Serotonin-norepinephrine reuptake side effects

Q Negiigibie capacity for inducing side-effect SNRI Serotonin-norepinephrine reuptake inhibitor... 

Serotonin-norepinephrine reuptake inhibitors (SNRIs) (e.g. duloxetine, venlafaxine and desvenlafax-ine) inhibit the reuptake of both serotonin and norepinephrine and are referred to as dual inhibitors or selective serotonin norepinephrine inhibitors . The SNRIs lack of anticholinergic side effects results in a distinct advantage over traditional TCAs [13,77,78]. For example, duloxetine is a potent, balanced inhibitor of serotonin and norepinephrine reuptake [79]. Venlafaxine inhibits serotonin reuptake at lower dosages and inhibits both serotonin and norepinephrine reuptake at higher dosages [70,80]. 

Relative Potencies of Norepinephrine and Serotonin Reuptake Blockade and Side-Effect Profile of Antidepressant Drugs... 

Tricyclic drugs have, as the name implies, a three-ring structure, and interfere with reuptake of norepinephrine and/or serotonin into axon terminals. Tricyclic drugs include imipramine (Tofranil), amitriptyline (Elavil), clomipramine (Anafranil), and nortriptyline (Pamelor, Aventil). Tricyclics have the occasional but unfortunate cardiovascular side effects of arrhythmia and postural hypotension. Newer, nontricyclic antidepressants have been developed that are collectively referred to as SSRIs. These have a potent and selective action on serotonin, and lack the cardiovascular side effects of the tricyclics. These include fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), and fluvoxamine (Luvox). A fifth SSRI, citalopram (Celexa) has been used in Europe and has recently been approved in the United States. Venlafaxine (Effexor) blocks reuptake of norepinephrine and serotonin, while bupropion (Wellbutrin) acts on both dopamine and norepinephrine. 

Venlafaxine (Effexor, Effexor XR). Venlafaxine works by blocking the reuptake of both serotonin and norepinephrine. Because of this dual action, some believe that venlafaxine may be more effective than the SSRIs when treating severe depression. Its side effects and toxicity are similar to the SSRIs with abdominal discomfort, sexual dysfunction, and anxiety being commonly reported. At higher doses, it may mildly elevate blood pressure therefore, blood pressure should be checked periodically. When stopping venlafaxine, serotonin discontinuation symptoms may be especially problematic. Therefore, gradually tapering of the dose every 2-4 weeks is recommended. 

The newest appetite suppressant, sibutramine (Meridia), works by blocking the reuptake of both serotonin and norepinephrine. It does not stimulate nerve cells to release serotonin, as do fenfluramine and dexfenfluramine. Administered at 20 mg/ day, sibutramine effectively reduces weight in obese patients, but its use has not been assessed in eating disorder patients. The most common side effects of this medication are insomnia, dry mouth, and constipation. It has not been associated with the more serious heart and lung complications observed with fenfluramine and dexfenfluramine. Because sibutramine acts in part through modulation of norepinephrine, there is no rational basis for coadministering phentermine, which acts via this same mechanism. 

Tricyclic Antidepressants (TCAs). The tricyclic antidepressants are believed to act mainly by increasing norepinephrine and/or serotonin reuptake inhibition. The few studies that have evaluated their use in the treatment of BPD were not promising. Given those disappointing results in conjunction with the prominent side effects and danger in overdose, TCAs are not generally recommended for the treatment of BPD. 

As we move forward with our discussion, we ll devote a section of this chapter to each of the key neurotransmitter systems that psychotropic medications interact with. We will discuss the following systems norepinephrine, dopamine, serotonin, GABA, acetylcholine, and histamine. Within each of the sections is a description of the effects that can be anticipated when a medication enhances the activity of that transmitter (reuptake inhibitors or agonists), and the effects to expect when a medication interferes (receptor antagonists) with the activity of that same transmitter. We will then describe strategies that can be implemented to help minimize and/or manage these side effects. 

Side effects, mainly due to serotonin reuptake inhibition include G1 upset, nervousness, and sexual dysfunction. SSRls are associated with an increased risk of falls. Hyponatraemia due to SIADH is an uncommon, but important side effect in elderly patients. Selective serotonin and norepinephrine reuptake inhibitors (S SNRls) such as venlafaxine and duloxetine are also useful in older patients. Other heterocyclic antidepressants of importance in older patients because of relative safety include bupro-prion and mirtazepine. They are reserved for patients with resistance to or intolerance of SSRls. Currently, trazodone is used mostly for sleep disturbance in depression in doses of 50-100 mg at bedtime. The monoamine oxidase inhibitors phenelzine. 

