Lecture 5.1

Question 1

What does St John’s Wort do?

Answer 1

It inhibits the reuptake of serotonin, dopamine, and norepinephrine.

Question 2

What do opioids do?

Answer 2

They bind to opioid receptors and produce analgesic effects.

Question 3

What does non-selective mean?

Answer 3

Affecting multiple processes or sites than intended.

Question 4

What does irreversible mean?

Answer 4

Long-lasting and complete inactivation.

Question 5

What is a monoamine oxidase?

Answer 5

An enzyme that breaks down.

Question 6

What is MAO-a?

Answer 6

An enzyme that metabolizes serotonin, melatonin, epinephrine, and norepinephrine.

Question 7

What is MAO-b?

Answer 7

An enzyme that metabolizes phenethylamine and benzylamine.

Question 8

What are contraindications?

Answer 8

A specific situation, condition, or factor that makes a particular treatment or procedure potentially harmful or inadvisable for a patient.

Question 9

What is Tyramine?

Answer 9

Involved in regulation of blood pressure and is an enhancer of norepinephrine effects.

Question 10

What are tricyclic antidepressants (TCAs)?

Answer 10

A class of drugs, with imipramine approved by the FDA producing marked effects in MDD, increasing energy, appetite, improved sleep, and greater sociability.

Question 11

What is arrhythmia?

Answer 11

Irregular heartbeat.

Question 12

What is tachycardia?

Answer 12

Fast heartbeat.

Question 13

What are 2 historical antidepressants?

Answer 13

St John’s Wort and opioids.

Question 14

Is St John’s Wort still used today?

Answer 14

Yes, it’s currently promoted as a short-term treatment for mild-moderate depression and is just as effective as standard treatments.

Question 15

Although St John’s Wort is safe for up to 12 weeks, it weakens what?

Answer 15

It weakens the effects of antidepressants, birth control, heart medications, blood thinners, and statins.

Question 16

What are the side effects of St John’s Wort?

Answer 16

Birth defects (animal studies). Colic in breastfed babies. Gastrointestinal symptoms. Insomnia. Headache. Dizziness.

Question 17

What are 3 major limitations for opioid use?

Answer 17

Widely unregulated, causing increased risk of dependence and addiction. Advent to modern antidepressants, but are no longer used. Endogenous opioid system is involved in mood regulation.

Question 18

What are the 2 first-generation antidepressants?

Answer 18

MAOIs and TCAs.

Question 19

What were deemed ‘suicide inhibitors’ and why?

Answer 19

Original MAOIs, as they were non-selective and irreversible, meaning the enzyme can never function properly again until new ones are synthesized by neuronal DNA.

Question 20

In comparison to original MAOIs, what do modern MAOIs focus on being?

Answer 20

Selective and reversible.

Question 21

What are the 2 important types of amines as the mechanism of function (deriving from monoamine oxidase)?

Answer 21

Biogenic amines and sympathomimetic amines.

Question 22

What are examples of biogenic and sympathomimetic amines?

Answer 22

○ Biogenic amines (serotonin / dopamine / norepinephrine / epinephrine / histamine).
○ Sympathomimetic amines (tyramine / benzylamine / phenethylamine).

Question 23

What are the 2 isoenzymes throughout the body?

Answer 23

MAO-a and MAO-b.

Question 24

What do both MAO-a and MAO-b target?

Answer 24

Dopamine, tyramine, and tryptamine.

Question 25

Why can MAOIs specifically target MAO-a and MAO-b?

Answer 25

Because both MAO-a and MAO-b are present in the presynaptic terminal.

Question 26

MAOI-A drugs inhibit MAOs that target what?

Answer 26

Norepinephrine, dopamine, and serotonin.

Question 27

MAOI-B drugs inhibit MAOs that target what?

Answer 27

Dopamine primarily.

Question 28

In earlier versions, MAOIs were described as acting in what way?

Answer 28

Irreversibly 'turned off', where MAO can never function as a MAO again, so the brain must wait for new MAOs to be synthesized.

Question 29

In later versions, MAOIs were described as acting in what way?

Answer 29

As the drug wears off, MAO function returns to normal.

Question 30

How are MAOIs administered?

Answer 30

Almost always as oral tablets, but they're also available in skin patches.

