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Hydralazine HCl (Apresoline, Adrolazine , Apresrex), the hydrochloride salt of hydralazine, is a potent and direct-acting smooth muscle relaxant and vasodilator used for the treatment of hypertension. It acts as a vasodilator primarily in arteries and arterioles.
Physicochemical Properties
| Molecular Formula | C8H8N4.HCL | |
| Molecular Weight | 196.63686 | |
| Exact Mass | 196.051 | |
| CAS # | 304-20-1 | |
| Related CAS # | Hydralazine;86-54-4 | |
| PubChem CID | 3637 | |
| Appearance | White to off-white solid powder | |
| Boiling Point | 491.9ºC at 760 mmHg | |
| Melting Point | 273°C | |
| Flash Point | 251.3ºC | |
| LogP | 1.724 | |
| Hydrogen Bond Donor Count | 2 | |
| Hydrogen Bond Acceptor Count | 4 | |
| Rotatable Bond Count | 1 | |
| Heavy Atom Count | 12 | |
| Complexity | 150 | |
| Defined Atom Stereocenter Count | 0 | |
| SMILES | 0 |
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| InChi Key | ZUXNZUWOTSUBMN-UHFFFAOYSA-N | |
| InChi Code | InChI=1S/C8H8N4.ClH/c9-11-8-7-4-2-1-3-6(7)5-10-12-8;/h1-5H,9H2,(H,11,12);1H | |
| Chemical Name | phthalazin-1-ylhydrazine; hydrochloride | |
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| HS Tariff Code | 2934.99.9001 | |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
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| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
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| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion Taking oral hydralazine with food improves the bioavailability of the drug. An intravenous dose of 0.3mg/kg leads to an AUC of 17.5-29.4µM\*min and a 1mg/kg oral dose leads to an AUC of 4.0-30.4µM\*min. The Cmax of oral hydralazine is 0.12-1.31µM depending on the acetylator status of patients. <10% of hydralazine is recovered in the feces; 65-90% is recovered in the urine. The volume of distribution is 1.34±0.79L/kg in congestive heart failure patients and 1.98±0.22L/kg in hypertensive patients. The majority of hydralazine clearance is extrahepatic- 55% for rapid acetylators and 70% for slow acetylators. The average clearance in congestive heart failure patients is 1.77±0.48L/kg/h, while hypertensive patients have an average clearance of 42.7±8.9mL/min/kg. Metabolism / Metabolites Acetylation is a minor metabolic pathway for hydralazine; the major pathway is hydroxylation followed by glucuronidation. There are 5 identified metabolic pathways for hydralazine. Hydralazine can be metabolized to phthalazine or α-ketoglutarate hydrazone. These metabolites can be further converted to phthalazinone or hydralazine can be metabolized directly to phthalazinone. Hydralazine can undergo a reversible converstion to the active hydralazine acetone hydrazone. Hydralazine is spontaneously converted to the active pyruvic acid hydrazone or the pyruvic acid hydrazone tricyclic dehydration product, and these metabolites can convert back and forth between these 2 forms. Hydralazine can be converted to hydrazinophthalazinone, which is further converted to the active acetylhydrazinophthalazinone. The final metabolic process hydralazine can undergo is the conversion to an unnamed hydralazine metabolite, which is further metabolized to 3-methyl-s-triazolophthalazine (MTP). MTP can be metabolized to 9-hydroxy-methyltriazolophthalazine or 3-hydroxy-methyltriazolophthalazine; the latter is converted to triazolophthalazine. Hydralazine has known human metabolites that include hydralazine N-acetyl. Biological Half-Life Hydralazine has a half life of 2.2-7.8h in rapid acetylators and 2.0-5.8h in slow acetylators. The half life in heart failure patients is 57-241 minutes with an average of 105 minutes and in hypertensive patients is 200 minutes for rapid acetylators and 297 minutes for slow acetylators. Hydralazine is subject to polymorphic acetylation; slow acetylators generally have higher plasma levels of hydralazine and require lower doses to maintain control of pressure. However, other factors, such as acetylation being a minor metabolic pathway for hydralazine, will contribute to differences in elimination rates. |
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| Toxicity/Toxicokinetics |
