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At least 19 recordsLinked to original sources

PubMed1979

Pharmacokinetics of hydralazine, apparent hydralazine and hydralazine pyruvic acid hydrazone in humans.

Hydralazine is an antihypertensive vasodilator agent. Lack of specific assay techniques for its measurement have delayed elucidation of its pharmacokinetic profile. This study compares the plasma profiles of hydralazine, measured both by a specific and by a previously published nonspecific assay and of a major plasma metabolite, hydralazine pyruvic acid hydrazone. After po and iv administration of hydralazine, peak hydralazine levels were lower (7-33%) and plasma half lives were shorter (15-31%) when measured by the specific technique. The mean plasma half life of the pyruvic acid hydrazone was 156 min and mean urinary clearance, 28 ml/min. The plasma profile of hydralazine and of the major metabolite, the pyruvic acid hydrazone, do not appear to correspond to the duration of antihypertensive effect of administered hydralazine.

Acetylation↗

PubMed1978

Interference in assays for hydralazine in humans by a major plasma metabolite, hydralazine pyruvic acid hydrazone.

The present study showed that published spectrophotometric and GLC methods for hydralazine in plasma do not distinguish between the drug and a major plasma metabolite, hydralazine pyruvic acid hydrazone. These methods involve the acid treatment of the sample, which hydrolyzes that hydrazone back to hydralazine. A specific GLC assay for the hydrazone was developed and involves its selective extraction from plasma and transformation to 3-trifluoromethyl-s-triazolo[3,4-a]phthalazine. This derivative could be sensitively measured by GLC using an electron-capture detector. With this procedure, it was shown that most "apparent hydralazine" in plasma is the hydrazone, which forms rapidly from hydralazine and endogenous pyruvic acid. Previous work indicated that the hydrazone was inactive when administered intravenously to rabbits.

Chromatography, Gas↗

PubMed1979

Pharmacokinetics and cardiovascular effects in rabbits of a major hydralazine metabolite, the hydralazine pyruvic-acid hydrazone.

The hydrazone of hydralazine and pyruvic acid (HPH) has been recognized as a quantitatively important metabolite of hydralazine in human plasma. We evaluated the disposition of [14C] HPH after its i.v. administration to normal, anephric and probenecid-pretreated rabbits. Renal clearance of HPH in normal rabbits exceeded the glomerular filtration rate by a factor of 3 to 4 and accounted for 80 to 90% of the total body clearance. Active tubular secretion was established by the effect of probenecid pretreatment to reduce the renal clearance of HPH by 80%. Total body clearance of HPH in anephric rabbits was 10% of that of normal animals, emphasizing the minor importance of metabolic conversion for the overall disposition of HPH. HPH in a maximum dose of 50 mumol/kg i.v. had no hypotensive effect in renal hypertensive rabbits and did not interfere with the subsequent hypotensive response to hydralazine. This HPH dose produced plasma levels at least 50 times in excess of those reported in humans after administration of therapeutic doses of parent hydralazine. HPH is consequently of negligible clinical significance, despite the relatively high plasma concentration of this metabolite which occurs after administration of parent hydralazine.

Animals↗

PubMed1979

High-pressure liquid chromatographic assay for hydralazine in human plasma.

A specific high-performance liquid chromatographic assay for hydralazine in human plasma was developed. Plasma hydralazine is reacted with 10 microliter of p-anisaldehyde for 7 min at room temperature to form hydralazine p-anisaldehyde hydrazone. This derivative is extracted into ethyl acetate, and the solvent is removed by evaporation. The residue is reconstituted in 100 microliter of methanol, and 90 microliter is injected onto a reversed-phase column. The mobile phase is 32% acetonitrile in 0.75 M acetate buffer, pH 3.4, at a flow rate of 2 ml/min. The retention time of hydralazine p-anisaldehyde hydrazone is 6.5 min. The average coefficient of variation over 10-200 ng/ml is 5.5%, and the sensitivity limit is 5 ng/ml. Under the assay conditions, hydralazine pyruvic acid hydrazone, a known plasma metabolite of hydralazine, yields less than 0.1% hydralazine. Detectable plasma hydralazine levels of 5-20 ng/ml were found 10-30 min after a 0.5-mg/kg oral dose of hydralazine hydrochloride was given to a male volunteer.

