NTA Level 5 • Semester 1 • PST05104

Pharmacodynamics of Antidepressants

Pharmacology and Therapeutics • Source Session/Topic 32

Full source-text version: all educational wording from the extracted learning source is retained; only presenter/tutor metadata and web-layout noise are removed, while formatting is improved for readability.

Session 32: Pharmacodynamics of Antidepressants

Total Session Time: 120 minutes

Prerequisites

None

Learning Tasks

By the end of this session students are expected to be able to:

Explain pathophysiology of depression

Describe mechanism of action of Antidepressants

Describe drug interactions associated with Antidepressants

Describe side effects of Antidepressants

Describe contraindications of Antidepressants

Resources Needed:

Flip charts, marker pens, and masking tape

Black/white board and chalk/whiteboard markers

Computer and LCD projector

SESSION OVERVIEW

Step

Time

Activity/

Content

Step

Time

Activity/

Content

Step

Time

Method

Content

Method

05 minutes

Presentation

Introduction, Learning tasks

20 minutes

Presentation

Pathophysiology of depression

45 minutes

Presentation/

Mechanism of Action of Antidepressants

45 minutes

Buzzing

Mechanism of Action of Antidepressants

Buzzing

20 minutes

Presentation/

Drug Interactions Associated With

20 minutes

brainstorming

Antidepressants

brainstorming

Antidepressants

10 minutes

Presentation

Side Effects of Antidepressants

PST 05104 Pharmacology & Therapeutics

251

NTA Level 5 Semester 1 Facilitator Guide

10 minutes

Presentation/

Contraindications of Antidepressants

10 minutes

Brainstorming

Contraindications of Antidepressants

Brainstorming

05 minutes

Presentation

Key Points

05 minutes

Presentation

Evaluation

PST 05104 Pharmacology & Therapeutics 252 NTA Level 5 Semester 1 Facilitator Guide

SESSION CONTENTS

STEP 1: Presentation of Session Title and Learning Tasks (5 minutes)

READ or ASK students to read the learning tasks and clarify

ASK students if they have any questions before continuing.

STEP 2: Pathophysiology of Depression (20 minutes)

Monoamine theory of depression suggest that depression is due to a cerebral deficiency of monoamines particularly noradrenaline (NA), 5-hydroxytryptamine (5HT) and methyltyrosine.

The following actions of drugs support the above theory: Reserpine -depletes neuronal stores of noradrenaline (NA) and 5-hydroxytryptamine (5HT) and α-methyltyrosine, which inhibits NA synthesis causing depression, Tricyclic antidepressants (TCA) of the amitriptyline type (which raise the synaptic concentration of NA and 5HT) are antidepressant and Monoamine oxidase inhibitors (MAOIs, which increase total brain NA and 5HT) are antidepressant.

Another theory of depression is the serotonin-only hypothesis.

o This theory emphasizes the role of 5HT and downplays that of NA in the causation of depression, and is backed by the effectiveness of the selective serotonin reuptake inhibitors, or SSRI class of drugs, in the treatment of depression.

STEP 3: Mechanism of Action of Antidepressants (45 minutes)

Activity: Buzzing (5 minutes)

ASK students to pair up and buzz on the following question for 2 minutes

How do antidepressants produce their pharmacological effects?

ALLOW few pairs to respond and let other pairs add on points not mentioned

WRITE their response on the flip chart/board

CLARIFY and SUMMARIZE by using the content below

Tricyclic Antidepressants (TCAs)

Examples include amitriptyline, desipramine, imipramine, nortriptyline, clomipramine, trimipramine, doxepin, maprotiline

PST 05104 Pharmacology & Therapeutics 253 NTA Level 5 Semester 1 Facilitator Guide

The monoamine hypothesis suggests that depression is caused by a deficiency of synaptic neurotransmitters such as serotonin (5-HT), NA, and dopamine. Serotonin, in particular, is associated with mood.

Normally, 5-HT and NA are released from presynaptic vesicles into the synaptic cleft, where they travel to postsynaptic receptors.

Once released from these postsynaptic receptors, 5-HT and NA are removed from the synaptic cleft by reuptake transporters located on the presynapse.

The TCAs inhibit the reuptake of serotonin (5-HT) and NA into the presynaptic cell body, increasing the amount of 5-HT and NA available to bind to postsynaptic receptors.

TCAs antagonize other receptors: muscarinic, histamine (H1), adrenergic (α1) receptors. This accounts for their extensive list of side effects.

Selective Serotonin Reuptake Inhibitors (SSRIs)

Examples include fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram and escitalopram.

The monoamine hypothesis suggests that depression is caused by a deficiency of synaptic neurotransmitters such as serotonin (5-HT), norepinephrine, and dopamine. Serotonin, in particular, is associated with mood.

