Anxiety and Depression (MC) - Block 3 Flashcards
1
Q
The more lipophilic the drugs, the more its able to?
A
- PPB
- Have high Vd and DOA
- Have longer half-lives
- Rapidly absorb
2
Q
Have active metabolites leads to ____?
A
accumulation of the drug
3
Q
What occurs during N-dealkylation?
A
3 amine to 2
2 amine to 1
4
Q
What occurs during MOA metabolism?
A
Primary amine to aldehyde
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
6
Q
What are the sx of serotoninc syndrome?
A
- Fever
- Tremor
- Coma
- Sz
- Death
7
Q
What is the side effects that are caused by serotonin?
A
Depression
OCD
Panic
Bulimia
8
Q
What are the side effects that are caused by too much serotonin?
A
- Anx
- Insomnia
- Sexxual dysfunction
- GI disturbances
- Serotonin syndrome
9
Q
What is the function of serotonin and NE?
A
5HT + NE = parallel, independent pathways
5HT: changes in mood
NE: Increased drive
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
11
Q
Decribe the underlying mechanism of reuptake inhibitors?
A
12
Q
Describe the onset of antidepressants?
A
Maximum benefit is not achieved till 1-2 months
13
Q
Describe tserotonin reuptake before drug?
A
14
Q
Describe the immediate effects of SSRIs?
A
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
16
Q
What are the long term effects of SSRI?
A
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
18
Q
Lag time/delay is likely caused by?
A
Inhibitory feedback mechanisms
19
Q
Describe the long term effects of NE reuptake inhibition?
A
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
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
22
Q
Describe the selectivity of TCAs?
A
Tertiary: non-selective, dual affinity for NET and SERT
Secondary: selective for NET
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
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)
25
What are the types of tertiary amine TCAs?
Amitriptyline (Elavil)
Imipramine
Doxepin (Sinequam)
Chlorimipramine/Clomipramine
Trimipramine
26
27
Describe the selectivity of secondary amine TCAs?
More selective for NET – less anticholinergic/sedative:
* Narrow therapeutic-to-toxicity ratios due to heavy metabolism by CYPs
28
What are the secondary TCAs and what are they a metabolite of?
Imipramine -> **Desipramine**
Amitriptyline -> **Nortriptyline**
Nortriptyline -> **Protriptyline**
Loxapine -> **Amoxapine**
29
What are the selective secondary TCAs? Non-selective?
**Selective:** Desipramine, Protriptyline
**Non-selective:** Nortriptyline, amoxapine
30
TCAs DDI?
High PPB drugs, anticholinergic, sympathomimetic drugs
* Increased risk for serotonin syndrome
31
TCA metabolism?
CYP2D6 (genetic polymorphism and narror TI)
32
What occur syndrome can occur from TCA besides serotonin syndrome?
Discontinuation syndrome
33
What are ADRs of TCAs?
**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
34
What is the endogenous ligand of SSRI?
Serotonin
35
How does SSRI differ from TCAs?
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
36
What is the general characterisitcs of SSRI?
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
37
SAR of SSRI?
Electronegative para substitution -> good selectivity
38
What are you elecronegative groups?
Cl, I, F, B, CN, NO2
39
How does selectivity/affintiy differ in different SSRI drugs?
All equally effective over time
40
SSRIs
| ADR, DDI
**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
41
What are you seratonin side effects?
N, D, insomnia, HA, sexual dysfunction
42
What is discontinuation syndrome?
DZ, paresthesias that occurs 2 days after abrupt drug withdrawal and generally resolves in 2-3 weeks
43
What is the the difference between SSRI and TCA ADRs?
**SSRI:** more NE and SE uptake inhibition ADRs
**TCA:** More anti-a1, antibholinergic, antihistamine ADRs
44
Types of SSRIs?
