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Current Hypertension Reports Aug 2017Preeclampsia is characterized by blood pressure greater than 140/90 mmHg in the second half of pregnancy. This disease is a major contributor to preterm and low birth... (Review)
Review
Preeclampsia is characterized by blood pressure greater than 140/90 mmHg in the second half of pregnancy. This disease is a major contributor to preterm and low birth weight babies. The early delivery of the baby, which becomes necessary for maintaining maternal well-being, makes preeclampsia the leading cause for preterm labor and infant mortality and morbidity. Currently, there is no cure for this pregnancy disorder. The current clinical management of PE is hydralazine with labetalol and magnesium sulfate to slow disease progression and prevent maternal seizure, and hopefully prolong the pregnancy. This review will highlight factors implicated in the pathophysiology of preeclampsia and current treatments for the management of this disease.
Topics: Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Delivery, Obstetric; Endothelium, Vascular; Female; Humans; Hydralazine; Infant, Low Birth Weight; Infant, Newborn; Inflammation; Ischemia; Labetalol; Magnesium Sulfate; Placenta; Pre-Eclampsia; Pregnancy; Premature Birth
PubMed: 28689331
DOI: 10.1007/s11906-017-0757-7 -
Pediatric Nephrology (Berlin, Germany) May 2019Neonatal hypertension is increasingly recognized as dramatic improvements in neonatal intensive care, advancements in our understanding of neonatal physiology, and... (Review)
Review
Neonatal hypertension is increasingly recognized as dramatic improvements in neonatal intensive care, advancements in our understanding of neonatal physiology, and implementation of new therapies have led to improved survival of premature infants. A variety of factors appear to be important in determining blood pressure in neonates, including gestational age, birth weight, and postmenstrual age. Normative data on neonatal blood pressure values remain limited. The cause of hypertension in an affected neonate is often identified with careful diagnostic evaluation, with the most common causes being umbilical catheter-associated thrombosis, renal parenchymal disease, and chronic lung disease. Clinical expertise may need to be relied upon to decide the best approach to treatment in such patients, as data on the use of antihypertensive medications in this age group are extremely limited. Available data suggest that long-term outcomes are usually good, with resolution of hypertension in most infants. In this review, we will take a case-based approach to illustrate these concepts and to point out important evidence gaps that need to be addressed so that management of neonatal hypertension may be improved.
Topics: Administration, Intravenous; Antihypertensive Agents; Birth Weight; Blood Pressure; Blood Pressure Determination; Clinical Decision-Making; Gestational Age; Humans; Hydralazine; Hypertension; Incidence; Infant, Newborn; Infant, Newborn, Diseases; Infant, Premature; Intensive Care Units, Neonatal; Kidney; Labetalol; Neuroblastoma; Reference Values; Renal Artery Obstruction; Severity of Illness Index; Treatment Outcome
PubMed: 29808264
DOI: 10.1007/s00467-018-3977-4 -
American Journal of Nephrology 2020Despite its approval in 1953, hydralazine hydrochloride continues to be used in the management of resistant hypertension, a condition frequently managed by nephrologists... (Review)
Review
BACKGROUND
Despite its approval in 1953, hydralazine hydrochloride continues to be used in the management of resistant hypertension, a condition frequently managed by nephrologists and other clinicians. Hydralazine hydrochloride undergoes metabolism by the N-acetyltransferase 2 (NAT2) enzyme. NAT2 is highly polymorphic as approximately 50% of the general population are slow acetylators. In this review, we first evaluate the link between NAT2 genotype and phenotype. We then assess the evidence available for genotype-guided therapy of hydralazine, specifically addressing associations of NAT2 acetylator status with hydralazine pharmacokinetics, antihypertensive efficacy, and toxicity.
