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Exam 4 lecture 2 Flashcards

1
Q

What is the concentration at which drug occupies 50% of receptors? What is 1 order above that limit? One order below?

A

1 order above- Kd=90%
1 order below- Kd=10%

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2
Q

What percent occupancy do we need dopamine receptors for antipsychotic efficacy?

A

60-70%

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3
Q

How can we measure dopamine receptor occupancy and serotonin receptor occupancy?

A

PET

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4
Q

Receptor occupancy and antipsychotic effect of risperidone?

A

Risperidone has doses either 3 or 6 mg/day. in 3 mg, 3 of 4 pts free of EPS and 3 of 4 pts have good receptor occupancy, for 6 mg/day, all patients are abpve threshold but 3 of 4 will have EPS.

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5
Q

What are the drug induced movement disorders

A

Extrapyramidal symptoms (30-50%)
Tardive dyskinesia
Neuroleptic malignant syndrome (NMS)

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6
Q

What percent of people have EPS? What are the symptoms? When does it occur?

A

Occurs in 30-50% of people
occurs early, days/weeks, reversible

symptoms-
Dystonia- increased muscle tone
Pseudoparkinsonism- muscle rigidity
Tremor
Akathisia- restelssness

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7
Q

Drug therapy to treat EPS?

A

-Benztropine (Cogentin), trihexyphenidyl (Artane), or akineton (Biperiden) –anticholinergic agents

– Diphenhydramine (Benadryl) – Antihistamine

– Amantadine (Symmetrel) – Dopamine releasing agent

– Propranolol – used for akathisia

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8
Q

Rationale for using anticholinergics to treat EPS

A

Neuron gets excitatory input from Ach. Gets inhibitory signaling from dopamine.
If we block receptors using D2 antagonists all dopamine signaling is gone and we have a relative excess in Ach signaling. Use anticholinergic.

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9
Q

What percent of people will have Tardive dyskinesia? When does it occur? Reversible? Symptoms? Monitoring? MOA?

A

20-40%, occurs late, months to a year. They are irreversible.

symptoms- mouth- Rhythmic involuntary movements
Choreiform- irregular purposslessness
Athetoid- worm like
Axial hyperkinesias- To and Fro movemnts

Monitoring- AIMS (abnormal involuntary movement scale). Check every 6 months

Unknown MOA- thought to be neuroadaptive response following chronic antagonists

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10
Q

Treatment of tardive dyskinesia

A

Prevention! Use the least risky agent at the
lowest dose possible and monitor
1. Reduce dose of current agent
2. Change to a different drug; possibly a newer agent
3. Eliminate anticholinergic drugs
4. VMAT inhibitors

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11
Q

What are the newer drug therapies for TD

A

VMAT2 inhibitors

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12
Q

What are some VMAT inhibitors for tardive dyskinesia and huntingtons (which do they treat)

A

Tetrabenzine (xenazine)- huntingtons chorea
valbenzine (ingrezza)- TD
Deutetrabenazine- both

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13
Q

VMAT2 MOA? Use?

A

Vesicular monoamine transporter 2
Prevents dopamine from being packaged in synaptic vesicles (If dopamine is not going into vesicles, it is being metabolized, so they deplete dopamine)

Used as add on treatment to treat tardive dyskinesia associated with antischizophrenia medication.

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14
Q

What is NMS? symptoms? treatment?

A

EPS symptoms with fever.
impaired cognition- agitation, delirium, coma
muscle rigidity

treatment
restore dopamine balance - discontinue drug
- DA agonist, diazepam or dantrolene

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15
Q

What are the therapeutic uses of antipsychotic drugs

A

Treatment of psychosis
Anxiety treatment (Overkill)
mood disorders (mania and depression)
Tourettes

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16
Q

How long does it take to treat psychosis with antipsychotics?
How do antipsychotics treat mood disorders?
How to treat tourettes with antipsychotics

A

Treatment of psychosis- 2-3 weeks for effectiveness, 6 weeks to 6 months for maximal effectiveness

Mood disorders
mania- secondary to lithium, used in combination
depression- accompanied by agitation and delusions

Tourettes
treat with pimozide

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17
Q

What are some miscellaneous uses of antipsychotics? What drugs do we use?

