? |
Tardive Dyskenisia - it can be difficult or impossible to treat
15-30%; elderly and mood disorder pt at highest risk
Drugs that cause EPS most likely |
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What are the "early" EPS reactions with typical anti-psychotics?
Among typicals, what drugs have highest risk?
Among atypicals? |
Acute dystonic reactions Parkinsonism
Typicals: high potency have highest risk, thioridazine has lowest risk (musc activity?)
Atypicals: paliperidone & risperidone have highest risk |
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T/F
You can rechallenge a patient who has experienced Neuroleptic Malignant Syndrome. |
True, but you need to be very careful and would probably try with an atypical.
Atypicals implicated only in rare, anecdotal reports or something like NMS |
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What are choreoathetoid movements? |
involuntary, repetitive movements |
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It has so many problems, so why Clozapine? |
- good for some refractory patients - only AP fda approved to reduce suicide |
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What are the antimuscarinic effects associated with clozapine? |
constipation
sialorrhea - due to M4 agonism |
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T/F
Tolerance can develop towards the M, α, and H related side effects of anti-psychotics. |
True |
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What side effects are associated with α1-blockade?
What AP's are highest risk? |
orthostatic hypotension (can even cause fainting) - esp. elderly patients
Highest Risk: Low potency phenothiazines (chlorpromazine), clozapine, Illoperidone, other atypicals |
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What side effects are associated with H1 antagonism?
What AP's are highest risk? |
sedation (esp. elderly) rebound insomnia if abrupt discontinuation
Highest Risk: low potency phenothiazines (chlorpromazine), atypicals (esp. clozapine) |
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What are the two major metabolic issues associated with anti-psychotics? |
dyslipidemia
hyperglycemia |
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What is the cause of dyslipidemia in AP use?
What AP's are associated with the highest risk? |
moa unknown
Highest Risk: clozapine, olanzapine
Thought to be non-weight-dependent Usually resolves w/in 6 weeks of discontinuation |
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What AP's are most associated with risk of hyperglycemia? |
clozapine, olanzapine, low potency phenothiazines
although no evidence for risk of other atypicals, all atypicals have warning about hyperglycemia
Patients should receive metabolic monitoring and pharmacologic/non-pharmacologic therapies |
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What are the ocular complications associated with chlorpromazine? |
abnormal pigmentation of eyelids, conjunctiva, cornea & lens deposits → visual impairment
- may resolve with discontinuation of drug
→ chlorpromazine not used much anymore |
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What is the ocular complication associated with thioridazine? |
"browning" of vision due to retinal deposits
- max daily dose is limited to reduce risk
→ thioridazine not used much anymore |
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What is the seizure risk for anti-psychotics? |
Most lower seizure threshold → warning for seizure risk on all AP's
Risk is very low except clozapine & chlorpromazine
Most can safely be used in epileptics with careful dose titration and prophylaxis --- keep in mind that most AE's have PK interactions |
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QT slide 58 |
QT slide 58 |
