Pharm: Antipyschotics

Question 1

Aripiprazole

Answer 1

• atypical antipsychotic

USE: schizophrenia and BPD (both positive and negative sx)

MOA: medium D2/5-HT2a ratio (partial agonist of dopamine)

• high clinical potency
• very low EPS
• very low sedative action
• low hypotensive action

(NOTE: has higher D2 potency, w/out EPS d/t being a partial agonist of D2) - maintains 25% dopamine response level

ADRs: lower weight gain liability, novel mechanism

SE: dizziness, hypotension, nausea, vomiting

Question 2

Quetiapine

Answer 2

• atypical antipsychotic
• low D2/5HT ratio (low affinity at both receptors!)
• low potency
• very low PES
• medium sedative and hypotensive actions

MOA: has higher affinity at H1 and α1 receptors leads to sedation and orthostatic hypotension
- minimal EPS, no PRL

ADR’s * similar to olanzapine w/ less w/g

• requires twice a day dosing
• somnolence!!!
• QT prolongation

Question 3

Risperidone

Answer 3

• atypical antipsychotic

MOA: high affinity for 5-HT2A receptors, D2 and a1 receptors, little affinity for muscarinic receptors

• very low D2/5HT ratio
• high potency
• low EPS, sedative and hypotensive actions

ADRs:

• broad efficacy, little or no EPS at low doses
• see EPS and hypotensive actions at high doses!
• Risk for intraoperative floppy iris syndrome

** has highest potential for EPS and hyperPRL compared to other atypical agents

Question 4

Olanzapine

Answer 4

• atypical antipsychotic
• low D2/5HT ratio
• high potency
• low EPS and hypotensive
• medium sedative action

** effective against negative and positive sx; very little EPS

ADRS: WEIGHT GAIN!!! dose related lowering of seizure threshold (not first choice d/t really high risk of weight gain)

CI: diabetes

Question 5

Ziprasidone

Answer 5

• atypical antipsychotic

MOA: binds very high to 5-HT2

• low D2/5HT ratio
• medium potency
• low EPS, sedative, hypotensive actions

ADR: less weight gain than clozapine, minimal sedation
** QT prolongation!!!

CI: people w/ MI, arrhythmia, CHF

Question 6

Lurasidone

Answer 6

• atypical antipsychotic
• Newer agent approved for treatment of schizophrenia and bipolar depression (recent marketing)
• Binds D2 and 5-HT2A receptors with high affinity

ADR: Similar side effect profile to ziprasidone, except more sedation and no QT prolongation

Question 7

Clozapine

Answer 7

special use atypical antipsychotic (not first line, but most efficacious)

USE: schizophrenia thats resistant to other tx, and w/ suicidal ideation!

• very low D2/5HT ratio
• medium potency
• very low extrapyramidal and sedative action
• medium hypotensive action
• • has been shown to reduce suicide attempts in pts. w/ schizoaffective disorder at high risk for suicide!
• • may benefit tx resistant pts, w/ little EPS

ADRs:

• may cause agranulocytosis in up to 2% of pts!
• myocarditis!
• dose-related lowering of seizure threshold (seizures CI)
• severe w/g, hyperglycemia
• orthostatic hypotension, antimuscarine SE’s

d/t these ADR’s its usually reserved for suicidal pts.

Question 8

QT prolongation

Answer 8

ziprasidone

quetiapine

Question 9

Haloperidol

Answer 9

• typical high potency antipsychotic agent
• medium D2/5HT ratio
• high clinical potency
• very high extrapyramidal SE’s
• low sedative and hypotensive actions
• generic available but ** severe EPS!!!

Question 10

Chlorpromazine

Answer 10

• typical low potency antipsychotic agent
• phenothiazine derivative
• high D2/5HT ratio
• low clinical potency
• medium extrapyramidal toxicity
• high sedative action and hypotensive action
• generic and inexpensive
• many AEs, esp. autonomic

Question 11

general MOA’s of antipsychotics?

