Tricyclic Antidepressants (TCAs)

Tricyclic antidepressants (TCAs) are a class of medications primarily used to treat depression. They inhibit the reuptake of neurotransmitters such as norepinephrine and serotonin into the presynaptic neuron. If discovered today, they might have been referred to as SNRIs (serotonin-norepinephrine reuptake inhibitors) due to their mechanism of action, except for their differences in adverse effects relative to this newer class of antidepressants.

Mechanism of Action

• Inhibition of Neurotransmitter Reuptake: TCAs and amoxapine are potent inhibitors of the neuronal reuptake of norepinephrine and serotonin into presynaptic nerve terminals. Some TCAs are relatively selective inhibitors of norepinephrine reuptake.

• Blocking of Receptors: TCAs also block serotonergic, α-adrenergic, histaminic, and muscarinic receptors. These actions are likely responsible for many of their adverse effects.

Indications

• Major depressive disorder (third- or fourth-line therapy)

• Neuropathic pain (e.g., peripheral neuropathy, diabetic neuropathy)

• Chronic pain (including fibromyalgia)

• Migraine prophylaxis

• Clomipramine specifically: OCD

• Imipramine specifically: nocturnal enuresis ( bedwetting in children,limited use due to side effects)

• Some patients with panic disorder also respond to TCAs.

• Nortriptyline specifically: Prevention of migraine headache, treatment of chronic pain syndromes, and insomnia.

Adverse Effects

• Antihistaminic effect: Sedation, Weight gain

• Block α-adrenergic receptors, causing orthostatic hypotension, dizziness, and reflex tachycardia.

• Anticholinergic adverse effects: Blurred vision, Xerostomia, Urinary retention, Constipation, Mydriasis, Hyperthermia, Dry skin

• Cardiotoxicity due to Na+ channel inhibition in the myocardium that may precipitate life-threatening arrhythmias in an overdose situation

• Tremor

• Respiratory depression

• Hyperpyrexia

• Anticholinergic symptoms

• Bone marrow depression

• Low incidence of sexual dysfunction.

The three Cs of tricyclic poisoning: Convulsions, Coma, and Cardiac conduction abnormalities (prolonged QTc).

Contraindications:

• Not to be used during the acute recovery phase post-myocardial infarction (heart attack).

• Avoid in patients with a known hypersensitivity to TCAs or related compounds.

• Concomitant use with MAO inhibitors is contraindicated due to risks of hyperpyretic crises, severe seizures, and potentially death. A two-week gap is advised between discontinuing MAO inhibitors and starting TCAs.

Note 1: Tertiary amines, like amitriptyline and doxepin, tend to cause significant drowsiness, so it's best to take them at bedtime. Often, they're prescribed to help with sleep because of this sedative effect.

Note 2: It's important to use TCAs with caution in patients with bipolar disorder, as they may cause a switch to manic behavior. They have a narrow therapeutic index and may exacerbate certain medical conditions. Close monitoring and limited quantities are recommended for suicidal patients.