Dopamine and norepinephrine reuptake inhibitors

Table 21.11. Pharmacokinetics of the Dopamine and Norepinephrine Reuptake Inhibitors (DNRIs) and Serotonin Receptor Modulators (SRMs) ...

MAOI, monoamine oxidase inhibitor NaSSA, noradrenergic and specific serotonergic antidepressant NDRI, norepinephrine and dopamine reuptake inhibitor SARI, serotonin antagonist and reuptake inhibitor SNRI, serotonin and norepinephrine reuptake inhibitor SSRI, selective serotonin reuptake inhibitor TCA, tricyclic antidepressant. 

FIGURE 38-1. Primary assessment and initial treatment for complaint of excessive daytime sleepiness. RLS, restless-legs syndrome NPSG, nocturnal polysomnography OSA, obstructive sleep apnea DA, dopamine agonist MSLT, multiple sleep latency test BZDRA, benzodiazepine receptor agonist SNRI, serotonin and norepinephrine reuptake inhibitor TCA, tricyclic antidepressant CPAP, continuous positive airway pressure. 

After more than a decade of use, bupropion (24) is considered a safe and effective antidepressant, suitable for use as first-line treatment. In addition, it is approved for smoking cessation and seasonal affective disorder. It is also prescribed off-label to treat the sexual dysfunction induced by SSRIs. Bupropion is often referred to as an atypical antidepressant and has much lower affinity for the monoamine transporters compared with other monoamine reuptake inhibitors. The mechanism of action of bupropion is still uncertain but may be related to inhibition of dopamine and norepinephrine reuptake transporters as a result of active metabolites [71,72]. In a recently reported clinical trial, bupropion extended release (XL) had a sexual tolerability profile significantly better than that of escitalopram with similar re-... 

Venlafaxine is a serotonin and norepinephrine reuptake inhibitor that potentiates norepinephrine, serotonin, and dopamine neurotransmitter activity in the CNS by inhibiting their neuronal reuptake. Effexor, Effexor XR are used in treatment of major depressive disorder. Effexor XR is used in treatment of generalized anxiety disorder and treatment of social anxiety disorder. 

Reuptake inhibitors, which include the tricyclic and tetracyclic antidepressants (TCAs and TeCAs),the SSRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline), the serotonin and norepinephrine reuptake inhibitors (SNRIs duloxetine, milnacipran, and venlafaxine), and the norepinephrine and dopamine reuptake inhibitor (bupropion). 

Listing of antidepressants grouped by principal mechanism of action in the synapse. Abbreviations MAOI—irreversible = irreversible monoamine oxidase inhibitor MAOI—reversible = reversible monoamine oxidase inhibitor NDRl = norepinephrine/ dopamine reuptake inhibitor NRI = norepinephrine reuptake inhibitor NSRl = norepinephrine/serotonin reuptake inhibitor NSSA = norepinephrine/specific serotonin agonist SRI = serotonin reuptake inhibitor SRl/serotonin-2 blocker = serotonin reuptake inhibitor and serotonin-2 receptor antagonist. 

Pharmacology Venlafaxine and its active metabolite, 0-desmethylvenlafaxine (ODV), are potent inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake. 

Pharmacology Although the mechanism of the antidepressant and central pain inhibitory action of duloxetine in humans is unknown, it is believed to be related to its potentiation of serotonergic and noradrenergic activity in the CNS. Preclinical studies have shown that duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake. 

D. Mirtazapine acts at serotonin and adrenergic receptors and does not effect reuptake of neurotransmitters. Venlafaxine is a mixed serotonin-norepinephrine reuptake inhibitor. Bupropion inhibits norepinephrine and dopamine reuptake. 

Mechanism of Action An antidepressant that appears to inhibit serotonin and norepinephrine reuptake at CNS neuronal presynaptic membranes is a less potent inhibitor of dopamine reuptake. Therapeutic Effect Relieves depression. Pharmacokinetics Well absorbed from the G1 tract. Protein binding greater than 90%. Extensively metabolized to active metabolites. Excreted primarily in urine and, to a lesser extent, in feces. Half-life 8-17 hr. 

FIGURE 6-48. Shown here is the icon of a norepinephrine and dopamine reuptake inhibitor (NDRI). In this case, four of the five pharmacological properties of the tricyclic antidepressants (TCAs) (Fig. 6—27) were removed. Only the norepinephrine reuptake inhibitor (NRI) portion remains to this is added a dopamine reuptake inhibitor action (ORI). 