Answer 11

All effective antipsychotics block D2 receptors to some degree, however atypical antipsychotics tend to block 5-HT2A receptors more potently than D2 receptors

Where does dopamine act?
1 - inhibition of dopamine in mesolimbic-mesocortical pathway (xs dopa here leads to positive sx), (dopa loss here mediates negative sx)
2 - nigrostriatal pathway, inhibition of dopamine here causes EPS
3- tuberoinfundibular system: regulates prolactin release –> hyperprolactinemia

D2 receptors are only dopamine receptors shown to play a role in action of antipsychotics

• • D2 binding correlated with antipsychotic potency and extrapyramidal toxicity!
• • atypical antipsychotics are effective at lower D2 receptor occupancy levels, thus in general have less EPS

Question 12

Use of antipsychotics?

Answer 12

USE: acute control and maintenance of schizophrenia

• (for catatonic episode use benzos)
• also useful for acute mania, BPD, schizoaffective disorder, behavioral disturbance dementia, psychotic depression, tourettes, disturbed behavior w/ AD

Question 13

first line tx of schizophrenia?

Answer 13

All atypical antipsychotics (except clozapine and olanzapine)

Question 14

agranulocytosis?

Answer 14

clozapine

Question 15

suicidal pt?

Answer 15

clozapine

Question 16

myocarditis?

Answer 16

clozapine

Question 17

EPS sx of antipsychotics?

Answer 17

• pseudoparkinsonism
• akathisia = uncontrolled restlessness
• acute dystonic reactions

(these can often be treated w/ anticholinergic agent like benztropine)

** never use Levodopa !

dopamine blockade = PD syndrome, akathisia, dystonias
supersensitive to dopa receptors = tardive dyskinesia (choreathetoid mvmts of tongue and body)
muscarinic blockade = toxic confusional state

Question 18

ANS sx of antipsychotics?

Answer 18

muscarinic blockade = loss of accomodation, dry mouth, dificulty urinating, constpiation

alpha adrenergic blockade = orthostatic hypotension, imipotence, sedation, dizziness

Question 19

endocrine sx of antipsychotics?

Answer 19

amenorrhea, galactorrhea, infertility, impotence

d/t dopamine receptor blockade –> hyperPRL

Question 20

hyperprolacinemia sx?

Answer 20

d/t loss of inhibition of PRL secretion by dopamine
* most seen w/ risperidone

least seen w/ olanzapine, quetiapine, aripiprazole -

Question 21

weight gain?

Answer 21

high risk: clozapine** > olanzapine **
intermediate risk: iloperidone, paliperidone, quetiapine, risperidone
lowest risk: aripiprazole, lurasidone, ziprasidone

** hyperglycemia and ketoacidosis may develop in people w/ DM

Question 22

lowest risk of tardive dyskinesia?

Answer 22

quetiapine or clozapine

Question 23

lowest risk of weight gain?

Answer 23

lowest risk: aripiprazole, lurasidone, ziprasidone

Question 24

typical vs. atypical MOA:

Answer 24

Typical: Block dopamine receptors - Especially D2

• Clinical efficacy correlates with this action (increased EPS as a result)
• Messy pharmacology; side effects result from action at muscarinic, histamine, and adrenergic receptors

Typical SE’s: high EPS, highly effective against positive sx, intermediate risk of w/g, LOWER COST

Atypical: Exhibit higher affinity for 5-HT2A receptors than D2 receptors

• Also block DA receptors, including D2
• Clinical efficacy is not necessarily correlated with D2 blockade

Atypical SEs:

• less prone to cause EPS and tardive dyskinesia
• efficacious for positive and neg. sx
• some have high weight gain!
• HIGHER COST

Question 25

A 42-year-old woman develops akathisias, parkinsonian-like dyskinesias, galactorrhea, and amenorrhea as a consequence of psychotropic drug therapy. What drug-receptor-based mechanism, occurring in the central nervous system, most likely caused these responses?

Answer 25

blockade of dopamine receptors

Question 26

Akathisia tx?

