Alexander M. M. Shepherd

Resting and maximal forearm skin blood flows are reduced in hypertension.

To find whether the vasodilator capacity of nonacral skin is reduced in hypertension, we measured forearm blood flow by venous occlusion plethysmography in 10 seated normotensive (mean +/- SD mean arterial pressure, 94 +/- 5 mm Hg) and 10 hypertensive (112 +/- 9 mm Hg) men at rest for 39 minutes while the forearm was heated with water at 42 degrees C, a maneuver known to selectively and maximally vasodilate skin. Blood pressure, measured every 5 minutes, did not change with heating. We found that in the normotensive group resting forearm blood flow was higher (3.64 +/- 1.12 versus 2.48 +/- 0.58 ml/100 ml tissue per minute, p less than 0.001; normotensive group versus hypertensive group) and resting forearm vascular resistance lower (30.17 +/- 10.99 versus 48.88 +/- 17.37 mm Hg.min.100 ml tissue per minute, p less than 0.05; normotensive group versus hypertensive group), and maximal forearm blood flow with local heating was higher (29.32 +/- 11.99 versus 18.19 +/- 4.50 ml/100 tissue per minute, p less than 0.018; normotensive group versus hypertensive group and vascular resistance lower (4.07 +/- 1.04 versus 6.54 +/- 1.17 mm Hg.min.100 ml tissue per minute, p less than 0.005; normotensive group versus hypertensive group). To find whether this degree and duration of local warming maximally vasodilated the skin in hypertensive subjects (as it does in normotensive subjects), we measured forearm skin blood flow before and during local heating plus 10 minutes of ischemia using a laser Doppler flowmeter.(ABSTRACT TRUNCATED AT 250 WORDS)

Hydralazine kinetics after single and repeated oral doses

In reports on hydralazine kinetics plasma hydralazine levels have been measured with nonspecific assay techniques. The techniques used also include acid‐labile hydralazine metabolites and therefore markedly overestimate hydralazine levels. We have developed specific, sensitive assay methods for the measurement of hydralazine and its major plasma metabolite, hydralazine pyruvic acid hydrazone (HPH). By these methods, we determined hydralazine and HPH kinetics after single and repeated oral doses of hydralazine in eight hypertensive patients. Hydralazine bioavailability in the fast acetylator group (9.5% single dose, 6.6% repeated doses) and in the slow acetylator group (31.3% single dose, 39.3% repeated doses) was phenotype dependent. Peak plasma levels were lower than those reported with nonspecific assays: 0.32 μM for the single dose and 0.14 μM for repeated doses in the fast acetylator group and 1.03 μM for the single dose and 0.96 μM repeated doses in the slow acetylator group. There was no alteration in kinetics and no cumulation in plasma on repeated administration. HPH plasma levels were proportional to those of hydralazine in both acetylator groups and were 2.5 to 4 times as high as those of hydralazine. Elimination half‐lifes were phenotype independent, ranging from 4 to 6 hr. HPH cumulated in the rapid but not in the slow acetylator group after repeated doses of hydralazine.

Intradermal microdialysis: kinetics of iontophoretically delivered propranolol in forearm dermis.

Intradermal microdialysis permits us to measure the concentration in dermis of drugs applied to the skin. Microdialysis is especially efficient in sampling water-soluble molecules. Consequently, it appears particularly suitable to study current based delivery systems like iontophoresis that deliver ions or highly polar molecules. The purpose of this work was to evaluate the adequacy of a skin microdialysis technique to characterize and quantify the dermatopharmacokinetics of iontophoretically delivered propranolol in the dermis of healthy human volunteers. Linear microdialysis probes were inserted in the subjects forearm skin and an iontophoresis device was installed above them. Constant current was applied for two periods of 1 h each separated by a 1-h interval. Dialysate samples were collected every 6 min for 4.4 h and analyzed by HPLC. Probes were always placed in the dermis as measured by ultrasonography. Propranolol was detectable in the dialysate. It was possible to build detailed concentration vs. midtime profiles that mirrored the current applied. Elimination rate from the dermis had first-order kinetics and was similar in all subjects. Quantification of the absorption process, indexed by lag-time and area under the concentration curve showed a high inter- and intrasubject variability that did not correlate with probe depth.

Plasma concentration and acetylator phenotype determine response to oral hydralazine.

