Pharmacology of antipsychotic agents Flashcards
All antipsychotics have some propensity to lengthen
QTc intervals but these vary widely
What are the four pathways for the dopaminergic system in the brain?
Nigrostriatal pathway, mesolimbic pathway, mesocortical pathway, tuberinfundibular pathway
What is the hypothetical function of the Nigrostriatal pathway?
Neurons start in the substantia nigra and project to to the striatum for control of motor function. The death of neurons in this pathway can result in Parkinson’s disease.
What is the hypothetical function of the Mesolimbic pathway?
Neurons project from the ventral tegmental area to the nucleus accumbens, amygdala, and hippocampus. They play a role in reward and desire, addiction, motivation, and emotional response. If not functioning properly they can cause hallucinations.
What is the hypothetical function of Mesocortical Pathway?
Neurons project from the ventral tegmental area to the prefrontal cortex. They are involved in memory and creation of memories. Amnesia and memory issues are a result of inappropriate functioning of this pathways.
What is the hypothetical function of Tuberinfundibular pathway?
Neurons start in the hypothalamus and project to the pituitary gland. They play a role in hormonal regulation, maternal behavior and nurturing, pregnancy, and sensory processes. malfunctioning of these pathways can cause hallucinations and interpersonal issues.
CAΨs
Conventional antipsychotics
What receptors do conventional antipsychotics affect?
non-elective dopamine receptor antagonism
What are the three categories of conventional antipsychotics?
phenothiazines, butyrophenones, and thioxanthines
Neuroleptic agents that affect a variety of receptors including dopaminergic receptor sites.
What are phenothiazines
Phenothiazides are used to treat…
psychosis including schizophrenia; violent agitated, disturbed behavior, and mania secondary to bipolar disorder.
Phenothiazides work by binding to
dopamine (D1 and D2), muscarinic, histamine H1, and serotonergic 5HT2 receptors.
Phenothiazides also possess peripheral
adrenergic receptor blockage and quinidine-like cardiac effects.
Phenothiazides may do what to seizure thresholds?
lower them
What are the signs of clinical toxicity in someone taking phenothiazides?
sedation, coma, hypotension, EPS, and cardiac arrythmias
What type of side effects can be seen with phenothiazides?
Anticholinergic effects including blurred vision, decreased GI motility, delirium, agitation, hallucination, hyperthermia, tachycardia, and seizures
Name 9 types of phenothiazides?
Chlorpromazine, fluphenazine, mesoridazine, perphenazine, prochlorperazine, promazine, thiridazine, Trifluoperazine and triflupromazine
This conventional antipsychotic group is similar to phenothiazides, though probably with less antiadrenergic, anti-histaminic and anticholinergic, and more anti-dopaminergic effects.
Butyrophenones
What are the nine types of Butyrophenones?
Haloperidol, Droperidol, Bromperidol, Benperidol, Tifluperidol, Melperone, Piamperone, Moperone, Fluanisone
This conventional antipsychotic is more selective D2 agonists and are used most often in children and adolescents. Their side effect profile is like other conventional antipsychotics but also includes restless leg syndrome.
Thioxanthenes
What are the seven types of thioxanthenes?
Flupentixol, thiotixene, zuclopenthixol, chlorprothixene, lucanthone, clopenthixol, hycanthone
What is a causative factor in the undesirable side effects in conventional antibiotics?
to block adequate numbers of D2 receptors in the mesolimbic dopamine pathway to quell positive symptoms, one must simultaneously block the same number of D2 receptors throughout the brain, and this causes undesirable side effects.
When dopamine D2 receptors in the tuberoinfundibular DA pathway are also blocked by conventional antipsychotics it can cause…
sedation, motor issues, increased plasma prolactin concentrations (hyperprolactinemia).
Hyperprolactinemia can cause conditions such as
galactorrhea (breast secretions), amenorrhea, and may interfere with fertility, demineralization of bones, gynecomastia, sexual dysfunction and weight gain
When dopamine D2 receptors in the nigrostriatal DA pathway are also blocked by conventional antipsychotics this causes
EPS such as akathisia, tremors, dystonia, parkinsonism, tardive dyskinesia
The blockade of histamine H1 receptors in conventional antipsychotic drugs causes
weight gain and drowsiness
The blockade of a1-adrenergic receptors in conventional antispsychotic drugs causes
cardiovascular side effects such as orthostatic hypotension and drowsiness
Low potency conventional antipsychotics require higher doses but
in addition low potency agents tend to have more of the unwanted side effects and are more sedating in general then high potency ones
AAΨ
Atypical Antipsychotics
What differentiates AAΨ from CAΨ in terms of effectiveness and side effects.
AAΨ have a clinical profile of equal positive symptom antipsychotic actions, but lo EPS and hyperprolactinemia compared to conventional
The current atypical antipsychotics as a class are defined as
serotonin-dopamine antagonists with simultaneous serotonin 5HT2A receptor antagonism that accompanies D2 agonism.
AAΨ have additional properties that are important such AS
antidepressant actions
All antipsychotics are effective for psychotic mania but atypical antipsychotics appear to have greater efficacy for
nonpsychotic mania
Which AAΨ has the best anecdotal and clinical evidence for utility in various anxiety disorders
quetiapine
What are the three receptors that are blocked by AAΨ that theoretically are responsible for causing sedation?
M1 Muscarinic cholinergic receptors, H1 Histamine receptors, and a1 adrenergic receptors.
