Pharmacology of Combined α-β-Blockade I

Sumary

Several compounds of the chemical class arylethanolamines have been shown to possess combined α- or vasodilator and β-adrenoceptor blocking properties. The first drug was labetalol (AH5158)[5-(1-hydroxy-2)1-methyl-3-phenylpropyl(amino)-ethyl(salicylamide)]. Others include medroxalol, bucindolol and YM-09538, which differ from labetalol either by the nature of the substitution on the primary benzene ring and/or on the terminal nitrogen. All of these drugs are non-selective β-blockers, except for bucindolol whose selectivity has not been carefully defined.

The rationale for the development of this group of drugs was the knowledge that blockade of one adrenoceptor subtype causes reflex stimulation of the other, i.e. vasoconstriction after nonspecific β-blockade and tachycardia after β-blockade. Since both of these compensatory responses act to prevent a fall in blood pressure, a relatively weak blockade of both receptor types should act synergistically to produce a lowering of blood pressure with minimal physiological disturbance.

Haemodynamic studies have confirmed that the additional α-blocking properties of labetalol produce a pattern of haemodynamic changes unlike that of propranolol and other simple β-adrenoceptor blocking agents. Peripheral vascular resistance, which falls acutely during the initial administration of the drug, tends to fall further during prolonged administration and the pulse rate tends to remain only slightly lower than pretreatment levels. In addition, at normal dose levels cardiac output is maintained by a compensatory increase in stroke volume. Thus, blood pressure is lowered largely by a reduction in vascular resistance, and although the heart rate falls significantly during exercise, the cardiac output is maintained by an increase in stroke volume. This pattern of events is different to that seen with β-blocking agents which consistently reduce cardiac output during exercise.

Currently labetalol is the only member of this group of drugs which is in established clinical use. Its antihypertensive efficacy has been confirmed in many studies and it has been shown to be effective in the management of both hypertensive emergencies and in the long term management of severe hypertension. It is particularly valuable in allowing a reduction in the number of drugs required for adequate blood pressure control. The early theoretical prediction that postural hypotension would occur with high doses is now acknowledged to be labetalol’s major dose-limiting side effect.

Most of the available pharmacokinetic data on labetalol were derived from studies which utilised a fluorimetric assay. This has recently been superseded by more specific high pressure liquid chromatographic procedures. The drug is absorbed rapidly after oral administration and the bioavailability varies from 10 to 80% in different subjects. The apparent volume of distribution is high (200–800L) and radiochemical analysis in animals has shown high levels of accumulation in the lung, liver and kidney with little present in the brain. The drug’s half-life is between 3 and 3.5 hours and it is eliminated mainly by hepatic metabolism with the production of several biologically inactive glucuronides which are excreted in the urine and bile.

At present there is limited information concerning the effect of labetalol on plasma adrenaline (epinephrine), noradrenaline (norepinephrine), renin, glucose, insulin and lipid levels. Labetalol interferes with the spectrophotometric assay procedures for catecholamines, and in the differential fluorimetric assays it produces a peak which interferes with the estimation of adrenaline resulting in abnormally high values. With long term administration most investigators have found little alteration in plasma adrenaline and noradrenaline concentrations. A modest increase in plasma volume with suppression of renin levels has also been reported during long term therapy. However, administration of a diuretic in combination with labetalol has been reported to prevent the expansion of blood volume and suppression of plasma renin levels. Most data so far available suggest the drug has little effect on either low density lipoprotein (LDL) or high density lipoprotein (HDL) cholesterol or triglyceride levels. It may produce a small increase in fasting blood glucose levels but with little alteration in insulin activity or in the response to an oral glucose tolerance test. One recent report suggests that administration of labetalol during pregnancy may be associated with an increased concentration of prostacyclin (PGI₂) metabolites in plasma.

Overall, it appears that drugs such as labetalol which combine two synergistic actions have a potential advantage over free combinations of simple β-blocking drugs or calcium antagonists with diuretics or vasodilators in simplifying therapy and should find increasing use in the management of hypertension.