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Infectious Final > Antidepressants > Flashcards

Antidepressants Flashcards

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1
Q

What was the first TCA?

A

Imipramine

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2
Q

Describe imipramine activity:

A

It is a combo of both imipramine and desimpramine activity. Desimpramine is a 2ndary amine formed through N-demethylation.

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3
Q

What is the half-life of imipramine? Desipramine?

A

8-12 hours and 7-60 hours

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4
Q

What drug is 50X more potent than imipramine? How?

A

Clomipramine. It is more selective for the 5HT reuptake.

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5
Q

Which drug is the only halogenated TCA used to treat depression? What is the function?

A

Clomipramine. To increase selectivity for inhibiting serotonin reuptake.

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6
Q

What TCA has the highest antimuscarinic and sedative SE’s?

A

Amitriptyline (dibenzocycloheptane)

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7
Q

What is amitriptyline’s t1/2?

A

16-90 hours

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8
Q

What is the metabolite of amitriptyline achieved through N-demethylation?

A

Nortriptyline (2ndary amine)

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9
Q

Compare amitriptyline and nortriptyline:

A

Amitriptyline has a symmetrical ring system, and nortriptyline is less sedating with fewer antimuscarinic SE’s.

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10
Q

What mixture is doxepin used as? What isomer is more active?

A

It is a mixture of 85% E and 15% Z, Z isomer is more active.

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11
Q

What is the half-life of doxepin? It’s metabolite?

A

t1/2 = 15 hours to get to N-desmethyldoxepin. The half-life of the metabolite is ~30 hours.

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12
Q

What are Zonalan and Silenor?

A

They are doxepin used in a topical cream (5% Zonalan) and a sleep aid (Silenor -central effects). They take advantage of doxepin’s SE profile.

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13
Q

What is the 2nd generation TCA that is tetracyclic?

A

Maprotiline

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14
Q

What benefits do this extra ring give Maprotiline?

A

Less flexibility, more rigidity. This gives more selectivity for inhibiting NET over SERT (~500 fold)

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15
Q

What does a 2ndary amine give a TCA?

A

Selectivity for NET over SERT

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16
Q

Does maprotiline have antimuscarinic effects? What theory is used to hypothesize why?

A

Reduced sedation and antimuscarinic effects, but still some. Possibly because of 2ndary amine.

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17
Q 
Tell me about tranylcypromine: 
what kind of core?
Structurally what is it related to?
Reversible inhibition?
Problems with other enzymes?
A

It is an MAO with a phenylethylamine core, with a cyclized amphetamine.
Irreversibly covalently modify MAO active site.
High selectivity means doesn’t cause problems at other enzymes.

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18
Q

Describe the radical process of tranylcypromine:

A

Cyclized part splits apart and a double bond forms at the nitrogen.

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19
Q

What MAOI is believed to be a prodrug?

A

Isocarboxazid

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20
Q

What releases the active drug from Isocarboxazid?

A

Amide hydrolysis releases benzyl hydrazine, which then inactivates MAO.

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21
Q

What type of drug is phenylzine?

A

An MAOI with a phenyl ethyl and a hydrazine. A reactive radical results in irreversible MAO inactivation.

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22
Q

What transdermal patch is used to treat Parkinson’s?

A

Selegiline, an MAO-B inhibitor. Interferes with dopamine metabolism and serotonin receptors.

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23
Q

Do SSRI’s have 2ndary or tertiary amine selectivity?

A

No, it does not seem to change selectivity in a pattern.

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24
Q

What type of amine is fluoxetine? What is the selectivity?

A

A secondary amine. Selective ~30 fold SERT over NET.

