Antipsychotic Agents - Filtz Flashcards
What is the primary mechanism of action of antipsychotic agents?
D2 antagonism
What is the difference between psychoses and neuroses?
Psychoses are mental disorders characterized by rifts in rational thought, inappropriate processing of sensory information, and disturbed views of reality. Generally not recognized as psychotic symptoms by the sufferer (not sure which are real and which are not).
Neuroses are abnormal reactions to an external state that is generally recognized as such by the sufferer.
What are positive symptoms of psychoses?
Overt symptoms: delusions, paranoia, hallucinations (usually auditory), disordered thoughts, bad sense of time, loose ideation, inappropriate emotional response.
What is synesthesia?
The production of one sense by stimulating another sense or part of the body.
What is good about loose ideation?
It is thought that people with a little bit of loose ideation are kind of geniuses in their own way… less inhibition and different ways of thinking than most people.
What disease states involve psychoses?
schizophrenia Delirium in dementia Manic psychoses PTSDs Drug-induced (amphetamine, steroid, LSD, ketamine, PCP, sedative/hypnotic)
What % of the population is affected with schizophrenia?
about 1%
Are men or women more affected by schizophrenia?
Men and women equally
Is there just one type of schizophrenia?
No, there are many subtypes.
What is the age of onset of schizophrenia?
15-25 years
What type of symptoms preceded psychosis?
Positive symptoms, such as odd behaviors, talking to oneself, etc. In kids, they are usually socially withdrawn, flat affect, keep to themselves, talk to themselves (more than most).
What is the mortality rate with schizophrenia? Outlook?
This is a chronic disease state for most individuals, but a fraction of people “break out” after meds and care home, and it doesn’t come back. Variable. High mortality rate (10%). Often the hallucinations tend to diminish by age 55 or so if they are left untreated and make it through.
What is the best measure/prodromal sign of whether a kid has schizophrenia or will soon have it?
Illicit drug use by the age of 9: self-medication.
What negative symptoms are involved in schizophrenia?
Flat affect
Anhedonia and apathy
Lack of volition
Social and emotional withdrawal
Disorganized speech, thinking, and behavior
Impaired attention (because of running commentary)
Poor self-care
What is the biggest take-away when treating people with schizophrenia?
They need empathy, not judgement. Try to understand what they are going through, and the reasons that it is hard for them to stay compliant.
What does the development of schizophrenia have to do with?
It is a neurodevelopment disorder, with genetic and environmental causes. Anatomic irregularities are present, such as enlarged cerebral ventricles, reduced cortical mass (gray matter), hypofrontality (reduced processing in the prefrontal cortex).
What increases susceptibility to schizophrenia?
Perinatal insults and traumatic early life events
What kind of treatment options are out there to treat schizophrenia?
Frontal lobotomy (permanently debilitating)
Psychotherapy (ineffective by itself)
Cognitive Behavioral Therapy (improve social skills, life skills, personal hygiene, etc - teach them)
Self-medication with nicotine (very common)
Antipsychotics
What does treatment with antipsychotics usually do in schizophrenia?
Reduces auditory hallucinations
Brings awareness of running commentary, and a recognition that it is not real
Which method is most effective? How effective is it? What changes about the relapse rate?
Neuroleptics or major tranquilizers (aka antipsychotics) are the most effective means of treating psychotic symptoms. Less effective on social problems, still need CBT.
Effective on 70% of psychotic patients (still 30% untreatable)
Reduces 12 month relapse rate from 90% w/o drugs to 40% w/ drugs.
When do the effects begin?
- Tranquilizer
- Diminished psychotic symptoms
- Full antipsychotic effects
- Improvement may be seen up to…
Tranquilizing effects may be seen in minutes to hours (vitamin I)
Diminished psychotic symptoms within 24-28 hours
Full antipsychotic effects evolve over 2-8 weeks
Improvement may continue for up to 6 months
What do the antipsychotics have in common about how they work?
They are all D2 dopamine receptor antagonists or weak partial agonists.
The antipsychotic affinity for D2 receptors correlates with average clinical dose (approximating potency)
What subtypes of dopamine receptors are D2?
D2, D3, D4
True or false: in antipsychotics, potency and affinity of drugs are directly related?
True
In the G-alpha-i receptor, what happens to adenylyl cyclase?
It decreases
What type of symptoms do antipsychotics cause?
PD-like symptoms from the nigrostriatal pathway
What are the dopaminergic pathways in the brain?
- mesocortical (VTA to frontal and prefrontal cortex)
- mesolimbic (VTA to nucleus accumbent in limbic area)
- nigrostriatal (Substantia nigra to striatum in basal ganglia)
- tuberoinfundibular (hypothalamus to pituitary) - endocrine
What does VTA stand for?
ventral tegmental area
What are the 1st gen antipsychotics?
