Exam 2 - 507: Pharmacology of Antidepressants

Learning Objectives

• Describe the pathophysiology of depression

• Classify the individual antidepressants in drug classes

• Describe the mechanism of action (MOA) of the different groups of antidepressants

• Explain the side effects of the different groups of antidepressants

• Explain possible drug-food interactions

• Explain possible drug-drug interactions

• Assess different antidepressants for their use in therapy

What is the pathophysiology of depression?

• Cann occur as depression only or

• Alternating with periods of mania (Bipolar disorder)

What is the monoamine hypothesis?

• Deficiency & imbalance of the neurotransmitters

  • Serotonin (5-HT = 5-hydroxytryptamine)

  • Norepinephrine (NE, Noradrenaline)

• And their inter-relationship with dopamine

Antidepressant therapy aims to correct transmitter deficiency/imbalance

What is the functional group found in common monoamines?

NH₂ - amines

What are the anitdepressant agents we use?

• 1. Tricyclic Antidepressants (TCAs)

• 2. MonoamineOxidaseInhibitors(MAOIs)

• 3. Selective Serotonin Reuptake Inhibitors(SSRI)

• 4. Selective Noradrenaline Reuptake Inhibitors (NARIs)

• 5. Selective 5-HT/NE Reuptake Inhibitors(SNRIs)

• 6. AtypicalAntidepressants

How can serotonergic and noradrenergic transmitter concentrations be increased/balanced?

• Electrical signal is translated into a chemical signal

• Transmission is facilitated by the neurotransmitter

• Neurotransmitter is recycled by reuptake in pre-synaptic cell NET

• Partially repackaged and reused, partially destroyed by enzyme MAO

• By increasing or decreasing the amount of neurotransmitter in the synaptic cleft, medications can make it more or less likely that a message will be transmitted to the next cell

What the MOA of MAO inhibitors?

• MAO is an enzyme that breaks down transmitter that isn’t stored in vesicles = cellular housekeeping

• MAO inhibitors increase the amount of neurotransmitter that is capable to be released in the synapse

• Inhibition of MAO prevents degradation of neurotransmitters and therefore increase their availability

What are the two subtypes of MAO inhibitors? Which NT do they prefer?

• MAO-A → prefers 5-HT, but also metabolizes NE and DA

• MAO-B → prefers DA

Inhibition of which subtype, A or B, is responsible for antidepressant effect?

MAO-A inhibition

Which MAO-Is have irreversible effect?

Isocarboxazide

Phenelzine

Tranylcypromine

These drugs form covalent bonds with NTs

Which MAO-I has a reversible effect?

Moclobemide

Which MAO-I is selective for MAO-B Parkinson treatment (depletion of dopamine)?

Selegiline

Why are MAO-Is not used commonly today?

• Drug-drug and drug-food interaction due to MAO in GI to metabolize tyramine.

• MAO inhibition leads to tyramine build-up.

What is the tyramine effect?

It is a severe irreversible/nonselective MAOI side effect

• Life threatening hypertension

• Nonselective = inhibits MAO-A & B (MAO-A = intestinal & brain, MAO-B hepatic enzymes)

• Amines such as tyramine from dietary sources accumulate and exert their effects systemically

How to tricyclic antidepressants (TCAs) exert their effect?

• Interfering with reuptake. The cell is recycling the neurotransmitter.

• TCAs block the channel that takes them back into the presynaptic cell.

• Neurotransmitter stays in the synaptic cleft longer, which increases the likelihood to bind to the postsynaptic receptor.

What is the MOA of TCAs?

Inhibit the reuptake of 5-HT & NE

• Different TCAs have different level of selectivity: e.g. Desipramine more selective NET than SERT inhibitor

• TCAs block many other receptors: alpha-adrenergic, histamine, and muscarinic receptors

Inhibition of which receptors leads to what side effects?

• Inhibition of:

  • Alpha receptor: orthostatic hypotension& dizziness

  • Histamine receptor: sedation

  • Muscarinic receptors: anticholinergic effects like blurred vision, dry mouth, constipation, urinary retention

  • Cardiac Na+ channels: antiarrhythmic effect, can lead to cardiac conduction abnormalities

Which TCA’s are used today?

Amitriptyline (Elavil)

Amoxapine(Asendin)

Clomipramine(Anafranil)

Desipramine(Norpramin)

Doxepin(Sinequan)

Imipramine(Tofranil)

Maprotiline(Ludiomil)

Nortriptyline (Pamelor)

Protriptyline (Vivactil)

What is the MAO os SSRIs? Besides depression, what else can they be used for?

Inhibition of serotonin reuptake only

• Also used for psychiatric disorders besides depression: anxiety, PTSD,OCD

What generation antidepressant drug are SSRIs?

2nd generation

What generation antidepressant are TCAs and MAO-Is?

1st generation

Which side effects are seen with SSRI use?

• Serotonin syndrome risk if taken with other substances that increase serotonin

  • CNS: Increased heart rate, insomnia

  • Spinal: Sexual side effects (erectile dysfunction)

  • GI & CNS: vomiting & diarrhea

• Withdrawal: temporary deficiency in synaptic serotonin = headache, nausea, vomiting, sleep disturbances, agitation

What are our SSRI agents?

Citalopram(Celexa)

Escitalopram (Lexapro)

Fluoxetine (Prozac)

Paroxetine (Paxil)

Sertraline (Zoloft)

What are NARIs and what is their MOA?

Selective Noradrenaline reuptake inhibitors

• They inhibit the reuptake of noradrenaline only

What are NARI's their role in therapy?

• Effective only on Noradrenaline reuptake

• Treatment option for people who have not responded to SSRIs

Which NARIs are used?

Atomoxetine (Strattera) - for ADHD

Reboxetine (Edronax)

What are SNRIs and what is their MOA?

SNRIs = Selective 5-HT/NE Reuptake Inhibitors(SNRIs)

• They inhibit the reuptake of NEand HT-5

What other uses do SNRIs have?

Effective in fibromyalgia and neuropathy pain

What side effects are seen with SNRI use?

Comparable to SSRI

Increased blood pressure and heart rate

Which SNRIs do we use?

Venlafaxine (Effexor)

Desvenlafaxine (Pristiq)

Duloxetine(Cymbalta)

Levomilnacipran (Fetzima)

What are our atypical antidepressants?

Bupropion (Wellbutrin)

Mirtazapine (Remeron)

Trazodone (Desyrel)

Nefazodone (Serzone)

Vilazodone (Viibryd)

Vortioxetine (Trintellix & Brintellix)

They have unique MOAs

What is Bupropion’s MOA and other uses?

Weak NE and DA reuptake inhibitor

Used for nicotine withdrawal symptoms

What is Mirtazapine’s MOA and other uses?

Presynaptic alpha-2 receptor antagonist

Increases neuronal transmission, antihistaminic

What are Trazodone’s and Nefazodone’ MOA?

Reuptake of serotonin and block postsynaptic serotonin receptors of subtype A

• Activation of subtype 5-HT 2A contributes to depression.

Antihistaminic and blocks alpha-1 receptor (=sedative effects)

What is Vilazodone’s MOA?

Stimulates 5HT receptors and SERT inhibition