Desvenlafaxine and venlafaxine

SNRIs are chemically unrelated to each other. Venlafaxine was discovered in the process of evaluating chemicals that inhibit binding of imipramine. Venlafaxine s in vivo effects are similar to those of imipramine but with a more favorable adverse-effect profile. All SNRIs bind the serotonin (SERT) and norepinephrine (NET) transporters, as do the TCAs. However, unlike the TCAs, the SNRIs do not have much affinity for other receptors. Venlafaxine and desvenlafaxine are bicyclic compounds, whereas duloxetine is a three-ring structure unrelated to the TCAs. Milnacipran contains a cyclopropane ring and is provided as a racemic mixture. 

The serotonin-norepinephrine reuptake inhibitors include venlafaxine and duloxetine. Venlafaxine is an inhibitor of 5-HT and NE reuptake and a weak inhibitor of DA reuptake. Desvenlafaxine (Pristiq) was recently approved by the FDA. The dose is 50 mg once daily. 

Jann MW, SpratUn V, Momary K, Zhang H, Turner D, Penzak SR, et al. Lack of a pharmacokinetic drug-drug interaction with venlafaxine extended-release/indinavir and desvenlafaxine extended-release/indinavir. Eur J CHn Pharmacol 2012 68(5) 715-21. 

As the first SNRI drug approved, venlafaxine has become one of the first-line choices for depression and anxiety disorder [45,46]. An active metabolite, desvenlafaxine (19), is also under clinical development for the treatment of major depressive disorders [47], Preclinical studies also indicate that 19 may be effective in relieving vasomotor symptoms associated with menopause (e.g., hot flushes and night sweats) [47,48]. Desvenlafaxine is reported to be in clinical development for the treatment of fibromyalgia and neuropathic pain, as well as vasomotor symptoms associated with menopause [68]. 

The SNRIs include venlafaxine, its metabolite desvenlafaxine, and duloxetine. Another SNRI, milnacipran, is in late clinical trials in the USA but has been available in Europe for several years. In addition to their use in major depression, other applications of the SNRIs include the treatment of pain disorders including neuropathies and fibromyalgia. SNRIs are also used in the treatment of generalized anxiety, stress urinary incontinence, and vasomotor symptoms of menopause. 

Venlafaxine is a weak inhibitor of NET, whereas desvenlafaxine, duloxetine, and milnacipran are more balanced inhibitors of both SERT and NET. Nonetheless, the affinity of most SNRIs tends to be much greater for SERT than for NET. The SNRIs differ from the TCAs in that they lack the potent antihistamine, -adrenergic blocking, and anticholinergic effects of the TCAs. As a result, the SNRIs tend to be favored over the TCAs in the treatment of MDD and pain syndromes because of their better tolerability. 

The SNRIs have relatively fewer CYP450 interactions than the SSRIs. Venlafaxine is a substrate but not an inhibitor of CYP2D6 or other isoenzymes, whereas desvenlafaxine is a minor substrate for CYP3A4. Duloxetine is a moderate inhibitor of CYP2D6 and so may elevate TCA and other CYP2D6 substrate levels. Like all serotonergic antidepressants, SNRIs are contraindicated in combination with MAOIs. 

Duloxetine Moderately selective blockade of NET and SERT Acute increase in serotonergic and adrenergic synaptic activity otherwise like SSRIs Major depression, chronic pain disorders fibromyalgia, perimenopausal symptoms Toxicity Anticholinergic, sedation, hypertension (venlafaxine) Interactions Some CYP2D6 inhibition (duloxetine, desvenlafaxine)... 

Hypertension Although venlafaxine has been reported to be associated with a dose-dependent increase in hypertension, and the product information lists increases in blood pressure (BP) as a potential adverse effect, there had been no previous reports implicating desvenlafaxine in hypertension [56 ]. 

Myositis There has been one case report and at least two pharmacovigilance reports of venlafaxine-induced myositis with normal dosing [57 ], but no prior reports of this occurring with desvenlafaxine. Fxulfier, experience in venlafaxine overdose suggests that it can be potentially toxic to skeletal muscle and can lead to elevations of creatine kinase (CK) and even rhabdomyolysis in very large doses [59 ]. 

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