Hydralazine

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Hydralazine
Skeletal formula of hydralazine
Ball-and-stick model of the hydralazine molecule
Systematic (IUPAC) name
1-hydrazinylphthalazine
Clinical data
Trade names Apresoline
AHFS/Drugs.com Monograph
MedlinePlus a682246
License data
Pregnancy
category
  • AU: C
  • US: C (Risk not ruled out)
Routes of
administration
Oral, intravenous
Legal status
Legal status
Pharmacokinetic data
Bioavailability 26-50%
Protein binding 85-90%
Metabolism Hepatic
Biological half-life 2-8 hours, 7-16 hours (renal impairment)
Excretion Renal
Identifiers
CAS Number 86-54-4 YesY
ATC code C02DB02 (WHO)
PubChem CID 3637
IUPHAR/BPS 7326
DrugBank DB01275 YesY
ChemSpider 3511 YesY
UNII 26NAK24LS8 YesY
KEGG D08044 YesY
ChEBI CHEBI:5775 YesY
ChEMBL CHEMBL276832 YesY
Chemical data
Formula C8H8N4
Molar mass 160.176 g/mol
  (verify)

Hydralazine (Apresoline) is a direct-acting smooth muscle relaxant used to treat hypertension by acting as a vasodilator primarily in arteries and arterioles. By relaxing vascular smooth muscle, vasodilators act to decrease peripheral resistance, thereby lowering blood pressure and decreasing afterload.[1]

However, this only has a short term effect on blood pressure, as the system will reset to the previous, high blood pressure needed to maintain pressure in the kidney necessary for natriuresis. The long-term effect of antihypertensive drugs comes from their effects on the pressure natriuresis curve. It belongs to the hydrazinophthalazine class of drugs.[2]

It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.[3]

Medical use[edit]

Hydralazine is not used as a primary drug for treating hypertension because it elicits a reflex sympathetic stimulation of the heart (the baroreceptor reflex).[4] The sympathetic stimulation may increase heart rate and cardiac output, and in patients with coronary artery disease may cause angina pectoris or myocardial infarction.[1] 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.[1] In the UK, labetalol tends to be the first-line beta-blocker.

Hydralazine is used to treat severe hypertension, but again, it is not a first-line therapy for essential hypertension. However, hydralazine is the first-line therapy for hypertension in pregnancy, with methyldopa.[5] It has also been used successfully as a treatment for myelodysplastic syndrome in its capacity as a DNA methyltransferase inhibitor.[6]

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

Side effects[edit]

Very common (>10% frequency) side effects include:[7]

Common (1-10% frequency) side effects include:[7][8]

  • Flushing
  • Hypotension
  • Anginal symptoms
  • Joint ache
  • Positive test for ANF
  • Gastrointestinal disturbances
  • Diarrhoea
  • Nausea
  • Vomiting
  • Joint swelling
  • Muscle aches
  • Oedema (sodium and water retention)

Uncommon (0.1-1% frequency) side effects include:[7][8]

  • Nasal congestion
  • Heart failure
  • Dizziness
  • Rash
  • Lupus-like syndrome
  • Protein in the urine
  • Increased plasma creatinine
  • Blood in the urine
  • Glomerulonephritis
  • Jaundice
  • Liver enlargement
  • Hepatitis
  • Agitation
  • Weight loss
  • Appetite loss
  • Anxiety
  • Blood dyscrasias
  • Increased lacrimation
  • Conjunctivitis
  • Nasal congestion
  • Dyspnoea
  • Pleural pain
  • Fever
  • Malaise
  • Hypersensitivity reactions

Rare (<0.1% frequency) side effects include:[7][8]

  • Paradoxical pressor responses
  • Pins and needles (might be reversed by pyridoxine administration)
  • Peripheral neuritis
  • Polyneuritis
  • Tremor
  • Paralysed bowel
  • Acute kidney failure
  • Urinary retention
  • Depression
  • Hallucinations
  • Haemolytic anaemia
  • Leucocytosis
  • Lymphadenopathy
  • Pancytopenia
  • Splenomegaly
  • Agranulocytosis
  • Exophthalmos
  • Retroperitoneal fibrosis

Contraindications[edit]

Contraindications include:[7]

  • Known hypersensitivity to hydralazine or dihydralazine
  • Idiopathic systemic lupus erythematosus and related diseases
  • Severe tachycardia and heart failure with a high cardiac output (e.g. in thyrotoxicosis)
  • Myocardial insufficiency due to mechanical obstruction (e.g. in the presence of aortic or

mitral stenosis or constrictive pericarditis).

