The tricyclic antidepressants (TCAs) were the most widely used drugs to treat clinical depression prior to the SSRIs after imipramine (Tofranil) was shown to be effective for treating depression in the 1950s. TCAs primarily work by increasing the level of norepinephrine in the brain and, to a lesser extent, serotonin levels. Some TCAs also are antihistamines (which block the action of histamine) or anticholinergic (which blocks the action of acetylcholine, a neurotransmitter). These additional actions allow for uses of TCAs other than for treating depression as well as introduce additional side effects.

A TCA’s chemical structure is composed of three conjoined rings. If the nitrogen atom on the center ring is a tertiary amine, the drug belongs to the first-generation TCAs; most side effects associated with TCAs are more pronounced with first-generation TCAs. If it is a secondary amine, the drug is a second-generation tricyclic. TCAs may inhibit the antihypertensive effect of clonidine (Catapres). Therefore, combining TCAs with clonidine may lead to dangerous elevations in blood pressure. TCAs may affect the heart’s electrical conduction system. Combining TCAs with drugs that also affect the heart’s conduction system (disopyramide, pimozide, procainamide) may increase the frequency and severity of an abnormal heart rate and rhythm [10]. Combining TCAs with carbamazepine (Tegretol) may result in lower TCA blood levels because carbamazepine increases the breakdown of TCAs, potentially reducing the effect of TCAs. TCAs may increase the blood pressure-elevating effect of epinephrine, norepinephrine, dopamine, phenylephrine, and dobutamine.

It is generally believed that the TCAs are equally potent with regard to treatment of depression. On the other hand, all of the TCAs cause some anticholinergic symptoms, orthostatic hypotension, cardiac dysrhythmia, and sedation. However, they do so in varying degrees when compared with their efficacy as antidepressants. This differing side effect profile serves as the basis for much of the strategy employed by practitioners prescribing these drugs. For example, a drug that causes a greater degree of sedation might be chosen preferentially for patients experiencing insomnia as part of their symptomatology. Similarly, practitioners might avoid drugs that have greater anticholinergic activity in patients who have glaucoma or reflux disease, for example. The degree of cardiac dysrhythmia potential is essentially the same for TCAs, and they should be avoided in patients with known cardiac conduction abnormalities such as second-degree or higher atrioventricular blocks. It has been shown that despite their potential for causing cardiac dysrhythmias, they may paradoxically show some anti-dysrhythmic activity. Also of note is the fact that despite the electrocardiographic (ECG) changes that occur with these drugs, the changes tend to dissipate with ongoing treatment, implying some sort of tolerance on the part of the cardiac conduction system to these effects.

Commonly, seizure activity associated with antidepressant therapy is seen after an acute overdose. Dose‐dependent seizure activity has been traditionally reported with imipramine, amitriptyline, clomipramine, and maprotiline. Bupropion, while not a TCA, is well known for its risk of seizures – especially in higher doses or in patients with predisposing factors like family history.

Anesthetic management of patients who are on TCAs revolves around the side effects of these medications and their interactions with other drugs. The mechanism of the antidepressant effects of TCAs involves enhancement of serotonergic and noradrenergic activity. TCAs’ inhibition of histaminergic, cholinergic, and α1-adrenergic activity is responsible for many of their side effects. The main concerns for these patients being treated with a TCA center around the cardiovascular system and the interaction of the drug with a specific neurotransmitter, such as norepinephrine. Since the administration of TCAs causes an increase of this neurotransmitter to be stored in noradrenergic nerve terminals, the administration of indirect-acting vasopressors such as ephedrine may cause an exaggerated release of epinephrine. This effect is most pronounced with acute treatment and gradually dissipates after the first 2–3 weeks. Caution is therefore advised with regard to using drugs with sympathomimetic effects on patients receiving TCAs. TCAs’ anticholinergic effects can potentially cause a problem to anesthesiologists, because many drugs used by anesthesiologists are anticholinergics or have anticholinergic effects. Preoperatively, some anesthesiologists employ scopolamine for its sedative, anxiolytic, and antisialagogic properties. Intraoperatively, glycopyrrolate and atropine are both used for their anticholinergic properties. Pancuronium, which has significant anticholinergic effects, is still used for procedures requiring a long period of muscle relaxation, especially cardiac surgery. Atropine and glycopyrrolate have been noted to have increased muscarinic activity in the presence of TCAs, and the administration of pancuronium has been documented to precipitate tachydysrhythmias in a sample of patients studied. Furthermore, there is the possibility that preoperative treatment with scopolamine may increase the incidence of emergence delirium, although there are no formal studies that support this suspicion.