Antipsychotics Exam 3 Flashcards
(111 cards)
1
Q
When were the first antipsychotics developed?
A
- 1950s
2
Q
Psychosis definiton
A
- loss of contact from reality
- cannot differentiate fantasy from reality
3
Q
Schizophrenia
A
- psychotic episodes but clear sensorium
- marked thinking disturbances
4
Q
clear sensorium
A
- oriented to person, place, and thing but difficulty in perception, thought, affect, daily functioning
5
Q
Schizophrenia Etiology (cause)
A
- neurodevelopmental/neurodegenerative disorder
- has a genetic component –> complex trait, genetic/environmental interactions
- generally young onset of age (1/2 before age 25)
- certain birth months higher risk for schizophrenia - viral infections peak at diff times of year
6
Q
Idental twin with schizophrenia risk?
A
- 40-65% risk of developing disease if identical twin has it
7
Q
Positive Schizophrenia symptoms
A
- present in people w/ schizophrenia but absent in a healthy person
- reflect excess or dysfunction of normal function
- delusions, unusual thoughts, hallucinations, disorganized thought and behavior
8
Q
Negative Schizophrenia symptoms
A
- present in a healthy person but absent in people with schizophrenia
- difficulty showing emotions, poverty of speech, decreased pleasure or motivation
9
Q
alogia
A
- inability to speak
10
Q
anhedonia
A
inability to feel pleasure
11
Q
avolition
A
lack of motiviation
12
Q
affective flattening
A
- loss of emotional expressiveness
13
Q
Cognitive schizophrenia symptoms
A
- impaired attention, working memory, executive function
14
Q
Which symptoms easiest to treat?
A
- positive symptoms
15
Q
Schizophrenia Hypotheses (3)
A
- Dopamine
- Serotonin
- Glutamate
16
Q
Dopamine Hypothesis
A
- earliest neurotransmitter concept
- doesn’t explain all aspects of schizophrenia
- still important for understanding schizophrenia symptoms
- most/all antipsychotic drugs impact DA signaling (D2 receptors)
- “out of tune” dopaminergic activity (in some brain regions) may contribute to schizophrenia
17
Q
4 major dopaminergic systems
A
- Nigrostriatal pathway
- Mesolimbic pathway
- Mesocortical pathway
- Tuberoinfundibular pathway
18
Q
Nigrostriatal pathway: DA levels in schizophrenia, what pathway is normally involved in, start and end of pathway regions?
A
- normal DA levels in schizophrenia
- pathway part of extra pyramidal nervous system -> motor function and movement
- pathway also involved in parkinson’s dysfunction
- substantia nigra to dorsal striatum
19
Q
Mesolimbic Pathway: DA levels in schizophrenia, what pathway is involved in, start and end of pathway regions?
A
- DA levels too high
- thought to drive positive symptoms
- closely related to behavior and psychosis
- cell bodies in midbrain ventral tegmentum project to limbic system
20
Q
Mesocortical Pathway: DA levels in schizophrenia, what pathway is involved in, start and end of pathway regions?
A
- DA levels too low
- probably contribute to neg and cognitive symptoms
- closely related to behavior and psychosis
- cell bodies in midbrain ventral tegmentum project ot neocortex/mesocortex
21
Q
Tuberoinfundibular system: DA levels in schizophrenia, what pathway is involved in, start and end of pathway regions?