Fluoxetine (Prozac, Sarafem)
Paroxetine (Paxel)
Citalopram (Celexa)
Escitalopram (Lexapro)
Sertraline (Zoloft)
Fluvoxamine
45
Fluoxetine
| PK, Cautions, What contributes to selectivity
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
46
Paroxetine
| PK, What contributes to selectivity
**PK:** Inhibits CYP2D6 irreversibly through mechanism based inhibition from reactive metabolite
* Non-linear/lang term effects
**Selectivity:** F
47
How is Citalopram an improvement from other SSRIs?/
No first pass metabolism -> higher bioavailability
* Less PPB
47
What is Lexapro?
S-enatiomer of citalopram that is more slective and active
* R-enantiomer conteracts S
48
Between Lexapro and and Celexa which has a high ADR risk?
Citalopram because its a racemic mixture
49
Citalopram
| Selectivity
NC
50
Sertraline
| Selectivity, PK
**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
How does fluvoxamine differ from other SSRIs?
Nontricyclic, only nonchiral (less potent)
52
Fluvoxamine
| Selectivity, PK
**Selectivity:** CF3
**PK:** nonlinear
53
What are you nonlinear SSRI?
Fluoxetine
Paroxetine
Fluvoxamine
54
What SSRI has least affect on CYPs?
Citalopram
55
SNRI MOA?
Inhibits both NET and SERT -> combination produces greater efficacy
* Possesses low affinity at other neurotransmitter receptos -> low side effect potential
56
SNRI
| ADR
1. Serotonergic effects
2. Noradrenergic effects
3. CNS activation
4. DC syndrome
57
TYpes of SNRI?
1. Venlafaxine (Effexor)
2. Desvenlafaxine (Pristiq, Kedezla)
3. Levomilacprin
4. Duloxetine (Cymbalta)
58
Venlafaxine
| MOA, ADR, PK
**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
How does desvenlafaxine differ from venlafaxine? ADR?
Equiactive metabolite with hydroxyl group
**ADR:** N
60
Levomilnacprin
| MOA, PK, ADR
**MOA:** Higher affinity for 5-HT reuptake
**PK:** Slower onset of action than TCAs
**ADR:** Generally safe
61
Duloxetine
| MOA, PK, ADR
**MOA:** slightly higher affinity for SERT
**PK:** CYP2D6 inhibitor and produces
**ADR:** reactive metabolite causes jaundice like conditions
62
What is first MOAI?
Isoniazid: Antitubercular
63
What are the cons of using MAOIs?
Hepatotox due to hydrazine reactive group
64
Why could MAOI be consequenctial?
Many drugs are metabolized by MAOI, inhibition leads to accumulation
65
Describe the potential of MAOIs?
Irreversible inactivation, effects can be seen up to 2 weeks after dc the drug
Onset takes a few days
66
Describe the MOA of MAOIs?
67
What are the effects of irreversible MOA-A and B inhibition?
1. Increase free 5-HT and NE, and other amines
68
Types of MOA irreversible inhibitors?
Phenelzine
Isocarboxazid
Tranylcypromine
Selegiline
69
MOA irreversible inhibitors SAR?
* Message: Contains reactive groups that form irriversible bonds to FAD
* Contains an address: directs drug to MOA
70
What are the metabolism issues with tranylcypromine?
Inhibits other metabolizing enzymes (MAO, CYP2C19, 2D6, 2C9)
71
What is the metabolism issue with phenelzine?
Interindividual variability in plasma concentrations due to slow/fast acetylators
72
What is the metabolism issue with selegiline?
Metabolized to meth/amphetampine by CYP2B6 and CYP3A4
73
MOAI
| ADR, DDI
**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
What are the sx of HTN crisis?
HA, tachycardia, cardia arrhythmia, stroke
75
How does Moclobemide differ from other MAOIs?
Reversible MAO-A inhibitor antidepressant (RIMA): can be displaced by tyramine if ingested
76
What are natural DA and NE Reuptake Inhibitors?
CNS stimulants: methamphetamine, diethylpropion, cathinone
77
What DA and NE Reuptake Inhibitor is designed to have no metabolites with sympathomimetic or anorexigenic properties?
Bupropion due to T-butyl group -> no N-dealkylation
78
What are the considerations of DA and NE Reuptake Inhibitors?
