Hydralazine

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Hydralazine
Skeletal formula of hydralazine
Ball-and-stick model of the hydralazine molecule
Names
Trade namesApresoline, BiDil, others
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)
  (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]

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. "Hydralazine". International Drug Price Indicator Guide. Retrieved 8 December 2016.
  9. Hamilton R (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 145. ISBN 9781284057560.
  10. "The Top 300 of 2020". ClinCalc. Retrieved 11 April 2020.
  11. "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 RA, Harvey PA, Mycek MJ (2000). Lippincott's Illustrated Reviews: Pharmacology (2nd ed.). Philadelphia: Lippincott Williams & Wilkins. p. 190.
  14. Bhushan V, Lee TT, Ozturk A (2007). First Aid for the USMLE Step 1. New York: McGraw-Hill Medical. p. 251.
  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

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