Hydralazine

Last updated

Hydralazine
Hydralazine.svg
Hydralazine-based-on-xtals-3D-bs-17.png
Clinical data
Trade names Apresoline, BiDil, others
AHFS/Drugs.com Monograph
MedlinePlus a682246
License data
Pregnancy
category
  • AU:C
Routes of
administration 		By mouth, intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 26–50%
Protein binding 85–90%
Metabolism Liver
Onset of action 5 to 30 min [2]
Elimination half-life 2–8 hours, 7–16 hours (renal impairment)
Duration of action 2 to 6 hrs [2]
Excretion Urine
Identifiers
  • 1-hydrazinylphthalazine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.001.528 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C8H8N4
Molar mass 160.180 g·mol−1
3D model (JSmol)
  • NNc1c2ccccc2cnn1
  • InChI=1S/C8H8N4/c9-11-8-7-4-2-1-3-6(7)5-10-12-8/h1-5H,9H2,(H,11,12) Yes check.svgY
  • Key:RPTUSVTUFVMDQK-UHFFFAOYSA-N Yes check.svgY
   (verify)

Hydralazine, sold under the brand name Apresoline among others, is a medication used to treat high blood pressure and heart failure. [2] This includes high blood pressure in pregnancy and very high blood pressure resulting in symptoms. [3] It has been found to be particularly useful in heart failure, together with isosorbide dinitrate, for treatment of people of African descent. [2] It is given by mouth or by injection into a vein. [3] Effects usually begin around 15 minutes and last up to six hours. [2]

Contents

Common side effects include headache and fast heart rate. [2] It is not recommended in people with coronary artery disease or in those with rheumatic heart disease that affects the mitral valve. [2] In those with kidney disease a low dose is recommended. [3] Hydralazine is in the vasodilator family of medications, so it is believed to work by causing the dilation of blood vessels. [2]

Hydralazine was discovered while scientists at Ciba were looking for a treatment for malaria. [4] It was patented in 1949. [5] It is on the World Health Organization's List of Essential Medicines. [6] In 2022, it was the 121st most commonly prescribed medication in the United States, with more than 5 million prescriptions. [7] [8]

Medical use

Hydralazine is not used as a primary drug for treating hypertension because it elicits a reflex sympathetic stimulation of the heart (the baroreceptor reflex). [9] The sympathetic stimulation may increase heart rate and cardiac output, and in people with coronary artery disease may cause angina pectoris or myocardial infarction. [10] Hydralazine may also increase plasma renin concentration, resulting in fluid retention. To prevent these undesirable side effects, hydralazine is usually prescribed in combination with a beta blocker (e.g., propranolol) and a diuretic. [10]

Hydralazine is used to treat severe hypertension, but is not a first-line therapy for essential hypertension. Hydralazine is often used to treat hypertension in pregnancy, though, with either labetalol and/or methyldopa. [11]

Hydralazine is commonly used in combination with isosorbide dinitrate for the treatment of congestive heart failure in black populations. This preparation, isosorbide dinitrate/hydralazine, was the first race-based prescription drug. [12]

It should not be used in people who have tachycardia, heart failure, constrictive pericarditis, lupus, a dissecting aortic aneurysm, or porphyria. [13]

Adverse effects

Prolonged treatment may cause a syndrome similar to lupus, which can become fatal if the symptoms are not noticed and drug treatment stopped. [13] Hydralazine is within the top three drugs that is known to induce systemic lupus and this adverse drug event is dose dependent yet significant.

Very common (>10% frequency) side effects include headache, tachycardia, and palpitations. [13]

Common (1–10% frequency) side effects include flushing, hypotension, anginal symptoms, aching or swelling joints, muscle aches, positive tests for atrial natriuretic peptide, stomach upset, diarrhea, nausea and vomiting, and swelling (sodium and water retention). [13]

Interactions

It may potentiate the antihypertensive effects of: [13]

Drugs subject to a strong first-pass effect such as beta blockers may increase the bioavailability of hydralazine. [13] The heart rate-accelerating effects of epinephrine (adrenaline) are increased by hydralazine, and coadministration may lead to toxicity. [13]