Adult↗

PubMed1979

Influence of short-term oral hydralazine therapy on exercise hemodynamics in patients with severe chronic heart failure.

Changes in left ventricular performance were evaluated in 14 patients with functional New York Heart Association class III or IV chronic heart failure before and after the addition of oral hydralazine to conventional therapy. With conventional therapy, cardiac output increased from 3.4 +/- 0.8 (mean +/- 1 standard deviation) at rest to 4.7 +/- 1.4 liters/min during exercise. This increase in cardiac output on exercise during conventional therapy was mainly due to an increase in heart rate. After the addition of hydralazine, cardiac output at rest increased to 5.0 +/- 1.4 liters/min. The increase in cardiac output was essentially due to an increase in stroke volume. This enhanced stroke volume after hydralazine therapy was maintained during exercise. Hydralazine therapy did not change either the left ventricular filling pressure at rest or the magnitude of increase in left ventricular filling pressure during exercise. Nevertheless, increased cardiac output and stroke volume with similar changes in left ventricular filling pressure during exercise indicated improved left ventricular performance after hydralazine therapy. After short-term hydralazine therapy, symptom-limited peak exercise work load, duration of exercise and maximal oxygen consumption during exercise did not increase. Clinical follow-up at 2 months after long-term therapy revealed subjective improvement in exercise tolerance in 13 of the 14 patients.

Administration, Oral↗

PubMed1979

High-performance liquid chromatographic studies of reaction of hydralazine with biogenic aldehydes and ketones.

To understand hydrazone formation in hydralazine metabolism, the reaction of hydralazine with various biogenic aldehydes and ketones (acetone, pyruvic acid, acetoacetic acid, formaldehyde, and acetaldehyde) in pH 7.4 buffer was studied for potential alterations in hydralazine pharmacokinetics secondary to alcoholism and diabetes. The corresponding hydrazones were isolated, and their structures were characterized. High-performance liquid chromatography was used to monitor the reactions. An aqueous solvent reversed-phase liquid chromatographic system was used to separate hydralazine and its derivatives. Reaction of hydralazine with formaldehyde or acetaldehyde produced the corresponding hydrazones. Formation of an s-triazolo ring system yielded the known s-triazolo[3,4-alpha]phthalazine and 3-methyl-s-triazolo[3,4-alpha]phthalazine metabolites, which also were isolated and characterized and suggested nonenzymatic metabolism.

Aldehydes↗

PubMed1978

Effects of hydralazine on canine muscarinic ganglion stimulation.

The effects of hydralazine upon the caudal pressor responses during occlusion of the abdominal aorta and vena cava evoked by: (1) preganglionic electrical stimulation of the lumbar sympathetic chain, (2) neostigmine and (3) McN-A-343 were investigated in the anesthetized dog. Hydralazine (10 microgram/kg, i.v.) produced a small but significant reduction of the pressor response to lumbar electrical stimulation prior and following blockade of nicotinic transmission with chlorisondamine (1.0 mg/kg). However, hydralazine was not effective in blocking the pressor responses elicited by neostigmine and McN-A-343. On the other hand, small doses of atropine (20 microgram/kg) produced a blockade of residual pressor responses evoked by all three stimuli. On the basis of these findings, the site of action of hydralazine appears to be different from that of atropine. It is proposed that hydralazine affects ganglionic transmission by acting at sites other than muscarinic in nature.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗

PubMed1979

Comparison of haemodynamic effects of oral hydralazine and prazosin hydrochloride in patients with chronic congestive heart failure.

The comparative haemodynamic effects of oral prazosin hydrochloride and hydralazine were evaluated in 11 patients with chronic congestive heart failure. The maximum total dose of prazosin received by an individual varied up to 25 mg. Ten patients received a maximum of 75 mg and one received 50 mg of hydralazine at six-hour intervals. There was no significant change in heart rate with either drug. Decrease in mean arterial and left ventricular filling pressures were modest and similar with both agents. With prazosin, the average cardiac index increased 20 per cent and systemic vascular resistance decreased 20 per cent. By contrast, hydralazine increased cardiac index by 58 per cent and decreased systemic vascular resistance by 40 per cent. The increase in stroke work and stroke volume indices was significantly greater with hydralazine than with prazosin. These findings suggest that in some patients with severe chronic congestive heart failure, improvement in left ventricular performance may be greater with hydralazine than with prazosin.

