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Pharmacodynamics of
AntidepressantsJose de Leon, MD
(11-13-15)http://www.ncbi.nlm.nih.gov/pubmed/25196459
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Learning ObjectivesAfter completing this presentation, the participant should
be able to:
1) Appreciate the relevance of pharmacodynamics for
antidepressant efficacy.
2) Appreciate the relevance of pharmacodynamics for
antidepressant safety.
3) Summarize frequent adverse drug reactions (ADRs)
including a) sleepiness/ insomnia, b) weight changes,
c) withdrawal symptoms, d) sexual ADRs, and e)
gastro-intestinal ADRs.
4) Remember that, on rare occasions, antidepressants can
kill your patients by contributing to arrhythmias,
serotonin syndrome or hemorrhages.
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WarningThis is an extraordinarily long presentation:
1) You may need to read it more than once until you have
become familiar with key aspects. More importantly,
you need to practice every day and review the pharma-
dynamics of drugs when any of your patients are
taking antidepressants in the context of polypharmacy.
2) Our understanding of brain pharmacodynamics is
limited; therefore, there are many disagreements in the
literature. In the process of summarizing, Dr. de Leon
had to made arbitrary decisions with which other
authors may not agree.
3) As Dr. de Leon is not an expert in this area, for the
“Do Not Forget” Section, he selected a recent review
on frequent ADRs in primary care.
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Abbreviations■ ADH: antidiuretic hormone
■ ADHD: attention deficit-hyperactivity disorder
■ ADR: adverse drug reaction
■ DDI: drug-drug interaction
■ GI: gastro-intestinal
■ HERG: ether-a-go-go-related gene
■ OCD: obsessive-compulsive disorder
■ SIADH: syndrome of inappropriate ADH secretion
Neurotransmission
■ 5HT: serotonin
■ α: alpha adrenergic
■ H: histamine
■ M: muscarinic
■ MT: melatonin
■ norepinephrine=noradrenaline. Not abbreviated.
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Abbreviations for Antidepressants
■ Antidepressants that are not included:□ MAOIs: monoamine oxidase inhibitors □ nefazadone
■ This presentation focuses on:□ TCAs: tricyclic antidepressants, and□ newer compounds:
● SNRIs: serotonin-norepinephrine inhibitors
● SSRIs: selective serotonin reuptake inhibitors
● Others: the rest
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Lecture Content
1. Efficacy 2. Safety3. Pharmacokinetics:
Facilitator of Pharmacodynamics
4. “Do Not Forget” Section
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1. Efficacy 1.1. Depression 1.2. OCD1.3. Anxiety1.4. Pain1.5. Weight Loss1.6. Smoking Cessation1.7. ADHD1.8. Insomnia1.9. Cataplexy1.10. Some Types of Urinary Incontinence1.11. Menopausal Vasomotor Symptoms
Lecture Content on Efficacy
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2.1. Brain 2.2. Periphery (with/without brain)
Lecture Content on Safety
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2.1. Brain 2.1.1. Weight Gain
2.1.2. ↓ Seizure Threshold
2.1.3. ↓ Dopaminergic Activity
2.1.4. Psychotic Exacerbation
2.1.5. Insomnia
2.1.6. Sedation
2.1.7. Memory Impairment
Lecture Content on Safety: Brain Mechanisms
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2.2.1. Nausea and Vomiting
2.2.2. Tachycardia and/or Hypertension
2.2.3. Orthostatic Hypotension
2.2.4. Diarrhea
2.2.5. Sexual ADRs
2.2.6. Hyperlipidemia
2.2.7. Anticholinergic Symptoms
2.2.8. Urinary Symptoms
2.2.9. Mydriasis
2.2.10. Hyperhydrosis
2.2.11. Osteoporosis
2.2.12. Discontinuation/Withdrawal Syndrome
2.2.13. Risk for Bleeding
2.2.14. Serotonin Syndrome
2.2.15. Arrhythmias
2.2.16. Neutropenia
2.2.17. Hyponatremia
2.2.18. Liver Injury
Lecture Content on Safety: Periphery Mechanisms
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1. Pharmacodynamics
of Antidepressant
Efficacy
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1. Pharmacodynamics of Antidepressant Efficacy
1.1. Depression
1.2. OCD
1.3. Anxiety
1.4. Pain
1.5. Weight Loss
1.6. Smoking Cessation
1.7. ADHD
1.8. Insomnia
1.9. Cataplexy
1.10. Some Types of Urinary Incontinence
1.11. Menopausal Vasomotor Symptoms
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1.1. Depression
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1.1. Depression
■ Textbooks
□ usually report that the majority of antidepressants act by
inhibiting the reuptake of transporters,
□ but they also usually acknowledge that this is not a
definitively proven theory, since the chronology of reuptake
inhibition does not match the chronology of antidepressant
response.
