Page 553 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 30 Antidepressant Agents 539

N NH
CH 2 CH 2 CH 2 NH CH 3
N C Cl

O
Amoxapine Maprotiline

N
CH 3
CI
N N O
C CH NH C(CH )
3 3
CH 3
Mirtazapine Bupropion

FIGURE 30–5 Structures of the tetracyclics, amoxapine, maprotiline, and mirtazapine and the unicyclic, bupropion.

sexual effects. It has a tetracyclic chemical structure and belongs CH CH NH NH
to the piperazino-azepine group of compounds. 2 2 2
Mirtazapine, amoxapine, and maprotiline have tetracyclic
structures. Amoxapine is the N-demethylated metabolite of loxa-
pine, an older antipsychotic drug. Amoxapine and maprotiline Phenelzine
share structural similarities and side effects comparable to the
TCAs. As a result, these tetracyclics are not commonly prescribed
in current practice. Their primary use is in MDD that is unre- CH CH NH 2
sponsive to other agents. Vilazodone has a multi-ring structure CH 2
that allows it to bind potently to the serotonin transporter but
minimally to the dopamine and norepinephrine transporter. Tranylcypromine

E. Monoamine Oxidase Inhibitors
Arguably the first modern class of antidepressants, monoamine PHARMACOKINETICS
oxidase inhibitors (MAOIs) were introduced in the 1950s but
are now rarely used in clinical practice because of toxicity and The antidepressants share several pharmacokinetic features
potentially lethal food and drug interactions. Their primary use (Table 30–1). Most have fairly rapid oral absorption, achieve
now is in the treatment of depression unresponsive to other anti- peak plasma levels within 2–3 hours, are tightly bound to plasma
depressants. However, MAOIs have also been used historically to proteins, undergo hepatic metabolism, and are renally cleared.
treat anxiety states, including social anxiety and panic disorder. In However, even within classes, the pharmacokinetics of individual
addition, selegiline is used in the treatment of Parkinson’s disease antidepressants varies considerably.
(see Chapter 28).
Current MAOIs include the hydrazine derivatives phenelzine A. Selective Serotonin Reuptake Inhibitors
and isocarboxazid and the nonhydrazines tranylcypromine, The prototype SSRI, fluoxetine, differs from other SSRIs in
selegiline, and moclobemide (the latter is not available in the some important respects (Table 30–1). Fluoxetine is metabo-
USA). The hydrazines and tranylcypromine bind irreversibly and lized to an active product, norfluoxetine, which may have plasma
nonselectively with MAO-A and -B, whereas other MAOIs may concentrations greater than those of fluoxetine. The elimination
have more selective or reversible properties. Some of the MAOIs half-life of norfluoxetine is about three times longer than fluox-
such as tranylcypromine resemble amphetamine in chemical etine and contributes to the longest half-life of all the SSRIs. As a
structure, whereas other MAOIs such as selegiline have amphet- result, fluoxetine has to be discontinued 4 weeks or longer before
amine-like metabolites. As a result, these MAOIs tend to have an MAOI can be administered to mitigate the risk of serotonin
substantial CNS-stimulating effects. syndrome.