SUMMARY
There is a critical need to use hydralazine in some patients with resistant hypertension. Available evidence supports a significant link between genotype and NAT2 enzyme activity as 29 studies were identified with an overall concordance between genotype and phenotype of 92%. The literature also supports an association between acetylator status and hydralazine concentration, as fourteen of fifteen identified studies revealed significant relationships with a consistent direction of effect. Although fewer studies are available to directly link acetylator status with hydralazine antihypertensive efficacy, the evidence from this smaller set of studies is significant in 7 of 9 studies identified. Finally, 5 studies were identified which support the association of acetylator status with hydralazine-induced lupus. Clinicians should maintain vigilance when prescribing maximum doses of hydralazine. Key Messages: NAT2 slow acetylator status predicts increased hydralazine levels, which may lead to increased efficacy and adverse effects. Caution should be exercised in slow acetylators with total daily hydralazine doses of 200 mg or more. Fast acetylators are at risk for inefficacy at lower doses of hydralazine. With appropriate guidance on the usage of NAT2 genotype, clinicians can adopt a personalized approach to hydralazine dosing and prescription, enabling more efficient and safe treatment of resistant hypertension.
Topics: Antihypertensive Agents; Arylamine N-Acetyltransferase; Dose-Response Relationship, Drug; Drug Resistance; Humans; Hydralazine; Hypertension; Nephrology; Pharmacogenomic Testing; Pharmacogenomic Variants; Practice Guidelines as Topic; Precision Medicine; Treatment Outcome
PubMed: 32927458
DOI: 10.1159/000510433 -
F1000Research 2022: Preeclampsia is a highly prevalent disease among pregnant women. In the event of hypertensive emergency, nifedipine, labetalol, and hydralazine are assigned as... (Randomized Controlled Trial)
Randomized Controlled Trial
: Preeclampsia is a highly prevalent disease among pregnant women. In the event of hypertensive emergency, nifedipine, labetalol, and hydralazine are assigned as first-line therapies in preeclampsia. Further studies are needed to compare the effectiveness of these drugs to find the most cost-effective drug with minimal side effects. This study aimed to compare the effectiveness of these drugs in lowering blood pressure during hypertensive emergencies in severe preeclampsia. : 60 pregnant women with severe preeclampsia were recruited in this multiple centre double-blind randomized clinical trial from May 2021 to April 2022 in Indonesia. The patients were divided equally into three groups and treated with three doses of nifedipine, labetalol, and hydralazine, respectively within one hour with 20 minutes interval. The effectiveness was measured based on systolic and diastolic blood pressures, and mean arterial pressure (MAP). The observation was carried out until five hours post-third dose administration. : The blood pressure was reduced significantly after the administration of the first to the third dose of each antihypertensive (p<0.05). A single dose administration, four, one, and three patients had 20% MAP reduction in nifedipine, labetalol, and hydralazine group. Three, seven, and one patient had a failure of reaching 20% MAP reduction even after receiving the third dose. The effectiveness of the drugs to achieve 20% reduction of MAP could be ranked as follows: nifedipine>labetalol>hydralazine (57.49%, 42.13%, and 40.87%, respectively) for single dose and hydralazine>nifedipine>labetalol (111.3%, 85.12%, and 90.04%, respectively) for triple dose. : Nifedipine is the most effective drug to reduce the blood pressure when single dose administration is used, but requires more doses to further reduce the blood pressure. Hydralazine is the most effective when the drug administration is maxed up to three doses within 60 minutes with 20 minutes interval. TCTR20221014007 (14/10/2022).
Topics: Female; Humans; Pregnancy; Labetalol; Nifedipine; Pre-Eclampsia; Antihypertensive Agents; Hydralazine
PubMed: 37273965
DOI: 10.12688/f1000research.125944.2 -
The New England Journal of Medicine Nov 2004We examined whether a fixed dose of both isosorbide dinitrate and hydralazine provides additional benefit in blacks with advanced heart failure, a subgroup previously... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
BACKGROUND
We examined whether a fixed dose of both isosorbide dinitrate and hydralazine provides additional benefit in blacks with advanced heart failure, a subgroup previously noted to have a favorable response to this therapy.
METHODS
A total of 1050 black patients who had New York Heart Association class III or IV heart failure with dilated ventricles were randomly assigned to receive a fixed dose of isosorbide dinitrate plus hydralazine or placebo in addition to standard therapy for heart failure. The primary end point was a composite score made up of weighted values for death from any cause, a first hospitalization for heart failure, and change in the quality of life.
