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Drug Action III > Anxiety and Depression (MC) - Block 3 > Flashcards

Anxiety and Depression (MC) - Block 3 Flashcards

1
Q

The more lipophilic the drugs, the more its able to?

A
  1. PPB
  2. Have high Vd and DOA
  3. Have longer half-lives
  4. Rapidly absorb
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2
Q

Have active metabolites leads to ____?

A

accumulation of the drug

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3
Q

What occurs during N-dealkylation?

A

3 amine to 2
2 amine to 1

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4
Q

What occurs during MOA metabolism?

A

Primary amine to aldehyde

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5
Q

What is the cause of serotonin syndrome?

A

When 2 agents that increase seratonin are taken together:
* If one is DC and has a long t1/2 it may need a wash out period

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6
Q

What are the sx of serotoninc syndrome?

A
  1. Fever
  2. Tremor
  3. Coma
  4. Sz
  5. Death
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7
Q

What is the side effects that are caused by serotonin?

A

Depression
OCD
Panic
Bulimia

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8
Q

What are the side effects that are caused by too much serotonin?

A
  1. Anx
  2. Insomnia
  3. Sexxual dysfunction
  4. GI disturbances
  5. Serotonin syndrome
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9
Q

What is the function of serotonin and NE?

A

5HT + NE = parallel, independent pathways
5HT: changes in mood
NE: Increased drive

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10
Q

What is the overall function of reuptake inhibtiors?

A

Change presynaptic and postsynaptic sensitivity of neurons:
* Induces synaptic and neuronal plasticity in serotonergic and/or noradrenergic neurons -> long-term changes in neurochemistry
* 5-HT and NE modulate a large number of other neurotransmitter systems

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11
Q

Decribe the underlying mechanism of reuptake inhibitors?

A
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12
Q

Describe the onset of antidepressants?

A

Maximum benefit is not achieved till 1-2 months

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13
Q

Describe tserotonin reuptake before drug?

A
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14
Q

Describe the immediate effects of SSRIs?

A
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15
Q

What is lag time?

A

Elevated levels of NT -> inhibitory autoreceptor stimulation down regulates activity of rate-limiting enzymes TPH and TH -> reduces rate of neuronal firing
* Initial exporsure to antidepressants may not significantly increase postsynaptic signaling

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16
Q

What are the long term effects of SSRI?

A
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17
Q

How does AD contribute to lag time?

A

Chronic use of antidepressants -> inhibitory autoreceptors are down-regulated -> enhancement of neurotransmission
* Drug causes gradual desensitization of autoreceptors -> increased neurotransmission

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18
Q

Lag time/delay is likely caused by?

A

Inhibitory feedback mechanisms

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19
Q

Describe the long term effects of NE reuptake inhibition?

A
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20
Q

Is there one drug that can treat all patients with depression?

A

No, Some patients may respond better to serotonergic agent, others to noradrenergic agent. Some may respond to both

Selection of med is a guessing games and dependent on a patient’s response

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21
Q

Describe the overall SAR and PK of TCAs?

A

SAR:
* 6-76 rings
* Side chain usually 3 carbon atoms with terminal amine (secondary or tertiary)

PK: very lipophilic -> high PPB and Vd

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22
Q

Describe the selectivity of TCAs?

A

Tertiary: non-selective, dual affinity for NET and SERT
Secondary: selective for NET

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23
Q

How does tert TCA selectivty contribute to ADRs?

A

Narrow therapeutic window with anticholinergic, antihistaminic, a1-antiadrenergic, cardiac, and weak dopamine reuptake blocking ADRs

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24
Q

Describe the metabolism of tert amine TCA?

A

Good absorption but low bioavailability due to extensive N-dealkylation to secondary amine TCAs (active metabolite)

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25
Q

What are the types of tertiary amine TCAs?

A

Amitriptyline (Elavil)
Imipramine
Doxepin (Sinequam)
Chlorimipramine/Clomipramine
Trimipramine

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26
Q
A
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27
Q

Describe the selectivity of secondary amine TCAs?

A

More selective for NET – less anticholinergic/sedative:
* Narrow therapeutic-to-toxicity ratios due to heavy metabolism by CYPs

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28
Q

What are the secondary TCAs and what are they a metabolite of?