A
- DA levels normal in schizophrenia
- blocks prolactin release when not needed
- cell bodies in hypothalamus control DA release into pituitary portal circulation
22
Q
Technical def of inverse agonist
A
- 5HT2A receptors have some constitutive action in ABSENCE of serotonin
- these inverse agonists would BLOCK this constitutive action when binding
- will just refer to them as antagonists
23
Q
Serotonin Hypothesis of schizophrenia
A
- LSD (Lysergic acid diethylamide) and mesacaline are 5-HT agonists
- 5-HT2A receptors modulate release of DA in the cortex, limbic region, and striatum
- 5-HT2C receptor stim also modulates dopaminergic activity
- atypical antipsychotics antagonize 5-HT2A receptors and can modulate DA release in brain regions
24
Q
Glutamate Hypothesis of Schizophrenia
A
- antag on NMDA receptors can mimic schizophrenia symptoms (pos, neg, and cognitive)
- thought that hypo-function of NMDA receptors may be present in schizophrenia
25
4 families of typicals
- Phenothiazine derivatives
- Thioxanthene derivatives
- Butyophenone derivatives
- miscellaneous structures
- "The Brother Married Pam"
26
Phenothiazine Derivatives: 3 subfamilies, most potent, most side effects, 1 fact
- were once the most widely used of the antipsychotics
- 3 subfamilies: aliphatic, piperidine, piperazine
- piperazine most potent --> need to be given at lower doses
- aliphatic and piperidine derivatives more side effects
* at doses required to have an effect, have effects on other neurotransmitter receptors as well (H1, a1, M)
27
1 drug to know for each of the subfamilies of phenothiazines...
- aliphatic: chlorpromazine
- piperidine: thioridazine
- piperazine: perphenazine
28
Thioxanthene derivatives 1 fact and 1 drug
- high potency
| - thiothixene only one we need to know
29
Does lower dose = better efficacy?
- not always
30
Butyrophenone derivatives (1) (closely related to which other drug), 1 fact, and how does compare to phenothiazines?
- haloperidol
- closely related to pimozide (miscellaneous typical)
- most widely used typical
- compared to phenothiazines --- very good D2 antag, tends to cause D2 side effects (movement-related)
31
Miscellaneous Structures (typicals): 1 drug, what is it used for
- "Newish" typicals
- pimozide
- limited usage b/c of concerns of heart impacts
- used to control tics in tourette's
- dopaminergic dysfunction thought to cause the tics (verbal and motor)
32
Atypicals mech
- block 5-HT2A and D2 receptors
| - more activity at 5-HT2A
33
Very recently approved atypicals (2)
- cariprazine and brexpiprazole (info on note sheet)
34
Do antipsychotics have affinity for only one receptor?
- no, can fit multiple receptors
| - explains both efficacy and adverse profile
35
Dopaminergic Receptors--> how many types, how many families, general info
- 5 types of DA receptors
- grouped into two families (D1 and D2 families)
- families can be expressed in diff regions of the brain, diff downstream outputs, some can be found both pre- and post-synaptically
36
Typical antipsychotic agents in regards to binding dopamine receptors and efficacy
- block D2 receptors stereo-selectively
| - binding affinity to D2 but not D1 is very strongly correlated with antipsychotic and extrapyramidal potency
37
Actions at D3 or D4 or D1 important for antipsychotics?
- nope
38
Secondary negative symptoms
- neg symptoms caused by treatment itself
- usually happens with strong D2 antags (typicals)
- antagonize mesocortical pathway
39
Blocking D2 receptors: Nigrostriatal effects
- block D2 results in EPS b/c levels are normal in schizophrenia
40
Blocking D2 receptors: Mesolimbic effects
- block D2 results in relief from positive symptoms b/c levels are too high in schizophrenia
41
Blocking D2 receptors: Mesocortical effects
- block D2 results in aggravated negative and cognitive symptoms b/c levels are too low in schizophrenia
42
Blocking D2 receptors: Tuberoinfundibular effects
- block D2 results in increased prolactin release.. hyperprolactinemia b/c levels are normal in schizophrenia
43
Pharmacodynamics: Dopaminergic receptors and blockage
- typical drugs must be given in doses sufficient to achieve 60-75% occupancy of striatal D2
* some atypicals on lower end of that range
- Occupancy of striatal D2 receptors >78% run risk for EPS
44
dopamine tuner
- aripiprazole
| - partial agonist so can increase dopamine when too low and decrease when too high b/c competes for receptors
45
Serotonin in the Nigrostriatal tract overview (pharmacodynamics)
- DA levels normal in schizophrenia
- blocking in this pathway causes EPS
