Antidepressant Pharmacology Flashcards
1
Q
- First line treatment for depressive disorders?
- Efficacy between the SSRIs?
- Differences in what? 2
A
- First line treatment of depressive disorders
- No real differences in efficacy
- Difference in side effects and half lives
2
Q
SSRIs in the order of development
6
A
- Fluoxetine (Prozac) 1987
- Sertraline (Zoloft)
- Paroxetine (Paxil)
- Citalopram (Celexa)
- Fluvoxamine (Luvox)
- Escitalopram (Lexapro) 2002
3
Q
SSRIs are used to treat various psychiatric conditions
11
A
- Depression
- Panic disorder
- Obsessive-compulsive disorder
- Generalized anxiety disorder
- Social anxiety disorder
- Post traumatic stress disorder
- Body dysmorphic disorder
- Bulimia nervosa
- Binge eating disorder
- Premenstrual dysphoric disorder
- Somatoform disorders
4
Q
SSRIs block what?
A
reabsorption of serotionin
5
Q
SSRIs MOA
3
A
- Block the presynaptic serotonin reuptake pump
- Increases the time that serotonin is available in the synapse
- Increases postsynaptic receptor occupancy
6
Q
SSRIs pharmacokinetics
- Well absorbed where?
- Reach peak plasma levels when?
- Metabolism and elimination occur where?
- Metabolites are inactive except for _________ has an active metabolite
A
- Well absorbed in the GI tract
- Reach peak plasma levels in 1-8 hours
- liver
- fluoxetine
7
Q
SSRIs downstream effects
1. Increased production of neuroprotective proteins such as what?
- Down-regulation of 5HT1A receptors (5HT1A receptors when bound with serotonin inhibits the neuron from releasing serotonin) so less inhibition = what?
A
- brain-derived neurotrophic factor
2. more firing and increased serotonin release in the presynaptic neuron
8
Q
SSRI half life:
- Half life range is what?
- Except for what?
A
- In general elimination half life range is 20-30 hours
2. Except for fluoxetine (Prozac) half life is up to 3 days and it’s active metabolite can last 4-16 days
9
Q
Fluvoxamine’s (Luvox) half life is about what?
A
15 hours
10
Q
Which SSRIs inhibit liver enzymes less than other SSRI’s? 2
A
Citalopram and escitalopram
2D6, 2C9, 2C19, 2B6, 3A4, 1A2
- Different ones in each SSRI
- Citalopram and escitalopram don’t seem to be affected by these
11
Q
SSRIs: Drug interactions. Use with caution with what drugs?
Contraindicated if taking ______ within 2 weeks due to risk of serotonin syndrome
Paroxetine and fluoxetine are contraindicated with what?
A
- Azole antifungals
- Macrolide antibiotics
- Omeprazole
- Hepatic impairment
MAOis
tamoxifen used to treat breast cancer
12
Q
SSRI Side effects
top 3
A
Sexual dysfunction (17%) Drowsiness (17%) Weight gain (12%)
Dizziness (11%) Insomnia (11%) Anxiety (11%) Diaphoresis Diarrhea hyperprolactinemia Headache Dry mouth Blurred vision Nausea Rash or pruritis Tremor Constipation Diarrhea SIADH hyponatremia
13
Q
Withdrawal syndrome if abrupt discontinuation
6
More common in which SSRIs? 2
A
- Dysphoria
- Dizziness
- GI distress
- Fatigue
- Chills
- Myalgias
More common with fluvoxamine and paroxetine (shorter half lives)
14
Q
SSRI response time?
2
A
- Some will feel better in a few weeks
2. Others 4-6 weeks
15
Q
SSRI administration
- Dosing how often?
- Take when? 2
- Education?
A
- Usually once daily dosing
2.
-If it makes them sleepy have them take it at night
-If is causes insomnia have them take it in the AM - Warn of common side effects like HA, dizziness, nausea, diarrhea when first starting so they know that these side effects are expected
16
Q
SSRI Duration of therapy:
3
A
- For many it is lifelong
- Don’t stop it for 1 year after the resolution of symptoms
- Stopping the medication too early may cause recurrence of a severe depressive episode
17
Q
Citalopram (Celexa) 20-40mg: Good to use when?
