hydralazine

Hydralazine is not used as a primary drug for treating hypertension because it elicits a reflex sympathetic stimulation of the heart (the baroreceptor reflex).{{cite journal | vauthors = Kandler MR, Mah GT, Tejani AM, Stabler SN, Salzwedel DM | title = Hydralazine for essential hypertension | journal = The Cochrane Database of Systematic Reviews | issue = 11 | pages = CD004934 | date = November 2011 | pmid = 22071816 | doi = 10.1002/14651858.CD004934.pub4 }} The sympathetic stimulation may increase heart rate and cardiac output, and in people with coronary artery disease may cause angina pectoris or myocardial infarction. 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.

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.{{cite book | vauthors = Bhushan V, Lee TT, Ozturk A | title = First Aid for the USMLE Step 1. | location = New York | publisher = McGraw-Hill Medical | date = 2007 | page = 251 }}

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.{{cite journal | vauthors = Ferdinand KC, Elkayam U, Mancini D, Ofili E, Piña I, Anand I, Feldman AM, McNamara D, Leggett C | display-authors = 6 | title = Use of isosorbide dinitrate and hydralazine in African-Americans with heart failure 9 years after the African-American Heart Failure Trial | journal = The American Journal of Cardiology | volume = 114 | issue = 1 | pages = 151–9 | date = July 2014 | pmid = 24846808 | doi = 10.1016/j.amjcard.2014.04.018 | url = http://www.ajconline.org/article/S0002-9149(14)00975-8/pdf | doi-access = free }}

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

Prolonged treatment may cause a syndrome similar to lupus, which can become fatal if the symptoms are not noticed and drug treatment stopped. 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.{{cite web|title=Hydralazine Tablets 50mg|url=https://www.medicines.org.uk/emc/medicine/24412|work=UK Electronic Medicines Compendium|date=7 September 2016|language=en|url-status=live|archive-url=https://web.archive.org/web/20170227063940/https://www.medicines.org.uk/emc/medicine/24412|archive-date=27 February 2017}}

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).

It may potentiate the antihypertensive effects of:

{{div col|colwidth=22em}}

• Vasodilators
• Calcium antagonists
• ACE inhibitors
• Diuretics
• Antihypertensives
• Tricyclic antidepressants
• Major tranquillisers
• Ethanol (alcohol)
• Diazoxide

{{div col end}}

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

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.{{Cite journal| vauthors = Gurney AM, Allam M | title = Inhibition of calcium release from the sarcoplasmic reticulum of rabbit aorta by hydralazine | journal = British Journal of Pharmacology | volume = 114 | issue = 1 | pages = 238–244 | date = January 1995 | pmid = 7712024 | pmc = 1510175 | doi = 10.1111/j.1476-5381.1995.tb14931.x }}{{Cite journal| vauthors = Ellershaw DC, Gurney AM| title = Mechanisms of hydralazine induced vasodilation in rabbit aorta and pulmonary artery | journal = British Journal of Pharmacology | volume = 134 | issue = 3 | pages = 621–631 | date = October 2001 | pmid = 11588117 | pmc = 1572994 | doi = 10.1038/sj.bjp.0704302 }} By relaxing vascular smooth muscle, vasodilators act to decrease peripheral resistance, thereby lowering blood pressure and decreasing afterload.{{cite book | vauthors = Harvey RA, Harvey PA, Mycek MJ | title = Lippincott's Illustrated Reviews: Pharmacology. | edition = 2nd | location = Philadelphia | publisher = Lippincott Williams & Wilkins | date = 2000 | page = 190 }} The exact mechanism of action of hydralazine is unknown, at least as of 1981.{{cite journal | vauthors = Reece PA | title = Hydralazine and related compounds: chemistry, metabolism, and mode of action | journal = Med Res Rev | volume = 1 | issue = 1 | pages = 73–96 | date = 1981 | pmid = 7050561 | doi = 10.1002/med.2610010105 | url = }}

Metabolic products include the N-acetyl derivative, pyruvic acid hydrazone, and acetone hydrazone, each of which may also contribute to reducing blood pressure.{{cite journal |title= Direct-acting vasodilators |vauthors= Cohn JN, McInnes GT, Shepherd AM |journal= Journal of Clinical Hypertension |year= 2011 |volume= 13 |issue= 9 |pages= 690–692 |doi= 10.1111/j.1751-7176.2011.00507.x |pmid= 21896152 |pmc= 8108999 }}

Hydralazine belongs to the hydrazinophthalazine class of drugs.{{cite journal | vauthors = Schroeder NA | title = The effect of 1-hydrasinophthalasine in hypertension | journal = Circulation | volume = 5 | issue = 1 | pages = 28–37 | date = January 1952 | pmid = 14896450 | doi = 10.1161/01.cir.5.1.28 | doi-access = free }}

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,{{cite web|title=Hydralazine|url=https://www.drugbank.ca/drugs/DB01275|publisher=Drugbank|access-date=4 March 2017|url-status=live|archive-url=https://web.archive.org/web/20170304114322/https://www.drugbank.ca/drugs/DB01275|archive-date=4 March 2017}}{{cite web|title=hydralazine|url=https://pubchem.ncbi.nlm.nih.gov/compound/hydralazine#section=Physical-Description|publisher=PubChem|access-date=4 March 2017|language=en|url-status=live|archive-url=https://web.archive.org/web/20170304115216/https://pubchem.ncbi.nlm.nih.gov/compound/hydralazine#section=Physical-Description|archive-date=4 March 2017}}[https://docs.google.com/viewer?url=patentimages.storage.googleapis.com/pdfs/US2484029.pdf US2484029]; see Example 1 and the first scientific publications of its blood pressure-lowering activities appeared in 1950.{{cite journal | vauthors = Reubi FC | title = Renal hyperemia induced in man by a new phthalazine derivative | journal = Proceedings of the Society for Experimental Biology and Medicine | volume = 73 | issue = 1 | pages = 102–103 | date = January 1950 | pmid = 15402536 | doi = 10.3181/00379727-73-17591 | s2cid = 32603042 }} It was approved by the FDA in 1953.{{cite web|title=New Drug Application (NDA) 008303 Company: NOVARTIS Drug Name(s): Apresoline|url=http://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=008303|publisher=FDA|access-date=26 February 2017|url-status=live|archive-url=https://web.archive.org/web/20170226135437/http://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=008303|archive-date=26 February 2017}}

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

Hydralazine has also been studied as a treatment for myelodysplastic syndrome in its capacity as a DNA methyltransferase inhibitor.{{cite journal | vauthors = Singh V, Sharma P, Capalash N | title = DNA methyltransferase-1 inhibitors as epigenetic therapy for cancer | journal = Current Cancer Drug Targets | volume = 13 | issue = 4 | pages = 379–99 | date = May 2013 | pmid = 23517596 | doi = 10.2174/15680096113139990077 }}

{{Reflist}}

{{Nonsympatholytic vasodilatory antihypertensives}}

{{Monoamine metabolism modulators}}

{{Hydrazines}}

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