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Pharmacology (Dustin, Ben) > B7-9: Antidepressants (Cyclic, MAOI, SSRI/SNRI, NE/5-HT Antagonists) + Manic phase bipolar treatment > Flashcards

B7-9: Antidepressants (Cyclic, MAOI, SSRI/SNRI, NE/5-HT Antagonists) + Manic phase bipolar treatment Flashcards

1
Q

Background:

What was the early pathophysiological theory for the etiology of depression / mania?

(What drug affecting molecules in this pathway helped support this theory?)

A

Monoamine Theory

a deficiency / excess of monoamine transmission contributed to depression / mania, respectively

(Reserpine, a VMAT blocker, caused depression in 50% of patients)

(other support for theory includes studies showing functional genetic polymorphism of SERT and reduction of 5-HT metabolites in CNS resulting in adverse behavioral changes)

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2
Q

What are the 3 main categories of antidepressant drugs in use?

A
  1. Reuptake Inhibitors - TCAs and SSRIs
  2. Atypical Antidepressants - have adrenergic/5-HT receptor-antagonizing and/or unique reuptake inhibition mechanisms
  3. Monoamine Oxidase Inhibitors (MAOIs) - selective vs. non- and reversible vs. irreversible
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3
Q

Background:

What are the steps of serotonin + melatonin synthesis? (4)

(Which step is rate-limiting?)

(Since the antidepressants in use don’t really work on these steps, I don’t think much will be asked about this in MCQs, but it’s good background to have for oral exams.)

A
  1. Tryptophan Hydroxylase - Trp > 5-hydroxytryptophan (5-HTP) (RATE-LIMITING)
  2. Aromatic AA Decarboxylase - 5-HTP > 5-hydroxytryptamine (serotonin / 5-HT)
  3. 5-HT N-acetylase - 5-HT > N-acetyl 5-HT
  4. 5-hydroxyindole O-methyltransferase - N-acetyl 5 -HT > melatonin
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4
Q

Background:

What are the two enzymes responsible for the breakdown of monoamine NTs in the body?

Their location (which cell types + where in the cell)?

A
  1. MAO - on outer mitochondrial membrane with flavin cofactor; MAO-A degrades 5-HT and NE in GI tract + nerve endings, MAO-B degrades phenylethylamines in platelets + glia, both degrade DA and tyramine
  2. COMT - both intra-/extracellular; requires Mg2+ and S-adenosyl-Met
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5
Q

Background:

What are the important inactivated metabolites made in the CNS from NE, DA and 5-HT?

(They can be detected in blood / urine samples to indicate levels of monoamine NTs in the body.)

A
  1. NE - MAO/COMT make MHPG (3-methoxy-4-OH-phenylglycol)
  2. DA - MAO/COMT make HVA (homovanillic acid)
  3. 5-HT - MAO and aldehyde dehydrogenase make 5HIAA (5-OH indole acetic acid)
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6
Q

Background:

What nuclei / loci in the brain are the main sites of NE and 5-HT output to other CNS sites?

(What are the general CNS functions regulated by NE + 5-HT?)

A
  1. Norepinephrine - locus coeruleus (rhomboid fossa!) and lateral tegmental area (ventral midbrain) to widespread cortical/subcortical sites; regulates arousal, mood and BP
  2. Serotonin - midline raphe nuclei (throughout brainstem) to widespread cortical/subcortical sites; regulates sleep, mood, sexual function and appetite
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7
Q

Basics:

What is the aim of antidepressant treatment over the initial weeks of therapy?

Over months / years?

A
  • Weeks: relief of acute symptoms BUT anti-depressants generally take 4-6 weeks to take effect
  • Months: prevention of relapse (“maintenance therapy”)
  • Years: prevention of repeat episodes (“prophylactic therapy”)

(Note that suicide risk is highest in the first two months of treatment. Risk is highest in young adults 18-25. Antidepressants generally carry black-box warnings about this. This may be due to early effects of increased motivation + energy levels interacting with remaining depressive symptoms as the patient slowly improves.)

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8
Q

Basics:

What is the efficacy of antidepressants within the first 6-12 weeks of treatment?

And how effective are they overall at achieving remission?

A
  • Many (~38%) patients have no response in the first 6-12 weeks
  • In more than half of patients, remission can not be achieved
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9
Q

Basics:

How long is antidepressant treatment generally?

And in patients with repeated episodes?

