Page 551 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 30 Antidepressant Agents 537

H
N
O
F C
3
O O CH
O CH 2
CH CH NHCH 3 F
2
2
Fluoxetine Paroxetine

N C
O NHCH 3
CH 3
CH 2 CH 2 CH 2 N
CH 3
CI

CI
F
Citalopram, Sertraline
escitalopram

FIGURE 30–3 Structures of several selective serotonin reuptake inhibitors (SSRIs).

1. Selective serotonin-norepinephrine reuptake S
inhibitors—The SNRIs include venlafaxine, its metabolite CH CH 2 CH NHCH 3
desvenlafaxine, duloxetine, and levomilnacipran. Levomil- 2
nacipran is the active enantiomer of a racemic SNRI, mil- O
nacipran. Milnacipran has been approved for the treatment of
fibromyalgia in the USA and has been used in the treatment of
depression in Europe for many years. In addition to their use in
major depression, SNRIs have applications in the treatment of
pain disorders including neuropathies and fibromyalgia. SNRIs Duloxetine
are also used in the treatment of generalized anxiety, stress urinary
incontinence, and vasomotor symptoms of menopause.
2. Tricyclic antidepressants—The TCAs were the domi-
CH 3 nant class of antidepressants until the introduction of SSRIs in
N the 1980s and 1990s. Nine TCAs are available in the USA, and
CH 3
they all have an iminodibenzyl (tricyclic) core (Figure 30–4).
The chemical differences between the TCAs are relatively
HO subtle. For example, the prototype TCA imipramine and its
metabolite, desipramine, differ by only a methyl group in
RO
the propylamine side chain. However, this minor difference
R = CH : Venlafaxine results in a substantial change in their pharmacologic profiles.
3
R = H : Desvenlafaxine Imipramine is highly anticholinergic and is a relatively strong
serotonin as well as norepinephrine reuptake inhibitor. In con-
SNRIs are chemically unrelated to each other. Venlafaxine was trast, desipramine is much less anticholinergic and is a more
discovered in the process of evaluating chemicals that inhibit bind- potent and somewhat more selective norepinephrine reuptake
ing of imipramine. Venlafaxine’s in vivo effects are similar to those inhibitor than is imipramine.
of imipramine but with a more favorable adverse-effect profile. At present, the TCAs are used primarily in depression that
All SNRIs bind the serotonin (SERT) and norepinephrine (NET) is unresponsive to more commonly used antidepressants such
transporters, as do the TCAs. However, unlike the TCAs, the as the SSRIs or SNRIs. Their loss of popularity stems in large
SNRIs do not have much affinity for other receptors. Venlafaxine part from relatively poorer tolerability compared with newer
and desvenlafaxine are bicyclic compounds, whereas duloxetine is a agents, difficulty of use, and lethality in overdose. Other uses
three-ring structure unrelated to the TCAs. Milnacipran contains a for TCAs include the treatment of pain conditions, enuresis,
cyclopropane ring and is provided as a racemic mixture. and insomnia.