A

huntingtons chorea
-tetrabenazine, deutetrabenazine

intractable hiccups
-chlorpromazine

Alcohol withdrawals (hallucinations)
- haloperidol

Nausea and vomiting
-metoclopramide, promethazine

Potentiation of opiates and sedatives
-droperidol

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18
Q

What are some pharmacologic effects of antipsychotics

A

Behavioral effects- Unpleasant in normal subjects or reversal of s/s of psychosis in affected individuals

Neuroleptic syndrome- Suppress emotion, initiative and interests. may resemble negative symptoms

Block conditioned avoidance response in animal studies

reduce spontaneous activity, aggressive and impulsive behavior

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19
Q

Know this for exam

What are the types of adverse pharmacologic effects of antipsychotics

A
  1. Autonomic
  2. CNS
  3. Endocrine
  4. other
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20
Q

Know this for exam

What are the mechanisms of autonomic adverse pharmacologic effects of antispychotics? WHat are the different manifestations of these mechanisms?

A

Autonomic has muscarinic cholinoceptor blockade MOA and alpha adrenoceptor blockade MOA

Muscarinic cholinoceptor blockade is manifested by loss of accomodation, dry mouth, difficulty urinating, constipation

alpha adrenoceptor blockade is manifested by orthostatic hypotension, impotence, failure to ejaculate

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21
Q

What are the different mechanisms of CNS advrese pharmacologic adverse effects of antipsychotics? What are the manifestations of these mechanisms

A

Dopamine receptor blockade- manifestations include parkinsosns syndrome, akathisia, dystonias

Supersensitivity of dopamine receptors- manifested by tardive dyskinesia

muscarinic blockade- manifested by toxic-confusional state

Histamine (H1) receptor blockade- sedation

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22
Q

What are the different mechanisms of endocrine adverse pharmacological effects of antipsychotics? How are they manifested?

A

Dopamine receptor blockade resulting in hyperprolactinemia. Manifested by Amenorrhea-galactorrhea, infertility, impotence

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23
Q

How does weight gain happen in antipsychotics

A

H1 and 5ht2C blockade

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24
Q

precautions and contraindications of antipsychotics

A

cardiovascular
parkinsosn disease
Epilepsy (clozapine will lower seizure threshold)
Diabetes

