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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
Q

Severe side effects with MAO-I

A

HA
Drowsiness
Dry mouth
Weight gain
Orthostatic Hypotension
Sexual dysfunction
**Have limited use

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26
Q

What foods and drugs should be avoided with MAO-i?

A

Foods with tyramine, such as cheese, sour cream, beer, avocados

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27
Q

Why should tyramine substances be avoided with MAO-I?

A

Hypertensive crisis

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28
Q

MAO-I interaction with OTCs, such as

A

Cold preparations and diet pills

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29
Q

MAO-I interaction with RX

A

TCAs, SSRIs, L-DOPA

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30
Q

Which herbal product has MAOI activity and can therefore be used for depression

A

St. John’s Wort

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31
Q

Process of reuptake

A

Co-transporter binds outside of the cell, then it is engulfed, and then released inside of the cell

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32
Q

Site of action of reuptake blockers

A

Link to protopedia serotonin transporter

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33
Q

Indications for Tricyclic antidepressants

A

Depression
Panic Disorder
Chronic pain
Enuresis (bed wetting)

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34
Q

Overdose/toxicity of tricyclic antidepressants

A

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.

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35
Q

MOA of tertiary amines

A

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

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36
Q

Major side effects of tertiary amines

A

Sedation
Autonomic side effects
Weight gain

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37
Q

Other side effects of tertiary amines

A

Conduction disturbances of the heart

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38
Q

Tertiary amines

A

Imipramine (Tofranil)
Amitriptyline (Elavil)
Clomipramine (Anafranil)
Doxepin (Adapin, Sinequan)

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39
Q

Impramine (tofranil)

A

Metabolized to desipramine
-Used for enuresis and ADHD

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40
Q

Amitriptyline (Elavil)

A

Metabolized to nortriptyline

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41
Q

What are clomipramine and trimipramine used for?

A

OCD
**SE of clomipramine is having an orgasm while yawning

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42
Q

Secondary amines
**Most tertiaries are metabolized to these

A

Desipramine (Norpramin)
Nortriptyline (Pamelor)
Protriptyline (Vivactil)
Maprotiline (Ludiomil)

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43
Q

Which secondary amine is tetracyclic so it has reduced side effects

A

Maprotiline

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44
Q

MOA of secondary amines

A

Better NET inhibitors than SERT

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45
Q

Side effects of secondary amines

A

Less sedation
Less anticholinergic
Less autonomic
Less weight gain
Less cardiovascular than tertiary amines

46
Q

In general, side effects of all TCAs (secondary and tertiary) are…

A

Anticholinergic, CV (elderly), neurological, weight gain
**Remember pts may be suicidal due to existing depression

47
Q

Mechanism of SSRIs

A
  1. Block 5HT pumps
  2. Increase 5HT in synapse
  3. 5HT remains active longer
48
Q

Meds that are SSRIs

A

Fluoxetine (Prozac)
Fluvoxamine (Luvox)
Paroxetine (Paxil)
Sertraline (Zoloft)
Citalopram (Celexa)
Escitalopram oxalate (Lexapro)

49
Q

Fluoxetine has _____ (lots/little) autonomic SE and ___ (lots/some/no) sedation

A

Little
No (some may become agitated/excited on it)

50
Q

SSRIs have (few/lots) of SE

A

Few, so they are commonly prescribed

51
Q

Does a pt taking an SSRI feel better immediately?

