Noradrenaline Desipramine

Antidepressants are used in the treatment of neuropathic pain and headache. They include the classic tricyclic compounds and are divided into nonselective nor-adrenaline/5-HT reuptake inhibitors (e.g., amitriptyline, imipramine, clomipramine, venlafaxine), preferential noradrenaline reuptake inhibitors (e.g., desipramine, nortriptyline) and selective 5-HT reuptake inhibitors (e.g., citalopram, paroxetine, fluoxetine). The reuptake block leads to a stimulation of endogenous monoaminer-gic pain inhibition in the spinal cord and brain. In addition, tricyclics have NMDA receptor antagonist, endogenous opioid enhancing, Na+ channel blocking, and K+ channel opening effects which can suppress peripheral and central sensitization. Block of cardiac ion channels by tricyclics can lead to life-threatening arrhythmias. The selective 5-HT transporter inhibitors have a different side effect profile and are safer in cases of overdose [3]. 

Noradrenaline transporters (NAT) are localized in the presynaptic plasma membrane of adrenergic nerve terminals. They belong to a family of proteins with 12 putative transmembrane proteins which are responsible for recycling of released neurotransmitters (noradrena-line/adrenaline, dopamine, serotonin, amino acid transmitters) back into the presynaptic nerve ending. Noradrenaline transporters can be blocked by a number of different antidepressant drags, including tricyclic antidepressants (e.g. desipramine) and selective noradrenaline reuptake inhibitors (e.g. reboxetine). 

Figure 4.8 Noradrenaline concentration in dialysis samples from probes implanted in the rat frontal cortex. Spontaneous efflux of noradrenaline is stable throughout a 4h sampling period ( extended basals ) but is increased markedly when either the noradrenaline reuptake inhibitor, desipramine (5 pM), or the a2-adrenoceptor antagonist, atipamezole (0.5 pM), is infused into the extracellular fluid via the microdialysis probe ( retrodialysis )...

All TCAs are either secondary- or tertiary-amines of a dibenzazepine nucleus (Fig. 20.3), and they all inhibit neuronal reuptake of noradrenaline and/or 5-HT but are much less potent as dopamine reuptake blockers. A common claim is that secondary amines (e.g. desipramine) are preferential inhibitors of noradrenaline uptake whereas the tertiary derivatives (e.g. imipramine, doxepin and amitryptyline) preferentially inhibit 5-HT uptake. However, when Richelson and Pfenning (1984) actually compared the effects of a wide range of antidepressants on the synaptosomal uptake of [ H]monoamines in vitro, and compared their A s, instead of merely ranking /C50S collected from different studies, they found that tertiary- and secondary-substituted compounds were equi-potent inhibitors of [ H]noradrenaline uptake. Moreover, all the TCAs turned out to be more potent inhibitors of [ H]noradrenaline than of [ H]5-HT uptake. Tertiary amines are even less convincing inhibitors of 5-HT reuptake in vivo, because any such action is diminished by their metabolism to secondary amines (e.g. imipramine to desipramine amitriptyline to nortriptyline). Only clomipramine retains any appreciable 5-HT uptake blocking activity in vivo with (an unimpressive) five-fold selectivity for 5-HT versus noradrenaline. 

Desipramine An active metabolite of imipramine that is more selective for inhibiting noradrenaline reuptake into the presynaptic neuron. 

Mateo Y, Pineda J, Meana JJ. 1998. Somatodendritic alpha2-adrenoceptors in the locus coeruleus are involved in the in vivo modulation of cortical noradrenaline release by the antidepressant desipramine. J Neurochem 71(2) 790-798. 

Rapid relapse following administration of the tyrosine hydroxylase inhibitor alpha-methyl-tyrosine to depressed patients who respond to a noradrenaline reuptake inhibitor such as desipramine... 

Reboxetine is the only selective and reasonably potent noradrenaline reuptake inhibitor available clinically at the present time. Reboxetine has a chemical structure not dissimilar from viloxazine, an antidepressant which was of only limited clinical interest in the 1970s because of its weak efficacy and unacceptable side effects (nausea, vomiting and occasionally seizures). Unlike the secondary amine TCA antidepressants, such as maprotiline, desipramine, nortriptyline and protriptyline, reboxetine does not affect any other transporter or receptor system and therefore is largely devoid of TCA and SSRI-like side effects. In clinical trials, reboxetine has been shown to be as effective as the SSRIs in the... 

The addition of a nonselective noradrenaline reuptake inhibitor, desipramine, to an SSRl, fluoxetine, has been reported to be associated with a more rapid downregulation of P-adrenoceptors in rats than seen with either treatment on its own [B. M. Baron et al. 1988). This observation suggests that the addition of desipramine to fluoxetine might be associated with more rapid response and therefore possibly improved response. 

The only current evidence to support this view is the finding that the addition of desipramine to fluoxetine was better than desipramine alone in the treatment of patients with depression (J. C. Nelson et al. 1991). Desipramine alone resulted in the expected improvement of approximately 20% at week 1 and 40% at 2 weeks in 52 patients. In patients treated with the combination of fluoxetine and desipramine, the response was greatly accelerated, and a response of 42% was seen at the first week of treatment. At the end of 4 weeks of treatment, 71 % of the 14 patients on combined treatment were in complete remission compared with only 14% of those receiving desipramine alone. This study provides some evidence of the better efficacy seen with a double action on both noradrenaline and serotonin, but firm conclusions cannot be drawn because of the open nature of the investigation. 

