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Pharmacology MidTerm > Antidepressants > Flashcards

Antidepressants Flashcards

1
Q

What are the symptoms of depression?

A

Sadness.
Despair.
Lack of pleasure.
Sleep and appetite changes.
Loss of energy.
Suicidal thoughts.

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2
Q

What are the two types of depression?

A

Unipolar: Major depressive disorder.
Bipolar: Bipolar disorder.

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3
Q

What are the symptoms of bipolar disorder (mania)?

A

Alteration between depression and euphoria.
Enthusiasm.
Rapid thought and speech.
Self-confidence.
Impaired judgement.

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4
Q

What are the monoamines?

A

Dopamine.
Norepinephrine.
Serotonin.

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5
Q

What is the monoamine hypothesis?

A

Depression is caused by a defect in the activity of monoamines, and the overexpression of monoamine receptors.

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6
Q

What is the strategy of treatment for depression?

A

Antidepressants are administered to enhance the actions of norepinephrine and/or serotonin in the brain.

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7
Q

What is the mechanism of action of selective serotonin reuptake inhibitors (SSRIs)?

A

They selectively inhibit serotonin reuptake, leading to an increased concentration of serotonin in the synaptic cleft.

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8
Q

What does the “selective” in “selective serotonin reuptake inhibitors” (SSRIs) mean?

A

They are selective as their selectivity for the serotonin transporter is 300 to 3000 times greater compared to the norepinephrine transporter.

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9
Q

What are the most common SSRI drugs?

A

Fluoxetine.
Citalopram.
Escitalopram.
Fluvoxamine.
Paroxetine.
Sertraline.

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10
Q

Why are SSRIs preferred as a first-line treatment for depression?

A

Because they target serotonin reuptake without significantly affecting muscarinic, α-adrenergic, and histamine H1 receptors.

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11
Q

(SSRIs) and (SNRIs) target serotonin reuptake without significantly affecting muscarinic, α-adrenergic, and histamine H1 receptors.

What is the consequence of this characteristic?

A

As a result, they cause fewer side effects associated with these receptors:
Postural hypotension.
Sedation.
Dry mouth.

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12
Q

Tricyclic depressants target serotonin reuptake while affecting muscarinic, α-adrenergic, and histamine H1 receptors.

What is the consequence of this characteristic?

A

As a result, they cause effects associated with these receptors:
Postural hypotension.
Sedation.
Dry mouth.

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13
Q

When do we use tricyclic antidepressants, MAO inhibitors, etc. to treat depression instead of SSRIs?

A

When the patient doesn’t respond to SSRIs.

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14
Q

Do SSRIs improve the mood shortly after they are taken?

A

No. It usually takes at least two weeks to improve mood, with maximum effects up to 12 weeks or more.

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15
Q

Why is the therapeutic effect of antidepressants delayed and not immediate?

A

Initially increased serotonin worsens symptoms by reducing its own release. However, over time, receptor desensitization improves serotonin transmission and mood.

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16
Q

Why shouldn’t the treatment of depression be less than 6 months?

A

The risk of relapse is greatest during the first 6 months after recovery.

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17
Q

Approximately 40% of depressed patients never respond to an antidepressant. Why?

A

Genetic factor.

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18
Q

What if a patient doesn’t respond to an antidepressant?

A

Patients who do not respond to one antidepressant may respond to another, and approximately 80% or more will respond to at least one antidepressant drug.

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19
Q

What are the therapeutic uses of SSRIs in addition to depression?

A

Obsessive compulsive disorder (fluoxetine).
Panic disorder.
Generalized anxiety disorder.
Post traumatic stress disorder.
Social anxiety disorder.
Premenstrual dysphoric disorder.
Bulimia nervosa (only fluoxetine!)

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20
Q

What are the extra therapeutic uses of fluoxetine?

A

Obsessive compulsive disorder.
Bulimia nervosa.

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21
Q

What are the pharmacokinetics of sertraline?

A

Only sertraline undergoes significant first-pass metabolism.

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22
Q

Why should we be careful when using fluoxetine if we plan to introduce a drug that interacts with it?

A

The metabolite of the s-enantiomer (s-norfluxoetine) is as potent as the parent compound, causing the drug to have a longer half-life (50 hours), so it is used once weekly.

The long half-life of fluoxetine can result in drug-drug interactions if a drug that interacts with fluoxetine is introduced too early. So caution should be used when fluoxetine is used.

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23
Q

How are SSRIs excreted?