■ Even less agreement is found concerning the mechanism
of action of:
□ mirtazapine, or
□ trazadone.
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1.1. Mechanism of Action: Transporters
■ Inhibitors of noradrenaline and serotonin transporters:
□ Desvenlafaxine, duloxetine and venlafaxine
□ Levomilnacipran and milnacipran (not in the USA)
□ TCAs
■ Selective inhibitors of the serotonin transporter: SSRIs
■ Selective inhibitors of the serotonin transporter and
serotonin receptor antagonists
□ Vilazodone: partial agonism of the 5-HT1A receptor.
□ Vortioxetine: ● antagonist: 5-HT3A and 5-HT7
● partial agonist: 5-HT1B
● agonist: 5-HT1A
■ Inhibitor of noradrenaline and dopamine transporters:
□ Bupropion
■ Selective inhibitor of noradrenaline transporter: Reboxetine
(not in the USA)
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1.1. Mechanism of Action: Others
■ Trazadone: □ 5-HT2 antagonist, and
□ m-CPP (its major metabolite): 5-HT2C agonist
■ Mirtazapine: □ α2 adrenergic receptor antagonist and/or
□ 5-HT2A and 5-HT2C antagonist
■ Agomelatine (not in the USA):
□ Melatonergic analogue (MT1/MT2 agonist) and
□ 5-HT2C antagonist
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1.2. OCD
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1.2. OCD■ Inhibition of the serotonin transporter:
□ SSRIs: first line
Approved in USA: ● fluoxetine
● fluvoxamine
● paroxetine
● sertraline
□ Clomipramine
■ SNRIs (off-label):
□ Desvenlafaxine
□ Duloxetine
□ Venlafaxine
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1.3. Anxiety
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1.3. Anxiety
■ It is usually assumed the mechanism is
the same as for depression.
■ Specificity for specific disorders
is doubtful, but only some drugs have
been studied for approval.
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1.3.1. Generalized Anxiety Disorder
■ Approved in the USA:
□ Duloxetine
□ Escitalopram
□ Paroxetine
□ Venlafaxine
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1.3.2. Social Anxiety
■ Approved in the USA:
□ Paroxetine
□ Sertraline
□ Venlafaxine
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1.3.3. Panic Disorder
■ Approved in the USA:
□ Paroxetine
□ Sertraline
□ Venlafaxine
■ TCAs:effective but off-label
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1.3.3. Panic Disorder
■ Second-generation antidepressant meta-analysis:
http://www.ncbi.nlm.nih.gov/pubmed/23111544
□ superior to placebo for panic symptoms:
citalopram>sertraline>paroxetine>fluoxetine>venlafaxine
□ superior to placebo for overall anxiety symptoms:
paroxetine>fluoxetine>fluvoxamine>citalopram>venlafaxine
>mirtazapine
□ lower drop-outs than placebo:
>venlafaxine>fluoxetine>sertraline>paroxetine>citalopram>
mirtazapine
□ not different from placebo in drop-outs:
fluvoxamine and reboxetine
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1.4. Pain
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1.4. Pain
■ Inhibition of the noradrenalin transporter:
appears more important.
■ TCAs: frequently used (off-label)
■ Approved in the USA for fibromyalgia:
□ Duloxetine
□ Milnacipran
■ Duloxetine is also approved in the USA for:
□ Diabetic peripheral neuropathy
□ Chronic musculoskeletal pain
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1.5. Migraine
Prophylaxis
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1.5. Migraine Prophylaxis
■ Mechanism of action: unknown.
■ Off-label in the USA:
□ TCAs: amitriptyline (better studied)
□ Venlafaxine: less data
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1.6. Weight Loss
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1.6. Weight Loss
■ Bupropion:
inhibition of dopamine transporter
□ Off-label in the USA
□ In combination with naltrexone, it is
approved in the USA for obesity.
