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Drug Action III > Antipsychotics (Pharm & MC) - Block 3 > Flashcards

Antipsychotics (Pharm & MC) - Block 3 Flashcards

1
Q

Descrbe the differences between agonists, antagonists, and inverse agonist?s

A
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2
Q

Differentiate the dopamine receptors?

A

D1-type (D1 and 5): increase cAMP
D2- type (D2, 3, and 4): decrease cAMP

No correlation of D1, 3, 4 affinity with antipsychotic efficacy

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3
Q

What are the dopamine tragets for antipsychotic activity?

A

D2 and 5

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4
Q

What is the natural ligand for antisychotics?

A

Dopamine

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5
Q

FGA

MOA, Indication

A

MOA::Antagonists of D2 receptor
Indication: Schizo, psychiatric illneses with agitation, aggressive, and impulsive behaviors, impaired reasoning
* Treats positive schizo sx over negative

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6
Q

What is the average relapse of patients who DC FGA?

A

6 months

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7
Q

What are the major metabolizing enzymes for FGA?

A

CYP2D6, 1A2, 3A4
* many have active metabolites and vary in F
* No significant DDIs

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8
Q

FGA ADRs?

A

Due to GPCR activity:
* H1, a1 and 2 antagonismL sedation orthostatic hypotension, sexual dysfunction
* Muscarinic (M1-5) antagonism: cardiac, opthalmic, GI, urinary effects
* D2 antagonism: EPS (acute dystonia, akathisia, parkisonian-like sx), elevated prolactin

  • Tardive dyskinesia
  • Weight gain (H1 aand 5HT2c)
  • Neurolptic malignant syndrome (hyperthermia)
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9
Q

How do you treat paarkinsonian?

A

Antimuscarinics/amantadine

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10
Q

How do you treat akathisia?

A

Propranolol

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11
Q

Describe D2 receptor occupancy?

A

Therapeutic: 60-75%
Enhanced prolactin: 72%
EPS: 80%

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12
Q

What is tardive dyskinesia?

A

Involuntary, repetitive, choreiform movements of face (NOT a dystonia), eyelids, mouth, tongue, extremities and trunk
* DC and switch to SGA

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13
Q

What is NMS?

A

Life threatening in patients extremely sensitive to EP effects
* muscle rigidity followed by high fever
* 2 weeks of initiation or dose change

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14
Q

What is the tx for NMS?

A

DC neuorleptic and give supportive tx:
1. IV benzodiazepine (agitation, psychomotor hyperactivity, muscular rigidity)
2. Dopamine agonists (bromocriptine or amantadine)
3. Dantrolene

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15
Q

What is the tx for EPS?

A

Anticholinergics: benzotropine, trihexyphenidyl
Antihis: Benadryl

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16
Q

Why is FGA neurotoxic?

A

Metabolism into a neurotoxic metabolite

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17
Q

What is the cause of tardive dyskinesia?

A

Neuroleptic-induced dopamine hypersensitivity

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18
Q

What is the tx for tardive?

A

Vesicular monoamine transporter 2 inhibitor (VMT-2i):
* Reduces dopamine loading into synaptic vescicles -> reduced levels of DA in cleft

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19
Q

Types of VMT2 inhibitors?

A
  1. Deutetrabenazine
  2. Valbenazine
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20
Q

When are patients expected to gain weight with antipsychotics? Why is that a problem?

A

10 weeks
* can lead to the development of T2DM, CV dx, HTN, HLD

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21
Q

AP that have a greater risk for weight gain?

A

Quetiapine, olanzapine, clozapine

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22
Q

What are neuroleptics?

A

Takes hold of the CNS to suppress movement nd behavior

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23
Q

What structures make up a long acting neuroleptic?

A

The conversion of hydroxyl to long chain fatty acid ester (lipophilic)
* lewer ADR

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24
Q

What are the long acting neuroleptics?

A

Enanthate ester: IM Q1-2W
Deconate ester: IM Q2-3W

Fluphenazine, haloperidol, perphenazine

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25
Q

Describe the SAR of phenothiazines?

