Lecture 4: Antidepressants

Question 1

What is the MONOAMINE HYPOTHESIS?

Answer 1

Enhancement of monoamine neurotransmission.

Question 2

what does RESERPINE do?

a. What happens to peeps who are treated with this drug?

Answer 2

Depletes neurons of NR and 5-HT

a. Develop depression

Question 3

Why do we think it takes 2-3 weeks for Antidepressant effect to work?

Answer 3

we think it’s due to NEURONAL PLASTICITY.

Question 4

What is the NEUROTROPHIC HYPOTHESIS

Answer 4

Loss of Neurotrophic agents may contribute to depression. We think it’s due to BDNF. This can lead to NEURONAL LOSS in the HIPPOCAMPUS

Question 5

What is the NEUROENDOCRINE HYPOTHESIS?

Answer 5

Depression due to DYSREGULATION of the HPA Axis. Peeps w/depression may have increased Glucocorticoid release in response to stress.

Question 6

What is the LONG-TERM treatment w/Antidepressants?

Answer 6

They Down Regulate Auto-receptors. Increases Firing rate of Amine Neurons

Question 7

TCAs

1. What do they inhibit?
2. Tertiary Amines do what?
   a. Major side effect?
   b. What 2 are there? (AI)
3. Secondary Amines do what?
   a. Side effects? (2)
   b. What 2 are there? (ND)

Answer 7

1. Uptake of NE and 5-HT
2. Inhibit 5HT and NE Re-UPTAKE
   a. They’re very sedating
   b. Amitriptyline and Imipramine
3. More effect on NE Re-Uptake
   a. Less sedating, FEWER CARDIOVASCULAR EFFECTS
   b. Nortriptyline and Desipramine

Question 8

TCAs

1. What other 3 Receptors do they BLOCK?
2. Abuse potential?
3. What do they do for depressed patients?

Answer 8

1. A-ADRENERGIC, HISTAMINE, and MUSCARINIC RECEPTORS
2. Low. Don’t produce euphoria
3. Improve mood, increase appetite, and improve sleep patterns

Question 9

TCAs: Pharmacokinetics

1. How do you take them?
2. Length of Half Life?
3. What metabolizes them?

Answer 9

1. oral
2. Long
3. Liver: DRUG INTERACTIONS COMMON

Question 10

TCAs: Pharmacological Effects

1. CNS
   a. drowsiness and sedation occurs form blockade of what receptors?
   b. Which drugs are more sedating?
   c. Analgesia results from ACTIVATION of what? What does this do?

d. Impairment of memory and cognition due to effects of what?

Answer 10

1. a. of HISTAMINE RECEPTORS
   b. Tertiary Amines
   c. of Descending Noradrenergic Pathways in spinal cord; Increases Endorphin Release and Decreases Substance P release

d. Anticholinergic Effects

Question 11

TCAs: Pharmacological Effects

1. Peripheral
   a. What can develop in the Heart?

Answer 11

1. a. Cardiac Arrhythmias. (TORSADES DE POINTES)

Question 12

TCAs: Uses

1. Depression or PANIC DISORDER
   a. Why are they not used often for this?
   b. What gets used in its place?
   c. What TCA is considered the STANDARD of EFFICACY in DEPRESSION?
2. Chronic Pain
   a. Best at what doses?
3. Fibromyalgia
   a. TCAs treat this. What do we think causes it?
4. ENURESIS: What drug is used?

Answer 12

1. a. Due to Toxicity and Side Effects
   b. SSRIs more commonly used
   c. Imipramine
2. a. Much lower than those for treating depression. (10% of that used for Depression)
3. a. it’s muscle pain. Thought to be caused by Poor Sleep. Dose is much lower than those needed for Antidepressant
4. Imipramine is commonly used for this purpose

Question 13

TCAs: Side Effects

1. What results in blurred vision, tachycardia, constipation, dry mouth, palpitations?
   a. Effects are more common with which compounds?
2. CARDIOVASCULAR EFFECTS due to what?
3. What is VERY COMMON?
4. What do we see in patients w/history of seizures and in children?
5. What happens to ADH?
6. What happens to sexual use?
7. Can they be used in pregnancy?

