Pharmacokinetics The pharmacokinetics of TCAs are complex, as reflected in
Pharmacokinetics The pharmacokinetics of TCAs are complex, as reflected in
the diversity of half-lives (10 to 40 hours). TCAs are primarily absorbed in the small intestine, reaching peak plasma levels two to six hours after oral administration. Absorption can be affected by changes in gut motility. The drugs are extensively metabolized in the liver on first pass through the portal system. They are lipophilic, have a large volume of distribution, and are highly protein-bound (85–95%). TCAs are metabolized to active metabolites in the liver by hepatic microsomal enzymes and excreted by the kidneys. The rate of metabolism can vary genetically; 7 to 9% of the white population are slow hydrox- ylators. There is a large range of elimination half-lives.
TCAs as a class have a relatively narrow therapeutic index; there is a significant risk of toxicity with blood levels of only two to six times the therapeutic level. A 1-week supply can be fatal in overdose, as blood concentrations of greater than 1000 ng/dl are correlated with prolongation of the QRS complex and arrhythmias. TCAs are commonly ingested agents by which patients successfully commit suicide by overdose.
MAOIs are also well absorbed from the gastrointestinal tract. Their short half-life of one to two hours is not particularly relevant as they bind irreversibly with MAO. Thus, the activity of these drugs depends less on pharmacokinetics and more on the synthesis of new MAO to restore normal enzyme activity. This synthesis requires approximately two weeks. This class of drugs is little used due to their potentially dangerous interac- tions with sympathomimetics and foods containing tyramine.
Each of the six SSRI agents (fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram and its S-enantiomer escitalopram) selectively block the reuptake of serotonin presynaptically, though each drug differs structurally from the others. As a result, these agents differ in their pharmacokinetic profiles. Many SSRIs are, like the TCAs, highly protein bound though the proportions of citalopram and escitalopram that are protein-bound are 80 and 56% respectively. In contrast,
Antidepressants available in the United States PRICE INDEX:
RECOMMENDED CLASS
(DOLLAR COST OF AVERAGE DOSE/d) ∗∗
NAME
GENERIC
HOW SUPPLIED
DOSE PER DAY ∗
TCAs Amitriptyline
Tablets (mg): 10, 25, 50, 75, 100, 150
150 mg
Oral solution: 10 mg/5mL IM: 10 mg/mL
Imipramine
Tablets (mg): 10, 25, 50
150 mg
Capsules (mg): 75, 100, 125, 150
Nortriptyline
Oral solution: 10 mg/5 mL
75 mg
Capsules (mg): 10, 25, 50, 75
150 mg Amoxapine
Desipramine
Tablets (mg): 10, 25, 50, 75, 100, 150
300 mg Doxepin
Tablets (mg): 25, 50, 100, 150
Oral solution: 10 mg/mL
150 mg
Capsules (mg): 10, 25, 50, 75, 100, 150
Protriptyline
45 mg Trimipramine
Tablets (mg): 5, 10
150 mg Clomipramine
Tablets (mg): 25, 50, 100
150 mg Maprotiline
Tablets (mg): 25, 50, 75
150 mg MAOIs
Tablets (mg): 25, 50, 75
Isocarboxazid
30 mg Phenelzine
Tablets: 10 mg
60 mg Tranylcypromine
Tablets: 15 mg
Tablets: 10 mg
40 mg
(Continued) PRICE INDEX:
RECOMMENDED CLASS
(DOLLAR COST OF AVERAGE DOSE/d) ∗∗
NAME
GENERIC
HOW SUPPLIED
DOSE PER DAY ∗
SSRIs Fluoxetine
Oral solution: 20 mg/5mL
60 mg
Tablets (mg): 10, 20, 40 Delayed release capsules: 90 mg (“Prozac Weekly”)
Sertraline
Oral solution: 20 mg/mL
100 mg
Tablets (mg): 25, 50, 100
Paroxetine
Oral solution: 10 mg/5mL
40 mg
Tablets (mg): 10, 20, 30, 40
Paroxetine controlled release
40 mg Fluvoxamine
Controlled release tablets (mg): 12.5, 25, 37.5
200 mg Citalopram
Tablets (mg): 25, 50, 100
Oral solution: 10 mg/5 mL
40 mg
Tablets (mg): 10, 20, 40
Escitalopram
Oral solution: 1 mg/1 mL
20 mg
Tablets (mg): 5, 10, 20
Atypical Bupropion
300 mg Bupropion sustained release
Tablets (mg): 75, 100
300 mg Bupropion extended release
Sustained release (mg): 100, 150
300 mg Trazodone
Extended release (mg): 150, 300
100 mg SNRI
Tablets (mg): 50, 100, 150, 300
Venlafaxine
Tablets (mg): 25, 37.5, 50, 75, 100
225 mg
225 mg Duloxetine
Extended release (mg): 37.5, 75, 150
60 mg Mixed serotonin
Tablets (mg): 20, 30, 60
300 mg antagonist/ reuptake inhibitors
Nefazodone
Tablets (mg): 50, 100, 150, 200, 250
Mixed serotonin/ Mirtazapine
45 mg noradrenaline
Tablets (mg): 15, 30, 45
Dissolvable tablets (mg): 15, 30, 45
antagonists
∗ Recommended dose derived from Lexi-comp online. The price index is a rough calculation, assuming an average recommended dose for the treatment of major depression, and assuming that the most efficient dosing regimen, and least expensive tablet choice, is prescribed. When available, generic prices are used. Prices were
derived from 2006 Cardinal Health wholesale price guide provided by the Pharmacy Department of the New York State Institute.