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25
What are drugs that have a high 5-HT2a/D ratio
Haloperidol, fluphenazine, chlorpromazine, thiothixene
26
What does a drug having a high 5 HT 2a/D ratio mean?
Drugs will tend to have a higher risk of EP symptoms (Good at D2 blockers. but not good 5HT2a blockers)
27
If a drug has high propensity to cause hypotensive effects, what receptors does it block?
alpha (chlorpromazine)
28
Which receptors are responsibe for sedation?
Histamine
29
What are typical 1st gen antipsychotics characterized by?
More movement problems, increased EPS and tardive dyskinesia due to strong D2 block
30
Be able to recognize key structural features of phenothiazine antipsychotics
Chlorpromazine is three hexane groups. The 2 wide ones have double bonds, the middle one has S on top and N on bottom
31
What are some aliphatic phenothiazines and their uses
Chlorpromazine- no longer 1st line promethazine- used for H1 antagonist properties
32
What are some piperidine phenothiazines and their uses
Thioridazine- sedation, hypotension, anticholinergic Fluphenazil- EPS prochlorperazine- antiemetic perphenazine- CATIE studies compared perphenazine to newer agents in combo with anticholinergics. FOund perphenazine + anticholinergics were just as effective as newer agonists
33
Name antipsychotics and their side effects
Thioxanthines- modest EPS butyrophenones (haloperidol)- EPS
34
What are some miscellaneous antispychotic? What are their uses?
Molindone- may cause moderate EPS Pimozide is used in tourettes disease tics
35
Name antipsychotic drugs and their key points
Chlorpromazine- 1st antipsychotic, antihistamine side effets promethazine- ANtihistamine, antiemetic Thioridazine- Many SE, anticholinergic, sedation, sexual dysfunction, cardiovascular Fluphenazine- EPS Prochlorperazine- antiemetic Perphenazine- CATIE studies- combination with anticholinergics Thiothixene- modest EPS Haloperidol- EPS Molindone- Moderate EPS Pimozide- tourettes disease, suppress motor and vocal tics
36
What are atypical (second generation) antipsychotics characterized by compared to typical antipsychotics
Reduced EPS Efficacy for negative symptoms Similar or enhanced 5HT2a receptor antagonism vs D2 More metabolic problems linked to diabetes (greater risk in pts <50) (in olanzapine and clozapine) (less evidence in quetapine and risperidone)
37
why do typical antipsychotics lead to movement disorders
They block D2 receptors (post synaptic dopamine receptors).
38
MOA of atypical antispsychotics
D2 and 5HT 2A receptor antagonist that blocks presynaptic 5HT2A receptor. Leads to increase in synthesis and release of dopamine that competes for D2 receptors, restoring normal movement.
39
What is the 1st antipsychotic? side effects? When to use?
Clozapine side effects- agranulocytosis (this is why it is 2nd or 3rd line therapy, even though it is very effective) anticholinergic, antihistamine disorders (reduce D2 potency and reduce movement disorders)
40
Name the atypical antipsychotics and their key points
Clozapine- 1st atypical antipsychotic, agranulocytosis, risk of diabetes, superior efficacy Olazapine- weight gain, risk of diabetes Quetiapine- Metabolite with antidepressant activity, hypotension, sedation Risepridone- 5HT2a/D2 receptor antagonist Ziprasidone- 5HT2a/D2, a1 affinity, prolongs QT interval lurasidone- 5HT2a/D2, reudced metabolic effects, rapid titration Aripiprazole- High 5HT2a/D2 affinity, partial agonist activity
41
What are some antipsychotic drugs under investigation
Dual M1/M4 muscarinic agonist combined with peripheral muscarinic antagonist 5HT receptor ligands (14 receptors, 5HT3)
42
How do partial agonists affect dopaminergic activity
Partial agonists like aripiprazole bring dopaminergic activity down if we have high dopaminergic activity Partial agonists like aripiprazole bring dopaminergic activity up if we have low dopaminergic activity
43
What are D2/D3 receptor partial agonist drugs? Side effects?
Brexipiprazole- less akathisia vs aripiprazole cariprazine- D2/D3 partial agonist with greater affinity for D3. Akathisia is high Lumateperone- partial D2 agonist presynaptic receptor/antagonists
44
What are some key features that define psychotic disorders? Define them?
Delusions- fixed and false beliefs that are not amenable to change even with conflicting evidence Hallucinations- Perception-like-experiences that occur without an external stimulus (usually auditory, visual, tactile or olfatory) Disorganized thinking and speech- switching from one topic to another, unrelated answers to questions Negative symptoms
45
Disease onset of schizophrenia
Men- late teens, early 20s Women- late 20s, early 30s
46