A
  • Usually 4-9 months in patients with a single depressive episode
  • Treatment should continue for years in patients with ≥ 2 episodes
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10
Q

Background:

What change in serotonergic / noradrenergic systems is strongly correlated with clinical improvements from antidepressant use?

A

Receptor Downregulation

  • antidepressants increase monoamine levels by reuptake / MAO inhibition etc. > MAs continously stimulate inhibitory α-2 and 5-HT1A receptors > receptors are down-regulated > monoaminergic neurons become disinhibited, releasing even more MAs
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11
Q

Name the 4 important tricyclic antidepressants (TCAs).

What is their mechanism of action?

(One of the 4 is slightly different. Which one and how?)

A
  • imipramine, amitriptyline, clomipramine - 5-HT + NE reuptake inhibition
  • maprotiline - primarily NE reuptake inhibition (tetracyclic structure)
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12
Q

Besides 5-HT and NE reuptake inhibition…

what 4 physiological mechanisms do TCAs inhibit and what are the resulting side effects?

(3 of these are more common/benign mechanisms to interfere with… but one is much more severe and very important)

A
  1. H1 histamine receptors - sedation, dizziness, confusion, weight gain
  2. α1 receptors - orthostatic hypotension, reflex tachycardia, dizziness
  3. M receptors - anticholinergic effects (dry mouth, constipation, urinary retention, blurred vision, confusion, cognitive impairment)
  4. Cardiac HERG-type K+ Channels - can result in life-threatening ventricular arrhythmias
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13
Q

What are the indications for TCAs?

(5)

(Extra: name the specific TCAs used for 3 of these indications)

A
  1. Depression
  2. Panic Disorders - imipramine, clomipramine
  3. Noctural Enuresis (bed wetting)
  4. Neuropathic Pain - amitriptyline, clomipramine
  5. Migraine Prophylaxis - amitriptyline
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14
Q

How are TCAs administered?

How often do they need to be taken (half-life) ?

What are their important interactions?

A
  • Administered orally only once daily due to their 25-30 hr half-life
  • Interactions: potentiate alcohol’s respiratory depressive effect; may cause serotonin syndrome (fever, seizure, coma) if co-administered with MAOIs
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15
Q

Name 5 important SSRIs.

(+ 1 extra only mentioned in Kato’s practical with its special indication)

(What is their mechanism of action?)

A
  1. Fluoxetine - trade name Prozac
  2. Fluvoxamine
  3. Paroxetine
  4. Sertraline
  5. Citalopram + Escitalopram
  6. Dapoxetine - for premature ejaculation (remember dapoxetine is for the D!)

(Unlike TCAs they only inhibit 5-HT reuptake via SERT, not NE via NET, and do not inhibit H/alpha/M receptors.)

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16
Q

What are the 5 main indications for SSRIs?

A
  1. Depression - as 1st choice treatment
  2. Anxiety Disorders
  3. OCD
  4. Bulimia Nervosa - but not anorexia
  5. Premenstrual Dysphoric Disorder - special depressive form of PMS
  6. (Premature Ejaculation treated w/ dapoxetine)
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17
Q

What are the adverse effects of SSRIs?

(Via which receptors? How can some of these be avoided?)

A

Preferred over TCAs due to lack of H/alpha/M receptor effects…

  • 5-HT2 stimulation - anxiety (usually fades w/ time), insomnia, decreased libido, and delayed ejaculation
  • 5-HT3 stimulation - nausea, vomit, GI upset, diarrhea, and headache (can help GI sx to take SSRI with food)
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18
Q

What is the most dangerous possible complication of SSRI treatment?

With which SSRI is this most likely and how can it be avoided?

A

Serotonin Syndrome

  • concomittant admin with MAOIs or admin of MAOI too soon after SSRI discontinuation > pathological 5-HT level increase > muscle rigidity, cramps, hyperthermia + hypertension
  • fluoxetine takes 4-6 weeks to be adequately eliminated before MAOI admin. also difficult to establish steady state dosage due to complicated distribution
19
Q

Which SSRIs have shorter durations of action? Which have longer?

(Approximate half-lives?)

A
  1. Paroxetine / Sertraline - shorter; t1/2 ~25-35 hrs
  2. Fluoxetine - longer; its active metabolite norfluoxetine has t1/2 ~7-9 days
20
Q

How long does it take for SSRIs to become effective?

What can be done to help with this?

A
  • onset takes 2-3 weeks and max benefit may not be seen until 12 weeks or more
  • sometimes a benzodiazepene is given for immediate anxiolysis and slowly discontinued as the SSRI takes effect
21
Q

What are the 6 categories of atypical antidepressants?

