Slides Antidepressants CNS Pharmacology

The Antidepressants
With Dr. PJ Shukle
Opio Dennis, opiodennisk@yahoo.com

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The Antidepressants
Robin Williams Kurt Cobain Whitney Houston Marilyn Monroe
1951 - 2014 1967 - 1994 1963 - 2012 1926 - 1962
Day donaldson, Kurt Cobain New "Solo Album" Of Unreleased Tracks To Be Released, https://flic.kr/p/x2qosc CC BY 2.0
Overview
• Monoamine oxidase inhibitors (MAOIs)
• Technically
• correct, but
1. Serotonin-Norepinephrine Reuptake Inhibitors
not used in
2. practice or
3. Others in textbooks
• )

Drug Mechanisms
Noradrenergic neuron Serotonergic neuron
- MAO inhibitors -
Metabolites MAO MAO Metabolites
α2 receptor
-
Depression is the result of low levels of
serotonin orMirazapine
norepinephrine in the
NE reuptake synaptic cleft. 5-HT reuptake
- NE receptor 5-HT receptor -
Desipramine, Fluoxetine,
maprotiline trazodone
Postsynaptic neuron

Drug Mechanisms
- MAO inhibitors -
α2 receptor
-
Mirtazapine
NE reuptake 5-HT reuptake
Desipramine, Fluoxetine,
Postsynaptic neuron

Monoamine Oxidase Inhibitors (MAOIs)
- MAO inhibitors -
α2 receptor
Monoamine oxidase inhibitors
-
will reduce the breakdown of Mirtazapine
5-HT reuptake
norepinephrine and serotonin in NE reuptake
the pre-synaptic neuron. - NE receptor 5-HT receptor -
Desipramine, Fluxetine,
Postsynaptic neuron

- MAO inhibitors -
α2 receptor
The increased amounts of -

Mirtazapine
norepinephrine and serotonin NE reuptake 5-HT reuptake
are stored in the vesicles.
Postsynaptic neuron

- MAO inhibitors -
α2 receptor
When the nerve fires, the -

Mirtazapine
increased amount of transmitter is NE reuptake 5-HT reuptake
released into the synaptic cleft.
Postsynaptic neuron

Nonselective MAO-A/MAO-B inhibitors
• Phenelzine, tranylcypromine, and 21 others
Nonselective MAO-A inhibitors
• Moclobemide (MannerixR)
Selective MAO-B inhibitors
• Selegiline (DeprenylR

Side effects due to increased NE in nerve terminals:
• Peripheral autonomic sympathomimetic effects
• May lower blood pressure
• Seizure threshold reduced (increased risk of seizures)

In the absence of indirect sympathomimetic:
• MAOIs cause a drop in blood pressure

In the presence of indirect sympathomimetic:
• MAOIs cause a rise in blood pressure
• MAOIs may cause severe hypertension in patients

taking tyramine
• Tyramine is metabolized by monoamine oxidase
• Found in:
• Aged cheeses, soybeans, beers, red wine
• Cured and processed meats

Tricyclic antidepressants inhibit - MAO inhibitors -

reuptake of norepinephrine and Metabolites MAO MAO Metabolites
α2 receptor
serotonin.
-
Mirtazapine
• Undergo first pass metabolism NE reuptake 5-HT reuptake
• High volumes of distribution - NE receptor 5-HT receptor -
• Not dialyzable maprotiline trazodone
Postsynaptic neuron

- MAO inhibitors -
peripheral tissues including: Metabolites MAO MAO Metabolites
α2 receptor
• Histamine (H1) -
Mirtazapine
• Muscarinic (MM) NE reuptake 5-HT reuptake

• Adrenergic (α)
This results in multiple side effects. maprotiline trazodone
Postsynaptic neuron

Older drugs,
H1 antagonism More side effects
• Sedation, drowsiness, weight gain Amitriptyline
ACh antagonism Doxepin

• Blurred eyes, dry mouth, constipation
Imipramine
α 1 antagonism
• Priapism, postural hypotension Nortriptyline
Desipramine
α 2 antagonism
• Dizziness, reflex tachycardia Newer drugs,
Fewer side effects

Older drugs,
More side effects
NE uptake inhibition Amitriptyline

• Dry mouth, urinary retention, tremor
Doxepin
5HT reuptake inhibition

Imipramine
• GI disturbances
Nortriptyline
5HT antagonism
• Nausea Desipramine
Newer drugs,
Fewer side effects

• Seizure threshold reduced
• Increased risk of seizure
• Also seen in MAOIs
• Additive effects with ethanol
• May antagonize methyldopa/clonidine

Coma
Convulsions Cardiotoxicity

- MAO inhibitors -
• α2 receptor
interactions in the periphery -
Mirtazapine
• There are still some other NE reuptake 5-HT reuptake
miscellaneous receptors that are
affected.
Postsynaptic neuron