SUMMARY The vasodepressor response to single and multiple oral doses of hydralazine, 1 mg/kg, was studied in hypertensive patients. The concentration of bydralazbe in plasma was measured both by a newly developed specific and a nonspecific assay similar to those used in previous studies. Acetylator phenotype was determined following oral sulfamethazine. Plasma hydralazine concentration peaked at 1 hour after administration and was undetectable 2 hours later. Apparent hydralazine was present in plasma in higher concentration and for a longer duration than hydralazine. The peak decreases in blood pressure (BP) were proportional to plasma hydralazine concentration following administration of both single and multiple doses and were substantially maintained for 8 hours. In contrast there was no significant correlation between decreases in BP and apparent hydralazine concentrations. The plasma concentration of hydralazine after a standard oral dose varied by as much as 15-fold among individuals and was lower in rapid than slow acetylator phenotype patients. The BP responses were positively correlated with plasma hydralazine concentrations and inversely correlated with acetylator indices. Low plasma concentrations may account for poor responses of some patients to conventional oral doses of hydralazine. The applicability of acetylator pbenotyping for individualization of hydralazine dosage regimens merits further evaluation.

Clinical pharmacokinetics of hydralazine

SummaryHydralazine is one of the most frequently prescribed drugs for the treatment of moderate to severe hypertension. In addition, it is being used increasingly for the treatment of congestive heart failure when more traditional approaches fail. Although hydralazine has been in clinical use for 30 years, there is insufficient information concerning dose-blood concentration and blood concentration-response relationships to formulate rational approaches for dosage individualisation. This paucity of data is primarily due to the fact that many previous methods for measurement of hydralazine in plasma were non-selective and measured circulating, inactive metabolites. Recently, more selective procedures have been developed and are being applied to the study of the pharmacokinetic behaviour of hydralazine in man.Hydralazine is very unstable in plasma in vitro (half-life of approximately 6 minutes at 37°C) and derivatisation of samples must be carried out very rapidly to avoid loss of drug. Studies in healthy volunteers and hypertensive patients indicated that after oral administration hydralazine undergoes extensive acetylator phenotype-dependent first-pass metabolism. Results using selective assay procedures indicate a mean fractional availability of about 0.30 to 0.35 for slow acetylators and 0.10 to 0.16 for rapid acetylators. Food may enhance the bio-availability. There is evidence that the first-pass effect is saturable.After intravenous administration acetylator phenotype is not a major determinant of hydralazine disposition. This indicates that a large fraction of systemic clearance is via metabolic pathways independent of acetylator phenotype. The fact that hydralazine rapidly forms a hydrazone with pyruvic acid in plasma or whole blood can account for a significant proportion of systemic clearance. However, formation of other hydrazones or adducts cannot be ruled out. Besides acetylation, oxidative metabolism accounts for a significant proportion of elimination since 4-(2-acetylhydrazino) phthalazin-1-one is a major urinary metabolite. This compound can only occur if oxidation precedes acetylation since the product of hydralazine acetylation is 3-methyl-s-triazolo [3,4a] phthalazine and would not yield the 2-acetylhydrazino derivative upon subsequent oxidation. Less than 10% of a dose is present in urine as hydralazine or acid-labile conjugates of hydralazine.Clearance and apparent volume of distribution appear to be lower and half-life longer in older hypertensive patients than in young healthy volunteers, but the 2 populations were studied by different research groups using different experimental designs and different assay methods. Further studies are needed to determine whether the differences really exist. Similarly, the effects of renal failure on the pharmacokinetics of hydralazine are not yet understood. In addition, the use of hydralazine in resistant congestive heart failure requires that the influences of this disease stale on kinetics be determined.Hydralazine has been shown to increase the bioavailability of propranolol and may similarly influence other drugs that undergo significant first-pass metabolism.Although there is not a temporal relationship between antihyperlensive response and plasma hydralazine concentrations, the maximal change in mean arterial pressure correlates in magnitude with either the peak hydralazine concentration or the area under the plasma hydralazine concentration-lime curve.It appears that determination of acetylation ability may serve as a practical guide for individualisation of oral hydralazine dosage regimens.

Dose-Response Characteristics of Mibefradil, a Novel Calcium Antagonist, in the Treatment of Essential Hypertension*

The aim of this study was to determine the dose-response characteristics of the calcium antagonist, mibefradil, and to evaluate its antihypertensive efficacy and safety in varying doses in patients with mild-to-moderate hypertension. Three hundred and three eligible patients were randomized to receive once-daily 6.25-, 12.5-, 25-, 50-, 100-, 150-, or 200-mg mibefradil doses or placebo for 4 weeks. Repeated blood pressure measurements and electrocardiographic recordings were obtained for the 24 h following the last dose of the placebo run-in period and for the first and last doses of randomized treatment. A statistically significant (P < .001 versus placebo) and clinically relevant drop in sitting diastolic blood pressure (SDBP) both at trough and at peak was observed in the 50-, 100-, 150-, and 200-mg mibefradil dose groups (trough placebo-corrected reductions: -4.9, -9.1, -9.9, and -11.9 mm Hg, respectively), with a significant dose-response relationship (P < .001) and high response rates. Trough/peak ratios for the placebo-corrected change from baseline to week 4 in SDBP were >85% for the 50- and 100-mg doses and 68% and 69% for the 150- and 200-mg doses, respectively. The full antihypertensive effect of mibefradil was achieved within 1 week of treatment. Reductions in sitting systolic blood pressure (SSBP) closely paralleled those in SDBP. The antihypertensive effect of mibefradil was associated with a slight dose-dependent decrease in heart rate and increase in the pulse rate (PR) electrocardiographic interval [corrected]. The appropriate therapeutic dose range of mibefradil in the management of mild-to-moderate essential hypertension is 50 to 100 mg.

