Cns Pharmacology: Antidepressant Agents

Front 1

Monoamine hypothesis of affective disorders


What is the final common pathways of all drugs that are effective in treating depression?

Back 1

elevation of NE in the synapse

Front 2

Monoamine hypothesis of affective disorders

Therapeutic activity of antidepressant drugs takes about 3 weeks to become apparent. Why is this?

Back 2

thought to be due to compensatory changes in the following receptors:

-presynaptic alpha2
-postsynaptic beta

The antidepressant drugs cause down regulation - or desensitization - of the receptors.

Front 3

Monoamine hypothesis of affective disorders

Etiology of depression may be related to what receptor ratio?

Back 3

may be related to elevated postsynaptic beta/alpha1 ratio

This elevated ratio declines after several weeks of anti-depressant therapy since many drugs desensitize post-synaptic beta receptors.

Front 4

Monoamine hypothesis of affective disorders

Which group of adrenergic receptors is not desensitized by antidepressant drugs?

Back 4

postsynaptic alpha1 receptors are NOT desensitized

(postsynaptic beta & presynaptic alpha2, however, ARE desensitized)

Front 5

Name the neurotransmitters that are degraded by MAO-A.

Name the neurotransmitter that is degraded by MAO-B.

Back 5

MAO-A degreades NE & 5-HT

MAO-B degrades DA

Front 6

Describe differences between phenylzine and tranylcypromine.

Back 6

Phenylzine: irreversible inhibition of MAO-A and MAO-B

Tranylcypromine: prolonged, reversible inhibition of MAO-A

Front 7

Besides the effects on alpha2 and beta receptors, MAOI's cause compensatory changes in this receptor.

Back 7

serotonergic receptors in the limbic system

Front 8

Name the 2 MAOI's discussed in class.

Back 8

1) phenylzine
2) tranylcypromine

Front 9

The structure of tranylcypromine resembles that of this adrenergic agonist.

Back 9

The structure of tranylcypromine resemebles that of amphetamine.

Front 10

Which foods should a patient taking phenlyzine be advised NOT to eat?

Back 10

Patient taking a MAOI, such as phenylzine, should not eat foods high in tyramine, like beer & yellow cheese. This could lead to fatal HTN crisis.

Front 11

An MAOI and this pain reliever should not be administered together, as hyperpyrexia and convulsions may occur.

Back 11

Concurrent administration of a MAOI and MEPERIDINE may cause hyperpyrexia and. convulsions

Front 12

What toxic effect may result from the concomitant use of more than one antidepressant?

Back 12

Serotonin syndrome (muscle rigidity, hyperpyrexia, convulsions, coma, even death)

Front 13

Besides the toxic effects that can occur due to high levels of tyramine, administration of meperidine, & use of more than one antidepressant, what are the toxic effects of MAOIs?

Back 13

-postural hypotension (2ndary to peripheral alpha1 desensitization)

-insomnia, impotence, CNS stimulation (2ndary to excessive autonomic activity)

-weight gain (uncertain mechanism)

Front 14

Describe the specific toxic effects of each class of antidepressant in the case of an overdose (Learning Objective #3):

-MAOI
-TCA
-SSRI

Back 14

MAOI: CNS depression & cardiovascular collapse

TCA: cardiac conduction defects

SSRI: it is difficult for a patient to OD on SSRIs - this is a reason why SSRIs are so often prescribed to treat depression

Front 15

Name the 2 TCA's discussed in class.

Back 15

1) amitriptyline
2) imipramine

Front 16

Just as the structure of tranylcypromine resembles amphetamine, which class of drugs does the structure of TCA resemble?

Back 16

Structure of TCA resembles phenothiazine antipsychotic drugs.

(However, TCA is not effective in treating psychosis).

Front 17

TRUE OR FALSE

MAOI's and TCA produce CNS stimulation.

Back 17

FALSE

MAOI's produce CNS stimulation BUT... TCA's do NOT produce CNS stimulation.

Front 18

TRUE OR FALSE

TCA's can cause sedation or fatigue.

Back 18

TRUE

Front 19

Describe the mechanism of action of TCA's

Back 19

TCA's increase synaptic concentrations of NE and/or 5-HT by inhibiting reuptake pumps

Front 20

Why don't TCA serum levels correlate with their therapeutic activity?

Back 20

-Pump inhibition occurs w/in hours of dose but therapeutic activity does not occur for several weeks because TCA's must induce changes in receptor sensitivity.