Bupropion (WellbutrinR and ZybanR)
• Is used in both depression and smoking cessation
• Used in depression as an add-on to other drugs
• Antagonizes central NE/5-HT reuptake
• Antagonizes nicotine receptors
• Side effects:
• Anxiety, agitation, dry mouth
• Aggravation of psychosis
• Seizures at high doses

Maprotiline, Amoxapine
Mirtazapine (RemeronR)
• Antagonizes NE/serotonin reuptake
• Antagonizes serotonin receptors directly
• Increases release by antagonizing presynaptic α2 adrenoreceptors
• Decreased feedback inhibition
• Side effects:
• Weight gain
• Sedating

- MAO inhibitors -
α2 receptor
•
to reuptake actions -
Mirtazapine
•
on peripheral tissues - NE receptor 5-HT receptor -
Postsynaptic neuron

Duloxetine (CymbaltaR)
• Depressive disorders
• Neuropathic pain
• Diabetic neuropathy
Venlafaxine (EffexorR, Effexor XRR)
• Has less affinity for NE than duloxetine
• Side effects:
• Increased blood pressure
• Withdrawal symptoms, even after missing one dose!

-
- MAO inhibitors -
• A relatively targeted activity against Metabolites MAO MAO Metabolites
α2 receptor
the serotonin (5-HT) receptor, which is
g-protein mediated, and located in the -
Mirtazapine
neocortex. NE reuptake 5-HT reuptake
• This results in antianxiety and - NE receptor 5-HT receptor -

antidepressant action. Desipramine, Fluxetine,
Postsynaptic neuron

-
Block the 5-HT2A receptor

• A G-protein coupled receptor located in the neocortex
Short-acting; May be prescribed 2- to 3 times a day
Nefazodone
• Not used much anymore because of CYP 3A4 activity
Trazodone
• Commonly used as a sleep aid

• Allosteric inhibition
- MAO inhibitors -
• Minimal effects on NE uptake α2 receptor
-
• Bind at a different site Mirtazapine
• Minimal side effects
• This results in antianxiety and Desipramine, Fluoxetine,

antidepressant action. maprotiline trazodone
Postsynaptic neuron

• Citalopram (CelexaR)
• Escitalopram (LexaproR)
• Fluoxetine (ProzacR)
•
• Fluvoxamine (LuvoxR)
• Fewer, almost minimal side effects
• Paroxetine (PaxilR)
• Sertraline (ZoloftR)
• 33 others

Toxicity
• Headache, nausea, anxiety, agitation
• use a low dose benzodiazepine
• Extrapyramidal side effects
• Akathisia, dyskinesias, dystonic reactions

(see dystonic reactions ANS pharmacology 1)

Drug interactions
Fluoxetine (ProzacR) inhibits CYP450 2D6 and 3A4.

Will increase plasma levels:
• Dextromethorphan
• Propranolol
• Tamoxifen
• Tricyclic antidepressants
Fluvoxemine (LuvoxR) inhibits CYP 1A2.
Citalopram (CelexaR) affects fewer drugs and CYP.

Serotonin Syndrome
• First described as a reaction between MAOIs and
• Life-threatening:
CNS stimulation Cardiovascular stimulation GI stimulation
• Severe muscle rigidity, • Tachycardia • Increased bowel sounds,

myoclonus, hyperreflexia diarrhea
• Unstable blood pressures
• Hyperthermia
• Seizures, mydriasis

M ental status change
A gitation T achycardia
D iarrhea I ncreased reflexes
A taxia P yrexia
M yoclonus S weating
S hivering

Review
• Used in major depressive disorder
•
But are not more effective
• trazadone)
• Selected agents may be used in:
• Parkinsonianism (selegiline) see next lecture
• Smoking cessation (venlafaxine)
• Chronic pain (amitriptyline, duloxetine,

venlafaxine)
• Diabetic neuropathy (duloxetine)

Question 1: CNS Pharmacology 2
false?
A. Selective serotonin reuptake inhibitors may take up to 2 weeks to have

an effect.
B. Combining them with MAOIs may lead to serotonin syndrome.
C. Are competitive inhibitors of the serotonin receptor in nerve endings.
D. Work as well as tricyclic antidepressants, but have fewer side effects.

false?
A. Selective serotonin reuptake inhibitors may take up to 2 weeks to have

an effect.
B. Combining them with MAOIs may lead to serotonin syndrome.
C. Are competitive inhibitors of the serotonin receptor in nerve endings.
D. Work as well as tricyclic antidepressants, but have fewer side effects.

Pick the correct statement.
A. Citalopram has a large number of drug interactions compared to other
B. MAOIs will have reduced activity when consumed with tyramine.
C. Fluoxetine will interact with multiple medications including tamoxifen.
D.
epilepsy.