Venlafaxine (Effexor) inhibits the reuptake of both serotonin and norepinephrine at their respective presy-naptic sites. This drug does not have significant effects at muscarinic, histamine, or a-adrenergic receptors and therefore is devoid of many of the side effects associated with the TCAs. Venlafaxine and its active metabo-... 

Tricyclic antidepressants (TCAs) modulate various brain neurotransmitters, especially norepinephrine and serotonin, by blocking reuptake presynaptically. The secondary amines (desipramine, nortriptyline) are more selective for noradrenergic function and have less side effects in sensitive populations. Advantages of this class of drugs include their relative long half life (approximately 12 hours), absence of abuse potential, and putative positive effects on mood and anxiety, sleep, and tics. 

SSRIs were developed in an attempt to formulate reuptake-blocking drugs that lacked the troublesome side effects of TCAs. Of the five pharmacological properties of TCAs—blockade of muscarinic receptors, blockade of histamine Hj receptors, blockade of aj-adrenergic receptors, norepinephrine reuptake blockade, and serotonin reuptake inhibition—only the last remains intact in SSRIs. This selectivity has... 

Many inhibitors of the amine transporters for norepinephrine, dopamine, and serotonin are used clinically. Although specificity is not absolute, some are highly selective for one of the transporters. Many antidepressants, particularly the older tricyclic antidepressants can inhibit norepinephrine and serotonin reuptake to different degrees. This may lead to orthostatic tachycardia as a side effect. Some antidepressants of this class, particularly imipramine, can induce orthostatic hypotension presumably by their clonidine-like effect or by blocking 04 receptors, but the mechanism remains unclear. 

Bupropion (Wellbutrin, Zyban] Primarily inhibits dopamine reuptake little effect on norepinephrine or serotonin Low sedative, anticholinergic, and cardiovascular side effects also used as an intervention to quit cigarette smoking May cause overstimulation (insomnia, tremor) and induce psychotic symptoms... 

Reserpine, a drug used for the treatment of high blood pressure, was known to have the side effect of depression. Upon studying this effect, scientists observed that this drug caused a depletion of the amine neurotransmitters serotonin and norepinephrine. Neurotransmitters transmit information from one nerve to another across a synapse. The neurotransmitters are than reabsorbed by the first nerve in the process called reuptake. 

Sibutramine (Meridia), a weight-loss drug introduced in 1998, inhibits the reuptake of the brain chemicals norepinephrine, dopamine, and serotonin, but does not promote monoamine release like the amphetamines. Yet the drug has been linked to serious side effects, including rapid heart rate, increased blood pressure, heart disease, stroke, seizure, and mental impairments. In March 2002, Italy s Health Ministry announced that it was immediately withdrawing all sibutramine products from the market due to health-related problems. Also, Meridia was the subject of a class action lawsuit filed in the United States. 

Venlafaxine (Effexor, 11.57) blocks the reuptake of serotonin and norepinephrine from the synaptic junction and acts as an antidepressant (Scheme 11.5). The primary metabolic pathway of venlafaxine is (9-demethylation (11.58), which is mediated by CYP2D6. CYP2D6 has variable activity across different populations. Groups with a more active form of CYP2D6 tend to show more side effects from venlafaxine. 

Other antidepressant drugs that primarily affect serotonin reuptake include trazodone [TRAZ oh done], fluvoxamine [floo VOX a meen], nefazodone [ne FAZ oh don], paroxetine [pah ROX a teen], sertraline [SIR trah leen], and venlafaxine [vin lah FACKS in]. These SSRIs differ from fluoxetine in their relative effects on the reuptake of serotonin and norepinephrine. They do not seem to be more efficacious than fluoxetine, but their profiles of side effects are somewhat different. There is a high variability among patients in the rate of elimination of these drugs (including fluoxetine), and failure to tolerate one drug should not preclude a trial of another SSRI. 

In humans, a prominent effect of cocaine consists in increased vigilance and elevated mood. While cocaine itself is not used clinically, several catecholamine and serotonin reuptake blockers are used as antidepressants. Imipramine (Figure 10.13) is a classic but not so very specific in addition to inhibiting the reuptake of serotonin and of norepinephrine, it also has antihistaminic and antimuscarinic activity. This will lead to side effects in both the central nervous system and the peripheral autonomic system. A prominent one is the causation or deterioration of cardiac arrhythmias due to its antimuscarinic action. 

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