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Therapeutics P2 Winter Semester > PHRM 845-FINAL EXAM > Flashcards

PHRM 845-FINAL EXAM Flashcards

Antidepressants

1
Q

History and Background of antidepressants

A

 1950s: Imipramine (1st TCA) as the 1st
antidepressant
 Isoniazid (MAOI) an antituberculosis drug
 Additional TCAs
 Present: SSRIs, atypicals, and dual acting

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2
Q

Goals of therapy with antidepressants

A

Alleviate signs and symptoms

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3
Q

Types of depression

A

Reactive (most common)
MDD (major depressive disorder)
Bipolar affective

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4
Q

What generally causes reactive depression?

A

Death, trauma, stress

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5
Q

Depression is a common mental illness of the general population.
-It impacts ___% of the population
-Underdiagnosed–why?
-Undertreated
-___ if left untreated

A

10%
Hesitancy to get treated–suck it up and put a smile on your face
Suicidal

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6
Q

Physiological features of depression

A

-decreased sleep, appetite changes, fatigue, psychomotor dysfunctions
– Other: menstrual irregularities, palpitations, constipation, headaches and nonspecific body aches

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7
Q

Psychological features of depression

A

dysphoric mood, worthlessness, excessive guilt, loss of interest/pleasure in all or most activities

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8
Q

Cognitive features of depression

A

Decreased concentration; suicidal ideation

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9
Q

Diagnosis of depression

A

Not due to drugs, medical condition, or bereavement

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10
Q

Drug-induced depression

A

-Antihypertensive and Cardiovascular
~reserpine, methyldopa, propranolol, metoprolol, prazosin, clonidine, digitalis
-Sedative-Hypnotics
~alcohol, benzodiazepines, barbiturates, meprobamate
-Anti-inflammatory and Analgesics
~indomethacin, phenylbutazone, opiates, pentazocine
-Steroids
~corticosteroids, oral contraceptives, estrogen withdrawal
-Misc: anti-parkinson, anti-neoplastic, neuroleptics
**See if something changes prescription-wise or OTC

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11
Q

Neuroendocrine hypothesis of depression

A

 Changes in Hypothalamic-Pituitary-Adrenal (HPA) Axis
 Overactivity of HPA and elevated CRF found in almost all
depressed patients
 Overactivity of HPA may desensitize feedback response
in hypothalamus and pituitary
 Elevated CRF causes insomnia, anxiety, and decreased
appetite and libido
 Antidepressants and ECT reduce CRF levels–can reverse depression symptoms

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12
Q

Symptoms associated with depression for neuroendocrine hypothesis

A

CRF1
Arousal
Anxiety-like behavior
Disruption of sexual behaviors
Disruption of sleep

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13
Q

Neurotrophic hypothesis of depression

A

 Brain-derived neurotrophic factor (BDNF) is critical in
– Neural plasticity, resilience, neurogenesis
 Stress and pain decrease BDNF levels in animals
 Decrease in volume (5-10%) of hippocampus (memory
and regulates HPA)
 BDNF has “antidepressant” activity in animals
 Depressed patients have reduced BDNF levels
 Antidepressants increase BDNF levels and may increase
hippocampal volume
 (however, some animal studies have provided opposing
evidence, BDNF knock out animals and increase BDNF
following stress)

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14
Q

In neurotrophic hypothesis, what is the effect of BDNF on neuronal growth?

A

The more BDNF=more sprouting=neurons can reconnect

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15
Q

Antidepressant impact on BDNF

A

Antidepressants increase monoamines which increases BDNF

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16
Q

Integration of all the hypothesis of depression

A

 HPA and steroid abnormalities regulate BDNF levels
 Hippocampal glucocorticoid receptors are activated by
cortisol during stress (decreasing BDNF)
 Chronic activation of monoamine receptors increases BDNF signaling (> 2 weeks)
 Chronic activation of monoamine receptors leads to a downregulation of the HPA axis

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17
Q

Main classes of antidepressants

A

-MAOIs = Monoamine Oxidase Inhibitors
-TCAs = Tricyclic Antidepressants; tertiary and
secondary amines (a.k.a. SNRIs, see below)
-SSRIs = Selective-Serotonin Reuptake Inhibitors
-SNRIs = Serotonin-Norepinephrine Reuptake Inhibitors
-5-HT2 Antagonists
Tetracyclic and Unicyclic Antidepressants

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18
Q

Response to antidepressants is ____(rapid/delayed)

A

Delayed; ensure patient knows about delay in feeling; SSRI causes immediate increase in serotonin, but depression will not be better (takes days-weeks for effect)

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19
Q

Why does therapy take 2-3 weeks for effect?

