Exam 4 lecture 2 Flashcards
What is the concentration at which drug occupies 50% of receptors? What is 1 order above that limit? One order below?
1 order above- Kd=90%
1 order below- Kd=10%
What percent occupancy do we need dopamine receptors for antipsychotic efficacy?
60-70%
How can we measure dopamine receptor occupancy and serotonin receptor occupancy?
PET
Receptor occupancy and antipsychotic effect of risperidone?
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.
What are the drug induced movement disorders
Extrapyramidal symptoms (30-50%)
Tardive dyskinesia
Neuroleptic malignant syndrome (NMS)
What percent of people have EPS? What are the symptoms? When does it occur?
Occurs in 30-50% of people
occurs early, days/weeks, reversible
symptoms-
Dystonia- increased muscle tone
Pseudoparkinsonism- muscle rigidity
Tremor
Akathisia- restelssness
Drug therapy to treat EPS?
-Benztropine (Cogentin), trihexyphenidyl (Artane), or akineton (Biperiden) –anticholinergic agents
– Diphenhydramine (Benadryl) – Antihistamine
– Amantadine (Symmetrel) – Dopamine releasing agent
– Propranolol – used for akathisia
Rationale for using anticholinergics to treat EPS
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.
What percent of people will have Tardive dyskinesia? When does it occur? Reversible? Symptoms? Monitoring? MOA?
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
Treatment of tardive dyskinesia
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
What are the newer drug therapies for TD
VMAT2 inhibitors
What are some VMAT inhibitors for tardive dyskinesia and huntingtons (which do they treat)
Tetrabenzine (xenazine)- huntingtons chorea
valbenzine (ingrezza)- TD
Deutetrabenazine- both
VMAT2 MOA? Use?
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.
What is NMS? symptoms? treatment?
EPS symptoms with fever.
impaired cognition- agitation, delirium, coma
muscle rigidity
treatment
restore dopamine balance - discontinue drug
- DA agonist, diazepam or dantrolene
What are the therapeutic uses of antipsychotic drugs
Treatment of psychosis
Anxiety treatment (Overkill)
mood disorders (mania and depression)
Tourettes
How long does it take to treat psychosis with antipsychotics?
How do antipsychotics treat mood disorders?
How to treat tourettes with antipsychotics
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
What are some miscellaneous uses of antipsychotics? What drugs do we use?
huntingtons chorea
-tetrabenazine, deutetrabenazine
intractable hiccups
-chlorpromazine
Alcohol withdrawals (hallucinations)
- haloperidol
Nausea and vomiting
-metoclopramide, promethazine
Potentiation of opiates and sedatives
-droperidol
What are some pharmacologic effects of antipsychotics
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
Know this for exam
What are the types of adverse pharmacologic effects of antipsychotics
- Autonomic
- CNS
- Endocrine
- other
Know this for exam
What are the mechanisms of autonomic adverse pharmacologic effects of antispychotics? WHat are the different manifestations of these mechanisms?
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
What are the different mechanisms of CNS advrese pharmacologic adverse effects of antipsychotics? What are the manifestations of these mechanisms
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
What are the different mechanisms of endocrine adverse pharmacological effects of antipsychotics? How are they manifested?
Dopamine receptor blockade resulting in hyperprolactinemia. Manifested by Amenorrhea-galactorrhea, infertility, impotence
How does weight gain happen in antipsychotics
H1 and 5ht2C blockade
precautions and contraindications of antipsychotics
cardiovascular
parkinsosn disease
Epilepsy (clozapine will lower seizure threshold)
Diabetes
What are drugs that have a high 5-HT2a/D ratio
Haloperidol, fluphenazine, chlorpromazine, thiothixene
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)
If a drug has high propensity to cause hypotensive effects, what receptors does it block?
alpha
(chlorpromazine)
Which receptors are responsibe for sedation?
Histamine
What are typical 1st gen antipsychotics characterized by?
More movement problems, increased EPS and tardive dyskinesia due to strong D2 block
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
What are some aliphatic phenothiazines and their uses
Chlorpromazine- no longer 1st line
promethazine- used for H1 antagonist properties
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
Name antipsychotics and their side effects
Thioxanthines- modest EPS
butyrophenones (haloperidol)- EPS
What are some miscellaneous antispychotic? What are their uses?
Molindone- may cause moderate EPS
Pimozide is used in tourettes disease tics
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
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)
why do typical antipsychotics lead to movement disorders
They block D2 receptors (post synaptic dopamine receptors).
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.
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)
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
What are some antipsychotic drugs under investigation
Dual M1/M4 muscarinic agonist combined with peripheral muscarinic antagonist
5HT receptor ligands (14 receptors, 5HT3)
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
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
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
Disease onset of schizophrenia
Men- late teens, early 20s
Women- late 20s, early 30s
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.
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
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)
Is oral antipsychotic drug therapy 1st line or IM depot therapy?
Oral is 1st line unless patient presents reasons to consider IM drug therapy
compare efficacy for typical (older) vs atypical (newer) agents
Efficacy for positive symptoms is similar to atypical antipsychotics
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
What antipsychotics are assiciated with akathisia more than others
Partial agonists (stabilize dopamine transmission)
what boxed warnings do all partial agonists have?
Suicidal thoughts/behaviors
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
Which drugs are “the pines”?
Asenapine
Clozapine
Olanzapine
Quetiapine
associated with significantly less EPS/ Higher weight gain than others
Asenapine dosage form, substrate and side effects
Sublingual and patch formulations
1A2 substrate
QTc prolongation
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
Olanzapine Substrate, side effects, warning
1A2 substrate
Significant weight gain and sedation
High risk metabolic syndrome
DRESS warning
Quetiapine substrate, side effects? Boxed warning?
3A4 substrate
QTc prolongation
Weight gain and sedation
Boxed warning for suicidal ideation
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
Monitoring clozapine
Monitoring timelines weekly x 6 months, then every 4 weeks
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
What drugs are referred to as the “dones”
Iloperidone
Lurasidone
Ziprasidone
Risperidone
Paliperidone
Iloperidone substrate? Side effets?
2D6 substrate
Higher risk for orthostasis and syncope
QTc prolongation
Lurasidone substrate? side effects?
3A4 substrate
higher risk for akathisia
warning for suicidal thoughts (adjunct for bipolar depression)
Take with food to increase bioavailability?
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)
Risperidone substrate? Side effects?
2D6 substrate (minor 3A4)
EPS, hyperprolactinemia, weight gain, sedation, orthostasis
Paliperidone side effects? How is it eliminated?
EPS, hyperprolactinemia, weight gain, sedation, orthostasis
QTc prolongation
Renally eliminated. Dose adjustment in renal impairement
Lumateperone side effects? substrate?
Low risk for EPS or akathisia
Low risk for weight gain or metabolic side effects
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