A
concerned about drug interactions (doesn’t have the P450 enzyme inhibition as strong as the other SSRIs)
18
Q
Citalopram (Celexa) 20-40mg: Risk of what at doses over 40mg or those at high risk for arrhythmia?
A
QT prolongation
19
Q
What pts are at high risk for arrhythmia while taking celexa?
3
A
- Hepatic impairement
- Age > 60 years
- On other CYP219 inhibitors (cimetidine)
20
Q
Escitalopram (Lexapro) 10-20mg
- Its an isomer of what?
- advantage?
A
- Isomer of citalopram
2. Similar to citalopram as has fewer drug interactions then others in the class
21
Q
Fluoxetine (Prozac) 20-40mg daily
- Contraindicated with what?
- More likely to cause what than others?
- Least likely to cause what?
A
- Contraindicated with Tamoxifen
- More likely to cause activation than the others
- Least problems with weight gain
22
Q
Fluvoxamine (Luvox) 50-200mg daily
- Dosing schedule?
- Weight gain?
- More likely to have which SE compared to other SSRIs? 2
A
- Twice daily dosing if at 200mg daily
- Weight gain up to 2.6% of body weight
- More likely to have nausea and sedation compared to most other SSRIs
23
Q
Paroxetine (Paxil) 20-40mg daily
- Contraindicated with who?
- Common SE? 2
- Withdrawl symptoms?
- Weight gain?
A
- Contraindicated with Tamoxifen
- Nausea and sedation more likely to occur than most others
- Significant withdrawal symptoms
- Causes the most weight gain among the SSRIs (up to 3.6% of baseline)
WITHDRAWL SYMTPOMS
24
Q
Sertraline (Zoloft) 50-200mg daily
-More likely tot cause what than others?
A
More likely to cause diarrhea than the others
25
1. What is a big risk as the pt starts feeling better?
2. Possible increases in what other things? 2
3. Can affect what in males?
1. May increase the risk of suicide as the patient recovers (risk greatest in ages 18-24)
2.
- May increase the risk of abnormal bleeding
- Possible increase in bone fractures
3. May affect male fertility
Abnormal levels of DNA fragmentation in sperm were noted compared to baseline 50% vs 10%
26
What are the SNRIs? 3
1. Venlafaxine (Effexor)
2. Duloxetine (Cymbalta)
3. Desvenlafaxine (Pristiq)
27
SNRIs act on which neurotransmitters? 2
When would we use these?
Act on both serotonin and norepinephrine
Can use for treatment of depression if intolerable side effects or poor response to first line SSRI therapy
28
Other uses for SNRIs
```
Panic disorder
Generalized anxiety disorder
Social anxiety disorder
OCD
PTSD
Body dysmorphic disorder
Diabetic peripheral neuropathy
Fibromyalgia
Menopausal hot flashes
```
29
SNRI Pharmacokinetics
1. Food decreased what but not what in absorption?
2. Which ones do not significantly inhibit P450 enzymes? 2
3. Which one does?
1. Food decreases the rate of absorption but not the degree of absorption
2. Desvenlafaxine and venlafaxine do not significantly inhibit P450 enzymes
3. Duloxetine moderately inhibits P450 enzymes so will have more drug interactions
30
SNRI side effects
| three most common
1. Nausea*
2. Dizziness*
3. Diaphoresis*
Sexual dysfunction
Sedation
Agitation
Fatigue
Diarrhea
Constipation
Anorexia
Insomnia
Dry mouth
Orthostatic hypotension
31
Desvenlafaxine (Pristiq) 50-100mg daily
1. Most commonly causes what?
2. Monitor for what?
1. Most commonly causes nausea
| 2. Monitor for elevation of blood pressure
32
Duloxetine (Cymbalta) 30-60 mg daily
1. Cojntraindicated in who?
2. Avoid in who? 2
3. Indicated specifically for which pts? 2
4. Weight gain?
1. Contraindicated in
- uncontrolled angle closure glaucoma
2. Avoid in severe renal or liver impairment
3. Indicated for diabetic neuropathy and fibromyalgia
4. Weight gain of 7% of baseline when treated with 80 mg
33
Venlafaxine (Effexor)