A

Imipramine -> Desipramine
Amitriptyline -> Nortriptyline
Nortriptyline -> Protriptyline
Loxapine -> Amoxapine

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29
Q

What are the selective secondary TCAs? Non-selective?

A

Selective: Desipramine, Protriptyline
Non-selective: Nortriptyline, amoxapine

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30
Q

TCAs DDI?

A

High PPB drugs, anticholinergic, sympathomimetic drugs
* Increased risk for serotonin syndrome

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31
Q

TCA metabolism?

A

CYP2D6 (genetic polymorphism and narror TI)

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32
Q

What occur syndrome can occur from TCA besides serotonin syndrome?

A

Discontinuation syndrome

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33
Q

What are ADRs of TCAs?

A

Anticholinergic: Dry mouth, constipation, urinary retention, blurred vision
Antiadrenergic: Orthostatic hypotension (especially for elderly patients)
Antihistaminic: Weight gain, sedation
Sodium channels: Increased cardiotoxicity or frequency of seizures
Norepinephrine reuptake: sexual dysfunction
Serotonin reuptake: GI upset

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34
Q

What is the endogenous ligand of SSRI?

A

Serotonin

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35
Q

How does SSRI differ from TCAs?

A
  1. High affinity and selectivity for the SERT
  2. Low affinity for receptors that cause ADRs of TCAs with larger TI
  3. No inhibiton of fast sodium chaneels
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36
Q

What is the general characterisitcs of SSRI?

A
  1. High lipophilicity -> high absorption and PPB
  2. High Vd -> long DOA
  3. Long half-life
  4. High toxic to therapeutic ration
  5. Extensively metabolized by CYPs
  6. Steady-state plasma levels reached in 7 – 10 days
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37
Q

SAR of SSRI?

A

Electronegative para substitution -> good selectivity

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38
Q

What are you elecronegative groups?

A

Cl, I, F, B, CN, NO2

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39
Q

How does selectivity/affintiy differ in different SSRI drugs?

A

All equally effective over time

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40
Q

SSRIs

ADR, DDI

A

ADR: Increased serotonergic tone
DDI: Potential for serotonin syndrome with other serotonergic agents (i.e. MAOIs)
* Need washout for 2-5 weeks when switching SSRI to MAOI
* Sudden discontinuation -> discontinuation syndrome

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41
Q

What are you seratonin side effects?

A

N, D, insomnia, HA, sexual dysfunction

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42
Q

What is discontinuation syndrome?

A

DZ, paresthesias that occurs 2 days after abrupt drug withdrawal and generally resolves in 2-3 weeks

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43
Q

What is the the difference between SSRI and TCA ADRs?

A

SSRI: more NE and SE uptake inhibition ADRs
TCA: More anti-a1, antibholinergic, antihistamine ADRs

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44
Q

Types of SSRIs?

A

Fluoxetine (Prozac, Sarafem)
Paroxetine (Paxel)
Citalopram (Celexa)
Escitalopram (Lexapro)
Sertraline (Zoloft)
Fluvoxamine

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45
Q

Fluoxetine

PK, Cautions, What contributes to selectivity

A

Prozac, Saradem
PK: very long half life and inhibtis own metabolism (CYP2D6) and CYP2C19, CYP3A4
Caution: inhibiton of metabolism and long half-life -> long washout perioid with switching therapies
Selectivity: CF3

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46
Q

Paroxetine

PK, What contributes to selectivity

A

PK: Inhibits CYP2D6 irreversibly through mechanism based inhibition from reactive metabolite
* Non-linear/lang term effects
Selectivity: F

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47
Q

How is Citalopram an improvement from other SSRIs?/

A

No first pass metabolism -> higher bioavailability
* Less PPB

47
Q

What is Lexapro?

A

S-enatiomer of citalopram that is more slective and active
* R-enantiomer conteracts S

48
Q

Between Lexapro and and Celexa which has a high ADR risk?

