Antidepressant MoAs Flashcards
List the tertiary amines
“AICD”
Amitryptiline
Amoxapine
Imipramine
Clomipramine
Doxepin
List the secondary amines
Desipramine
Maprotiline
Nortryptiline
Imipramine, the first TCA, is closely related to which other psych med (non-TCA)?
Chlorpromazine
Imipramine was derived from?
Methylene blue (antihistamine)
Tertiary TCAs have highest affinity for ___
blocking 5HT reuptake
Secondary amines have high affinity for _____
blocking NE reuptake
Tertiary amines are metabolized to ____
secondary amines in the liver
TCA association: Panic disorder with agoraphobia
Imipramine
TCA assocation: GAD
Impirapmine and doxepin
TCA Association: OCD
clomipramine (FDA approved)
TCA assocation: enuresis
Imipramine (NOT FIRST LINE)
Cardiac side effects of TCAs are mediated by ___
Na and Calcium channels
Compared to SSRIs, TCAs are less likely to cause …
sexual side effects, weight gain, and sleep disturbance
Most serotonergic TCA
Clomipramine
Most anticholinergic and alpha TCA
Amitriptyline
Most noradrenergic, low anticholinergic TCA
Desipramine
Low anticholinergic TCA
Nortriptyline
Most antihistamine TCA
Doxepin
Closest TCA to nortriptyline but may be more noradrenergic
Protriptyline
TCA Pharmacokinetics
fast absorption in small intestine. T1/2 vary from 10-70 hours (once qd).
Nortriptyline and doxepin exist in liquid solutions.
The tertiary TCAs are ________ and other enzymes, leading to the formation of secondary TCAs
demethylated by 2C19
In the case of amitriptyline and imipramine, they are converted to the secondary TCAs ________
nortriptyline and desipramine
delirium due to anticholinergic and antihistamine effects, especially with _______
amitriptyline
Increased risk of seizures, up to 2% with ———
clomipramine
Which class of meds: avoid in narrow- angle glaucoma (is fine in chronic open-angle glaucoma)
TCAs
Least orthostatic TCA
Nortryptiline
increased LFTs are associated with ——— (TCAs)
imipramine and desipramine
Usual cause of death in TCA overdose
cardiac arrhythmia
Which are the tetracyclic antidepressants?
Amoxapine and Maprotiline
Amoxapine (Asendin)
derived from mid-potency antipsychotic, loxapine. May have TD and may have greater risk of seizures than other TCAs.
Amoxapine mechanism
Increases 5-HT, NE, and blocks DA.
It is the only TCA/tetracyclic with both antidepressant and antipsychotic properties.
Has an active metabolite.
Half-life is 8 hours, but the active metabolite has a half-life of >30 hours.
Maprotiline (Ludiomil)
greatly differs from the others in that it lacks 5-HT reuptake inhibition and primarily acts to inhibit NE reuptake.
Is a strong antihistamine, is sedating. Is less anticholinergic and alpha blocking than amitriptyline.
Half-life is 30–60 hours.
Fun fact: first SSRI was actually ———
zimelidine (now banned for causing Guillain- Barre syndrome and other sometimes fatal side effects)
Best SSRI in pregnancy?
Fluoxetine has most data
SSRIs approved for OCD
fluvoxamine, paroxetine, sertraline, and fluoxetine Use higher doses than in MDD
SSRIs approved for use in panic disorder
People’S Freaking
Paroxetine, Sertraline, Fluoxetine
(But you can try other SSRIs, and don’t forget benzos)
SSRIs approved for bulemia and anorexia
Fluoxetine
SSRI FDA Approvals in children
fluoxetine for the treatment of depression fluoxetine, fluvoxamine, and sertraline for the treatment of OCD.
FDA Antidepressant black Box Warning
under the age of 24. This was based upon meta-analyses that showed increased risk of suicidal thoughts and behaviors, in addition to aggression and hostility in children treated with SSRIs.
SSRI Pharmacokinetic takeaways:
Regarding CYP interaction, fluvoxamine has the most interaction with 1A2, 2C, and 3A inhibition (with minimal 2D6 inhibition).
Fluoxetine and paroxetine are the strongest 2D6 inhibitors, with sertraline having moderate inhibition.
SSRI Pharmacodynamic takeaways
citalopram and escitalopram are the most selective inhibitor of 5-HT reuptake, having little inhibition of DA, NE, histamine, or GABA.
Fluoxetine weakly inhibits NE reuptake and binds to 5-HT2C.
Sertraline weakly inhibits NE and DA reuptake.
Paroxetine has significant anticholinergic activity at higher doses.
Which SSRIs are most selective for blocking only serotonin reuptake?
citalopram and escitalopram are the most selective inhibitor of 5-HT reuptake
SSRI drug interactions - Big picture
2D6 inhibitors will slow the metabolism of carbamazepine, diazepam, phenytoin, and antineoplastic agents.
Sertraline may displace warfarin from proteins, leading to increased PTT.
Fluvoxamine increases concentrations of multiple BZD, warfarin, clozapine, carbamazepine, methadone, propranolol, and diltiazem. It has little interaction with lorazepam.