A
  1. EWG (F, Br, Cl, I, halogens) to attract porotnated amine - pulls amine so it mimics the dopamine amine configuration
  2. Amine with three carbon separation from other nitrogen is necessary
  3. Piperazine ring is generally more potent
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26
Q

Pros and cons of phenothiazines?

A

Active at D, 5HT, adrenergic, cholinergic, His receptors: good for efficacy but bad for ADRs

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27
Q

Types of phenothiazines?

A
  1. Chlorpromazine
  2. Thioridazine
  3. Perphenazine
  4. Fluphenazine
  5. Trifluoperazine
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28
Q

What drug was removed from the market due to torsades de pointed? Other ADRs?

A

Thioridazine
ADR: retinal depositis -> browing of vision

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29
Q

Chlorpromazine

PK, ADR

A

PK: low F however, metabolites may be excreted in urine weeks after last dose
ADR: deposits in anterior portions of eye (cornea, lens)
* Accentuates normal proccess of aging the lens

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30
Q

Describe the SAR of thiothixenes?

A

Needs to be Cis conformation to increse activity of EWG pulling N groups

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31
Q

Describe the SAR of butyrophenones?

A

Needs keto and tertiary amine with 3 carbons in between

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32
Q

Haloperidol

ADR, Dosage forms

A

ADR: higher affinity for D2 -> higher incidence of EPS
* no anticolinergic action

Form: Decanoate: depot maintencae therapy inj Q4-6W

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33
Q

High D2 potency can cause ____, while low D2 potency causes ___?

A

EPS, hyperprolactemia

Anticholinergic, 5-HT, adrenergic: sedation, weight gain, orthostatic hypotension

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34
Q

What is the difference between dihyrdoindolone and diphenylbutlypiperidines?

A

Diphenylbutylpiperidine: Pimozide
Dihydroindolone: molindone

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35
Q

What is a pimozide?

A

Antagonist of D2, 3, 4 used or uncontrolled outbursts from Tourettes

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36
Q

How does SGA differ from FGA?

A

Reduces EPS byt antagonism of both D2 and 5-HT2a:
* 5-HT2a antagonism increases dopamine release in the cortex, stabilizes DA levels in frontal lobe -> improving negative sx

Some are partial 5-HT1A agonists
Some act on GPCRs (serotonin, adrenergic, muscarinic, histamine)

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37
Q

May issues of SGA?

A

Weight gain and metabolic dysregulation or 5-HT antagonism
* LEss NMS and TD

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38
Q

What is the difference between benzazepines and benzisoxazoles/benzisothiazoles?

A
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39
Q

MOA of SGA?

A
40
Q

Advantages of SGA?

A
  1. Fewer negative sx
  2. Less TD
  3. Less noncompliace
  4. Less dysphoria
  5. Better cognition
  6. Fewer EPS
41
Q

Types of benzazepines?

A
  1. Clozapine
  2. Olanzapine
  3. Quetiapine
  4. Loxapine
42
Q

Clozapine

MOA, Indication, ADR, PK

A

MOA: less potnt D2 due to N palcement
* Affinity for D1-5, M1-5, 5-HT2A-2C, 5-HT6-7, H1 and α1 receptors

Indication: tx-resistant schizo
ADR: minimal EPS, no TD with long term use
* Fatal agranulocytosis and cardiomyopathy
* Highest weight gain besides olanzapine and sedation/sz
* Titration to avoid orthostatic hypotension

PK: active metabolite and metabolized by CYP1A2
* Caffeine and cigarettes affect
* Exception regarding relapse – discontinuation is rapid and severe, don’t DC aburptly unless needed to

43
Q

Olanzapine

PK, BBW

A

Zyprexa
PK: nighttime dosing due to sedation, direct glucoronidation -> less DDI
BBW: no agranulocytosis, post injection delirium and sedation syndrome

44
Q

What is Lybalvi?

