Adrenolytic activity

The symptoms of overdose are to some extent predictable from the antimuscarinic and adrenolytic activity of these drugs. Excitement and restlessness, sometimes associated with seizures, and rapidly followed by coma, depressed respiration, hypoxia, hypotension and hypothermia are clear signs of TCA overdose. Tachycardia and arrhythmias lead to diminished cardiac function and thus to reduced cerebral perfusion, which exacerbates the central toxic effects. It is generally accepted that dialysis and forced diuresis are useless in counteracting the toxicity, but activated charcoal may reduce the absorption of any unabsorbed drug. The risk of cardiac arrhythmias may extend for several days after the patient has recovered from a TCA overdose. 

The butyrophenones and diphenylbutylpiperidines differ from the phenothia-zines and thioxanthines in that they are not tricyclic structures. The first butyrophenone to be developed was haloperidol, and this is the most widely used, potent neuroleptic. Unlike many of the phenothiazines, these neuroleptics largely lack antihistaminic, anticholinergic and adrenolytic activity they are also non-sedative in therapeutic doses. Their potent antidopaminergic activity renders them likely to cause extrapyramidal side effects. Of the various butyrophenones shown in Figure 11.10, benperidol has been selectively used to suppress asocial sexual behaviour. 

The new aporphine alkaloid oliveroline (13) exhibits antiparkinsonian activity, while oliveridine (AT-methyl-14) and oliverine (N-deoxy-18) cause a dose-dependent hypotension in normal rats followed by a secondary hypertension. In the isolated rabbit ear, oliveridine has a vasodilating effect comparable to that of papaverine.55 Cabudine, which corresponds to l,2-methylenedioxy-3-hydroxy-methyl-9-methoxydehydroaporphine, possesses adrenolytic activity.56... 

Rothlin and Hamet have studied the action of gambirine on the isolated rabbit uterus chiefly with respect to its adrenolytic activity. Gambirine (1 500,000) exerts a stimulating action on this preparation, augmenting tonus as well as frequency and amplitude of rhythmic contractions. This concentration of gambirine reverses the motor effect of epinephrine (209). 

Ketanserin a 5-HT2A antagonist with aj-adrenolytic activity is clinically used as an antihypertensive agent. The precise molecular mechanism of action is still a matter of debate. 

Recent experiments carried out by BOLME and coworkers (39) now raise the question of whether the receptors involved in reducing blood pressure are epinephrine receptors or noradrenaline receptors. These workers found that in rats small doses of yohimbine and piper-oxan blocked the blood pressure lowering effect of clonidine, but did not influence the clonidine-induced increase in flexor reflex activity. This effect on the reflex mechanism is possibly mediated by noradrenaline receptors which can be blocked only by higher doses of a-adrenolytic agents. HtfKFELT et al. (40) consider that epinephrine terminals possibly innervate noradrenaline cell bodies at the locus coeruleus. 

In addition to its adrenergic neurone blocking activity (see p. 156) guanoxan has been shown [463] to have a protracted a-adrenolytic action in cats and dogs. Its resolution has been reported [464] and the two isomers were equipotent adren-... 

Racemic l-azido-3-aryloxy-2-propanols 35 was resolved by the lipase-catalyzed kinetic resolution using different acyl donors to access to the enantiomers in optically pure form.66 The reduction of the azide group can afford the l-amino-3-aryloxy-2-propanols, which is present in numerous biologically active compounds such as [3-adrenolytic drugs (/ -blockers) used in the treatment of angina pectoris, hypertension and other cardiac diseases. 

The activity spectrum of ergometrine (Fig. 7b) is quite different from that of ergotamine (Fig. 7a). It exerts a marked uterotonic effect, whereas its adrenolytic action is practically insignificant and the central nervous effects are only manifest after high doses. Ergometrine is therefore used mainly in obstetrics. In recent years it has been demonstrated that ergometrine exerts a pronounced antiserotonin effect. 

