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

anorgasmia, and ejaculatory delay; these effects may be more prominent
with paroxetine (Vaswani et al., 2003). Stimulation of 5-HT 3
receptors in the CNS and periphery contributes to GI effects, which
are usually limited to nausea but may include diarrhea and emesis.
Some patients experience an increase in anxiety, especially with the
initial dosing of SSRIs. With continued treatment, some patients also
report a dullness of intellectual abilities and concentration. In addition
a phenomenon of a residual “flat affect” can occur in an otherwise
successful treatment with SSRIs. A number of these side effects
may be difficult to distinguish from symptoms of depression.
In general, there is not a strong relationship between SSRI
serum concentrations and therapeutic efficacy. This finding is not
surprising given that most antidepressant studies have been conducted
at doses/plasma exposures which saturate the brain SERT,
consistent with the flat dose or exposure/efficacy relationships
observed. Thus, dosage adjustments are based more on evaluation
of clinical response and management of side effects than on measurements
of plasma drug concentrations.
Sudden withdrawal of antidepressants can precipitate a withdrawal
syndrome. For SSRIs or SNRIs, the symptoms of withdrawal
may include dizziness, headache, nervousness, nausea, and insomnia.
This withdrawal syndrome appears most intense for paroxetine
and venlafaxine compared to other antidepressants due to their relatively
short half- lives and, in the case of paroxetine, lack of active
metabolites. On the other hand, the active metabolite of fluoxetine,
norfluoxetine, has such a long t 1/2
(1-2 weeks) that few patients experience
any withdrawal symptoms when discontinuing fluoxetine.
Unlike the other SSRIs, paroxetine is associated with an
increased risk of congenital cardiac malformations. Epidemiological
data suggest that paroxetine might increase the risk of congenital cardiac
malformations when administered in the first trimester of pregnancy.
Venlafaxine also is associated with an increased risk of
perinatal complications. Therefore, these drugs should not be used in
pregnant women; careful consideration should be given to using these
mediations in women of reproductive potential, and these subjects
should be advised to avoid pregnancy while they are taking the drugs.
Serotonin- Norepinephrine Reuptake Inhibitors. The SNRIs have
desirable safety advantages over the TCAs (Table 15–4). SNRIs have
a side effect profile similar to that of the SSRIs, including nausea,
constipation, insomnia, headaches, and sexual dysfunction. The
immediate release formulation of venlafaxine can induce sustained
diastolic hypertension (systolic blood pressure > 90 mm Hg at consecutive
weekly visits) in 10-15% of patients at higher doses; this
risk is reduced with the extended- release form. This effect of venlafaxine
may not be associated simply with inhibition of NET, since
duloxetine does not share this side effect.
Serotonin Receptor Antagonists. The main side effects of mirtazapine,
seen in >10% of the patients in clinical trials, are somnolence,
increased appetite, and weight gain. A rare side effect of mirtazapine
is agranulocytosis. In the 2 patients having this side effect during the
pre- marketing phase in nearly 2800 patients, bone marrow function
recovered when mirtazapine treatment was discontinued. Trazodone
use is associated with priapism in rare instances; this should be considered
a medical emergency and surgical intervention may be
required. Nefazodone was voluntarily withdrawn from the market in
Europe and the U.S. after rare cases of liver failure were associated
with its use. Generic nefazodone is still available in the U.S.
Bupropion. At doses higher than that recommended for depression
(450 mg/day), the risk of seizures increases significantly. The use of
extended release formulations often blunts the maximum concentration
observed after dosing and minimizes the chance of reaching
drug levels associated with an increased risk of seizures.
Tricyclic Antidepressants. TCAs are potent antagonists at histamine
H 1
receptors; H 1
receptor antagonism contributes to the sedative
effects of TCAs (Table 15–4). Antagonism of muscarinic
acetylcholine receptors contributes to cognitive dulling as well as a
range of adverse effects mediated by the parasympathetic nervous system
(blurred vision, dry mouth, tachycardia, constipation, difficulty
urinating). Some tolerance does occur for these anticholinergic
effects, which are mitigated by titration strategies to reach therapeutic
doses over a reasonable period of time. Antagonism of α 1
adrenergic
receptors contributes to orthostatic hypotension and sedation.
Weight gain is another side effect of this class of antidepressants.
TCAs also have quinidine- like effects on cardiac conduction
that can be life threatening with overdose and limit the use of TCAs
in patients with coronary heart disease. This is the primary reason
that no more than a one- week supply should be provided to a new
patient; even during maintenance treatment, only a very limited supply
should be available to the patient at any given time. Like other
antidepressant drugs, TCAs also lower the seizure threshold.
Monoamine Oxidase Inhibitors. Hypertensive crisis resulting from
food or drug interactions is one of the life- threatening toxicities
associated with use of the MAOIs. Foods containing tyramine are a
contributing factor. MAO- A within the intestinal wall and MAO- A
and MAO- B in the liver normally degrade dietary tyramine.
However, when MAO- A is inhibited, the ingestion of certain aged
cheeses, red wines, sauerkraut, fava beans, and a variety of other
tyramine- containing foods leads to accumulation of tyramine in
adrenergic nerve endings and neurotransmitter vesicles and induces
norepinephrine and epinephrine release. The released catecholamines
stimulate postsynaptic receptors in the periphery,
increasing blood pressure to dangerous levels. These episodes can be
reversed by antihypertensive medications. Even when the patient is
highly vigilant, dietary indiscretions or use of prescription or overthe-
counter medications that contain sympathomimetic compounds
may occur, resulting in a potentially life- threatening elevation of
blood pressure. In comparison to tranylcypromine and isocarboxazid,
the selegiline transdermal patch is better tolerated and safer. Another
serious, life- threatening issue with chronic administration of MAOIs
is hepatotoxicity.
MAO- A inhibitors are efficacious in treating depression.
However, MAO- B inhibitors such as selegiline (with oral formulations)
are effective in treating depression only when given at doses
that block both MAO- A and MAO- B. Thus, these data emphasize
the importance of enhancing the synaptic availability of 5-HT and
NE as important mediating events for many antidepressant drugs.
While not available in the U.S., reversible inhibitors of MAO- A
(RIMAs, such as moclobemide) have been developed. Since these
drugs are selective for MAO- A, significant MAO- B activity remains.
Further, since the inhibition of MAO- A by RIMAs is reversible and
competitive, as concentrations of tyramine rise, enzyme inhibition is
surmounted. Thus, RIMAs produce antidepressant effects with
reduced risk of tyramine- induced hypertensive crisis.
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CHAPTER 15
DRUG THERAPY OF DEPRESSION AND ANXIETY DISORDERS