Hydralazine

Absorption

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.

Toxicity

The oral LD50 in rats is 173-187mg/kg and the highest known dose an adult human has survived is 10g orally.
Patients experiencing an overdose may present with hypotension, tachycardia, headache, flushing, myocardial ischemia, myocardial infarction, cardiac arrhythmia, and shock. Overdose can be treated through emptying the gastric contents and administering activated charcoal, though these treatments may cause further arrhythmias and shock. Supportive and symptomatic treatment should be administered.

Description

Cross-reactions between hydrazine derivatives occur. Hydralazine may sometimes cause flushing and reversible Lupus erythematosis

Chemical properties

Yiellow Solid

Originator

Apresoline HCl,Ciba,US,1952

The Uses of Hydralazine

Hydralazine is a non-nucleoside analog that inhibits DNA methylation and reactivates the expression of tumor suppressor genes. Non-selective MAO-A/B inhibitor; semicarbazide-sensitive amine oxidase inhibitor. Antihypertensive.

The Uses of Hydralazine

Inhibits DNA methyltransferase and modulates epigenetic regulation of gene expression. Non-selective MAO-A/B inhibitor; semicarbazide-sensitive amine oxidase inhibitor. Antihypertensive

The Uses of Hydralazine

Hydralazine is widely used cardiovascular drug dilating arterioies by relaxation of artetiolar smooth muscles.

Background

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.

Indications

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.

Definition

ChEBI: The 1-hydrazino derivative of phthalazine; a direct-acting vasodilator that is used as an antihypertensive agent.

Manufacturing Process

30 parts by weight of phthalazone are converted to 1-chlorophthalazine by the method described in Ber. d. deutsch. chem. Ges., vol 26, page 521 (1893). The freshly obtained yet moist chloro compound is heated on the water bath for two hours in a mixture of 100 parts by volume of ethyl alcohol and 90 parts by volume of hydrazine hydrate. Preferably after filtering, 1-hydrazinephthalazine crystallizes out in yellow needles on cooling.
It is filtered with suction and washed with cold ethyl alcohol. The compound is crystallized from methyl alcohol, and melts, when rapidly heated, at 172° to 173°C. On warming in alcoholic or aqueous hydrochloric acid, the hydrochloride of MP 273°C (with decomposition) is obtained.

brand name

Apresoline (Novartis); Dralzine (Teva).

Therapeutic Function

Antihypertensive

Biological Functions

The vasodilation produced by hydralazine (Apresoline) depends in part on the presence of an intact blood vessel endothelium. This implies that hydralazine causes the release of nitric oxide, which acts on the vascular smooth muscle to cause relaxation. In addition, hydralazine may produce vasodilation by activating K⁺ channels.

Contact allergens

Hydralazine is a hydrazine derivative used as a antihypertensive drug. Skin rashes have been described during treatment. Exposure occurs mainly in the pharmaceutical industry. Cross-sensitivity is frequent with hydrazine, which is considered to be a potent sensitizer.

Mechanism of action

Hydralazine exhibits an antihypertensive effect by directly relaxing smooth muscles of the vessels. It has an effect on arterial vessels while having a minimal effect on venous vessels. As a result, resistance of peripheral vessels decreases, and blood pressure is reduced (diastolic more than systolic).
It does not have a substantial effect on nonvascular smooth musculature or cardiac tissues. Homeostatic circulatory reflexes remain natural, and the resulting hypotension activates cardiovascular reflexes, which are expressed as an increase of heart work, power, and volume of cardiac output. Therefore, it is most effectively used in combination with β-blockers.

Pharmacokinetics

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.

Pharmacology

Hydralazine produces widespread but apparently not uniform vasodilation; that is, vascular resistance is decreased more in cerebral, coronary, renal, and splanchnic beds than in skeletal muscle and skin. Renal blood flow and ultimately glomerular filtration rate may be slightly increased after acute treatment with hydralazine. However, after several days of therapy, the renal blood flow is usually no different from that before drug use.
In therapeutic doses, hydralazine produces little effect on nonvascular smooth muscle or on the heart. Its pharmacological actions are largely confined to vascular smooth muscle and occur predominantly on the arterial side of the circulation; venous capacitance is much less affected. Because cardiovascular reflexes and venous capacitance are not affected by hydralazine, postural hypotension is not a clinical concern. Hydralazine treatment does, however, result in an increase in cardiac output.This action is brought about by the combined effects of a reflex increase in sympathetic stimulation of the heart, an increase in plasma renin, and salt and water retention. These effects limit the hypotensive usefulness of hydralazine to such an extent that it is rarely used alone.