A

Antidepressants cause the amount of neurotransmitter in the intrasynaptic space to
increase.
-Is the delay in clinical effect
due to…
 Activation of presynaptic
receptors?
 Presynaptic adaptation?
 Postsynaptic adaptation?
→ No one really knows!

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20
Q

Mechanism of MAOIs

A

NE and 5HT-2A are normally degraded by monoamine oxidase. This process is inhibited with MAOI resulting in an increased amount of NE and 5HT packaged in vesicles.

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21
Q

Non-selective MAO-I

A

-Phenelzine (Nardil)
-Tranylcypromine (parnate)
**Irreversible

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22
Q

Selective MAO-B

A

Selegiline (Eldepryl/Ensam)
**Used in PD
**Reversible

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23
Q

MAO-A selective

A

Moclobemide (Manerix)
**Not used in US
**Used in Europe to tx depression
**Reversible

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24
Q

MAO-I are ___ (reversible/irreversible)
Are they a good option?

A

Irreversible–receptor is gone until new receptors are formed

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25
Severe side effects with MAO-I
HA Drowsiness Dry mouth Weight gain Orthostatic Hypotension Sexual dysfunction **Have limited use
26
What foods and drugs should be avoided with MAO-i?
Foods with tyramine, such as cheese, sour cream, beer, avocados
27
Why should tyramine substances be avoided with MAO-I?
Hypertensive crisis
28
MAO-I interaction with OTCs, such as
Cold preparations and diet pills
29
MAO-I interaction with RX
TCAs, SSRIs, L-DOPA
30
Which herbal product has MAOI activity and can therefore be used for depression
St. John's Wort
31
Process of reuptake
Co-transporter binds outside of the cell, then it is engulfed, and then released inside of the cell
32
Site of action of reuptake blockers
Link to protopedia serotonin transporter
33
Indications for Tricyclic antidepressants
Depression Panic Disorder Chronic pain Enuresis (bed wetting)
34
Overdose/toxicity of tricyclic antidepressants
Extremely dangerous; depressed patients are more likely to be suicidal; Patients are more likely to commit self-harm or suicide 2 weeks into treatment **This is because normally patients are so depressed they don't have energy to take their own lives, but once tx starts to kick in, they get energy to do it.
35
MOA of tertiary amines
Inhibit NE and 5HT reuptake via NET and SERT -Also act as receptor ANTAgonists for antihistamine (H1), antimuscarinic, and antiadrenergic **Not great drugs and have lots of SE
36
Major side effects of tertiary amines
Sedation Autonomic side effects Weight gain
37
Other side effects of tertiary amines
Conduction disturbances of the heart
38
Tertiary amines
Imipramine (Tofranil) Amitriptyline (Elavil) Clomipramine (Anafranil) Doxepin (Adapin, Sinequan)
39
Impramine (tofranil)
Metabolized to desipramine -Used for enuresis and ADHD
40
Amitriptyline (Elavil)
Metabolized to nortriptyline
41
What are clomipramine and trimipramine used for?
OCD **SE of clomipramine is having an orgasm while yawning
42
Secondary amines **Most tertiaries are metabolized to these
Desipramine (Norpramin) Nortriptyline (Pamelor) Protriptyline (Vivactil) Maprotiline (Ludiomil)
43
Which secondary amine is tetracyclic so it has reduced side effects
Maprotiline
44
MOA of secondary amines
Better NET inhibitors than SERT
45
Side effects of secondary amines
Less sedation Less anticholinergic Less autonomic Less weight gain Less cardiovascular than tertiary amines
46
In general, side effects of all TCAs (secondary and tertiary) are...
Anticholinergic, CV (elderly), neurological, weight gain **Remember pts may be suicidal due to existing depression
47
Mechanism of SSRIs
1. Block 5HT pumps 2. Increase 5HT in synapse 3. 5HT remains active longer
48
Meds that are SSRIs
Fluoxetine (Prozac) Fluvoxamine (Luvox) Paroxetine (Paxil) Sertraline (Zoloft) Citalopram (Celexa) Escitalopram oxalate (Lexapro)
49
Fluoxetine has _____ (lots/little) autonomic SE and ___ (lots/some/no) sedation
Little No (some may become agitated/excited on it)
50
