Hydralazine

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Hydralazine
Hydralazine.svg
Systematic (IUPAC) name
1-hydrazinylphthalazine
Clinical data
Trade names Apresoline
AHFS/Drugs.com monograph
MedlinePlus a682246
Licence data US FDA:link
Pregnancy cat.
Legal status
Routes Oral, intravenous
Pharmacokinetic data
Bioavailability 26-50%
Protein binding 85-90%
Metabolism Hepatic
Half-life 2-8 hours, 7-16 hours (renal impairment)
Excretion Renal
Identifiers
CAS number 86-54-4 YesY
ATC code C02DB02
PubChem CID 3637
DrugBank DB01275
ChemSpider 3511 YesY
UNII 26NAK24LS8 YesY
KEGG D08044 YesY
ChEBI CHEBI:5775 YesY
ChEMBL CHEMBL276832 YesY
Chemical data
Formula C8H8N4 
Mol. mass 160.176 g/mol
 YesY (what is this?)  (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 shortterm effect on blood pressure, as the system will reset to the previous, high blood pressure necessary 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). 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.[4] It has also been used successfully as a treatment for myelodysplastic syndrome in its capacity as a DNA methyltransferase inhibitor.[5]

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:[6]

Common (1-10% frequency) side effects include:[6][7]

  • 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:[6][7]

  • 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:[6][7]

  • 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:[6]

  • 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:[6]

  • 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.[6] Epinephrine (adrenaline)'s heart rate-accelerating effects are increased by hydralazine, hence may lead to toxicity.[6]

Mechanism of action[edit]

Hydralazine binds to and activates gated potassium channels on vascular smooth muscle. The result is an efflux of potassium and a subsequent hyperpolarization of the cell. This prevents calcium-mediated activation and constriction of the smooth muscle, resulting in vasodilation. However, this induced vasodilation triggers the baroreflex resulting in tachycardia and vasoconstriction. Hydralazine is, therefore, not a great candidate for control of hypertension alone. It is often coadministered with a beta blocker to mitigate the effects of the baroreflex.

Hydralazine requires the endothelium to provide nitric oxide,[8] 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.[9]

Synthesis[edit]

Hydralazine synthesis:[10] U.S. Patent 2,484,029 DE848818 

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 Anaesthesia 35 (3): 242–248. doi:10.1007/BF03010617. PMID 3383316.  edit
  3. ^ "WHO Model List of EssentialMedicines". World Health Organization. October 2013. Retrieved 22 April 2014. 
  4. ^ Bhushan, Vikas, Tao T. Lee, and Ali Ozturk. First Aid for the USMLE Step 1. New York: McGraw-Hill Medical, 2007. 251.
  5. ^ 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. 
  6. ^ 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. 
  7. ^ 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.  edit
  8. ^ "antihtn". Retrieved 2008-10-05. 
  9. ^ 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. 
  10. ^ Druey, J.; Ringier, B. H. (1951). "Hydrazinderivate der Phtalazin- und Pyridazinreihe". Helvetica Chimica Acta 34: 195. doi:10.1002/hlca.19510340122.  edit