Page 563 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 30 Antidepressant Agents 549

by concurrent administration of nefazodone such that a reduction vilazodone is neither a potent inhibitor nor a strong inducer of any
in triazolam dosage by 75% is recommended. Likewise, adminis- CYP isoenzymes. It may be a mild inducer of CYP2C19.
tration of nefazodone with simvastatin has been associated with
20-fold increase in plasma levels of simvastatin. E. Monoamine Oxidase Inhibitors
Trazodone is a substrate but not a potent inhibitor of CYP3A4. MAOIs are associated with two classes of serious drug interac-
As a result, combining trazodone with potent inhibitors of tions. The first of these is the pharmacodynamic interaction of
CYP3A4, such as ritonavir or ketoconazole, may lead to substan- MAOIs with serotonergic agents including SSRIs, SNRIs, and
tial increases in trazodone levels. most TCAs along with some analgesic agents such as meperidine.
Vortioxetine is a substrate of CYP2D6 and 2B6, and it is rec- These combinations of an MAOI with a serotonergic agent may
ommended that the dose be cut in half when it is coadministered result in a life-threatening serotonin syndrome (see Chapter
with fluoxetine or bupropion. Inducers of CYP isoenzymes such as 16). The serotonin syndrome is thought to be caused by over-
rifampin, carbamazepine, and phenytoin will lower serum levels of stimulation of 5-HT receptors in the central gray nuclei and
vortioxetine and may require increasing the dose of vortioxetine. the medulla. Symptoms range from mild to lethal and include
a triad of cognitive (delirium, coma), autonomic (hypertension,
D. Tetracyclic and Unicyclic Antidepressants tachycardia, diaphoreses), and somatic (myoclonus, hyperreflexia,
Bupropion is metabolized primarily by CYP2B6, and its metabo- tremor) effects. Most serotonergic antidepressants should be dis-
lism may be altered by drugs such as cyclophosphamide, which is continued at least 2 weeks before starting an MAOI. Fluoxetine,
a substrate of 2B6. The major metabolite of bupropion, hydroxy- because of its long half-life, should be discontinued for 4–5 weeks
bupropion, is a moderate inhibitor of CYP2D6 and so can raise before an MAOI is initiated. Conversely, an MAOI must be dis-
desipramine levels. Bupropion should be avoided in patients tak- continued for at least 2 weeks before starting a serotonergic agent.
ing MAOIs. The second serious interaction with MAOIs occurs when an
Mirtazapine is a substrate for several CYP450 enzymes includ- MAOI is combined with tyramine in the diet or with sympatho-
ing 2D6, 3A4, and 1A2. Consequently, drugs that inhibit these mimetic substrates of MAO. An MAOI prevents the breakdown
isozymes may raise mirtazapine levels. However, mirtazapine is of tyramine in the gut, and this results in high serum levels
not an inhibitor of these enzymes. The sedating effects of mir- that enhance peripheral noradrenergic effects, including raising
tazapine may be additive with those of CNS depressants such as blood pressure dramatically. Patients on an MAOI who ingest
alcohol and benzodiazepines. large amounts of dietary tyramine may experience malignant
Amoxapine and maprotiline share most drug interactions com- hypertension and subsequently a stroke or myocardial infarction.
mon to the TCA group. Both are CYP2D6 substrates and should Thus, patients taking MAOIs require a low-tyramine diet and
be used with caution in combination with inhibitors such as fluox- should avoid foods such as aged cheeses, tap beer, soy products,
etine. Amoxapine and maprotiline also both have anticholinergic and dried sausages, which contain high amounts of tyramine
and antihistaminic properties that may be additive with drugs that (see Chapter 9). Similar sympathomimetics also may cause
share a similar profile. significant hypertension when combined with MAOIs. Thus,
Since vilazodone is primarily a substrate of CYP3A4, strong over-the-counter cold preparations that contain pseudoephed-
CYP3A4 inhibitors such as ketoconazole can increase the serum rine and phenylpropanolamine are contraindicated in patients
concentration of vilazodone by 50% or more. On the other hand, taking MAOIs.

SUMMARY Antidepressants

Pharmacokinetics,
Subclass, Drug Mechanism of Action Effects Clinical Applications Toxicities, Interactions
SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs)
• Fluoxetine Highly selective blockade of Acute increase of Major depression, anxiety Half-lives from 15–75 h • oral activity
• Citalopram serotonin transporter (SERT) serotonergic synaptic disorders • panic disorder • Toxicity: Well tolerated but cause sexual
• Escitalopram • little effect on activity • slower changes in • obsessive-compulsive dysfunction • risk of serotonin syndrome
• Paroxetine norepinephrine transporter several signaling pathways disorder • post-traumatic with MAOIs • Interactions: Some CYP
• Sertraline (NET) and neurotrophic activity stress disorder inhibition (fluoxetine 2D6, 3A4;
• perimenopausal vasomotor fluvoxamine 1A2; paroxetine 2D6)
symptoms • eating disorder
(bulimia)

• Fluvoxamine: Similar to above but approved only for obsessive-compulsive behavior
(continued)