Normally, 5-HT is released from presynaptic vesicles into the synaptic cleft, where it

travels to postsynaptic receptors.

Once released from these postsynaptic receptors, 5-HT is removed from the synaptic cleft by reuptake transporters located on the presynapse. Once it is taken up

presynaptically, it is degraded.

SSRIs bind to this reuptake transporter, preventing the removal of 5-HT and leading to increased 5-HT available to bind to postsynaptic receptors.

Serotonin-Noradrenaline Reuptake Inhibitors (SNRIs)

Examples include venlafaxine, desvenlafaxine, duloxetine and milnacipran

Once released from these postsynaptic receptors, 5-HT and NA are removed from the

synaptic cleft by reuptake transporters located on the presynapse. Once they are taken up presynaptically, they are degraded.

SNRIs bind to these reuptake transporters, preventing the removal of 5-HT and NA

and leading to increased availability to bind to postsynaptic receptors.

Venlafaxine has much higher affinity for the serotonin reuptake transporter, and at low

doses acts more like an SSRI. It is not until higher doses are used that it also blocks noradrenaline reuptake.

o Conversely, milnacipran blocks serotonin and noradrenaline reuptake equally, whereas the other agents in this class fall somewhere between these two.

PST 05104 Pharmacology & Therapeutics 254 NTA Level 5 Semester 1 Facilitator Guide

Monoamine oxidase Inhibitors (MAOIs)

Examples include :Selective to MAO-B: Selegiline, rasagiline, Selective to MAO-A:

Moclobemide and Nonselective inhibitors: phenelzine and tranylcypromine

o MAO degrades catecholamines, serotonin, and other endogenous amines in the CNS as well as in the periphery.

o There are two key isoenzymes: MAO-A which degrades epinephrine, norepinephrine, and serotonin and MAO-B which degrades phenylethylamine. Both degrade dopamine.

o The purpose of MAO inhibition is therefore to increase levels of these substances within the body, specifically the CNS. The efficacy of these agents is a result of their actions within the CNS, whereas the side effects are largely mediated by their actions outside of the CNS.

Noradrenergic and Specific Serotonergic Antidepressants (NaSSAs)

Mirtazapine increases noradrenergic and serotonergic neurotransmission via central

α2 adrenoceptors.

The increased release of 5HT stimulates 5HT1 receptors, whilst 5HT2 and 5HT3

receptors are blocked. H1 receptors are also blocked.

This combination of actions appears to be associated with antidepressant activity, anxiolytic and sedative effects.

STEP 4: Drug Interactions Associated with Antidepressants (20 minutes)

Activity: Brainstorming (5 minutes)

Ask students to brainstorm on the following question:

What are drug interactions associated with antidepressants drugs?

ALLOW few students to respond

WRITE their responses on the flip chart/ board

CLARIFY and SUMMARISE by using the content below

Tricyclic Antidepressants (TCAs)

Examples include amitriptyline, desipramine, imipramine, nortriptyline and others. o Most TCAs exhibit some degree of CP450 enzyme inhibition.

o The most prominent inhibitors are amitriptyline, imipramine, clomipramine, and doxepin, mainly at CYP2C19.

PST 05104 Pharmacology & Therapeutics 255 NTA Level 5 Semester 1 Facilitator Guide

Selective Serotonin Reuptake Inhibitors (SSRIs)

Examples include fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram and others. o The SSRIs inhibit multiple CYP450 isozymes.

o Fluoxetine and paroxetine inhibit the CYP2D6 isoenzyme, and this can lead to clinically important drug interactions with drugs such as tricyclic antidepressants (TCAs), carbamazepine, or vinblastine.

o There is also a very serious interaction with thioridazine (see Contraindications).

Serotonin-Noradrenaline Reuptake Inhibitors (SNRIs)

Examples include: venlafaxine, desvenlafaxine, duloxetine, milnacipran

o Duloxetine and (to a lesser extent) venlafaxine are inhibitors of CYP2D6.

Monoamine oxidase Inhibitors (MAOIs)

Examples include: Selective to MAO-B: Selegiline, rasagiline, Selective to MAO-A:

Moclobemide and Nonselective inhibitors: phenelzine and tranylcypromine

o Hypertensive crisis occurs because of a drug-drug or drug-food interaction, leading to increased levels of norepinephrine and subsequent rapid elevation in blood pressure. Before the triggering factors (tyramine-rich foods) were identified, this interaction limited the utility of these agents.