Adult↗

PubMed1979

Comparison of haemodynamic effects of oral prazosin, oral hydralazine, and intravenous nitroprusside in same patients with chronic heart failure.

The haemodynamic effects of oral prazosin and hydralazine were evaluated in patients with refractory heart failure and compared with those of intravenous nitroprusside in the same patients. Both oral agents were well tolerated and appeared to have beneficial haemodynamic effects. Prazosin and hydralazine produced similar increases in cardiac output associated with a similar decrease in systemic vascular resistance. Prazosin and hydralazine produced similar increases in cardiac output associated with a similar decrease in systemic vascular resistance. Prazosin resulted in a more significant decline in left ventricular filling pressure and pulmonary vascular resistance than did hydralazine. Haemodynamic alterations induced by prazosin were similar to those induced by nitroprusside, which suggests a relatively balanced reduction of preload and afterload. With hydralazine, the increase in cardiac output without change in left ventricular filling pressure or pulmonary vascular resistance suggests minimal effect on preload but significant reduction in afterload.

Adult↗

PubMed1975

Hydralazine-induced lupus erythematosus-like syndrome.

A reversible syndrome resembling systemic lupus erythematosus and induced by hydralazine hydrochloride therapy is a well-recognized phenomenon in adults but does not seem to have been reported in children. A 9-year-old girl had fever, arthralgias, modest joint swelling, splenomegaly, antinuclear antibodies (ANAs), anitbodies against native and denatured DNA, and positive LE cell preparations after nine months of hydralazine hydrochloride therapy, 120 mg/day. Clinical findings returned to normal within four weeks of discontinuing the drug therapy, and serological abnormalities disappeared after 11 months. Like previously reported patients, the child is white and has a slow acetylation phenotype. It is not known whether children receiving hydralazine are as susceptible to this complication as adults. Periodic ANA determinations may be advisable for children receiving hydralazine, especially if they are white and have a slow acetylation phenotype.

Acetylation↗

PubMed1976

Effects of hydralazines on canine muscarinic ganglion transmission.

The effects of hydralazine, dihydralazine and 4-propyl-1-hydrazinophthalazine (4-propylhydralazine) were investigated on reflex pressor responses to increased intracranial fluid pressure (IIP) during occlusion of the abdominal aorta and the vena cava (MVO). It has been shown that application of MVO, caudal to the renal arteries, produces two independent vascular zones in the animal (Steinberg and Hilton, 1966a). Increasing intracranial fluid pressure during MVO elicits a reflex pressor response which consists of two components. One component is blocked by the nicotinic ganglionic blocking agent, chlorisondamine, and the other component is blocked by small doses of atropine. It was found that hydralazine and dihydralazine were effective in blocking residual pressor responses following partial blockade of reflex pressor responses to IIP with chlorisondamine. 4-Propylhydralazine, which is chemically similar to hydralazine and dihydralazine, was less active in inhibiting the residual pressor responses. It is suggested that hydralazine may act in part by interfering with muscarinic ganglionic transmission.

Animals↗

PubMed1978

Effect of timolol plus hydrochlorothiazide plus hydralazine on essential hypertension.

The effect on hypertension of hydrochlorothiazide 100 mg daily plus timolol 20-60 mg daily versus hydrochlorothiazide plus placebo and of hydrochlorothiazide plus timolol plus hydralazine 40-200 mg daily versus hydrochlorothiazide plus placebo plus hydralazine was evaluated in a double-blind, randomized, crossover study in 38 patients with hypertension. Hydrochlorothiazide plus timolol was more effective than hydrochlorothiazide plus placebo in lowering both supine and standing systolic and diastolic blood pressures. Hydrochlorothiazide plus timolol plus hydralazine was a very effective regimen in lowering both supine and standing systolic and diastolic blood pressure. The patients tolerated this regimen well with greater hypotensive activity and a lower incidence of side effects than on hydrochlorothiazide plus placebo plus hydralazine.

Adult↗

PubMed1979

Colorimetric determination of hydralazine with 9-chloroacridine.