48 HANDBOOK OF PSYCHIATRIC DRUGS
however, they have varying half-lives ranging from approxi- mately 24 hours to several days.
All SSRIs are well absorbed and not generally affected by food administration, though sertraline is an exception to this rule – its blood level may be increased by food. All have large volumes of distribution and are extensively protein-bound. They are metabolized by hepatic microsomal enzymes and are potent inhibitors of these enzymes. The only serotonin reup- take inhibitor with an active metabolite is fluoxetine, whose metabolite norfluoxetine has a half-life of 7 to 15 days. Thus, it may take several months to achieve steady state with this agent. This is considerably longer than citalopram (half-life 1.5 days) or sertraline and paroxetine (half-lives 24 hours).
There is no correlation between half-life and time to onset. Drugs with shorter half-lives have an advantage in cases where rapid elimination is desired (e.g., in the case of an allergic reaction). Drugs with a longer half-life may also have advan- tages: fluoxetine, for example, has been successfully given in
a once-weekly dosing during the continuation phase of treat- ment and a once-weekly formulation of this drug is currently available. All serotonin reuptake inhibitors are eliminated in the urine as inactive metabolites. Both fluoxetine and paroxe- tine are capable of inhibiting their own clearance at clinically relevant doses. As such, they have nonlinear pharmacokinetics: changes in dose can produce proportionately large plasma levels.
Citalopram and its S-enantiomer escitalopram are the most recent SSRIs to be introduced in the Untied States; The Food and Drug Administration (FDA) approved citalopram in 1998 and escitalopram in 2002. Of the available SSRIs, these are the most selective for serotonin receptor blockade; escitalopram is 100 times more potent than the R-enantiomer.
As with most other antidepressants, bupropion under- goes extensive first pass metabolism in the liver. The parent compound has a half-life of 10 to 12 hours, but has three active metabolites. One, threohydrobupropion, has a half-life of
35 hours and is relatively free in plasma (it is only 50% protein- bound). There is considerable individual variability in the levels of bupropion and its metabolites. Trazodone has a relatively short half-life of three to nine hours; as a result of this and its
ANTIDEPRESSANTS 49 apparent lack of active metabolites plasma levels of trazodone
can be quite variable, requiring divided dosing. Venlafaxine has a short half-life (4 hours); however, it is available in an extended release formulation that allows once- daily dosing. It appears to have a dual effect, in which at lower doses it primarily acts on the serotonin transporter, and clinically significant norepinephrine reuptake inhibition is not seen until higher doses are used (150 mg/day and above).
Nefazodone has relatively low bioavailability, and a short half-life (2–8 hours), and thus it is usually given in twice-daily doses. Mirtazapine has a half-life of 13 to 34 hours.
Duloxetine is the second selective inhibitor of nore- pinephrine and serotonin to be introduced in the United States. Compared with venlafaxine it has relatively greater effect on 5-HT reuptake in vitro but the clinical significance of this difference is unclear. The half-life of duloxetine is 8–17 hours (mean 12 hours).
The SSRIs are also, to varying degrees, potent inhibitors of the P450 hepatic enzyme system. The result is increased blood levels of concomitant agents that are also metabolized by this enzymatic system. Switching from an SSRI to another antide- pressant group illustrates the clinical relevance. For example, when a patient changes from fluoxetine to venlafaxine, the inhibition of the P450 2D6 isozyme will reduce venlafaxine metabolism for several weeks. The resulting increase in the venlafaxine blood level can hasten the development of side effects. The aware clinician can avoid this by starting with a lower than usual initial dose and titrating upward slowly.