Dihydralazine

Structural formula
General
Non-proprietary name	Dihydralazine
other names	1,4-dihydrazinophthalazine ( IUPAC ) ; Dihydralazinum ( Latin ) ;
Molecular formula	C 8 H 10 N 6
Brief description	Orange needles
External identifiers / databases
EC number	207-605-0
ECHA InfoCard	100.006.914
PubChem	10230
DrugBank	DB12945
Wikidata	Q408370
Drug information
ATC code	C02 DB01
Drug class	Vasodilator , acting on the smooth muscles; Antihypertensive drug;
properties
Molar mass	190.21 g · mol -1
Physical state	firmly
Melting point	180 ° C (decomposition); 225 ° C (mesilate); 240–246 ° C (sulfate; decomposition);
pK s value	4.06; 8.06
safety instructions
	Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS hazard labeling ; no classification available
Toxicological data	300 mg kg −1 ( LD 50 , mouse , iv )
	As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Dihydralazine is a vasodilator , i.e. a vasodilator drug , which is used primarily during pregnancy as an antihypertensive agent , i.e. for high blood pressure therapy. The active ingredient was first patented by CIBA in 1949 . In Germany it is available under the trade name Nepresol ^® ; Generics are also on the market. The related hydralazine is also often used worldwide . The sulfate and the mesilate (finely crystalline yellow salts) are used.

pharmacology

Mode of action and pharmacokinetics

Dihydralazine relaxes the smooth muscle cells of the blood vessels, thereby dilating arteries and arterioles, which leads to a decrease in peripheral resistance. The exact mechanism at the molecular level that leads to cell relaxation is not yet known.

The effect occurs after intravenous application after about 15 minutes and then lasts for three to four hours. Dihydralazine has a bioavailability of 30 to 50% and is subject to a high first-pass effect due to acetylation, although there is a difference between fast and slow acetylators. It is metabolized in the liver, where it is acetylated. The total clearance of dihydralazine is about 8,000 ml per minute (regardless of the acetylation status), its half-life is 2.2–2.6 hours (depending on the acetylation status). It has a volume of distribution of 7 l / kg.

The main area of application of dihydralazine is intravenous therapy for severe preeclampsia . There it is the first choice, as the perfusion of the uterus and placenta is not affected. However, as it passes into breast milk, breastfeeding should not be carried out after administration. In principle, it can be used for long-term oral therapy, but it is no longer suitable because of the side effects.

Another application is the treatment of chronic kidney diseases, from which about 15% of adults in Germany suffer. Epigenetically modified connective tissue cells (fibroblasts) of the kidneys are considered to be the trigger: The epigenetic disconnection of the "RASAL1" gene causes the progression of chronic kidney failure. Traces of the changes can be seen with a test in the blood. The drug "Dihydralazine" reverses the harmful changes. The addition of methyl groups to DNA modifies kidney cell genome in such a way that the kidney becomes chronically ill. Dihydralazine has been used as a blood pressure medication since 1947. The protective effect for the kidneys was long overlooked because dihydralazine only protects chronically ill kidneys if it is administered well below the dose that lowers blood pressure. With the detection of harmful DNA methylation in the blood, an individual therapy response to dihydralazine can now be proven.

Side effects

In 90% of cases, dihydralazine provides adequate blood pressure regulation. In nine randomized studies in which dihydralazine was compared with other antihypertensive drugs, there was an accumulation of side effects and treatment failure in the dihydralazine group in only one study.
As a result of the arterial dilation , orthostatic dysregulation , pulsating headaches and a so-called " flush ", a reddening of the skin on the face that is accompanied by a feeling of heat, up to drug-induced lupus erythematosus , which, however, usually resolves quickly after stopping the drug. In addition, reflex tachycardia and angina pectoris can occur as a sympathetic counter-regulation. A further counter-regulation by activating the renin-angiotensin-aldosterone system can lead to reduced sodium ions and water excretion, which in turn can result in edema .

Individual evidence

↑ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ Entry on dihydralazine. In: Römpp Online . Georg Thieme Verlag, accessed on June 30, 2019.
↑ This substance has either not yet been classified with regard to its hazardousness or a reliable and citable source has not yet been found.
↑ Entry on dihydralazine in the ChemIDplus database of the United States National Library of Medicine (NLM), accessed on November 28, 2018.
↑ Björn Tampe, Desiree Tampe, Elisabeth M. Zeisberg, Gerhard A. Müller, Wibke Bechtel-Walz, Michael Koziolek, Raghu Kalluri, Michael Zeisberg: Induction of Tet3-dependent Epigenetic Remodeling by Low-dose Hydralazine Attenuates Progression of Chronic Kidney Disease. In: EBioMedicine . Volume 2, number 1, 2015, pp. 19-36, doi : 10.1016 / j.ebiom.2014.11.005 . ( free full text )

[roempp-1] ↑ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ Entry on dihydralazine. In: Römpp Online . Georg Thieme Verlag, accessed on June 30, 2019.

[NV-2] This substance has either not yet been classified with regard to its hazardousness or a reliable and citable source has not yet been found.

[ChemIDplus-3] Entry on dihydralazine in the ChemIDplus database of the United States National Library of Medicine (NLM), accessed on November 28, 2018.

[4] Björn Tampe, Desiree Tampe, Elisabeth M. Zeisberg, Gerhard A. Müller, Wibke Bechtel-Walz, Michael Koziolek, Raghu Kalluri, Michael Zeisberg: Induction of Tet3-dependent Epigenetic Remodeling by Low-dose Hydralazine Attenuates Progression of Chronic Kidney Disease. In: EBioMedicine . Volume 2, number 1, 2015, pp. 19-36, doi : 10.1016 / j.ebiom.2014.11.005 . ( free full text )