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OS6- Psychiatry > Pharmocology and Therapeutics of Antidepressant Agents > Flashcards

Pharmocology and Therapeutics of Antidepressant Agents Flashcards

1
Q

Monoamine Hypothesis

A

–Depression: due to deficiency in NE and/or 5-HT in the CNS

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2
Q

■Neurotransmitter Receptor Hypothesis

A

–Changes in the relative density or sensitivity of certain receptor processes (α2 and β adrenergic receptors)

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3
Q

Genetic Component of affective disorders

A

–related to the circadian abnormalities in depression

–mutations in clock genes have been discovered that accelerate or delay circadian cycles

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4
Q

Glutamate Hypothesis of Depression

A

■Glutamate

–involved in excitatory transmission that plays a central role in mediating the complex emotional/cognitive changes associated with depression

–also likely represents the actual final common pathway of therapeutic treatments for depression and other mood/anxiety disorders.

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5
Q

N-methyl-D-aspartate receptor (NMDA-R: glutamate-gated cation channels) antagonists possess antidepressant-like action example

A

–Esketamine

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6
Q

Neuroendocrine Factors in Depression

A

Dysregulation of the HPA axis

•Hypersecretion of cortisol [adrenal gland]

  1. Blunted TSH response to TRH
  2. Blunted GH response to hypoglycemia

■Normally, low blood sugar stimulates the hypothalamus to produce and release hormones that increase growth hormone synthesis and release in the pituitary gland

  1. Altered 24hr rhythm of prolactin secretion

■elevation of PRL levels during the evening, several hours before sleep; morning PRL levels were slightly higher than normal

  1. Sex steroids

■Estrogen deficiency states and severe testosterone deficiency-associated with depressive symptoms

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7
Q

Cardio drugs that cause depression

A

Clonidine

Guanethidine

Metyldopa

Reserpine

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8
Q

Anticonvulsant drugs that cause depression

A

Phenobarbital

Topiramate

Vigabatrin

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9
Q

Hormonal agents that cause depression

A

Corticosteroids

Tamoxifen

GnRH agonists

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10
Q

Immunologic agents that cause depression

A

Interferon-a

Interferon-B

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11
Q

Retinoic acid derivatives that cause depression

A

Isoretinoin

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12
Q

. Tricyclic Antidepressants

A

Tertiary Amines (5-HT)

    • Imipramine (Prototype)
    • Amitriptyline

Secondary Amines (NE)

    • Desipramine (Prototype)
    • Nortriptyline
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13
Q

Non-selective Monoamine Oxidase Inhibitors

A
    • Phenelzine
    • Isocarboxazid
    • Tranylcypromine
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14
Q

Selective Monoamine Oxidase Inhibitors

A

MAO-A: Breaks down 5-HT, DA and NE

•Crorgyline

MAO-B: Breaks down DA:

• Selegiline and Rasagiline

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15
Q

First Generation antidepressants

A

■TCAs and MAOIs

■Limited efficacy:

–20-30% of patients remain unresponsive

■Delayed onset of therapeutic effects:

–up to 6 weeks

■Troublesome side effects

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16
Q

Second generation antidepressants

A
  • Considered “atypical
  • Amoxapine (D2 Blocker)
  • Bupropion

■(NE & DA re-uptake inhibitor)

  • Mirtazepine

■antagonizes presynaptic α2 presynaptic autoreceptors

  • Maprotiline
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17
Q

Third generation antidepressants

A

SNRIs [Serotonin & Norepinephrine Re-uptake Inhibitors]

  • Venlafaxin
  • Desvenlafaxin
  • Duloxetine

5- HT2 Antagonists

  • Trazodone
  • Nefazodone

Rebexetine [NE Selective Re-uptake Inhibitor]

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18
Q

Tricyclic Antidepressants (TCAs) mechanism of action

A

■Inhibit the extra-neuronal re-uptake mechanisms for NE and 5-HT

■Block NE and 5-HT pre-synaptic transporters

■Increases NE and 5-HT in synapse

Also:

–α-1 and α-2 adrenergic

–5-HT2

–Muscarinic cholinergic

–H1

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19
Q

Tricyclic Antidepressants (TCAs) absorption

A
  • Good after oral administration
  • Lipophilic Drug
  • Highly bound to plasma proteins and tissue
  • Large volume of distribution
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20
Q

Tricyclic Antidepressants (TCAs) metabolism

A
  • substrates of the CYP2D6 system
  • oxidized in the liver and conjugated with glucuoronic acid
  • polar metabolites are excreted in urine
  • less than 5% excreted as unchanged compounds
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21
Q