  • Isolated right-ventricular heart failure due to pulmonary hypertension (cor pulmonale)
  • Dissecting aortic aneurysm

Interactions[edit]

It may potentiate the antihypertensive effects of:[7]

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

Drugs subject to a strong first-pass effect such as beta-blockers may increase the bioavailability of hydralazine.[7] Epinephrine (adrenaline)'s heart rate-accelerating effects are increased by hydralazine, hence may lead to toxicity.[7]

Mechanism of action[edit]

Hydralazine causes arterial vasodilation by an, as of yet, unclarified mechanism. Hydralazine requires the endothelium to provide nitric oxide,[9] thus only causes vasodilation in vivo with functional endothelium. Hydralazine will not cause vasodilation in vitro in an isolated blood vessel.

Activation of hypoxia-inducible factors has been suggested as a mechanism.[10]

See also[edit]

References[edit]

  1. ^ a b c Harvey, Richard A., Pamela A. Harvey, and Mark J. Mycek. Lippincott's Illustrated Reviews: Pharmacology. 2nd ed. Philadelphia: Lipincott, Williams & Wilkins, 2000. 190.
  2. ^ Bourreli, B.; Pinaud, M.; Passuti, N.; Gunst, J. P.; Drouet, J. C.; Remi, J. P. (1988). "Additive effects of dihydralazine during enflurane or isoflurane hypotensive anaesthesia for spinal fusion". Canadian Journal of Anesthesia 35 (3): 242–248. doi:10.1007/BF03010617. PMID 3383316. 
  3. ^ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014. 
  4. ^ Kandler MR, Mah GT, Tejani AM, Stabler SN, Salzwedel DM. Hydralazine for essential hypertension. Cochrane Database of Systematic Reviews 2011, Issue 11. Art. No.: CD004934. DOI: 10.1002/14651858.CD004934.pub4.
  5. ^ Bhushan, Vikas, Tao T. Lee, and Ali Ozturk. First Aid for the USMLE Step 1. New York: McGraw-Hill Medical, 2007. 251.
  6. ^ Candelaria, M; Herrera, A; Labardini, J; González-Fierro, A; Trejo-Becerril, C; Taja-Chayeb, L; Pérez-Cárdenas, E; Cruz-Hernández, E; Arias-Bofill, D; Vidal, S; Cervera, E; Dueñas-Gonzalez, A (5 October 2010). "Hydralazine and magnesium valproate as epigenetic treatment for myelodysplastic syndrome. Preliminary results of a phase-II trial". Annals of Hematology 90 (4): 379–387. doi:10.1007/s00277-010-1090-2. PMID 20922525. 
  7. ^ a b c d e f g h "PRODUCT INFORMATION APRESOLINE® (hydralazine hydrochloride 20 mg powder for injection ampoule)" (PDF). TGA eBusiness Services. Link Medical Products Pty Ltd. 27 March 2005. Retrieved 13 February 2014. 
  8. ^ a b c Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3. 
  9. ^ "antihtn". Retrieved 2008-10-05. 
  10. ^ Knowles HJ, Tian YM, Mole DR, Harris AL (July 2004). "Novel mechanism of action for hydralazine: induction of hypoxia-inducible factor-1alpha, vascular endothelial growth factor, and angiogenesis by inhibition of prolyl hydroxylases". Circ. Res. 95 (2): 162–9. doi:10.1161/01.RES.0000134924.89412.70. PMID 15192023.