Reuptake, inhibition

Mode of action Enzyme inhibition Reuptake inhibition Receptor antagonism... 

Monoamine oxidase inhibition Serotonin reuptake inhibition Norepinephrine reuptake inhibition Dopamine reuptake inhibition a2-Adrenergic receptor blockade Serotonin-2A receptor blockade Serotonin-2C receptor blockade Serotonin-3 receptor blockade op-Adrenergic receptor blockade Histamine-1 receptor blockade Muscarinic cholinergic receptor blockade... 

In neurochemical terms, amphetamine and cocaine boost monoamine activity. Amphetamine has a threefold mode of action first, it causes dopamine and noradrenaline to leak into the synaptic cleft second, it boosts the amount of transmitter released during an action potential and third, it inhibits the reuptake of neurotransmitter back into presynaptic vesicles. These three modes all result in more neurotransmitter being available at the synapse, thus generating an increase in postsynaptic stimulation. Cocaine exerts a similar overall effect, but mainly by reuptake inhibition. The main neurotransmitters affected are dopamine and noradrenaline, although serotonin is boosted to a lesser extent. These modes of action are outlined in Chapter 3, and the neurochemical rationale for drug tolerance is covered more fully in Chapter 10. The main differences between amphetamine and cocaine are their administration routes (summarised above) and the more rapid onset and shorter duration of action for cocaine. 

Primarily serotonin (5-H1) at lower doses, norepinephrine (NE) at higher doses, and dopamine at very high doses, balanced 5-HT and NE reuptake inhibition. 

Because of the continued need for better drugs to treat depression and the opportunities for new clinical indications, efforts to discover novel monoamine reuptake inhibitors continue unabated. This review will highlight developments in the discovery of novel agents that work via monoamine reuptake inhibition primarily based on publications that have appeared between 2005 and early 2007. New clinical indications for monoamine reuptake inhibitors will also be highlighted. A comprehensive review of publications on monoamine reuptake inhibitors between 2000 and July 2005 is available [3]. Approaches for the treatment of depression involving the augmentation of monoamine reuptake inhibitors with other CNS receptor modulators, and non-monoamine-based strategies have also been reviewed recently [6-8]. 

Many psychoactive drugs act to alter neurotransmitter functions either through effects on their synthesis, metabolism or reuptake or by directly affecting the receptors for naturally occurring compounds. For example, drugs such as prozac increase serotoniner-gic activity by selective serotonin reuptake inhibition (SSRI). 

Saint-John s- wort AntidepressantHypericin Monoamine reuptake inhibition ... 

Muller WE, Singer A, Wonnemann M, Hafner U, Rolli M, Schafer C. (1998). Hyperforin represents the neurotransmitter reuptake inhibiting constituent of hypericum extract. Pharmacopsychia y. 31(suppl 1) 16-21. 

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. 

These include trazodone and a derivative of its metabolite nefazodone, both of which are strongly sedative, an effect which has been attributed to their potent alpha-1 receptor antagonism rather than to any antihistaminic effects. A main advantage of these drugs in the treatment of depression is that they appear to improve the sleep profile of the depressed patient. Their antidepressant activity is associated with their weak 5-HT reuptake inhibition and also a weak alpha-2 antagonism. However, unlike most of the second-generation antidepressants, neither drug is effective in the treatment of severely depressed patients. Furthermore, there is some evidence that trazodone can cause arrythmias, and priapism, in elderly patients. 

Briley, M. (1998). Milnacipran, A Well-Tolerated Specific Serotonin and Norepinephrine Reuptake Inhibiting Antidepressant, CNS Drug Reviews, 4 137-148. 

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. 

The neurochemical effects of the tricyclic antidepressants are blockade of the re-uptake of norepinephrine and for some drugs also serotonin by nerve terminals in the CNS and peripherally. This reuptake inhibition results in higher concentrations of the neurotransmitters at their receptors sites. There is little or no effect on DA neurotransmission. The tricyclic antidepressants have varying affinities for U2... 

This group includes compounds with actions on a range of neurotransmitter systems. Their antidepressant efficacy is mediated by reuptake inhibition of serotonin and noradrenaline, although side-effects such as sedation may also be useful. Their use in anxiety disorders is supported by a long history of clinical experience and a reasonable evidence base from controlled trials. Studies support the use of clomipramine (a potent serotonin reuptake inhibitor) in panic disorder and OCD (Lecrubier et al. 1997 Clomipramine Collaborative Study Group 1991), of imipramine in panic disorder and GAD (Cross-National Collaborative Panic Study 1992 Rickels et al. 1993), and of amitriptyline in PTSD (Davidson et al. 1993a). No controlled studies support the use of TCAs in social anxiety disorder. 

Mechanism of Action A sympathomimetic amine that produces CNS and respiratory stimulation, mydriasis, bronchodilation, a pressor response, and contraction of the urinary sphincter Directly effects alpha and beta receptor sites in peripheral system. Enhancesreleaseof norepinephrine by blocking reuptake, inhibiting monoamine oxidase. Therapeutic Effect Increases motor activity, mental alertness decreases drowsiness, fatigue. 

In general, herbal remedies, including St. John s wort, echinacea, kava kava, and ginkgo, should be avoided. St John s wort is considered an herbal remedy with some serotonergic reuptake inhibition properties and is purported to be helpful with depression. It is sometimes used concurrently with SSRI medications by patients who assume it is relatively free of adverse side effects. 

Elko, C.J., Burgess, J.L., and Robertson, W.O. (1998) Zolpidem-associated hallucinations and serotonin reuptake inhibition a possible interaction. / Toxicol Clin Toxicol 36 195-203. 

Trazodone is a triazolopyridine derivative, with relatively weak serotonin reuptake inhibition. Trazodone also has antagonist activity at 5-HTia and 5-HTic sites (Haria et ah, 1994). Trazodone s active metabolite, m-CPP, serves as a direct serotonin agonist. 

Venlafaxine, a bicyclic phenylethlamine, exerts its therapeutic effect through the reuptake inhibition of serotonin and norepinephrine and, to a lesser degree, dopamine (Thase, 1996). Serotonergic reuptake appears most prominent at lower doses, and noradrenergic activity is more prominent at higher doses. It has no sig-... 

Atomoxetine exerts its therapeutic efficacy through the selective reuptake inhibition of norepinephrine. Its receptor occupancy profile shows minimal affinity for cholinergic, histaminic, serotonergic, or a-adrenergic receptors (Spencer et al., 1998). 

Methylphenidate possesses two asymmetric carbon moieties, giving rise to four optical isomers d-threo, /-threo, d-erythro, and /-erythro (Patrick et ah, 1987). There is stereoselectivity in receptor site binding and its relationship to response. The standard preparation is comprised of the threo racemate as it appears to be the central nervous system (CNS) active form (Patrick et ah, 1987 Hubbard et ah, 1989). In addition, in rats, the d-methylphenidate isomer shows greater reuptake inhibition of DA and NE than the /-isomer (Patrick et ah, 1987). D-Methylphenidate is now available under the brand name Focalin. 

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