■ Fluoxetine: some weight loss,
according to meta-analysis:
limited to the acute phase of treatment.http://www.ncbi.nlm.nih.gov/pubmed/21062615
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1.7. Smoking Cessation
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1.7. Smoking Cessation
■ Bupropion:
inhibition of dopamine transporter
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1.8. ADHD
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1.8. ADHD
■ Bupropion:
□ Inhibition of noradrenergic and
dopamine transporters
□ Off-label in the USA
□ Superior to placebo in adults
http://www.ncbi.nlm.nih.gov/pubmed/22176279
■ Other antidepressants: very limited data
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1.9. Insomnia
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1.9. Insomnia
■ Antagonism of brain H1 receptors
(daily sedation can be a problem)
All drugs are off-label in the USA:
□ Amitriptyline
□ Mirtazapine
□ Trazadone
■ Agonism of brain MT2 receptors
□ Agomelatine (not approved in the USA)
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1.10. Cataplexy
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1.10. Cataplexy
■ Suppression of REM sleep:
Off-label in the USA:
□ TCAs
□ Venlafaxine
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1.11. Some Types of
Urinary Incontinence
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1.11. Some Types of Urinary Incontinence
■ Noradrenergic mechanisms are important.
■ Stress urinary incontinence:
□ Duloxetine: off-label in the USA
■ Nocturnal enuresis in children:
□ Imipramine
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1.12. Menopausal
Vasomotor Symptoms
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1.12. Menopausal Vasomotor Symptoms
■ Including:
□ Hot flashes
□ Night sweats
■ Off-label in the USA
□ SNRIs
□ SSRIs
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2. Pharmacodynamics
of Antidepressant
Safety
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2. Pharmacodynamics of Antidepressant Safety
2.1. Brain
2.2. Periphery (with/without brain)
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2.1. Brain
Pharmacodynamics
of Antidepressant
Safety
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2.1. Brain Pharmacodynamics of Antidepressant Safety
2.1.1. Weight Gain
2.1.2. ↓ Seizure Threshold
2.1.3. ↓ Dopaminergic activity
2.1.4. Psychotic Exacerbation
2.1.5. Insomnia
2.1.6. Sedation
2.1.7. Memory Impairment
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2.1.1. Weight Gain
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2.1.1. Weight Gain■ Mechanism: ↑ appetite
□ TCAs: H1 & M antagonistsAmitriptyline (worst)
□ Mirtazapine: H1 & 5HT2C antagonist□ Paroxetine: H1antagonist
■ Agomelatine: 5HT2C antagonist□ Not enough long-term data □ Case reports: associated with weight
gain
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2.1.2.
↓ Seizure Threshold
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2.1.2. ↓ Seizure Threshold
■ Unknown mechanism
■ Versus placebo: http://www.ncbi.nlm.nih.gov/pubmed/17223086
□ Worse:● Bupropion
● TCAs
□ Better: other newer compounds
■ Fluoxetine:
□ Anti-seizure activity: animal
models
□ Seizures: according to case reports
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2.1.3.
↓ Dopaminergic Activity
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2.1.3. ↓ Dopaminergic Activity
■ Mechanism not well understood.
■ ↓ Dopaminergic activity manifests as:
□ Akathisia (rare): SSRIs
□ Other extrapyramidal symptoms
(rare): all antidepressants
□ Hyperprolactinemia (rare):
probably all antidepressants
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2.1.4. Psychotic
Exacerbations
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2.1.4. Psychotic Exacerbations
■ Rare and manifest as:
□ New psychotic episodes
□ Psychotic exacerbations
■ Described in connection with:
□ Bupropion: inhibition of dopamine
transporter
□ TCAs: unknown mechanism
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2.1.5. Insomnia
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2.1.5. Insomnia
■ In all new antidepressants
except agomelatine.
■ Mechanisms:
□ Stimulation 5HT2: SSRIs
□ Blockade noradrenaline transporter:
● Bupropion
● Reboxetine
● SNRIs
□ ↑ Noradrenergic activity: high doses
of mirtazapine.
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2.1.6. Sedation
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2.1.6. Sedation
■ Antidepressants used to treat insomnia
can cause sedation.
■ Mechanism:
□ H1 antagonism:
● TCAs
● Mirtazapine
● Trazadone
□ MT2: agonism
● Agomelatine (not in the USA)
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2.1.7. Memory
Impairment
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2.1.7. Memory Impairment
■ Mechanism: blockade of brain Mreceptors
■ Blockade of M1 and M2 receptors has been associated with impairedlearning and memory in animal studies.
■ Potent compounds in high doses or in vulnerable patients (demented)can cause confusion/delirium.