Reboxetine is a pure noradrenaline reuptake inhibitor that is licensed as an antidepressant in the United Kingdom. Reboxetine has established efficacy based on placebo-controlled studies both in the short and the long term. Previous noradrenaline reuptake inhibitors, such as desipramine, nortriptyline, and maprotiline, have been relatively selective for noradrenaline compared... 

The older tricyclic agents show less than a ten-fold selectivity in inhibiting noradrenaline over that for 5-HT (e.g. desipramine, imipramine, nortriptyline) through amitryptyline. which shows virtually no selectivity, to trazodone, zimelidine and clomipramine, which are somewhat 5-HT selective. The newer Serotonin-Selective Reuptake Inhibitors (SSRIs) show a higher selectivity for inhibition of 5-HT reuptake in the brain, and have a different pharmacology. Examples clinically used include citalopram, fluoxetine, fluvoxamine, nefazodone, paroxetine, sertraline, trazodone and venlafaxine. Experimental agents include 6-nitroquipazine, alaproclate, litoxetine, indatraline and p-CIT. 

Noradrenaline is transported by uptake systems that have been extensively studied. On release of noradrenaline from sympathetic nerve varicosities in the peripheral nervous system, it is subject to two uptake systems. Uptake 1 (UJ is a reuptake process where the noradrenaline is recovered by the nerve via a process that has a high affinity but relatively low maximum rate, whereas a second process, uptake 2 (Uj), clears noradrenaline from the tissues into extraneuronal sites by a low affinity, but fast, process (which is inhibited by GLUCOCORTICOIDS, phenoxybenzamine and normetanephrine). The first - the neuronal system - has been studied in detail, and is essentially the same process as used for dopamine and 5-hydroxytryptamine in the CNS. The U transport protein has now been cloned, and is one of a famiiy of transporter proteins which act as co-transporters for Na, Cl and the amine, driven by the ATP-generated electrochemical gradient for Na . This Ui noradrenaline reuptake process is inhibited by cocaine and amphetamine (thus accounting for some of their actions, particularly within the CNS), phenoxybenzamine and the extensive class of tricyclic and related compounds that are used as ANTIDEPRESSANTS (e.g. desipramine). 

Evidence accumulated in 1978 for a catecholamine receptor supersensitivity theory of depression. 8 The therapeutic action of antidepressants may be due to delayed post-synaptic changes in receptor sensitivity, rather than to acute events like uptake. Various drugs, including TCA, mianserin, viloxazine and iprindol, as well as electroconvulsive therapy (ECT), but not selective 5-HT uptake inhibitors, caused central alpha-adrenoceptor subsensitivity in rats as measured by noradrenaline (NA)-associated adenylate cyclase or by receptor binding. In vivo, the effects were associated with chronic but not acute treatment, paralleling the clinical effects. MAOI may cause similar effects on chronic but not acute treatment. , 24-27 Brain NA turnover in rats was decreased by chronic desipramine and other TCA, but unaffected by iprindol and increased by mianserin.3,28... 

Amphetamines (release Cocaine (prevent re-uptake of DA) Euphoria, hypervigilance, Anxiety, stereotyped behavior, grandiosity, paranoia, tachycardia, pupillary dilation Depression, fatigue, f fkX- CwiSrbictioi Noradrenaline system, NAC pathway (dopaminergic) 1 Antipsychotics or benzodiazepines bromocriptine, amantadine, desipramine Increased use among white professionals, cardiac arrhythmias... 

Entacapone and imipramine did not interact adversely in a single-dose study. Similarly, tolcapone and desipramine did not interact adversely. Nevertheless, the manufacturers of entacapone and tolcapone recommend caution if they are used with tricyclic antidepressants or other drugs that inhibit noradrenaline (norepinephrine) uptake, such as maprotiline or venlafaxine. 

In these pharmacological studies, no important interaction between enta-capone and imipramine or between tolcapone and desipramine was detected. Nevertheless, the manufacturer of entacapone says there is limited clinical experience of the use of entacapone with tricyclic antidepressants, and they therefore recommend caution. Similarly, the manufacturers of tolcapone suggest that caution should be exercised with desipramine and any drugs that are potent noradrenaline (norepinephrine) uptake inhibitors such as maprotiUne and venlafaxine. ... 

Five patients taking nortriptyline, desipramine or other unnamed tricyclic antidepressants experienced adverse reactions, some of them severe (throbbing headache, chest pain) following the injection of Xylestesin (lidocaine with 1 25 000 noradrenaline) during dental treatment. Several episodes of marked increases in blood pressure, dilated pupils, intense malaise, violent but transitory tremor, and palpitations have b n reported in patients taking unnamed tricyclic antidepressants when they were given... 

In an in vitro system that generated HO from FeS04-H202, bromocriptine dose-dependently (IC50 = 11.25 0.89x 10" M) quenched HO radicals, but did not inhibit their formation (Ogawa et al. 1994). Pre-treatment with bromocriptine (5mg/kg, i.p., 7 days) completely protected against the decrease in mouse striatal dopamine and its metabolites induced by intraventricular injection of 6-hydroxy-dopamine (40 pg) after intraperitoneal administration of desipramine (25 mg/kg, administered i.p. 30 min after the final injection to block noradrenaline re-uptake sites), but similar pre-treatment with L-DOPA/carbidopa (75/7.5 mg/kg, i.p, 7 days) showed only partial protective effect. 

Imipramine is the prototype TCA and was the first clinically potent antidepressant dmg. Imipramine and its deriratives are iminodibenzyl derivatives (Kg. 18.16). Both desipramine and lofepramine appear to be more selective towards noradrenaline reuptake (NA) whereas the remaining derivatives are considered to be more non-selective towards SERF and NAT (5-HT/NA), respectively. 

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