Reserpine effects

Since the main clinical use for antisympathotonics is in the treatment of essential hypertension, such drugs will be discussed in Chapter 20 in more detail. The alkaloid reserpine from Rauwolfia serpentina was the first drug used clinically to reduce sympathetic tone. Reserpine reduce the ability of storage and release of various transmitters (adrenaline, noradrenaline, serotonine and dopamine) by an irreversible destruction of the axonal vesicle membranes. The duration of the reserpine effect is actually determined by the de novo synthesis of these structure. Beside various central side effects like sedation, depression, lassitude and nightmares the pattern of unwanted effects of reserpine is determined by the shift of the autonomic balance towards the parasympathetic branch myosis, congested nostrils, an altered saliva production, increased gastric acid production, bardycardia and diarrhea. As a consequence of the inhibition of central dopamine release, reserpine infrequently shows Parkinson-like disturbances of the extrapyramidal system. 

Benzodiazepines - A supraspinal site of action has been demonstrated for chlordiazepoxide and diazepam as well as for meprobamate.88 xhe anticonvulsant action of chlordiazepoxide resembles that of dilantin instead of that of acetazolamide, being antagonized by reserpine but not by 0 -methyl DOPA or Ct-methyltyrosine.89 This antagonistic effect of reserpine is reduced by a-methyl DOPA, serotonin and amphetamine. The reserpine effect is thus obtained by some means other than its catecholamine-depleting action and the anticonvulsant action of chlordiazepoxide is not mediated by catecholamines. 

There were several reports of new MAO inhibitors. The following compounds had, in addition to this action, some of the pharmacological properties of the antidepressants. Compound an analogue of pargyline, exhibited anti-reserpine and excitatory effects in mice 5. In a series of cyclic derivatives of N-aminoephedrine, 33. had anti-reserpine effects and... 

Several of the naturally occurring indoles also have clinical importance. The dimeric vinca alkaloid vincristine and closely related compounds were among the first of the anti-mitotic class of chemotherapeutic agents for cancer[14]. The mitomycins[15] and derivatives of ellipticine[16] are other examples of compounds having anti-tumour activity. Reserpine, while not now a major drug, was one of the first compounds to show beneficial effects in treatment of mental disorders[17]... 

Research for an antidepressant among non-tricyclic compounds with pharmacological effects qualitatively different from those of the conventional tricyclic compounds led to the preparation and testing of a series of indazole derivatives for reserpine-like activity in mice. l-[3-(Dimethylamino)propyl]-5-methyl-3-phenyl-l//-indazole (FS-32 692) antagonizes reserpine-induced effects and potentiates amphetamine-induced self-stimulation and l-Dopa-induced increase in motor activity. FS-32 produces an anticholinergic action mainly on the central nervous System, while the action of imipramine occurs centrally as well as peripherally (79AF511). 

VMATs are irreversibly inhibited by the potent antihypertensive drug reserpine. The depressive effects of reserpine helped to formulate the original monoamine hypothesis of affective disorders. Reseipine also appears to interact with the transporters near the site of substrate recognition. Tetrabenazine, which is used in treatment of movement disorders, inhibits VMAT2 much more potently than VMAT1, consistent with the less hypotensive action of this agent. 

Levodopa interacts with many different drugs. When levodopa is used with phenytoin, reserpine, and papaverine, there is a decrease in response to levodopa The risk of a hypertensive crisis increases when levodopa is used with the monoamine oxidase inhibitors (see Chap. 31). Foods high in pyridoxine (vitamin B6) or vitamin B6 preparations reverse the effect of levodopa However, when carbidopa is used with levodopa, pyridoxine has no effect on the action of levodopa hi fact, when levodopa and carbidopa are given together, pyridoxine may be prescribed to decrease the adverse effects associated with levodopa... 

Iproniazid also prevents the reserpine syndrome in rats. Reserpine blocks vesicular uptake of monoamines which, as a consequence, leak from the storage vesicles into the cytosol. Although these monoamines would normally be metabolised by MAO, they are conserved when a MAO inhibitor (MAOI) is present, and so co-administration of reserpine and a MAOI leads to accumulation of monoamines in the neuronal cytosol. It is now known that, when the concentration of cytoplasmic monoamines is increased in this way, they are exported to the synapse on membrane-bound monoamine transporters. The ensuing increase in monoamine transmission, despite the depletion of the vesicular pool, presumably accounts for the effects of iproniazid on the behaviour of reserpine-pretreated rats. 

These experiments provide evidence that DA and/or its reactive metabolites are likely involved in MDMA-induced changes in the serotonergic system. When DA synthesis was inhibited with MT, or when DA innervation was interrupted by 6-OHDA lesions, the effects of MDMA were prevented or attenuated. Depletion of DA with reserpine, or inhibition of DA uptake with GBR 12909, also attenuated the effects of MDMA on the serotonergic system. 

Berger, U. Grzanna, R. and Molliver, M.E. Depletion of serotonin using p-chlorophenylalanine (PCPA) and reserpine protects against the neurotoxic effects of p-chloroamphetamine (PCA) in the brain. Exp Neurol 103 111-115, 1989. 

The re-examination of the clinical reports showing that most people who were given reserpine did not become depressed was not published until 1971, a few years after the chemical-imbalance theory had been popularized by Schildkraut and Coppen. But a decade before their influential articles were written, there had been a carefully controlled clinical trial on the effects of reserpine on mood.17 Far from confirming the belief that it made people depressed, the study seemed to show the reverse. Rather than making healthy people depressed, reserpine seemed to make depressed people better. As described by Michael Shepherd, the senior author of the study, in 1956 ... 

When Schildkraut introduced the monoamine theory of depression, he admitted that there was little direct evidence for it. Instead, it was based on the supposed effectiveness of antidepressant medication and the mistaken belief that reserpine makes people depressed. Schildkraut acknowledged that Most of this evidence is indirect, deriving from pharmacological studies with drugs such as reserpine, amphetamine and the monoamine oxidase inhibitor antidepressants which produce affective changes. 21 A half-century has passed since his chemical-imbalance theory of depression was introduced, and the presumed effectiveness of antidepressants remains the primary evidence in its support. But as we have seen, the therapeutic effects of antidepressants are largely due to the placebo effect, and this pretty much knocks the legs out from under the biochemical theory. 

Costentin, J., Duterte-Boucher, D., Panissaud, C., and Michael-Titus, A. Dopamine D, and D2 receptors mediate opposite effects of apomorphine on the body temperature of reserpinized mice. Neuropharmacology. 29 31, 1990. 

Reserpine inhibits the synaptic vesicular storage of the monoamines dopamine, serotonin and noradrenaline. As a result they leak out into the cytoplasm where they are inactivated by monoamine oxidase this causes their long-lasting depletion. The resulting low levels of dopamine underlie the antipsychotic actions of reserpine (Chapter 11), whereas the reduced noradrenaline levels underlie its antihypertensive actions. Finally, the resulting low levels of serotonin and noradrenaline mean that reserpine also induces depression. These severe side effects mean that reserpine is no longer used clinically as a treatment for schizophrenia (Chapter 11). 

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