HCAs have low therapeutic indices. Side effects are common and often occur with customary dosages, even though serum levels may be within the designated therapeutic range. The majority of side effects are either anticholinergic or cardiotoxic.
Anticholinergic side effects are the most common. They are particularly likely to occur with concomitant use of other drugs with anticholinergic properties, such as low-potency antipsychotics, antiparkinsonian agents, antihistamines, and over-the-counter sleeping remedies. Both peripheral and central effects may occur. Peripheral effects include dry mouth, metallic taste, blurred vision, constipation, paralytic ileus, urinary retention, tachycardia, and exacerbation of narrow-angle glaucoma. Central effects include sedation, mydriasis, agitation, and delirium. Mild to moderately severe anticholinergic effects may be managed by dosage reduction, change to a medication with fewer anticholinergic properties, or addition of urecoline, 10 to 25 mg PO three times daily. For acute urinary retention, urecoline, 2.5 to 5 mg may be given subcutaneously. When anticholinergic effects become life-threatening, physostigmine, 1 to 2 mg administered very slowly IV, may be used. If physostigmine toxicities ensue, the effects can be reversed with IV atropine sulfate, 0.5 mg for each 1.0 mg of physostigmine administered.
Cardiac side effects of HCAs may include nonspecific T-wave changes, prolonged QT interval, varying degrees of AV block, and atrial and ventricular dysrhythmias. Orthostatic hypotension from a-adrenergic blockade may be significant, particularly in the elderly.
HCA therapy may also be complicated by allergic obstructive jaundice; decreased seizure threshold (especially with maprotiline, clomipramine, and amoxapine); and, very rarely, agranulocytosis.
Trazodone has little in common with other HCAs. It lacks significant anticholinergic or cardiac conduction effects but may be associated with marked sedation, ventricular dysrhythmias, and significant orthostatic hypotension. It may also cause priapism, a urologic emergency.
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