Anti-Psychotics

Question 1

What is the mechanism of action of BOTH typical and atypical anti-psychotics?

Answer 1

Competitively ANTAGONIZES post-synaptic dopamine D2 receptors of the CNS (especially in the mesolimbic-frontal system)

Question 2

What is the difference between atypical and typical drugs? Do they have different mechanisms of action?

Answer 2

SAME mechanism of D2 blockade
DIFFERENT in terms of:
1) side effects - Atypical have LESS typical EPS side effects
2) Additional blockade - Atypical have HIGHER serotonin:DA blockade ratio than typical

Question 3

How are dosages and affinity properties of an anti-psychotic related to achieve therapeutic efficacy, specifically at the D2 receptor level?

Answer 3

HIGH AFFINITY anti-psychotics require LOW doses HIGHER POTENCY - achieve efficacy X (decrease DA)
LOW AFFINITY anti-psychotics require HIGHER dose LOWER POTENCY- achieve efficacy X (decrease DA)

Question 4

How are dosage and affinity properties of an anti-psychotic related, specifically in the D1 receptor level?

Answer 4

NO correlation between potency and affinity in the D1 level

RESULT: D2 receptor targeting = Most important for schizophrenia treatment

Question 5

Describe the pharmacokinetic properties (ADME) of anti-psychotics.

Answer 5

A - High first-pass transformation, lipid-soluble and enters CNS, crosses placental + BBB
D - Bound extensively to plasma proteins, High Vd as it sequesters in lipid compartments
M - HIGH metabolism: Oxidative (Cyp3A4, Cyp2D6) + glucuronidation/sulfation/other conjugation to create more polar metabolites
E - LITTLE excretion unchanged bec of extensive metabolism

Question 6

What is the clearance property of MOST of the anti-psychotics?

Answer 6

SLOW clearance due to LONG HALF-LIVES (12-75hrs) due to sequestration in lipid compartments

Question 7

How can the variable side effects of anti-psychotics be explained?

Answer 7

1) Anti-psychosis: All target D2 receptors
2) Variable Side effects: Different anti-psychotics also act on various receptors [serotonin, alpha-adrenergic, muscarinic, histamine receptors

Question 8

What are the two classes of anti-psychotics?

Answer 8

ATYPICAL

TYPICAL

Question 8

What drug interactions do you have to be careful when administering?

Answer 8

Other drugs that are either CYP3A4 or CYP2D6 inhibitors/inducers
CYP3A4 Inhibitors - GRAPEFRUIT JUICE, AZOLE anti-fungals, HIV protease inhibitors
CYP2D6 Inhibitors - SSRIs (FLUOXETINE, PAROXETINE) + BUPROPRION

Question 9

CLINICAL TOXICOLOGY: What are Extrapyramidal effects (EPS)? Which class of anti-psychotics presents EPS more?

Answer 9

Parkinson-like syndrome: Bradykinesia + Rigidity + Tremor
TYPICAL anti-psychotics = MORE EPS
MOST SEVERE EPS - Tardive dyskinesia

Question 10

CLINICAL TOXICOLOGY: A common side effect of anti-psychotics is DYSTONIA. What is DYSTONIA and what are 2 possible treatments for ACUTE, PAINFUL DYSTONIA?

Answer 10

DYSTONIA = twisting motions resulting from severe muscle contractions
TREATMENTS
1) DIPHENHYDRAMINE (Benadryl) - Sedative anti-histamine with anti-cholinergic properties
2) BENZTROPINE - Anti-muscarinic agent

Question 11

CLINICAL TOXICOLOGY: What is the MOST UNWANTED effect of anti-psychotic drugs? Is it reversible or irreversible? When does this side effect present itself (immediately after onset of treatment or later)?

Answer 11

TARDIVE DYSKINESIAS (EPS symptom) = Choreoathetoid movements of LIP muscles + buccal cavity
May be IRREVERSIBLE
Presents itself after SEVERAL YEARS of treatment but may also present as early as 6mo after initiation

Question 12

CLINICAL TOXICOLOGY: What is the most likely treatment plan of TARDIVE DYSKINESIAS?

Answer 12

DISCONTINUE or REDUCE current anti-psychotic dosage

Question 13

CLINICAL TOXICOLOGY: Which class of anti-psychotics presents more intermediate autonomic effects?

