DEFINING THE EFFECTS OF ANTIHYPERTENSIVE AGENTS

o Response to Debrisoquine Depends on Hydroxylation Phenotype Marked interindividual differences in debrisoquine dose requirements of hypertensives have been shown to depend on a genetically determined ability to convert the drug to the 4-hydroxy metabolite. Seven volunteers with normal BP, phenotyped according to their 4-hydroxylating ability, took a 20mg tablet of debrisoquine, and lying and standing BP were measured hourly. The 4 extensive metabolisers showed little or no response to the drug. By comparison, the 3 non-metabolisers showed a statistically significant orthostatic hypotensive effect. They also showed dose-dependent metabolism. It is suggested that debrisoquine should be started at low doses (1 0-20mg) to avoid overdosing of non-metabolisers; or phenotype should be determined before starting treatment.

'. Idle, J.R. eta!.: Life Sciences 22: 979 (Mar (978)

o Action of Labetalol Seems to be Renin Independent Combined a- and ~-adrenoceptor blockade with labetalol may effectively reduce BP in patients with essential hypertension, the effect being more pronounced in the upright position, according to a study in 18 patients. They were treated for 6 weeks with labetalol alone (in increasing doses) or in combination with the diuretic chlorthalidone (I OOmg I day). Maximal doses of labetalol averaged 1460 and 650mg/day, respectively.

• With labetalol alone, significant changes (p < 0.05) included a transient decrease in supine BP (maximum J I %); persistent reduction in upright BP, pulse rate (20 %) and plasma renin activity (40 %)j and gains in body weight (1.7 %) and blood volume (I 7 %). There was a 7 -fold rise in adrenaline (epinephrine) excretion rate and a mild increase in plasma potassium. Plasma aldosterone and noradrenaline (norepinephrine) excretion rate were unchanged.

• After 6 weeks' combination therapy, BP reduction was greater (p < 0.02) than after labetalol alone in supine and upright positions. Blood volume and plasma potassium decreased (p < 0.05), plasma renin doubled (p < 0.02) and plasma aldosterone did not change.

Although orthostatic hypotension and several other side-effects were common with large doses, they occurred infrequently with the doses used in combination therapy and were often transient. Although plasma renin activity decreased with labetalol alone, it increased during combined therapy and there was no significant correlation between renin and BP during single-drug treatment.

- Weidmann, P. et al.: American Journal of Cardiology 4 I: 570 (Mar 1978) .

o Sodium Restriction Maximises the Antihypertensive Effect of Propranolol Results of a study in 12 hypertensive patients suggest that sodium restriction is important in managing hypertensi~n with propranolol ('Inderal').

• After 4-14 weeks on propranolol (average 270mg/ day) with normal sodium intake, there was a decrease in plasma renin activity, a variable tendency to an increase in body weight and plasma volume and 5mm Hg decrease in mean arterial pressure.

• With sodium restriction alone, BP was reduced significantly, and with addition of propranolol there was a further significant decrease of8mm Hg (p < 0.01).

• Propranolol did not alter the BP reduction obtained with sodium depletion and acute diuretic therapy (I OOmg hydrochlorothiazide).

• Propranolol did not affect the increase in plasma renin activity induced by sodium depletion and diuretic therapy. Owens, C.J. and Brackett, N.C.: Southern Medical Journal 7 I: 43 (Jan 1978)

INPHARMA 27th May, 1978 p13