71: Cyclic Antidepressants

71: Cyclic Antidepressants Erica L. Liebelt HISTORY AND EPIDEMIOLOGY The term cyclic antidepressant (CA) refers to a group of pharmacologically related xenobiotics used for treatment of depression, neuralgic pain, migraines, enuresis, and attention deficit hyperactivity disorder. Most CAs have at least three rings in their chemical structure. They include the traditional tricyclic antidepressants (TCAs) imipramine, desipramine, amitriptyline, nortriptyline, doxepin, trimipramine, protriptyline, and clomipramine, as well as other cyclic compounds such as maprotiline and amoxapine. Imipramine was the first TCA used for treatment of depression in the late 1950s. However, the synthesis of iminodibenzyl, the “tricyclic” core of imipramine, and the description of its chemical characteristics date back to 1889. Structurally related to the phenothiazines, imipramine was originally developed as a hypnotic for agitated or psychotic patients and was serendipitously found to alleviate depression. From the 1960s until the late 1980s, the TCAs were the major pharmacologic treatment for depression in the United States. However, by the early 1960s, cardiovascular and central nervous system (CNS) toxicities were recognized as major complications of TCA overdoses. The newer CAs developed in the 1980s and 1990s were designed to decrease some of the adverse effects of older TCAs, improve the therapeutic index, and reduce the incidence of serious toxicity. Other CAs include the tetracyclic drug maprotiline and the dibenzoxapine drug amoxapine. The epidemiology of CA poisoning has evolved significantly in the past 30 years, resulting in great part from the introduction of the selective serotonin reuptake inhibitors (SSRIs) and other newer antidepressants for the treatment of depression. Although the use of CAs for depression has decreased over the past 20 years, other medical indications, including chronic pain, obsessive- compulsive disorder, and, particularly in children, enuresis and attention deficit hyperactivity disorder have emerged, resulting in their continued use. The antidepressants are a leading cause of drug- related self-poisonings in the developed world, primarily because of their ready availability to people with depression or chronic pain who by virtue of their diseases are at high risk for overdose. However, despite the increase in SSRI use and overdose, patients with TCA overdoses continue to have higher rates of hospitalization and fatality than do those with SSRI overdose. Children younger than 6 years have consistently accounted for approximately 12% to 13% of all CA exposures reported to poison centers during each of the last 15 years (Chap. 136). Despite the emergence of the SSRIs in the early 1990s, TCAs are still frequently prescribed by pediatric office based practices for many of the conditions noted above. Following the October 2004 US Food and Drug Administration Black Box Warning about the increased risk of suicidal behavior associated with antidepressant use, several reports have described significant declines in antidepressant dispensing in children compared to historical trends.25 Nevertheless, CA poisoning likely will continue to be among the most lethal unintentional drug ingestions in younger children because only one or two adult-strength pills can produce serious clinical effects in young children. PHARMACOLOGY In general, the TCAs can be classified into tertiary and secondary amines based on the presence of a methyl group on the propylamine side chain (Table 71–1). The tertiary amines amitriptyline and imipramine are metabolized to the secondary amines nortriptyline and desipramine, respectively, which themselves are marketed as antidepressants. In therapeutic doses, the CAs produce similar pharmacologic effects on the autonomic system, CNS, and cardiovascular system. However, they can be distinguished from each other by their relative potencies.112 TABLE 71–1. Cyclic Antidepressants—Classification by Chemical Structure View Large | Favorite Table At therapeutic doses, CAs inhibit presynaptic reuptake of norepinephrine and/or serotonin, thus functionally increasing the amount of these neurotransmitters at CNS receptors. The tertiary amines, especially clomipramine, are more potent inhibitors of serotonin reuptake, whereas the secondary amines are more potent inhibitors of norepinephrine reuptake. Although these pharmacologic actions formed the basis of the monoamine hypothesis of depression in the 1960s, antidepressant actions of these drugs appear to be much more complex. Extensive research has led to the “receptor sensitivity hypothesis of antidepressant drug action,” which postulates that following chronic CA administration, alterations in the sensitivity of various receptors are responsible for