Phar 442 -Antidepressants

Front 1

What are the symptoms of major depression?

Back 1

1) Intense sadness & despair

2) Mental Slowing and loss of concentration

3) Loss of Energy, diminished interests

4) Agitation and feelings of worthlessness

Front 2

"Antidepressants reverse the effects of other depressant drugs" True or False?

Back 2

FALSE

Front 3

"Antidepressant drugs act on ________ synaptic transmission in the brain"

Back 3

Monoaminergic

Front 4

What regulates Noradrenergic neurons?

Back 4

By Norepineprhine (NE) receptors

Front 5

What are the different sites of Presynaptic α-2 receptors?

Back 5

Axon terminals and the Soma & Proximal Dendrites (somatodendritic autoreceptors)

Front 6

What is the function of Presynaptic α-2 receptors?

Back 6

Functions to inhibit NE release acting as a "protective brake" for the NE neuron from excessive transmitter release

Front 7

What are the receptors found post-synaptically on Noradrenergic Neurons?

Back 7

α-1, α-2, β-1 adrenergic receptors

Front 8

What are the methods of Norepinephrine inactivation in Noradrenergic Neurons?

Back 8

1) Reuptake transporter pump

2) Enzymatic Degradation via COMT (Catechol-O-Methyl Transferase)[found in synaptic cleft]

3) Enzymatic Degradation via Monoamine Oxidase (MAO)[found in the presynaptic terminal]

Front 9

What regulates Serotoninergic Neurons?

Back 9

>20 Serotonin receptors

Front 10

Where are 5HT1D & 5HT1B receptors found and what is their function?

Back 10

Found in Presynaptic axon terminals, when agonized will inhibit transmitter release

Front 11

Where are 5HT1A receptors found and what is their function?

Back 11

Found in somatodendritic sites, when agonized will inhibit spike genesis & transmission

Front 12

Where are 5HT2A receptors found and what is their function?

Back 12

Found postsynaptically, when agonized, postsynaptic excitation and action potentials occur (via production of G-proteins and Second Messengers)

Front 13

What are the methods of 5-HT inactivation in Serotoninergic Neurons?

Back 13

1) Presynaptic transport pump selective for 5HT 2) MAO metabolizes 5HT to an inactive metabolite in the presynaptic terminals

Front 14

Which Dopamine receptor is well studied and is stimulated for the treatment of Parkinson's Disease?

Back 14

D2

Front 15

Which Dopamine receptor is blocked for the treatment of Schizophrenia?

Back 15

D2

Front 16

What are the methods of DA inactivation in Dopaminergic Neurons?

Back 16

1) Same enzymes that inactivate NE: namely MAO (presynaptic terminal) and COMT (synaptic cleft)

2) Presynaptic re-uptake transporter selective for DA

Front 17

What is the Biogenic Amine Theory of Depression ?

Back 17

It infers that something is wrong with the receptors for the key monoamine neurotransmitters.

It could be due to a

i) Depletion of monoamine neurotransmitters

ii) Abnormalities in receptors themselves

iii) Some problem with signal transduction of the neurotransmitter message

Front 18

What is the origin of the Biogenic Amine Theory of Depression?

Back 18

1) Drugs that deplete biogenic amines (e.g. Reserpine) tends to produce a state of depression in mentally normal people

2) Drugs that increase biogenic amines (e.g TCAs,MAO) at the synaptic level tends to alleviate depression

Front 19

What are examples of Tricyclic Antidepressants (TCAs)?

Back 19

i) Imipramine --> Desipramine

ii) Amityptiline --> Nortriptyline

iii) Trimipramine --> Protrityline

iv) Clomipramine

v) Doxepine

Front 20

What is the MOA of Tricyclic Antidepressants (TCAs)?

Back 20

1) Blocks the neuronal uptake of the Biogenic Amines (5HT & NA)

2) Down-regulation of 5HT receptors in the Brain

Front 21

"Tertiary Amines preferentially block the reuptake of _____"

Back 21

Serotonin (5-HT)

Front 22

"Secondary Amines preferentially block the reuptake of ______"

Back 22

Noradrenaline (NA)

Front 23

Why is the neuronal uptake for Biogenic Amines theory of TCAs considered flawed?

Back 23

If TCAs rapidly block the uptake (in hours) yet the drugs must generally be administered for 2 weeks to see clinical improvement.

Atypical antidepressant drugs (e.g. Trazodone, Iprindole, Mionserin) do not block biogenic amine uptake yet are just as effective clinically

Front 24

What are the side effects of TCAs?