schizophrenia Link to substance use and effects on antipsychotics
Smoking is associated with induction of 1A2 (due to hydrocarbons not nicotine) which decreases the serum concentration of 1A2 substarte antipsychotics Marijuana, cocaine and amphetamines can hasten the onset of schizophrenia, exacerbate symptoms, and reduce time to relapse Substance use treatment can be successfully achieved along with mental health treatment in patients with schizophrenia, should be undertaken at the same time.
47
Where in the brain do we get EPS symptoms? What structure in brain causes excess dopamine hallucinations in schizophrenia? Where in brain are cognitive issues caused in schizophrenia?
Substantia nigra causes EPS Mesolimbic pathway- excess dopamine causes hallucinations Prefrontal cortex- cognitive issues
48
What are things to consider when doing antipsychotic drug therapy
Doses per day Side effects previous drug therapy Cost of drug COncomitant drug therapy Monitoring? (labs, weight, ECG)
49
Is oral antipsychotic drug therapy 1st line or IM depot therapy?
Oral is 1st line unless patient presents reasons to consider IM drug therapy
50
compare efficacy for typical (older) vs atypical (newer) agents
Efficacy for positive symptoms is similar to atypical antipsychotics
51
Most commonly used typical antipsychotic? side effects? Efficacy?
Haloperidol. Routine or PRN More EPS with higher potency typicals Are very effective for treating the positive symptoms, but are likley to worsen negative and cognitive symptoms
52
What antipsychotics are assiciated with akathisia more than others
Partial agonists (stabilize dopamine transmission)
53
what boxed warnings do all partial agonists have?
Suicidal thoughts/behaviors
54
What are partial agonist drugs? enzyme substrates and side effects?
Aripiprazole- 2D6 and 3A4 substrate, moderate akathisia, low weight gain Brexipiprazole- 2D6 and 3A4 substrate, moderate akathisia, low-moderate weight gain Cariprazine- 3A4 substrate, moderate akathisia, low moderate weight gain
55
Which drugs are "the pines"?
Asenapine Clozapine Olanzapine Quetiapine associated with significantly less EPS/ Higher weight gain than others
56
Asenapine dosage form, substrate and side effects
Sublingual and patch formulations 1A2 substrate QTc prolongation
57
Clozapine boxed warning, substrate, side effects
1A2 substrate Boxed warning- neutropenia, orthostasis, bradycardia, syncope, seizures, myocarditis, cardiomyopathy side effects- sedation, weight gain, constipation, hypersalivation, dry mouth, GI hypomotility QTc prolongation
58
Olanzapine Substrate, side effects, warning
1A2 substrate Significant weight gain and sedation High risk metabolic syndrome DRESS warning
59
Quetiapine substrate, side effects? Boxed warning?
3A4 substrate QTc prolongation Weight gain and sedation Boxed warning for suicidal ideation
60
How to use asenapine? warning? What to do if given with strong 1A2 inhibitor?
Apply 1 patch Q24hrs, rotate patch to minimize application site rxns Warnings for QTc prolongation Reduce dose of patch if gven with strong 1A2 inhibitor
61
Monitoring clozapine
Monitoring timelines weekly x 6 months, then every 4 weeks
62
Why is olanzapine given with samidorphan? What is samidorphan?
Samidorphan reduces weight gain risk Samidorphan is an opioid antagonist with preferential activity at mu opioid receptor
63
What drugs are referred to as the "dones"
Iloperidone Lurasidone Ziprasidone Risperidone Paliperidone
64
Iloperidone substrate? Side effets?
2D6 substrate Higher risk for orthostasis and syncope QTc prolongation
65
Lurasidone substrate? side effects?
3A4 substrate higher risk for akathisia warning for suicidal thoughts (adjunct for bipolar depression) Take with food to increase bioavailability?
66
Ziprasidoe substrate? warning and contraindication
Contraindication- QTc prolongation DRESS earning Take with food to increase absorption and bioavailability 3A4 substrate (1/3) and aldehyde oxidase (2/3) Less worry for p450 interactions)
67
Risperidone substrate? Side effects?
2D6 substrate (minor 3A4) EPS, hyperprolactinemia, weight gain, sedation, orthostasis
68
Paliperidone side effects? How is it eliminated?
EPS, hyperprolactinemia, weight gain, sedation, orthostasis QTc prolongation Renally eliminated. Dose adjustment in renal impairement
69
Lumateperone side effects? substrate?
Low risk for EPS or akathisia Low risk for weight gain or metabolic side effects
70
Pimavanserin use? MOA? Substarate?
Treatment of hallucinations or delusions in patient with parkinsons disease MOA- inverse agonist and antagonist at serotonin (5HT)2A 3A4 substrate

Therapeutics (38 decks)

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