- Serotonin neuron synapses to DA neuron
- interneuron is GABA (when 5HT2A on this is bound with antagonist, also disinhibits DA release)
- 5HT-2A when antagonized, allow DA to be pumped out at its still normal level (serotonin inhibits DA release "dopamine break")
- 5HT-1A on the dendrite of the the 5HT neuron when bound with 5HT (agonized), inhibits serotonin release from the neuron and also promotes dopamine release (DA accelerator)
- 5-HT1A agonists and 5-HT2A antagonists have same effects
46
- how do second generations help limit EPS in terms of the nigrostriatal pathway
- allow more DA to be released in this tract
- when you give a drug that is not completely specific for one receptor, cannot control where it goes
- some of second gen will block D2 receptors
- by antagonizing 5HT2A, there will be more dopamine released and can overcome D2 block by the same antipsychotic
47
Mesocortical pathway pharmacodynamics
- thought to be too little DA in this pathway in schizophrenia which causes neg and cog symptoms
- thought either DA neurons aren't making enough DA OR too much 5-HT (DA brake) at 2A receptors
- by 5HT2A antagonism, help DA neuron produce more DA
- might help with neg and cog symptoms
- controversial but know it wont make them worse
48
Mesolimbic pathway pharmacodynamics
- thought to be too much DA in this pathway causing Pos symptoms
- all hypothetical theories
- theory w/ 5HT2A antag in this pathway is that it doesn't raise levels higher
- may have indirect effects through glutaminergic neurons.. reduce glutamate release which reduces DA release in this pathway
- 5HT2A antag may help limit DA release
49
Tuberoinfundibular pathway pharmacodynamics
- thought to be normal DA levels in this pathway in schizophrenics
- blocking D2 receptors causes hyperprolactinemia because usually dopamine levels keep prolactin in check
- serotonin also promotes prolactin release, so block 5HT2A, lowers prolactin release
- diff atypicals can have diff impacts on prolactin levels so mech is still unclear
50
Overall purpose of antipsychotics
- stop positive symptoms and limit the other side effects
51
Side effects of Muscarinic cholinoceptor blockade and what nervous system
- (sympathetic effects) loss of accommodation, dry mouth, difficulty urinating, constipation
- autonomic nervous system
52
side effects of a-adrenoceptor blockade and what nervous sytem
- orthostatic hypotension, impotence, failure to ejaculate
| - autonomic nervous system
53
side effects of dopamine receptor blockade in nigrostriatal pathway and what nervous system
- this is D2 blockade
- parkinsonism, dystonias
- central nervous system
54
side effects of supersensitivity of dopamine receptors
- tardive dyskinesia
| - CNS
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Akathisia --> what blockade and what is it?
- unknown mechanism
- blockade affects CNS
- feeling of motor restlessness (sometimes grouped as EPS w/ parkinson and dystonias)
56
dopamine-receptor blockade resulting in hyperprolactinemia causes what side effects? and what system
- causes amenorrhea-galactorrhea, infertility, impotence
| - affects endocrine system
57
possibly combined H1 and 5-HT2C blockade can cause what side effect?
- weight gain
| - most likely due to increased appetite
58
Acute Dystonia
- true EPS
- mech: acute DA antagonism
- spasms of muscles of tongue, face, neck, back
- may mimic seizures
- NOT HYSTERIA
- time of maximal risk is 1-5 days when first taking antipsychotics (esp in young that have never taken one before)
- treatment: curative by antiparkinsonism agents
59
Akathisia
- motor restlessness
- NOT anxiety or agitation
- mechanism: unknown (seen too with atypicals)
- treatment: reduce dose or change drug
- benzos and propranolol may help
60
Parkinsonism
- true EPS
- mech: DA antagonism
- bradykinesia, rigidity, mask tremor, shuffling gait
- elderly at greatest risk
- treatment: reduce dose or change drug; antiparkinsonism drugs may help
61
Perioral Tremor (rabbit syndrome)
- like a rabbit moving nose
- mech: unknown
- treatment: anti-parkinsonism drugs
62
Tardive Dyskinesia
- oral-facia dyskinesia, widespread choreoathetosis or dystonia
- elderly at greatest risk, does not appear for months or years taking drug (can also appear on withdrawal)
- mech: super-sensitivity or upregulation of DA receptors
- treatment: prevention crucial, treatment is unsatisfactory, may be reversible if caught early enough
63
among typicals highest potency has ____ risk of neurological effects.. also which lowest and why?