A

Excretion of SSRIs is primarily through the kidneys, except for paroxetine and sertraline, which also undergo fecal secretion.

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24
Q

Which two SSRI drugs have a special excretion profile?

A

Paroxetine and sertraline, which also undergo fecal secretion in addition to kidney excretion.

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25
Q

Describe the drug-drug interaction profile of citalopram and escitalopram

A

Citalopram and escitalopram have the least effect on the cytochrome P450 system, so they have the most favorable profile regarding drug-drug interactions.

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26
Q

How does food affect the absorption of sertraline?

A

Food has little effect on the absorption of SSRIs except for sertraline, food increases its absorption.

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27
Q

Which SSRIs should be taken at night?

A

Paroxetine and fluvoxamine as they have a sedating effect. This can be advantageous if the patient has sleep disturbances.

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28
Q

Which SSRIs should be taken at daytime?

A

Fluoxetine and sertraline.

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29
Q

Which SSRIs should insomniacs and anxious people avoid?

A

Fluoxetine and sertraline.

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30
Q

Which SSRIs are recommended for fatigued, depressed patients?

A

Fluoxetine and sertraline, due to their energizing effect.

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31
Q

Discuss the sexual dysfunction side effect associated with SSRIs.

A

SSRIs commonly cause sexual dysfunction in the form of loss of libido and delayed ejaculation.

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32
Q

How is the sexual dysfunction side effect associated with SSRIs managed?

A
  1. Switch to a drug which has a more favorable sexual side effect profile, such as bupropion.
  2. Use of PDE inhibitors, such as sildenafil.
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33
Q

What happens when SSRIs are overdosed?

A
  1. Seizures.
  2. Serotonin syndrome:
    - Hyperthermia.
    - Muscle rigidity.
    - Sweating.
    - Clonic muscle twitching.
    - Changes in mental status and vital signs (if used in conjugation with MAOIs).
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34
Q

Which SSRI is associated with weight gain?

A

Paroxetine.

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35
Q

How do SSRIs affect Parkinson patients?

A

SSRIs have been associated with extrapyramidal side effects, especially those with Parkinson’s disease, because they have an ability to block dopamine receptors.

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36
Q

What is the discontinuation syndrome associated with SSRIs?

A

A syndrome that occurs when the depressed patient stops taking SSRIs abruptly:
- Headache.
- Malaise.
- Flu-like symptoms.
- Agitation.
- Irritability.
- Nervousness.
- Sleep disturbances.

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37
Q

Which drug-drug interactions can cause serotonin syndrome when used with SSRIs?

A
  1. MAO inhibitors.
  2. Triptans.
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38
Q

Which drug-drug interaction is most serious for paroxetine?

A

Use of paroxetine with anesthetics can cause neuroleptic malignant syndrome.

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39
Q

How do SNRIs work?

A

They prevent the reuptake of serotonin and norepinephrine by blocking the transporters of these monoamines.

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40
Q

What are the most commonly used SNRIs?

A

Venlafaxine.
Desvenlafaxine.
Duloxetine.

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41
Q

When are SNRIs most commonly introduced/administered to a depressed patient?

A

They have been shown to be effective in treating depression in patients in whom SSRIs are ineffective. Thus, SNRIs have a higher efficacy than SSRIs.

42
Q

Why are SNRIs preferred over tricyclic antidepressants?

A

Because unlike tricyclic antidepressants, SNRIs have little activity at adrenergic, muscarinic, and histamine receptors and thus have fewer receptor-mediated adverse effects than TCAs.

43
Q

What other therapeutic effects (other than treating depression) are SNRIs associated with?

A

SNRIs are effective in relieving physical symptoms of neuropathic pain such as diabetic peripheral neuropathy.

44
Q

If a depressed patient complains from chronic pain, which antidepressant class is most appropriate for treating this type of depression?

A

Depressed patients complaining of chronic pain should take SNRIs. SSRIs are not effective in relieving chronic pain.

45
Q

What is venlafaxine?

A

Venlafaxine is a potent inhibitor of serotonin reuptake.

At high doses, venlafaxine also inhibits norepinephrine reuptake and also mildly inhibits dopamine reuptake.

46
Q

What is the drug-drug interaction profile of venlafaxine?

A

Venlafaxine has minimal inhibition of the CYP450 family. It is a substrate of CYP2D6.

47
Q

What is desvenlafaxine?

A

It is the active, demethylated metabolite of venlafaxine.