Mechanism of action

Hydralazine is a direct-acting smooth muscle relaxant and acts as a vasodilator primarily in resistance arterioles, also known as the smooth muscle of the arterial bed. The molecular mechanism involves inhibition of inositol trisphosphate-induced Ca2+ release from the sarcoplasmic reticulum in arterial smooth muscle cells. [14] [15] By relaxing vascular smooth muscle, vasodilators act to decrease peripheral resistance, thereby lowering blood pressure and decreasing afterload. [10] The exact mechanism of action of hydralazine is unknown, at least as of 1981. [16]

Metabolic products include the N-acetyl derivative, pyruvic acid hydrazone, and acetone hydrazone, each of which may also contribute to reducing blood pressure. [17]

Chemistry

Hydralazine belongs to the hydrazinophthalazine class of drugs. [18]

History

The antihypertensive activity of hydralazine was discovered by scientists at Ciba, who were trying to discover drugs to treat malaria; it was initially called C-5968 and 1-hydrazinophthalazine; Ciba's patent application was filed in 1945 and issued in 1949, [19] [20] [21] and the first scientific publications of its blood pressure-lowering activities appeared in 1950. [4] [18] [22] It was approved by the FDA in 1953. [23]

It was one of the first antihypertensive medications that could be taken by mouth. [9]

Research

Hydralazine has also been studied as a treatment for myelodysplastic syndrome in its capacity as a DNA methyltransferase inhibitor. [24]

Related Research Articles

<span class="mw-page-title-main">ACE inhibitor</span> Class of medications used primarily to treat high blood pressure

Angiotensin-converting-enzyme inhibitors are a class of medication used primarily for the treatment of high blood pressure and heart failure. This class of medicine works by causing relaxation of blood vessels as well as a decrease in blood volume, which leads to lower blood pressure and decreased oxygen demand from the heart.

<span class="mw-page-title-main">Hypertension</span> Long-term high blood pressure in the arteries

Hypertension, also known as high blood pressure, is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms itself. It is, however, a major risk factor for stroke, coronary artery disease, heart failure, atrial fibrillation, peripheral arterial disease, vision loss, chronic kidney disease, and dementia. Hypertension is a major cause of premature death worldwide.

<span class="mw-page-title-main">Beta blocker</span> Medications for abnormal heart rhythms

Beta blockers, also spelled β-blockers, are a class of medications that are predominantly used to manage abnormal heart rhythms (arrhythmia), and to protect the heart from a second heart attack after a first heart attack. They are also widely used to treat high blood pressure, although they are no longer the first choice for initial treatment of most people.

<span class="mw-page-title-main">Vasodilation</span> Widening of blood vessels

Vasodilation, also known as vasorelaxation, is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. Blood vessel walls are composed of endothelial tissue and a basal membrane lining the lumen of the vessel, concentric smooth muscle layers on top of endothelial tissue, and an adventitia over the smooth muscle layers. Relaxation of the smooth muscle layer allows the blood vessel to dilate, as it is held in a semi-constricted state by sympathetic nervous system activity. Vasodilation is the opposite of vasoconstriction, which is the narrowing of blood vessels.

<span class="mw-page-title-main">Hydrochlorothiazide</span> Diuretic medication

Hydrochlorothiazide, sold under the brand name Hydrodiuril among others, is a diuretic medication used to treat hypertension and swelling due to fluid build-up. Other uses include treating diabetes insipidus and renal tubular acidosis and to decrease the risk of kidney stones in those with a high calcium level in the urine. Hydrochlorothiazide is taken by mouth and may be combined with other blood pressure medications as a single pill to increase effectiveness. Hydrochlorothiazide is a thiazide medication which inhibits reabsorption of sodium and chloride ions from the distal convoluted tubules of the kidneys, causing a natriuresis. This initially increases urine volume and lowers blood volume. It is believed to reduce peripheral vascular resistance.

Antihypertensives are a class of drugs that are used to treat hypertension. Antihypertensive therapy seeks to prevent the complications of high blood pressure, such as stroke, heart failure, kidney failure and myocardial infarction. Evidence suggests that reduction of the blood pressure by 5 mmHg can decrease the risk of stroke by 34% and of ischaemic heart disease by 21%, and can reduce the likelihood of dementia, heart failure, and mortality from cardiovascular disease. There are many classes of antihypertensives, which lower blood pressure by different means. Among the most important and most widely used medications are thiazide diuretics, calcium channel blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers or antagonists (ARBs), and beta blockers.