Iontophoretic current and intradermal microdialysis recovery in humans

When microdialysis (MD) is used to study dermal delivery by iontophoresis, the effects of current may alter MD recovery through an increase in temperature, a change of pH, hyperemia, and dermal hydration. The objective of this work is to assess whether these effects of current may cause a measurable change in the retrodialysis of a model compound (sodium fluorescein, Fl). Two linear MD-probes were inserted in the forearm dermis of healthy human volunteers and perfused with Ringers solution containing Fl. Two identical iontophoresis chambers (IC, filled with NaCl in propylene glycol) were placed over the MD-probes. Each IC included a laser Doppler flowmetry probe to monitor skin blood flow. At one IC, current was applied for two periods of 30 min each, separated by 30 min of no current. No current was applied to the control site. Dialysate samples were collected every 5 min and analyzed for Fl by HPLC. Skin blood flow increased in response to iontophoresis, on average, 570% compared to the control site. However, there was no difference in the recovery of Fl between the current-active site versus the control site, and between the period with applied current versus the period with no current. In conclusion, iontophoretic current did not affect intradermal MD recovery.

Differential hemodynamic and sympathoadrenal effects of sodium nitroprusside and hydralazine in hypertensive subjects

Summary: The hemodynamic and sympathoadrenal effects of serial incremental doses of a mixed veno-arte-riolar dilator (intravenous sodium nitroprusside 0.0125–0.50 μg/kg/min) and a pure arteriolar dilator (bolus injections of hydralazine, 0.05–0.3 mg/kg) were compared in 18 subjects with uncomplicated essential hypertension. Blood pressure was reduced to the same extent over approximately the same time with both drugs. Sodium nitroprusside produced significant reduction in cardiac output (9%) and stroke volume (16%) despite an 11% increase in heart rate. Total peripheral resistance did not change. In contrast, hydralazine produced a significant (39%) reduction in peripheral resistance with a compensatory increase in heart rate (19%), stroke volume (20%), and cardiac output (42%). The catecholamine responses to the drugs differed both quantitatively and qualitatively. Administration of both drugs was associated with gradual increases in plasma norepinephrine, but the levels were consistently 40% higher with sodium nitroprusside for the same fall in blood pressure. No consistent change in plasma epinephrine was found with sodium nitroprusside, whereas with hydralazine, the concentration increased gradually after the blood pressure had been reduced by 9 mm Hg. This threshold was independent of the starting blood pressure. These differences in catecholamine response could reflect different patterns of regional sympathetic activation by the low pressure mechanoreceptors (sodium nitroprusside) and by the arterial baroreceptors (hydralazine). Neither drug has an ideal hemodynamic profile, particularly in subjects with cardiac disease, but a balanced combination of the two may produce a favorable hemodynamic profile and optimal hypotensive effect, minimizing the need for large doses of sympathetic inhibitors.

Direct‐Acting Vasodilators

J Clin Hypertens (Greenwich). 2011;13:690–692. ©2011 Wiley Periodicals, Inc.

Effects of advancing age on hypothalamic neurotransmitter content and on basal and norepinephrine-stimulated LHRH release

In order to elucidate possible mechanism(s) responsible for the age-related decline in LH secretion, basal and norepinephrine (NE)-stimulated LHRH release was measured from median eminence (ME) fragments of 4-, 11-, 18- and 27-month-old male F344 rats. Serum LH levels declined significantly between 11 and 18 months and were still lower at 27 months of age, while testosterone levels declined continuously between 4 and 27 months. Hypothalamic NE and dopamine (DA) content also declined significantly with age, while serotonin and 5-hydroxy-indoleacetic acid content increased with age. Despite the decline in serum LH levels with age, in vitro basal LHRH release increased gradually with age as did NE-stimulated LHRH release. These data suggest that the age-related reduction in LH secretion by the male rat is due to a reduction in hypothalamic NE metabolism and not to an inability of the LHRH neuron to respond to NE stimulation.