A

Citalopram because its a racemic mixture

49
Q

Citalopram

Selectivity

A

NC

50
Q

Sertraline

Selectivity, PK

A

Selectivity: Cl, Higher selectivity than other SSRIs or TCAs
PK: extensive metabolism
* Can decrease peak plasma concentration time from 8 to 6 hrs with food
* But metabolism is by a lot of enzymes -> less potential for DDIs

51
Q

How does fluvoxamine differ from other SSRIs?

A

Nontricyclic, only nonchiral (less potent)

52
Q

Fluvoxamine

Selectivity, PK

A

Selectivity: CF3
PK: nonlinear

53
Q

What are you nonlinear SSRI?

A

Fluoxetine
Paroxetine
Fluvoxamine

54
Q

What SSRI has least affect on CYPs?

A

Citalopram

55
Q

SNRI MOA?

A

Inhibits both NET and SERT -> combination produces greater efficacy
* Possesses low affinity at other neurotransmitter receptos -> low side effect potential

56
Q

SNRI

ADR

A
  1. Serotonergic effects
  2. Noradrenergic effects
  3. CNS activation
  4. DC syndrome
57
Q

TYpes of SNRI?

A
  1. Venlafaxine (Effexor)
  2. Desvenlafaxine (Pristiq, Kedezla)
  3. Levomilacprin
  4. Duloxetine (Cymbalta)
58
Q

Venlafaxine

MOA, ADR, PK

A

MOA: Preferentially inhibits 5-HT reuptake over NE and DA reuptake
ADR: Low risk for AE, but can have ardiotoxcity
PK: low bioavailability
* Weak inhibitor of CYP2D6

59
Q

How does desvenlafaxine differ from venlafaxine? ADR?

A

Equiactive metabolite with hydroxyl group
ADR: N

60
Q

Levomilnacprin

MOA, PK, ADR

A

MOA: Higher affinity for 5-HT reuptake
PK: Slower onset of action than TCAs
ADR: Generally safe

61
Q

Duloxetine

MOA, PK, ADR

A

MOA: slightly higher affinity for SERT
PK: CYP2D6 inhibitor and produces
ADR: reactive metabolite causes jaundice like conditions

62
Q

What is first MOAI?

A

Isoniazid: Antitubercular

63
Q

What are the cons of using MAOIs?

A

Hepatotox due to hydrazine reactive group

64
Q

Why could MAOI be consequenctial?

A

Many drugs are metabolized by MAOI, inhibition leads to accumulation

65
Q

Describe the potential of MAOIs?

A

Irreversible inactivation, effects can be seen up to 2 weeks after dc the drug

Onset takes a few days

66
Q

Describe the MOA of MAOIs?

A
67
Q

What are the effects of irreversible MOA-A and B inhibition?

A
  1. Increase free 5-HT and NE, and other amines
68
Q

Types of MOA irreversible inhibitors?

A

Phenelzine
Isocarboxazid
Tranylcypromine
Selegiline

69
Q

MOA irreversible inhibitors SAR?

A
  • Message: Contains reactive groups that form irriversible bonds to FAD
  • Contains an address: directs drug to MOA
70
Q

What are the metabolism issues with tranylcypromine?

A

Inhibits other metabolizing enzymes (MAO, CYP2C19, 2D6, 2C9)

71
Q

What is the metabolism issue with phenelzine?

A

Interindividual variability in plasma concentrations due to slow/fast acetylators

72
Q

What is the metabolism issue with selegiline?

A

Metabolized to meth/amphetampine by CYP2B6 and CYP3A4

73
Q

MOAI

ADR, DDI

A

ADI: orthostatic hypotension, weight gain, sexual dysfunction, insomnia, sudden DC syndrome
DDI:interactions with food -> hypertensive crisis from increased catecholamines
* Foods with large amounts of tyrramine or tryptophan

74
Q

What are the sx of HTN crisis?

A

HA, tachycardia, cardia arrhythmia, stroke

75
Q

How does Moclobemide differ from other MAOIs?

A

Reversible MAO-A inhibitor antidepressant (RIMA): can be displaced by tyramine if ingested

76
Q

What are natural DA and NE Reuptake Inhibitors?

