2-16 Anti-Depressants

Question 1

Name the MAOI’s (4)

Answer 1

1. Phenelzine
2. Isocarboxazid
3. Tranylcypromine
4. Selegiline

Question 2

Name the TCA’s (6)

Answer 2

1. Amitriptyline
2. Nortriptyline
3. Doxepin
4. Imipramine
5. Desipramine
6. Clomipramine

“AND IDC (i dont care)”

Question 3

Name the SSRI’s (6) (Selective Serotonin Reuptake Inhibitors)

Answer 3

1. Fluoxetine
2. Fluvozamine
3. Citalopram
4. Sertraline
5. Escitalopram
6. Paroxetine

Question 4

Name the SNRI’s (Selective Norepinephrine Reuptake Inhibitors) (3)

Answer 4

1. Duloxetine
2. Venlavaxine
3. Desvenlafaxine

I pop SNRI’s and watch DVD’s

Question 5

MAO-A vs MAO-B (which is primary?)

1. What does MAO-A do?
2. What does MAO-B do?
3. What function do they have in common?

Answer 5

1. MAO-A: metabolizes catecholamine (NE, Epi), 5HT (Key type)
2. MAO-B: metabolizes trace amines
3. MAO-A/B: both metabolize tyramine and DA

Question 6

Name the irreversible MAOIs (3)

What does it mean for them to be irreversible?

Answer 6

1. Phenelzine
2. Tranylcypromine
3. Selegiline

Once bound to MAO, enzyme must be replaced (takes 10-14 days)

Question 7

Reversible MAOI’s (1) How is it used here in the US?

How does their duration of action compare to irreversible MAOI’s

Answer 7

There is only meclobemide and it is not used in the US. It shows a shorter duration than irreversible MAO-I’s

Question 8

Key MAO AE’s (2)

1. What happens and why?
2. Potential clinical consequences?

Answer 8

HTN Crisis: “Cheese reaction” : Foods w/ high amounts of tyramine (aged cheeses, wines, cured meats) because they are normally metabolized by live MAO’s and if not metabolized serves as a pressor.

Must be careful if patient is on rec. drugs or already hypertensive (risk of ruptured aneurysm, stroke, etc.)

Serotonin Syndrome: MAO’s +SSRI’s/SNRI (or TCA’s)

Increased reflexes, myoclonus, autonomic dysfunction etc.

Question 9

How can selegiline be administered in order to minimize the “cheese reaction”?

Answer 9

Via transdermal patch

Question 10

What is the therapeutic site of action for TCA’s and in general, how do TCA’s differ from each other?

Answer 10

All TCAs block the reuptake pumps of both 5-HT and NE thus preventing their reuptake. Different TCAs differ in the magnitude of the re-uptake blockade of these amines.

Question 11

1. What is a T_ertiary TCA?_
2. Name them (2)
3. Compare how well they block 5-HT and NE

Answer 11

1. TCAs w/ 2 methyl groups of N
2. Imipramine and Amitriptyline
3. Equally block 5-HT and NE reuptake

Question 12

1. What is a Secondary TCA?
2. Name them (2)
3. Compare how well they block 5-HT and NE

Answer 12

1. TCA having 1 methyl group on N
2. Despramine and Nortriptyline
3. Preferentially blocks NE re-uptake vs 5-HT

Question 13

What is unique about the TCAs Clomipramine and Doxepin?

Answer 13

They are both tertiary TCAs but act like secondary.

Question 14

TCA Pharmacokinetics

1. Lipid solubility, protein binding, and volume of distribution (high or low?)
2. Is absorption rapid or slow?
3. T 1/2

Answer 14

1. High lipid solubility, high protein binding, large Vd
2. Rapid absorption: serum concentrations peak w/in a few hours
3. T 1/2 = 8-36 hrs

Question 15

Prominent TCA side-effects are due to their blocking actions on which receptors (3)? What are the key SE’s for blocking of each receptor?

Answer 15

1. H1 histamine receptors: sedation, weight gain
2. M1 muscarinic receptors: sedation, confusion
3. a1 adrenergic receptors: sedation, orthostatic hypotension, dizziness
4. SNRIs: sexual dysfunction (due to increased serotonin) and HTN and Diaphoresis (due to increased NE)

Question 16

Put the following (5) effects in order of least to greatest, in terms of the concentration of TCA needed to bring about the particular effect:

CNS toxicity, peripheral Ach receptor blockade, Antidepressant efficacy, CVS toxicity, Histamine receptor blockade

Answer 16

1. Histamine receptor blockade
2. Peripheral Ach receptor blockade
3. Antidepressant efficacy
4. CNS toxicity
5. CVS toxicity

Question 17

What (2) populations must you be careful with when prescribing TCAs?

Answer 17

1. Elderly- more sensitive to TCA side effects so minimize prescribing them
2. Pts w/ substance abuse issues- TCAs have an additive effect w/ CNS depressants (like alcohol, barbituates, opiates, and benzos)

Question 18

How large is the therapeutic window for TCAs?

Describe the clinical presentation of TCA overdose based on the receptors/ channels effected (4).