Indication, ADR

A

Olanzapine and Samidorphan
Samidorphan: opiod antagonist
Indication: schizo and bipolar 1 combo
ADR: less weight gain than Zyprexa

45
Q

Quetiapine

MOA, ADR, PK

A

Seroquel
MOA: Selective for M1 over other muscarinic receptors and 5-HT2A over 5-HT2C
ADR: cataracts at high doses (recommended initial and periodic eye exam)
PK: 100% F but first pass -> over 20 metabolites
* Metabolized by sulfoxidation

46
Q

Loxapine

MOA

A

High affinity for D2-type, 5-HT2-type and H1 receptors; low for muscarinic
* parent of amoxapine (antidepressant): affintiy for NE and 5-HT transporters

47
Q

Inhaled Loxapine?

Indication, Dosage Form, ADR

A

Indication: acute agitation associated with schizophrenia and bipolar disorder
Form: Patients requiring physical restraints
ADR: Bronchospasm -> resp distress and arrest
* Administer only in enrolled healthcare facility that can immediately manage acute bronchospasm

48
Q

Asenapine

ADR, PK, Dosage form

A

ADR: Less EPS and weight gain
PK: 24 t1/2
Form: transdermal and SL tablets
* DOn’t swallow, eat or drink for 10 minutes

49
Q

Benzisoxazoles/Benzisothiazoles

MOA

A

Combined chemical features from potent D2 antagonists (benzamides) with 5-HT2A antagonists (benzothiazolyl piperazine) -> dual antagonists with affinity for a1 and H1 receptors as well


















50










Q















Risperidone


MOA, ADR, PK




















A















Risperdal
MOA: High affinity for 5-HT2A and D2 receptors. Also H1 and α1-type receptors. No affinity for muscarinic
ADR: higher incidence of EPS at higher doses
PK: active metabolite -> paliperidone
* CYP2D6


Forms: LAI (risperidone Q2W or 1M, paliperidone - Q1,3,6M
* Paliperidon: OROS QAM



















51










Q















Ziprasidone


MOA, ADR




















A













Geodan
MOA: Binds to 5-HT2A, 5-HT2C, D2, α1, α2 and H1 receptors and partial agonist at 5HT1A
ADR: low weight gain despite H1 and 5-HT2C activity
* QT prolongation -> torsade de pointes (V tach)















52










Q















Lurasidone


MOA, PK




















A















MOA: Binds to 5-HT2A, 5-HT2C, D2, α1, α2 and H1 receptors
* No mascarinic/H1 ativity


PK: CYP3A4

















53










Q















Iloperidone


ADR, PK




















A













ADR: orthostatic hypotension (titrate to prevent)
PK: 2D6 and 3A4















54










Q













Types of Benzisoxazoles/Benzisothiazoles?


















A













    

  1. Risperidone (Risperdal)/Paliperidone
    2. 

  2. Ziprasidone (Geodon)
    3. 

  3. Lurasidone (Latuda)
    4. 

  4. Iloperidone
    5. 
















55










Q















How does Aripirprazole differ from other AP?


ADR, PK




















A















Lower EPS and hyperprolactemia from partial agonist of D2 receptors
Lower weight gain -> 5HT2C partial agonist


ADR: DZ, lightheadedness, drowsiness
PK: CYP2D6, Poor metabolizers may have ≈ 60% increase in plasma levels

















56










Q













Describe the mecahnism of Abilify?


















A













    

  1. Hyperdopaminergic enviornment, drug decreases DA activity and acts as an antagonist
    2. 

  2. Hypodopainergic environement, drug increases DA activity and acts as an agonist -> improves negative sx
    3. 
















57










Q













What are the formulations of aripiprazole?


















A















IM injections:
* Abilify maintena QM
* Aristada Q1M, Q6W, of bimonthly
* Aristada initio: one-time inj to start or restart after missed dose


Need to give current antipsychotic therapy (usually aripirazole) for 2 – 3 weeks following injection to maintain consistent levels

















58










Q















Brexipiprazole?