A

NO; serotonin goes up immediately, but does not make a patient feel better

52
Q

Uses for SSRIs

A

Depression
Alcoholism
OCD
Enuresis
PTSD
Eating disorders
Social phobia
Panic anxiety
PMDD
GAD

53
Q

SE of SSRI

A

N/V
HA
Sexual dysfunction
Anxiety
Tremor

54
Q

SSRI discontinuation syndrome
**IF abruptly stop the SSRI

A

“Brain zaps” (feel like they lose 10s of their life), dizziness, sweating, nausea, insomnia, tremor, confusion, vertigo

55
Q

Serotonin syndrome

A

EMERGENCY
When SSRI given with MAOI, TCAs, metoclopramide, tramadol, triptans, St. John’s Wort
**Way too much serotonin

56
Q

Symptoms of serotonin syndrome

A

Hyperthermia
Muscle rigidity
Restlessness
Myoclonus (sudden, brief, involuntary jerking)
Hyperreflexia
Sweating
Shivering
Seizures
Coma

57
Q

Treatment of serotonin syndrome

A

D/C med and manage symptoms; administer serotonin antagonist (cyproheptadine; methysergide); benzos to control myoclonus (involuntary jerking)

58
Q

SSRI and 5HT1A partial agonist examples

A

Vilazodone (Viibryd)
Vortioxetine (Brintellix)

59
Q

Vilazodone has similar 5HT1A actions to

A

Aripiprazole (Abilify)-atypical antipsychotic
Buspirone (Buspar)-partial 5HT1A for anxiety

60
Q

Vilazodone has ____ (increased/reduced) sexual side effect vs. pure SSRIs

A

Reduced

61
Q

Targets for Vortioxetine (Brintellix)

A

SERT, 5HT1A partial agonist, 5HT3

62
Q

Tetracyclic and unicyclic antidepressant examples

A

Maprotiline (Ludiomil)
Amoxapine (Ascendin)
Mirtazapine (Remeron)
Bupropion (Wellbutrin)

63
Q

Maprotiline (Ludiomil) is a _______

A

NET-inhibitor

64
Q

Amoxapine (Ascendin) is a ___

A

NET inhibitor and D2 antagonist (causes low dopamine levels and may lead to EPS-motor SE)

65
Q

Mirtazapine (Remeron) targets _____

A

Alpha-2 antagonist
5HT2 and 5HT3 antagonist
H1 antagonist
**NOT hitting transporters, only receptors

66
Q

Bupropion (Wellbutrin) is a ____

A

DAT inhibitor
NET and SERT inhibitor
**Hits transporters

67
Q

What can bupropion be used for

A

GAD
Smoking cessation using Zyban

68
Q

5HT2 antagonists/SERT inhibitor

A

Trazodone (Dyserel)

69
Q

Counseling point with trazodone

A

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
Q

Serotonin-Norepinephrine reuptake inhibitor (SNRI) target ____ and have (more/less) SE than previous ones.

A

NET and SERT
Less

**ALL behave similar to tertiary TCA with less SE

71
Q

Examples of SNRIs

A

Venlafaxine (Effexor)
Desvenlafaxine (Pristiq)
Duloxetine (Cymbalta)
Milnacipran (Ixel)
Levomilnacipran (Fetzima)

72
Q

Venlafaxine (Effexor)

A

NET and SERT inhibitor
Treats GAD and panic disorder
Diabetic neuropathy?
Migraine prophylaxis?

73
Q

Desvenlafaxine (Pristiq)

A

NET and SERT inhibitor
Tx of vasomotor sx associated with menopause?

74
Q

Duloxetine (Cymbalta)

A

NET and SERT inhibitor
Treats GAD
Treats peripheral neuropathy

75
Q

Milnacipran (Ixel)

A

NET and SERT inhibitor
Approved for fibromyalgia

76
Q

Levomilnacipran (Fetzima)

A

NET and SERT inhibitor
Active enantiomer of milnacipran

77
Q

Norepinephrine selective reuptake inhibitors (NSRIs)

A

NET selective

78
Q

Examples of NSRIs

A

Reboxetine (Vestra; Edronax)
Atomoxetine (Strattera)

79
Q

Reboxetine (Vestra; Edronax)

A

Possibly less SE than Prozac
FDA declined license for use in USA for unknown reasons

80
Q

Atomoxetine (Strattera)

A

Originally intended to be an antidepressant drug (not approved!)
**Now used for ADHD

81
Q

What should you do if a patient tried 2 SSRI and failed?

