1. Tricyclic and Tetracyclic Antidepressants Adverse Effects and Pharmacokinetics
In this presentation we discuss adverse effects and pharmacokinetics of tricyclic and tetracyclic antidepressants.
Flavio Guzmán, MD

2. Overview TCAs are not safe in overdose
TCAs have anticholinergic and antihistaminic effects
Elderly patients: careful with CV effects and central anticholinergic effects
TCAs half-life: 24 hours
Desipramine is metabolized mainly by CYP2D6
Let’s begin with an overview of the topic.
Unlike SSRIs and other antidepressants, tricyclics are not safe in overdose. As we’ll see in a couple of slides, this is linked to their risk of cardiac arrhythmia.
Tricyclics bind to a number of receptors, including muscarinic and histamine 1.
We need to be careful when prescribing them to elderly patients, mainly because of cardiovascular effects and central anticholinergic effects that may worsen cognitive impairment.
Regarding pharmacokinetics, tricyclics have an elimination half-life of 24 hours, this allows once a day dosing. The other important point is that desipramine is metabolized mainly by CYP2D6, this opens the potential for drug-drug interactions with other antidepressants.

3. Adverse Effects

4. Cardiovascular effects
Regarding cardiovascular effects, there are two side effects we should keep in mind.
The most common is orthostatic hypotension. The most severe, but certainly not the most common, is cardiac arrhythmia.
The most common CV effect: orthostatic hypotension
The most severe CV effect: cardiac arrhythmia

5. Orthostatic hypotension
Can occur with all TCAs ( less pronounced with nortriptyline)
Elderly population:
more likely to have preexisting hypotension
more vulnerable to consequences :
falls
hip fractures
So, let’s begin with orthostatic hypotension.
This side effect that can occur with all tricyclics, but it’s less pronounced with nortriptyline.
Why are we showing an elderly person here? This is because there are two factors that make orthostatic hypotension especially relevant in the elderly. The first, is that this population is more likely to have preexisting hypotension. The second is that the elderly are more vulnerable to the consequences of this side effect, such as falls and hip fractures.
Nelson, JC. Tricyclic and tetracyclic drugs. In: Essentials of Clinical Psychopharmacology, 3rd ed, Schatzberg, AF, Nemeroff, CB (Eds), American Psychiatric Publishing, 2013

6. TCAs and cardiac arrhythmias
Fast Na+ channel blockade
Delayed conduction
Cardiac arrhythmia
As we discussed two slides ago, cardiac arrhythmia is a severe cardiovascular effect.
So, what is the mechanism for this adverse effect? As we saw in the pharmacology video, tryciclics can block fast sodium channels. This affects the His ventricular bundle causing delayed conduction. Conduction delays can trigger cardiac arrhythmias.
Nelson, JC. Tricyclic and tetracyclic drugs. In: Essentials of Clinical Psychopharmacology, 3rd ed, Schatzberg, AF, Nemeroff, CB (Eds), American Psychiatric Publishing, 2013

7. TCAs are not safe in overdose
Risk of death by cardiac arrhythmia
Overdose
The risk of cardiac arrhythmias leads us to one of the key distinctive features of tricyclics. Unlike SSRIs and other first line antidepressants, tricyclics are not safe in overdose. Cardiac arrhythmia is the main cause of death in patients who overdose.
We should keep this in mind before prescribing tricyclics to depressed patients who are at risk of suicide attempts from overdose.
Nelson, JC. Tricyclic and tetracyclic drugs. In: Essentials of Clinical Psychopharmacology, 3rd ed, Schatzberg, AF, Nemeroff, CB (Eds), American Psychiatric Publishing, 2013

8. Cardiovascular side effects
TCAs might cause heart block
If preexisting conduction delay
Conduction problems are not likely
Orthostatic hypotension might occur
Adults without heart disease
Does this mean we should not use tricyclics for cardiovascular reasons? Let’s put cardiovascular side effects in context for different clinical situations.
If a patient has a preexisting conduction delay, then the possibility of tricyclics causing heart block is higher.
On the other hand, in adults without heart disease, conduction problems are not likely. Also, orthostatic hypotension might occur.
There is one relative contraindication for tricyclics: patients with ischemic heart disease.
Relative contraindication: patients with ischemic heart disease.
Nelson, JC. Tricyclic and tetracyclic drugs. In: Essentials of Clinical Psychopharmacology, 3rd ed, Schatzberg, AF, Nemeroff, CB (Eds), American Psychiatric Publishing, 2013

9. Anticholinergic Side Effects
Dry Mouth
Constipation
Blurred vision
Urinary hesitancy
Anticholinergic side effects are the result of the blockade of muscarinic receptors. Here we have a list with the four most important peripheral anticholinergic side effects:
dry mouth,
constipation,
blurred vision
and urinary hesitancy.
Although anticholinergic effects may be bothersome, usually they are not serious. The problem is if they become severe.
Urinary retention can be associated with stretch injuries to the bladder.
Constipation can progress to severe obstipation.

10. Anticholinergic Side Effects
Patients with narrow angle glaucoma: risk of ocular crisis
In patients with narrow angle glaucoma, anticholinergic effects can increase the risk of an ocular crisis. This is an acute condition associated with severe pain.

11. Anticholinergic Side Effects
Amitriptyline
Desipramine
Not all tricyclic drugs have the same affinity for muscarinic receptors. The drug with the highest risk of causing anticholinergic effects is amitriptyline, while the tricyclic with lowest affinity for muscarinic receptors is desipramine.