MOA, Indcation




















A















MOA: Partial agonist of D2, D3 and 5-HT1A
* antgonist at 5HT2a, 2b, 7 -> antidepressatn effects
* Antagonist at a1


ADR: more antagonist activity than Abilify -> decrease risk for agitation and restlessness and postivie sx

















59










Q















Cariprazine


MOA, ADR, PK




















A













MOA: D2 and 5-HT2A activity, but also D3 partial agonist (greater effects on negative sx)
ADR: akathisia, nervousness, insomnia, weight gain
PK: 2 major active metabolites















60










Q













What are your AP partial agonists?


















A













    

  1. Aripiprazole
    2. 

  2. Brexipiprazole
    3. 

  3. Cariprazine
    4. 

  4. Lumateperone
    5. 
















61










Q















Pimavanserin


MOA




















A













MOA: non-dopaminergic for PD psychosis
* Inverse agonist of 5-HT2A -> increase DA















62










Q















Lumateperone


MOA, ADR




















A















MOA: 5-HT2A antagonist, D2 presynaptic partial agonist and postsynaptic antagonist, D1 receptor-dependent modulator of glutamate, and serotonin reuptake inhibitor
* Acts synergistically through serotonergic, dopaminergic and glutamatergic systems


ADR: Somnolence, N, Dry mouth, DZ

















63










Q













What AP is an inverse agonist?


















A













Pimavanserin















64










Q















Lithium


MOA, PK




















A















MOA: Competes with sodium, potassium, calcium and magnesium cations at intracellular binding sites, sugar phosphatases, protein surfaces, carrier binding sites and transport sites
* Reduces signal transduction through phosphatidylnositl signaling pathway -> deplete pool of inositol -> can’t produce second messenger (DAG, and inositol 1, 4, 5, triphosphate_


PK: Lag in onset (1 – 3 weeks), effects remain for weeks – months after discontinuation
* Half-life increases with age


ADR: adherence is an issue



















65










Q













Common salt form of lithium?


















A













Carbonate















66










Q













What are the other affects of lithium?


















A















    

  1. Inhibits dopamine neurotransmission
    2. 

  2. Promotes GABAergoc neurotransmission
    3. 



Mainly used for mania

















67










Q













Lithium tox?


















A















> 1.5
Elderly: 0.5mEq/L


  • mUst monitor blood levels because therapeutic and toxic window is small


Adherecne is an issue

















68










Q













ADR of Lithium


















A













N, loss of appetite, diarrhea
* Increased urine -> excessive thirst
* Hypothyroidism, nephrogenic DI, renal dysfunction, arrhythmias, weight gain















69










Q













Drugs that increase Lithium concetration?


















A













Sodium depletion (exercise, vomiting, diarrhea, low sodium diet), NSAID, thiazides, ACEIs, ARB















70










Q













Drugs that decrease Li levels?


















A













High sodium diet, methylxanthines, urine alkalinzers/sodium bicarb















71










Q













How should you dc lithium?


















A













Don’t stop abruptly, dc over 4 weeks
* can lead to recurrence of mania and depressive episodes















72










Q













What are the advantages of Li?


















A













    

  1. Extensive and long use
    2. 

  2. Acute and chroni efficacy
    3. 

  3. Safe in pregnancy
    4. 

  4. Moderare antidepressant
    5. 

  5. Anti suicide effects
    6. 
















73










Q













Dsadvantages ofLi?


















A













    

  1. Narrow TI
    2. 

  2. Renal and thyroid tox
    3. 

  3. Nuisance ADR
    4. 

  4. Weiht gain
    5. 

  5. Narrow spectrum of activity
    6. 

  6. Occasional depression induction
    7. 
















74










Q













What are your mood stabilizers?


















A













    

  1. Divalproex sodium
    2. 

  2. Carbamazepine
    3. 

  3. Lamotrigine
    4. 

  4. oxcarbazepine
    5. 
















75










Q













What is the target and tox levels for Depakote?


















A













Target: 75 mcg/mL
Tox: >125 mcg/mL















76










Q













ADr of Divalproex?


















A













More tolerated than carbamazepine and LI with the exception of GI upset















77










Q













Advantages of Divalproex?


















