Levomilnacipran (1S, 2R/F2695) is an enantiomer of milnacipran, a serotonin/norepinephrine (5-HT/NE) reuptake inhibitor. Levomilnacipran is pharmacologically more active as compared with racemic mixture and dextromilnacipran (1R, 2S/F2696). The safety of the drug is also higher than the safety of a racemate, resulting in a beneficial impact on the therapeutic effect. Pierre Fabre and Forest Laboratories are developing levomilnacipran extended release (ER) [FETZIMA™], an enantiomer of milnacipran, for the treatment of major depressive disorder (MDD). In addition, Pierre Fabre (the originator of the compound) is developing the drug to improve recovery in patients with ischaemic stroke.

Dextromilnacipran (1R, 2S/F2696) is an enantiomer of milnacipran, a serotonin/norepinephrine (5-HT/NE) reuptake inhibitor. Dextromilnacipran is pharmacologically less active as compared with racemic mixture and levomilnacipran (1S, 2R/F2695).

Desvenlafaxine is a dual serotonin and norepinephrine reuptake inhibitor in vitro and in vivo that demonstrates good brain-to-plasma ratios. Desvenlafaxine has demonstrated antidepressant effects in preclinical studies. Pfizer is developing an oral, extended-release formulation of desvenlafaxine for the treatment of major depressive disorder. Desvenlafaxine has been registered and is available on the market for the treatment of major depressive disorder in adults.

Duloxetine (brand names Cymbalta, Yentreve, and in parts of Europe, Xeristar or Ariclaim) is indicated for the acute and maintenance treatment of major depressive disorder (MDD), as well as acute management of generalized anxiety disorder. Also used for the management of neuropathic pain associated with diabetic peripheral neuropathy, and fibromyalgia. Has been used in the management of moderate to severe stress urinary incontinence (SUI) in women. It is manufactured and marketed by Eli Lilly and Company. Duloxetine has not yet been FDA approved for stress urinary incontinence or for fibromyalgia. Duloxetine is a selective SNRI (selective serotonin-norepinephrine reuptake inhibitor). Duloxetine is a systemic drug therapy which affects the body as a whole. Known also under the code name LY248686, it is a potent dual reuptake inhibitor of serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine (NE), possessing comparable affinities in binding to NE- and 5-HT transporter sites. It is a less potent inhibitor of dopamine reuptake.

Atomoxetine is indicated for the treatment of Attention-Deficit/Hyperactivity Disorder. The precise mechanism by which atomoxetine produces its therapeutic effects in Attention-Deficit/Hyperactivity Disorder (ADHD) is unknown, but is thought to be related to selective inhibition of the pre-synaptic norepinephrine transporter. Most common adverse reactions are: nausea, vomiting, fatigue, decreased appetite, abdominal pain, and somnolence, constipation, dry mouth, dizziness, erectile dysfunction, and urinary hesitation. Atomoxetine is a substrate for CYP2D6 and hence concurrent treatment with CYP2D6 inhibitors such as bupropion (Wellbutrin) or fluoxetine (Prozac) is not recommended, as this can lead to significant elevations of plasma atomoxetine levels.

Venlafaxine is an arylalkanolamine serotonin-norepinephrine reuptake inhibitor, which is sold under several brand names; one of them is venlafaxine hydrochloride. Venlafaxine hydrochloride is a venlafaxine extended release tablets, which are indicated for the treatment of major depressive disorder (MDD). Efficacy of venlafaxine in MDD was shown in both short-term trials and a longer-term trial in MDD. A major depressive episode (DSM-IV) implies a prominent and relatively persistent depressed mood or the loss of interest or pleasure in nearly all activities, representing a change from previous functioning, and includes the presence of at least five of the following nine symptoms during the same two-week period. In addition, venlafaxine hydrochloride is indicated for the treatment of social anxiety (SAD), also known as social phobia. Social Anxiety Disorder (DSM-IV) is characterized by a marked and persistent fear of 1 or more social or performance situations in which others expose to unfamiliar people or to possible scrutiny the person. Exposure to the feared situation almost invariably provokes anxiety, which may approach the intensity of a panic attack. The feared situations are avoided or endured with intense anxiety or distress. The mechanism of the antidepressant action of venlafaxine in humans is believed to be associated with its potentiation of neurotransmitter activity in the CNS. Preclinical studies have shown that venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), are potent inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake.

Droxidopa (Northera, Chelsea Therapeutics) is a synthetic catecholamino acid precursor of norepinephrine indicated for the treatment of orthostatic dizziness or lightheadedness in adult patients with symptomatic neurogenic orthostatic hypotension (NOH) caused by primary autonomic failure, dopamine beta-hydroxylase deficiency, and non-diabetic autonomic neuropathy. Droxidopa was approved as oral therapy in February 2014 under the FDA’s accelerated approval program. Droxidopa is directly metabolized to norepinephrine by dopadecarboxylase. The specific mechanism of action of the drug is not known completely, but it is supposed to exert the pharmacological effects through norepinephrine and not through the parent molecule or other metabolites. It increases blood flow to the brain by stimulating peripheral arterial and venous vasoconstriction.

Ephedrine (l-form) is an alkaloid, which was initially purified from Ephedra plant. The extract form Ephedra has been used in China for medicinal purposes for several thousand years. Ephedrine acts as an agonist at alpha- and beta-adrenergic receptors and indirectly causes the release of norepinephrine from sympathetic neurons. The drug crosses the blood brain barrier and stimulates the central nervous system. Ephedrine products are now banned in many countries, as they are a major source for the production of the addictive compound methamphetamine. FDA has approved ephedrine only for the treatment of clinically important hypotension occurring in the setting of anesthesia.

O-Desmethyl tramadol (O-Desmethyltramadol, O-DSMT) is a metabolite of tramadol. O-Desmethyltramadol is an opioid analgesic and the main active metabolite of tramadol. (+)-O-Desmethyltramadol is the most important metabolite of tramadol produced in the liver after tramadol is consumed. This metabolite is considerably more potent as a μ-opioid agonist than the parent compound. O-desmethyl tramadol, inhibits 5-hydroxytryptamine type 2C receptors expressed in xenopus oocytes. O-desmethyl tramadol inhibits functions of M(1) receptors but has little effect on those of M(3) receptors. O-desmethyl tramadol has been widely used clinically and has analgesic activity.