DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

408 antipsychotics are synergistic for the treatment of psychotic depression.
Tertiary amine TCAs (e.g., doxepin, amitriptyline) have been
used for many years in relatively low doses for treating insomnia. In
addition, because of the role of norepinephrine and serotonin in pain
transmission, these drugs are commonly used to treat a variety of
pain conditions.
SECTION II
NEUROPHARMACOLOGY
Mechanism of Action. The inspiration for the development of both
SSRIs and SNRIs derived from the appreciation that a salient pharmacological
action of TCAs is antagonism of serotonin and norepinephrine
transporters (Table 15–2). The antidepressant action of
TCAs was discovered during clinical trials in schizophrenic patients;
imipramine had little effect on psychotic symptoms but had beneficial
effects on depressive symptoms (Hollister, 1981). In addition
to inhibiting NET somewhat selectively (desipramine, nortriptyline,
protriptyline, amoxapine) or both SERT and NET (imipramine,
amitriptyline), these drugs also block other receptors (H 1
, 5-HT 2
, α 1
,
and muscarinic). Given the superior activity of clomipramine over
SSRIs, some combination of these additional pharmacological
actions may contribute to the therapeutic effects of TCAs. One TCA,
amoxapine, also is a dopaminergic receptor antagonist; its use,
unlike that of other TCAs, poses some risk for the development of
extrapyramidal side effects such as tardive dyskinesia.
Monoamine Oxidase Inhibitors
MAOIs have efficacy equivalent to that of the TCAs but are rarely
used because of their toxicity and major drug and food interactions
(Hollister, 1981). The MAOIs approved for treatment of depression
include tranylcypromine (PARNATE, others), phenelzine (NARDIL), and
isocarboxazid (MARPLAN). Selegiline (EMSAM) is available as a transdermal
patch and approved for use in the treatment of depression;
transdermal delivery may reduce the risk for diet- associated hypertensive
reactions (described later).
Mechanism of Action. The MAOIs nonselectively and irreversibly
inhibit both MAO- A and MAO- B, which are located in the mitochondria
and metabolize (inactivate) monoamines, including 5-HT
and NE (Chapter 8). Selegiline inhibits MAO- B at lower doses, with
effects on MAO- A at higher doses. Selegiline also is a reversible
inhibitor of monoamine oxidase, which may reduce the potential for
serious adverse drug and food interactions. While both MAO- A and
MAO- B are involved in metabolizing 5-HT, only MAO- B is found
in serotonergic neurons (Chapter 13).
Pharmacokinetics
The metabolism of most antidepressants is mediated by hepatic CYPs
(see Table 15–3). Some antidepressants inhibit the clearance of other
drugs by the CYP system, as discussed in the following section, and
this possibility of drug interactions should be a significant factor in
considering the choice of agents.
Selective Serotonin Reuptake Inhibitors. All of the SSRIs are
orally active and possess elimination half- lives consistent with oncedaily
dosing (Hiemke and Hartter, 2000). In the case of fluoxetine,
the combined action of the parent and the desmethyl metabolite norfluoxetine
allows for a once weekly formulation (PROZAC WEEKLY).
CYP2D6 is involved in the metabolism of most SSRIs and the
SSRIs are at least moderately potent inhibitors of this isoenzyme
(Table 15–3). This creates a significant potential for drug interaction
for post- menopausal women taking the breast cancer drug and estrogen
antagonist, tamoxifen (Chapter 62); the parent molecule is converted
to a more active metabolite by CYP2D6, and SSRIs may
inhibit this activation and diminish the therapeutic activity of tamoxifen.
Since venlafaxine and desvenlafaxine are weak inhibitors of
CYP2D6, these antidepressants are not contraindicated in this clinical
situation. However, care should be used in combining SSRIs
with drugs that are metabolized by CYPs 1A2, 2D6, 2C9, and 3A4
(e.g., warfarin, tricyclic antidepressants, paclitaxel).
Serotonin- Norepinephrine Reuptake Inhibitors. Both immediate
release and extended- release (tablet or capsule) preparations of venlafaxine
(EFFEXOR XR, others) produces steady state-levels of drug in
plasma within 3 days. The elimination half- lives for the parent venlafaxine
and its active and major metabolite desmethyl venlafaxine
are 5 and 11 hours, respectively. Desmethylvenlafaxine is eliminated
by hepatic metabolism and by renal excretion. Venlafaxine dose reductions
are suggested for patients with renal or hepatic impairment.
Duloxetine has a t 1/2
of 12 hours. Duloxetine is not recommended for
those with end- stage renal disease or hepatic insufficiency.
Serotonin Receptor Antagonists. Mirtazapine has an elimination
t 1/2 of 16-30 hours. Thus, dose changes are suggested no more often
than 1-2 weeks. Clearance of mirtazapine is decreased in the elderly
and in patients with moderate to severe renal or hepatic impairment.
Pharmacokinetics and adverse effects of mirtazapine may have an
enantiomer-selective component (Brockmöller et al., 2007). Steadystate
trazodone is observed within 3 days following either a twice
or three times daily dosing regimen. Nefazodone has a t 1/2
of only
2-4 hours; its major metabolite hydroxynefazodone has a t 1/2
of
1.5-4 hours.
Bupropion. The terminal phase of bupropion elimination has a t 1/2
of 21 hours. The elimination of bupropion involves both hepatic and
renal routes. Patients with severe hepatic cirrhosis should receive a
maximum dose of 150 mg every other day while consideration for a
decreased dose should also be made in cases of renal impairment.
Tricyclic Antidepressants. The TCAs, or their active metabolites,
have plasma exposure half- lives of 8-80 hours; this makes oncedaily
dosing possible for most of the compounds (Rudorfer and
Potter, 1999). Steady- state concentrations occur within several days
to several weeks of beginning treatment. TCAs are largely eliminated
by hepatic CYPs (see Table 15–3). Determination of plasma
levels may be useful in identifying patients who appear to have toxic
effects and may have excessively high levels of the drug, or those
in whom lack of absorption or noncompliance is suspected. Dosage
adjustments of TCAs are typically made according to patient’s clinical
response, not based on plasma levels. Nonetheless, monitoring
the plasma exposure has an important relationship to treatment
response: there is a relatively narrow therapeutic window, as discussed
below.
About 7% of patients metabolize TCAs slowly due to a variant
CYP2D6 isoenzyme, causing a 30-fold difference in plasma concentrations
among different patients given the same TCA dose. To
avoid toxicity in “slow metabolizers,” plasma levels should be
monitored and doses adjusted downward.
Monoamine Oxidase Inhibitors. MAOIs are metabolized by acetylation,
although the end products are incompletely characterized.