-Also, serum levels do not correlate with therapeutic activity due to high lipid solubility, extensive binding to serum proteins and many active metabolites.

Front 21

Besides the effects related to drug interactions and overdose, describe the toxicity and side effects of TCA's.

Back 21

-arrythmia, tremor, insomnia (sympathomimetic)

-sedation with tolerance developing after 2 weeks (antihistaminic)

-dry mouth, blurred vision, tachycardia, urinary retention (antimuscarinic)

Front 22

TCA effects can be enhanced by use of these 2 drugs.

Back 22

1) antipsychotics
2) methylphenidate

These drugs interfere w/ hepatic metabolism.

Front 23

TCA effects can be reduced by use of this class of drug.

Back 23

Barbiturates increase hepatic metabolism of TCA's, thereby reducing TCA effects.

Front 24

If your patient is taking amitriptyline (a TCA) and she is experiencing pronounced sedative effects, you might ask her if she is also taking and/or using these 2 CNS depressants:

Back 24

1) alcohol
2) barbiturates

These can produce additive sedative effects, as they are CNS depressants

Front 25

TRUE OR FALSE

Second/Third generation antidepressants are better tolerated and much more effective compared to TCA's.

Back 25

FALSE

2nd/3rd generation antidepressants have fewer "promiscuous" receptor blockage activity and DO tend to be better tolerated than TCA's... HOWEVER, 2nd/3rd are NOT more effective compared to TCA's.

Front 26

List the 7 2nd/3rd generation antidepressants discussed inclass.

Back 26

1) trazodone
2) nefazodone
3) venlafaxine
4) bupropion
5) amoxapine
6) maprotiline
7) mirtazipine

Front 27

Describe the difference between 2nd/3rd generation antidepressants and TCAs.

Back 27

2nd/3rd generation antidepressants inhibit 5-HT reuptake to a greater extent than NE.

TCA's equally inhibit both NE and 5-HT reuptake pumps.

Front 28

These 2 drugs inhibit 5-HT 2A receptors and inhibit 5-HT reuptake moreso than NE reuptake.

Back 28

trazodone & nefazodone

They are 2nd/3rd generation antidepressants.

Front 29

Describe trazodone side effects & the receptors involved in these side effects .

Back 29

Trazodone can
1) induce prapism due to alpha1 blockage

2) induce drowsiness due to H1 receptor blockage

Front 30

Venlafaxine

Back 30

-2nd/3rd generation antidepressant

-5-HT >>> NE pump inhibition
-inhibit DA reuptake
-effective in treating major depression & anxiety

Front 31

Bupropion

Back 31

-2nd/3rd generation antidepressant

-weak inhibition of monoamine reuptake
-significant side effect is dose-dependent increase in seizures
-contraindicated in patients taking Zyban for smoking cessation
-contraindicated in epileptic patients

Front 32

Amoxapine

Back 32

-2nd/3rd generation

-antipsychotic metabolite
-extrapyramidal side effects due to DA receptor antagonism

Front 33

Maprotiline

Back 33

-2nd/3rd generation

-potent NE reuptake inhibitor
-few sedative side effects

Front 34

Mirtazipine

Back 34

-2nd/3rd generation

-blocks 5-HT and alpha2 receptors (UNIQUE!)
-also blocks H1 receptor which can lead to sedation
-likely to induce weight gain

Front 35

For each patient below, name the 2nd/3rd generation antidepressant that you might NOT WANT to presribe

1) Patient who smokes 1 pack a day and is taking Zyban
2) Patient who is morbidly obese and is trying to lose weight
3) Patient with a history of seizures

Back 35

1) Patient taking Zyban // bupropion

2) Obese patient trying to lose weight // mirtazipine

3) Patient with history of seizures // bupropion

Front 36

Which class of antidepressants is the most prescribed class for treatment of depression and anxiety disorders?

Back 36

SSRI's

Front 37

Describe the mechanism of SSRIs.

Back 37

They inhibit 5-HT reuptake

Front 38

What is the SSRI prototype drug?

Back 38

fluoxetine (Prozac)

Front 39

Describe the half-life of SSRIs.

Back 39

SSRIs have a long half life (>50h). In addition, each SSRI has active metabolites.

Front 40

While SSRIs are usually well tolerated, list some of their side effects.