Incidence of sexual dysfunction on SSRIs
50-80%
Common treatment for SSRI-induced sexual dysfunction
decreasing the dose, adding bupropion (increases DA) or buspirone (antagonism of 5-HT via autoreceptor), or use of sildenafil
SSRIs with most GI side effects
- Sertraline and Fluvoxamine - nausea, diarrhea, vomiting are most common with these. Mediated through 5-HT3.
- Paroxetine is associated with constipation (anticholinergic).
SSRI that commonly causes anxiety
fluoxetine
SSRI that commonly causes insomnia
fluoxetine
Common SE of SSRIs
Sexual, GI, anxiety, insomnia, sedation, emotional blunting. More rarely, seizures (0.2%), platelet issues (binding),
Best SSRI in breast feeding mothers?
Sertraline (data?)
Which SSRI should make you think about getting an EKG to look at the QTc
Citalopram is known to cause QTc prolongation. Do not higher than 40mg.
Sertraline generic quirks
Commonly has bruising and hair loss. The original medication was often sedating, leading to pm dosing. The generic often has the opposite effect, with patients initially experiencing feelings of restlessness, anxiety, and hypervigilance (which are problematic considering sertraline is used for anxiety). Have seen a couple cases of bruxism which improves with buspirone. Seen Torsades and neutropenia x1 recently with sertraline.
Medication associated with pulmonary hypertension in newborns of mothers who took it.
Paroxetine
Paroxetine generic quirks
I avoided this medication for a long time due to fear of weight gain and sexual side effects. Now that the side effects of citalopram are more apparent, I am less hesitant to use paroxetine (a medication that may have better efficacy than citalopram).
Vilazodone is like an SSRI with ____
5-HT1A agonism (like buspirone). Similar to combining citalopram + buspirone.
Vilazodone side effect profile
Fewer sexual side effects and weight gain than other SSRIs.
Discontinuation symptoms may occur if stopping quickly.
Watch out for QTc prolongation at high doses.
Vilazodone is metabolized by ____
CYP 3A4
Vilazodone dosing
Start at 10mg, up by 10 mg per week. Goal of 40mg daily. Max dose ~80mg.
Venlafaxine indications
FDA approved for MDD, GAD, Panic Disorder, Social Anxiety Disorder. Has been used for diminishing symptoms of menopause, treating chronic pain, and dual diagnosis of MDD and cocaine dependence.
Venlafaxine is metabolized by _____
2D6
Venlafaxine is metabolized to ____
desvenlafaxine
Venlafaxine dosing
IR is most associated with nausea and often is started in low doses of 37.5 mg twice daily (use in the am and at 1pm due to risk of insomnia if taken at bedtime).
As dose increases, affinity for NE transporter increases. As a result, HTN and anxiety are more associated with higher doses of the medication.
When taken as the XR, the maximum dose is 375 mg
Desvenlafaxine dosing
therapeutic dose of 50 mg (which happens to be the starting dose) with no significant data to support improved efficacy of 100 mg.
Venlafaxine dosing (and side effect) pearl
As dose increases, affinity for NE transporter increases. As a result, HTN and anxiety are more associated with higher doses of the medication.
Duloxetine indications
FDA approved for MDD, Diabetic peripheral neuropathy, fibromyalgia, GAD, Chronic musculoskeletal pain.
Also used for stress urinary continence (duloxetine increases the tone of the urethral sphincter and will be marketed as Yantreve), neuropathic pain/chronic pain, other anxiety disorders.
Duloxetine mechanism
similar to venlafaxine (5-HT and NE reuptake blockade) but has equal affinity for 5-HT and NE transporters at all doses.
Duloxetine dosing
There is little data to show greater clinical efficacy in doses above 60 mg for the treatment of depression. BID dosing may reduce side effects seen with once-daily dosing. Starting dose is 20 or 30 mg.
Duloxetine side effects
similar to venlafaxine, including nausea, dizziness, constipation, insomnia, and sexual dysfunction. Less likely to cause HTN. May increase Hgb A1c in long term treatment. Potentially increases LFTs (especially in hepatically compromised patients). Discontinuation syndrome can occur.
Is bupropion generic less effective?
We don’t know, but - In 2007, in response to multiple patient reports about the generic Bupropion XL having more side effects and being less efficacious than Wellbutrin XL, the FDA concluded that the discrepancy was due to “natural mood variation.”
Bupropion indications
FDA approved for MDD, seasonal affective disorder, nicotine addiction (smoking cessation under Zyban brand name, generally used in combination with nicotine substitutes),
Also used for BMD (less likely to precipitate mania in BMD I than TCAs and in BMD II than most other antidepressants), ADHD, cocaine detoxification (reducing cravings), hypoactive sexual desire disorder due to SSRIs.
Bupropion dosing
available in immediate release IR (BID or TID), sustained release SR (used BID), and extended release ER (once daily). The active ingredient is the same in each. The IR reaches peak concentration in 2 hours, SR in 3 hours and ER in 5 hours. The half-life is 12 hours
Bupropion mechanism of action
Mechanistically, bupropion inhibits the reuptake of DA and NE.