Clinical Use

Hydralazine is generally reserved for moderately hypertensive ambulatory patients whose blood pressure is not well controlled either by diuretics or by drugs that interfere with the sympathetic nervous system. It is almost always administered in combination with a diuretic (to prevent Na⁺ retention) and a β-blocker, such as propranolol (to attenuate the effects of reflex cardiac stimulation and hyperreninemia). The triple combination of a diuretic, β-blocker, and hydralazine constitutes a unique hemodynamic approach to the treatment of hypertension, since three of the chief determinants of blood pressure are affected: cardiac output (β-blocker),plasma volume (diuretic), and peripheral vascular resistance (hydralazine).
Although hydralazine is available for intravenous administration and has been used in the past for hypertensive emergencies, it is not generally employed for this purpose. The onset of action after intravenous injection is relatively slow, and its actions are somewhat unpredictable in comparison with those of several other vasodilators.

Side Effects

Most side effects associated with hydralazine administration are due to vasodilation and the reflex hemodynamic changes that occur in response to vasodilation. These side effects include headache, flushing, nasal congestion, tachycardia, and palpitations. More serious manifestations include myocardial ischemia and heart failure. These untoward effects of hydralazine are greatly attenuated when the drug is administered in conjunction with a β-blocker.
When administered chronically in high doses, hydralazine may produce a rheumatoidlike state that when fully developed, resembles disseminated lupus erythematosus.

Synthesis

Hydralazine, 1-hydrazinonaphthalazine (22.6.4), is synthesized by the oxidative chlorination of phthalide with simultaneous hydrolysis of product, which results in hydroxyphthalide (22.6.1), which upon reaction with hydrazine changes to phthalazone (22.6.2). This undergoes a reaction with phosphorous oxychloride, forming 1-chlorophthalazine (22.6.3), in which substitution of the chlorine atom with hydrazine gives the desired hydralazine (22.6.4).

Metabolism

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.

Metabolism

Hydralazine is well absorbed (65–90%) after oral administration. Its peak antihypertensive effect occurs in about 1 hour, and its duration of action is about 6 hours.
The major pathways for its metabolism include ring hydroxylation, with subsequent glucuronide conjugation and N-acetylation. Hydralazine exhibits a first-pass effect in that a large part of an orally administered dose is metabolized before the drug reaches the systemic circulation. The first-pass metabolism occurs in the intestinal mucosa (mostly N-acetylation) and the liver. The primary excretory route is through renal elimination, and about 80% of an oral dose appears in the urine within 48 hours. About 10% is excreted unchanged in the feces.
Approximately 85% of the hydralazine in plasma is bound to plasma proteins. Although this does not appear to be a major therapeutic concern, the potential for interactions with other drugs that also bind to plasma proteins does exist. The plasma half-life of hydralazine in patients with normal renal function is 1.5 to 3 hours.
Interestingly, the half-life of the antihypertensive effect is somewhat longer than the plasma half-life. This may occur because hydralazine is specifically accumulated in artery walls, where it may continue to exert a vasodilator action even though plasma concentrations are low.
The plasma half-life of hydralazine may be increased fourfold or fivefold in patients with renal failure. If renal failure is present, therefore, both the antihypertensive and toxic effects of hydralazine may be enhanced. Since N-acetylation of hydralazine is an important metabolic pathway and depends on the activity of the enzyme N-acetyltransferase, genetically determined differences in the activity of this enzyme in certain individuals (known as slow acetylators) will result in higher plasma levels of hydralazine; therefore, the drug’s therapeutic or toxic effects may be increased.

Purification Methods

It crystallises from MeOH. UV: max 656nm at pH ~11. It complexes with Bi3+ , Zn2+ , Fe2+ and Co2+ .