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2.1.7. Muscarinic Blockade
■ High potency: □ Amitriptyline □ Clomipramine □ Protriptyline
■ Moderate potency: □ Doxepin□ Imipramine□ Nortriptyline □ Trimipramine
■ Low potency (relevant only in high doses):□ Amoxapine□ Desimipramine □ Maprotiline □ Mirtazapine □ Paroxetine
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2.1.7. Muscarinic Blockade: Unclear
■ Anti-muscarinic activity is seen in some studies, but not in others:
□ Citalopram□ Escitalopram □ Fluoxetine□ Sertraline □ Trazadone
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2.2. Peripheral
Pharmacodynamics
of Antidepressant
Safety
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2.2. Peripheral Pharmacodynamics of Antidepressant Safety
2.2.1. Nausea and Vomiting
2.2.2. Tachycardia and/or Hypertension
2.2.3. Orthostatic Hypotension
2.2.4. Diarrhea
2.2.5. Sexual ADRs
2.2.6. Hyperlipidemia
2.2.7. Anticholinergic Symptoms
2.2.8. Urinary Symptoms
2.2.9. Mydriasis
2.2.10. Hyperhidrosis
2.2.11. Osteoporosis
2.2.12. Discontinuation/Withdrawal Syndrome
2.2.13. Risk for Bleeding
2.2.14. Serotonin Syndrome
2.2.15. Arrhythmias
2.2.16. Neutropenia
2.2.17. Hyponatremia
2.2.18. Liver Injury
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2.2.1. Nausea and Vomiting
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2.2.1. Nausea and Vomiting
■ Mechanism: inhibition of serotonin transporter.
■ Common in newer antidepressants;most frequent cause ofdiscontinuation in the first 30 days
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2.2.1. Nausea and Vomiting
■ Probably worse: □ Desvenlafaxine □ Duloxetine □ Venlafaxine
■ Probably intermediate: □ SSRIs□ Vilazodone□ Vortioxetine
■ Probably lower risk:□ Levomilnacipran□ Milnacipran
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2.2.1. Nausea and Vomiting
■ Be aware:□ mirtazapine, and□ TCAsmay help with some nausea and have been used for “psychogenic vomiting”.
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2.2.2. Tachycardia
and/or
Hypertension
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2.2.2. Tachycardia and/or Hypertension
■ Probable mechanism:
inhibition of noradrenalin transporter
■ Rare in RCTs.TCAs are associated with hypertension inpharmacoepidemiology studies.
■ Review on hypertension: http://www.ncbi.nlm.nih.gov/pubmed/18652794
□ Venlafaxine: definitively associated□ Desvenlafaxine and milnacipran:
also associated□ Duloxetine: be cautious in hypertensive patients.
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2.2.3. Orthostatic
Hypotension
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2.2.3. Orthostatic Hypotension
■ Mechanism: blockade α1■ Tolerance is important and can be avoided
by titration.■ Definitively associated with:
□ TCAs □ Trazadone
■ Mirtazapine: □ Very low α1 affinity□ Rarely associated with syncope
■ Venlafaxine: □ No α1 affinity□ Associated with orthostatic changes
in geriatric patients
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2.2.4. Diarrhea
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2.2.4. Diarrhea
■ Mechanism: unknown
■ Definitively more frequent with:□ Sertraline
■ Others: □ Vilazodone □ Vortioxetine
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2.2.5. Sexual ADRs
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2.2.5. Sexual ADRs
■ Serotoninergic mechanisms:□ Stimulation of 5TH2 and 5TH3
□ Effect of serotonin on nitric oxide production
■ ♀: □ ↓ Libido □ Others
■ ♂: □ Erectile dysfunction □ Problems with orgasm□ ↓ Libido
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2.2.5. Sexual ADRs■ Frequent:
□ SNRIs□ SSRIs□ TCAs
■ > Placebo: □ Vilazodone□ Vortioxetine
■ Very low risk: □ Agomelatine□ Reboxetine
■ No different than placebo: □ Bupropion□ Mirtazapine
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2.2.5. Sexual ADRs: Priapism
■ It is rare but does occur with trazadone.