SSRIs have (few/lots) of SE
Few, so they are commonly prescribed
51
Does a pt taking an SSRI feel better immediately?
NO; serotonin goes up immediately, but does not make a patient feel better
52
Uses for SSRIs
Depression Alcoholism OCD Enuresis PTSD Eating disorders Social phobia Panic anxiety PMDD GAD
53
SE of SSRI
N/V HA Sexual dysfunction Anxiety Tremor
54
SSRI discontinuation syndrome **IF abruptly stop the SSRI
"Brain zaps" (feel like they lose 10s of their life), dizziness, sweating, nausea, insomnia, tremor, confusion, vertigo
55
Serotonin syndrome
**EMERGENCY** When SSRI given with MAOI, TCAs, metoclopramide, tramadol, triptans, St. John's Wort **Way too much serotonin
56
Symptoms of serotonin syndrome
Hyperthermia Muscle rigidity Restlessness Myoclonus (sudden, brief, involuntary jerking) Hyperreflexia Sweating Shivering Seizures Coma
57
Treatment of serotonin syndrome
D/C med and manage symptoms; administer serotonin antagonist (cyproheptadine; methysergide); benzos to control myoclonus (involuntary jerking)
58
SSRI and 5HT1A partial agonist examples
Vilazodone (Viibryd) Vortioxetine (Brintellix)
59
Vilazodone has similar 5HT1A actions to
Aripiprazole (Abilify)-atypical antipsychotic Buspirone (Buspar)-partial 5HT1A for anxiety
60
Vilazodone has ____ (increased/reduced) sexual side effect vs. pure SSRIs
Reduced
61
Targets for Vortioxetine (Brintellix)
SERT, 5HT1A partial agonist, 5HT3
62
Tetracyclic and unicyclic antidepressant examples
Maprotiline (Ludiomil) Amoxapine (Ascendin) Mirtazapine (Remeron) Bupropion (Wellbutrin)
63
Maprotiline (Ludiomil) is a _______
NET-inhibitor
64
Amoxapine (Ascendin) is a ___
NET inhibitor and D2 antagonist (causes low dopamine levels and may lead to EPS-motor SE)
65
Mirtazapine (Remeron) targets _____
Alpha-2 antagonist 5HT2 and 5HT3 antagonist H1 antagonist **NOT hitting transporters, only receptors
66
Bupropion (Wellbutrin) is a ____
DAT inhibitor NET and SERT inhibitor **Hits transporters
67
What can bupropion be used for
GAD Smoking cessation using Zyban
68
5HT2 antagonists/SERT inhibitor
Trazodone (Dyserel)
69
Counseling point with trazodone
Very sedative, so it can only be taken at night. Get right into bed because it is a strong hypnotic-->pt will feel refreshed in the morning **It is an off-label hypnotic (alpha1 and H1 with 5HT2)
70
Serotonin-Norepinephrine reuptake inhibitor (SNRI) target ____ and have (more/less) SE than previous ones.
NET and SERT Less **ALL behave similar to tertiary TCA with less SE
71
Examples of SNRIs
Venlafaxine (Effexor) Desvenlafaxine (Pristiq) Duloxetine (Cymbalta) Milnacipran (Ixel) Levomilnacipran (Fetzima)
72
Venlafaxine (Effexor)
NET and SERT inhibitor Treats GAD and panic disorder Diabetic neuropathy? Migraine prophylaxis?
73
Desvenlafaxine (Pristiq)
NET and SERT inhibitor Tx of vasomotor sx associated with menopause?
74
Duloxetine (Cymbalta)
NET and SERT inhibitor Treats GAD Treats peripheral neuropathy
75
Milnacipran (Ixel)
NET and SERT inhibitor Approved for fibromyalgia
76
Levomilnacipran (Fetzima)
NET and SERT inhibitor Active enantiomer of milnacipran
77
Norepinephrine selective reuptake inhibitors (NSRIs)
NET selective
78
Examples of NSRIs
Reboxetine (Vestra; Edronax) Atomoxetine (Strattera)
79
Reboxetine (Vestra; Edronax)
Possibly less SE than Prozac FDA declined license for use in USA for unknown reasons
80
Atomoxetine (Strattera)
Originally intended to be an antidepressant drug (not approved!) **Now used for ADHD
81
What should you do if a patient tried 2 SSRI and failed?
Try something more favorable for NET than 5HT or change med classes
82
Triple blocker or "Triple Reuptake Inhibitor" (TRI)
Serotonin-Norepinephrine-Dopamine reuptake inhibitor (SNDRIs) **Example: cocaine
83
NMDA antagonist
**Rapidly acting antidepressant
84
CNS effects of esketamine
Depression, drug interactions
84
Clinically used NMDA antagonists
Esketamine (Spravato)--used in conjugation with oral antidepressant
84
Examples of NMDA antagonists
Ketamine (subanesthetic doses) Scopolamine (Also muscarinic antagonist) Lanicemine ("low trapping") GLYX-13 partial NMDA antagonist
84
Mechanism of "low trapping" NMDA antagonist