Back 24

1) Anticholinergic muscarinic receptor blockade (constipation, blurred vision, dry mouth, drowsiness)

2) α1-receptor blockade (Dizziness, orthostatic hypotension, reflex tachycardia, drowsiness)

3) H1-Histamine receptor blockade (weight gain, drowsiness)

4) An overdose blocks Na channels (Cardiac arrhythmias, seizures)

5) Sedation

6) Conversion to mania or hypomania

Front 25

Which TCAs are more likely to have Anticholinergic, muscuranic receptor blockade? (i.e. Constipation, Blurred Vision, Dry mouth, Drowsiness)

Back 25

More common with Amitriptyline, Imipramine, Doxepin

Front 26

Which TCAs are least likely to have Anticholinergic, muscuranic receptor blockade? (i.e. Constipation, Blurred Vision, Dry mouth, Drowsiness)

Back 26

Less common with Desipramine

Front 27

Which TCAs are more likely to have Sedation?

Back 27

More common with Amitriptyline, Trimipramine, Doxepin (tertiary forms)

Front 28

Which TCAs are least likely to have Sedation?

Back 28

Less common with Protriptyline, Desipramine (secondary form)

Front 29

"TCAs do NOT elevate mood in normal subjects" True or False?

Back 29

TRUE

Front 30

"TCAs are Drugs of Abuse" True or False?

Back 30

FALSE

Front 31

What are the symptoms of TCA Overdose?

Back 31

Hyperpyrexia, Arrhythmias, Hypertension, Delirium, Seizures = Serotonin Syndrome

Front 32

What are examples of Selective Serotonin Reuptake Inhibitors (SSRIs)?

Back 32

Fluoxetine, Fluvoxamine, Paroxetine, Sertraline, Citalopram, Escitalopram

Front 33

What is the MOA of SSRIs?

Back 33

Selectively blocks the neuronal reuptake of 5-HT; i) acutely block the 5HT reuptake pumps increasing 5HT levels preferentially in the somatodendritic area of the serotonin neuron

ii) Increased 5HT following SSRI administration leads to 5HT1A receptor down regulation and more 5HT neuron impulses (spike activity)

Front 34

What are the side effects of SSRIs?

Back 34

Generally SSRIs are better tolerated than TCAs

1) GI Distress (constipation, diarrhea)

2) Sexual Dysfunction

3) Relatively safer in cases of overdose compared to TCAs

Front 35

Which side effects are more likely to occur in SSRIs than TCAs?

Back 35

Insomnia, Anxiety and Agitation are more common with SSRIs than with TCAs

Front 36

Which side effects are less likely to occur in SSRIs than TCAs?

Back 36

Anticholinergic symptoms (constipation, blurred vision, dry mouth, drowsiness), Sedation and Dizziness are less likely with SSRIs than with TCAs

Front 37

What are examples of Monoamine Oxidase Inhibitors (MAOIs)?

Back 37

Phenelzine, Tranylcypromine, Isocarboxazide

Front 38

What is the MOA of Monoamine Oxidase Inhibitors?

Back 38

1) Irreversible inhibitors of MAO

2) Non-selective MAO inhibition (MAO(a) and MAO(b))

Front 39

"MAOIs have a greater potenital for toxcitiy particularly with drug interaction, compared to other Antidepressants" True or False?

Back 39

TRUE

Front 40

What are the side effects of MAOIs?

Back 40

1) Weight Gain

2) Sexual Dysfunction

3) CNS Stimulation: Agitation

4) CV System: Orthostatic Hypotension

Front 41

When is a Hypertensive Crisis likely to occur In patients who take MAOIs?

Back 41

In patients who eat a lot of Tyramine containing foods (like Beer, Smoked meats and aged cheeses)

Front 42

What are examples of Reversible MAO(a) Inhibitors (RIMAs)?

Back 42

Meclobemide

Front 43

What is the MOA of RIMAs?

Back 43

In the presence of a RIMA, the accumulation of NE caused by Tyramien can displace the binding of RIMA off MAO.

MAO, now devoid of its inhibitor can catabolize NE and thus prevent the dangerous accumulation NE

Front 44

What are the benefits of RIMAs over MAOIs?

Back 44

1) Less potential for "Tyramine Interaction"

2) Less potential for Interaction with 5-HT uptake blockers??

Front 45

What are examples of Noradrenaline and Dopamine Reuptake Inhibitors (NDRIs)?

Back 45

Bupropion

Front 46

What is the MOA of NA & DA reuptake Inhibitors?