Bupropion pharmacodynamics
Is metabolized to active metabolite hydroxybupropion by CYP2B6 (inhibited by fluoxetine).
Hydroxybupropion itself inhibits 2D6. Bupropion has affinity for DA transporters while hydroxybupropion has more selective affinity for NE transporters
Bupropion and utox
Bupropion may have a false positive UDS for amphetamines
Bupropion side effects
seizure risk is 2% with 600 mg and 0.1% with 300-450 mg (the SR and ER at same doses has risk of 0.05%, equivalent to the other antidepressants). Side effects most common include headache, insomnia, dry mouth, tremor, and nausea. Severe anxiety and panic disorder can be worsened by bupropion. Can worsen psychosis and delirium due to dopaminergic activity.
Mirtazapine mechanism (general)
Uknown exactly how - a tetracyclic antidepressant that is both serotonergic and noradrenergic through a mechanism different from serotonin reuptake blockade or monoamine oxidase inhibition.
Mirtazapine half-life
30 hours
Mirtazapine mechanism (detailed)
Works to increase 5-HT at the 1A receptor (the main site for the antidepressant actions of most antidepressants).
It does this by blocking the 5-HT2A, 5-HT2C and 5-HT3 receptors, resulting in all serotonin being directed to the 5-HT1A receptor.
As a result, there are less sexual and GI side effects than other antidepressants.
Additionally, it increases NE and DA transmission (recall 5-HT2C normally inhibits DA—think atypical antipsychotic mechanism of action).
Strong histamine affinity causes sedation and weight gain. There is minimal anticholinergic effect
Mirtazapine dosing tips
Starting dose ranges from 7.5 to 15 mg.
Increasing dose above 30 mg leads to higher NE effects and less sedation
Mirtazapine side effects
Somnolence occurs in >50% (worsened by alcohol or other sedatives), increases appetite and cholesterol, reduction of ANC (monitor for fever, chills, sore throat), and agranulocytosis.
levomilnacipran (Fetzima) indication
MDD
Levomilnacipran (Fetzima) MOA
The L-enantiomer of Milnacipran (Savella, FDA approved for fibromyalgia)), levomilnacipran is also dual serotonin and norepinephrine reuptake inhibitor.
However, it has much higher selectivity for reuptake blockade of NE than 5-HT reuptake blockade
levomilnacipran side effects
HTN, tachycardia, GI symptoms (N/V, constipation), hyperhidrosis, urinary hesitancy/retention, erectile dysfunction
Iproniazid (trivia)
Was the first MAOi (1958-1961), but was pulled from the market because of hepatotoxicity
List the MAOIs
STRIP’M
selegiline (Eldepryl)
tranylcypromine (Parnate)
rasagiline (Azilect)
isocarboxazid (Marplan)
phenelzine (Nardil)
moclobemide (Manerix)
Which MAOI is available transdermally?
Selegiline
What is MAO and what does it do?
It is found on the outer mitochondrial membrane, where it degrades monoamine neurotransmitters (NE, 5HT, DA, Epi, Tyramine).
MAO-A breaks down what?
Think MOA-A = “All” (unlike B, which only does a couple)
Breaks down: NE, Epinephrine, 5-HT, DA and tyramine
MAO-B breaks down
DT
dopamine and tyramine
MAO indications
MDD
- Some data may show that phenelzine may better treat atypical depression (hypersomnia and hyperphagia) than TCAs
- May treat depression in Bipolar Disorder better than TCAs with less hypomania/mania
- Depression associated with TBI
- Tranylcypromine was included in the STAR*D trials as an effective option in treatment-resistant depression.
anxiety, phobias, pain, migraines, depression associated with TBI.
Which TCAs are structurally related to amphetamines and may have a stimulant effect on the brain?
Stimulating The Persons
- Selegiline
- Tranylcypromine
- Phenelzine
MAO half-life pearls
Serum half-lives can be ~2-3 hours but have tissue half-lives with longer times.
HOWEVER - They irreversibly inactivate MAOIs, thus the effect can last up to 2 weeks, even with a single dose.
What is Moclobemide?
Moclobemide is a reversible MAO-A inhibitor and has fewer side effects and less dietary restrictions. It is not approved for use in the United States at this time
What % of patients on SSRIs gain weight?
Up to 30%, especially with paroxetine
Vortioxetine dosing
Most of my patients are on 20mg, some did better on 30, and none (so far) did better (or worse) on 40 vs. 30. 10 is ok, kinda like 10 of Prozac or 50-75 of Zoloft.
There is definitely data in GAD, not yet in OCD, though there is no reason to anticipate it would not help in OCD. It’s just an SSRI with mild 1a partial agonism like Buspar and some fancy blocking of serotonin receptors subtypes.
It has antagonistic action at 5-HT3, like ondansetron, which is thought to have efficacy in OCD augmentation indirectly through blocking of 5-HT3. Not that this means much from a clinical standpoint.