- Phenothiazines and related thioxanthines
- Butyrophenones and related
What are the phenothiazines and related thioxanthines?
Chlorpromazine
Thioridazine
Fluphenazine
Thiothixene
Which is the “grandparent of all antipsychotics?”
Chlorpromazine
What are the butyrophenones and related antipsychotics?
These are more D2 selective:
- Haloperidol (still in use, effective and cheap)
- Pimozide (for terets)
What are the 2nd generation antipsychotics?
Dibenzazepines (clozapine, loxapine, olanzapine, quetiapine)
Others (risperidone, ziprasidone, aripiprazole, lurasidone, etc.)
What drug is the gold standard as an antipsychotic? Why?
clozapine. It seems to treat a subset of people that would otherwise be unreached.
What are the side effects of antipsychotics on the nigrostriatal pathway?
- initiation and control of movement and muscle tone
- Selectively degenerated in PD
- Involved in OCD
- Antagonism of D2 receptor in the basal ganglia produces extrapyramidal side effects (EPS)
What do EPS symptoms look like? How soon after dosing do they usually occur?
- Akathisia (constant movement) - after a few months
- Dystonia (torticollus, spasms of neck and face muscles, ocular dysfunction) - early, within 1-2 doses
- Respiratory distress - pharyngeal/laryngeal dysfunction
- Pseudo-PD - around 6 months
If you see dyskinesias, does it necessarily mean that you are seeing EPS effects?
No, it could be several things, such as EPS, psychosis itself, or PD-like dyskinesias associated with the disease or treatment.
When you use a D2 antagonist, what is the effect?
You are inhibiting an inhibition of ACh, so you get a greater response than if there was no D2 agonists at all. Response is greater.
What do you need to offset the imbalance of dopamine caused by D2 antagonists?
Muscarinic antagonists block both the direct and indirect pathway, and “reset” the motor output imbalance.
What are tardive dyskinesias?
Involuntary movements of the tongue, lips, head and neck. Can include eye rolling, tongue rolling, grimacing, and lip smacking.
What % of people get tardive dyskinesias? What is it related to?
It occurs in up to 50% of people being treated with antipsychotics long-term (after a few years). It is frequently irreversible, and severity is related to dose, duration of treatment, and gender.
EPS or motor side effects:
- what is it related to?
- How do you treat?
- Gender susceptibility?
- What can EPS lead to?
- What does selectivity of antipsychotics have to do with EPS?
- Do 1st gen or 2nd gen cause more side effects?
- Related to dose: usually initial high bolus dose or initial depot injection
- Treat by decreasing dose, changing drugs, adding anti-PD drugs
- Women are more sensitive than men
- EPS can lead to irreversible tardive dyskinesias
- Less selective antipsychotics cause less EPS than the selective ones
- In general, the 1 st generation drugs cause more EPS
How is muscarinic receptor affinity correlated with EPS?
Muscarinic receptor affinity is inversely correlated with EPS. So the antimuscarinic with high affinity (a low Kd value) has a low frequency of EPS. In contrast, a high Kd value (low affinity) has a higher frequency of EPS.
What is an example of an antipsychotic with a high affinity for M1 receptors?
Thioridazine and clozapine = low EPS
What is an example of an antipsychotic with a low affinity for M1 receptors?
Fluphenazine and haloperidol = high EPS frequency
When an imbalance of dopamine occurs with D2 antagonists (too much signal in D1), what is the result?
EPS
When there is not enough signal at the D2 receptors, super sensitization occurs. What is the result of this?
Tardive dyskinesia
What are the side effects associated with the tuberinfundibular pathway?
Prolactin-related
What effects does D2 antagonism have on the tuberinfundibular pathway?
Increased prolactin release (increased lactation, gynecomastia, disturbed thermal regulation, amennorhea, infertility, sexual dysfunction).
What prolactin level increases the risk of breast cancer?
Levels over 100 ng/mL. Antipsychotics generally do not get to this level.
Compare 1st and 2nd generation antipsychotics:
1) Affinity for 5-HT2 receptors
2) Affinity for D2 receptors
3) Incidence of EPS and endocrine SE’s
4) Which as a first line therapy?
1) SGA’s have higher affinity for 5-HT2 receptors
2) SGA’s have lower affinity for D2 receptor by 5-50X
3) SGA’s generally have lower incidence of EPS and endocrine SE’s
4) SGA’s are recommended as first line therapies
Serotonergic CNS pathways:
- projections from the raphe to the prefrontal cortex, hypothalamus, limbic areas, spinal reflex areas, and basal ganglia
- 5HT2 receptors modulate dopamine release
What theory explains lower EPS associated with combination 5-HT2 antagonism with lower affinity D2 antagonism?
