DOES ANTIHYPERTENSIVE EFFECT RELATE TO DOSE AND PLASMA lEVELS?

o Effect of Clonidine is Related to Plasma Levels at Low Concentrations Oral doses of clonidine hydrochloride (300j.lg) had qualitatively similar effects on BP, sedation and saliva production in 5 essential hypertensives as in normotensive subjects, and similar peak plasma levels and half-lives. The drug did not accumulate during chronic oral dosing. They developed some tolerance to the sedative and salivary flow effects, but not to the antihypertensive effect. Reduction in saliva flow and clonidine plasma levels were linearly related. The antihypertensive effect was also related to plasma level at low concentrations, but at plasma levels > 1.5 ng / ml the antihypertensive effect was diminished. Wing, L.M.H. et aI.: European Journal of Clinical Pharmacology 12: 463 (No 6, 1977)

o Methyclothiazide: Some Patients Respond Early, Others Later A study in 120 patients with essential hypertension identified 2 types of thiazide responders - early and late. After a 2-week placebo period, they took methyclothiazide 5mg/ day for 6 weeks, then non-responders continued on 5mg or I Omg/ day for another 6 weeks. 50 % of patients responded with a significant diastolic BP reduction within 4 weeks. Late responders (27.3 %) showed a modest reduction in diastolic BP during the first 4 weeks of treatment, followed by a plateau for about 2 weeks. BP then fell significantly again during the next 6 weeks. Doubling the dose did not significantly affect this late response. Hypokalaemia was more common in early responders. Soghikian, K. and Bartenbach, D,E,: Southern Medical Journal 70: 1397 (Dec 1977)

o A Diuretic Should be Given for Several Days before Starting Bethanidine After 2 weeks on diuretic therapy with benzthiazide, bethanidine was added in 3 daily doses in 12 hypertensive patients. Mean standing diastolic BP was reduced from 112 to 9\ mm Hg in II patients after 2-\2 months' treatment. The mean total daily dose ofbethanidine was 79mg (range 30-150mg). Plasma levels (mean O.65j.lM; range O.I-2.8IlM) correlated with dose, but there was less correlation between dose and antihypertensive effect. After sudden withdrawal from chronic dosing (6 patients) the orthostatic effect of beth ani dine was lost within 12 hours, but the half-life of elimination from plasma was 39 hours. After several days on a diuretic, bethanidine should be started at 1 Omg tid and increased by I 0-20mg every 1-2 weeks, depending on response and toleration. Corder, C.N ,: Journal of Clinical Pharmacology 18: 249 (May-Jun 1978)

o Hydrochlorothiazide Plasma Levels Correlate with Dose but Not with BP Reduction A linear relationship was found between the plasma concentration of hydrochlorothiazide before and 5 hours after a dose in 9 previously untreated hypertensive patients, but there was no relationship between plasma concentration and BP reduction. The patients took hydrochlorothiazide 12.5,25,50 and 75mg for 2 weeks after 4 weeks on placebo. 12.5mg significantly reduced BP in lying and sitting positions but not in the standing position. Doubling the dose reduced BP very little more. The mean steady state concentration was lling/mi with the 75mg dose. Beerman, B. and Groschinsky-Grind, M.: European Journal of Clinical Pharmacology 13: 195 (No 3, 1978)

o No Correlation between Bendroflumethiazide Plasma Level and Effect on BP Either After 4 weeks on placebo, 8 hypertensive patients were given bendroflumethiazide 2.5mg and KCll.5g daily for 2 weeks; then bendroflumethiazide 5mg plus KCll.5mg daily for 2 weeks. Peak bendroflumethiazide levels occurred after 2.3 hours and averaged 23ng/ ml after 2.5mg, and 50ng/ml after 5mg. After 2.5mg the plasma level was too low for kinetic analysis. Plasma half-life after 5mg averaged 4.1 hours. The renal clearance ofbendroflumethiazide was significantly lower (p < 0.05) after 5mg than after 2.5 mg, although creatinine clearance was unchanged. There was no correlation between bendroflumethiazide plasma levels and effect on BP.

, Beermann, B. et aI.: European Journal of Clinical Pharmacology 13: 119 (No 2, 1978)

INPHARMA 1st July, 1978 p15