Exam #02 (Antipsychotics) Flashcards
Why is schizophrenia thought to be a paradoxical disease?
B/c there are positive and negative symptoms arising from excess DA and not enough DA, respectively
Positive symptoms of schizophrenia arise from excess DA in what tract of the brain?
mesolimbic tract
Negative symptoms of schizophrenia arise from reduced DA in what tract of the brain?
mesocortical tract
List the (3) positive symptoms of schizophrenia.
- Hallucinations
- Delusions
- Disorganized thinking
List the (3) negative symptoms of schizophrenia.
- Blunted affect
- Emotional withdrawal
- Poor rapport
Cognitive symptoms may result from INCREASED/DECREASED dopamine in the medial prefrontal cortex?
DECREASED
What (4) NT are implicated in schizophrenia?
- DA
- Glutamate
- Serotonin
- GABA
What is the difference between typical antipsychotic and atypical antipsychotic drugs? Indicate MOA and SE profile
Typical Antipsychotics
MOA: DA antagonists (D2)
SE: primary side effects are extrapyramidal side effects (EPS) which are movement abnormalities
Atypical antipsychotics
MOA: primarily 5-HT2A antagonism but can also have some DA antagonism
SE: reduced or no EPS (b/c less D2 antagonism) but significant increase in other side effects
True or False - most antipsychotic drugs today treat positive symptoms of schizophrenia?
True
What 2 drugs led to the DA hypothesis of schizophrenia? What is the DA hypothesis?
- Chlorpromazine - DA antagonist
- Reserpine - depletes synaptic DA
Modulating DA may Tx schizophrenia
What would a “perfect” DA-based antipsychotic look like (indicate MOA in specific areas of brain)?
- Drug would act as a DA antagonist in mesolimbic neurons where excess DA is
AND
- Drug would act as a DA agonist in the mesocortical, limbic, and prefrontal cortex neurons where reduced DA is
AND
- Drug would have no effect on nigrostriatal neurons
What is the key structural feature regarding the SAR of Phenothiazines?
The affinity to D2 receptor is determined by how easily the basic amine can fold over and lie over the ring containing the substituent. This is the conformation required to make it a D2 antagonist
What helps keep the Nitrogen up over the aromatic ring in a phenothiazine drug?
the electron-withdrawing group
When the basic amine folds up over the aromatic ring, the lone pair of electrons from the basic amine dissociates and that electron density is pulled away from the ring by the electron withdrawing group stabilizing the basic amine above the ring and maintaining D2 antagonist activity
True or False - the basic amine of phenothiazines has significant structural tolerance and can be changed to modify ADME properties?
True
Identify what antipsychotic group the following drug is from:
Triflupromazine (Vesprin)
Phenothiazine
Identify what antipsychotic group the following drug is from:
Thioridazine (Mellaril)
Phenothiazine
Identify what antipsychotic group the following drug is from:
Mesorindazine (Serentil)
Phenothiazine
Identify what antipsychotic group the following drug is from:
Prochlorperazine (Compazine)
Phenothiazine
Identify what antipsychotic group the following drug is from:
Perphenazine (Trilafon)
Phenothiazine
Would a phenothiazine antipsychotic with anticholinergic SE be MORE or LESS likely to cause EPS (extrapyramidal SE)?
Less likely
EPS liabilities are less when strong anticholinergic effects are present
True or False - anticholinergic activity of phenothiazine antipsychotics counter whatever changes occur in the substantia nigra that cause the EPS?
True
Phenothiazine antipsychotics sedative effect is a result of blocking which receptor type?
H1 antagonism
Phenothiazine antipsychotics HYPOtensive effects is a result of blocking which receptor type?
alpha-1 antagonism
What does the S in thioxanthenes and phenothiazines mimic that contribute to their effectiveness?
S mimics the 3-OH of dopamine
The optimal chain length (carbons) that optimizes the interaction of basic nitrogen with an electron poor ring for a Phenothiazine is?
3-carbons
Name a structural difference between phenothiazines and thioxanthenes?
How are they different in terms of metabolism?
phenothiazines have a S and N in the middle ring, while thioxanthenes have only a S in the middle ring
Phenothiazine rings can be hydroxylated but Thioxanthene rings cannot
True or False - phenothiazines are extensively metabolized and give several active and inactive metabolites?
True
What is the most active metabolite of a phenothiazine?
7-hydroxy metabolite
What are (3) essential SAR of Butyrophenones?
- 4 carbon chain
- “phenone”
- substituted or unsubstituted aryl
Which group of antipsychotics are Haloperidol (Haldol) and Droperidol (Inapsine) from?
Butyrophenones
2nd generation Butyrophenones replaced a ketone with an additional phenyl group. How did this affect its activity?
2nd generation Butyrophenones are potent D2 antagonists, potent 5-HT2A antagonists with less EPS than 1st generation
Name (1) 2nd generation Butyrophenone.
Pimozide (Orap)
Name (9) SE of typical antipsychotic drugs?
- EPS (movement disorders)***
- neuroleptic malignant syndrome
- sedation (from H1 antagonism)
- weight gain
- dyslipidemia
- hyperprolactinemia
- DM
- prolonged QTc
9 CV effects
***EPS - inability to initiate movement or inability to remain motionless
How are EPS treated?
with anticholinergics
Which antipsychotic group is Clozapine (Clozaril) from?
Tricyclic antipsychotic
hasmultiple receptor activities: D2 antagonist, 5-HT2A antagonist, 5-HT1A partial agonist (helps cognitive symptoms
Which antipsychotic group is Risperidone from?
Benzisoxazole
Which antipsychotic group is Olanzapine (Zyprexa) from?
Tricyclic antipsychotic
hasmultiple receptor activities: D2 antagonist, 5-HT2A antagonist, 5-HT1A partial agonist (helps cognitive symptoms
Which antipsychotic group is Sulpride (Meresa) from?
Benzamide
Which antipsychotic group is Remoxipride (Roxiam) from?
Benzamide
Which antipsychotic group is Ziprasidone (Geodon) from?
Benzisothiazole
True or False - Aripiperazole (Abilify) can help positive symptoms, negative symptoms, and cognitive symptoms all while limiting EPS?
True - it acts as an antagonist in the limbic tissue (where DA is too high), partial agonist in the cortical tissue (where DA is low) and partial agonist in striatal tissue (which decreases EPS)
True or False - Abilify is a potent D2 partial agonist and potent 5-HT2A antagonist?
True
Which miscellaneous atypical antipsychotic has primarily 5-HT2A antagonism with almost no D2 antagonism and therefore no EPS?
Sertindole (Serdolect)
Name (2) recently approved atypical antipsychotics?
- Asenapine
2. Iloperidone
Name (3) cognitive symptoms of schizophrenia.
- impaired executive functioning
- memory impairment
- attention deficits