48
Q

What is the benefit of using desvenlafaxine?

A

Depressed patients suffering from liver problems can take desvenlafaxine instead of venlafaxine.

49
Q

What is duloxetine?

A

An antidepressant of the SNRI class that inhibits serotonin and norepinephrine at all doses.

50
Q

How is duloxetine metabolized?

A

Duloxetine is extensively metabolized in the liver to numerous metabolites. It should not be administered to patients with hepatic insufficiency.

The metabolites are excreted in the urine, so it is not recommended for use in patients with end-stage renal disease.

51
Q

Why does duloxetine have a long half-life?

A

Because it is highly bound to plasma albumin.

52
Q

Duloxetine has another use in addition to being an antidepressant. What is this use?

A

It can be used to manage joint pain.

53
Q

What is levomilnacipran?

A

An antidepressant of the SNRI class that is an enantiomer of milnacipran (an older SNRI used for the treatment of depression and fibromyalgia).

54
Q

How is levomilnacipran metabolized?

A

by CYP3A4.

55
Q

What are the side effects associated with SNRIs?

A

SNRIs have many of the serotonergic adverse effects associated with SSRIs.

In addition, SNRIs may also have noradrenergic effects, including:
- Increased blood pressure and heart rate.
- CNS activation, such as insomnia, anxiety, and agitation.

All SNRIs have been associated with a discontinuation syndrome resembling that seen with SSRI discontinuation.

56
Q

Compare between SSRIs and SNRIs on how they affect CYP450.

A

SNRIs have relatively fewer CYP450 interactions than SSRIs.

57
Q

What is bupropion, and what is it used for?

A

An atypical antidepressant that is a weak dopamine and norepinephrine reuptake inhibitor.

58
Q

Besides treating depression, what other therapeutic uses is bupropion indicated for?

A

It can also be used to manage the withdrawal symptoms for nicotine in tobacco users trying to quit smoking. How the drug does this is unknown, but the drug may mimic nicotine’s effects on dopamine and norepinephrine and may antagonize nicotinic receptors.

It is also useful in the management of seasonal affective disorder.

59
Q

What are the pharmacokinetics of bupropion?

A

It has a short half-life, so it requires more than once a day dose.

60
Q

What is the side effect profile of bupropion?

A

Bupropion has virtually no direct effects on the serotonin system.

Unlike SSRIs, bupropion doesn’t cause sexual side effects.

It doesn’t block muscarinic, histaminergic, or adrenergic receptors.

61
Q

Who should avoid taking bupropion?

A

Patients at risk for seizures or who have eating disorders such as bulimia, as bupropion is occasionally associated with CNS stimulation (agitation, insomnia, and anorexia), so it has an increased risk for seizures at high doses.

62
Q

What is the drug-drug interaction profile for bupropion?

A

Generally, bupropion has a low risk of drug-drug interactions.

63
Q

Mirtazapine has a complex pharmacology. Describe it.

A

It is an antagonist of 5-HT type 2 and 5-HT type 3 receptors.

Inhibition of 5-HT type 2A receptors in both animal and human studies is associated with substantial antianxiety, antipsychotic, and antidepressant effects.

By blocking presynaptic alpha-2 adrenoceptors, it enhances the release of both norepinephrine and 5-HT.

64
Q

What are the side effects of mirtazapine?

A

It stimulates appetite, leading to weight gain.
It has a sedating effect due to its potent antihistamine effect.
It has no muscarinic side effects and it doesn’t interfere with sexual performance.

65
Q

What are the clinical uses of 5-HT2 antagonists, like mirtazapine?

A

Depressed patients suffering from sleep problems.

66
Q

What are nefazodone and trazodone?

A

They are weak inhibitors of serotonin reuptake. They instead block postsynaptic 5-HT2A receptors.

With chronic use, these agents may desensitize 5-HT1a presynaptic autoreceptors, and thereby increase serotonin release.

67
Q

Compare nefazodone and trazodone?

A

Nefazodone:
- Weak inhibitor of both serotonin transporter and norepinephrine transporter.

Trazodone:
- A weak selective inhibitor of serotonin transporter.
- Has weak-to-moderate presynaptic alpha-adrenergic blocking properties.
- It is a modest antagonist of the H1 receptor.

68
Q

What are the side effects of 5-HT2 antagonists like nefazodone and trazodone?

