Hydralazine

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Hydralazine
Skeletal formula of hydralazine
Ball-and-stick model of the hydralazine molecule
Names
Trade namesApresoline, BiDil, others
  • 1-hydrazinylphthalazine
Clinical data
Main usesHigh blood pressure (including in pregnancy)[1][2]
Pregnancy
category
  • AU: C
  • US: C (Risk not ruled out)
Routes of
use		By mouth, intravenous
Onset of action5 to 30 min[2]
Duration of action2 to 6 hrs[2]
Defined daily dose100 mg[3]
External links
AHFS/Drugs.comMonograph
MedlinePlusa682246
Legal
License data
Legal status
Pharmacokinetics
Bioavailability26–50%
Protein binding85–90%
MetabolismLiver
Elimination half-life2–8 hours, 7–16 hours (renal impairment)
ExcretionUrine
Chemical and physical data
FormulaC8H8N4
Molar mass160.180 g·mol−1
3D model (JSmol)
  • n2nc(c1ccccc1c2)NN
  • InChI=1S/C8H8N4/c9-11-8-7-4-2-1-3-6(7)5-10-12-8/h1-5H,9H2,(H,11,12) checkY
  • Key:RPTUSVTUFVMDQK-UHFFFAOYSA-N checkY
  (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.[4] 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.[4] Effects usually begin around 15 minutes and last up to six hours.[2]

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.[4] Hydralazine is in the vasodilator family of medications and 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.[5] It was patented in 1949.[6] It is on the World Health Organization's List of Essential Medicines.[7] The wholesale cost in the developing world is about US$2.78–9.11 per month.[8] In the United States treatment costs about $50–100 per month.[9] In 2017, it was the 105th most commonly prescribed medication in the United States, with more than seven million prescriptions.[10][11]

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).[12] The sympathetic stimulation may increase heart rate and cardiac output, and in people with coronary artery disease may cause angina pectoris or myocardial infarction.[13] 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 β-blocker (e.g., propranolol) and a diuretic.[13] Beta-blockers licensed to treat heart failure in the UK include bisoprolol, carvedilol, and nebivolol.[citation needed]

Hydralazine is used to treat severe hypertension, but again, it is not a first-line therapy for essential hypertension. However, hydralazine is often used to treat hypertension in pregnancy, with methyldopa.[14]

Hydralazine is commonly used in combination with isosorbide dinitrate for the treatment of congestive heart failure in self-identified African American populations. This preparation, isosorbide dinitrate/hydralazine, was the first race-based prescription drug.[15]

It should not be used in people with tachycardia, heart failure, who have constrictive pericarditis, who have lupus, a dissecting aortic aneurysm, or porphyria.[16]

Dosage

The defined daily dose is 100 mg by injection.[3] For high blood pressure in pregnancy it can be given as 5 mg over about 3 minutes by injection into a vein.[1] If after 20 minutes the BP is not improved the dose can be repeated up to 20 mg total.[1] It can also be given as an infusion starting at 200 to 300 micrograms/minute and than decreased to 50 to 150 micrograms/minute.[1]

Side effects

Prolonged treatment may cause a syndrome similar to lupus which can become fatal if the symptoms are not noticed and drug treatment stopped.[16]

Very common (>10% frequency) side effects include headache, high heart rate, and palpitations.[16]

Common (1–10% frequency) side effects include flushing, hypotension, anginal symptoms, aching or swelling joints, muscle aches, positive tests for ANP, stomach upset, diarrhea, nausea, and vomiting, and swelling (sodium and water retention).[16]

Interactions

It may potentiate the antihypertensive effects of:[16]

Drugs subject to a strong first-pass effect such as β-blockers may increase the bioavailability of hydralazine.[16] Epinephrine (adrenaline)'s heart rate-accelerating effects are increased by hydralazine, hence may lead to toxicity.[16]