A spectrophotometric assay for hydralazine hydrochloride based on the interaction of the drug with 9-chloroacridine has been developed. The interaction shows an absorption maximum at 460 nm and is affected by temperature, heating time, and quantity of acridine reagent used. Color development is maximum when the drug is heated in the presence of a 30-fold molar excess of the acridine in a 50 +/- 1 degree C water bath for 1 hr. The method detects hydralazine hydrochloride in the 10(-5)--10(-6)M range with sensitivity to 0.2 micrograms/mL and 3--4% accuracy. Typical calibration data obtained from linear regression analysis of absorbance at various drug concentrations show r = 0.9997 (n = 6). Hydralazine can be determined in dosage forms that also contain varying quantities of reserpine and hydrochlorothiazide. The 9-chloroacridine method is as sensitive as other spectrophotometric procedures for hydralazine but also more accurate and precise, and involves fewer manipulative steps.

Acridines↗

PubMed1978

Haematological changes in experimental hydralazine-induced collagen-like syndrome in guinea pigs.

Haematological studies were carried out in hydralazine-induced collagen-like syndrome in guinea pigs. 37.5 per cent of animals were found to be LE-positive. It was found that long-term administration of hydralazine caused a decrease of erythrocyte count, a decrease of haemoglobin concentration and a decrease of haemoglobin content in individual red blood cell as well as a decrease of a single erythrocyte volume. A significant leukopenia was shown in LE-positive subgroup of hydralazine-treated guinea pigs. The obtained results confirmed the similarity of hydralazine syndrome to systemic lupus erythematosus.

Animals↗

PubMedDate not supplied

Hydralazine therapy in hypertensive patients with idiopathic systemic lupus erythematosus.

Seven hypertensive patients with idiopathic systemic lupus erythematosus were treated with hydralazine. They received a mean daily dose of 203 mg for a mean duration of 21 months. All were taking prednisone alone or in combination with azathioprine. During therapy with hydralazine, there were no new symptoms nor exacerbation of pre-existing symptoms attributable to systemic lupus. Laboratory parameters, including antinuclear antibody titers and complement levels, either improved or remained stable. The results indicate that hydralazine can be safely used in hypertensive patients with systemic lupus who are receiving concomitant immunosuppressive therapy.

Adult↗

PubMed1979

Identification and quantitation of hydrazine in the urine of patients treated with hydralazine.

Hydrazine has been identified by gas chromatography-mass spectrometry in the 0- to 24-hr urine of patients administered hydralazine. With a specific gas chromatographic assay procedure, the amount of hydrazine in the 0- to 24-hr urine was determined in patients treated with various doses of hydralazine. The amount of hydrazine detected in the urine was greater in the slow acetylator phenotype than in the rapid acetylator phenotype. Studies indicated that hydrazine was not produced by chemical breakdown of hydralazine or its known metabolites in urine and therefore was unlikely to be a urinary artefact formed by chemical decomposition in the urine.

Acetylation↗

PubMed1979

Kinetic studies of hydralazine reaction with acetaldehyde.

In vitro kinetic studies of the reaction of hydralazine with acetaldehyde at physiological concentrations and pH were conducted. This reaction, which leads to the formation of 3-methyl-S-triazolo[3,4-a]phthalazine, may occur in the plasma and may represent an alternative pathway for hydralazine metabolism. The reaction of hydralazine with acetaldehyde followed second-order kinetics with an activation energy of 16.9 kcal/mole. At 37 degrees, the half-life of the reaction for a colution containing 2.3 microgram of acetaldehyde/ml and 1 microgram of hydralazine/ml was 4.5 hr. The rate increased with increasing acetaldehyde concentrations.

Acetaldehyde↗

PubMed1979

Genetic effects of hydralazine.

Hydralazine and its acetone condensation product (ACP) were found to induce base-pair substitution mutations in the Salmonella/microsomal activation test system and to display genetic toxicity in the PolA+/A- test system. Incubation with a rat-liver microsomal fraction did not affect the genetic toxicity of either compound. Other derivatives of hydralazine, including the major metabolite, 3-hydroxy-methyl-s-triazolo-[3,4a]phthalazine, did not yield any evidence of genetic toxicity nor were they metabolically convertible to a toxic product. Therefore, individuals who convert hydralazine to MTP slowly, the "slow acetylators", would be expected to be at risk.

Drug Evaluation, Preclinical↗