<span class="mw-page-title-main">Atenolol</span> Beta blocker medication

Atenolol is a beta blocker medication primarily used to treat high blood pressure and heart-associated chest pain. Although used to treat high blood pressure, it does not seem to improve mortality in those with the condition. Other uses include the prevention of migraines and treatment of certain irregular heart beats. It is taken orally or by intravenous injection. It can also be used with other blood pressure medications.

<span class="mw-page-title-main">Indapamide</span> Thiazide-like diuretic drug

Indapamide is a thiazide-like diuretic drug used in the treatment of hypertension, as well as decompensated heart failure. Combination preparations with perindopril are available. The thiazide-like diuretics reduce risk of major cardiovascular events and heart failure in hypertensive patients compared with hydrochlorothiazide with a comparable incidence of adverse events. Both thiazide diuretics and thiazide-like diuretics are effective in reducing risk of stroke. Both drug classes appear to have comparable rates of adverse effects as other antihypertensives such as angiotensin II receptor blockers and dihydropyridine calcium channel blockers and lesser prevalence of side-effects when compared to ACE-inhibitors and non-dihydropyridine calcium channel blockers.

<span class="mw-page-title-main">Isosorbide dinitrate</span> Chemical compound

Isosorbide dinitrate is a medication used for heart failure, esophageal spasms, and to treat and prevent chest pain from not enough blood flow to the heart. It has been found to be particularly useful in heart failure due to systolic dysfunction together with hydralazine. It is taken by mouth or under the tongue.

<span class="mw-page-title-main">Methyldopa</span> Medication used to treat high blood pressure

Methyldopa, also known as α-methyl-L-DOPA and sold under the brand name Aldomet among others, is a medication used for high blood pressure. It is one of the preferred treatments for high blood pressure in pregnancy. For other types of high blood pressure including very high blood pressure resulting in symptoms other medications are typically preferred. It can be given by mouth or injection into a vein. Onset of effects is around 5 hours and they last about a day.

<span class="mw-page-title-main">Isosorbide mononitrate</span> Chemical compound

Isosorbide mononitrate, sold under many brand names, is a medication used for heart-related chest pain (angina), heart failure and esophageal spasms. It can be used both to treat and to prevent heart-related chest pain; however, it is generally less preferred than beta blockers or calcium channel blockers. It is taken by mouth.

<span class="mw-page-title-main">PDE5 inhibitor</span> Vasodilating drug

A phosphodiesterase type 5 inhibitor is a vasodilating drug that works by blocking the degradative action of cGMP-specific phosphodiesterase type 5 (PDE5) on cyclic GMP in the smooth muscle cells lining the blood vessels supplying various tissues. These drugs dilate the corpora cavernosa of the penis, facilitating erection with sexual stimulation, and are used in the treatment of erectile dysfunction (ED). Sildenafil was the first effective oral treatment available for ED. Because PDE5 is also present in the smooth muscle of the walls of the arterioles within the lungs, two PDE5 inhibitors, sildenafil and tadalafil, are FDA-approved for the treatment of pulmonary hypertension. As of 2019, the wider cardiovascular benefits of PDE5 inhibitors are being appreciated.

Alpha-1 blockers constitute a variety of drugs that block the effect of catecholamines on alpha-1-adrenergic receptors. They are mainly used to treat benign prostatic hyperplasia (BPH), hypertension and post-traumatic stress disorder. Alpha-1-adrenergic receptors are present in vascular smooth muscle, the central nervous system, and other tissues. When alpha blockers bind to these receptors in vascular smooth muscle, they cause vasodilation.

<span class="mw-page-title-main">Hypertensive emergency</span> Very high blood pressure and signs of organ damage

A hypertensive emergency is very high blood pressure with potentially life-threatening symptoms and signs of acute damage to one or more organ systems. It is different from a hypertensive urgency by this additional evidence for impending irreversible hypertension-mediated organ damage (HMOD). Blood pressure is often above 200/120 mmHg, however there are no universally accepted cutoff values.

<span class="mw-page-title-main">Carvedilol</span> Blood pressure medication

Carvedilol, sold under the brand name Coreg among others, is a beta blocker medication, that may be prescribed for the treatment of high blood pressure (hypertension) and chronic heart failure with reduced ejection fraction. Beta-blockers as a collective medication class are not recommended as routine first-line treatment of high blood pressure for all patients, due to evidence demonstrating less effective cardiovascular protection and a less favourable safety profile when compared to other classes of blood pressure-lowering medications.