RESULTS
The study was terminated early owing to a significantly higher mortality rate in the placebo group than in the group given isosorbide dinitrate plus hydralazine (10.2 percent vs. 6.2 percent, P=0.02). The mean primary composite score was significantly better in the group given isosorbide dinitrate plus hydralazine than in the placebo group (-0.1+/-1.9 vs. -0.5+/-2.0, P=0.01; range of possible values, -6 to +2), as were its individual components (43 percent reduction in the rate of death from any cause [hazard ratio, 0.57; P=0.01] 33 percent relative reduction in the rate of first hospitalization for heart failure [16.4 percent vs. 22.4 percent, P=0.001], and an improvement in the quality of life [change in score, -5.6+/-20.6 vs. -2.7+/-21.2, with lower scores indicating better quality of life; P=0.02; range of possible values, 0 to 105]).
CONCLUSIONS
The addition of a fixed dose of isosorbide dinitrate plus hydralazine to standard therapy for heart failure including neurohormonal blockers is efficacious and increases survival among black patients with advanced heart failure.
Topics: Adult; Aged; Black People; Double-Blind Method; Drug Combinations; Drug Therapy, Combination; Female; Heart Failure; Humans; Hydralazine; Isosorbide Dinitrate; Male; Middle Aged; Nitric Oxide Donors; Quality of Life; Survival Analysis; Treatment Outcome; Vasodilator Agents
PubMed: 15533851
DOI: 10.1056/NEJMoa042934 -
Journal of Clinical Hypertension... Sep 2011KEY POINTS AND PRACTICAL RECOMMENDATIONS: • Hydralazine and minoxidil act by dilating resistance arterioles, thus reducing peripheral resistance, with no dilating... (Review)
Review
KEY POINTS AND PRACTICAL RECOMMENDATIONS: • Hydralazine and minoxidil act by dilating resistance arterioles, thus reducing peripheral resistance, with no dilating effect on the venous side of the circulation. • There is a baroreflex-mediated venoconstriction, resulting in an increase in venous return to the heart, along with a direct catecholamine-mediated positive inotropic and chronotropic stimulation of the heart. • Hydralazine therapy is usually combined with a sympathetic inhibitor to prevent expression of this reflex, as well as with a diuretic agent to prevent sodium retention caused by reduction in renal perfusion pressure. • Hydralazine is indicated in the long-term therapy of essential hypertension, in the short-term therapy of pregnancy-induced hypertension and eclampsia, and in the therapy of hypertensive crisis. • Adverse effects include the anticipated tachycardia, fluid retention, and headache, caused by the vasodilation, especially in the early days of therapy, but may frequently be prevented by the concomitant use of a β-blocker. • As with other drugs that are N-acetylated, there is a low risk of lupus-like syndrome with high doses and long-term use. • Because of the severity of adverse effects with minoxidil, its usage is limited to persons with severe hypertension unresponsive to other treatments. • Hirsutism, a common side effect of minoxidil, is particularly bothersome in women and reverses in a few months after discontinuation. • Sodium nitroprusside is used in the intensive care setting to lower pressure in hypertensive crisis or to treat severe left ventricular failure, particularly valuable when elevated pressure or severe left ventricular failure threatens the patient's survival. • Although nitrates have not achieved widespread use as antihypertensive agents, they are effective in producing sustained blood pressure (BP) reductions when added to other antihypertensive regimens.
Topics: Antihypertensive Agents; Hirsutism; Humans; Hydralazine; Hypertension; Minoxidil; Tachycardia; Treatment Outcome; Vasodilator Agents
PubMed: 21896152
DOI: 10.1111/j.1751-7176.2011.00507.x -
Diabetes, Obesity & Metabolism Oct 2022To determine, using a mouse model of obesity, whether low-dose hydralazine prevents obesity-related chronic kidney disease (CKD).
AIM
To determine, using a mouse model of obesity, whether low-dose hydralazine prevents obesity-related chronic kidney disease (CKD).
METHODS
From 8 weeks of age, male C57BL/6 mice received a high-fat diet (HFD) or chow, with or without low-dose hydralazine (25 mg/L) in drinking water, for 24 weeks. Biometric and metabolic variables, renal function and structural changes, renal global DNA methylation, DNA methylation profile and markers of renal fibrosis, injury, inflammation and oxidative stress were assessed.
