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

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SECTION II
NEUROPHARMACOLOGY
Drug Interactions
Selective Serotonin Reuptake Inhibitors. Most antidepressants,
including the SSRIs, exhibit drug- drug interactions based on their
routes of metabolism CYPs. Paroxetine and, to a lesser degree, fluoxetine
are potent inhibitors of CYP2D6 (Hiemke and Hartter, 2000).
The other SSRIs, outside of fluvoxamine, are at least moderate
inhibitors of CYP2D6. This inhibition can result in disproportionate
increases in plasma concentrations of drugs metabolized by CYP2D6
when doses of these drugs are increased. Fluvoxamine directly inhibits
CYP1A2 and CYP2C19; fluoxetine and fluvoxamine also inhibit
CYP3A4. A prominent interaction is the increase in TCA exposure
that may be observed during co- administration of TCAs and SSRIs.
Another important drug- drug interaction with SSRIs occurs
via a pharmacodynamic mechanism. MAOIs enhance the effects of
SSRIs due to inhibition of serotonin metabolism. Administration of
these drugs together can produce synergistic increases in extracellular
brain serotonin, leading to the serotonin syndrome. Symptoms
of the serotonin syndrome include hyperthermia, muscle rigidity,
myoclonus, tremors, autonomic instability, confusion, irritability,
and agitation; this can progress toward coma and death. Other drugs
that may induce the serotonin syndrome include substituted amphetamines
such as methylenedioxymethamphetamine (Ecstasy), which
directly releases serotonin from nerve terminals. The primary treatment
is stopping all serotonergic drugs, administering nonselective
serotonin antagonists, and supportive measures.
Since currently available MAOIs bind irreversibly to MAO
and block the enzymatic metabolism of monoaminergic neurotransmitters,
SSRIs should not be started until at least 14 days following
discontinuation of treatment with an MAOI; this allows for synthesis
of new MAO. For all SSRIs but fluoxetine, at least 14 days should
pass prior to beginning treatment with an MAOI following the end
of treatment with an SSRI. Since the active metabolite norfluoxetine
has a t 1/2
of 1-2 weeks, at least 5 weeks should pass between
stopping fluoxetine and beginning an MAOI.
Serotonin- Norepinephrine Reuptake Inhibitors. While 14 days
are suggested to elapse from ending MAOI therapy and starting venlafaxine
treatment, an interval of only 7 days after stopping venlafaxine
is considered safe before beginning an MAOI. Duloxetine has a
similar interval to initiation following MAOI therapy, but requires
only a 5-day waiting period to begin MAOI treatment after ending
duloxetine. Failure to observe these required waiting periods can
result in the serotonin syndrome, as noted above for SSRIs.
Serotonin Receptor Antagonists. Trazodone dosing may need to be
lowered when given together with drugs that inhibit CYP3A4.
Mirtazapine is metabolized by CYPs 2D6, 1A2, and 3A4, but does
not potently inhibit any of these isoenzymes. Trazodone and nefazodone
are weak inhibitors of serotonin uptake and should not be
administered with MAOIs due to concerns about the serotonin syndrome.
However, it is unclear whether these drugs appreciably block
brain SERT at doses used in the treatment of depression.
Bupropion. The major route of metabolism for bupropion is
CYP2B6. While there does not appear to be any evidence for metabolism
by CYP2D6 and this drug is frequently administered with
SSRIs, the potential for interactions with drugs metabolized by
CYP2D6 should be kept in mind until the safety of the combination
is firmly established.
Tricyclic Antidepressants. Drugs that inhibit CYP2D6, such as
SSRIs, may increase plasma exposures of TCAs. Other drugs that
may act similarly are phenothiazine antipsychotic agents, type 1C
anti- arrhythmic drugs, and other drugs with antimuscarinic, antihistaminic,
and α adrenergic antagonistic effects. TCAs can potentiate
the actions of sympathomimetic amines and should not be used concurrently
with MAOIs or within 14 days of stopping MAOIs.
Monoamine Oxidase Inhibitors. A large number of drug- drug interactions
lead to contraindications for simultaneous use with MAOIs.
CNS depressants including meperidine and other narcotics, alcohol,
and anesthetic agents should not be used with MAOIs. Meperidine
and other opioid agonists in combination with MAOIs also induce
the serotonin syndrome. As discussed earlier, SSRIs and SNRIs are
contraindicated in patients on MAOIs, and vice versa, to avoid the
serotonin syndrome. In general, other antidepressants such as TCAs
and bupropion also should be avoided in patients taking an MAOI.
Anxiolytic Drugs
A variety of agents and drug classes provide anxiolytic effects. The
primary treatments for anxiety- related disorders include the SSRIs,
SNRIs, benzodiazepines, the azipirone buspirone, and beta adrenergic
antagonists (Atack, 2003). Historically, TCAs, particularly
clomipramine, and MAOIs have been used for the treatment of some
anxiety- related disorders, but their use has been supplanted by drugs
with lower toxicity. Specific issues relating to mechanism of action,
adverse effects, pharmacokinetics, and drug interactions are discussed
earlier and in Chapters 16 and 17.
The SSRIs and the SNRI venlafaxine (discussed earlier) are
well tolerated with a reasonable side effect profile; in addition to
their documented antidepressant activity, they also have have anxiolytic
activity with chronic treatment. The benzodiazepines are effective
anxiolytics as both acute and chronic treatment. There is concern
regarding their use because of their potential for dependence and
abuse as well as negative effects on cognition and memory.
Buspirone, like the SSRIs, is effective following chronic treatment.
In acts, at least in part, via the serotonergic system, where it is a partial
agonist at 5-HT 1A
receptors. Buspirone also has antagonistic
effects at dopamine D 2
receptors, but the relationship between this
effect and its clinical actions is uncertain. β adrenergic antagonists,
particularly those with higher lipophilicity (e.g., propranolol and
nadolol) are occasionally used for performance anxiety such as fear
of public speaking; their use is limited due to significant side effects
such as hypotension.
The antihistamine hydroxyzine and various sedative- hypnotic
agents have been used as anxiolytics, but are generally not recommended
because of their side effect profiles. Hydroxyzine, which produces
short- term sedation, has been used in patients that cannot use
other types of anxiolytics (e.g., those with a history of drug or alcohol
abuse where benzodiazepines would be avoided). Chloral hydrate has
been used for situational anxiety, but there is a narrow dose range where
anxiolytic effects are observed in the absence of significant sedation,
and, therefore, the use of chloral hydrate is not recommended.
Clinical Considerations with Anxiolytic Drugs. The choice of pharmacological
treatment for anxiety is dictated by the specific anxietyrelated
disorders and the clinical need for acute anxiolytic effects
(Millan, 2003). Among the commonly used anxiolytics, only the