Hydralazine/isosorbide dinitrate, sold under the brand name Bidil, is a fixed-dose combination medication used to treat self-identified Black people with congestive heart failure. It is a combination of hydralazine hydrochloride and isosorbide dinitrate.

<span class="mw-page-title-main">Drug-induced lupus erythematosus</span> Medical condition

Drug-induced lupus erythematosus is an autoimmune disorder caused by chronic use of certain drugs. These drugs cause an autoimmune response producing symptoms similar to those of systemic lupus erythematosus (SLE). There are 38 known medications to cause DIL but there are three that report the highest number of cases: hydralazine, procainamide, and quinidine. While the criteria for diagnosing DIL has not been thoroughly established, symptoms of DIL typically present as muscle pain and joint pain. Generally, the symptoms recede after discontinuing use of the drugs.

<span class="mw-page-title-main">Hydrazinophthalazine</span> Drug class

Hydrazinophthalazines are a class of antihypertensive drugs characterized by a phthalazine ring system with a hydrazine group attached. The most notable member of this class is hydralazine, a medication used to treat high blood pressure and heart failure. Hydrazinophthalazines act as direct-acting smooth muscle relaxants, primarily affecting resistance arterioles to cause vasodilation. This pharmacological action results in decreased peripheral resistance and lowered blood pressure. While hydralazine is the most well-known compound in this class, other related drugs such as dihydralazine also belong to the hydrazinophthalazine family and exhibit similar antihypertensive properties. These compounds have been in clinical use since the mid-20th century, with hydralazine being discovered in the 1940s and approved by the FDA in 1953.

Orthostatic syncope refers to syncope resulting from a postural decrease in blood pressure, termed orthostatic hypotension.

The modern history of hypertension begins with the understanding of the cardiovascular system based on the work of physician William Harvey (1578–1657), who described the circulation of blood in his book De motu cordis. The English clergyman Stephen Hales made the first published measurement of blood pressure in 1733. Descriptions of what would come to be called hypertension came from, among others, Thomas Young in 1808 and especially Richard Bright in 1836. Bright noted a link between cardiac hypertrophy and kidney disease, and subsequently kidney disease was often termed Bright's disease in this period. In 1850 George Johnson suggested that the thickened blood vessels seen in the kidney in Bright's disease might be an adaptation to elevated blood pressure. William Senhouse Kirkes in 1855 and Ludwig Traube in 1856 also proposed, based on pathological observations, that elevated pressure could account for the association between left ventricular hypertrophy to kidney damage in Bright's disease. Samuel Wilks observed that left ventricular hypertrophy and diseased arteries were not necessarily associated with diseased kidneys, implying that high blood pressure might occur in people with healthy kidneys; however, the first report of elevated blood pressure in a person without evidence of kidney disease was made by Frederick Akbar Mahomed in 1874 using a sphygmograph. The concept of hypertensive disease as a generalized circulatory disease was taken up by Sir Clifford Allbutt, who termed the condition "hyperpiesia". However, hypertension as a medical entity really came into being in 1896 with the invention of the cuff-based sphygmomanometer by Scipione Riva-Rocci in 1896, which allowed blood pressure to be measured in the clinic. In 1905, Nikolai Korotkoff improved the technique by describing the Korotkoff sounds that are heard when the artery is ausculted with a stethoscope while the sphygmomanometer cuff is deflated. Tracking serial blood pressure measurements was further enhanced when Donal Nunn invented an accurate fully automated oscillometric sphygmomanometer device in 1981.

