Mechanism of action at the synaptic level
The pharmacological effect of tricyclic compounds is achieved through several consecutive stages at the synaptic level:
- Competitive blockade: the active substance binds to specialized carrier proteins located on the presynaptic membrane.
- Mediator accumulation: substances such as norepinephrine, serotonin, and dopamine remain in the synaptic cleft longer than usual.
- Receptor stimulation: the increased concentration of mediators actively stimulates postsynaptic receptors.
- Adaptation: after two to three weeks of regular use, an adaptive response develops, manifesting as a decrease in the density and sensitivity of central adrenergic receptors (down-regulation).
Pharmacodynamics and psychotropic spectrum
The intrinsic antidepressant effect of TCAs does not appear immediately: due to the need for receptor remodeling, a latent period of 2–3 weeks occurs.
- Sedative effect: develops significantly earlier than the antidepressant effect.
- Amitriptyline: characterized by pronounced sedative properties.
- Imipramine: capable of producing a psychostimulatory effect against the background of a depressed mood.
Safety profile and adverse effects
Because tricyclic antidepressants do not exhibit high receptor selectivity, they have a broad spectrum of adverse effects:
- M-anticholinergic activity: causes dry mouth, tachycardia, constipation, and urinary retention.
- Alpha-adrenolytic activity: leads to a decrease in blood pressure and the development of hypotension.
Drug interactions
When prescribing therapy, it is important to strictly follow the rules of drug combination:
- Absolute contraindication: it is strictly forbidden to combine TCAs with non-selective monoamine oxidase inhibitors.
- Washout period: an interval of at least 2 weeks must be observed between the discontinuation of MAO inhibitors and the initiation of tricyclic antidepressants.
Briefly: answers to topical questions
What other medications belong to the TCA group, apart from amitriptyline and imipramine?
In addition to amitriptyline and imipramine, the tricyclic antidepressant group (non-selective monoamine reuptake inhibitors) includes the following drugs:
- Clomipramine — used, among other indications, as a second-line drug for tension headache.
- Doxepin — a classical representative of non-selective inhibitors.
- Pipofezine — used in treatment regimens to combat pathological craving for psychoactive substances.
What are the contraindications for TCA use, apart from taking MAO inhibitors?
In addition to taking MAO inhibitors, absolute contraindications for prescribing tricyclic antidepressants include the following somatic pathologies:
- Heart disease
- Glaucoma
- Prostatic hyperplasia
- Chronic constipation
Furthermore, drugs of this group are strictly contraindicated in the treatment of psychoses caused by antituberculosis drug poisoning. In addition, TCAs are not recommended for use in patients with multiple system atrophy due to the high risk of worsening respiratory disorders and autonomic failure (orthostatic hypotension, urinary retention).
What other receptors do TCAs block besides M-cholinergic receptors and alpha-adrenergic receptors?
Besides M-cholinergic and alpha-adrenergic receptors, tricyclic antidepressants are also capable of blocking histamine receptors.
Non-selective monoamine reuptake inhibitors have a broad receptor profile, which leads to a large number of side effects. Histamine receptor blockade is one of the causes of adverse reactions during therapy with drugs of this group. Unlike TCAs, selective serotonin reuptake inhibitors have only a negligible effect on these receptors.
What are the symptoms of acute tricyclic antidepressant poisoning?
Symptoms of acute tricyclic antidepressant poisoning: the clinical picture resembles phenothiazine poisoning. Coma is preceded by a period of agitation, and sometimes convulsions.
During the coma stage, the following are observed:
- Cardiac disorders: tachycardia, atrial fibrillation, atrioventricular or intraventricular block.
- Psychotic episodes with delirium-like hallucinations.
- Intestinal and urinary bladder atonia.
TCAs — Tricyclic Compounds of Aggressive mediators (block norepinephrine and serotonin reuptake, requiring a 2–3 week wait for the effect).
Class and exam questions
Why does the antidepressant effect of TCAs develop only after 2–3 weeks?
This is due to the adaptation mechanism of central adrenergic receptors (so-called down-regulation), in which their density and sensitivity decrease after 2–3 weeks of continuous administration.
What is the main contraindication for tricyclic antidepressants?
An absolute contraindication is the combination of TCAs with non-selective monoamine oxidase inhibitors. The interval between their administration must be at least 2 weeks.
Which key representatives of the TCA group are highlighted in pharmacology?
Key representatives of non-selective tricyclic antidepressants are amitriptyline and imipramine.
What else to study on this topic
- General classification of antidepressants and the place of TCAs in section 15.2.1
- Non-selective (nialamide) and selective (moclobemide) monoamine oxidase inhibitors
- Antidepressants from other groups (tianeptine, mirtazapine)
- Differences in the psychotropic activity spectrum between amitriptyline and imipramine
- Clinical manifestations of M-cholinolytic and alpha-adrenolytic action
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