Clinical Pharmacokinetics of Hydralazine

Thomas M. Ludden, J. L. McNay, A. M.M. Shepherd, M. S. Lin

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

Hydralazine 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.

Original languageEnglish (US)
Pages (from-to)185-205
Number of pages21
JournalClinical Pharmacokinetics
Volume7
Issue number3
DOIs
StatePublished - Jun 1982

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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