Answer 13

1. CHOLINERGIC BLOCKADE
   a. Tertiary Compounds
2. Alpha 1 block. (AVOID TCAs in patients w/Myocardial Infarction)
3. WEIGHT GAIN
4. DECREASE IN SEIZURE THRESHOLD
5. INAPPROPRIATE ADH SECRETION
6. SEXUAL DYSFUNCTION is very common
7. YES

Question 14

TCAs: OVERDOSE

1. What can happen?
2. Treatment?

Answer 14

They’re very dangerous when Overdosed. Depressed pt’s can be suicidal….so do small amts at first, no refill.

2. Cardiac monitoring, supportive care; Gastric Lavage and Charcoal; Magnesium and Isoproteronal and cardia pacing for Torsades de pointes.

Lidocaine, propranolol, and phenytoin to manage arrhythmias and/or prevent seizures

Sodium bicarbonate and potassium chloride to restore acid base balance

Question 15

TCAs: Drug Interactions

1. What can Cause SEROTONIN SYNDROME?
   a. What is it?
   b. When should you stop TCAs?
2. Combination of what can cause TCAs to reach Toxic Levels?

Answer 15

1. MAOIs and TCAs together
   a. Severe CNS toxicity: Hyperpyrexia, Convulsions, Coma
   b. 2-3 wks before administration of a MAOI
2. FLUOXETINE and other SSRIs

Question 16

1. What is Serotonin Syndrome?

2. Best way to avoid it?

Answer 16

1. CNS toxicity. (restlessntess, muscle twitches, heperreflexia, sweating, tremor, convulsions, coma)
2. Give at LEAST 2 Wks after stopping MAOIs before starting Antidepressants.

Question 17

SSRIs

1. Why are they the DOC now for Depression?
2. How long does it take for the action to develop?

Answer 17

1. Mild Side Effects

2. 2-3 wks, like the TCAs

Question 18

SSRIs: Pharmacokinetics

1. Best way to take them?
2. Half Life?
3. Are metabolites active?
   a. What is Fluoxetine converted to, and how long does it last?
4. What 2 drugs cause SIGNIFICANT inhibition of the Hepatic CYP2D6? What does this do?

Answer 18

1. Oral
2. 2-3 days
3. Yes
   a. Norfluoxetine. 7-9 days
4. Fluoxetine and Paroxetine

Question 19

SSRIs: Uses

1. Depression: How effective are they?
   a. Are we worried about Overdose?
2. Panic Disorder: DOC for this and what else?
3. OCD: Which SSRI is the DOC?
4. Social Anxiety: What drug is the DOC for this?
5. Bulimia: SSRIs may be effective in doing what?
6. Alcoholism: Use of SSRIs help improve what?
7. Children and Teenagers:

Answer 19

1. Very effective
   a. No. Because they have basically no CARDIAC TOXICITY
2. and AGORAPHOBIA
3. PAROXETINE
4. PAROXETINE (Paxil)
5. in Decreasing episodes of Binging and Purging in Bulimics
6. Abstinence
7. Helps w/depression, but suicide can be a risk in the first months of starting on SSRIs

Question 20

SSRIs: Side Effects

1. GI: What symptoms?
2. CNS: What happens?

Answer 20

1. Nausea, diarrhea, constipation, loss of appetite
2. STIMULATION: anxiety and insomnia (MOST OFTEN with FLUOXETINE). SERTRALINE may also cause insomnia. Take these in the morning)

PAROXETINE: can cause sedation, so should be taken at NIGHT

Question 21

SSRIs: Drug Interactions

1. Fluoxetine inhibits what 2 things?
2. MAOIs: Can cause what?
   a. MAY also occur with what 2 things?
3. TCAs: Inhibits what?
4. WARFARIN: What can occur?
5. PHENYTOIN or CARBAMAZEPINE: Increased what?
6. B-BLOCKERS: Inhibition of what?
7. OPIODS: What drug interaction?

Answer 21

1. CYP3A4 and 2D6
2. SEROTONIN SYNDROME
   a. w/St. John’s Wort or amphetamines
3. Metabolism, and increases TCA concentration and toxicity
4. Increased risk of bleeding, due to inhibition of warfarin metabolism
5. Increased Anticonvulsant levels and possible toxicity
6. of metabolism by fluoxetine increases concentration of Beta Blockers, that can cause Heart Block and Hypotension.
7. Fluoxetine inhibits conversion of some opiods to active compound, so they are less effective in tx of pain.

