1(2H-Phthalazinon-hydrazon

Pharmaceuticals

Pharmaceuticals -> Listed in ZINC15

0.7

1.0

<1mg/mL

2.61e+00 g/L

Breast Feeding; Lactation; Milk, Human; Antihypertensive Agents; Vasodilator Agents

Pharmaceuticals

Antihypertensive medicines

172-173 °C

172 - 173 °C

Danger

H301 (100%): Toxic if swallowed [Danger Acute toxicity, oral]

P264, P270, P301+P316, P321, P330, P405, and P501 (click each P-code to see the statement)

The GHS information provided by 1 company from 1 notification to the ECHA C&L Inventory.

Danger

H317: May cause an allergic skin reaction [Warning Sensitization, Skin]

Acute Tox. 3 (100%)

Skin sensitization - Category 1

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.

Skin Sensitizer - An agent that can induce an allergic reaction in the skin.

Hydralazine has been reported to cause headaches, nausea, flushing, hypotension, palpitations, tachycardia, dizziness, and angina.

Published reports of toxicity with acute use of hydralazine are uncommon. Signs of toxicity include hypotension, tachycardia, headaches, and generalized flushing. Chronic toxicity could lead to DILE. There is no specific treatment for an overdose other than supportive therapy. Fluids should be given initially, followed by vasopressors if hypotension persists despite fluid resuscitation. Tachycardia or ischemia can be treated with beta-blockers with attention to blood pressure prior to administration.

Hydralazine

Group 3: Not classifiable as to its carcinogenicity to humans

Volume 24: (1980) Some Pharmaceutical Drugs

1987

1987

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

hydralazine

DILI Positive

Oral

DOI:10.1016/j.drudis.2019.09.022

C - Cardiovascular system

QC - Cardiovascular system

C02DB02

Hydralazine interferes with calcium transport to relax arteriolar smooth muscle and lower blood pressure. Hydralazine has a short duration of action of 2-6h. This drug has a wide therapeutic window, as patients can tolerate doses of up to 300mg. Patients should be cautioned regarding the risk of developing systemic lupus erythematosus syndrome.

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.

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.

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.

26NAK24LS8

HYDRALAZINE

Physiologic Effects [PE] - Arteriolar Vasodilation

Established Pharmacologic Class [EPC] - Arteriolar Vasodilator

Hydralazine is an Arteriolar Vasodilator. The physiologic effect of hydralazine is by means of Arteriolar Vasodilation.

Drugs used in the treatment of acute or chronic vascular HYPERTENSION regardless of pharmacological mechanism. Among the antihypertensive agents are DIURETICS; (especially DIURETICS, THIAZIDE); ADRENERGIC BETA-ANTAGONISTS; ADRENERGIC ALPHA-ANTAGONISTS; ANGIOTENSIN-CONVERTING ENZYME INHIBITORS; CALCIUM CHANNEL BLOCKERS; GANGLIONIC BLOCKERS; and VASODILATOR AGENTS.

Drugs used to cause dilation of the blood vessels.

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.

A Peripheral vasodilator used as an antihypertensive agent; [ChemIDplus]

Use (kg; approx.) in Germany (2009): >100