Antipsychotics (Pharm & MC) - Block 3 Flashcards
1
Q
Descrbe the differences between agonists, antagonists, and inverse agonist?s
A
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
3
Q
What are the dopamine tragets for antipsychotic activity?
A
D2 and 5
4
Q
What is the natural ligand for antisychotics?
A
Dopamine
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
6
Q
What is the average relapse of patients who DC FGA?
A
6 months
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
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)
9
Q
How do you treat paarkinsonian?
A
Antimuscarinics/amantadine
10
Q
How do you treat akathisia?
A
Propranolol
11
Q
Describe D2 receptor occupancy?
A
Therapeutic: 60-75%
Enhanced prolactin: 72%
EPS: 80%
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
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
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
15
Q
What is the tx for EPS?
A
Anticholinergics: benzotropine, trihexyphenidyl
Antihis: Benadryl
16
Q
Why is FGA neurotoxic?
A
Metabolism into a neurotoxic metabolite
17
Q
What is the cause of tardive dyskinesia?
A
Neuroleptic-induced dopamine hypersensitivity
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
19
Q
Types of VMT2 inhibitors?
A
- Deutetrabenazine
- Valbenazine
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
21
Q
AP that have a greater risk for weight gain?
A
Quetiapine, olanzapine, clozapine
22
Q
What are neuroleptics?
A
Takes hold of the CNS to suppress movement nd behavior
23
Q
What structures make up a long acting neuroleptic?
A
The conversion of hydroxyl to long chain fatty acid ester (lipophilic)
* lewer ADR
24
Q
What are the long acting neuroleptics?
A
Enanthate ester: IM Q1-2W
Deconate ester: IM Q2-3W
Fluphenazine, haloperidol, perphenazine
25
Describe the SAR of phenothiazines?
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
26
Pros and cons of phenothiazines?
Active at D, 5HT, adrenergic, cholinergic, His receptors: good for efficacy but bad for ADRs
27
Types of phenothiazines?
1. Chlorpromazine
2. Thioridazine
3. Perphenazine
4. Fluphenazine
5. Trifluoperazine
28
What drug was removed from the market due to torsades de pointed? Other ADRs?
Thioridazine
**ADR:** retinal depositis -> browing of vision
29
Chlorpromazine
| PK, ADR
**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
30
Describe the SAR of thiothixenes?
Needs to be **Cis** conformation to increse activity of EWG pulling N groups
31
Describe the SAR of butyrophenones?
Needs keto and tertiary amine with 3 carbons in between
32
Haloperidol
| ADR, Dosage forms
**ADR:** higher affinity for D2 -> higher incidence of EPS
* no anticolinergic action
**Form:** Decanoate: depot maintencae therapy inj Q4-6W
33
High D2 potency can cause ____, while low D2 potency causes ___?
EPS, hyperprolactemia
Anticholinergic, 5-HT, adrenergic: sedation, weight gain, orthostatic hypotension
34
What is the difference between dihyrdoindolone and diphenylbutlypiperidines?
Diphenylbutylpiperidine: Pimozide
Dihydroindolone: molindone
35
What is a pimozide?
Antagonist of D2, 3, 4 used or uncontrolled outbursts from Tourettes
36
How does SGA differ from FGA?
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)
37
May issues of SGA?
Weight gain and metabolic dysregulation or 5-HT antagonism
* LEss NMS and TD
38
What is the difference between benzazepines and benzisoxazoles/benzisothiazoles?
39
MOA of SGA?
40
Advantages of SGA?
1. Fewer negative sx
2. Less TD
3. Less noncompliace
4. Less dysphoria
5. Better cognition
6. Fewer EPS
41
Types of benzazepines?
1. Clozapine
2. Olanzapine
3. Quetiapine
4. Loxapine
42
Clozapine
| MOA, Indication, ADR, PK
**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
Olanzapine
| PK, BBW
Zyprexa
**PK:** nighttime dosing due to sedation, direct glucoronidation -> less DDI
**BBW:** no agranulocytosis, post injection delirium and sedation syndrome
44
What is Lybalvi?
| Indication, ADR
Olanzapine and Samidorphan
**Samidorphan:** opiod antagonist
**Indication:** schizo and bipolar 1 combo
**ADR:** less weight gain than Zyprexa
45
Quetiapine
| MOA, ADR, PK
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
Loxapine
| MOA
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
Inhaled Loxapine?
| Indication, Dosage Form, ADR
**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
Asenapine
| ADR, PK, Dosage form
**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
Benzisoxazoles/Benzisothiazoles
| MOA
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
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50
Risperidone
| MOA, ADR, PK
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
Ziprasidone
| MOA, ADR
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
Lurasidone
| MOA, PK
**MOA:** Binds to 5-HT2A, 5-HT2C, D2, α1, α2 and H1 receptors
* No mascarinic/H1 ativity
**PK:** CYP3A4
53
Iloperidone
| ADR, PK
**ADR:** orthostatic hypotension (titrate to prevent)
**PK:** 2D6 and 3A4
54
Types of Benzisoxazoles/Benzisothiazoles?
1. Risperidone (Risperdal)/Paliperidone
2. Ziprasidone (Geodon)
3. Lurasidone (Latuda)
4. Iloperidone
55
How does Aripirprazole differ from other AP?
| ADR, PK
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
Describe the mecahnism of Abilify?