Back 40

-nausea
-insomnia
-anxiety
-decreased libido
-erectile dysfunction

These are 2ndary to excessive 5-HT

Front 41

Describe mechanism of lithium as a mood-stabilizing drug.

Back 41

Depresses noradrenergic or serotonergic transmission by decreasing formation of postsynaptic 2nd messengers

Front 42

TRUE OR FALSE

Lithium is effective at preventing manic episodes but is not used in acute treatment of the manic phase of bipolar disorder.

Back 42

TRUE

Front 43

Lithium levels must be kept between 0.6-1.2 mEq/L. What happens if lithium reaches 1.5-3 mEq/L?

Above 3 mEq/L?

Back 43

> 1.5-3 mEq/L : ataxia, drowsiness, muscle rigidity

> 3 mEq/L : cardiac arrythmia, seizures, coma

Front 44

Describe elimination of lithium.

Back 44

Lithium is eliminated almost entirely by the kidney. Renal excretion is related to sodium intake, so sodium loading causes an increased Li excretion, while sodium depletion causes Li retention.

Front 45

What are the mild, yet common, side effects of lithium that occur within the first week of administration?

Back 45

-GI irritation
-muscular weakness
-tremors
-edema

Tolerance usually develops to these side effects.

Front 46

Name the 2 idiosyncratic toxicities of lithium.

Back 46

1) nontoxic goiter and decreased T3 and T4 levels

2) renal toxicity resembling nephrogenic diabetes insipidus

Front 47

Regarding drug interactions with lithium, name the 2 drugs discussed that can cause Li intoxication.

Back 47

1) Diuretics, especially thiazides: Na depletion leads to Li retention

2) NSAIDS: they increase Li reabsorption

Front 48

List the 5 clinical uses of antidepressants as discussed in class.

Back 48

1) major depression
2) enuresis (TCA)
3) ADHD (atmoxetine)
4) anxiety (SSRIs -- which also treat phobias, OCD, PTSD)
5) ?? efficacy in the case of treating chronic pain, fibromyalgia, migraines

Front 49

Learning Objective #1

List the primary targets of the following:

1) MAOIs
2) TCAs
3) 2nd/3rd generation
4) SSRIs

Back 49

Learning Objective #1

List the primary targets of the following:

1) MAOIs: inhibit MAO-A and/or MAO-B; induce compensatory changes in alpha2, beta and serotonergic receptors

2) TCAs: inhibit NE and/or 5-HT reuptake pumps; eventually induce receptor sensitivity changes

3) 2nd/3rd generation: inhibit 5-HT reuptake to a greater extent than NE

4) SSRIs: inhibit 5-HT reuptake pumps

Front 50

Learning Objective #2

List common adverse effects of the following:


1) MAOIs
2) TCAs
3) 2nd/3rd generation
4) SSRIs

Back 50

List common adverse effects of the following:


1) MAOIs: postural hypotension, insomnia, CNS stimulation, weight gain

2) TCAs: arrythmia, tremor, insomnia, dry mouth, blurred vision, tachycardia, urinary retention, initial sedation followed by tolerance

3) 2nd/3rd generation: specific to particular drug but includes prapism, drowsiness, seizures, extrapyramidal side effects, weight gain

4) SSRIs: nausea, insomnia, anxiety, decreased libido

Front 51

Learning Objective #2

Identify drug and dietary interactions for the following:


1) MAOIs
2) TCAs
3) 2nd/3rd generation
4) SSRIs

Back 51

Identify drug and dietary interactions for the following:


1) MAOIs: tyramine & hypertensive crisis; meperidine & hyperpyrexia + convulsions

2) TCAs: antipsychotics & methyphenidate cause enhanced TCA effects; barbiturates cause reduced TCA effects; EtOH & barbiturates cause sedative effects

3) 2nd/3rd generation: bupropion is contraindicated in patients taking Zyban for smoking cessation

4) SSRIs: nothing specific, but as always, serotonin syndrome may result with use of other antidepressants

Front 52

Learning Objective #3

How do you treat TCA overdose?

How do you treat serotonin syndrome?

Back 52

Treating TCA overdose: pacing required

Treating serotonin syndrome: intravenous fluids, oxygen therapy, cooling blankets, medications for high blood pressure, and a ventilator to support breathing

Front 53

Learning Objective #4

What effects does lithium have on neurotransmitter action?

Back 53

Lithium depresses noradrenergic or serotonergic transmission by decreasing formation of postsynaptic 2nd messengers