Adrenolytic Drugs

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. 

Mention should be made at this juncture of the role of adrenolytic drugs as inhibitors of inflammation. Spector and Willoughby found that diben-amine hydrochloride antagonizes the anti-inflammatory effect of iproniazid, but other workers have shown that adrenolytic drugs themselves reduce capillary permeability , and that dibenamine hydrochloride suppresses the tuberculin reaction in the guinea-pig . 

Substitutions in position 8 indicate that the benzene ring of phenylalanine required for pressor activity is not needed for inhibition of uptake. The relative importance of direct and indirect action for vascular smooth-muscle stimulation is not yet known. Indeed, either the pressor response or the vascular contraction in vitro evoked by angiotensin is not blocked by adrenolytic drugs. 

In some new / -adrenolytic drugs (e.g. propranolol), not only the substitutions on the ring, but also the lengthening of the side-chain from ethanolamine to oxypropanolamine appears to play a very important rdle the relation of this to the receptor is not yet clearly understood. 

Sapirstein and Reed (152) studied the effect of two dioxane derivatives, Foumeau 883 and Foumeau 933, on hypertensive rats. Like yohimbine, F 883 (diethylaminomethylbenzodioxane) is both sympatholytic and adrenolytic while F 933 (piperidinomethylbenzodioxane) is only adrenolytic (5,6). The syinpatholytic-adrenolytic drug, F 883, lowered the blood pressure of sixteen late hypertensive rats to a nearly normal level but did not change the blood pressure of normotensive rats. The adrenolytic compound, F 933, had no effect on the blood pressure of late hypertensive rats. 

The administration of low doses of PCP to rodents induces hyperactivity and stereotypy (Chen et al. 1959 ). The observation that neuroleptics such as chlorpromazine, haloperidol, and pimozide, and adrenolytics such as alpha-methyl paratyrosine antagonize these behavioral effects of PCP suggests that they are mediated by facilitation of central dopaminergic neurotransmission (Murray and Horita 1979). The actions of PCP on central dopaminergic neurotransmission may be similar to amphetamine. A dose of PCP (2.5 mg/kg) in rats, which has no effects when given alone, enhances the behavioral effects of 1 and 3 mg/kg of d-amphetamine (Balster and Chait 1978). PCP, like dopamine, has also been shown to suppress plasma prolactin (Bayorh et al. 1983). However, the firm establishment of an excl usive relationship between dopamine neuro-transmission and PCP effects is difficult because of the prominent interactions of this drug with other neurotransmitter systems. 

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. 

Mitotane (Figure 39-5) has adrenolytic properties in dogs and to a lesser extent in humans. This drug is administered orally in divided doses up to 12 g daily. About one-third of patients with adrenal carcinoma show a reduction in tumor mass. In 80% of patients, the toxic effects are sufficiently severe to require dose reduction. These include diarrhea, nausea, vomiting, depression, somnolence, and skin rashes. The drug has been withdrawn from the market in the USA but is available on a compassionate basis. 

This drug (Figure 39-5) is a dichloro analog of the insecticide DDT that was first found to be adrenolytic in dogs. Subsequently, it was found to be useful in the treatment of an adrenocortical carcinoma, and it is labeled for this clinical indication. The drug produces tumor regression and reduces the excessive adrenal steroid secretion that often occurs with this malignancy. Toxicities are listed in Table 55-6. 

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 ... 

P-Adrenolytics belong to a large group of cardiovascular drugs used in the clinical treatment of heart failure. 

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