It doesn’t have a name, but the theory suggests that antipsychotics that combine 5-HT2 antagonism with lower affinity D2 antagonism have fewer EPS because 5HT modifies dopamine in the basal ganglia.
How does blocking 5HT2 receptors affect dopamine?
There are 5HT2 receptor on dopaminergic neurons that modulate dopamine release. Normally, agonist activity at the 5HT2 receptor would prevent dopamine release. If there is antagonist activity at that dopaminergic neuron, then the dopamine would not be released. If the antagonist signal is blocked, then the dopamine is not prevented from being released.
If you prevent developing EPS, what are your chances of developing tardive dyskinesia?
Greatly reduced your chances
What drugs have a low frequency of EPS?
(2nd gen) clozapine quietiapine (1st gen) thioridazine Other 2nd gens are relatively low, except for risperidone, which is moderate
What drugs have a high incidence of EPS?
(1st gen) Fluphenazine Haloperidol Thiothixene Chlorpromazine and risperidone are moderate
Which drugs are highly sedating?
chlorpromazine
thioridazine
clozapine
quetiapine
Which drugs do not have much sedation?
Fluphenazine Haloperidol Thiothixene Olanzapine Risperidone Ziprasidone Aripiprazole
Which drugs have a high risk of hypotension?
Chlorpromazine
Thioridazine
clozapine
Which drugs have anticholinergic side effects?
High: thioridazine moderate: chlorpromazine clozapine olanzapine
Which drugs are most associated with weight gain?
High: clozapine olanzapine chlorpromazine thioridazine Moderate: quetiapine risperidone paiperidone Iloperidone (Aripiprazole may be low to moderate)
What are the effects of alpha-1 antagonism?
Blocks construction of blood vessels, causing hypotension
Heart rate may increase due to baroreflex
What are the effects of muscarinic cholinergic antagonism?
It blocks the affect of ACh to slow the heart rate down, causing tachycardia. Also, it dries you up.
What are the effects of H1 antagonism?
H1 antagonism is the act of an antihistamine.
- Drowsiness
- Sedation
- Anti-nausea effects on vestibular apparatus
When is H1 antagonism useful?
In acute treatment of florid psychoses with agitation - people who haven’t slept and are wired. This will calm them down.
Not for patients on prophylactic or chronic therapy who are responding well to treatment.
What can cause the weight gain associated with antipsychotics?
5HT2 antagonism
H1 antagonism
alpha-1 adrenergic receptor blockade?
What physiologic things are occurring that makes someone gain weight with antipsychotics?
Increased appetite Increased fat storage Slow metabolism Sleep apnea Hypercholesterolemia Insulin insensitivity and hyperglycemia
What monitoring should a patient have in terms of weight gain issues if they are on an antipsychotic?
Lipids
Weight
HbA1c
BP
What drugs are associated with low weight gain, or are neutral?
Ziprasidone
Molindone
Haloperidol
Asenapine
What is considered large weight gain?
4-6kg
What is considered moderate weight gain?
1-3 kg
What drugs have the highest risk of QT prolongation?
ziprasidone, pimozide, thioridazine
What activities increase the risk of QT prolongation?
- muscarinic and alpha-1 antagonist activities
- weight gain and cardiovascular disease increase
- smoking
What are elderly patients taking antipsychotics at risk of when they have dementia-related psychosis?
Sudden death: 4.5% compared to 2.6%. Cardiovascular or infectious.
What syndrome is possibly related to D2 antagonism, that people are vulnerable to with EPS, that manifests itself with hyperthermia and diaphoresis, altered mental status, fluctuating blood pressure and pulse, tremor, and acute renal failure?
Neuroleptic malignant syndrome. It is very rare.
How do you treat neuroleptic malignant syndrome?
- Immediately discontinue all antipsychotic medications
- Dantrolene may be helpful
- Bromocriptine may be helpful
How is neuroleptic malignant syndrome related to serotonin syndrome?
Muscle metabolism significantly increases, which is why Dantrolene is useful.
What kind of hypersensitivity reactions can occur with antipsychotic medications?
- From phenothiazines, primarily (5%)
- Dermal reactions including rash and photosensitivity
- Ocular opacities of the cornea and lens
- Jaundice
Which antipsychotic has the highest alert for hypersensitivity reactions?
Asenapine: serious hypersensitivity and anaphylaxis alert. Probably shouldn’t be on the market - no special features.