A

CNS stimulants: methamphetamine, diethylpropion, cathinone

77
Q

What DA and NE Reuptake Inhibitor is designed to have no metabolites with sympathomimetic or anorexigenic properties?

A

Bupropion due to T-butyl group -> no N-dealkylation

78
Q

What are the considerations of DA and NE Reuptake Inhibitors?

A

ADR: sympathomimetic and/or anorexigenic (N-dealkylation)

Extensive metabolism to active metabolites with long DOA

79
Q

Bupropion

MOA, PK, ADR

A

Aplenzin, Forfivo, Wellbutrin
MOA: Bupropion inhibits DA reuptake at DA presynaptic neuronal membrane and inhibits release of DA and NE; also noncompetitive antagonist of several nAChRs
* Plasma concentrations are higher than parent drug with longer DOA
* Similar pharmacologic properties to bupropion

PK: CYP2D6 inhibitor
ADR: Risk of serious seizures with antiseizures, insomnia, N,DZ, tremor
* NO sexual dysfunction due to no serotonin activity

80
Q

What is an example NMDA antagonist for psch?

A

Auxility (dextromethorphan-bupropion)

81
Q

Auxillary

MOA, ADR

A

Dextromethorphan: active at NMDA receptor and σ-1 receptor (heavily metabolized by CYP2D6)
Bupropion: Inhibits CYP2D6
ADR: seratonin sx for dex

82
Q

What is the function of Serotonin Receptor Modulators?

A

Modulate concnetration of 5-HT in brain:
* Receptors can also modulate other neurotransmitters
* Enhance noradrenergic or serotonergic transmission

83
Q

MOA of SRMs?

A
  • 5-HT2A antagonist and reuptake inhibitor; active metabolite is 5-HT2c agonist
  • α1-adrenergic antagonist but doesn’t affect DA or NE reuptake, little anticholinergic activity, no cardiovascular toxicity
84
Q

SAR of SRM?

A

Serotonin Receptor Modulators = phenylpiperazines

However, open para postition can need to hepatotoxicity

85
Q

Examples of SRM?

A

Trazodone
Nefazodone
Vortioxetine
Vilazodone (Viibryd)
Mirtazapine (Remeron)

86
Q

Trazodone

ADR

A

Desyrel
ADR: Hypotension, high sedation (difficult to titrate to AD doses), GI, hepatotoxic (2 reactive metabolites)

87
Q

Describe the metabolism of trazodone?

A
88
Q

Nefazodone

BBW, PK, ADR

A

BBW: hepatotoxic due to open para across N
PK: potent CYP3A4 inhibitor
ADR: Sedation, GI disturbances, orthostatic hypotension (α1-adrenergic antagonist)
* Less sedation than trazodone

89
Q

Vortioxetine

MOA, PK, ADR

A

MOA: Antagonist at 5-HT3, 5-HT7 and 5-HT1D, partial agonist at 5-HT1B, agonist at 5-HT1A; and reuptake inhibitor
PK: Metabolized by CYP2D6
ADR: GI effects, sexual dysfunction, headaches, insomnia

90
Q

Vilazodone

MOA, ADR, BBW, DDI, PK

A

Viibryd
MOA: selective 5-HT1A receptor partial agonist (1 week onset of action) and reuptake inhibitor
ADR: Diarrhea, nausea, vomiting, sexual dysfunction
BBW: Suicidal ideation in young adults and children
DDI: NSAIDs/warfarin
PK: Extensively metabolized by CYP3A4

91
Q

Mirtazapine

MOA, ADR, Indication

A

Remeron
MOA: α2-adrenergic antagonist (increases release of NE) and 5-HT2 and 5-HT3 antagonist
* NaSSA – noradrenergic and specific serotonin antidepressant

ADR: anticholinergic, H1 receptor antagonist (-> sedation) and α1-adrenergic antagonist (-> orthostatic hypotension)
* Take at HS to avoid daytime sedation

Indication: Potent appetite stimulant -> weigh gain

92
Q

What are the general concepts of AD?