Question 31

What are Australian examples of MAOIs?

Answer 31

Phenelzine (Nardil) and Tranylcypromine (Parnate).

Question 32

What are the more common and predictable side effects of MAOIs? What are the less common but possible side effects of MAOIs?

Answer 32

○ More common and predictable, including: § Dry mouth. § Gastrointestinal upset. § Headache. § Sleep disturbances (insomnia / hypersomnia). § Dizziness / lightheadedness. § Skinn irritation (if taking the patch form of MAOIs). ○ Less common, but possible, including: § Muscle cramps. § Loss of libido. § Low blood pressure. § Pins and needles. § Interactions with anesthesia. § Serotonin syndrome.

Question 33

What are the 3 contraindications for MAOIs?

Answer 33

○ There's a significant risk factor for hypertensive crisis via tyramine. § As both MAO-a and MAO-b break down tyramine, and when MAOIs are taken, the excess isn't being removed by either isoenzyme, driving blood pressure up due to its build up. Eating foods high in tyramine compounds the effect (accumulates), including aged cheeses / cured meats / vegemite. ○ Other antidepressants, as well as some cold/flu and pain medications. ○ Withdrawal, causing agitation / insomnia / anxiety / flu-like symptoms.

Question 34

Compared to placebo, MAOIs are what?

Answer 34

More effective at reducing depressive symptoms, having significantly greater effect sizes for specific drugs. Less tolerated (for patches and tranylcypromine).

Question 35

Compared to CBT, MAOIs have greater dropout rates for which drugs?

Answer 35

Selegiline (patch). Tranylcypromine. Moclobemide. Phenelzine.

Question 36

Why was imipramine (a TCA) developed? Why was it named as a TCA?

Answer 36

It was developed as an antipsychotic to treat schizophrenia, but more potent alternatives were sought; named a TCA because of the 3 benzine ring molecular core (structure rather than mechanism of action).

Question 37

How do TCAs provide therapeutic action?

Answer 37

By inhibiting norepinephrine and serotonin reuptake transporters.

Question 38

TCA side effects are caused by blocking what?

Answer 38

Post-synaptic adrenergic a1 and a2 receptors. Post-synaptic muscarinic receptors. Post-synaptic histamine H1 receptors. Sodium channels in the heart and brain.

Question 39

What type of allosteric modulator are TCAs considered to be and why?

Answer 39

Negative allosteric modulator, because they bind to allosteric sites close to the neurotransmitter transporter so the neurotransmitter can't bind anymore.

Question 40

How are TCAs administered?

Answer 40

Oral tablets or capsules.

Question 41

What are Australian examples of TCAs?

Answer 41

Amitriptyline. Imipramine. Doxepine. Clomipramine.

Question 42

What are the more common and predictable side effects of TCAs? What are the less common but possible side effects of TCAs?

Answer 42

○ More common and predictable, including: § Dry mouth. § Constipation. § Dizziness. § Blurred vision. § Drowsiness. § Appetite/weight gain. § Sweating. § Memory impairments. ○ Less common, but possible, including: § Urinary retention. § Confusion. § Low blood pressure / fainting. § Arrhythmia. § Tachycardia. § Tremor. § Serotonin syndrome.

Question 43

What are the 4 contraindications for TCAs?

Answer 43

○ Overdosing due to the therapeutic window where more within a smaller timeframe can be fatal. ○ Seizures due to GABA antagonism effect, lowering seizure threshold. ○ Other antidepressants / caffeine / alcohol / history of heart, lung or kidney problems / mania. § Regular blood tests are needed to monitor hepatic and renal function. ○ Withdrawal, causing: § Gastrointestinal upset § Sleep disturbances. § Mania. § Restlessness. § Tingling/burning sensations. § Irritability. § Anxiety. § Headache. § Vivid dreams.

Question 44

Compared to placebo, TCAs are what?

Answer 44

More effective at reducing depressive symptoms. Less tolerated.

Question 45

Although MAOIs and TCAs are seemingly effective at reducing depressive symptoms, …?

Answer 45

They're associated with increased risk of negative side effects and serious interactions/reactions.

Question 46

When might MAOIs and TCAs be considered for treatment?

Answer 46

They may be considered a second-choice treatment where intolerance or a lack of response to other (safer/effective) antidepressants experienced.