Answer 26

if on haloperidol, might see more akathisia

• consider dose reduction if possible
• give Lorazepam (benzo), propranolol (beta blocker), or benztropine (antimuscarinic, antihistamine)

Question 27

tx of parkinsonian syndrome assoc. w/ haloperidol?

Answer 27

Benztropine, amantadine

Question 28

late vs. acute onset of AE on motor systems?

Answer 28

acute onset: Extrapyramidal symptoms

• Usually occurs within days of treatment initiation
• Direct result of D2 blockade in basal ganglia
• Treatable

Late-onset: Tardive dyskinesia

• Occurs after years of antipsychotic use
• Imbalance of cholinergic (relative deficiency) and dopaminergic (relative supersensitivity) activity
• May be irreversible
• • don’t give anticholinergics here

Question 29

tx of dystonia assoc. w/ haloperidol?

Answer 29

Switch to a different antipsychotic

Benztropine or diphenhydramine (prophylactic with IM haloperidol)

Question 30

tardive dyskinesia???

Answer 30

seen in late-onset

Motor dysfunction - stereotypical, repetitive, involuntary movements

• Lateral jaw movements
• Lip smacking or sucking
• Twisting and protrusion of the tongue
• Purposeless movements of the extremities

tx: Decrease the dose of the antipsychotic
- Initially the dyskinesia will get worse
- Over the next several weeks it may improve
- Consider switching to quetiapine or clozapine

Question 31

A 33-year-old female patient who has been treated with haloperidol presents at the ED. Her husband reports that she has complained of rapidly worsening fever and muscle stiffness, and she has “the shakes” (tremor). Her level of consciousness is diminishing. Her temperature is 104ºF, and her blood creatine kinase level is elevated. What is the most likely explanation for these findings?

Answer 31

Answer: neuroleptic malignant syndrome

Rare (0.5-1.0%) but life-threatening (10-20% mortality)

Tetrad of clinical features:

• Fever
• Muscle rigidity
• Mental status changes
• Autonomic instability

Treatment

• Cardiovascular support
• Stop antipsychotics and anticholinergics
• Antipyretics for symptoms
• Dopamine agonist (e.g., bromocriptine) can be used, evidence for efficacy is limited
• Muscle relaxants (e.g., diazepam or dantrolene)

Question 32

Case; Chlorpromazine and haloperidol can be considered prototypes of two relatively old but still-used antipsychotic drug classes: the phenothiazines and the butyrophenones, respectively. While many of the actions and side effects of these drugs are qualitatively similar, they are different quantitatively: that is, in terms of incidence and severity. Which effect or side effect typically occurs more frequently, is usually more severe, and has a relatively rapid onset, with haloperidol?

Answer 32

haloperidol is high potency, resulting in high EPS

Question 33

We perform a meta-analysis on the ability of various antipsychotic drugs to cause constipation, urinary retention, blurred vision, and dry mouth—all of which reflect significant blockade of muscarinic receptors in the peripheral nervous system. Which of the following drugs most likely caused these unwanted effects?

Answer 33

chlorpromazine! its very promiscuous, it works at various other receptors: histamine, adrenergic and cholinergic receptors

Question 34

haloperidol vs. chlorpromazine?

Answer 34

Haloperidol: higher affinity for D2 antagonist: lower affinity for others (D2 > D4 > α1 > 5-HT2A > D1 > H1)

• Highly effective against positive symptoms; some effect on negative symptoms
• Greater potential for extrapyramidal side effects than some typical (and all atypical) antipsychotics

Chlorpromazine: Relatively promiscuous with high affinity for several receptors:
α1 > H1 ≈ D2 = 5-HT2A > D4 > D1
- Low potency as an antipsychotic; useful for other indications (e.g., antiemetic)
- Greater potential for antimuscarinic and anti-alpha-adrenergic side effects!!!

Question 35

tx for schizophrenia w/ suicidal ideaation?

Answer 35

clozapine

Question 36

what works as antiemetic?

Answer 36

chlopromazine

Question 37

atypical agent most likely to cause EPS effects?

Answer 37

riperidone