Antidepressants Flashcards Preview

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Flashcards in Antidepressants Deck (31):
1

Classes of antidepressants

MAOIs, TCAs, Aytipicals, SSRIs, SNRIs

2

Therapeutic goal

increase availability of NE and/or serotonin @ central synapses
-BLACKBOX WARNING: increased suicide risk for teenagers & children on anti-depressants
-MAO-A preferentially catabolizes 5-HT & NE, MAO-B preferentially catabolizes beta-phenylethylamine
- DA & tyramine metab by both isozymes equally

3

MAOIs

Phenelzine
Tranylcypromine
Isocarboxazid
Selegiline
RIMA drugs

4

Phenelzine
Tranylcypromine
Isocarboxazid

-MOA: irreversibly inhibit both isozymes of MAO (A and B)
(NE and Serotonin) are preferentially catabolized by MAO-A
→irreversible and non-selective
-PHARM: extensive first pass effect
-USE: when patient does not respond to other treatments
-atypical depression

5

Selegiline

-MOA: (S)Selective MAO-B-I
→irreversible inhibition of MAO A and B at high concentrations
-PHARM: w/in usual Tx dose range, primarily protects dopa
-extensive first pass effect
-transdermal admin avoids the first pass effects and mitigates some of the food interactions
-USE: also used in Tx Parkinson's Disease
-at higher concentrations its used for depression

6

RIMA drugs

-MOA: (S)Selective MAO-A-I
RIMA: reversible Inhibition of MAO-A
-USE: depression
not available in the US

7

Phenelzine
Tranylcypromine
Isocarboxazid
Selegiline
RIMA drugs

AE

- weight gain
-activity of NS MAOIs > t½ b/c covalently bond w/ enzyme
-Food & drug interactions { NS blockade of both isozymes → ↓ dietary tyramine metabolism → NE release @ sympathetic neurons → (no MAO metabolism) → dramatic HTN (competitive selective MAO-A are less likely to produce this interaction)
-Drug Interactions do not use w/ meperidine, other opiates, sympathomimetics, TCAs, L-DOPA, SSRIs, SNRI’s → may lead to serotonin syndrome
-use with tranylcypromine can cause CNS stimulation in overdose
-postural hypotension (↑ dopamine @periphery, formation of "false transmitter" octopamine)

8

TCAs

Amitriptyline
Clomipramine
Imipramine (prototype)
Nortriptyline
Desipramine

9

Amitriptyline
Clomipramine
Imipramine (prototype)
Nortriptyline
Desipramine

MOA, pharm

-inhibit the reuptake of 5HT & NE from synaptic cleft by blocking 5HT & NE reuptake transporters
-do NOT affect DA reuptake
-also hits Histamine H1 receptor


Pharmacokinetics:
• Dosed once a day and at night because of their sedating effects
• Metabolized by CP450 extensively so can interact with other drugs than inhibit this system (ie fluoxetine)

10

Amitriptyline
Clomipramine
Imipramine (prototype)
Nortriptyline
Desipramine

Use

-not used commonly because of the AE and toxicity
-used for depression that doesn’t respond to more commonly used antidepressants
-at lower doses used to treat pain
-can be used for migraine prophylaxis
-imipramine: used for enuresis (bed wetting)
-clomipramine: OCD
→ neither of the above are the preferred agents

11

Amitriptyline
Clomipramine
Imipramine (prototype)
Nortriptyline
Desipramine

AE

3C’s: coma, convulsions and cardiotoxicity
-quinidine like effect leading to conduction delays → widening of the QRS complex and arrhythmias → reverse cardiac toxicity with sodium bicarb
-confusion and hallucinations in elderly that are susceptible to anticholinergic effects
Sedation (H1 and M blockade)
-Tremor and insomnia
-Dry mouth & gut/urinary effects (M blockade)
-Orthostatic hypotension (alpha1 blockade)
-Lowered seizure threshold
-Weight gain
-sexual side effects
-can be discontinuation syndrome and serotonin syndrome

-Drug interactions:
-sympathomimetic amines, ethanol
(due to central H1 or M blockade?)

12

Clomipramine, specific comments

blocks both but primarily inhibits serotonin reuptake

13

Nortriptyline specific comments

-active metabolite of parent drug is more selective for NE

14

Desipramine specific comments

-more selective for NE

15

Atypical antidepressants

Bupropion
Mirtazapine
Trazodone

16

Bupropion

Atypical antidepressant
-MOA: it resembles amphetamine in chemical structure and has CNS activating properties → causes release of NE and some dopamine
-PHARM: extensive first pass metabolism leads to a short half life so more than once a day dosing may be required
-USE: atypical depression and smoking cessation
-ADHD (off label)
-AE: no sexual side effects
-agitation, insomnia, anorexia
Drug interactions: some CP450 interactions
→should not be combined with MAOIs