A













    

  1. Strong acute efficacy data
    2. 

  2. Some long-term data
    3. 

  3. Broad activity spectrum
    4. 

  4. “Loading” doses are rapidly effective
    5. 

  5. Effective for anxiety & migraine
    6. 

  6. Less toxic than Li+
    1.
    7. 
















78










Q













Disadvantages of Divalproex sodium?


















A













    

  1. Nausea
    2. 

  2. Weight gain
    3. 

  3. Nuisance ADR
    4. 

  4. Less effective for pure Bipolar depression
    5. 

  5. NTD
    6. 

  6. Caution with pancreatitis and PCOS
    7. 
















79










Q













Carbamazepine use in bipolar?


















A













Biggest disadvantge of drug is DDI
PK: CYP450 induction
Therapuetic: 6-12 mcg/mL
Tox: >15 mcg/mL















80










Q













Advantages of carbemazepine


















A













    

  1. Strong acute efficacy
    2. 

  2. Broad acitivty spectrum
    3. 

  3. Possuble antidepressant use
    4. 

  4. Long history of use
    5. 

  5. No weightgain
    6. 
















81










Q













Disadvantages of carbamazepine?


















A













    

  1. Loss in effectiveness over time
    2. 

  2. Autoinduction and DDI
    3. 

  3. Blood dyscrasias
    4. 

  4. Narrow TI
    5. 

  5. Acute ADR
    6. 
















82










Q













What drug has fewer ADRs compared to carbemazepine?


















A













Oxcarbazepine















83










Q













Advantages of oxcarbazepine?


















A













    

  1. Like carbamazepine
    2. 

  2. More rapid dose titration
    3. 

  3. Milder ADR profile than carbamazepine (less bone marrow, liver effects and drowsiness)
    4. 

  4. No lab required (except sodium)
    5. 

  5. Fewer DDI
    6. 
















84










Q













Disadvantages of oxcarbazepine?


















A













    

  1. L=Off label for bipolar
    2. 

  2. Reduced effectiveness of low-dose oral contraceptives
    3. 

  3. Carbamazepine-like adverse effects (DZm somnolence, diplopia)
    4. 

  4. Hyponatremia
    5. 
















85










Q













Advantages of lamotrigine?


















A













    

  1. Controlled data
    2. 

  2. Well tolerates (no weight gain, labs, sedation, cognitive dulling)
    3. 

  3. Neuroprotective (Blocks glutamatergic Na+ channels)
    4. 
















86










Q













Disadvantages of Lamotrigine


















A













    

  1. Slow dosage titration
    2. 

  2. Skin issues (SJS)
    3. 

  3. Valproate will double serum levels
    4. 
















87










Q













What are the off label bipolar drugs?


















A













    

  1. Levitiraceta and zonisamide
    2. 

  2. Topiramate
    3. 

  3. Gabapentin
    4. 
















88










Q













What is the used of SGA as mood stabilizers?


















A













Nearly all are approved for bipolar
* Weight gain and DI-DM (Olanzapine&raquo_space;> Risperidone > Aripiprazole) - Montior weight Q3-6M, BG Q6-12M
* Hypertriglyceridemia (Olanzapine, Clozapine&raquo_space; Risperidone)















89










Q















What is symbyax?


Indication, Monitor




















A















Olanzapine/Fluoxetine: approved for bipolar depression and tx-resistant depression


Montior: mania and hypomania

















90










Q













Lithium BBW?


















A













Toxicity















91










Q













Carbamazepine BBW?


















A













Aplastc anemia, agranulocytosis, serious rash















92










Q













Lamotrigine BBW?


















A













SJS















93










Q













Valproate BBW?


















A













Hepatotox, tetragenocity, pancreatitis















94










Q













Clozapine BBW?


















A













Agranulocytosis, seizures, myocarditis, CV and respiratory effects, dementia-related psychosis















95










Q













All psychotics BBW?


















A













Should not be used for dementia related psychosis






























Drug Action III (23 decks)


























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