Back 46

Blocks NE Reuptake

Front 47

"With NDRIs (e.g. Bupropion), a hydroxylated metabolite is more potent in blocking NE reuptake than its parent compound" True or False?

Back 47

TRUE

Front 48

When would Bupropion be a good choice?

Back 48

Good for individuals with SSRI induced sexual dysfunction, ADHD or treatment of Smoking Cessation

Front 49

What are the side effects of NDRIs (e.g. Bupropion)?

Back 49

In general, fewer Ses than with TCAs/SSRIs

1) Insomnia

2) CNS Stimulation

3) Headaches

4) Nausea

5) Seizures

Front 50

What are the benefits of Buproprion?

Back 50

Less sexual dysfunction compared with SSRIs, only marginal weight gain, orthostatic hypotension

Front 51

What are examples of 5-HT, NA and DA Reuptake Blockers (SNRIs)?

Back 51

Venlafaxine, Duloxetine

Front 52

What is the MOA of SNRIs?

Back 52

1) Inhibits the reuptake of Serotonin(5-HT) and NA

2) Weak, if any α, cholinergic or Histamine receptor blockade

Front 53

Why are SNRIs considered to have a "dose dependent MOA"?

Back 53

At low doses, it is essentially an SSRI.

At medium doses, NA uptake is blocked.

At high doses, similar to Bupropion.

Front 54

What are the side effects of SNRIs?

Back 54

1) Nausea

2) Drowsiness

3) Dizziness

4) Sexual Dysfunction

5) Headache

6) Anxiety

7) Hypertension (with high doses)

Front 55

What are examples of 5-HT2 Antagonists and 5-HT Reuptake Inhibitors (SARI)?

Back 55

Trazodone

Front 56

What is the MOA of SARI (e.g. Trazodone)?

Back 56

1) Potent blocker of 5HT2A receptors (reducing anxiety, insomnia and myoclonus)

2) Moderate 5-HT reuptake blocker, but less than TCAs or SSRIs

3) Also blocks α receptors & Histamine receptors

Front 57

"Trazodone potently blocks NE reuptake" True or False?

Back 57

FALSE

Front 58

What are the side effects of Trazodone?

Back 58

1) Orthostatic Hypotension

2) Sedation

Front 59

What are examples of NA and Specific 5-HT Antagonist (NaSSAs)?

Back 59

Mirtazapine

Front 60

What is the MOA of NaSSAs (e.g. Mirtazapine)?

Back 60

1) α2 antagonism on presynaptic autoreceptors of noradrenergic neurons (enhances NA neurotransmission

2) α2 antagonism on presynaptic heteroreceptors of serotonergic neurons (enhances 5-HT neurotransmission)

Front 61

What are the side effects of NaSSAs?

Back 61

5HT2A --> Sedation, reduced sexual dysfunction

5HT2C --> Anxiolytic action, weight gain

5HT3 --> No Nausea

H1--> Weight Gain & Sedation

Front 62

What are the relevant drug interactions for TCAs?

Back 62

1) MAOIs (serotonin syndrome) :

2) Guanethidine (Hypertension)

3) Clonidine: (Hypertension)

4) Adrenergics

5) CNS depressants:(Enhances the effects of alcohol)

6) Agents which bind to plasma proteins

Front 63

What are the relevant drug Interactions for SSRIs?

Back 63

1) MAOIs

2) CNS Depressants

Front 64

What are the relevant drug interactions for MAOIs?

Back 64

1) Tyramine Containing Foods (Hypertensive Crisis; because of irreversible MAO(a) inhibitors in the gut) [Nausea, Headache, Vomitting, Palpitations, Cerebral Hemorrhage, Death]

2) Serotonin Syndrome [Hyperpyrexia, Hyperexcitability, Motor Restlessness, Coma/Death]

Front 65

Which antidepressant drugs affect Serotonin levels?

Back 65

All of them EXCEPT NA & DA reuptake Inhibitors (NDRIs) e.g. Bupropion

Front 66

Which antidepressant drugs affect Noradrenaline levels?

Back 66

All of them EXCEPT Selective Serotonin Reuptake Inhibitors and RIMAs (at high doses)

Front 67

Which antidepressant drugs affect Ach levels?

Back 67

TCAs, SARIs, NassAs

Front 68

Which antidepressant drugs affect Histamine levels?

Back 68

TCAs, SARIs, NassAs

Front 69

Which antidepressant drugs affect Dopamine levels?

Back 69

MAOIs, RIMAs, NDRIs, SNRIs