Cardiovascular system, serotonin effects

The triazolopyridine trazodone does not have an appreciable effect on the re-uptake of the neurotrans-mittors dopamine or noradrenaline. It is a weak inhibitor of serotonin re-uptake but is a potent antagonist of the serotonin 5-HT2 receptor. Clinical experience has shown unpredictable efficacy. Trazodone has little antimuscarinic activity and has little if any action on cardiac conduction. Like mianserin it can therefore safely be used in patients for which anticholinergics are contraindicated and there are no absolute contraindications for patients with concomitant diseases of the cardiovascular system. 

Serotonin (4.109, 5-hydroxytryptamine, 5-HT) is a central neurotransmitter that is also found peripherally in the intestinal mucosa and in blood platelets, where its role is incompletely elucidated it even occurs in plants such as bananas. Although there is an enormous literature on the biochemistry and pharmacology of serotonin, our knowledge of its biological role remains somewhat fragmented. The diverse physiological effects of 5-HT influence the cardiovascular system, the cerebrovascular system, the digestive... 

Fluoxetine selectively blocks the uptake of serotonin. It is devoid of anticholinergic properties and hence has little or no effect on the cardiovascular system, including orthostatic hypotension or arrhythmias. 

Serotonin (5-hydroxytryptamine [5-HT]) produces its effects through a variety of membrane-bound receptors, located in the central and peripheral nervous systems and in non-neuronal tissues in the gastrointestinal tract, cardiovascular system, and blood. The knowledge of the anatomical localization of the receptors is an important step forward for the understanding of their function. Several techniques allow the microscopic visualization of the sites of expression of these receptors in the tissues. In this review, we will attempt to summarize the available information on the neuroanatomical organization of each one of the 5-HT receptor subtypes. 

Serotonin (5-hydroxytryptamine, 5-HT) is synthesised in enterochromaffin cells, largely in the gut, and also extensively taken up into blood platelets from which it is released to have vascular effects. It has complex effects on the cardiovascular system, varying with the vascular bed and its physiological state it generally constricts arterioles and veins and induces blood platelet aggregation it stimulates intestinal and bronchial smooth muscle. Carcinoid tumours secrete serotonin and symptoms may be benefited by serotonin antagonists, e.g. cyproheptadine, methysergide and sometimes by octreotide (see Index). It is a neurotransmitter in the brain. 

The postsynaptic physiological effects of serotonin are varied and widespread. The administration of serotonin leads to powerful smooth-muscle effects in the cardiovascular and gastrointestinal systems. Vasodilation and hypotension may result, partly through central effects, if the serotonin concentration in the CNS is increased by administration of the serotonin precursor 5-hydroxytryptophan. Unlike serotonin, this precursor can cross the blood-brain barrier. Intestinal mobility is also influenced by serotonin. 

The modest improvements achieved in selectivity with respect to serotonin reuptake inhibition may also have been achieved with an isoenzyme system. Moclobemide, which was introduced in Sweden, reversibly inhibits monoamine oxidase A (RIMA). It is likely that this eliminates the severe hypertensive drug and food interactions that so severely limit the usefulness of the very effective earlier MAO inhibitors, since tyramine is now metabolized. An additional benefit of such agents may be a lack of cholinergic and cardiovascular effects. 

There are two issues of concern which are associated with irreversible MAOIs involving the display of liver toxicity, particularly with hydrazines, and the permanent inactivation of both MAO-A and -B isoforms. The replacement of MAOs requires protein synthesis which may take up to 14 days. From the antidepressant viewpoint, only a selective blockage of serotonin metabolism may be of interest in order to increase serotonin availability. However, this long-term effect significantly reduces metabolism of a variety of other biogenic amines, which leads to their accumulation, which is not necessarily desired. This leads to an excessive availability of tyramine and others, which ultimately leads to increased release of noradrenaline that may result in the stimulation of cardiovascular sympathetic nervous system activity. As a consequence, potentially fatal hypertensive crises and cerebral haemorrhage can occur (Fig. 18.22). This phenomenon has often been termed the cheese effect, in order to reflect the fact that tyramine is present in a variety of foods such as wine, cheese and other fermented food and drink products. It would appear, however, that under carefully controlled and restricted dietary conditions such a risk can be minimised. 

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