CH2-CH2-NH一NH2 Phenelzine CH一CH-NH2 \/ CH2 Tranylcypromine Figure 30-5.Some monoamine oxidase inhibitors.Phenelzine is the hydrazide of phenylethylamine (see Figure 9-3),whereas tranylcypromine has a cyclopropyl amine side chain and closely resembles dextroamphetamine.These agents are unselective and produce an extremely long-lasting inhibition of the enzyme.Selegiline,which is partially selective for MAO-B,is shown in Figure 28-2. Pharmacokinetics A.TRICYCLIC ANTIDEPRESSANTS Most tricyclics are incompletely absorbed and undergo significant first-pass metabolism.As a result of high tissue protein binding and relatively high lipid solubility,volumes of distribution tend to be very large.Tricyclics are metabolized by two major routes:transformation of the tricyclic nucleus and alteration of the aliphatic side chain.Monodemethylation of tertiary amines leads to active metabolites such as desipramine and nortriptyline(which are themselves available as drugs;Figure 30-1). B.SECOND-GENERATION AND SUBSEQUENT ANTIDEPRESSANTS The pharmacokinetics of these drugs are similar to those of the TCAs(Table 30-1). Some have active metabolites.Trazodone and venlafaxine have short plasma half-lives,which mandates divided doses during the day when beginning treatment, although once-a-day dosing may be possible later.Extended-release forms of bupropion and venlafaxine allow for once-a-day dosing in some patients from the outset. C.SELECTIVE SEROTONIN REUPTAKE INHIBITORS The pharmacokinetic parameters of these drugs are summarized in Table 30-1. Fluoxetine is notable for the long half-life of its active metabolite,norfluoxetine(7-9 days at steady state).This long tip has allowed the introduction of a formulation for once-weekly dosing.Sertraline and paroxetine have pharmacokinetic parameters similar to those of tricyclics.Citalopram and fluvoxamine resemble fluoxetine.Figure 30-5. Some monoamine oxidase inhibitors. Phenelzine is the hydrazide of phenylethylamine (see Figure 9-3), whereas tranylcypromine has a cyclopropyl amine side chain and closely resembles dextroamphetamine. These agents are unselective and produce an extremely long-lasting inhibition of the enzyme. Selegiline, which is partially selective for MAO-B, is shown in Figure 28-2. Pharmacokinetics A. TRICYCLIC ANTIDEPRESSANTS Most tricyclics are incompletely absorbed and undergo significant first-pass metabolism. As a result of high tissue protein binding and relatively high lipid solubility, volumes of distribution tend to be very large. Tricyclics are metabolized by two major routes: transformation of the tricyclic nucleus and alteration of the aliphatic side chain. Monodemethylation of tertiary amines leads to active metabolites such as desipramine and nortriptyline (which are themselves available as drugs; Figure 30-1). B. SECOND-GENERATION AND SUBSEQUENT ANTIDEPRESSANTS The pharmacokinetics of these drugs are similar to those of the TCAs (Table 30-1). Some have active metabolites. Trazodone and venlafaxine have short plasma half-lives, which mandates divided doses during the day when beginning treatment, although once-a-day dosing may be possible later. Extended-release forms of bupropion and venlafaxine allow for once-a-day dosing in some patients from the outset. C. SELECTIVE SEROTONIN REUPTAKE INHIBITORS The pharmacokinetic parameters of these drugs are summarized in Table 30-1. Fluoxetine is notable for the long half-life of its active metabolite, norfluoxetine (7-9 days at steady state). This long t1/2 has allowed the introduction of a formulation for once-weekly dosing. Sertraline and paroxetine have pharmacokinetic parameters similar to those of tricyclics. Citalopram and fluvoxamine resemble fluoxetine