References

  1. ↑ "Prescription medicines: registration of new generic medicines and biosimilar medicines, 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 30 March 2024.
  2. 1 2 3 4 5 6 7 8 "Hydralazine Hydrochloride". The American Society of Health-System Pharmacists. Archived from the original on 21 December 2016. Retrieved 8 December 2016.
  3. 1 2 3 World Health Organization (2009). Stuart MC, Kouimtzi M, Hill SR (eds.). WHO Model Formulary 2008. World Health Organization. p. 280. hdl: 10665/44053 . ISBN   9789241547659.
  4. 1 2 Wermuth CG (2 May 2011). The Practice of Medicinal Chemistry. Academic Press. p. 12. ISBN   9780080568775. Archived from the original on 26 February 2017.
  5. ↑ Progress in Drug Research/Fortschritte der Arzneimittelforschung/Progrés des recherches pharmaceutiques. Birkhäuser. 2013. p. 206. ISBN   9783034870948. Archived from the original on 20 December 2016.
  6. ↑ World Health Organization (2023). The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. hdl: 10665/371090 . WHO/MHP/HPS/EML/2023.02.
  7. ↑ "The Top 300 of 2022". ClinCalc. Archived from the original on 30 August 2024. Retrieved 30 August 2024.
  8. ↑ "Hydralazine Drug Usage Statistics, United States, 2013 - 2022". ClinCalc. Retrieved 30 August 2024.
  9. 1 2 Kandler MR, Mah GT, Tejani AM, Stabler SN, Salzwedel DM (November 2011). "Hydralazine for essential hypertension". The Cochrane Database of Systematic Reviews (11): CD004934. doi:10.1002/14651858.CD004934.pub4. PMID   22071816.
  10. 1 2 3 Harvey RA, Harvey PA, Mycek MJ (2000). Lippincott's Illustrated Reviews: Pharmacology (2nd ed.). Philadelphia: Lippincott Williams & Wilkins. p. 190.
  11. ↑ Bhushan V, Lee TT, Ozturk A (2007). First Aid for the USMLE Step 1. New York: McGraw-Hill Medical. p. 251.
  12. ↑ Ferdinand KC, Elkayam U, Mancini D, Ofili E, Piña I, Anand I, et al. (July 2014). "Use of isosorbide dinitrate and hydralazine in African-Americans with heart failure 9 years after the African-American Heart Failure Trial". The American Journal of Cardiology. 114 (1): 151–9. doi: 10.1016/j.amjcard.2014.04.018 . PMID   24846808.
  13. 1 2 3 4 5 6 7 "Hydralazine Tablets 50mg". UK Electronic Medicines Compendium. 7 September 2016. Archived from the original on 27 February 2017.
  14. ↑ Gurney AM, Allam M (January 1995). "Inhibition of calcium release from the sarcoplasmic reticulum of rabbit aorta by hydralazine". British Journal of Pharmacology. 114 (1): 238–244. doi:10.1111/j.1476-5381.1995.tb14931.x. PMC   1510175 . PMID   7712024.
  15. ↑ Ellershaw DC, Gurney AM (October 2001). "Mechanisms of hydralazine induced vasodilation in rabbit aorta and pulmonary artery". British Journal of Pharmacology. 134 (3): 621–631. doi:10.1038/sj.bjp.0704302. PMC   1572994 . PMID   11588117.
  16. ↑ Reece PA (1981). "Hydralazine and related compounds: chemistry, metabolism, and mode of action". Med Res Rev. 1 (1): 73–96. doi:10.1002/med.2610010105. PMID   7050561.
  17. ↑ Cohn JN, McInnes GT, Shepherd AM (2011). "Direct-acting vasodilators". Journal of Clinical Hypertension. 13 (9): 690–692. doi:10.1111/j.1751-7176.2011.00507.x. PMC   8108999 . PMID   21896152.
  18. 1 2 Schroeder NA (January 1952). "The effect of 1-hydrasinophthalasine in hypertension". Circulation. 5 (1): 28–37. doi: 10.1161/01.cir.5.1.28 . PMID   14896450.
  19. ↑ "Hydralazine". Drugbank. Archived from the original on 4 March 2017. Retrieved 4 March 2017.
  20. ↑ "hydralazine". PubChem. Archived from the original on 4 March 2017. Retrieved 4 March 2017.
  21. ↑ US2484029; see Example 1
  22. ↑ Reubi FC (January 1950). "Renal hyperemia induced in man by a new phthalazine derivative". Proceedings of the Society for Experimental Biology and Medicine. 73 (1): 102–103. doi:10.3181/00379727-73-17591. PMID   15402536. S2CID   32603042.
  23. ↑ "New Drug Application (NDA) 008303 Company: NOVARTIS Drug Name(s): Apresoline". FDA. Archived from the original on 26 February 2017. Retrieved 26 February 2017.
  24. ↑ Singh V, Sharma P, Capalash N (May 2013). "DNA methyltransferase-1 inhibitors as epigenetic therapy for cancer". Current Cancer Drug Targets. 13 (4): 379–99. doi:10.2174/15680096113139990077. PMID   23517596.
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