- highest potency, highest risk
- thioridazine has lowest (antimuscarinic activity)
* in nigrostriatal tract, DA (brake) and ACh (accelerator) have opposite effects on GABA
* antimuscarinic activity at M1 may help to balance out the D2 blockade
64
Among atypicals, which two have highest risk of neurological effects
- paliperidone and risperidone have highest risk
65
Neuroleptic Malignant Syndrome
- rare but life-threatening
- thought to be caused by D2 receptor blockade
- "severe form of EPS"
- symptoms: parkinsonism, autonomic instability, muscle breakdown/rigidity
- severe cases can last for a week after discontinuance
- high potency in high doses generally causes this
66
Tardive Dyskinesia general info
- late-occurring, abnormal choreoathetoid movements
- most important side effect of antipsychotics b/c no effective treatments (some spontaneous resolve)
- cause (hypothesis): knee jerk rxn to D2 antag in the nigrostriatal tract (increase sensitivity/upregulation)
- 15-30% of patients treated long-term
- elderly and potentially mood disorder patients more sensitive
- early recognition important because no treatments
67
Pharmacodynamics: Endocrine Effects
- hyperprolactinemia correlates with D2 antagonism
- most atypicals have a low risk of hyperprolactinemia (exceptions are risperidone and paliperidone)
- good correlation between high D2 antagonism and highest risk of hyperprolactinemia
- symptoms in women: amennorhea, galactorrhea, infertility, osteoporosis, abnormal milk production
- symptoms in men: loss of libido, impotence, abnormal breast growth
68
Adverse Rxns: antimuscarinic effects
- M1 blockade in both CNS and PNS
- of typicals --> most prominent in low potency phenothiazines (need higher dose to see effect, then get effect from M1 block)
- of atypicals --> most prominent in clozapine (strongly associated with constipation)
- concern for anticholinergic effects in elderly
69
Clozapine and antimuscarinic actions
- strongly associated with constipation
| - M4 agonism by clozapine --> sialorrhea
70
why is there a concern for anticholinergic effects in the elderly?
- block receptors for ACh, potential to exacerbate dementia
71
Adverse Rxns: Alpha 1 blockade
- orthostatic hypotension
- elderly patients particular concern --> already poor vasomotor tone
- low potency phenothiazines also problem with this
- clozapine and Iloperidone - relative risk higher
- other atypicals also have effects
72
Adverse Rxns: H1 antagonism
- sedation
- typicals: low potency phenothiazines
- of the atypicals, clozapine highest risk but many have effects
- some tolerance to this may develop (good)
- rebound insomnia/sleep disturbance
- elderly are sensitive to this
73
Adverse Rxns: Weight gain
- H1 antagonism, augmented by 5-HT2C antagonism
- among typicals, low potency agents have highest risk
- among atypicals, clozapine and olanzapine frequently result in large increases in weight
- some level of weight gain seen with most antipsychotics (may be because placebo in these trials, during psychotic episodes, tend to lose weight)
74
Adverse Rxns: Metabolic Issues
- two biggest additional metabolic issues
1. dyslipidemia (primarily elevated serum triglycerides and also cholesterol)
2. impaired glycemic control (mech unclear)
- other risk factors can contribute, ex lifestyle factors (80-90% of people with schizophrenia smoke)
- recommended use of metabolically more benign agents for initial treatment of all patients where long-term treatment is expected
- patients should receive metabolic monitoring and appropriate pharmacologic/non-pharmacologic (counseling about food intake, exercise) therapies
75
Adverse Rxns: Dyslipidemia
- low potency phenothiazines can raise levels
- significant elevation seen for clozapine and olanzapine
- thought to be weight-independent, occurs within weeks of starting medication, resolves within 6 wks after discontinuation
- weight-independent: can occur before weight gain starts
76
Adverse Rxns: Hyperglycemia
- first noted with low-potency phenothiazines
- among atypicals, clozapine and olanzapine have greatest risk
- although no evidence supporting that other atypicals cause this, all atypicals have warning about hyperglycemia
- USUALLY reversible upon drug discontinuation or switching to a more metabolically benign agent
77
Clozapine and olanzapine extra fact regarding side effects and efficacy
- they are most useful in some patients even though they have these side effects
- may have use when other drugs fail
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Adverse Reactions: Ocular Complications (2 drugs)
- Chlorpromazine - commonly causes abnormal pigmentation of eyelids, conjunctiva, cornea, and lens
- Thioridazine - can cause retinal deposits that are associated with browning of vision
- maximum daily dose limited to reduce the risk of this complication