■ Blockade α1 (& α2) in periphery
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2.2.6. Hyperlipidemia
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2.2.6. Hyperlipidemia:
■ Indirect: Weight-mediated
■ Direct in lipid metabolism:□ Mirtazapine
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2.2.7. Anticholinergic
Symptoms
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2.2.7. Anticholinergic Symptoms
■ Antimuscarinic symptoms■ Blockade of peripheral M receptors■ Symptoms:
□ Tachycardia: M2 heart □ Constipation: M3 colon□ Dry mouth: M1 and M3 salivary
glands □ Urinary retention: M3 detrusor
muscle in bladder □ Blurred vision: M3 eye
http://www.ncbi.nlm.nih.gov/pubmed/21495973
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2.2.7. Muscarinic Blockade
■ High potency: □ Amitriptyline □ Clomipramine□ Protriptyline
■ Moderate potency: □ Doxepin □ Imipramine □ Nortriptyline □ Trimipramine
■ Low potency (relevant only in high doses):□ Amoxapine□ Desimipramine □ Maprotiline □ Mirtazapine □ Paroxetine
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2.2.7. Muscarinic Blockade: Unclear■ In some studies anti-muscarinic activity but not in others:
□ Citalopram□ Escitalopram □ Fluoxetine□ Sertraline □ Trazadone
■ Reboxetine: □ Can cause: ● Dry mouth
● Constipation● Urinary retention, on rare occasions
□ It is believed affinity for muscarinic receptors is too low. □ No anti-muscarinic metabolites have been identified.□ These symptoms may occur through noradrenergic
mechanisms.
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2.2.7. Risk for Heat Stroke
■ Potent anti-muscarinic TCAs:↓ sweating
■ Rare but potentially lethal (elderly)
■ Other risk factors:
□ Polypharmacy (additive effects):
● Antipsychotic: temperature regulation
● Topiramate/zonisamide: ↓ sweating
by inhibition of carbonic anhydrase
□ After heat exposure:
● High temperatures in summer, or
● Intense exercise
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2.2.8. Urinary Symptoms
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2.2.8. Urinary Symptoms
■ Symptoms:□ Dysuria □ Urinary retention□ Sensation of incomplete bladder
emptying■ Mechanisms: noradrenergic■ Antidepressants:
□ SNRIs□ Reboxetine
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2.2.9. Mydriasis
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2.2.9. Midryasis
■ Risk for patients with uncontrolled narrow-angle glaucoma
■ Mechanisms: inhibition of noradrenergic transporter
■ Antidepressants:□ SNRIs□ Reboxetine□ TCAs
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2.2.10. Hyperhidrosis
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2.2.10. Hyperhidrosis
■ Frequency:□ Uncommon in all antidepressants□ Common (5-14%) in SSRIs or SNRIs,
according to a recent articlehttp://www.ncbi.nlm.nih.gov/pubmed/23638448
■ Mechanisms: □ Peripheral noradrenergic □ Central serotonergic
■ Treatment:□ Terazosin: α1 blocker (be careful
with orthostatic hypotension)http://www.ncbi.nlm.nih.gov/pubmed/23638448
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2.2.11. Osteoporosis
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2.2.11. Osteoporosis
■ After many years of treatment:□ Not well-studied□ Associated with SSRIs in
pharmacoepidemiological studies
■ Mechanisms: □ Serotonergic mechanisms
in bone tissue
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2.2.12. Discontinuation/
Withdrawal Syndrome
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2.2.12. Discontinuation/Withdrawal Syndromes
2.2.12.1. Newer Compounds
2.2.12.2. TCAs: Cholinergic
Rebound
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2.2.12.1. Discontinuation
Syndrome: Newer Compounds
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2.2.12.1. Discontinuation Syndrome: Newer Compounds
■ Frequency: □ High: paroxetine and venlafaxine□ Intermediate: others □ Very rare if it exists: fluoxetine
due to long half-life■ Absent:
□ Agomelatine□ Reboxetine
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2.2.12.1. Discontinuation Syndrome: Newer Compounds
■ Mechanisms: not well-understood■ Most frequent:
□ Acute headaches□ Dizziness □ Nausea
■ Others: □ Lethargy and sleep disturbances□ Psychological symptoms:
● Anxiety● Agitation● Irritability ● Poor concentration
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2.2.12.1. Withdrawal Syndrome: Newer Compounds
■ The literature is confusing.
■ Chouinard & Chouinard proposed a new classification with diagnostic criteria. http://www.ncbi.nlm.nih.gov/pubmed/25721565
After SSRI or SNRI withdrawal:□ New withdrawal symptoms □ Rebound withdrawal□ Persistent post-withdrawal disorder
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2.2.12.2. TCAs:
Cholinergic Rebound
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2.2.12.2. Cholinergic Rebound: TCAs
■ Mechanisms: □ Sudden discontinuation of TCAs□ Cholinergic rebound due to lack of
muscarinic blockade■ Symptoms:
□ Nausea/vomiting □ Diarrhea□ Diaphoresis □ Restlessness □ Insomnia
■ They respond to anticholinergic drugs.