Affect of tricyclic Antidepressants (TCAs) on sleep

A
  • Increases stage 4 sleep
  • Increases latency and decreases the total time spent in REM sleep
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22
Q

TCA withdrawal

A

malaise, chills, muscle aching

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23
Q

TCA CNS side effects

A
  • Confusion (antimuscarinic)
  • Insomnia, restlessness, feelings of fatigue and weakness
  • Tolerance develops

Sedation, weakness & fatigue

  • Increased risk of tonic-clonic seizures
  • Increase in ‘switch process’
  • transition from depression to hypomania or mania

•Aggravation of psychosis

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24
Q

Desipramine side effects

A

increased risk of death in patients with a family history of sudden cardiac death, conduction disturbances, and dysrhythmias

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25
Q

. Tricyclic Antidepressants side effects: Image

A
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26
Q

TCA overdose treatment

A

■Gastric lavage, early in treatment

–Administration of activated charcoal

■Cardiotoxicity: Phenytoin

■Seizures: Diazepam

■Anticholinergic Effects: Physostigmine

■Hypertension: Short-acting α- adrenergic blockers

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27
Q

TCAs have additive CNS depression with

A

■ethanol, barbiturates, benzodiazipines, & opiods

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28
Q

TCAs reversal antihypertensive action of __________.

A

–guanethidine by blocking transport into sympathetic nerve endings

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29
Q

TCAs Increase concentration of _________ because they have a shared metabolic pathway

A

phenytoin

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30
Q

TCAs Potentiate the pressor effects of __________.

A

adrenaline

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31
Q

What drugs does TCA interact with?

A

■Cimethidine - Increases levels of TCAs

■Clonidine - Produces a hypertensive crisis when combined with TCAs

■Oral contraceptives - Increase TCA levels

■Salicylates - Increases TCA levels (Decrease binding of TCAs

■Quinidine - Increase in arrhythmias

■L-dopa - Increases TCA levels

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32
Q

Clinical applications of TCAs

A
  • Major depression unresponsive to other antidepressant drugs
  • Chronic pain disorders
  • Neuropathic conditions: diabetic neuropathy
  • Insomnia
  • Obsessive-compulsive disorder
  • (clomipramine: selective for SERT transporter)
  • Enuresis (imipramine)
  • Migranie (Amitriptyline)
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33
Q

•MAOIs mechanism of action

A
  • bind to and inactive the active site of the enzyme inside the pre-synaptic terminal
  • block oxidative deamination of NE, DA, and 5-HT
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34
Q

Monoamine Oxidase Inhibitors clinical uses

A

■Atypical Depression

■OCD

■Panic attacks

■Anxiety

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35
Q

MAO Inhibitor side effects

A

■Excessive cardiovascular stimulation

  • Hepatotoxicity
  • Orthostatic hypotension
  • Weight gain [over-eating of carbohydrates]
  • Fluid retention in lower extremities
  • Impaired sexual function

•Anorgasmia (highest of all antidepressant drugs)

  • Irreversible, non-selective drugs
  • Amphetamine-like properties →
  • Activation and restlessness
  • Sleep disturbances:
    • Insomnia, reduced sleep time
    • Decrease in REM sleep with REM-rebound following abrupt withdrawal
  • Confusion
  • Sedation (phenelzine)
36
Q

MAO Inhibitor acute overdose

A

–Agitation, hyperthermia, insomnia and seizures

37
Q

MAOI withdrawal symptoms

A

■With sudden discontinuation

–Delirium-like presentation with psychosis, excitement and confusion

38
Q

MAOI interaction with tyramine

A

  • Increase in blood pressure
  • Hyperthermia, tachycardia, arrhythmias, agitation
  • Headache, vomiting, chest pain, muscle twitching

Treat with: α-adrenergic blockers, i.v. [Phentolamine]

39
Q

Serotonin syndrome

A

Triad of Symptoms (mild to lethal)

•Cognitive Effects:

  • Delirium, agitation, and coma

•Autonomic Effects:

  • Hypertension, tachycardia, hyperthermia
  • Diaphoresis, dilated pupils
  • Hyperactive bowel sound, diarrhea

•Somatic Effects:

  • Hyper-reflexia, tremor, myoclonus, seizures
40
Q

Management of serotonin syndrome

A
  • Removal of the precipitating drugs
  • Supportive Care:
  • Mainstay of Therapy
    • administration of intravenous fluids and correction of vital signs
  • Control of agitation
    • Sedation with benzodiazepines
  • Control of autonomic instability and hyperthermia
    • Administration of 5-HT2A antagonists
      • cyproheptadine
41
Q