79
Pharmacodynamics: EEG effects (brain)
- cause shifts in patterns of EEG freq
- most LOWER seizure threshold
- warning for seizure risk on all antipsychotic agents (risk very low except for clozapine [3-5%] and chlorpromazine also higher risk)
- most can still be used safely in epileptics with careful dose titration and prophylaxis
80
Pharmacodynamics: CV effects
- major concern for antipsychotics is impact on cardiac phys
- concern about ventricular arrhythmias and SCD
- all carry warning about QTc prolongation
- some have black box warnings (torsade/fatal arrhythmias)
- concern for patients with risk factors for QTc prolongation and interactions with other drugs that prolong QTc
81
QT interval and QTc
- electrical depol and repol of ventricles
| - way of normalizing QT intervals in those with different HRs
82
Why do antipsychotics have effects on CV? ex. with one drug
- Thioridazine inhibits NA channels at high doses (also Ca channels potentially), many antipsychotic drugs block the Ikr channel
- Ikr channel: K efflux channel to repolarize
83
Thought that atypicals had less impact on heart phys.. is this now known to be true?
- no, also dose-dependent risk for sudden cardiac death
| - no difference between typicals and atypicals
84
Which drug sometimes associated with myocarditis
- clozapine
85
Dose-dependent increased risk for SCD was found for antipsychotic users of typical and atypical agents alike compared to antipsychotic nonusers
- tru
86
Adverse Rxns: Toxic or allergic rxns - Chlorpromazine
- Chlorpromazine can rarely cause cholestatic jaundice, also can cause skin rxn and photosensitivity
- cholestatic jaundice thought to maybe be from impurities in early forms of the drug, older formulations w/ higher doses
87
Adverse Rxns: Toxic or allergic rxns - Clozapine
- approx 1% of patients treated with clozapine develop agranulocytosis (loss of immune cells)
- greatest risk first 6 months
- serious and potentially fatal
- discontinue, do not retry
- appears to be reversible upon discontinuation
- blood count monitoring is required (at first more often than later on)
- cause could be genetics combined with toxic metabolites
88
Adverse Rxn: DRESS
- Drug reaction with eosinophilia and systematic symptoms
- skin eruption (rash), systemic symptoms (including hematopoietic system [bone marrow and lymph nodes]), and visceral involvement
- lymph node swelling as well
- only 23 total cases ever
- 10% mortality
- immune response to drug, herpes virus reactivation
89
Adverse Rxns: Behavioral Effects
- side effects can lead to non-compliance.. this may be improved by dosing at night w/ sedation
- drug-induced akinesia may produce "pseudo-depression" that may respond to antiparkinson agents
* caused by movement disorders or too high of a dose
* decreasing dose may improve symptoms
90
Psychiatric indications for antipsychotics as a whole (schizophrenia and bipolar)
- primary indication: schizophrenia (except catatonic form)
* catatonic is more difficult to treat.. with benzos first and then if they get better, antipsychotics
- psychotic bipolar disorder (BP1)
* typicals not usually used because of concerns with tardive dyskinesia/ EPS
* atypicals (w/ some exceptions) are FDA approved for acute mania
* maintenance therapy in mania becoming more common; some atypicals approved as monotherapy/adjunct for maintenance
91
Psychiatric indications for antipsychotics as a whole (depression, schizoaffective disorder, delusional disorder)
- MDD
* when psychotic features present
* atypicals are affective as adjunct therapy in treatment-resistant depression
* most have limited antidepressant benefit as monotherapies (if they are good as monotherapies, probably b/c of metabolites)
- Schizoaffective disorders
* characteristics of both schizophrenia and affective disorders (continuum)
- delusional disorder (not many studies)
* more rare, paranoid disorder, delusions prominent
92
Other psychiatric indications for antipsychotics
- substance-induced psychosis
- tourette's syndrome (tics)
- psychotic symptoms of delirium and dementia (off label for dementia - warnings of increased mortality (reason unclear))
- irritability in autism (a few FDA approved)
- adjunct in anxiety disorders (OCD, PTSD)
93
Wrongly promoted for which indication
- small doses for relief of anxiety associated with minor emotional disorders
94
Nonpsychiatric indications for antipsychotics
- some phenothiazines with shorter side chains have considerable H1 antagonism
- Butyrophenone droperidol can be used in neuroleptanesthesia, also used to decrease postoperative or postprocedure nausea and vomiting
- chlorpromazine: uncontrollable hiccups
- Prochlorperazine (phenothiazine) is promoted primarily as an antiemetic
95
What receptor does clozapine act on for sialogoge action?