12. Antihistaminic Side Effects
TCAs block H1 receptors
Antihistaminic side effects:
Many tricyclic antidepressants have clinically significant antihistaminic effects through blockade of histamine 1 receptors. Blockade of these receptors is associated with sedation and weight gain.
Regarding antidepressants and weight change, remember that tricyclics, paroxetine, mirtazapine and MAOIs are associated with drug-induced weight gain.
Sedation
Weight gain
Nelson, JC. Tricyclic and tetracyclic drugs. In: Essentials of Clinical Psychopharmacology, 3rd ed, Schatzberg, AF, Nemeroff, CB (Eds), American Psychiatric Publishing, 2013

13. CNS Side Effects: Confusion / Delirium
Tricyclics can cause confusion or delirium through anticholinergic effects in the central nervous system. The incidence of delirium is dose dependent.
We need to keep in mind that patients with dementia can be affected by drugs with anticholinergic effects. Tricyclics with strong anticholinergic activity such as amitriptyline should be avoided.
Blockade of CNS histamine 1 receptors causes sedation which can contribute to the risk of delirium.
Nelson, JC. Tricyclic and tetracyclic drugs. In: Essentials of Clinical Psychopharmacology, 3rd ed, Schatzberg, AF, Nemeroff, CB (Eds), American Psychiatric Publishing, 2013

14. Other effects Seizures Sexual dysfunction
TCAs can reduce seizure threshold
Sexual dysfunction
Associated with serotonergic activity
Other side effects include seizures and sexual dysfunction.
Tricyclics can lower seizure threshold. This is a dose dependent side effect, higher doses increase seizure incidence.
Sexual dysfunction is associated with serotonergic activity, this side effect can impact treatment adherence. You can review this side effect in our tutorial for antidepressant-induced sexual dysfunction.
Hirsch, M; Birnbaum, R. Unipolar depression in adults and tricyclic and tetracyclic drugs: Pharmacology, administration and side effects. In: UpToDate, Roy-Byrne, P (Ed), UpToDate, Waltham, MA. (Accessed on June 25, 2014.)

15. Pharmacokinetics

16. Pharmacokinetics of TCAs
Half life:
Around 24 hours for most TCAs
Exception: amoxapine – 8 hours
The elimination half-life for most tricyclics is around 24 hours. This allows once a day dosing, usually at bedtime because of sedating effects.
The exception is amoxapine, which has a half-life of around 8 hours.
Hirsch, M; Birnbaum, R. Unipolar depression in adults and tricyclic and tetracyclic drugs: Pharmacology, administration and side effects. In: UpToDate, Roy-Byrne, P (Ed), UpToDate, Waltham, MA. (Accessed on June 25, 2014.)

17. Desipramine and CYP2D6 Desipramine is metabolized mainly by CYP2D6
No major alternative pathways
CYP2D6 inhibitors can raise desipramine levels:
Fluoxetine, paroxetine
Duloxetine
Bupropion
Some antipsychotics
Desipramine is metabolized mainly by CYP2D6. Unlike other tricyclics, there are no major alternative pathways for desipramine metabolism. This makes inhibition of this isoenzyme very influential in desipramine’s blood levels.
CYP2D6 inhibitors can raise desipramine levels, these include the SSRIs fluoxetine and paroxetine, duloxetine, bupropion and some antipsychotics. In extensive metabolizers, fluoxetine and paroxetine can raise desipramine levels three to fourfold.
Nelson, JC. Tricyclic and tetracyclic drugs. In: Essentials of Clinical Psychopharmacology, 3rd ed, Schatzberg, AF, Nemeroff, CB (Eds), American Psychiatric Publishing, 2013

18. Tertiary tricyclics are metabolized by several pathways
Tertiary tricyclics CYP1A2, CYP3A4, CYP2C19.
Many alternative pathways
CYP inhibitors less likely to raise blood levels.
Unlike desipramine, tertiary tricyclics are metabolized by several enzymes: CYP1A2, CYP3A4, CYP2C19. This offers many alternatives in case one of these isoenzymes is inhibited. This means that drug interactions are less likely to raise blood levels and be clinically significant .
Nelson, JC. Tricyclic and tetracyclic drugs. In: Essentials of Clinical Psychopharmacology, 3rd ed, Schatzberg, AF, Nemeroff, CB (Eds), American Psychiatric Publishing, 2013

19. Key points
TCAs can cause orthostatic hypotension and cardiac arrhythmias
Baseline ECG to patients over 40 years
Antihistaminic effects include sedation and weight gain
Anticholinergic effects put elderly patients at risk for cognitive dysfunction
The key points for this video are the following.
Tricyclics can cause orthostatic hypotension and cardiac arrhythmias. It is recommended a baseline ECG to patients over 40 years. Younger patients can be screened by history of cardiac disease and do not require an ECG if the history is negative.
Antihistaminic effects include sedation and weight gain.
Anticholinergic effects put elderly patients at risk for cognitive dysfunction.
Hirsch, M; Birnbaum, R. Unipolar depression in adults and tricyclic and tetracyclic drugs: Pharmacology, administration and side effects. In: UpToDate, Roy-Byrne, P (Ed), UpToDate, Waltham, MA. (Accessed on June 25, 2014.)

20. Key points Most TCAs have an elimination half-life of around 24 hours
Once a day dosing
Desipramine levels are increased by CYP2D6 inhibitors
Most tricyclics have an elimination half-life of around 24 hours, this allows once a day dosing.
Finally, desipramine levels are increased by CYP2D6 inhibitors