antidepressant effects. Chronic TCA administration alters the number and/or function of central β-adrenergic and serotonin receptors. In addition, TCAs modulate glucocorticoid receptor gene expression and cause alterations at the genomic level of other receptors.8 All of these actions likely play a role in the antidepressant effects of TCAs. Additional pharmacologic mechanisms of CAs are responsible for their side effects with therapeutic dosing and clinical effects following overdose. All of the CAs are competitive antagonists of the muscarinic acetylcholine receptors, although they have different affinities. The CAs also antagonize peripheral α1-adrenergic receptors. The most prominent effects of CA overdose result from binding to the cardiac sodium channels, which is also described as a membrane-stabilizing effect (Fig. 71–1) (Chap. 16). The tricyclic antidepressants are potent inhibitors of both peripheral and central postsynaptic histamine receptors. Finally, animal research demonstrates that the CAs interfere with chloride conductance by binding to the picrotoxin site on the γ-aminobutyric acid (GABA)–chloride complex.102 FIGURE 71–1. Effects of cyclic antidepressants (CAs) on the fast sodium channel. (A) Sodium depolarizes the cell, which both propagates conduction; allowing complete cardiac depolarization; and opens voltage-dependent Ca2+channels, producing contraction. (B) CAs and other sodium channel blockers alter the conformation of the sodium channel, slowing the rate of rise of the action potential, which produces both negative dromotropic and inotropic effects. (C) Raising the Na+ gradient across the affected sodium channel speeds the rate of rise of the action potential, counteracting the drug-induced effects. Raising the pH removes the CA from the binding site on the Na+ channel. See Fig. 71–3 for the effects noted on the electrocardiograph. View Full Size | Favorite Figure | Download Slide (.ppt) Amoxapine is a dibenzoxapine CA derived from the active antipsychotic loxapine. Although it has a three-ringed structure, this drug has little similarity to the other tricyclics. It is a potent norepinephrine reuptake inhibitor, has no effect on serotonin reuptake, and blocks dopamine receptors. Maprotiline is a tetracyclic antidepressant that predominantly blocks norepinephrine reuptake. Both of these CAs have a slightly different toxic profile than the traditional TCAs.55,56,112 PHARMACOKINETICS AND TOXICOKINETICS The CAs are rapidly and almost completely absorbed from the gastrointestinal (GI) tract, with peak concentrations 2 to 8 hours after administration of a therapeutic dose. They are weak bases (high pKa). In overdose, the decreased GI motility caused by anticholinergic effects and ionization in gastric acid delay CA absorption. Because of extensive first-pass metabolism by the liver, the oral bioavailability of CAs is low and variable, although metabolism may become saturated in overdose, increasing bioavailability. The CAs are highly lipophilic and possess large and variable volumes of distribution (15–40 L/kg). They are rapidly distributed to the heart, brain, liver, and kidney, where the tissue to plasma ratio generally exceeds 10:1. The octanol/water partition coefficient (Log P) is an often cited measure of lipid-solubility with the Log D representing Log P at physiological pH—a more representative measure. The latter pharmacologic property becomes important when evaluating the potential effectiveness of lipid emulsion therapy for CA toxicity. Some examples of Log D values for CAs are amitriptyline, 3.96; nortriptyline, 2.86; imipramine, 2.06; desipramine, 1.05; and doxepin, 2.93. Less than 2% of the ingested dose is present in blood several hours after overdose, and serum CA concentrations decline biexponentially. The CAs are extensively bound to α1-acid glycoprotein (AAG) in the plasma, although differential binding among the specific CAs is observed.2 Changes in AAG concentration or pH can alter binding and the percentage of free or unbound drug.87,95 Specifically, a low blood pH (which often occurs in a severely poisoned patient) may increase the amount of free drug, making it more available to exert its effects. This property serves as one basis for alkalinization therapy (see below). The CAs undergo demethylation, aromatic hydroxylation, and glucuronide conjugation of the hydroxy metabolites. The tertiary amines imipramine and amitriptyline are demethylated to desipramine andnortriptyline, respectively. The hydroxy metabolites of both tertiary and secondary amines are pharmacologically active and may contribute to toxicity. The glucuronide metabolites are inactive. Genetically based differences in the activity of the CYP2D6 enzymes, which are responsible for hydroxylation of

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