RESULTS
The HFD-fed mice developed obesity, with glucose intolerance, hyperinsulinaemia and dyslipidaemia. Obesity increased albuminuria and glomerulosclerosis, which were significantly ameliorated by low-dose hydralazine in the absence of a blood pressure-lowering effect. Obesity increased renal global DNA methylation and this was attenuated by low-dose hydralazine. HFD-induced changes in methylation of individual loci were also significantly reversed by low-dose hydralazine. Obese mice demonstrated increased markers of kidney fibrosis, inflammation and oxidative stress, but these markers were not significantly improved by hydralazine.
CONCLUSION
Low-dose hydralazine ameliorated HFD-induced albuminuria and glomerulosclerosis, independent of alterations in biometric and metabolic variables or blood pressure regulation. Although the precise mechanism of renoprotection in obesity is unclear, an epigenetic basis may be implicated. These data support repurposing hydralazine as a novel therapy to prevent CKD progression in obese patients.
Topics: Albuminuria; Animals; Diet, High-Fat; Disease Models, Animal; Fibrosis; Hydralazine; Inflammation; Kidney; Male; Mice; Mice, Inbred C57BL; Obesity; Renal Insufficiency, Chronic
PubMed: 35635331
DOI: 10.1111/dom.14778 -
Journal of the American Heart... Feb 2023Background Recent studies have suggested that cardiac nitrosative stress mediated by pathological overproduction of nitric oxide (NO) via inducible NO synthase (iNOS)...
Background Recent studies have suggested that cardiac nitrosative stress mediated by pathological overproduction of nitric oxide (NO) via inducible NO synthase (iNOS) contributes to the pathogenesis of heart failure with preserved ejection fraction (HFpEF). Other studies have suggested that endothelial NO synthase (eNOS) dysfunction and attenuated NO bioavailability contribute to HFpEF morbidity and mortality. We sought to further investigate dysregulated NO signaling and to examine the effects of a NO-based dual therapy (sodium nitrite+hydralazine) following the onset of HFpEF using a "2-hit" murine model. Methods and Results Nine-week-old male C57BL/6 N mice (n=15 per group) were treated concurrently with high-fat diet and N(ω)-nitro-L-arginine methyl ester (L-NAME) (0.5 g/L per day) via drinking water for 10 weeks. At week 5, mice were randomized into either vehicle (normal saline) or combination treatment with sodium nitrite (75 mg/L in the drinking water) and hydralazine (2.0 mg/kg IP, BID). Cardiac structure and function were monitored with echocardiography and invasive hemodynamic measurements. Cardiac mitochondrial respiration, aortic vascular function, and exercise performance were also evaluated. Circulating and myocardial nitrite were measured to determine the bioavailability of NO. Circulating markers of oxidative or nitrosative stress as well as systemic inflammation were also determined. Severe HFpEF was evident by significantly elevated E/E', LVEDP, and Tau in mice treated with L-NAME and HFD, which was associated with impaired NO bioavailability, mitochondrial respiration, aortic vascular function, and exercise capacity. Treatment with sodium nitrite and hydralazine restored NO bioavailability, reduced oxidative and nitrosative stress, preserved endothelial function and mitochondrial respiration, limited the fibrotic response, and improved exercise capacity, ultimately attenuating the severity of "two-hit" HFpEF. Conclusions Our data demonstrate that nitrite, a well-established biomarker of NO bioavailability and a physiological source of NO, is significantly reduced in the heart and circulation in the "2-hit" mouse HFpEF model. Furthermore, sodium nitrite+hydralazine combined therapy significantly attenuated the severity of HFpEF in the "2-hit" cardiometabolic HFpEF. These data suggest that supplementing NO-based therapeutics with a potent antioxidant and vasodilator agent may result in synergistic benefits for the treatment of HFpEF.
