Page 555 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 30 Antidepressant Agents 541

2. Tricyclic antidepressants—The TCAs tend to be well metabolized by CYP3A4 with minor contributions by CYP2C19
absorbed and have long half-lives (Table 30–1). As a result, most and CYP2D6. Only 1% of vilazodone is excreted unchanged in
are dosed once daily at night because of their sedating effects. the urine.
TCAs undergo extensive metabolism via demethylation, aromatic
hydroxylation, and glucuronide conjugation. Only about 5% E. Monoamine Oxidase Inhibitors
of TCAs are excreted unchanged in the urine. The TCAs are The different MAOIs are metabolized via different pathways
substrates of the CYP2D6 system, and the serum levels of these but tend to have extensive first-pass effects that may substan-
agents tend to be substantially influenced by concurrent adminis- tially decrease bioavailability. Tranylcypromine is ring hydrox-
tration of drugs such as fluoxetine. In addition, genetic polymor- ylated and N-acetylated, whereas acetylation appears to be a
phism for CYP2D6 may result in low or extensive metabolism minor pathway for phenelzine. Selegiline is N-demethylated
of the TCAs. and then hydroxylated. The MAOIs are well absorbed from the
The secondary amine TCAs, including desipramine and nor- gastrointestinal tract.
triptyline, lack active metabolites and have fairly linear kinetics. Because of the prominent first-pass effects and their tendency to
These TCAs have a wide therapeutic window, and serum levels are inhibit MAO in the gut (resulting in tyramine pressor effects), alter-
reliable in predicting response and toxicity. native routes of administration are being developed. For example,
selegiline is available in both transdermal and sublingual forms that
bypass both gut and liver. These routes decrease the risk of food
C. 5-HT Receptor Modulators interactions and provide substantially increased bioavailability.
Trazodone and nefazodone are rapidly absorbed and undergo
hepatic metabolism. Both drugs are bound to protein and have PHARMACODYNAMICS
limited bioavailability because of extensive metabolism. Because
of their short half-lives split dosing is generally required when As previously noted, all currently available antidepressants enhance
these drugs are used as antidepressants. However, trazodone is monoamine neurotransmission by one of several mechanisms.
often prescribed as a single dose at night as a hypnotic in lower The most common mechanism is inhibition of the activity of
doses than are used in the treatment of depression. Both trazo- SERT, NET, or both monoamine transporters (Table 30–2). Anti-
done and nefazodone have active metabolites that also exhibit depressants that inhibit SERT, NET, or both include the SSRIs
5-HT antagonism. Nefazodone is a potent inhibitor of the and SNRIs (by definition) and the TCAs. Another mechanism
2
CYP3A4 system and may interact with drugs metabolized by for increasing the availability of monoamines is inhibition of their
this enzyme (see Drug Interactions). Vortioxetine is not a potent enzymatic degradation (by the MAOIs). Additional strategies for
inhibitor of CYP isoenzymes. However, it is extensively metabo- enhancing monoamine tone include binding presynaptic autore-
lized through oxidation by CYP2D6 and other isoenzymes and ceptors (mirtazapine) or specific postsynaptic receptors (5-HT
2
then undergoes subsequent glucuronic acid conjugation. It is antagonists and mirtazapine). Ultimately, the increased availability
tightly bound to protein and has linear and dose-proportional of monoamines for binding in the synaptic cleft results in a cas-
pharmacokinetics.
cade of events that enhance the transcription of some proteins and
the inhibition of others. It is the net production of these proteins,
D. Tetracyclic and Unicyclic Agents including BDNF, glucocorticoid receptors, β adrenoceptors, and
Bupropion is rapidly absorbed and has a mean protein binding of other proteins, that appears to determine the benefits as well as the
85%. It undergoes extensive hepatic metabolism and has a sub- toxicity of a given agent.
stantial first-pass effect. It has three active metabolites including
hydroxybupropion; the latter is being developed as an antidepres- A. Selective Serotonin Reuptake Inhibitors
sant. Bupropion has a biphasic elimination with the first phase The serotonin transporter (SERT) is a glycoprotein with 12 trans-
lasting about 1 hour and the second phase lasting 14 hours. membrane regions embedded in the axon terminal and cell body
Amoxapine is also rapidly absorbed with protein binding membranes of serotonergic neurons. When extracellular serotonin
of about 85%. The half-life is variable, and the drug is often binds to receptors on the transporter, conformational changes
−
+
given in divided doses. Amoxapine undergoes extensive hepatic occur in the transporter and serotonin, Na , and Cl are moved
+
metabolism. One of the active metabolites, 7-hydroxyamoxapine, into the cell. Binding of intracellular K then results in the release
is a potent D blocker and is associated with antipsychotic effects. of serotonin inside the cell and return of the transporter to its
2
Maprotiline is similarly well absorbed orally and 88% bound to original conformation. SSRIs allosterically inhibit the transporter
protein. It undergoes extensive hepatic metabolism. by binding the SERT receptor at a site other than the serotonin
Mirtazapine is demethylated followed by hydroxylation and binding site. At therapeutic doses, about 80% of the activity of
glucuronide conjugation. Several CYP isozymes are involved in the transporter is inhibited. Functional polymorphisms exist for
the metabolism of mirtazapine, including 2D6, 3A4, and 1A2. SERT that determine the activity of the transporter (Table 30–2).
The half-life of mirtazapine is 20–40 hours, and it is usually dosed SSRIs have modest effects on other neurotransmitters. Unlike
once in the evening because of its sedating effects. TCAs and SNRIs, there is little evidence that SSRIs have promi-
Vilazodone is well absorbed (Table 30–1), and absorption nent effects on β adrenoceptors or the norepinephrine transporter,
is increased when it is given with a fatty meal. It is extensively NET. Binding to the serotonin transporter is associated with tonic