Benefits of Second gen antidepressants

A
  • Modify Transmitter Function More Selectively
  • Target Specific Symptoms
  • Increased Onset of Action
  • Reduced Side Effects
  • Better than Placebo
  • 20-40% Effective in Unipolar Depression
  • Safer if Taken in Overdose
42
Q

Bupropion side effects

A

–Seizures

–Increase in suicidal ideation

–Less anti-cholinergic activity

–Low cardiotoxicity

–Insomnia. Agitation

–Nausea, Anxiety, Weight loss

43
Q

Mirtazapine Clinical Indications:

A

•Beneficial in patients who tolerate sedative effects and do not respond well to SSRIs and cannot tolerate sexual or other adverse effects of other antidepressants

44
Q

Mirtazapine mechanism of action

A

■Alpha 2 blocker

–Inhibition of alpha 2 autoreceptor leads to CA release (NE and 5-HT)

■Antagonizes 5-HT 2 and 5-HT3 receptors

45
Q

Mirtazapine side effects

A
  • Greater sedative effects (strong H1 blockade) than other 2nd and 3rd generations drugs
  • Likely to cause weight gain (useful in elderly)
  • Minimal inhibitory effects on CYP450 metabolizing enzymes
  • Reversible white blood cell disorders (neutropenia and agranulocytosis)
46
Q

Bupropion metabolized in the liver by ______ to ________.

A

CYP2B6; hydroxybupropion

47
Q

Bupropion mechanism of action

A

■accumulates & contribute to antidepressant activity by blocking NET

  • Weak dopamine and NE re-uptake inhibition
  • Enhances extracellular dopamine levels in nucleus accumbens
48
Q

Bupropion side effects

A
  • Headache
  • Dry Mouth
  • De novo Seizures [especially in high doses]
  • More prominent in patients with eating disorders
  • Suicidal thoughts or other mood changes
  • Tends to have a mild appetite-suppressing effect
  • Mild weight loss
  • Causes less weight gain than SSRIs
49
Q

Benefits of buproprion

A

•Unique among antidepressants

  • It does not cause major sexual dysfunction

•No significant cytochrome p450 enzyme interaction

  • can be safely co-administered with most medications with the exception of MAOIs

•No significant withdrawal symptoms upon discontinuation

50
Q

Bupropion contraindications

A

■Patients with seizures disorders, anorexia nervosa, or bulimia

51
Q

Buproprion drug interactions

A

■Carbamazepine reduces blood levels of bupropion

■Some medications with p450 inhibiting properties could increase the blood level of bupropion, raising the risk of seizure

■Interacts with MAOIs, DA precursors and agonists

52
Q

•Six primary SSRIs

A
  • Fluoxetine (Prozac)
  • Sertraline (Zolof)
  • Paroxetine (Paxil)
  • Fluvoxamine (Luvox)
  • Citalopram (Celexa)
  • Escitalopram (Lexapro)
53
Q

SSRIs are all _____ metabolized

A

Hepatically

54
Q

SSRIs produce changes in sleep architecture. How?

A

•decreased REM latency and decreased total REM sleep

55
Q

•Antidepressant effects of SSRIs often do not appear for __________ after initiation of treatment

A

3 to 6 weeks

56
Q

SSRIs advantages

A

•Broad -spectrum efficacy :

  • Depression
  • Panic disorder
  • OCD
  • Social anxiety disorder
  • Post-traumatic stress disorder

•Useful in treating the elderly with anxiety or OCD

57
Q

SSRIs disadvantages

A
  • Reduced efficacy in depressed patients [55 -70%]
  • Pharmacokinetic interaction [inhibition of cytochrome P450 liver enzymes]
  • SIADH
  • Serotonin Syndrome: Due to dangerous high levels of brain 5-HT [May be FATAL]
  • Sexual effects: (stimulation of pontine medullary bodies in spinal cord)
  • delayed or impaired orgasm in women
  • inhibited ejaculation in men

•Changes in sleep architecture

  • decreased REM latency and decreased total REM sleep
58
Q

SSRIs use in preganancy

A
  • Teratogenicity: When taken during first trimester
  • Increase in cleft palate, and several types of heart defects
  • Paroxetine (Category D)
  • Possible postnatal complications: pulmonary hypertension
59
Q

•Discontinuation Effects of SSRIs

A

–Headache, nausea, dizziness,

–May include a flu-like reaction and strange sensations of vision or touch

60
Q

Side Effects of SSRIs

A

■Anxiety

■Insomnia

■GI Distress

■Sexual Dysfunction

■Syndrome of Inappropriate Antidiuretic Hormones (SIADH)

Most dangerous :

■Suicidal ideation in children and young adults [FDA Warning]

■Serotonin Syndrome

61
Q

Citalopram side effects

A

–Prolonged QT interval

■causes arrhythmias such as torsades de pointes (TdP), a potentially life-threatening ventricular arrhythmia.