Topics: Mice; Male; Animals; Heart Failure; Sodium Nitrite; Stroke Volume; NG-Nitroarginine Methyl Ester; Disease Models, Animal; Drinking Water; Mice, Inbred C57BL; Hydralazine; Nitric Oxide Synthase
PubMed: 36752224
DOI: 10.1161/JAHA.122.028480 -
The Cochrane Database of Systematic... Feb 2013Most deaths of infants with chronic lung disease (CLD) are caused by respiratory failure, unremitting pulmonary artery hypertension (PAH) with cor pulmonale, or... (Review)
Review
BACKGROUND
Most deaths of infants with chronic lung disease (CLD) are caused by respiratory failure, unremitting pulmonary artery hypertension (PAH) with cor pulmonale, or infection. Although the exact prevalence of PAH in infants with CLD is unknown, infants with CLD and severe PAH have a high mortality rate. Except for oxygen supplementation, no specific interventions have been established as effective in the treatment for PAH in premature infants with CLD. Little has been proven regarding the clinical efficacy of vasodilators and concerns remain regarding adverse effects.
OBJECTIVES
To review current evidence for the benefits and harms of hydralazine therapy to infants with persistent hypoxemic respiratory failure.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE via PubMed and EMBASE, and other clinical trials registries through November 2011 using the standard search strategy of the Cochrane Neonatal Review Group. We searched these databases using a strategy combining a variation of the Cochrane highly sensitive search strategy for identifying randomised trials in MEDLINE; sensitivity-maximising version with selected MeSH and free-text terms: hydralazine, vasodilator agent, antihypertensive agent, heart diseases, lung diseases, respiratory tract diseases, infant, and randomised controlled trial.
SELECTION CRITERIA
We considered only randomised controlled trials and quasi-randomised trials for inclusion. We included low birth weight (LBW) infants with persistent hypoxemic respiratory failure who were treated with any type of hydralazine therapy.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed trial quality according to pre-specified criteria.
MAIN RESULTS
We found no studies meeting the criteria for inclusion in this review.
AUTHORS' CONCLUSIONS
There was insufficient evidence to determine the safety and efficacy of hydralazine in LBW infants with persistent hypoxemic respiratory failure. Since hydralazine is inexpensive and potentially beneficial, randomised controlled trials are recommended. Such trials are particularly needed in settings where other medications such as sildenafil, inhaled nitric oxide (iNO), or extracorporeal membrane oxygenation (ECMO) are not available.
Topics: Antihypertensive Agents; Humans; Hydralazine; Hypoxia; Infant; Infant, Newborn; Infant, Premature; Respiratory Insufficiency; Vasodilator Agents
PubMed: 23450605
DOI: 10.1002/14651858.CD009449.pub2 -
Cardiovascular Drugs and Therapy Apr 2023Hydralazine, doxazosin, and verapamil are currently recommended by the Endocrine Society as acceptable bridging treatment in those in whom full cessation of...
PURPOSE
Hydralazine, doxazosin, and verapamil are currently recommended by the Endocrine Society as acceptable bridging treatment in those in whom full cessation of antihypertensive medication is infeasible during screening for primary aldosteronism (PA). This is under the assumption that they cause minimal to no effect on the aldosterone-to-renin ratio, the most widely used screening test for PA. However, limited evidence is available regarding the effects of these particular drugs on said ratio.
METHODS
In the present study, we retrospectively assessed the changes in aldosterone, renin, and aldosterone-to-renin values in essential hypertensive participants before and after treatment with either hydralazine (n = 26) or doxazosin (n = 20) or verapamil (n = 15). All samples were taken under highly standardized conditions.
RESULTS
Hydralazine resulted in a borderline significant rise in active plasma renin concentration (19 vs 25 mIU/L, p = 0.067) and a significant fall in the aldosterone-to-renin ratio (38 vs 24, p = 0.017). Doxazosin caused declines in both plasma aldosterone concentration (470 vs 330 pmol/L, p = 0.028) and the aldosterone-to-renin ratio (30 vs 20, p = 0.020). With respect to verapamil, we found no statistically significant effect on any of these outcome variables.
CONCLUSION
We conclude that the assumption that these drugs can be used with little consequence to the aldosterone-to-renin cannot be substantiated. While it is possible that they are indeed the best option when full antihypertensive drug cessation is infeasible, the potential effects of these drugs must still be taken into account when interpreting the aldosterone-to-renin ratio.
Topics: Humans; Aldosterone; Renin; Doxazosin; Hyperaldosteronism; Verapamil; Retrospective Studies; Hypertension; Antihypertensive Agents; Hydralazine
PubMed: 34515895
DOI: 10.1007/s10557-021-07262-3