17

Mirtazapine

Atypical antidepressant
-MOA: Direct Antagonist to:
5HT-2A, 5HT-2C (G protein coupled)
5HT-3(only ligand ion channel of any MAO receptors)
H1
α2 receptors (so enhances NE & 5HT release)
→ inhibits autoregulation of NE and 5HT neurons (because blockade of alpha 2 auto receptors prevents feedback inhibition of the release of NE)
-PHARM: half life of 20-40 hours → usually dosed once a day in the night because of the sedating properties
-USE: could be used in melancholic depression
-because of the antihistamine properties the drug is sedating so can be used in depressed patients that have trouble sleeping
-AE: enhances appetite → weight gain
-sedating
-does not interfere with sexual function
Drug interactions: some CP450 interactions
-sedating properties may be additive with other CNS depressants like ethanol or benzodiazepines

18

Trazodone

Atypical antidepressant
-MOA: major metabolite acts as a 5HT2A antagonist
-also inhibits the reuptake of serotonin
→thus enhances 5HT transmission at postsynaptic 5HT1A receptors and other 5HT2 receptors but only at high doses; at lower doses acts as an antagonist at histamine and alpha adrenergic receptors
→blocks 5HT reuptake and inhibit 5HT2A receptors postsynaptically
-PHARM: low bioavailability b/c its rapidly metabolized → if used as an antidepressant would need 2x/day dosing
-more often admin once a day at a low dose at night for its sedative properties
-USE: hypnotic
-treats insomnia with low doses but may augment the effect of other antidepressants
-AE: sedation, GI upset (less pronounced than SSRIs and SNRIs)
-sexual side effects are uncommon
-alpha adrenergic blockade leads to hypotension and priapism (long erection; rare)
Drug interactions: substrate for CYP3A4, so combination with potent inhibitors of cytochrome like ritonavir or ketoconazole may increase levels of trazodone greatly

19

SSRIs

Citalopram
Fluoxetine
Fluvoxamine
Paroxetine
Sertraline

20

Citalopram
Fluoxetine
Fluvoxamine
Paroxetine
Sertraline

MOA

Highly selective for 5-HT reuptake pump
-inhibits the reuptake of serotonin into the presynaptic terminal
-therapeutic lag of 2-4 weeks, even though the pharmacological effect occurs shortly after dosing

Fluoxetine60 hr)
Significant drug interactions

21

Citalopram Pharm

Greatest selectivity for 5HT

22

Fluoxetine Pharm

3rd greatest selectivity for 5HT
t1/2 ~ 48 hr – longest half life → must be discontinued 4 weeks before switching to an MAOI
N-desmethylfluoxetine ~240 hrs

23

Sertraline Pharm

2nd’greatest selectivity for 5HT
-also inhibits DA reuptake (so affects Parkinson’s)

24

Citalopram
Fluoxetine
Fluvoxamine
Paroxetine
Sertraline

Use

aside from major depression (typical), these drugs are also used for generalized anxiety disorder, PTSD, OCD, panic disorder, and PMDD

25

Citalopram
Fluoxetine
Fluvoxamine
Paroxetine
Sertraline

AE

Drug-drug interactions(inhibit P450 2D6)
- serotonin syndrome: specific drug interaction w/ MAOIs → agitation, tremor, hypertension, hyperthermia, cardiovascular dysfunction → cardiovascular collapse, death; when switching, use washout period ≥ 2 wk
-N/D
-Sexual dysfunction (affects libido & performance)
-discontinuation syndrome → dizziness, tingling, or numbing of skin
- ↓ platelet aggregation → ↓ platelet 5-HT & ↓ thrombogenic actions of platelet disruption {Platelets take up 5-HT from portal circulation by a 5-HT transporter that is blocked by SSRI’s, 5-HT released from platelets (by usual stimuli) causes local vasoC (5-HT2A, 5-HT1B) & platelet aggregation (5-HT2A), SSRI’s ↓probability of new infarcts after MI, modest ↑of risk for bleeding when combined with aspirin}
-sweating, suicide

26

SNRIs

Duloextine
Venlafaxine

27

Duloextine
Venlafaxine

MOA

-Duloxetine inhibits the serotonin and NE transporter
-Venlafaxine inhibits the serotonin transporter and the NE transporter only at high doses
-these drugs do not bind histamine, alpha adrenergic, and muscarinic receptors, so they are better tolerated than TCAs

28

Duloextine Pharm

-half life: 11 hours
-extensively metabolized by CP450 so shouldn’t be given to patients with hepatic insufficiency
-highly protein bound

29

Venlafaxine Pharm

-half life: 11 hours
-has an active metabolite generated by CP450 but doesn’t go under extensive metabolism

30

Duloextine
Venlafaxine

USE

-major depression, atypical depression (venlafaxine), generalized anxiety, stress urinary incontinence, vasomotor symptoms of menopause, pain of diabetic neuropathy (duloxetine)

31

Duloextine
Venlafaxine

AE

-relatively mild compared to TCAs
-some overlap w/ SSRIs (nausea)
-may have noradrenergic effects including increased BP, HR, and CNS activity (insomnia, anxiety, agitation)
-high doses of venlafaxine may cause adverse cardiac effects
-discontinuation and serotonin syndromes are possible
-mild drug interactions → most serious interaction is with MAOIs to produce serotonin syndrome