Hydrogenation of the double bond in position 9-10 of the lysergic acid moiety results in fundamental changes in the pharmacodynamic action, as a comparison of the activity spectra of ergotamine (Fig. 7a) and dihydroergotamine (Fig. 7c) makes evident. The vasoconstrictor and uterotonic effects of the dihydrogenated derivative have been markedly attenuated, as has the stimulation of central structures, so that these effects are hardly elicited by therapeutic doses. On the other hand the adrenolytic effect and the central inhibition of the vasomotor centers are markedly enhanced. This is manifested clinically in vasodilatation, hypotension, and a certain sedative action. 

Chromens and their derivatives are an important class of compounds possessing antiestrogenic, [165] potassium channel agonist, hypotensive [166], vasodilator, antihypertensive, p-adrenolytic [167] and antimicrobial activity [168]. Moreover, some derivatives show high antagonistic affinity for the retinoic acid receptor [169]. 

Tropinone enamines (28) have been prepared, with morpholine and piperidine respectively, and cyanoethylation of (28) gives the 2-j8-cyanoethyl derivative (29). On the other hand, quaternization with methyl iodide of (28) gave the quaternary salt showing adrenolytic and antihistaminic activity. 

C. Anticholinergic Hallucinogens (Clinical Effects) -Neubauer et al.9t claim that antagonism to Ditran may require both adrenolytic and cholinomimetic activities. Bauer d FlUgel93 were able to inhibit the psychotomimetic effects of Bayer 1443 and Ditran by the prior administration dihydro-ergotamine. Increased urinary excretion of catecholamine and serotonin metabolites after the administration of N-methyl-3-pyrrolidyl phenylcyclopentylglycolate was demonstrated by Bente et al. 9 ... 

As in the antispasmodic series, a tertiary amino group will generally elicit a greater cholinergic blockade than a secondary or primary amino moiety and, hence, produce a greater number of side effects associated with cholinolytic activity. Similarly, adrenolytic properties are shown mainly by tertiary amines rather than their secondary or primary amine precursors. 

Spector and Willoughby - have pointed out that the vascular changes in the acute inflammatory reaction may be due to the destruction of local vasoconstrictor substances such as adrenaline. Evidence in favour of this mechanism includes the observation that increased capillary permeability after thermal injury is suppressed by iproniazid and other monoamine oxidase inhibitors. Such inhibitors are known to inhibit the conversion of adrenaline, noradrenaline, 5-hydroxytryptamine and other amines to inactive metabolites. The authors provide evidence that the action of the monoamine oxidase inhibitors on capillary permeability is dependent on their anti-enzymic activity and not on some other unrelated property. Nevertheless, the evidence remains indirect an attempt to detect pressor amines in the plasma of burned animals was unsuccessful. The potentiating effect of bretylium and the antagonistic action of an adrenolytic substance, dibenamine, on the action of iproniazid suggest that it is local depots of adrenaline rather than noradrenaline or 5-hydroxytryptamine which are involved. Independent support for this suggested role of catecholamines... 

In contrast to aceclidine in which introduction of a methyl radical in position 6 of the quinuclidine ring [compound (LVI)] led to a sharp reduction in activity, introduction of the same radical in the same position of the oxylidine molecule had not appreciable effect on the activity. The hydrochloride of 6-methyl-3-benzoyloxyquinuclidine [compound LXIV)] did not differ significantly from oxylidine in its hypotensive, adrenolytic, anticholinergic or sedative activities. 

Activities in a series related to the adrenolytic compound XVII were found to show considerable structural specificity. XVII is being... 

Many new phenylpiperazine derivatives with combined neurological and hypotensive properties have been described5 54 gf these, AP 1161 (24), a CNS depressant with weaker adrenolytic action than chlorpromazine but stronger antiserotonin activity has been recommended for clinical trial as a psychotropic drug ... 

A chemically unique lysergic acid congener (XV, PIA) produced sustained lowering of blood pressure in hypertensive dogs and normotensive catsr The mechanism appeared to be a-blockade which was more easily reversible than that of diben-amine. Con >ound XVI was found to be a strong adrenolytic devoid of oxytocic activity ... 

Glaucine, bulbocapnine, corydine, and isocorydine all exhibited adrenolytic action in anesthetized cats and rabbits, glaucine having the highest activity. Unlike the other three bases, glaucine showed strong antitussive properties in tolerable doses, and did not cause catalepsy. ... 

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