1. Essentially an SSRI at doses ≤ _______ daily at
2. May increase what?
3. Increases risk of what? \
4. Adjust dose in what pts? 2
5. What do you have to remeber if taking a pt off this?
6. Can cause what cardiac symptom?
1. 150mg
2. May increase blood pressure
3. Increased risk of upper GI bleed
4. Adjust dose in hepatic and renal impairment
5. Needs a slow taper off of it to avoid withdrawal symptoms
6. Can cause QT prolongation
WITHDRAWL SYMPTOMS
34
SNRI summary:
1. ______ occurs in about 20% of patients
2. Administration with_______seems to help reduce the nausea
3. _________ could be a significant issue with duloxetine especially at higher doses
4. ___________ occurs about as frequently as the SSRIs
5. Could elect to not taper up on the what?
6. Watch what?
1. Nausea
2. food
3. Weight gain
4. Sexual dysfunction
5. starting dose
6. blood pressure
35
TCAs:
1. What are the tertiary amines?5
- More potent at blocking what?
2. What are the secondary amines? 3
- more potent at blocking what?
1.
- Amitriptyline
- Clomipramine
- Doxepin
- Imipramine
- Trimipramine
More potent at blocking uptake of serotonin
More side effects
2.
- Desipramine
- Nortriptyline
- Protriptyline
More potent at blocking uptake of norepinephrine
36
TCAs?
1. Usually avoided in clinical practice for the treatment of depression due to what?
2. Highly sedating so are often used for what? 2
1. anticholinergic side effects
2.
- insomnia and for those with
- night time neuropathic pain or fibromyalgia
37
TCAs MOA? 1
Also block? 3
1. Inhibit reuptake of serotonin and norepinephrine
Also block
1. muscarinic,
2. histamine and
3. alpha-adrenergic receptors
38
TCA Pharmacokinetics
1. Rapid and near complete absorption from the what?
2. First pass metabolism in the what?
3. Binds to proteins and only the ________ is active
4. Elimination half life is about what?
5. Most have what?
1. small intestine
2. liver
3. free portion
4. 24 hours
5. active metabolites
39
TCA Cardiac side effects 3
In patients over 40 we need to screen for what?
1. Heart block,
2. ventricular arrhythmias,
3. sudden death
In patients over 40 need to screen for cardiac conduction system disease with an EKG before initiation of therapy
40
TCAs
1. Lower what threshold?
2. Increase risk of what?
3. Block histamine receptors causing what? 4
4. Block acetylcholine receptors causing what? 4
5. Very dangerous in ________due to their broad spectrum
1. Lower the seizure threshold
2. Increase in bone fractures
3. Block histamine receptors causing
- sedation,
- increased appetite,
- confusion,
- delirium
4. Block acetylcholine receptors causing
- blurred vision,
- constipation,
- dry mouth,
- urinary retention
5. Overdose
41
TCAs: Not well tolerated in the elderly
| why?
1. Orthostatic hypotension
2. Anticholinergic side effects
3. Heavily sedating
4. Cardiac side effects
42
MAOi: Which two drugs?
Phenelzine (Nardil)
| Tranylcypromine (Parnate)
43
MAOi: Drug-drug interactions cause? 2
MAOi: Dietray restrictions?
Why is it poorly tolerated?
1. Serotonin syndrome,
2. hypertensive crisis
Tyramine containing foods
Poorly tolerated due to side effects
Leave prescribing these up to the Psychiatrists
44
Other meds used for treating Depression symtpoms?
| 5
1. Trazodone (Desyrel)
2. Bupropion (Wellbutrin)
3. Mirtazapine (Remeron)
4. Vilazodone (Viibryd)
5. Vortioxetine (Brintellix)
45
Trazodone (Desyrel)
1. MOA?
2. Good for what at lower doses?
3. higher doses?