Answer 13

ATYPICAL - While it shows less EPS and less hyperprolactinemia, autonomic effects are more likely to present

Question 14

CLINICAL TOXICOLOGY: What are the adverse side effects of autonomic blockade when taking anti-psychotics?

Answer 14

ALPHA-BLOCKADE: Postural HYPOTENSION + EJACULATION failure
MUSCARINIC-BLOCKADE:
1) Atropine-Like Effects: Dry as a bone, Blind as a bat, Mad as a hatter, Hot as hell, Red as a beet, Full as a flask
2) CNS Toxic effects: Confusional states
3) URINARY RETENTION

Question 15

What other disorders can anti-psychotics treat short-term?

Answer 15

MAJOR DEPRESSION - Depression/Mood
MANIA - Depression/Mood
DELIRIUM/DEMENTIA - Cognitive
SCHIZOPHRENIA - Psychosis

Question 16

CLASS 1 ATYPICAL: Name the 6 ATYPICAL anti-psychotics.

Answer 16

“CORZAQ - Sounds like Coors, Zack - Zack likes drinking Coors”

1) CLOZAPINE
2) OLANZAPINE
3) RISPERIDONE
4) ZIPRASIDONE
5) ARIPRAZOLE
6) QUETIAPINE

Question 17

CLASS 2 TYPICAL: Name the 3 TYPICAL Anti-psychotics.

Answer 17

“T for typical, HC”

1) THIORIDAZINE
2) HALOPERIDOL
3) CHLORPROMRAXINE

Question 18

CLASS 1 ATYPICAL: Explain how ATYPICAL anti-psychotics REDUCE + sx and “APPEAR to reduce” - sx

Answer 18

ATYPICAL ANTI-PSYCHOTICS = Anti-D2 receptors + EVEN GREATER anti-5HT2 (serotonin) receptors

Question 19

CLASS 1 ATYPICAL: What are the general side effects? (*Hint: extrapyramidal symptoms [EPS], neurologic, cardiac, and body mass)

Answer 19

1) LESS EPS than TYPICAL (older drugs)
2) Seizures - Neurologic
3) Hypotension + Conduction deficits + Prolonged QT - Cardiac
4) Increased risk of Type 2 Diabetes, Hyperlipidemia, Weight Gain - Body Mass

Question 20

CLASS 1 ATYPICAL: What two activities does ARIPIPRAZOLE have?

Answer 20

1) PARTIAL agonist at D2 receptor

2) COMPETITIVE antagonist at D2 receptor UNTIL the partial agonist Emax is achieved

Question 21

CLASS 1 ATYPICAL: What is the proposed explanation for why ATYPICAL anti-psychotics present LESS EPS?

Answer 21

Atypical anti-psychotics are thought to produce GREATER DA blockade in MESOLIMBIC compared to nigrostriatal (nigrostriatal blockade = EPS)

Question 22

CLASS 1 ATYPICAL: What makes CLOZAPINE different from all other atypical anti-psychotics (CORZAQ)
(*Hint: Mechanism of action)

Answer 22

CLOZAPINE barely has any D2 receptor blockade

Instead, it has HIGH D4 blockade - D4 receptors are HIGHLY expressed in the MESOLIMBIC system (attributes for + sx)

Question 23

CLASS 1 ATYPICAL: Which atypical anti-psychotic particularly has lower EPS side effects (i.e. anti-D2 activity in the NIGROSTRIATAL system)?

Answer 23

CLOZAPINE - since it is not as good of a anti-D2 agent

Very good anti-D4 agent

Question 24

CLASS 1 ATYPICAL: Generally, how many times a day does a pt need to take his/her anti-psychotic? What are the two exceptions (*Hint 2 atypical)

Answer 24

Generally ONCE a day due to LONG HALF-LIFE
EXCEPTIONS:
“ZQ - exceptions at the last letters of the alphabet of CORZAQ”
1) ZIPRASIDONE
2) QUETIAPINE

Question 25

CLASS 1 ATYPICAL: Which choice of anti-psychotic is proven to be MOST EFFICACIOUS for treating treatment-refractory schizophrenia?