1. Hyperdopaminergic enviornment, drug decreases DA activity and acts as an antagonist
2. Hypodopainergic environement, drug increases DA activity and acts as an agonist -> improves negative sx
57
What are the formulations of aripiprazole?
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
Brexipiprazole?
| MOA, Indcation
**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
Cariprazine
| MOA, ADR, PK
**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
What are your AP partial agonists?
1. Aripiprazole
2. Brexipiprazole
3. Cariprazine
4. Lumateperone
61
Pimavanserin
| MOA
**MOA:** non-dopaminergic for PD psychosis
* Inverse agonist of 5-HT2A -> increase DA
62
Lumateperone
| MOA, ADR
**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
What AP is an inverse agonist?
Pimavanserin
64
Lithium
| MOA, PK
**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
Common salt form of lithium?
Carbonate
66
What are the other affects of lithium?
1. Inhibits dopamine neurotransmission
2. Promotes GABAergoc neurotransmission
Mainly used for mania
67
Lithium tox?
>1.5
>Elderly: 0.5mEq/L
* mUst monitor blood levels because therapeutic and toxic window is small
Adherecne is an issue
68
ADR of Lithium
N, loss of appetite, diarrhea
* Increased urine -> excessive thirst
* Hypothyroidism, nephrogenic DI, renal dysfunction, arrhythmias, weight gain
69
Drugs that increase Lithium concetration?
Sodium depletion (exercise, vomiting, diarrhea, low sodium diet), NSAID, thiazides, ACEIs, ARB
70
Drugs that decrease Li levels?
High sodium diet, methylxanthines, urine alkalinzers/sodium bicarb
71
How should you dc lithium?
Don't stop abruptly, dc over 4 weeks
* can lead to recurrence of mania and depressive episodes
72
What are the advantages of Li?
1. Extensive and long use
2. Acute and chroni efficacy
3. Safe in pregnancy
4. Moderare antidepressant
5. Anti suicide effects
73
Dsadvantages ofLi?
1. Narrow TI
2. Renal and thyroid tox
3. Nuisance ADR
4. Weiht gain
5. Narrow spectrum of activity
6. Occasional depression induction
74
What are your mood stabilizers?
1. Divalproex sodium
2. Carbamazepine
3. Lamotrigine
4. oxcarbazepine
75
What is the target and tox levels for Depakote?
**Target:** 75 mcg/mL
**Tox:** >125 mcg/mL
76
ADr of Divalproex?
More tolerated than carbamazepine and LI with the exception of **GI upset**
77
Advantages of Divalproex?
1. Strong acute efficacy data
1. Some long-term data
1. Broad activity spectrum
1. “Loading” doses are rapidly effective
1. Effective for anxiety & migraine
1. Less toxic than Li+
1.
78
Disadvantages of Divalproex sodium?
1. Nausea
2. Weight gain
3. Nuisance ADR
4. Less effective for pure Bipolar depression
5. NTD
6. Caution with pancreatitis and PCOS
79
Carbamazepine use in bipolar?
**Biggest disadvantge of drug is DDI**
**PK:** CYP450 induction
Therapuetic: 6-12 mcg/mL
Tox: >15 mcg/mL
80
Advantages of carbemazepine
1. Strong acute efficacy
2. Broad acitivty spectrum
3. Possuble antidepressant use
4. Long history of use
5. No weightgain
81
Disadvantages of carbamazepine?
1. Loss in effectiveness over time
2. Autoinduction and DDI
3. Blood dyscrasias
4. Narrow TI
5. Acute ADR
82
What drug has fewer ADRs compared to carbemazepine?
Oxcarbazepine
83
Advantages of oxcarbazepine?
1. Like carbamazepine
2. More rapid dose titration
3. Milder ADR profile than carbamazepine (less bone marrow, liver effects and drowsiness)
4. No lab required (except sodium)
5. Fewer DDI
84
Disadvantages of oxcarbazepine?
1. L=Off label for bipolar
2. Reduced effectiveness of low-dose oral contraceptives
3. Carbamazepine-like adverse effects (DZm somnolence, diplopia)
4. Hyponatremia
85
Advantages of lamotrigine?
1. Controlled data
2. Well tolerates (no weight gain, labs, sedation, cognitive dulling)
3. Neuroprotective (Blocks glutamatergic Na+ channels)
86
Disadvantages of Lamotrigine
1. Slow dosage titration
2. Skin issues (SJS)
3. Valproate will double serum levels
87
What are the off label bipolar drugs?
1. Levitiraceta and zonisamide
2. Topiramate
3. Gabapentin
88
What is the used of SGA as mood stabilizers?
Nearly all are approved for bipolar
* Weight gain and DI-DM (Olanzapine >>> Risperidone > Aripiprazole) - Montior weight Q3-6M, BG Q6-12M
* Hypertriglyceridemia (Olanzapine, Clozapine >> Risperidone)
89
What is symbyax?
| Indication, Monitor
Olanzapine/Fluoxetine: approved for bipolar depression and tx-resistant depression
Montior: mania and hypomania
90
Lithium BBW?
Toxicity
91
Carbamazepine BBW?
Aplastc anemia, agranulocytosis, serious rash
92
Lamotrigine BBW?
SJS
93
Valproate BBW?
Hepatotox, tetragenocity, pancreatitis
94
Clozapine BBW?
Agranulocytosis, seizures, myocarditis, CV and respiratory effects, dementia-related psychosis
95
All psychotics BBW?
Should not be used for dementia related psychosis