4. Watch for? 3
1. Serotonin antagonist and reuptake inhibitors
2. Good for sleep at low doses
3. If tolerated – functions as an antidepressant at higher doses
4. Watch for
- sedation,
- orthostasis,
- priapism
46
Bupropion (Wellbutrin): Uses include?3
1. Major Depressive disorder
2. ADHD
3. Smoking cessation
47
Bupropion
1. Drug interactions?
2. Inhibits the reuptake of what?
3. Three formulations?
1. Some inhibition of P450 2B6 pathway
2. Inhibits the reuptake of dopamine
3.
- IR 100-150mg TID
- SR 12 hour 150-300mg total daily dose
- XL 24 hour 150-300mg once daily
48
Bupropion
1. Structurally related to what?
2. Can cause what?
3. Lowers what threshold?
4. Avoid in who?
5. Withdrawl symtpoms?
1. Structurally related to amphetamine
2. Can cause anxiety
3. Lowers the seizure threshold
4. Avoid in bulemia
5. No withdrawal syndrome upon discontinuation
49
Bupropion
1. Mildly stimulating so good for patients with what? 3
2. Advantages? 2
3. Can be used as an add on to SSRIs for the treatment of what?
1.
- fatigue,
- hypersomnia, or
- poor concentration
2. No sexual side effects or weight gain
3. sexual side effects
50
Unique Bupropion Considerations
1. No sexual side effects
2. Smoking cessation
3. Comorbid ADHD
4. Often used with SSRI’s
5. Consider with sleepy, slowed down patients
51
Why is Bupropion often used with SSRIs? 2
Preg cat?
1. Augment antidepressant
2. Reverse sexual side effects
Pregnancy category C
52
Mirtazapine (Remeron) 15-45mg
| MOA? 2
1. Blocks adrenergic receptors leading to an increased release of norepinephrine and serotonin
2. Blocks serotonergic receptors and increases serotonin mediated neurotransmission
53
Mirtazapine (Remeron) 15-45mg:
| High affinity for what (1) receptors and low for what (3)?
1. H1
2.
- cholinergic,
- alpha 1 adrenergic and
- dopaminergic receptors
54
Mirtazapine
| SE? 4
1. Sedation
2. Weight gain
3. Less sexual side effects
4. Good for patients with nausea
55
Mirtazapine: USed of label for what?
1. Used off-label for insomnia
More pronounced at doses of 15mg vs. higher dose
2. Used off-label for appetite stimulant
56
Vilazodone (Viibryd)
1. MOA?
2. Appears to have the same SE profile as what?
3. Protein bound how?
4. Half life?
1. SSRI and 5-HT1A receptor agonist
2. Appears to have the same side effect profile of SSRIs (maybe less sexual SE)
3. 96-99% protein bound
4. Half-life 25 hours
57
Vortioxetine (Brintellix)
1. MOA?
2. SE profile?
3. What kind of inhibitor?
4. Half life?
5. Protein bound how?
1. SSRI and 5HT1A receptor agonist, 5HT3 receptor antagonist
2. Seems to have same side effect profile as the SSRI’s (maybe less sexual SE)
3. CYP2D6 inhibitor
4. Half-life 66 hours
5. 98% protein bound
58
1. What is serotonin syndrome?
| 2. Ranges in severity from?
1. Constellation of symptoms caused by an excess of serotonin
2. Ranges in severity from mild to fatal
59
Causes of serotonin syndrome:
1. Classically associated with what?
2. Can also occur when?
1. Classically associated with the simultaneous administration of two serotonergic agents
2. Can occur after initiation of a single serotonergic drug or increasing the dose
60
Drugs that can cause serotonin syndrome
1. Psych meds? 9
2. Pain meds? 4
3. Migraine meds? 2
4. Neurology meds? 4
5. OTC? 2
6. Antiemetics? 2
7. Street drugs? 4
8. ADHD? 2
9. GI? 2
1. Psych meds:
- SSRIs,
- SNRIs,
- TCA,
- MAOi,
- nefazadone,
- trazadone,
- bupropion,
- buspirone,
- lithium
2. Pain meds:
- pentaxocine (Talwin),
- meperidine (Demerol),
- tramadol,
- fentanyl,
- cyclobenzaprine (muscle relaxer, Flexeril)
3. Migraine meds:
- Triptans,
- ergots
4. Neurology meds:
- levodopa,
- carbidopa-levodopa,
- valproate,
- carbamezepine
5. OTC:
- dextromethorphan (Robitussin),
- St. John’s wort
6. Antiemetics:
- Odansetron (Zofran),
- ganisetron (Kytril)
7. Street drugs:
- cocaine,
- methamphetamine,
- MDMA (ecstasy),
- LSD
8. ADHD :
- amphetamine derivatives,
- dextroamphetamine
9. Some weight loss drugs and metaclopramide (Reglan) for gastric motility
61
Drugs that can cause serotonin syndrome
1. Psych meds? 9
2. Pain meds? 4
3. Migraine meds? 2
4. Neurology meds? 4
5. OTC? 2
6. Antiemetics? 2
7. Street drugs? 4
8. ADHD? 2
9. GI? 2
1. Psych meds:
- SSRIs,
- SNRIs,
- TCA,
- MAOi,
- nefazadone,
- trazadone,
- bupropion,
- buspirone,
- lithium
2. Pain meds:
- pentaxocine (Talwin),
- meperidine (Demerol),
- tramadol,
- fentanyl,
- cyclobenzaprine (muscle relaxer, Flexeril)
3. Migraine meds:
- Triptans,
- ergots
4. Neurology meds:
- levodopa,
- carbidopa-levodopa,
- valproate,
- carbamezepine
5. OTC:
- dextromethorphan (Robitussin),
- St. John’s wort
6. Antiemetics:
- Odansetron (Zofran),
- ganisetron (Kytril)
7. Street drugs:
- cocaine,
- methamphetamine,
- MDMA (ecstasy),
- LSD
8. ADHD :
- amphetamine derivatives,
- dextroamphetamine
9. Some weight loss drugs and metaclopramide (Reglan) for gastric motility
62
The majority of cases of serotonin syndrome present within 1.___ hours, and most within 2.___ hours, of a change in dose or initiation of a drug
1. 24
| 2. six
63
Serotonin syndrome PE
| 13
1. Hyperthermia,
2. agitation,
3. ocular clonus
4. Tremor,
5. akathisia,
6. deep tendon hyperreflexia
7. Inducible or spontaneous clonus,
8. muscle rigidity
9. Dilated pupils,
10. dry mucus membranes
11. Increased bowel sounds,
12. flushed skin, and
13. diaphoresis
Neuromuscular findings are typically more pronounced in the lower extremities.
64
HARM from serotonin syndrome
Hyperthermia
Autonomic instability (delirium)
Rigidity
Myoclonus
65
Signs and symptoms of serotonin syndrome: Mental status changes can include ?
1. anxiety,
2. agitated delirium
3. restlessness
4. disorientation
66
Autonomic manifestations of serotonin syndrome?
| 6
1. Diaphoresis
2. Tachycardia
3. Hyperthermia
4. Hypertension
5. Vomiting
6. Diarrhea
67
Neuromuscular hyperactivity in serotonin syndrome? 5
Which are common? 2
1. Tremor
2. muscle rigidity
3. Myoclonus
4. Hyperreflexia
5. bilateral Babinski sign
Hyperreflexia and clonus are common
Ankle clonus
Ocular clonus
68
Hunter criteria for serotonin syndrome?
| 6
1. Has taken a serotonergic agent PLUS (1)
2. Spontaneous clonus
3. Inducible clonus AND agitation or diaphoresis
4. Ocular clonus AND agitation or diaphoresis
5. Tremor and hyperreflexia
6. Hypertonia AND temp > 38C AND ocular clonus or inducible clonus
69
Treatment of serotonin syndrome?
| 8
1. DC serotonergic agents
2. Sedate using benzodiazepines (lorazepam)
3. Supplemental O2
4. IV fluids
5. Cardiac monitor
6. If BZDs don’t improve agitation the antidote is cyproheptadine
7. Temp > 41.1C (105.98F) immediate intubation and sedation.
8. Avoid acetaminophen
70
Symptom resolution
1. Often resolves when?
2. Which drugs carry the greatest risk?
1. Often resolves within 24 hours of discontinuing the serotonergic agent
2. Irreversible monoamine oxidase inhibitors (MAOIs) carry the greatest risk, and symptoms can persist for several days.