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25
What is the active metabolite of fluoxetine formed from N-dealkylation?
Norfluoxetine (primary amine).
26
Compare fluoxetine and norfluoxetine:
t1/2 = 1-3 days acute, 4-6 days chronic for fluoxetine t1/2 = 4-16 days Both are 2D6 inhibitors with potential for interactions
27
What SSRI can be dosed once weekly?
Prozac weekly: 90mg capsule DR takes advantage of long half-life.
28
What do all SSRI's have in common regarding metabolism?
P450 metabolism, especially 2D6. Usually multiple.
29
How do you use them with MAOI's?
Wait 2 weeks after MAO therapy to start fluoxetine. Wait 5 weeks after fluoxetine has stopped to start MAOI therapy.
30
What kind of inhibitors are MAOI's?
Irreversible inhibitors
31
What are EWG's good for with SSRI's?
Good for activity, selectivity
32
How many possible isomers does sertraline have?
4 possible, but only 1S, 4S enantiomer used
33
What selectivity does sertraline have?
1400 fold selective for SERT over NET
34
What is the half life of sertraline? It's metabolite?
24 hours and N-desmethylsertraline (less active as SSRI) is 62-104 hours.
35
What does sertraline inhibit?
Weak 2D6, not many drug interactions
36
What does CYP 2D6 do to paroxetine? What does paroxetine do to the enzyme?
Not methylation. Removes methylene to form inactive catechol metabolite. 50% of the time can irreversibly inhibit the 2D6 from reactive intermediate, which alkylates the enzyme.
37
What is the t1/2 of paroxetine?
22 hours
38
What is paroxetine used as?
Single 3S, 4R enantiomer
39
What is paroxetine selective for?
~300 fold SERT over NET
40
What is the primary amine SSRI?
Fluvoxamine
41
What does UV light do to fluvoxamine?
It isomerizes to inactive Z isomer.
42
What is the half-life and selectivity of fluvoxamine?
14-15 hour, ~600 fold SERT over NET
43
What is the metabolism and inhibition of fluvoxamine?
Extensive metabolism leaves no active metabolites. It is a potent inhibitor of 1A2 and 2C19.
44
What are the differences between citalopram and escitalopram?
Citalopram is a racemic mixture, while escitalopram is only the s enantiomer. Citalopram has a dosing limit based on Qt prolongation. Escitalopram has fewer histamine SE's.
45
Which SSRI is most selective for SERT over NET?
citalopram/escitalopram are >3,000 times more selective SERT over NET
46
Weakest P450 inhibitor of the SSRI?
citalopram/escitalopram
47
What is the half-lfe of citalopram? What does it metabolize to?
36 hours to metabolize to desmethylcitalopram, which is active but less so than parent compound.
48
Which multimodal SSRI has an m-chlorophenylpiperazine (mCpp) metabolite that may contribute to the overall antidepressant action? What is the metabolism pathway?
Trazodone. 3A4. Nefazodone also.
49
Trazodone: half-life, effects
Lacks antimuscarinic effects, t1/2 = 6 hours
50
What is mCpp a partial agonist for?
5HT-2c
51
Which multimodal SSRI has both an alpha-hydroxymetabolite and an mCpp metabolite that may contribute to the drug's action? What metabolism? What are the half-lives for the drug and each metabolite?
Nefazodone. 3A4 for both pathways. t1/2 of nefazodone = 2-4 hours, for alpha-hydroxymetabolite 1&1/2 - 4 hours, and mCpp 4-9 hours.
52
Both nefazodone and alpha-hydroxymetabolite inhibit what?
3A4
53
What are possible side effects of nefazodone?
Hepatic failure/hepatotoxicity
54
What is the multimodal SSRI with a 25 hour half-life and inactive metabolites?
Vilazodone. Inactive metabolites from a 3A4-mediated dealkylation.
55
What multimodal SSRI is structurally distinct from the "azodones" and has a half-life of 66 hours, along with an inactive metabolite? How is it distinct?
Vortioxetine. No EWG and ring system pattern is missing. CH3 is changed to CO2.
56
What enzyme is involved with Vortioxetine? What does it inhibit/induce?
2D6 is a major enzyme involved in forming the inactive product, but there is no P450 induction/inhibition.
57
What are the two metabolites of venlafaxine, and what type of activity do they have?
3A4 leads to an N-desmethylvenlafaxine with minimal SNRI activity, while 2D6 leads to a O-desmethylvenlafaxine which has activity and is a separate antidepressant.