A
  • Sedation due to their potent antihistamine effect. This necessitates dosing at bedtime.
  • Dose-related GIT SEs.
  • Priapism: uncommon sexual dysfunction but serious side effect requiring surgical intervention in one-third of the cases reported.
  • Mirtazapine is associated with weight gain.
  • Nefazodone has been associated with hepatotoxicity.
69
Q

What is the mechanism of action of tricyclic antidepressants?

A

Generally, they block norepinephrine and serotonin reuptake into the neuron.

  1. Inhibition of neurotransmitter reuptake (norepinephrine and serotonin).

They do not block dopamine transporters.

  1. Blocking of receptors:
    - Serotonergic.
    - Alpha-adrenergic.
    - Histaminic.
    - Muscarinic.
    This is responsible for the many of the adverse effects of TCAs.
70
Q

What are the most common tricyclic antidepressants?

A

Imipramine.
Amitriptyline.
Clomipramine.
Doxepin.
Trimipramine.
Nortriptyline.
Protriptyline.

Maprotiline and amoxapine are “tetracyclic” antidepressants (so they are not members of the tricyclic family). However, their pharmacology is so similar to that of the TCAs.

71
Q

What are maprotiline and desipramine?

A

Relatively selective inhibitors of norepinephrine reuptake.

72
Q

What are clomipramine and imipramine?

A

Tricyclic antidepressants that have a relatively very little affinity for norepinephrine transporter but potently bind serotonin transporter.

73
Q

What are the therapeutic actions of TCAs?

A

They elevate mood, improve mental alertness, increase physical activity, and reduce morbid preoccupation in 50 to 70 percent of individuals with major depression.

They do not commonly produce CNS stimulation or mood elevation in normal individuals.

They have a rare physical and psychological dependence rate.

They treat moderate to severe depression.

Panic disorder.

74
Q

Which tricyclic antidepressant is used to control bed-wetting in children?

A

Imipramine due to its antimuscarinic effect on bladder muscles.

75
Q

Which tricyclic antidepressant is used to treat migraine headaches and chronic pain syndromes?

A

Amitriptyline.

76
Q

Which tricyclic antidepressant is used to treat insomnia?

A

Doxepin.

77
Q

Which tricyclic antidepressant is used to manage obsessive compulsive disorder?

A

Clomipramine.

78
Q

What are the adverse effects of TCAs?

A
  1. Blockade of muscarinic receptors:
    - Blurred vision, xerostomia, urinary retention, sinus tachycardia, constipation, and aggravation of narrow-angle glaucoma.
  2. Blockade of alpha-adrenergic receptors:
    - Orthostatic hypotension, dizziness, and reflex tachycardia.
  3. Blockade of histamine receptors:
    - Sedation.
  4. Weight gain.
  5. Sexual dysfunction.
79
Q

Why should bipolar patients avoid taking tricyclic antidepressants at all costs, even during their depressed state?

A

They cause a switch to maniac behavior.

80
Q

Why should epileptics avoid taking tricyclic antidepressants at all costs?

A

At therapeutic doses, tricyclic antidepressants lower the seizure threshold and at toxic doses can cause life-threatening seizures (especially maprotiline).

81
Q

Why should Parkinsonism patients avoid taking amoxapine?

A

It can induce Parkinsonian syndrome due to its dopamine receptor antagonist properties.

82
Q

Which medical conditions are exacerbated by tricyclic antidepressant drug use?

A

Unstable angina, benign prostatic hyperplasia, epilepsy, and preexisting arrhythmias.

83
Q

When are MAO inhibitors used to treat depression?

A

When everything else fails. Their risk for drug-drug and drug-food interactions limits their use.

84
Q

Which MAO inhibitors are used to treat depression?

A

Phenelzine.
Tranylcypromine.
Carboxamide.
Selegiline.

85
Q

What is the function of monoamine oxidase (MAO)?

A

It functions as a safety valve to oxidatively deaminate and inactive any excess neurotransmitter molecules (norepinephrine, dopamine, and serotonin) that may leak out of synaptic vesicles when the neuron is at rest.

86
Q

How are MAO inhibitors classified?

A

By their specificity for MAO-A or MAO-B and whether their effects are reversible or irreversible.

87
Q

What are three common examples of irreversible, nonselective MAO inhibitors?

A

Phenelzine, tranylcypromine, and isocarboxazid.

88
Q

What is a common example of a reversible and selective MAO-A inhibitor?

A

Moclobemide.

89
Q

What is an example of an irreversible MAO-B inhibitor?