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2.2.13. Risk for Bleeding
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2.2.13. Risk for Bleeding; SSRIs
■ Rare but potentially lethal■ It can happen with SSRIs without
any other risk http://www.ncbi.nlm.nih.gov/pubmed/22424167
■ Typically in combination:□ Drugs with hemorrhagic risk□ Surgery□ Delivery
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2.2.13. Risk for Bleeding
■ Main mechanism: □ Serotonin depletion at platelets
due to inhibition of serotonin transporter
■ Other mechanisms: http://www.ncbi.nlm.nih.gov/pubmed/21190637
□ ↑ Gastric acid secretion: for upper gastrointestinal bleeding
□ ↓ Ischemic heart disease● ↓ Platelet reactivity● ↓ Endothelial reactivity● Inflammatory markers
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2.2.14. Serotonin Syndrome
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2.2.14. Serotonin Syndrome
■ Rare but potentially lethal.
■ Mechanism:↑ serotonin activity □ Central nervous system, and□ Periphery
■ Usually combinations ofserotonergic drugs
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2.2.14. Serotonin Syndrome
■ Main symptoms that warrant the diagnosis 1) Spontaneous clonus, 2) Inducible clonus with
agitation or diaphoresis, 3) Ocular clonus with
agitation or diaphoresis, or4) Tremor and hyperreflexia.
Hypertonia, T > 38oC (100.4oF)and ocular or inducible clonus
http://www.ncbi.nlm.nih.gov/pubmed/20433130 pdf available at PubMed.
■ Ocular clonus: slow, continuous, horizontal eye movements
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2.2.15. Arrhythmias
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2.2.15. Arrhythmias
2.2.15.1. Arrhythmias by TCAs
2.2.15.2. Torsades de Pointes
2.2.15.3. Risks for Brugada Syndrome
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2.2.15.1.
Arrhythmias
due to TCAs
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2.2.15.1. Arrhythmias due to TCAs
■ Blockade of heart sodiumrepolarizing channels
■ Manifests in:□ QRS widening □ QTc prolongation □ Ventricular arrhythmias
■ Dose-related:□ High serum concentrations □ An overdose can be lethal.
■ Narrow therapeutic window
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2.2.15.2.
Torsades de Pointes
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2.2.15.2. Torsades de Pointes
■ Blockade of heart potassiumrepolarizing channels which areencoded by the human ether-a-go-go-related gene (HERG).
■ Torsades de Pointes has beendescribed for:
□ Citalopram □ Fluoxetine □ Sertraline. http://www.ncbi.nlm.nih.gov/pubmed/25114780
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2.2.15.2. Torsades de Pointes
■ Most cases of drug-induced torsadesde pointes occur in the context ofsubstantial prolongation of the QTc interval, typically (>500 msec),but QTc alone is a relatively poorpredictor of arrhythmic risk in any individual patient.
■ Citalopram US prescribinginformation recommends against doses > 40 mg/day.
http://dailymed.nlm.nih.gov/dailymed/search.cfm?labeltype=all&query=CITALOPRAM
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2.2.15.2. Torsades de Pointes
■ The literature on clinical cases oftorsades de pointes is very complex.□ Cases frequently include
polypharmacy and DDIs with: ● A pharmacodynamic component:
multiple drugs with HERG channel inhibitory properties andsometimes
● A pharmacokinetic component: an inhibitor ↑ concentrations of one or several of the drugs
□ Other risk factors
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2.2.15.2. Torsades de Pointes
■ Other risk factors:
□ Geriatric age
□ Female gender
□ Bradycardia
□ Hypokalemia
□ Hypomagnesemia
■ Be careful when prescribing SSRIs
in patients with risk factors.
■ Be extremely careful when prescribing
SSRI-antipsychotic combinations in
patients with risk factors.
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2.2.15.3.
Brugada Syndrome
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2.2.15.3. Brugada Syndrome
■ Genetic channelopathy at heart repolarizing channels, either:□ Sodium □ Potassium □ Calcium
■ Characterized by:□ High incidence of ventricular
fibrillation and□ Specific ECG pattern:
● Pseudo right bundle branch block and
● Persistent ST elevation inV1 to V3.
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2.2.15.3. Brugada Syndrome
■ It is preferable to avoid:□ Fluoxetine □ Fluvoxamine □ Paroxetine
http://www.brugadadrugs.org/advisory-board/
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2.2.16. Neutropenia
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2.2.16. Neutropenia
■ Mechanism: unknown
■ Described with mirtazapine on rare occasions
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2.2.17. Hyponatremia
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2.2.17. Risk for Hyponatremia
■ Rare cases have been described with
all antidepressants, usually in
geriatric patients, particularly
females.