ADR: sympathomimetic and/or anorexigenic (N-dealkylation)
Extensive metabolism to active metabolites with long DOA
79
Bupropion
| MOA, PK, ADR
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
What is an example NMDA antagonist for psch?
Auxility (dextromethorphan-bupropion)
81
Auxillary
| MOA, ADR
**Dextromethorphan:** active at NMDA receptor and σ-1 receptor (heavily metabolized by CYP2D6)
**Bupropion:** Inhibits CYP2D6
**ADR:** seratonin sx for dex
82
What is the function of Serotonin Receptor Modulators?
Modulate concnetration of 5-HT in brain:
* Receptors can also modulate other neurotransmitters
* Enhance noradrenergic or serotonergic transmission
83
MOA of SRMs?
* 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
SAR of SRM?
Serotonin Receptor Modulators = phenylpiperazines
However, open para postition can need to hepatotoxicity
85
Examples of SRM?
Trazodone
Nefazodone
Vortioxetine
Vilazodone (Viibryd)
Mirtazapine (Remeron)
86
Trazodone
| ADR
Desyrel
**ADR:** Hypotension, high sedation (difficult to titrate to AD doses), GI, hepatotoxic (2 reactive metabolites)
87
Describe the metabolism of trazodone?
88
Nefazodone
| BBW, PK, ADR
**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
Vortioxetine
| MOA, PK, ADR
**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
Vilazodone
| MOA, ADR, BBW, DDI, PK
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
Mirtazapine
| MOA, ADR, Indication
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
What are the general concepts of AD?
1. Equal efficacy
2. Risk of increased suicidality
3. Lethal OD more common with MAOIs and TCAs
2. 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
Describe the sx remission timeline?
94
What drugs have the highest incidence for sexual disfunction?
SSRIs, SNRIs and MAOIs (especially paroxetine)
95
What drugs have the lowest incidence for sexual dysfunction?
Bupropion, mirtazapine, vilazodone and vortioxetine
96
What are augmentation stimulant strategies used for?
Atypical depression or sx of fatigue in tx-resistant depression
97
What are the types of augmentation stimulants?
| MOA, ADR
**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
Indications for St Johns wort?
Effective for mild-moderate depression
* Increases expression of intestinal P-gp and CYP3A4 in liver and intestine
99
What is esketamine?
First non-monoamine-specific agent approved for MDD
100
Esketamine
| MOA, Onset, ADR
**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
Electroconvulsive Therapy
| Indication, MOA, ADR, Onset
**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
MOA of benzos?
103
General characteristics of benzos?
Lipophillic -> high PPB, rapid absorption, half-life -> accumulation
104
Common ADRs of benzos?
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
Why are benzos good for anxiety?
1. Rapid onset
2. Relatively high TI
3. Low risk of DDIs
4. Minimal effects on cardiovascular/autonomic functions
5. acute anxiety
106
Describe benzo SAR?
107
Types of benzos
Chlordiazepoxide
Diazepam (Valium)
Clorazepate
Oxazepam/Lorazepam (Ativan)
108
Chlordiazepoxide
| PK
**PK:** long half-life, active metabolites -> accumulation
109
Diazepam
| PK
Valium
**PK:** accumulation due to active metabolites
110
Clorazepate
| PK
Prodrug, polar but metabolite = nonpolar -> long half-life
111
What is the difference between oxazepam and lorazepam?
**Oxazepam:** active metabolite of diazepam/chlordiazepoxide
* Short acting -> less accumulation and polar OH group
**Lorazepam:** 2’-chloro derivative of oxazepam
112
What AD is preffered due to having more favorable ADRs?
SSRIs
113
Buspirone
| MOA, PK, ADR
**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
Hydroxyzine
| MOA, ADR
**MOA:** antihistamine
**ADR:** sedative
115
Indications for b-blocks in depression and anxiety?
Good for symptom reduction: Reduce autonomic physiologic manifestations of anxiety
116
Prazosin
| MOA, Indication
**MOA:** a1 adrenergic antagonist (HTN and BPH)
**Indication:** Decreases occurrence of traumatic nightmares for PTSD
