What receptors do tricyclic antidepressants block?

October 11, 2025 •

3 min read

Tricyclic antidepressants (TCAs) were some of the first medications used to treat major depressive disorder, first introduced in 1959. While primarily known for their therapeutic action of blocking serotonin and norepinephrine reuptake, their full pharmacological profile is more complex. A key aspect of understanding TCAs is identifying what receptors do tricyclic antidepressants block, which is responsible for both their therapeutic benefits and their notable side effects.

Quick Summary

Tricyclic antidepressants block serotonin and norepinephrine reuptake transporters for their therapeutic effect. They also block muscarinic acetylcholine, histamine H1, and alpha-1 adrenergic receptors, causing significant anticholinergic, sedative, and hypotensive side effects. Different TCAs exhibit varied receptor affinities. In overdose, they can block cardiac sodium channels.

Key Points

Serotonin and Norepinephrine Transporters: TCAs block the reuptake of serotonin and norepinephrine, increasing their synaptic concentration and mediating the drug's primary therapeutic action.
Muscarinic Acetylcholine Receptors: Blocking these receptors causes anticholinergic side effects like dry mouth, blurred vision, and constipation.
Histamine H1 Receptors: Inhibition of H1 receptors leads to sedation, drowsiness, and weight gain, which are common adverse effects of TCAs.
Alpha-1 Adrenergic Receptors: TCAs block these receptors, resulting in orthostatic hypotension (dizziness and a drop in blood pressure when standing).
Cardiac Sodium Channels: In overdose, TCAs can block these channels in the heart, causing life-threatening cardiac arrhythmias.
Differing Affinities: Individual TCAs, particularly between tertiary and secondary amines, have different potencies for blocking various receptors, leading to varied side effect profiles.

Therapeutic Action: Blocking Neurotransmitter Reuptake

At the core of their therapeutic effect, tricyclic antidepressants (TCAs) primarily increase the levels of serotonin (5-HT) and norepinephrine (NE) in the brain. They achieve this by acting as competitive inhibitors for the presynaptic membrane transporters responsible for reuptaking these neurotransmitters: the serotonin transporter (SERT) and the norepinephrine transporter (NET).

Serotonin Transporter (SERT) Blockade: By inhibiting SERT, TCAs prevent the reabsorption of serotonin back into the nerve terminals. This increases the concentration of serotonin in the synaptic cleft, where it can continue to act on postsynaptic receptors. This action is linked to the improvement of mood and anxiety symptoms.
Norepinephrine Transporter (NET) Blockade: Similarly, TCAs block NET, which increases the amount of norepinephrine available in the synapse. This contributes to the antidepressant effects and is also believed to be a key mechanism for their use in managing chronic neuropathic pain.

Antagonism of Other Receptors and Associated Side Effects

The broad and non-selective binding profile of TCAs is what sets them apart from newer antidepressants and accounts for their wide range of adverse effects. The therapeutic benefits are often overshadowed by these undesirable off-target actions.

Muscarinic Acetylcholine Receptors

TCAs are competitive antagonists at muscarinic acetylcholine receptors, which are abundant in the brain and peripheral nervous system. Blocking these receptors leads to the classic anticholinergic side effects associated with these drugs.

Dry mouth (xerostomia): Reduced saliva production.
Blurred vision: Difficulty focusing, particularly for near objects.
Urinary retention: Difficulty urinating.
Constipation: Slowed gastrointestinal motility.
Tachycardia: Increased heart rate.

Histamine H1 Receptors

TCAs block histamine H1 receptors, an effect that has significant consequences for patients.

Sedation and drowsiness: This is a very common side effect, especially with tertiary amines like amitriptyline.
Weight gain: Blocking H1 receptors is linked to increased appetite and subsequent weight gain.

Alpha-1 Adrenergic Receptors

By antagonizing alpha-1 adrenergic receptors, TCAs interfere with the regulation of blood pressure.

Orthostatic hypotension: A sudden drop in blood pressure when standing, which can cause dizziness and increase the risk of falls, especially in elderly patients.

Cardiac Sodium Channels

Although not technically a receptor, TCAs can block cardiac fast sodium channels, an effect that is particularly dangerous in overdose situations.

Cardiotoxicity: This can lead to serious and potentially fatal cardiac arrhythmias, including a widened QRS complex and other conduction abnormalities seen on an electrocardiogram (ECG). This narrow therapeutic index is a major reason TCAs are not first-line treatments.

Tertiary vs. Secondary Amines: A Receptor Affinity Comparison

The class of TCAs is often divided into two sub-groups based on their chemical structure, which influences their receptor binding profile and side effects.


Receptor Target	Tertiary Amines (e.g., Amitriptyline, Imipramine)	Secondary Amines (e.g., Nortriptyline, Desipramine)
Serotonin (5-HT) Reuptake	Stronger inhibition	Weaker inhibition
Norepinephrine (NE) Reuptake	Weaker inhibition	Stronger inhibition
Muscarinic (Anticholinergic) Blockade	Stronger potency, more side effects	Weaker potency, fewer side effects
Histamine H1 Blockade	Stronger potency, more sedation	Weaker potency, less sedation
Alpha-1 Adrenergic Blockade	Stronger potency, higher risk of orthostatic hypotension	Weaker potency

The Broader Pharmacological Picture

The therapeutic effects of TCAs are believed to be linked to the reuptake inhibition of serotonin and norepinephrine, but the time lag in clinical response suggests a more complex mechanism involving downstream adaptive changes in the nervous system. The simultaneous blockade of multiple other receptors explains the less favorable side effect profile compared to modern antidepressants like Selective Serotonin Reuptake Inhibitors (SSRIs). Understanding these varied receptor interactions is crucial for clinicians to manage patient care, anticipate side effects, and determine when a TCA is an appropriate choice, often as a second-line treatment for treatment-resistant depression, neuropathic pain, or specific conditions like OCD. The complexity of their pharmacology also highlights the significant risk associated with TCA overdose due to cardiotoxicity.

Visit the NCBI bookshelf for more in-depth pharmacology of TCAs.

Frequently Asked Questions

The main therapeutic action of tricyclic antidepressants is to inhibit the reuptake of the neurotransmitters serotonin and norepinephrine, increasing their availability in the brain to improve mood and reduce pain.

TCAs are no longer a first-line treatment due to their significant side effect profile caused by non-selective receptor blockade, including anticholinergic, sedative, and cardiovascular effects, and their narrow therapeutic index, which increases the risk of serious complications in overdose.

Common anticholinergic side effects from TCA use include dry mouth, blurred vision, constipation, and urinary retention, all resulting from the blockade of muscarinic acetylcholine receptors.

TCAs cause sedation, drowsiness, and weight gain by blocking histamine H1 receptors, which are involved in regulating sleep and appetite.

The blockade of alpha-1 adrenergic receptors by TCAs can cause orthostatic hypotension, a condition where a person's blood pressure drops significantly upon standing, leading to dizziness or lightheadedness.

Tertiary amine TCAs, like amitriptyline, generally have a stronger blocking effect on muscarinic acetylcholine and histamine H1 receptors, leading to more pronounced anticholinergic and sedative side effects. Secondary amine TCAs, such as nortriptyline, tend to have less of these effects.

TCA overdose is particularly dangerous because these drugs can block cardiac fast sodium channels, leading to severe and potentially fatal cardiac arrhythmias, including a widened QRS complex and other conduction issues.