(Actually 4 categories + 2 single unique drugs)

A
  1. SSNRIs - selective 5-HT + NE reuptake inhibitors
  2. NRIs - selective NE reuptake inhibitors
  3. Bupropion - DA/NE reuptake inhibitor
  4. Tianeptine - 5-HT reuptake enhancer
  5. SERT/5-HT2A antagonists - also inhibit α1
  6. α2 / 5-HT antagonists - mirtazapine / mianserine
22
Q

What are the 2 important SNRIs?

Which one has dose-dependent effects and how?

What is their advantage over TCAs / SSRIs?

A
  • Venlafaxine + active metabolite desvenlafaxine - must be given 2x daily; inhibit SERT at all doses + NET at higher doses (thus can start with small dose + increase if ineffective without having to wait for elimination)
  • Duloxetine - inhib SERT/NET equally at all doses
  • Advantage: no H/alpha/M-related TCA-like effects; NET inhibition can be useful in neuropathic pain
23
Q

Aside from the usual SERT inhibition-related indications / side effects…

what are 4 unique indications of SNRIs?

And side effects?

A
  • Neuropathic pain disorders: 1) diabetic neuropathy, 2) postherpetic neuralgia, 3) fibromyalgia, and 4) Lower Back Pain
  • Side effects: hypertension and tachycardia due to increased NE
24
Q

What is the 1 important NRI drug?

Important side effect other than tachycardia/hypertension?

(Extra: indications?)

(Drug mentioned in Lippincott, seems less important, but on slides / notes.)

A

Reboxetine

  • weak anticholinergic effects + can cause sleep disturbances
  • (indications: major depressive disorder, panic disorder, ADHD)
25
Q

Which drug inhibits DAT / NET specifically?

Indications / contraindications?

Special administration?

A

Bupropion

  • Indications: stuporous depression - DA incr. can help with immobility; smoking cessation
  • Contraindications: epilepsy - may provoke seizure
  • Must be administered at 2x / day due to short half-life
26
Q

Which atypical antidepressant actually enhances neurotransmitter reuptake?

Indications?

A

Tianeptine

  • enhances 5-HT reuptake > strong anxiolytic
  • indicated for depression + anxiety related to alcohol withdrawal syndrome
27
Q

Which drugs are 5HT2A inhibitors + weak 5-HT reuptake inhibitors?

Extra actions + indications?

(Side effects?)

A

Trazodone + Nefazodone

  • 5HT2A inhib + weak α1 / H1 inhibition > sedation
  • Indication: depression with insomnia
  • (Side effects: orthostatic hypotension, dizziness, priapism [trazoBONEr] and hepatotoxicity [nefazodone])
28
Q

Which SERT-inhibiting drug has a special serotonergic mechanism that attenuates one of the common SSRI side effects?

(Not in lecture, but Kato + Lippincott mention it.)

A

Vilazodone

  • inhibits SERT + is also a 5HT1A partial agonist which attenuates the possible side effect of anxiety common to SSRIs
29
Q

What are the two α2 inhibitor antidepressants?

What other receptors do they effect?

Indications + side effects?

A

Mirtazapine (more used) + Mianserine (older)

  • also antagonize 5HT2 receptors (anxiolytic, sedative), 5HT3 (anti-emetic) and H1 (highly sedative)
  • useful in depression w/ insomnia
  • side effects: increased appetite + weight gain (but no impotence! just think of a calm, tired, hungry fat man with a raging boner who definitely will not vomit and you’ll never forget these…)
30
Q

Which atypical antidepressant can help to re-establish circadian rhythm in depressed patients with sleep disturbances?

Mechanism? Side effects?

A

Agomelatine

  • acts as a melatonin receptor and 5HT2C agonist
  • side effect: hepatotoxicity … must monitor liver enzymes
31
Q

Which MAOI is non-selective?

Other kinetic characterstics?

Indication?

A

Phenelzine

  • non-selective + irreversible MAOI
  • used in severe depression
32
Q

What are the 2 MAO-A selective MAOIs?

Other pharmacodynamics?

Indications? Dosing frequency?

A
  1. Moclobemide - reversible MAO-A inhib; indicated for depression + social phobias; given 2-3x/day + dose slowly titrated upward
  2. Clorgylline - irreversible; indicated for severe resistant depression; higher risk for cheese effect
33
Q

What is the selective MAO-B inhibitor?

Other important pharmacodynamics? Indications?