Hepatotoxicity Serum aminotransferase elevations during hydralazine therapy are considered uncommon. However, hydralazine has been clearly linked to cases of acute liver injury with jaundice as well as a delayed lupus-like syndrome. Two clinical patterns of hepatic injury have been described, associated with either a short (2 to 6 weeks) or long (2 months to more than a year) latency period. The clinically apparent liver injury is usually hepatocellular, although cholestatic forms have also been reported (Case 1). In cases with a short latency period, rash, fever and eosinophilia are common and the onset is typically abrupt and severe, and recovery is rapid. In cases with a longer latency (Case 2), the onset is more typically insidious, liver biopsy may resemble chronic hepatitis and demonstrate fibrosis, and autoantibodies are often present. The late form of hepatitis may also accompany the lupus-like syndrome that occurs with hydralazine, particularly in high doses when given for 6 months or more. Recovery can be prolonged. Autoantibodies to isoforms of the P450 system (CYP 1A2) have been identified in patients with hepatotoxicity due to the structurally related antihypertensive agent dihydralazine (available in Europe, but not the United States) and which is associated with a higher rate of hepatotoxicity than hydralazine. Likelihood score: A (well established cause of clinically apparent liver injury). Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation Limited milk level and infant serum level data and a long history of use in postpartum mothers indicate that hydralazine is an acceptable antihypertensive in nursing mothers, even those nursing newborns. ◉ Effects in Breastfed Infants No adverse effects reported in one infant breastfed for 8 weeks. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. Protein Binding Hydralazine is 87% protein bound in serum likely to human serum albumin. |
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| References | Proc Natl Acad Sci U S A.2007 Apr 10;104(15):6317-22;J Pharmacol Exp Ther.2004 Sep;310(3):1003-10. | ||
| Additional Infomation |
Hydralazine is the 1-hydrazino derivative of phthalazine; a direct-acting vasodilator that is used as an antihypertensive agent. It has a role as an antihypertensive agent and a vasodilator agent. It is a member of phthalazines, an azaarene, an ortho-fused heteroarene and a member of hydrazines. Originally developed in the 1950s as a malaria treatment, hydralazine showed antihypertensive ability and was soon repurposed. Hydralazine is a hydrazine derivative vasodilator used alone or as adjunct therapy in the treatment of hypertension and only as adjunct therapy in the treatment of heart failure. Hydralazine is no longer a first line therapy for these indications since the development of newer antihypertensive medications. Hydralazine hydrochloride was FDA approved on 15 January 1953. Hydralazine is an Arteriolar Vasodilator. The physiologic effect of hydralazine is by means of Arteriolar Vasodilation. Hydralazine is a commonly used oral antihypertensive agent that acts by inducing peripheral vasodilation. Hydralazine has been linked to several forms of acute liver injury as well as a lupus-like syndrome. Hydralazine has been reported in Achillea pseudopectinata with data available. Hydralazine is a phthalazine derivative with antihypertensive effects. Hydralazine exerts its vasodilatory effects through modification of the contractile state of arterial vascular smooth muscle by altering intracellular calcium release, and interfering with smooth muscle cell calcium influx. This agent also causes inhibition of phosphorylation of myosin protein or chelation of trace metals required for smooth muscle contraction, thereby resulting in an increase in heart rate, stroke volume and cardiac output. A direct-acting vasodilator that is used as an antihypertensive agent. See also: Hydralazine Hydrochloride (has salt form). Drug Indication Hydralazine is indicated alone or adjunct to standard therapy to treat essential hypertension. A combination product with isosorbide dinitrate is indicated as an adjunct therapy in the treatment of heart failure. Mechanism of Action Hydralazine may interfere with calcium transport in vascular smooth muscle by an unknown mechanism to relax arteriolar smooth muscle and lower blood pressure. The interference with calcium transport may be by preventing influx of calcium into cells, preventing calcium release from intracellular compartments, directly acting on actin and myosin, or a combination of these actions. This decrease in vascular resistance leads to increased heart rate, stroke volume, and cardiac output. Hydralazine also competes with protocollagen prolyl hydroxylase (CPH) for free iron. This competition inhibits CPH mediated hydroxylation of HIF-1α, preventing the degradation of HIF-1α. Induction of HIF-1α and VEGF promote proliferation of endothelial cells and angiogenesis. |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (10.58 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (10.58 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: 8.33 mg/mL (42.36 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication (<60°C). (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 5.0854 mL | 25.4272 mL | 50.8544 mL | |
| 5 mM | 1.0171 mL | 5.0854 mL | 10.1709 mL | |
| 10 mM | 0.5085 mL | 2.5427 mL | 5.0854 mL |