Clozapine, quetiapine, olanzapine, and iloperidone are all more potent
H1 antagonists than D2 antagonists
Only the pines clozapine, quetiapine, and olanzapine have high potency for
muscarinic receptors
All AAΨ have at least moderate binding potency to this receptor, but the most potent are clozapine, quetiapine, risperidone, and iloperidone
a1 adrenergic antagonism
Which two AAΨ have a high metabolic risk?
Clozapine and olanzapine
Which four AAΨ have a medium metabolic risk?
risperidone, paliperidone, quetiapine, iloperidone (weight only)
Which four AAΨ have a low metabolic risk?
ziprasidone, aripiprazole, lurasidone, iloperidone (low for dyslipidemia)
What are the four parameters that should be tracked when prescribing AAΨ?
weight (BMI), fasting triglycerides, fasting glucose, and blood pressure
What are the major factors that determine whether a patient progresses along the metabolic highway to premature death?
unmanageable factors: genetic makeup and age
Manageable factors: change in lifestyle
Most manageable factors: selection of the antipsychotic
How to remember the AAΨ
The pine (peenz), the dones (dohnz), two pips, and a rip, and the others
Identify the three pertinent “Pines”
Clozapine (clozaril), Olanzepine (Zyprexa), Quietiepine (Seroquel)
The presence of what in Clozapine is linked to its lack of EPS, tardive dyskinesia and hyperprolactinemia?
The presence of serotonin 5HT2A antagonism
The gold standard for efficacy in schizophrenia
Clozapine
Clozapine may have a particular niche in treating
aggression and violence in psychotic patients
Clozapine is the only antipsychotic documented to reduce the risk of this in schizophrenia
suicide in schizophrenia
Clozapine may reduce this in some patients with this problem, especially over long treatment intervals.
tardive dyskinesia
What is the most important thing to monitor with Clozapine?
Absolute neutrophil count for as long as they are treated with clozapine due to its occasionally fatal complication of agranulocytosis
Clozapine may have the greatest efficacy but also the most side effects among the AAΨ. Side effects include:
seizures, sedation, excessive salivation, myocarditis, and the greatest degree of weight gain and cardiometabolic risk
Due to its side effects and risks clozapine is considered
NOT first line, but is used when other antipsychotics fail
Olanzipine is BLANK potent than clozapine
more
Olazipine has LESS
EPS, sedation, prolactinemia
Olazipine has significant side effects such as
weight gain, cardiometabolic risks, dyslipidemia (elevating triglycerides) or diabetes,
As far as when to prescribe Olanzipine it is considered
second line
Quetiapine has a different formation that includes an active metabolite
norquetiapine
Quetiapine is BLANK potent than clozapine
MORE
Quetiapine has a robust
antidepressant effects
Quetiapine should be taken
at night because it is most sedating at its peak delivery shortly after taking it
The antipsychotic quetiapine is
an 800 mg ideally XR formulation
The antidepressant quetiapine is
300 mg ideally XR formulation
The sedative hypnotic quetiapine is
50 mg in the IR formulation
Quetiapine is the preferred atypical antipsychotic for patients with
Parkinson’s disease who require treatment for psychosis (as is clozapine)
Quetiapine has many side effects such as
weight gain, increase in fasting triglycerides, and insulin resistance
Name the four “dones” (dohnz)
Risperidone, Paliperidone (invega), ziprasidone (geodon), lurasidone (latuda)
This medication is available in a long term depot injectable formulation lasting for 2 weeks, an oral disintegrating tablet, and liquid formaluation
risperidone
What side effects are serious concern for risperidone?
it raises prolactin levels even at low doses, weight gain (especially in children), and dyslipidemia
This is the active metabolite of risperidone
Paliperidone
A big difference between paliperidone and risperidone IS
that paliperidone is eliminated upon urinary excretion and SO has few pharmacokinetic drug interactions and it comes in a sustained-release formulation
This AAΨ has a formulation for a depot long term administration of every 4 weeks and is currently the preferred depot AAΨ.
Paliperidone
What makes Ziprasidone unique?
It has little or no propensity for weight gain and little issue with dyslipidemia, elevation of fasting triglycerides, or insulin resistance
How should ziprasidone be taken?
Twice a day and with food (at least 500 calorie meal)
This AAΨ has an intramuscular dosage formulation for rapid use in urgent circumstances
ziprasidone
What cardiac complication can be caused by ziprasidone?
QTc prolongation
Lurasidone has a high affinity for
5HT7 and 5HT2A
What are the benefits of Lurasidone?
little sedation if dosed at night and little weight gain or dyslipidemia (may reverse previous weight gain or dyslipidemia associated with a different AAΨ). It has both antipsychotic and some antidepressant effects.
What are the two pips and a rip?
Aripiprazole (abilify), Brexipiprazole (Rexulti), Cariprazine (Vraylar)
Aripiprazole is a
D2 partial agonist and 5HT1A partial agonist
Aripiprazole is effective in treating
schizophrenia ages 13 and up, mania/mixed mania age 10 and older, and autism related irritability in children ages 6-17
Benefits of Aripiprazole include
little or no propensity for weight gain, dyslipidemia, elevation of fasting triglycerides or insulin resistance
Brexpiprazole is used to treat
schizophrenia, mania, agitation and psychosis in dementia
This AAΨ is still under investigation, but has the interesting potential for development as a weekly, biweekly, or even monthly oral depot
Cariprazine
What are the three “other” AAΨ
sulpiride, amisulpride, Sertindole
Conventional antipsychotics have lots of side effects due to
dopamine D2 antagonism
Atypical antipsychotics have decreased side effects because
D2 antagonism, D2 partial antagonism, 5HT2 antagonism and 5HT1A partial agonism