A
  1. Equal efficacy
  2. Risk of increased suicidality
  3. Lethal OD more common with MAOIs and TCAs
  4. Nearly all metabolized by ≥ 1 CYP
    * If > 1 in parallel -> unlikely to be affected by DDIs or polymorphisms
    * If CYP3A4, CYP2C18 or CYP2D6 -> potential for DDIs increases
93
Q

Describe the sx remission timeline?

A
94
Q

What drugs have the highest incidence for sexual disfunction?

A

SSRIs, SNRIs and MAOIs (especially paroxetine)

95
Q

What drugs have the lowest incidence for sexual dysfunction?

A

Bupropion, mirtazapine, vilazodone and vortioxetine

96
Q

What are augmentation stimulant strategies used for?

A

Atypical depression or sx of fatigue in tx-resistant depression

97
Q

What are the types of augmentation stimulants?

MOA, ADR

A

Methylphenidate and modafinil:
* MOA: Increases NE and DA actions by blocking re-uptake
* ADR: abuse potential

Amphetamine:
MOA: Increases NE and DA actions by blocking re-uptake
ADR: abuse potential

98
Q

Indications for St Johns wort?

A

Effective for mild-moderate depression
* Increases expression of intestinal P-gp and CYP3A4 in liver and intestine

99
Q

What is esketamine?

A

First non-monoamine-specific agent approved for MDD

100
Q

Esketamine

MOA, Onset, ADR

A

MOA: Noncompetitive antagonist of NMDA receptor
Onset: Rapid, but can produce dissociate sx and risk of
ADR: HTN, dissociative sx commin in the first 2 hr

101
Q

Electroconvulsive Therapy

Indication, MOA, ADR, Onset

A

Indication: Severe or life-threatening depression, and can’t take med
MOA: Increases sensitivity of postsynaptic 5-HT receptors and upregulation of 5-HT1A postsynaptic receptors
ADR: temporary short-term memory loss, headache
Onset: Quicker onset of response

102
Q

MOA of benzos?

A
103
Q

General characteristics of benzos?

A

Lipophillic -> high PPB, rapid absorption, half-life -> accumulation

104
Q

Common ADRs of benzos?

A
  1. Tolerance
  2. Abuse
  3. Withdrawal id DC abruptly
  4. risk of dependence, depression of
  5. CNS functions and amnestic effects
  6. Drowsiness, impaired judgement, diminished motor skills, anterograde amnesia
105
Q

Why are benzos good for anxiety?

A
  1. Rapid onset
  2. Relatively high TI
  3. Low risk of DDIs
  4. Minimal effects on cardiovascular/autonomic functions
  5. acute anxiety
106
Q

Describe benzo SAR?

A
107
Q

Types of benzos

A

Chlordiazepoxide
Diazepam (Valium)
Clorazepate
Oxazepam/Lorazepam (Ativan)

108
Q

Chlordiazepoxide

PK

A

PK: long half-life, active metabolites -> accumulation

109
Q

Diazepam

PK

A

Valium
PK: accumulation due to active metabolites

110
Q

Clorazepate

PK

A

Prodrug, polar but metabolite = nonpolar -> long half-life

111
Q

What is the difference between oxazepam and lorazepam?

A

Oxazepam: active metabolite of diazepam/chlordiazepoxide
* Short acting -> less accumulation and polar OH group
Lorazepam: 2’-chloro derivative of oxazepam

112
Q

What AD is preffered due to having more favorable ADRs?

A

SSRIs

113
Q

Buspirone

MOA, PK, ADR

A

MOA: Full agonist at presynaptic 5-HT1A receptor and partial agonist at postsynaptic 5-HT1A receptor
* Reduces hyperserotonergic tone in the brain

PK: axioselective, slower onset and not effective prn
ADR: Dizziness, nervousness, headache, tinnitus, GI distress, hallucinations, seizures

114
Q

Hydroxyzine

MOA, ADR

A

MOA: antihistamine
ADR: sedative

115
Q

Indications for b-blocks in depression and anxiety?

A

Good for symptom reduction: Reduce autonomic physiologic manifestations of anxiety

116
Q

Prazosin

MOA, Indication

A

MOA: a1 adrenergic antagonist (HTN and BPH)
Indication: Decreases occurrence of traumatic nightmares for PTSD

Drug Action III (23 decks)

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