Page 562 - Basic _ Clinical Pharmacology ( PDFDrive )

548 SECTION V Drugs That Act in the Central Nervous System

An overdose with an MAOI can produce a variety of effects The most serious interaction with the SSRIs are pharmacody-
including autonomic instability, hyperadrenergic symptoms, psy- namic interactions with MAOIs that produce a serotonin syn-
chotic symptoms, confusion, delirium, fever, and seizures. Man- drome (see below).
agement of MAOI overdoses usually involves cardiac monitoring,
vital signs support, and lavage. B. Selective Serotonin-Norepinephrine Reuptake
Compared with TCAs and MAOIs, the other antidepressants Inhibitors and Tricyclic Antidepressants
are generally much safer in overdose. Fatalities with SSRI over- The SNRIs have relatively fewer CYP450 interactions than the
dose alone are extremely uncommon. Similarly, SNRIs tend to be SSRIs. Venlafaxine is a substrate but not an inhibitor of CYP2D6
much safer in overdose than the TCAs. However, venlafaxine has or other isoenzymes, whereas desvenlafaxine is a minor substrate
been associated with some cardiac toxicity in overdose and appears for CYP3A4. Duloxetine is a moderate inhibitor of CYP2D6 and
to be less safe than SSRIs. Bupropion is associated with seizures in so may elevate TCA and levels of other CYP2D6 substrates. Since
overdose, and mirtazapine may be associated with sedation, disori- milnacipran is neither a substrate nor potent inducer of CYP450
entation, and tachycardia. With the newer agents, fatal overdoses isoenzymes, is not tightly protein bound, and is largely excreted
often involve the combination of the antidepressant with other unchanged in the urine, it is unlikely to have clinically significant
drugs, including alcohol. Management of overdose with the newer pharmacokinetic drug interactions. On the other hand, levomil-
antidepressants usually involves emptying of gastric contents and nacipran is reported to be a substrate of CYP3A4, and the dosage
vital sign support as the initial intervention.
of the drug should be lowered when combined with potent inhibi-
tors of CYP3A4 such as ketoconazole. Like all serotonergic antide-
DRUG INTERACTIONS pressants, SNRIs are contraindicated in combination with MAOIs.
Elevated TCA levels may occur when these drugs are combined
Antidepressants are commonly prescribed with other psychotropic with CYP2D6 inhibitors or from constitutional factors. About 7%
and nonpsychotropic agents. There is potential for drug interac- of the Caucasian population in the USA has a CYP2D6 polymor-
tions with all antidepressants, but the most serious of these involve phism that is associated with slow metabolism of TCAs and other
the MAOIs and, to a lesser extent, the TCAs. 2D6 substrates. Combination of a known CYP2D6 inhibitor and
a TCA in a patient who is a slow metabolizer may result in mark-
A. Selective Serotonin Reuptake Inhibitors edly increased effects. Such an interaction has been implicated,
The most common interactions with SSRIs are pharmacokinetic though rarely, in cases of TCA toxicity. There may also be additive
interactions. For example, paroxetine and fluoxetine are potent anticholinergic or antihistamine effects when TCAs are combined
CYP2D6 inhibitors (Table 30–4). Thus, administration with with other agents that share these properties such as benztropine
2D6 substrates such as TCAs can lead to dramatic and sometimes or diphenhydramine. Similarly, antihypertensive drugs may exac-
unpredictable elevations in the tricyclic drug concentration. The erbate the orthostatic hypotension induced by TCAs.
result may be toxicity from the TCA. Similarly, fluvoxamine, a
CYP3A4 inhibitor, may elevate the levels of concurrently admin- C. 5-HT Receptor Modulators
istered substrates for this enzyme such as diltiazem and induce Nefazodone is an inhibitor of the CYP3A4 isoenzyme, so it
bradycardia or hypotension. Other SSRIs, such as citalopram and can raise the level and thus exacerbate adverse effects of many
escitalopram, are relatively free of pharmacokinetic interactions. 3A4-dependent drugs. For example, triazolam levels are increased

TABLE 30–4 Some antidepressant–CYP450 drug interactions.

Enzyme Substrates Inhibitors Inducers
1A2 Tertiary amine tricyclic antidepressants (TCAs), dulox- Fluvoxamine, fluoxetine, moclobemide, Tobacco, omeprazole
etine, theophylline, phenacetin, TCAs (demethylation), ramelteon
clozapine, diazepam, caffeine
2C19 TCAs, citalopram (partly), warfarin, tolbutamide, Fluoxetine, fluvoxamine, sertraline, Rifampin
phenytoin, diazepam imipramine, ketoconozole, omeprazole
2D6 TCAs, benztropine, perphenazine, clozapine, halo- Fluoxetine, paroxetine, duloxetine, Phenobarbital, rifampin
peridol, codeine/oxycodone, risperidone, class Ic hydroxybupropion, methadone,
antiarrhythmics, β blockers, trazodone, paroxetine, cimetidine, haloperidol, quinidine,
maprotiline, amoxapine, duloxetine, mirtazapine ritonavir
(partly), venlafaxine, bupropion
3A4 Citalopram, escitalopram, TCAs, glucocorticoids, Fluvoxamine, nefazodone, sertraline, Barbiturates, glucocorti-
androgens/estrogens, carbamazepine, erythromycin, fluoxetine, cimetidine, fluconazole, coids, rifampin, modafinil,
2+
Ca channel blockers, levomilnacipran, protease erythromycin, protease inhibitors, carbamazepine
inhibitors, sildenafil, alprazolam, triazolam, vincristine/ ketoconazole, verapamil
vinblastine, tamoxifen, zolpidem