Block NMDA and keep in partially active state (excitatory) -- glutamate
85
How is esketamine administered?
Intranasal, phased dosing (twice weekly, weekly, and every 2 weeks)--VERY EXPENSIVE **Must be in presence of someone (can do MD on zoom call) **Only available through restricted program (REMS)
86
Tx for post-partum depression
SSRIs (fluoxetine and paroxetine) and venlafaxine -Others: CBT and counseling -Newer drug: Brexanolone (Zulresso)
87
MOA of Brexanolone (Zulresso)
Binds allosterically to GABA-A receptors to enhance its function
88
What happens to allopregnanolone levels during pregnancy? How about post-partum?
They increase; return to normal once the mother gives birth
89
Brexanolone ____ GABA-A receptors
Resensitizes; cannot gate Cl- so membrane potential goes up and spikes
90
Brexanolone is a _____ drug that is a ____ hr infusion and very expensive. **It is very effective, but not used much
REMS 60
91
New agents in development
-Psychedelics: MDMA (ecstasy), psilocybin, and LSD (acid) ----- doses will be much lower than people use for psychedelic effect. -5HT2C receptor antagonists -Metabotropic glutamate receptor agonists -Reversible inhibitors of monoamine oxidase-A (RIMA) ~Moclobemide ~Brofaromine ~Are as effective as TCAs and better tolerated
92
Non-pharmacological considerations for depression
-Electroconvulsive therapy: resets action potentials and a way to treat drug-resistant depression -Psychotherapy: counselor -Hospitalization: protect pt from themselves
93
Pharmacotherapeutic considerations
-Severity of depression (typically don't medicate for SAD) -Onset of drug action (SSRI could take weeks) -Endogenous vs. exogenous depression -Unipolar vs. bipolar -Drug selection -Dosing -Duration of tx -Compliance -Other factors
94
Do not take trazodone in ___ or SSRI in ____
AM; PM
95
Antidepressants (especially TCA) works on ___ pathways
Descending
96
Filbanserin (Addyi)
-"Female viagra" -Hypoactive sexual desire disorder -Originally created as antidepressant -Agonist of 5HT1A and an antagonist of 5HT2A/C -Regional selectivity in the prefrontal cortex -Controversial approval -NOT rapid acting
97
Approximately ___ % of americans have bipolar disorder. Onset is < ____ y/o
1.5-3 30
98
Etiology of bipolar disorder
-Genetic predisposition -Biological 5-HT and DA -Environmental (infections, birth complications, etc)
99
Types of bipolar disorder
-Bipolar I -Bipolar II -Cyclothymia disorder -Unspecified bipolar and related disorder -Substance-induced mood disorder
100
Symptoms of bipolar disorder
-Mania -Hypomania -Depression -Mixed mania and depression
101
What is mania?
Euphoria/elation, irritability/anger, impulsive high risk behavior, aggressive, grandiose ideas, decreased sleep and appetite, difficulty concentrating, delusions, flight of ideas, hallucinations
102
What is hypomania?
Less severe mania
103
Depression
Physiological and psychological symptoms of depression
104
Treatment of bipolar disorder
-Hospitalization -Psychotherapy -Pharmacotherapy (to stabilize neuronal signaling)
105
Pharmacotherapy of bipolar disorder
Mood stabilizers: lithium, anticonvulsant Atypical antipsychotic **CCB (verapamil, nimodipine) Combination tx + benzodiazepine
106
Actions of lithium
Ion similar to sodium -Variety of targets ("dirty drug") -Goes everywhere in the cell
107
Lithium (light) pharmacotherapy
-Mechanism not clearly understood (depletion of PIP2 and associated signaling--IP3 and PKC; modulate GSK3--phosphorylation and binding partners) -Small therapeutic index -Acute (give large loading dose) vs. chronic -Lag time for effectiveness -Loading dose
108
Anticonvulsants
-Valproic acid and sodium valproate **Multiple MOA ~Increase GABAergic tone (increase GAD activity, inhibit GABA transaminase) ~Block sodium channels ~Block T-type calcium channel ~Inhibits histone deacetylase (HDAC5)
109
Atypical antipsychotics
-Olanzapine (Zyprexa) -Olanzapine + fluoxetine (Symbyax) -Quetiapine (Seroquel) -Risperidone (Risperidol) -Ziprasidone (Geodone/Zeldox) -Lurasidone (Lutada) -Aripiprazole (Abilify)

Therapeutics P2 Winter Semester (29 decks)

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