A

Selegiline.
However, at high doses, it becomes a nonselective MAO inhibitor similar to other agents.

90
Q

What is the mechanism of action of MAO inhibitors?

A

They form stable complexes with the MAO enzyme, causing irreversible inactivation of MAO, resulting in an excess of norepinephrine, serotonin and dopamine into the synaptic space.

91
Q

What happens when liver and gut MAO enzyme is inhibited?

A

MAO in the liver and gut catalyzes oxidative deamination of drugs and potentially toxic substances, such as tyramine, which is found in certain foods, so it increases the incidence of drug-drug and drug-food interactions.

92
Q

Why does the antidepressant effect of MAO inhibitors persist for several weeks?

A

Enzyme regeneration, when irreversibly inactivated, varies, but it usually occurs several weeks after termination of the drug. Thus, when switching antidepressant agents, a minimum of 2 weeks delay must be allowed after termination of MAO inhibitors therapy and the initiation of another antidepressant from any other class.

93
Q

Which MAO inhibitors are associated with agitation and insomnia?

A

Selegiline and tranylcypromine have amphetamine-like stimulant effect that produces agitation and causes insomnia.

94
Q

When are MAO inhibitors used? (Therapeutic Uses)

A

MAO inhibitors are used to treat depression in patients who are unresponsive or allergic to TCAs or who experience strong anxiety.

Phobic states.

Atypical depression (labile mood, rejection sensitivity, and appetite disorders).

95
Q

What are the adverse effects of MAO inhibitors?

A

Tyramine effect (hypertensive crisis).

Tyramine is found in aged cheeses, meats, chicken liver, pickled or smoked fish, and red wines.

Orthostatic hypotension, weight gain, edema, and sexual dysfunction.

Drowsiness, blurred vision, dry mouth, dysuria, and constipation.

Combination of MAOIs and bupropion can produce seizures.

Tranylcypromine can cause hepatic dysfunction.

96
Q

Which two drugs are useful for managing tyramine-induced hypertension?

A

Phentolamine and prazosin.

97
Q

What are the drug-drug interactions associated with MAO inhibitors?

A

Serious hypertension can occur with concomitant administration of OTC cough and cold medications containing sympathomimetic amines (pseudoephedrine and phenylpropanolamine).

These can also be considered contraindications!

98
Q

What is bipolar affective disorder?

A

It is a maniac-depressive disorder that occurs in 1-3% of the adult population.

It may begin in childhood, but most cases are first diagnosed in the third and fourth decades of life.

The key symptoms of bipolar disorder in the maniac phase are:
- Excitement.
- Hyperactivity.
- Impulsivity.
- Disinhibition.
- Aggression.
- Diminished need for sleep.
- Psychotic symptoms in some patients.
- Cognitive impairment.

Depression in bipolar patients is phenomenologically similar to that of major depression, with the key features being:
- Depressed mood.
- Diurnal variation.
- Sleep disturbance.
- Anxiety.
- Sometimes psychotic symptoms.

99
Q

What is Lithium?

A

Lithium is not an antidepressant, nor it is a suppressant, nor it is euphoric or stimulating… It is a drug that helps stabilize the mood of bipolar disorder patients. (i.e., it prevents the occurrence of mania and depression in bipolar patients).

It is used for acute-phase illness as well as for prevention of recurrent maniac and depressive episodes.

It is used prophylactically for treating manic-depressive patients and in the treatment of maniac episodes (i.e., it is considered a mood stabilizer).

How it works is unknown, and its therapeutic index is low.

100
Q

What are the adverse effects of lithium?

A

Induces diabetes insipidus (dry mouth, polydipsia, polyuria, polyphagia). Can be treated by amiloride.

GI distress, fine hand tremor, dermatologic reactions, and sedation.

Adverse effects due to higher plasma levels may include ataxia, slurred speech, coarse tremors, confusion, and convulsions.

Avoid concurrent use with diuretics, as the loss of sodium increases lithium levels.

Thyroid function may be decreased, monitoring is needed.

101
Q

What drugs (other than lithium) are used to treat bipolar disorder?

A

Carbamazepine.
Valproic acid.
Lamotrigine.
Chlorpromazine.
Haloperidol.
Atypical antipsychotics (risperidone, olanzapine, ziprasidone, aripiprazole, asenapine, and quetiapine)
Benzodiazepines (used as adjunctive treatments for acute stabilization of patients with mania).

Pharmacology MidTerm (8 decks)

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