Unique advantages of clozapine:
- unique effectiveness in 25-30% of treatment-resistant patients
- No reported EPS
What are the toxicities of clozapine?
- Leukopenia can lead to agranulocytosis in 1.3% on clozapine. This leads to fatalities in 4-16% of cases.
- Myocarditis
- Cardiovascular collapse (hypotension, respiratory and/or cardiac arrest)
- Decreased seizure threshold
- Sedation, antimuscarinic effects (especially constipation)
What line agent is clozapine?
A third-line agent
Why does clozapine have so many side effects, but no EPS?
Because it hits so many different types of receptors.
Olanzapine:
- what is this similar in structure to?
- Does this have the same types of toxicities as clozapine?
- What level of effectiveness is this out of the antipsychotics?
- What line agent is this?
- What is the major side effect associated with this drug?
- clozapine
- lacks unique toxicities of clozapine
- 2nd most effect antipsychotic
- 3rd line agent because of its side effect
- Problematic weight gain is happening at effective doses.
Quetiapine:
- most problematic side effect?
- EPS possibility?
- Adrenergic blockade level?
- Weight gain/metabolic syndrome risk level?
- Sedating (can be useful to reduce anxiety and agitation)
- Low EPS (active metabolite is anti-muscarinic)
- Low adrenergic blockade (maybe why weight gain is so low)
- Moderate weight gain/risk of metabolic syndrome
Risperidone:
- Sedation level?
- What is a common problem?
- What do high doses increase the risk of? Why?
- What is it approved for in autism spectrum disorders?
- Lack of sedation
- Restlessness and agitation is a problem
- EPS risk is increased with high doses. The D2 antagonism is greater, which increases the risk of EPS.
- Approved for irritability in autism disorder in ages 5 and up
Paliperidone:
- What is this a metabolite of?
- What kind of dosing do you get with sustained released formulation?
- hydroxy metabolite of risperidone (similar pharmacological profile including restlessness and EPS)
- Sustained release form leads to once monthly dosing
Ziprasidone and Lurasidone:
- Any weight problems?
- EPS?
- What is the main problem with these meds? Is it equal for both drugs?
- Low weight gain
- Low EPS problems
- Problems with QT prolongation, less with lurasidone
Iloperidone:
- EPS?
- Anti-cholinergic effects?
- Weight gain?
- What is the main problem with this medication?
- Low EPS
- Anti-cholinergic effects
- Low weight gain
- Hypotension is a problem and requires dose titration
Asenapine:
- Weight gain?
- Sedation? From what?
- Off-label use?
- What is concerning?
- Minimal weight gain
- Extreme sedation from histamine receptor antagonism
- Off-label used to treat PTSD
- Serious hypersensitivity reactions
- Concern with EPS due to low affinity for muscarinic receptors
Aripiprazole:
- dopamine agonist/antagonist? What does this mean in terms of side effects?
- What kind of receptor sensitization does this have?
- What are some problems you can have?
- Efficacy?
- dopamine partial agonist (~30%)
- This means transient nausea rather than blocking nausea
- No endocrine disturbances (slight decrease in prolactin)
- No receptor desensitization (low risk for EPS or TD)
- Agitation may be a problem in some, alpha-a antagonism may be a cause of weight gain with time
Brexpiprazole:
- similar to what?
- What type of antagonism does it have?
- Histamine affinity?
- Common side effects?
- EPS risk?
- similar to aripiprazole but weaker D2 partial agonism
- partial agonist at 5HT1A
- antagonist at 5HT2 receptors
- alpha-1 antagonist
- low affinity for histamine receptors
- Akathisia and moderate weight gain
- low EPS and TD risk
Cariprazine:
- similar pharmacology to what?
- dopamine affinity?
- EPS?
- Weight gain?
- Aripiprazole (partial D2 agonist, 5HT1A partial agonist, 5HT2 antagonism)
- D3 partial agonist with higher D3 than D2
- EPS SEs in 1/4 to 1/3 of patients
- Low weight gain
What is the “choosing wisely initiative?”
Guidelines for prescribing antipsychotics. Suggests that proper evaluation always be used, 2 or more antipsychotics shouldn’t be used at the same time, don’t use as first-line for dementia, insomnia, or in kids besides psychotic disorders.
What other indications can antipsychotics be used for?
- Tourette’s (too much dopamine, use D2 antagonist)
- Neuroleptanesthesia (uses antipsychotic and fentanyl)
- Depression (in adjunct to antidepressants)
- Behavioral problems
- Bipolar
- Severe nausea and vomiting (D2 antagonism blocks)
- Intractable hiccups - thorazine only
- Insufficient lactation (inhibits D2 inhibition of prolactin release) - antagonist rather than partial agonist should be used.