Mechanism of action

It is a direct-acting smooth muscle relaxant and acts as a vasodilator primarily in resistance arterioles; the molecular mechanism involves inhibition of inositol trisphosphate-induced Ca2+ release from the sarcoplasmic reticulum in arterial smooth muscle cells.[17][18] By relaxing vascular smooth muscle, vasodilators act to decrease peripheral resistance, thereby lowering blood pressure and decreasing afterload.[13]

Chemistry

Hydralazine belongs to the hydrazinophthalazine class of drugs.[19]

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,[20][21][22] and the first scientific publications of its blood-pressure lowering activities appeared in 1950.[5][19][23] It was approved by the FDA in 1953.[24]

It was one of the first antihypertensive medications that could be taken by mouth.[12]

Research

Hydralazine has also been studied as a treatment for myelodysplastic syndrome in its capacity as a DNA methyltransferase inhibitor.[25]

Society and culture

Cost

The wholesale cost in the developing world is about US$2.78–9.11 per month.[8] In the United States treatment costs about $50–100 per month.[9] In 2017, it was the 105th most commonly prescribed medication in the United States, with more than seven million prescriptions.[10][11]

  • Hydralazine costs (US)

  • Hydralazine prescriptions (US)

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 "HYDRALAZINE injectable - Essential drugs". medicalguidelines.msf.org. Retrieved 2 September 2020.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 "Hydralazine Hydrochloride". The American Society of Health-System Pharmacists. Archived from the original on 21 December 2016. Retrieved 8 December 2016.
  3. ↑ 3.0 3.1 "WHOCC - ATC/DDD Index". www.whocc.no. Retrieved 2 September 2020.
  4. ↑ 4.0 4.1 4.2 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.
  5. ↑ 5.0 5.1 Wermuth CG (2011-05-02). The Practice of Medicinal Chemistry. Academic Press. p. 12. ISBN 9780080568775. Archived from the original on 2017-02-26.
  6. ↑ Progress in Drug Research/Fortschritte der Arzneimittelforschung/Progrés des recherches pharmaceutiques. Birkhäuser. 2013. p. 206. ISBN 9783034870948. Archived from the original on 2016-12-20.
  7. ↑ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  8. ↑ 8.0 8.1 "Hydralazine". International Drug Price Indicator Guide. Retrieved 8 December 2016.
  9. ↑ 9.0 9.1 Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 145. ISBN 9781284057560. Unknown parameter |name-list-format= ignored (help)
  10. ↑ 10.0 10.1 "The Top 300 of 2020". ClinCalc. Retrieved 11 April 2020.
  11. ↑ 11.0 11.1 "Hydralazine Hydrochloride - Drug Usage Statistics". ClinCalc. Retrieved 11 April 2020.
  12. ↑ 12.0 12.1 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.
  13. ↑ 13.0 13.1 13.2 Harvey, Richard A.; Harvey, Pamela A.; Mycek, Mark J. (2000). Lippincott's Illustrated Reviews: Pharmacology (2nd ed.). Philadelphia: Lippincott Williams & Wilkins. p. 190. Unknown parameter |name-list-format= ignored (help)
  14. ↑ Bhushan, Vikas; Lee, Tao T.; Ozturk, Ali (2007). First Aid for the USMLE Step 1. New York: McGraw-Hill Medical. p. 251. Unknown parameter |name-list-format= ignored (help)
  15. ↑ 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.
  16. ↑ 16.0 16.1 16.2 16.3 16.4 16.5 16.6 "Hydralazine Tablets 50mg". UK Electronic Medicines Compendium. September 7, 2016. Archived from the original on February 27, 2017.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ 19.0 19.1 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.
  20. ↑ "Hydralazine". Drugbank. Archived from the original on 4 March 2017. Retrieved 4 March 2017.
  21. ↑ "hydralazine". PubChem. Archived from the original on 4 March 2017. Retrieved 4 March 2017.
  22. ↑ US2484029; see Example 1
  23. ↑ 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.
  24. ↑ "New Drug Application (NDA) 008303 Company: NOVARTIS Drug Name(s): Apresoline". FDA. Archived from the original on 26 February 2017. Retrieved 26 February 2017.
  25. ↑ 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.

External links

External sites:
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