Answer 18

• Narrow therapeutic window
• Effects of overdose on…
  
  1. a1-adrenergic receptors: hypotension, respiratory depression
  2. M1 muscarinic receptors: confusion/delirium/altered mental status; respiratory depression
  3. H1 histamine receptors: confusion/delirium/ AMS; respiratory depression
  4. Blocks sodium channels in myocardium membranes: quinidine-like effects (prolonged action potential/ QRS interval); cardiac conduction defects and severe arrhythmias

Question 19

Which SSRI has a half-life longer than the others? Which has the smallest level of protein binding?

Answer 19

Longest half-life: Fluoxetine (1-4d) and its metabolite (7-15d) is signficantly longer than the others

Least protein binding: Escitalopram

Question 20

Which SSRI is the least selective for 5-HT? Which has the highest affinity for 5-HT?

Answer 20

least: Fluoxetine

most: paroxetine

Question 21

1. What (2) SSRIs use CYP2D6 for metabolism?
2. Which SSRI is the most likely of all SSRIs to have drug-drug interactions and why?

Answer 21

1. Paroxetine and Fluvoxamine both use CYP2D6
2. Fluvoxamine is the most likely to have DDI becomes it inhibits a number of CYP enzymes (1A2, 2C19, 2D6, and 3A4)

Question 22

What are the (5) potential adverse effects of SSRIs?

Answer 22

1. GI
2. Anxiety
3. CNS issues
4. Sexual Dysfunction
5. SSRI Discontinuation Syndrome: (dizziness, nausea, HA, insomnia, restlessness, unstable gait, brain “zaps”

Question 23

Which type of SSRI is most likely to lead to an SSRI discontinuation syndrome?

Answer 23

Most likely w/ short acting SSRIs.

Paroxetine > (effexor/pristiq)>> fluvoxamine > sertraline > citalopram >> fluoxetine

Question 24

Relative to their antidepressant effect, SSRI adverse effects often occur when?

Answer 24

AEs often occur prior to the onset of antidepressant efficacy

Question 25

1. Which SNRI has the greatest level of protein binding? 2. Which (2) SNRIs are most likely to cause discontinuation syndrome?

Answer 25

1. Duloxetine (Cymbalta) has the greatest level of protein binding 2. Venlafaxine and desvenlafaxine are most likely to lead to discontinuation syndrome (they have the shortest half-lives)

Question 26

1. What is the relationship between Venlafaxine and Desvenlafaxine? 2. How does this relationship impact metabolism of Desvenlafaxine? 3. How are the other SNRIs metabolized?

Answer 26

1. Desvenlafaxine is the _metabolite_ of venlafaxine. 2. Because it is a metabolite, **desvenlafaxine** only goes through _phase II_ metabolism. 3. Venlaxine and Duloxetine both are CYP2D6 substrates.

Question 27

1. SNRI Side Effects are dependent on what? 2. What are the SEs? (3 main categories)

Answer 27

1. Dose dependent SEs 2. Same as SSRI SEs + Increased BP and Diaphoresis

Question 28

Name the (2) atypical antidepressants

Answer 28

Mirtazapine and Bupropion

Question 29

_Mirtazapine_ 1. MOA 2. SEs 3. Protein binding

Answer 29

1. _MOA_: Noradrenergic and serotonin a2 adrenergic receptro antagonist (blocks presynaptic autoreceptors on NE and 5HT neurons) 2. _SEs_: Because it also blocks *histamine*, you can see wt gain, dry mouth, and sedation 3. Highly protein bound (85%)

Question 30

How are the sedation effects of Mirtazapine related to dose?

Answer 30

Counterintuitively, while highly sedating at low doses, Mirtazapine is less sedating at high doses and can actually even be stimulating

Question 31

_Buproprion_ 1. MOA 2. Metabolism 3. Protein binding

Answer 31

1. _MOA_: NE and DA reuptake inhiitor (NDRI) 2. Strong CYP2d6 inhibitor 3. Highly protein bound (85%)

Question 32

Buproprion SEs (4)

Answer 32

1. **SEIZURES** (at high doses) 2. Dry mouth 3. Nausea 4. Insomnia No risk of weight gain, sexual dysfunction, etc.

Question 33

_Nefazodone_ 1. MOA 2. SEs (1)

Answer 33

1. _MOA_: Blocks 5-HT reuptake 2. _SE_: Mild sedation

Question 34

_Vilazodone_ 1. MOA 2. SEs (1)

Answer 34

1. _MOA_: Blocks 5HT reuptake (partial agonist of 5-HT1A receptors) 2. _SEs_: GI (N/V/D) and Insomnia

Question 35

_Vortioxetine_ 1. MOA (4) 2. SEs (1)

Answer 35

1. _MOA_: * Blocks 5HT reuptake * Agonist at 5-HT1A * Partial agonist at 5-HT1B * Antagonist at: 5-HT3 & 5-HT7 2. _SEs_: GI (Nausea \> vomiting/diarrhea)

Question 36

1. What do you have to consider when switching from one MAOI to another? 2. What do you have to consider when switiching from any other antidepressant to an MAOI?

Answer 36

1. When moving from one irreversible MAOI to another, you need to wait for _neurons to regenerate MAO enzymes_ (usually 10-14 day). 2. When moving from any other antidepressant to an MAOI, you need to wait _5 half-lives_ before starting the MAOI