Answer 25

Treatment-refractory schizophrenia = + Sx shown to be resistant to anti-psychotics
CLOZAPINE

Question 26

CLASS 1 ATYPICAL: Which 2 anti-psychotics are MOST associated with significant weight gain + Hyperglycemia + increased risk of Type 2 Diabetes BLACKBOX on ALL ATYPICALS

Answer 26

“First two of CORZAQ”
CLONAZAPINE
OLANZAPINE

Question 27

CLASS 2 TYPICAL: Among the 3 typicals, which drug has the STRONGEST autonomic effects (alpha and muscarinic blockade) and which drug has the WEAKEST autonomic effects?

Answer 27

STRONGEST - THIORIDAZINE (first one of THC)

WEAKEST - HALOPERIDOL (second one of THC)

Question 28

CLASS 1 ATYPICAL: Albeit its superior anti-psychotic therapeutic effect, what is the most worrisome FATAL side effect (especially of CLOZAPINE!!)

Answer 28

Risk of AGRANULOCYTOSIS + Potential Seizures

Question 29

CLASS 2 TYPICAL: (NEUROLEPTICS) - What are the general side effects (*Hint: extrapyramidal symptoms, endocrine)

Answer 29

1) Typicals have MORE typical EPS than atypical (newer drugs) - Bradykinesia + mild rigidity + Tremor + Akathisia (subjective restlessness)
“2 hypokinesis and 2 hyperkinesis”
2) Reduced interest and initiative in the environment and emotions
3) Increased PROLACTIN secretion

Question 29

CLASS 2 TYPICAL: What can explain the GREATER EPS symptom presentation with TYPICAL anti-psychotic medication?

Answer 29

TYPICAL Anti-psychotics elicit greater DA blockade in the NIGROSTRIATAL system, moreso than ATYPICAL anti-psychotics

Question 31

CLASS 2 TYPICAL: Explain how TYPICAL anti-psychotics alleviate + symptoms, but NOT - symptoms of schizophrenia.

Answer 31

TYPICAL ANTI-PSYCHOTICS = Anti-D2 receptor antagonist at the NIGROSTRIATAL + MESOLIMBIC
Schizophrenia explained by:
1) INCREASED DA in mesolimbic (+ sx) - Typical anti-psychotics CAN relieve this
2) DECREASED DA in mesocortical (- sx) - Typical anti-psychotics can NOT relieve this

Question 32

CLASS 2 TYPICAL: Which anti-psychotic drug presents the most EPS? What is the molecular evidence of this?

Answer 32

HALOPERIDOL - Exhibits the strongest D2 blockade of the nigrostriatal system

Question 33

CLASS 2 TYPICAL: Which of the 3 typical anti-psychotics has the LOWEST risk of broad spectrum side-effects? Why?

Answer 33

HALOPERIDOL - Due to LACK OF blockade of other receptors unlike others that block many receptors in addition to D2

Question 34

CLASS 2 TYPICAL: What is the MOST SERIOUS side effect of typical anti-psychotics that may be FATAL in 10% of cases?

Answer 34

NEUROLEPTIC MALIGNANT SYNDROME = Muscle rigidity + Sweating impairment+ Autonomic instability

Question 35

CLASS 1 vs CLASS 2: Why might ARIPIPRAZOLE be preferred over HALOPERIDOL?

Answer 35

ARIPRAZOLE is also a partial D2 AGONIST, so its competitive antagonistic action will NOT completely inhibit the DA response completely
HALOPERIDOL is ONLY a competitive antagonist of D2 receptors -> Completely Inhibits DA response

Question 36

CLASS 1 vs CLASS 2: What AGE population and PREDOMINANT class of symptoms would you more likely administer a TYPICAL anti-psychotic over an atypical anti-psychotic?

Answer 36

“How to remember - older drugs (typical) used for older population”
ELDERLY POPULATION - Lower risk of EPS/hyperprolactinemia + Much higher risk associated with STOMAS
PREDOMINANT + Sx - TYPICAL anti-psychotics are stronger D2receptor antagonists

Question 38

CLASS 1 vs CLASS 2: What AGE population and PREDOMINANT class of symptoms would you more likely administer an ATYPICAL anti-psychotic over a typical anti-psychotic?

Answer 38

YOUNGER POPULATION: Avoid risk of EPS/hyperprolactinemia that increases with duration of medication usage
PREDOMINANT - Sx: Atypical anti-psychotics can alleviate BOTH positive and negative Sx