Pick the correct statement.
A. Citalopram has a large number of drug interactions compared to other
B. MAOIs will have reduced activity when consumed with tyramine.
C. Fluoxetine will interact with multiple medications including tamoxifen.
D.
epilepsy.

Case Study: CNS Pharmacology 2
A 66-year old senator presents to the ER with a rapid heart rate. He is

tremulous, diaphoretic, agitated, and combative. BP 166/110, HR 130.
He is hyperreflexic. He has peripheral clonus with exaggeration in the lower
extremities. He was recently placed on sertraline for depression.
His medications are sertraline, rosuvastatin, bisoprolol, valsartan, and

selegiline. Pick the true statement:
A. The sertraline has interacted with the bisoprolol, rendering it inactive.
B. The sertraline has interacted with the rosuvastatin, causing toxicity and
rhabdomyolysis.
C. The sertraline has interacted with his antiparkinsonian medication,

selegiline.
D. The sertraline has interacted with valsartan, precipitating a hypertensive

crisis.
Case Study: CNS Pharmacology 2
A 66-year old senator presents to the ER with a rapid heart rate. He is

tremulous, diaphoretic, agitated, and combative. BP 166/110, HR 130.
He is hyperreflexic. He has peripheral clonus with exaggeration in the lower
extremities. He was recently placed on sertraline for depression.
His medications are sertraline, rosuvastatin, bisoprolol, valsartan, and

selegiline. Pick the true statement:
A. The sertraline has interacted with the bisoprolol, rendering it inactive.
B. The sertraline has interacted with the rosuvastatin, causing toxicity and
rhabdomyolysis.
C. The sertraline has interacted with his antiparkinsonian medication,

selegiline.
D. The sertraline has interacted with valsartan, precipitating a hypertensive

crisis.
Dieses Dokument gehört: Opio Dennis
Hinweis: Dieses Dokument ist urheberrechtlich geschützt. Die Vervielfältigung,

Verbreitung, Wieder- bzw. Weitergabe und sonstige Nutzung ist ohne die schriftliche
Genehmigung der Lecturio GmbH nicht gestattet.


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The Antidepressants

With Dr. PJ Shukle

Opio Dennis, opiodennisk@yahoo.com

Robin Williams Kurt Cobain Whitney Houston Marilyn Monroe

1951 - 2014 1967 - 1994 1963 - 2012 1926 - 1962

• Monoamine oxidase inhibitors (MAOIs)

Opio Dennis, opiodennisk@yahoo.com

Noradrenergic neuron Serotonergic neuron

- NE receptor 5-HT receptor -

Opio Dennis, opiodennisk@yahoo.com

Noradrenergic neuron Serotonergic neuron

- NE receptor 5-HT receptor -

Opio Dennis, opiodennisk@yahoo.com

Noradrenergic neuron Serotonergic neuron

the pre-synaptic neuron. - NE receptor 5-HT receptor -

Opio Dennis, opiodennisk@yahoo.com

Noradrenergic neuron Serotonergic neuron

The increased amounts of -

Opio Dennis, opiodennisk@yahoo.com

Noradrenergic neuron Serotonergic neuron

When the nerve fires, the -

Opio Dennis, opiodennisk@yahoo.com

Nonselective MAO-A/MAO-B inhibitors

• Phenelzine, tranylcypromine, and 21 others

Nonselective MAO-A inhibitors

Selective MAO-B inhibitors

Opio Dennis, opiodennisk@yahoo.com

Side effects due to increased NE in nerve terminals:

• Peripheral autonomic sympathomimetic effects

• May lower blood pressure

• Seizure threshold reduced (increased risk of seizures)

Opio Dennis, opiodennisk@yahoo.com

In the absence of indirect sympathomimetic:

• MAOIs cause a drop in blood pressure

Opio Dennis, opiodennisk@yahoo.com

In the presence of indirect sympathomimetic:

• MAOIs cause a rise in blood pressure

• MAOIs may cause severe hypertension in patients

• Tyramine is metabolized by monoamine oxidase

• Aged cheeses, soybeans, beers, red wine

• Cured and processed meats

Opio Dennis, opiodennisk@yahoo.com

Tricyclic antidepressants inhibit - MAO inhibitors -

• High volumes of distribution - NE receptor 5-HT receptor -

Opio Dennis, opiodennisk@yahoo.com

- NE receptor 5-HT receptor -

Opio Dennis, opiodennisk@yahoo.com

ACh antagonism Doxepin

Opio Dennis, opiodennisk@yahoo.com

NE uptake inhibition Amitriptyline

5HT reuptake inhibition

Opio Dennis, opiodennisk@yahoo.com

• Increased risk of seizure

• Also seen in MAOIs

• Additive effects with ethanol

• May antagonize methyldopa/clonidine

Opio Dennis, opiodennisk@yahoo.com

Opio Dennis, opiodennisk@yahoo.com

Opio Dennis, opiodennisk@yahoo.com