62
Q

Paroxetine side effects

A

–FDA pregnancy Cat D: congenital Heart Defects

■Cardiac septal defects with 1st trimester exposure

–Has a mild affinity for muscarinic receptors and can cause more anticholinergic side effects than the other SSRIs (although much less than the tricyclic antidepressants)

63
Q

Fluoxetine, Fluvoxamine, Paroxretine side effects

A

–significant inhibition of Cytochrome P450 enzymes

■SSRIs reduce the rate of elimination of benzodiazepines and cause them to build up in the body

■Fluoxetine: Violence, suicidal behavior

64
Q

Which SSRI has the lowest risk of drug interactions?

A

Sertraline

65
Q

SSRIs compete with other drugs for metabolism by _________ or ______ isoenzymes

A

CYP2D6; CYP3A4

66
Q

Side effects of SSRIs Interaction with Dextromethorphan

A

Drowsiness and Dizziness

Nausea and Vomiting

Hyperactivity

Blurred Vision

Hallucinations (Visual and Auditory)

67
Q

SNRIs

A

Venlafaxine, Desvenlafaxine, Duloxetine (Cymbalta)

68
Q

SNRIs mechanism of action

A

•Inhibits the presynaptic re-uptake of 5-HT and NE

69
Q

Venlafaxine extensively metabolized in liver via _____ to _________.

A

CPY2D6; desvenlafaxine

70
Q

Which antidepressant has the lowest protein binding of all antidepressants?

A

Venlafaxine

71
Q

Clinical use for SNRIs

A
  • Preferred over TCAs for Major Depressive Disorder and
  • Pain Syndromes
  • GAD
  • Stress incontinence in women
72
Q

Trazodone mechanism of action

A
  • Direct antagonist effect at 5-HT2A postsynaptic receptor
  • Inhibits pre-synaptic α1-adrenergic receptor
  • Weak inhibitor of SERT
  • H1 receptor antagonist [sedation]
73
Q

Trazadone side effects

A
  • CNS: Dizziness, drowsiness, agitation, sedation
  • ANS: Orthostatic hypotension and priapisms

GIT disturbances

74
Q

Trazadone clinical use

A
  • Insomnia (low doses)
  • Not first line treatment for MDD
75
Q

Reboxetine mechanism of action

A

•selective NE reuptake inhibitor

76
Q

Reboxetine clinical use

A
  • Depression
  • Panic Disorder
77
Q

What SSRIs treat premenstrual Dysphoric Disorder?

A

• fluoxetine & sertraline

78
Q

■In the first week of March 2019, the FDA approved a drug for treatment-resistant severe depression called ____________.

A

Esketamine [Spravato]

79
Q

March 19, 2019, FDA approved Brexanalone [Zulresso], an analog of the endogenous human hormone allopregnanolone, and the first drug specifically approved/designed to treat _________

A

post partum depression

80
Q

Esketamine [Spravato] and Brexanalone [Zulresso] work on ________ receptors.

A

GABA

81
Q

Brexanalone side effects

A

headaches, drowsiness, and dizziness

■Sedation and sleep apnea

82
Q

Esketamine side effects

A

sedation and dissociation

Potential for abuse and misuse

■Increased risk of suicidal thoughts and behaviors in pediatric and young adult patients taking antidepressants.

83
Q

Esketamine contraindications

A

■Aneurysmal vascular disease

–(including thoracic and abdominal aorta, intracranial and peripheral arterial vessels), or

–arteriovenous malformation

■History of intracerebral hemorrhage

■Hypersensitivity to esketamine, ketamine, or any of the excipients

84
Q

Electroconvulsive Therapy clinical uses

A
  • Severely depressed or suicidal patients
  • Treatment resistant bipolar disorder
  • Acute but not chronic Schizophrenia
  • Acute Manic Episodes
85
Q

Electroconvulsive Therapy side effects

A
  • Cognitive impairment, confusion and memory loss, stroke
  • Nausea, vomiting, headache, muscle ache, jaw pain
86
Q

Electroconvulsive Therapy drug interactions

A

•Lithium and ECT: Severs cognitive impairment

ECT and antipsychotic drugs: Increased effectiveness

87
Q

Disadvantages of TMS

A

–may cause seizures

OS6- Psychiatry (27 decks)

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