Norepinephrine pharmacological properties

The neuronal membrane norepinephrine transporter (NET), the dopamine transporter (DAT) and the vesicular membrane transporter (VMAT-2), which is the same in all catecholamine-containing neurons, have similar numbers of predicted transmembrane segments. They have different numbers of amino acids, pharmacological properties and chromosomal localizations. 

It has been known for over 25 years that many of the tricyclic antidepressants (TCAs), e.g. imipramine and amitriptyline, are potent inhibitors of both norepinephrine and 5-HT reuptake. Some tricyclic antidepressants, e.g. desipramine, inhibit the uptake of norepinephrine much more potently than the uptake of 5-HT. Thus, it was unclear for some time whether the inhibition of 5-HT uptake played any role in the antidepressant action of those TCAs that possessed this pharmacological property. Recently, however, effective antidepressants such as fluoxetine, paroxetine and sertraline have been marketed and these SSRIs are much more potent inhibitors of the uptake of 5-HT than that of norepinephrine (Fig. 13-8). Thus, selective inhibition of the uptake of either norepinephrine or 5-HT can result in an antidepressant effect (Ch. 55). 

Paczkowski, F. A., Bonisch, H., and Bryan-Lluka, L. J. (2002) Pharmacological properties of the naturally occurring Ala(457)Pro variant of the human norepinephrine transporter. Pharmacogenetics 12,165-173. 

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... 

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). 

EDS is usually treated using amphetamine-like CNS stimulants or modaflnil, a novel wake-promoting compound unrelated to amphetamines. The most commonly used amphetamine-like compounds aremethamphetamine, D-amphetamine, methylpheni-date, pemoline, and mazindol. The most important pharmacological property of these compounds is to release catecholamines, i.e., dopamine and norepinephrine. Amphetamine-like compounds also share the property of blocking the reuptake and the degradation of these monoamines (monoamine oxidase inhibition at high doses). All these properties presynaptically enhance dopamine transmission, which are likely to contribute to the EEG arousal effects of amphetamines. 

Adrenergic receptors (ARs) are the interface between the sympathetic nervous system and the cardiovascular system. ARs include two major subtypes, a and P, based on their pharmacological properties and molecular structure. The a-ARs consist of three ar AR subtypes and three o -ARs. P-ARs are also classified into three well-characterized subtypes Pb p2, and P3. Although they respond to the same hormones (norepinephrine and epinephrine), a- and P-ARs differ significantly in the types of cellular responses they mediate. 

These effects are produced mostly by phenylpropanolamines present in the leaves. These include cathinone [4] (5 -a-aminopropiophenone), cathine [5] [(-)-IS, 2S-norpseudoephedrine] and (-) -IR, 2S-norephedrine (8). These substances have pharmacological properties similar to those of amphetamine [6] (81), as they induce the release and inhibit the uptake of dopamine and norepinephrine in CNS (82). In addition to the known phenylpropylamines, the presence of other amines such as meracathine, pseudomeracathine and meracathinone have been identified (83, 84). Cathinone, being a ketoamine base, is extremely unstable and, in particular, it can be transformed into (+)-norpseudoephedrine and (-)-norephedrine by an enzymatic reduction. It can also be oxidized to give 1-phenyl-l,2-propandione, while the cathinone dimers, such as 3,6-dimethyl-2,5-diphenylpyrazine are purely artifacts of the isolation (85). 

The pharmacologic properties of (—)-cathinone are similar to those of (+)-amphetamine, and both alkaloids possess central nervous system (CNS) excitatory activity and indirect neuronal excitement activity. That is to say, both alkaloids are incorporated at the sympathetic nerve ending and expel noradrenaline (NAdr = norepinephrine, NE) from the amine storage granule, and the expelled NE works as the effector. These activities seem to be the effects caused by chewing khat [11]. Cathine also possesses CNS excitatory activity, but the activity of cathine is less than that of cathinone [12]. 

Tricyclic antidepressants—so called because of the characteristic three-ring nucleus—have been used clinically for four decades (Figure 30-1). They closely resemble the phenothiazines chemically and, to a lesser extent, pharmacologically. Like the latter drugs, they were first thought to be useful as antihistamines with sedative properties and later as antipsychotics. The discovery of their antidepressant properties was a fortuitous clinical observation. Imipramine and amitriptyline are the prototypical drugs of the class as mixed norepinephrine and serotonin uptake inhibitors though they also have several other properties. 

These agents have many properties in common. Both are sympathomimetic amines that exert their pharmacologic action by interfering in the reuptake of serotonin and norepinephrine into the presynaptic nerve terminal, thereby increasing their brain levels. In the case of phentermine, there is an increased release of dopamine, whereas with sibutramine, the reuptake into the presynaptic nerve terminal of serotonin, norepinephrine, and to a lesser extent dopamine, is hindered. 

Fluoxetine (Prozac /Lilly), paroxetine (Paxil /GlaxoSmithKilne), and sertraline (Zoloft /Pfizer) are selective serotonin reuptake inhibitors (SSRIs) and are useful in the treatment of depression. These agents potentiate the pharmacological actions of the neurotransmitter serotonin by preventing its reuptake at presynaptic neuronal membranes. In addition to its SSRI properties, venlafaxine (EfFexor /Wyeth-Ayerst) also appears to be a potent inhibitor of neuronal norepinephrine reuptake and a weak inhibitor of dopamine reuptake thereby enhancing the actions of these neurotransmitters as well. Venlafaxine is indicated for use in anxiety and depression. 

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