■ Mechanism:
□ SIADH and/or ↑ ADH sensitivity
□ It is not understood how
antidepressants can cause it.
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2.2.18. Liver Injury
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2.2.18. Liver Injury
2.2.18.1. ↑ Liver Enzymes
2.2.18.2. Life-Threatening
Liver Injury
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2.2.18.1.
↑ Liver Enzymes
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2.2.18.1. ↑ Liver Enzymes
■ Mechanism: unknown
■ Agomelatine:
□ Up to 5% in 50 mg/day
■ Other antidepressants:
□ Rare
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2.2.18.2.
Life-Threatening
Liver Injury
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2.2.18.2. Life-Threatening Liver Injury
■ Mechanism:
□ Immuno-allergy or
□ Toxicity from metabolites
■ Risk: http://www.ncbi.nlm.nih.gov/pubmed/24362450
□ Agomelatine>
□ Bupropion, duloxetine, TCAs>
□ Others>
□ Lowest: citalopram, escitalopram,
fluoxetine and paroxetine
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3. Pharmacokinetics
Facilitates
Pharmacodynamics
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3. Pharmacokinetics Facilitates Pharmacodynamics
■ Pharmacokinetics facilitates pharmacodynamics.
■ Efficacy:
□ Sufficient drug concentration may be needed.
□ Once there is sufficient drug concentration,
pharmacodynamics determines efficacy.
■ Safety:
□ ADRs are dose-related: sufficient concentration
at the action site may be needed.
Pharmacokinetics plays a facilitator role.
□ When ADRs are not dose-related: small
concentrations at the action site may be enough.
Pharmacokinetics may not be relevant.
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3. Pharmacokinetics Facilitates Pharmacodynamics
■ Pharmacodynamics probably determines specific
ADRs in a patient when concentrations at the site of
action are sufficient for “toxicity”.
Too-high drug concentrations (pharmacokinetics):
contribute to poor safety in general.
■ Pharmacodynamic factors probably determine
□ Whether ADRs develop or not
□ Which ADRs
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4. The “Do Not Forget”
Section
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4. The “Do Not Forget” Section
■ This is a very long and complex presentation:
□ Efficacy: list 11 possible reasons for prescription
□ Safety brain mechanisms: list 7 ADRs
□ Safety periphery mechanisms: list 18 ADRs
■ Dr. de Leon is not an expert in this area but decided
to select for the “Do Not Forget Section”:
□ Common ADRs of antidepressants commonly
prescribed in the USA
□ Possible lethal ADRs
□ Reflections on TCAs
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4. The “Do Not Forget” Section
4.1. Common ADRs of
Antidepressants Commonly
Prescribed in the USA
4.2. Possible Lethal ADRs
4.3. Reflections on TCAs
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4.1. Common ADRs of
Antidepressants Commonly
Prescribed in the USA
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4.1. Common ADRs
■ A recent US antidepressant trial in primary care:
□ included a “Depression Medication Choice” aid, and
□ studied 11 antidepressants:
● citalopram ● desvenlafaxine
● escitalopram ● duloxetine
● fluoxetine ● venlafaxine
● paroxetine ● bupropion
● sertraline ● mirtazapine
● amitriptyline or nortriptyline as TCAshttp://www.ncbi.nlm.nih.gov/pubmed/26414670
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4.1. Common ADRs
■ Provide ratings on 6 issues with “+s” or “-s”:
□ Sleep
□ Weight changes
□ Stopping approaches
□ Sexual issues
□ Costs
□ Keep in mind GI ADRs and other issues.
The take home patient leaflets are provided in supplemental
material http://archinte.jamanetwork.com/article.aspx?articleid=2443367
and are summarized in the next slides.
■ The “Depression Medication Choice” aid appears to Dr.
de Leon to be an updated reasonable summary of the most
frequent antidepressants used in the USA. Experts may
disagree on some of the details on ADRs.