A

Selegiline

  • is an irreversible MAO-B inhibitor
  • indicated for Parkinson’s disease
34
Q

What are 4 important potential interactions when administering MAOIs?

And general side effects?

A

MAOIs can cause insomnia, agitation and sexual disturbances and can interact with…

  1. Sympathomimetics - increasing their effect
  2. TCAs / SSRIs - causing serotonin syndrome
  3. Pethidine - synthetic opioid; AKA meperidine / Demerol; MAOIs increase resp. depression / seizures
  4. Tyramine - cheese effect; esp. with irreversible MAOI
35
Q

What 4 categories of drugs are used to treat the manic phase of bipolar disorder?

(actually 1 single drug + 3 categories)

(which categories are used for chronic vs. acute treatment?)

A
  1. Lithium - as lithium carbonate; chronic tx only
  2. Anti-epileptics - valproate, carbamazepine, lamotrigine; acute and chronic tx
  3. Anti-Psychotics - quetiapine, olanzapine, risperidone; ziprasidone or aripiprazole (children / adolescents); for acute tx only
  4. Benzodiazepines - didn’t see definite info on BZDs but probably acute tx only
36
Q

What are the 2 indications for lithium carbonate?

What are its 4 mechanisms of action?

Which one is most likely responsible for its anti-manic effects? (answer will be the first of the 4 listed, other 3 mostly responsible for side effects)

A

Indicated for bipolar disorder (treats mania + inhibits re-entry into mania from depression) and unipolar depression (can enhance AD med effects)

  1. IP3-DAG Pathway Inhibition - Li inhibits inositol monophosphatase, decreasing IP3 levels
  2. Na permeability - Li influences cellular Na permeability
  3. Adenylate Cyclase inhibition - lowers cAMP
  4. Receptor Uncoupling - Li alters subunits of dopamine + other receptor-associated G proteins
37
Q

What are the important aspects of lithium carbonate’s pharmacokinetics?

(Administration, absorption, distribution, accumulation, reabsorption etc.)

A
  • Administered + absorbed well orally
  • Is excreted unchanged in urine + doesn’t bind serum proteins
  • Slowly accumulates in neuronal tissues developing effects after 1-3 weeks (so for chronic treatment only)
  • Is partly actively reabsorbed in the kidney, competing with Na+. Any condition with lower sodium levels will increase lithium reabsorption (exercise, diarrhea, diuretics) + thus increase toxicity risk
38
Q

What are lithium carbonate’s side effects?

(4 general + 4 more specific + how can one specific side effect be treated?)

A
  1. General: tremor, sedation, nausea, vomiting
  2. Hypothyroidism - G-protein uncoupling → ↓ TSH effect
  3. Interstitial Nephritis - renal accumulation → HS rxn
  4. Nephrogenic DI - ↓ ADH effect; can be treated with thiazide diuretics
  5. Teratogenicity - contraind. in pregnancy
39
Q

What are the symptoms of lithium toxicity?

Why is this so important specifically for lithium?

A
  • Hyperactivity, seizure and coma
  • Lithium has a very narrow therapeutic window; serum concentrations of 1.0-1.2 mmol/l are therapeutic and just 1.5-1.7 mmol/l is toxic
40
Q

Which 3 of the antiepileptic drugs are given to treat manic phases of bipolar disorder?

A
  1. Valproate
  2. Carbamazepine
  3. Lamotrigine

Can be used for both acute + chronic mania treatment

41
Q

Which 5 of the antipsychotic drugs can be used to treat mania in bipolar disorder?

How are they given?

Which two are specifically indicated in childhood / adolescent manic episodes?

A

Administered acutely in addition to lithium in manic phases, then discontinued as mania subsides, with lithium continued prophylactically even in depressive phases.

  1. Olanzapine
  2. Quetiapine
  3. Risperidone
  4. Ziprasidone - children/adolescents
  5. Aripiprazole - children/adolescents
42
Q

Give an example of a benzodiazepine used for treatment of manic episodes in bipolar disorder.

(Probably unimportant, just the 1 BDZ Kato mentioned here)

A

Clonazepam

43
Q

What drugs are used to treat depressive phases of bipolar disorder?

What are the risks of this + how are they dealt with?

A

TCAs (less so) or SSRIs (more so)

  • Increase the risk of onset of mania (10-60% increase with TCA; 4% with SSRI)
  • Co-administered with a mood stabilizer (lithium) to decrease mania risk

Pharmacology (Dustin, Ben) (17 decks)

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