A

Try something more favorable for NET than 5HT or change med classes

82
Q

Triple blocker or “Triple Reuptake Inhibitor” (TRI)

A

Serotonin-Norepinephrine-Dopamine reuptake inhibitor (SNDRIs)

**Example: cocaine

83
Q

NMDA antagonist

A

**Rapidly acting antidepressant

84
Q

CNS effects of esketamine

A

Depression, drug interactions

84
Q

Clinically used NMDA antagonists

A

Esketamine (Spravato)–used in conjugation with oral antidepressant

84
Q

Examples of NMDA antagonists

A

Ketamine (subanesthetic doses)
Scopolamine (Also muscarinic antagonist)
Lanicemine (“low trapping”)
GLYX-13 partial NMDA antagonist

84
Q

Mechanism of “low trapping” NMDA antagonist

A

Block NMDA and keep in partially active state (excitatory) – glutamate

85
Q

How is esketamine administered?

A

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
Q

Tx for post-partum depression

A

SSRIs (fluoxetine and paroxetine) and venlafaxine
-Others: CBT and counseling
-Newer drug: Brexanolone (Zulresso)

87
Q

MOA of Brexanolone (Zulresso)

A

Binds allosterically to GABA-A receptors to enhance its function

88
Q

What happens to allopregnanolone levels during pregnancy? How about post-partum?

A

They increase; return to normal once the mother gives birth

89
Q

Brexanolone ____ GABA-A receptors

A

Resensitizes; cannot gate Cl- so membrane potential goes up and spikes

90
Q

Brexanolone is a _____ drug that is a ____ hr infusion and very expensive.

**It is very effective, but not used much

A

REMS
60

91
Q

New agents in development

A

-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
Q

Non-pharmacological considerations for depression

A

-Electroconvulsive therapy: resets action potentials and a way to treat drug-resistant depression
-Psychotherapy: counselor
-Hospitalization: protect pt from themselves

93
Q

Pharmacotherapeutic considerations

A

-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
Q

Do not take trazodone in ___ or SSRI in ____

A

AM; PM

95
Q

Antidepressants (especially TCA) works on ___ pathways

A

Descending

96
Q

Filbanserin (Addyi)

A

-“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
Q

Approximately ___ % of americans have bipolar disorder. Onset is < ____ y/o

A

1.5-3
30

98
Q

Etiology of bipolar disorder

A

-Genetic predisposition
-Biological 5-HT and DA
-Environmental (infections, birth complications, etc)

99
Q

Types of bipolar disorder

A

-Bipolar I
-Bipolar II
-Cyclothymia disorder
-Unspecified bipolar and related disorder
-Substance-induced mood disorder

100
Q

Symptoms of bipolar disorder

A

-Mania
-Hypomania
-Depression
-Mixed mania and depression

101
Q

What is mania?

A

Euphoria/elation, irritability/anger, impulsive high risk behavior, aggressive, grandiose ideas, decreased sleep and appetite, difficulty concentrating, delusions, flight of ideas, hallucinations

102
Q

What is hypomania?

A

Less severe mania

103
Q

Depression

A

Physiological and psychological symptoms of depression

104
Q

Treatment of bipolar disorder

A

-Hospitalization
-Psychotherapy
-Pharmacotherapy (to stabilize neuronal signaling)

105
Q

Pharmacotherapy of bipolar disorder

A

Mood stabilizers: lithium, anticonvulsant
Atypical antipsychotic
**CCB (verapamil, nimodipine)
Combination tx + benzodiazepine

106
Q

Actions of lithium

A

Ion similar to sodium
-Variety of targets (“dirty drug”)
-Goes everywhere in the cell

107
Q

Lithium (light) pharmacotherapy

A

-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
Q

Anticonvulsants

A

-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
Q

Atypical antipsychotics

A

-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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