Medical Pharmacology: Drugs Used to Manage Depression

Medical Pharmacology Chapter 17: Antidepressant Agents

Antidepressant Medication : Side Effects²

A range of side effects is associated with administration of antidepressant medications with different side effects more likely to occur dependent on drug classification.

Blockade of muscarinic, cholinergic receptors:

Side effects associated with especially with tricyclic antidepressants (TCAs) include:
- Dry mouth
- Urinary retention
- Blurred vision
- Constipation
- Sinus tachycardia (mild) and possible
- Memory deficit.
Monoamine oxidase inhibitors (MAOI) are not anticholinergics; however, this agents induce anticholinergic-like side effects.

The underlying mechanism responsible for these side effects is antagonism at muscarinic-type acetylcholine receptors.

Clinical management of dry mouth, which may be very severe, includes use of sugarless gum or candy; whereas, constipation may be managed by either bulk laxatives with adequate hydration.

Urinary retention might be managed either by the use of the cholinomimetic (cholinergic agonist) bethanechol or by switching to another antidepressant class.

Bethanechol is a selective muscarinic (as opposed to nicotinic) cholinergic agonist which is resistant to hydrolysis by the acetylcholine hydrolyzing enzyme, acetylcholinesterase. The mechanism of action in this setting is based on the smooth muscle stimulatory activity of bethanechol.
Bethanechol (Urecholine)

2D model

Ball and Stick Model
Bethanechol (Urecholine)

3D Model

With respect to sinus tachycardia associated with tricyclic antidepressant administration, the mechanism highlights that the prominent autonomic tone at the SA node is muscarinic cholinergic.

**Sinus Tachycardia (150 beats/min)¹³³**

"ECG readout of an individual with sinus tachycardia. Here the heart rate is around 150."

**Atrial Tachycardia¹³⁵**

Attribution: Heartstart Skills Frasco https://www.youtube.com/watch?v=9RNhr36KlW0 (9/2009) Heartstart Skills Frasco YouTube Channel: https://www.youtube.com/channel/UCDG8UqA26LciIovorpr_bJQ "Atrial Tachycardia is caused by an irritated site in the atria. It is regularly-regular with visible P waves (unlike SVT where the P waves are absent). Intervention are focused on correcting the causes depending on the patient's stability."

This means that the normal activity of the autonomic nervous system depresses cardiac rate, an effect rapidly reversed with increased autonomic adrenergic activity. Blockade of the normal autonomic cholinergic effect as a result of cholinergic receptor blockade may result in increased heart rate.

**ECG rhythm review: Sinus rhythm, sinus bradycardia, sinus tachycardia¹³⁴**

Attribution: richACLE ECG Rhythm Review: Sinus Rhythm, Sinus Bradycardia, Sinus Tachycardia https://www.youtube.com/watch?v=mA3GuXQ6UTM (3/2010) richACLS YouTube Channel: https://www.youtube.com/channel/UC3HohCYz34uBrOVzMOg_c3A

**Examples of tricyclic antidepressant agents**
Drug Name	2D Structure	Anti- cholinergic
Amitriptyline (Elavil)
Clomipramine (Anafranil)
Doxepin (Sinequan)
Imipramine (Tofranil)
Trimipramine(Surmontil)

= 1⁺

= 2⁺

= 3⁺

Blockade of α-type adrenergic receptors:²

Blockade of α-adrenergic receptors is a mechanism for many common side effects, especially associated with older antidepressant agents.

These side effects include:

Orthostatic hypotension
- Orthostatic or postural hypotension is a reduced blood pressure noted upon standing. Normally, the tendency for blood pressure to fall upon standing is counteracted by an increase in vascular sympathetic tone which depends upon activation of α-adrenergic receptors. If these receptor sites are blocked by certain antidepressant drugs the compensatory effect is also blocked and blood pressure may decrease sufficiently to cause dizziness or result in falling. In elderly patients, falls may have especially severe consequences and caution must be used when prescribing antidepressant medications that cause orthostatic hypotension to this patient group.

Reflex tachycardia

Upon standing, increased sympathetic outflow normally increases vascular tone which maintains blood pressure.

In the presence of certain antidepressant medications which block peripheral α-adrenergic receptors this compensatory effect is lost and blood pressure falls.

The decrease in blood pressure is detected by baroreceptors and the autonomic nervous system increases output sympathetic adrenergic output to the heart, which increases rate and contractility.

The increased rate in this setting constitutes "reflex" tachycardia which in turn increases cardiac output, offsetting at least in part the hypotensive drug effect.

**Cardiac Output¹³⁶**

Attribution: virtualmedstudent The Physiology of Cardiac Output https://www.youtube.com/watch?v=0v8-O8P7kw8 virtualmedstudent YouTube Channel: https://www.youtube.com/channel/UCazD5iI-KgQXp7h-T3fEqQA

Dizziness
Flushing, and
Sweating (diaphoresis).

For management/prevention of orthostatic hypotension, drug dosage should be slowly increased or selection of safer agents represented by the SSRI drug group, nortriptyline, desipramine, or bupropion.
Antidepressant drugs that exhibit side effects associated with α-adrenergic receptor blockade include:
- Monoamine oxidase inhibitors (MAOIs)
- Tricyclic antidepressants (TCAs)
- Nefazodone (Serzone)
  - Nefazodone (Serzone)
- Trazodone (Desyrel)
  - Trazodone (Desyrel)

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