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4.1. Common ADRs (Depression Medication Choice Aid)
4.1.1. Sleep
4.1.2. Weight Change
4.1.3. Stopping Approach
4.1.4. Sexual Issues
4.1.5. GI ADRs
4.1.6. Other Issues
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4.1.1. Sleep
(Depression Medication Choice Aid)
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4.1.1. Sleep (Depression Medication Choice Aid)
■ Insomnia/sleepiness:
□ Insomnia: ++: ● bupropion
□ Sleepiness: ++: ● mirtazapine
● TCAs
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4.1.2. Weight Change
(Depression Medication Choice Aid)
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4.1.2. Weight Change (Depression Medication Choice Aid)
■ Weight:
□ Gain: ++++: ● escitalopram
● paroxetine
● mirtazapine
● TCAs
+++: ● citalopram
++: ● duloxetine
● venlafaxine
+: ● sertraline
□ Loss: -: ● duloxetine
--: ● bupropion
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4.1.3. Stopping Approach
(Depression Medication Choice Aid)
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4.1.3. Stopping Approach (Depression Medication Choice Aid)
■ Quitting will make you sick:
+++: ● paroxetine (sickness if you skip)
● venlafaxine (sickness if you skip)
+: ● citalopram
● escitalopram
● fluvoxamine
● sertraline
● desvenlafaxine (some risk of sickness if you skip)
● duloxetine (some risk of sickness if you skip)
● bupropion
● mirtazapine
● TCAs
■ No risk: ● fluoxetine
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4.1.4. Sexual Issues
(Depression Medication Choice Aid)
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4.1.4. Sexual Issues (Depression Medication Choice Aid)
■ Libido: □ Less: ---: ● paroxetine
--: ● TCAs-: ● citalopram
● escitalopram ● fluoxetine ● fluvoxamine● sertraline● desvenlafaxine ● duloxetine ● venlafaxine ● mirtazapine
□ More: ++: ● bupropion
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4.1.5. GI ADRs
(Depression Medication Choice Aid)
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4.1.5. GI ADRs (Depression Medication Choice Aid)
■ Fluvoxamine: more likely to causeconstipation, diarrhea or nausea
■ Sertraline: more likely to cause diarrhea
■ Venlafaxine: more likely to cause nausea/vomiting
■ TCAs: more likely to cause constipation, diarrhea or nausea
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4.1.6. Other Issues
(Depression Medication Choice Aid)
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4.1.6. Other Issues (Depression Medication Choice Aid)
■ Citalopram: risk of QTc prolongation■ Fluoxetine: DDIs (inhibit other drugs) ■ Fluvoxamine: no US approval for depression■ Paroxetine: risk of teratogenicity ■ Desvenlafaxine: hypertension issues ■ Duloxetine: hypertension issues
can help ease pain ■ Venlafaxine: hypertension and cardiac issues■ Bupropion: higher risk of seizure ■ Mirtazapine: starts to work more quickly■ TCAs: can help ease pain
not a good choice for the elderly
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4.2. Possible Lethal ADRs
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4.2. Possible Lethal ADRs
■ Dr. de Leon has reviewed >600 deaths at Kentucky
state mental health facilities since 2002:
□ Antipsychotics occasionally cause deaths.
□ Mood stabilizers occasionally cause deaths.
□ Antidepressants have not caused deaths.
There was not clear case of overdose only by
TCAs but TCAs are rarely prescribed.
■ Antidepressants can contribute to deaths through:
□ Arrhythmias
□ Serotonin syndrome
□ Hemorrhages
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4.3. Reflections on TCAs
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4.3. Reflections on TCAs
■ TCAs are rarely used as antidepressants by
non-psychiatrists.
■ Thus, TCA expertise may be a “niche”
skill that psychiatrists need to master.
If you use TCAs, you need expertise on:
□ ADRs: many are dose-related, including
risk for arrhythmias
□ TCA pharmacokinetics, including:
● CYP2D6 and CYP2C19 genotyping
● TDM
See “Antidepressant Pharmacokinetics”.
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References for Antidepressant Pharmacodynamics
l) 2014 article http://www.ncbi.nlm.nih.gov/pubmed/25196459 with
pdf http://uknowledge.uky.edu/psychiatry_facpub/40/ has the best
figures for all antidepressant pharmaco-
dynamics and focuses on AED DDIs.
2) 2014 article http://www.ncbi.nlm.nih.gov/pubmed/24494611 with
pdf http://uknowledge.uky.edu/psychiatry_facpub/42/ focuses on
DDIs between second-generation
antidepressants and second-generation
antipsychotics.
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Questions
-Please review the 10 questions in the pdf titled
“Questions on the Presentation: Pharmacodynamics of
Antidepressants”.
-You will find the answers on the last slide after the “Thank
you” slide. No peeking until you have answered all
the questions.
-If you do not answer all the questions correctly, please
review the Power Point presentation once again
to reinforce the pharmacological concepts.
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Thank you
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Answers
1. A 6. A
2. D 7. D
3. D 8. D
4. A 9. D
5. C 10. A