58
What is the half-life of venlafaxine?
4-5 hours
59
Does venlafaxine have affinity for M1, H1, or alpha1 receptors?
No
60
How is desvenlafaxine formed?
By venlafaxine undergoes 2D6 O-demethylation
61
What is the half-life of desvenlafaxine? Metabolism?
11 hours. Major- glucuronidation. Minor - 3A4 N-demethylation.
62
What SNRI is similar to fluoxetine and has 2D6 inhibition?
duloxetine. The inhibition leads to drug interactions.
63
What is the half-life of duloxetine?
12 hours
64
What is the metabolism of duloxetine?
1A2 and 2D6, napthyl ring hydroxylation and then glucuronidation lead to inactive product.
65
Levomilnacipran:
T1/2 = 12 hour Major metabolite is inactive (3A4 mediated, N-deethylation. Not a P450 inhibitor single 1S, 2R enantiomer is active
66
What atypical antidepressant has an amphetamine core structure?
Bupropion
67
What is the half-life of bupropion?
21 hours
68
What metabolism occurs and where? Active?
hydroxylation by 2B6 on one of the methyl groups on the turkey foot. Both are active.
69
What are the SE's of bupropion?
Restlessness and insomnia - could be associated with amphetamine core structure. Very little antimuscarinic or sedative SE's.
70
What does bupropion and its metabolite inhibit?
2D6
71
What is the half-life of mirtazipine?
20-40 hours
72
How is mirtazipine different than a TCA?
N-bearing ring attached to 2-atom bridge | Basic N is closer to tricyclic rings than a TCA, no antimuscarinic effects
73
Does mirtazipine inhibit P450s?
No
74
What are the drugs that block NE and 5HT transporters?
``` TCA's! Imipramine amitriptyline desipramine doxepin maprotiline ```
75
What are the SE's of the TCA's?
cardiovascular (higher HR, lower BP), histamine receptor antagonism (sleepy), weight gain, decreased seizure threshold, sexual SE. Toxicities = lethal in overdose, toxic sedative effects in combo with downers, cardiac effects, anticholinergic psychosis
76
What class of drugs block NE and 5HT breakdown?
MAOI's! phenelzineu tranylcypromine isocarboxazid
77
What are MAOI's useful for?
Atypical depression and narcolepsy
78
What are the adverse effects of MAOI's?
dry mouth, impotence, loss of libido, hepatotoxicity, overdose toxicities with serotonin (hyperthermia) and too much NE (hypertension, tachycardia, muscular agitation).
79
What can MAOI's interact with?
They can prolong half-lives of deaminated drugs. Serotonin syndrome, treatable with Dantrolene. Lots of food restrictions.
80
What are the 1st line agents for depression? Which is most efficacious?
SSRI's. They all are equally so.
81
What SSRI is most stimulating?
Fluoxetine
82
Which drugs are better for anxiety with depression?
Sertraline and paroxetine
83
Which SSRI has the shortest half-life?
Fluvoxamine
84
Which drugs has the largest selectivity for SERT over NET?
Citalopram and escitalopram.
85
Which SSRI has a side effect of hyponatremia in older patients?
Fluoxetine
86
What do the multimodal SSRI's do? What are they?
They have affinity for various 5HT receptor subtypes (in post-synaptic neuron) in addition to blocking SERT. Trazodone and nefazodone.
87
What do SSRI's do?
Block re-uptake of 5-HT
88
Which drugs do not have sexual SE's?
Bupropion, and nefazodone is marketed as having less, a well as mirtazipine.
89
What are the SNRI's?
``` They have affinity for both SERT and NET Venlafaxine duloxetine desvenlafaxine levomilnacipran ```
90
What are the SEs associated with SNRI's?
Similar to SSRI's, with additional NE SE's, such as mild hypertension, dry mouth, increased HR, dilated pupils
91
What is the mechanism for bupropion?
Inhibitor of central nicotinic receptors, inhibitor of NE and dopamine re-uptake. Stimulating, no anticholinergic SE's reported. Safe for bi-polar.
92
What is mirtazipine used for?
anxiety with depression (H1 antagonism = sleepy). Useful for treatment-resistant depression.
93
What is the mechanism for mirtazipine
Not well-understood. May block presynaptic auto-receptors.
94
What is hyperforin an ingredient in?
St. John's Wort. Standardized to this, but not the active ingredient.

Infectious Final (9 decks)

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