- M4 AGONIST
96
Anti-emetic effects
- DA antagonism in CRT zone/STN (solitary tract nucleus) has antiemetic effects
- Thioridazine, aripiprazole are exceptions to this
97
CATIE study
- clinical antipsychotic trials of intervention effectiveness
- 2005 large study of typical vs atypical agents in the US
- conclusions were no diff between atypicals and typicals
- but problems with study design: didn't look at tardive dyskinesia and doses weren't equal
98
Typicals vs Atypicals drug choice
- with pos symptoms, approx 70% of patients with schizophrenia will experience equal efficacy of typical and atypical agents
- typicals benefits: cheaper
- atypicals benefits: less risk EPS, tardive dyskinesia, and hyperprolactinemia but weight gain and metabolic issues with these agents
99
clozapine and suicide risk
- REDUCES suicide risk
100
With exception of ____ and _____, thought that most antipsychotics are equally effective for positive symptoms
- clozapine and olanzapine
101
patient response to drug is static/changing
- can change over time
102
is there a large range of dosages that are effective from one drug to another
- yes
103
most patients who recover from an acute schizophrenic episode do/do not need further drug therapy
- most need
| - on an "as needed" basis
104
olanzapine/fluoxetine combo FDA approved for what?
- depression in biopolar disorder
105
Pharmacokinetics of antipsychotics
- absorption quite high
- many undergo significant first-pass metabolism
- most highly lipid soluble, membrane or protein bound
- generally much longer clinical duration of action than estimated from their plasma half lives
- often takes time for drug effect to take place
- withdrawal can occur after stopping drug
- extensively metabolized by CYPs and then conjugations (some exceptions)
- considerations of interactions: changes in smoking behavior, drugs that impact CYP activity, combining antipsychotics with various other psychotropic drugs
106
do antipsychotics generally interfere with metabolism of other drugs at clinical doses?
- no
107
Time to recurrence of psychotic symptoms
- highly variable
- average time for relapse: 6 months with exception of clozapine (should never be discontinued abruptly unless side effects are medical emergencies)
108
Use of antipsychotics in special populations
- Pediatric: some approved (sensitive to EPS and weight gain, also hyperprolactinemia)
- Geriatric: sensitive to EPS, TD, orthostasis, sedation, anticholinergic effects.. potential for drug/drug interactions, weight gain less of an issue for elderly, riskf or cerebrovascular events and all-cause mortality with dementia
109
Use in pregnancy
- Category B or C
- available data indicate little to no toxicity
- all antipsychotics cross the placenta
- decisions should be decided individually
- issues in breast feeding due to low level of infant hepatic catabolic activity
110
Overdoses
- low potency typicals: risk of torsade and other extensions of known pharmacology
- high potency typicals: EPS, EKG changes
- atypicals: less of a risk of torsade, however in combo with other medications it can lead to fatality
111
Non-pharmacological treatment of schizophrenia
- psychosocial support, cognitive, and vocational rehabilitation
- ECT - last resort