STEP 5: Side Effects of Antidepressants (10 minutes)

Tricyclic Antidepressants (TCAs)

Examples include amitriptyline, desipramine, imipramine, nortriptyline and others.

o Anticholinergic: Dry mouth, Confusion, Urinary retention, Constipation, Blurred vision and increased intraocular pressure (IOP).

o Sedation: via blockade of histamine (H1) receptors.

o Serious Cardiovascular toxicities: are typically only seen when high doses are administered (see ―Important Notes‖). In high doses TCAs impair cardiac conduction, leading to a widening of the QRS complex and heart block, often accompanied by hypotension.

o Orthostatic hypotension: related to blockade of α1 receptors.

Selective Serotonin Reuptake Inhibitors (SSRIs)

Examples include fluoxetine, fluvoxamine, paroxetine, sertraline and others.

o Serotonin syndrome (SS) is a rare but potentially life-threatening elevation in serotonin, most commonly caused by concomitant use of SSRIs and MAOIs.

o Symptoms include: Hyperthermia, muscle rigidity, myoclonus, rapid fluctuations in vital signs (because of autonomic instability) and rapid fluctuations in mental status (confusion, irritability, extreme agitation, delirium, and coma).

o Sexual dysfunction may be both mechanical, as serotonin inhibits functions such as erections, ejaculation, lubrication, and orgasm, and central, as serotonin has an inhibitory effect on dopamine, a neurotransmitter believed to play an important role in arousal. Note: sexual dysfunction can also accompany depression.

o Gastrointestinal (GI) distress: Serotonin receptors are also found in the gut, and serotonin appears to have an effect on GI motility (cramping, diarrhoea, nausea) that

PST 05104 Pharmacology & Therapeutics 256 NTA Level 5 Semester 1 Facilitator Guide

becomes intolerable in some patients. Nausea and vomiting are also likely mediated by activation of serotonin receptors in the CNS.

Agitation, insomnia: These effects are likely via stimulation of central serotonin

receptors.

The intensity of this side effect can vary among the SSRI. In some cases, these side effects can be somewhat beneficial in patients who have fatigue or apathy and hypersomnia.

Serotonin-Noradrenaline Reuptake Inhibitors (SNRIs)

Examples include: venlafaxine, desvenlafaxine, duloxetine, milnacipran

Gastrointestinal (GI) distress, attributed to inhibition of serotonin reuptake, appears to

be most common with venlafaxine.

Stimulation of serotonin receptors in the brain likely mediates nausea. Serotonin receptors are also found in the gut, and serotonin appears to have an effect on GI motility that becomes intolerable in some patients, leading to cramping and diarrhoea.

Dizziness may occur although the mechanism is unknown.

Somnolence may be secondary to sleep disturbances, although the mechanism is

unknown.

Insomnia may occur due to stimulation of 5-HT receptors in the CNS. Both the length and quality of sleep may be impaired.

Sexual dysfunction, attributed to inhibition of serotonin reuptake, appears to be most

common with venlafaxine.

It may be both mechanical, as serotonin inhibits functions such as erections, ejaculation, lubrication, and orgasm, and central, as serotonin has an inhibitory effect

on dopamine, a neurotransmitter believed to play an important role in arousal.

Sweating: The mechanism for this effect has not been established.

Dry mouth is likely caused by NA.

Sustained hypertension is dose related. The elevation in blood pressure is likely caused by the pressor effects of increased NA. Patients should have blood pressure monitored.

Monoamine oxidase Inhibitors (MAOIs)

Examples include: Selective to MAO-B: Selegiline, rasagiline, Selective to MAO-A:

Moclobemide and Nonselective inhibitors: phenelzine and tranylcypromine

Sleep disturbances include insomnia.

The insomnia is likely a central stimulatory effect from the increased monoamines, although a mechanism has not been established. Moclobemide, a reversible and

selective MAO-A inhibitor, may cause fewer problems with sleep.

Weight gain is a common side effect of antidepressants; likely, increased monoamines play a role, but the mechanism has not been established.

Postural hypotension: The mechanism has not been established. This can be

problematic in elderly patients, leading to falls.

Sexual disturbances: Might be due to enhanced serotonin activity resulting to sexual dysfunction with these agents.

PST 05104 Pharmacology & Therapeutics 257 NTA Level 5 Semester 1 Facilitator Guide

Noradrenergic and Specific Serotonergic Antidepressants (NaSSAs) Examples include: Mirtazapine

o Sedation occurs because of blockade of histamine receptors. It tends to predominate at lower doses, as increasing NA at higher doses counteracts this effect.

o Increased appetite may be due to H1 antagonism, although the mechanism is unclear. Weight gain may be due to H1 antagonism

STEP 6: Contraindications of Antidepressants (10 minutes)

Activity: Brainstorming (5 minutes)

Ask students to brainstorm on the following question:

What are the contraindications of antidepressants? ALLOW few students to respond?