FIGURE 6—49- In this diagram, the norepinephrine reuptake inhibitor (NRI) and the dopamine reuptake inhibitor (DRI) portions of the NDRI molecule are shown inserted in the norepinephrine and the dopamine reuptake pumps, respectively, blocking them and causing an antidepressant effect. 

Unlike other agents approved for ADHD, atomoxetine does not have abuse potential and is not a scheduled substance Despite its name as a selective norepinephrine reuptake inhibitor, atomoxetine enhances both dopamine and norepinephrine in frontal cortex, presumably accounting for its therapeutic actions on attention and concentration... 

This herb is also known as St. Joan s wort, klamath weed, and goatweed. It has historically been used for many purposes, but most recently it is marketed as an antidepressant. In fact, it outsells all conventional antidepressants in Germany. The active constituent is hypericin that seems to act as a weak monoamine oxidase MAO inhibitor and a selective serotonin reuptake inhibitor (SSRI). Dopamine and norepinephrine uptakes are also mildly inhibited. St. John s wort is available in many forms, as a tablet, tea, tincture, and the raw dried herb. For best results, a tablet standardized to contain 0.3% hypericin should be taken Kira by Lichtwer Pharma is the most extensively studied. Randomized, placebo-controlled trials using 300 mg of St. John s Wort three times daily have found it to be superior to placebo in mild to moderate depression. Response rates are generally regarded as inferior to conventional antidepressants, including... 

There are two principal mechanisms for increasing synaptic monoamine levels. One is to block the reuptake of neurotransmitter after its excitation-coupled release from the neuronal terminal. Thus, blocking the action of the uptake carrier protein prevents clearance of the neurotransmitter from the synapse, leaving high concentrations in the synaptic cleft that can continue to exert a signaling effect. This mechanism is the one invoked to explain the action of cocaine, a potent inhibitor of monoamine reuptake at the dopamine, serotonin, and norepinephrine transporters, and of methylphenidate, which is a reuptake inhibitor at the dopamine and norepinephrine transporters (81)It should be noted, however, that methylphenidate also has the ability to induce the release of catecholamines stored in neuronal vesicles (82, 83). 

It was initially believed that the antidepressant effectiveness of MAOIs was the direct result of MAO inhibition. This acute effect decreases degradation of monoamines (e.g., norepinephrine, serotonin, or dopamine) stored in presynaptic neurons, thereby resulting in an increased amount of these neurotransmitters available at the synapse. More recent research indicates that this model does not fully explain the mechanism of MAOIs efficacy. For example, the positive (h-) stereoisomer of tranylcypromine is a poor antidepressant despite inhibiting MAO. The main pharmacologic difference between the negative (-) and + isomers of tranylcypromine is that the former has much weaker effects as a norepinephrine reuptake inhibitor in relation to its potency as an MAOI. The other MAOIs may also block the reuptake of selected neurotransmitters. However, like the non-MAOI uptake inhibitors, these acute effects often precede clinical antidepressant effects by weeks. More consistent with the 2- to 4-week lag in therapeutic effect, chronic treatment with a diverse number of MAOIs has been shown to reduce the number of a2- and P-adrenergic and serotonin (5-HT2) postsynaptic binding sites in the brain. 

Drugs that block binding sites include selective serotonin reuptake inhibitors (SSRIs). In 1970, the Eli Lilly Company developed fluoxetine (Prozac). Their research began with nizoxetine, a selective norepinephrine reuptake inhibitor. Of the compounds that inhibited reuptake of serotonin, norepinephrine, and dopamine, fluoxetine was the most potent and selective inhibitor of serotonin reuptake. It was approved for use by the FDA in December, 1987, and used to reduce excessive serotonin secretion from carcinoid tumors. 

Serotonin also affects the emotions of love and romance. Androgens, estrogens, oxytocin, and vasopressin increase the sex drive, whereas increased levels of synaptic serotonin, such as result from the taking of reuptake transporter inhibitors, suppress the sex drive and inhibit feelings of attraction by the opposite sex. Dopamine and norepinephrine increase the sex drive. 

Different types of antidepressants are supposed to work by different means. SSRIs (selective serotonin reuptake inhibitors) are supposed to increase serotonin levels. NDRIs (norepinephrine dopamine reuptake inhibitors) are supposed to increase norepinephrine and dopamine, rather than serotonin. These two types of antidepressants are supposed to be selective , affecting the... 

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