Question 22

SNRIs

1. VENLAFAXINE
   a. this and its Metabolite (what is it) affect what 2 things?
   b. Used for what 3 things?

Answer 22

1. a. Desvenlafaxine affect both SEROTONIN and NE UPTAKE

b. Depression, Neuropathic Pain, and Post-Menopausal Hot Flashes

Question 23

SNRIs

1. DULOXETINE (Cymbalta)
   a. Inhibits what?

b. Also effective in improving what symptoms?
c. Most Frequent adverse reactions?
d. Do not use in peeps w/what?

Answer 23

1. a. reuptake of both serotonin and NE Uptake
   b. Physical Symptoms
   c. Anorexia, drowsiness, headache, insomnia, dry mouth, nausea/vomiting
   d. w/liver disease or who drink a ton of alcohol.

Question 24

MAOIs

1. What does MAO do?
   a. Found where?
2. 2 Subtypes:
   a. MAO-A metabolizes what?
   b. MAO-B metabolizes what?

Answer 24

1. Breaks down circulating catecholamines and compounds ingested from food, like TYRAMINE
   a. Mitochondria in nerve terminals, in the liver, and in the intestinal mucosa.
2. a. NE, 5-HT, and Dopamine. Metabolizes amines in the periphery as well as in the brain. (so peripheral amine metabolism is affected)
   b. Mainly metabolizes Dopamine

Question 25

MAOIs 1. Phenelzine a. What does it do to MAO? b. When is it used? c. DOC? 2. Selegiline a. What does it do to MAO? b. Used in what disease?

Answer 25

1. a. Irreversibly inhibits BOTH MAO-A and MAO-B b. Depression that hasn't responded to other drugs. c. LAST DOC due to major side effects 2. a. Irreversibly Inhibits ONLY MAO-B b. Parkinson's

Question 26

MAOIs: Pharmacokinetics 1. Best way to take it? 2. What metabolizes it? 3. Effects of drug last how long after stopping the drug? a. Why?

Answer 26

1. Oral 2. Liver 3. 1-3 wks a. Long half lives and irreversible inhibition of MAO

Question 27

MAOIs: Side Effects 1. Hypertensive Crisis a. Irreversible inhibition of MAO in GI causes accumulation of what? b. This does what? c. This can lead to what occurring? d. How is hypertensive crisis treated? 2. What other two things are common?

Answer 27

1. a. of TYRAMINE b. Causes release of catecholamines from nerve endings and Adrenal Medulla c. SEVERE HYPERTENSIVE CRISIS which can cause fatal intracranial bleeding d. A-receptor Blocker 2. WEIGHT GAIN, and ANTICHOLINERGIC EFFECTS (headache, urinary retention, blurred vision, dry mouth)

Question 28

MAOIs: Drug Interactions 1. SEVERE HYPERTENSION can occur when taking what other drugs? 2. HYPERPYREXIA/SEROTONIN SYNDROME can occur with what drugs being taken with it?

Answer 28

1. OTC cold and cough medications, Phenylephrines, ephedrine, amphetamines 2. Meperidine, dextromethophan (OTC cough meds), TCAs, SSRIs

Question 29

Miscellaneous Antidepressants 1. Bupropion a. What does it INHIBIT? b. What can it be used for? c. Used to help pts with what? d. Side Effects Include what?

Answer 29

1. a. RE-UPTAKE of DOPAMINE b. Help crave nicotine, children with ADHD, alcoholism tx. c. with sexual dysfunction from SSRIs, or can be taken w/it to decrease sexual side effects d. Possible weight loss, CNS stimulation, possible seizures

Question 30

Miscelaneous Antidepressants 1. St. John's Wort a. Effective in what? b. Should not be used with what 3 types of drugs? Why? c. May prolong effects of what? d. Induces what?

Answer 30

1. a. Mild to moderate depression b. MAOIs, SSRIs, TCAs (Serotonin syndrome) c. of General anesthetics, so stop taking it 2-3 wks before any surgery d. Cytochrome P450, increases metabolism, and decreases effectiveness of DIGOXIN, warfarin, Antiretrovirals, Oral Contraceptives