WRITE their responses on the flip chart/ board

CLARIFY and SUMMARISE by using the content below

Tricyclic Antidepressants (TCAs)

o Avoid concomitant use of TCAs and MAOIs: TCAs increase serotonin concentrations in the synapse, whereas MAOIs inhibit the breakdown of serotonin.

o Concomitant use can therefore lead to excessive serotonin.

o When switching from a TCA to an MAOI, or vice versa, allow for a washout period of at least 2 weeks.

Selective Serotonin Reuptake Inhibitors (SSRIs)

o SSRIs and monoamine oxidase inhibitors (MAOIs): SSRIs increase serotonin concentrations in the synapse, whereas MAOIs inhibit the breakdown of serotonin. Concomitant use can therefore lead to excessive serotonin (see details in Side Effects). When switching from an SSRI to an MAOI, or vice versa, allow for a washout period of at least 1 to 2 weeks.

o SSRIs and thioridazine (an antipsychotic): Thioridazine elicits QT interval prolongation, and fluoxetine in particular enhances this effect by inhibiting the metabolism of thioridazine.

o A washout period of at least 5 weeks should elapse before someone who was on fluoxetine should be started on thioridazine, and fluoxetine should not be initiated for at least 2 weeks after discontinuation of thioridazine.

o The seriousness of these drug interactions has led to the withdrawal of thioridazine in many markets.

PST 05104 Pharmacology & Therapeutics 258 NTA Level 5 Semester 1 Facilitator Guide

Citalopram and pimozide: The combination of these two agents is associated with a greater risk of QT interval prolongation, although the mechanism is unknown.

Serotonin-Noradrenaline Reuptake Inhibitors (SNRIs)

Examples include: venlafaxine, desvenlafaxine, duloxetine, milnacipran

SNRIs and MAOIs: MAOIs inhibit the breakdown of serotonin. Concomitant use can therefore lead to excessive serotonin. When switching from an SNRI to an MAOI, or vice versa, allow for a washout period of at least 1 to 2 weeks.

Monoamine oxidase Inhibitors (MAOIs)

Examples include: Selective to MAO-B: Selegiline, rasagiline, Selective to MAO-A:

Moclobemide and Nonselective inhibitors: phenelzine and tranylcypromine

MAOI with sympathomimetics: nonselective MAOIs may potentiate the hypertensive effects of sympathomimetics, leading to a hypertensive crisis that can be fatal. Methylphenidate, dopamine, epinephrine, norepinephrine, and similar agents (methyldopa, l-dopa, l-tryptophan, l-tyrosine, and phenylalanine) should be avoided.

Foods with tyramine: See interactions of MAOIs

STEP 7: Key Points (5 minutes)

The choice is usually related to the side-effect profile of relevance to the particular patient.

Tricyclic antidepressants commonly cause antimuscarinic and cardiac effects.

Tricyclic antidepressants tend to increase appetite and weight, whereas SSRIs more commonly reduce appetite and weight.

SSRIs are associated with nausea, sexual dysfunction and sleep disturbance.

STEP 8: Evaluation (5 minutes)

What are the contraindications of TCAs?

What are side effects of MAOIs?

Why are MAOIs not preferred in patients consuming tyramine containing foods?

What are the main catecholamines that are deficient in depression?

PST 05104 Pharmacology & Therapeutics 259 NTA Level 5 Semester 1 Facilitator Guide

References

Katzung, B. G. (2018). Basic and clinical pharmacology. New York: Mcgraw Hill Education.

Santos, R. R., Rang, H. P., Dale, M. M., Ritter, J. M., & Flower, R. J. (2007). Rang & Dale Farmacologia. Rio de Janeiro: Elsevier.

Tripathi, K. (2018). Essentials of Medical Pharmacology. Place of publication not identified:

Jaypee Brothers Medical P.

Ministry of Health and Social Welfare. (2013). Standard Treatment Guidelines & National Essential Medicines List Tanzania Mainland (4th ed.). Dar es salaam, Tanzania government printers.

Robert L. Talbert, Gary C. Yee, Gary R. Matzke, Barbara G. Wells, L. Michael. (2014). Pharmacotherapy: A Pathophysiologic Approach (9th ed.). New York, McGraw-Hill Education.

Sally S.R, Jeanne C.S. (2000). Introductory Clinical Pharmacology (6th ed) New York, Lippincott Williams and Wilkins.

School of Pharmaceutical sciences. (2011).Tanzania Pharmaceutical Handbook (2nd ed.).

Dar es Salaam, ARDHI University press.

The Royal Pharmaceutical Society of Great Britain. (2007). Martindale, the Extra Pharmacopoeia (5TH ed). London, pharmaceutical press.

The Royal Pharmaceutical Society of Great Britain. 2009. British National Formulary (59th ed). London, BMJ Group and RPS Publishing.

PST 05104 Pharmacology & Therapeutics 260 NTA Level 5 Semester 1 Facilitator Guide

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