Activity hydralazine

Lowering the threshold ofT-cell activation Hydralazine, procainamide... 

In the cinnoline series only derivatives of 3- or 4-aminocinnoline have been found to exhibit biological activity. Some hydrazinophthalazines, in particular 1-hydrazino-(Hydralazin) and 1,4-dihydrazino-phthalazine (Dihydralazin), are excellent hypotensive and antihypertensive agents. 

Similarly, hypotensive activity is found in other analogues of hydralazine, including the very active endralazine (461) (79AF1835, 79AF1843), a pyrido[4,3-c]pyridazine. 

Hydrazinopyridazines such as hydralazine have a venerable history as anti hypertensive agents. It is of note that this biological activity is maintained in the face of major modifications in the heterocyclic nucleus. The key intermediate keto ester in principle can be obtained by alkylation of the anion of pi peri done 44 with ethyl bromo-acetate. The cyclic acylhydrazone formed on reaction with hydrazine (46) is then oxidized to give the aromatized compound 47. The hydroxyl group is then transformed to chloro by treatment with phosphorus oxychloride (48). Displacement of halogen with hydrazine leads to the formation of endralazine (49). ... 

Hydralazine and minoxidil cause direct arteriolar smooth muscle relaxation. Compensatory activation of baroreceptor reflexes results in increased sympathetic outflow from the vasomotor center, producing an increase in heart rate, cardiac output, and renin release. Consequently, the hypotensive effectiveness of direct vasodilators diminishes over time unless the patient is also taking a sympathetic inhibitor and a diuretic. 

Definitive treatment of preeclampsia is delivery, and this is indicated if pending or frank eclampsia (preeclampsia and convulsions) is present. Otherwise, management consists of restricting activity, bedrest, and close monitoring. Salt restriction or other measures that contract blood volume should be avoided. Antihypertensives are used prior to induction of labor if the DBP is >105-110 mm Hg, with a target DBP of 95-105 mm Hg. IV hydralazine is most commonly used IV labetalol is also effective. 

CYP450 antibodies leading to autoimmune hepatitis [68,69], Metabolic activation can also occur within the monocyte/macrophage and has been reported for many of the same xenobiotics (e.g., hydralazine) suggesting multiple mechanisms for xenobiotic autoimmune potential [68],... 

Hofstra, A. and Uetrecht, J.P., Metabolism of hydralazine to a reactive intermediate by the oxidizing system of activated leukocytes, Chemico-Biol. Interact., 89,183, 1993. 

Perry, H.M., Tane, M. and Camody, S. (1970). Relationship of acetyl transferase activity to antinuclear antibodies and toxic symptoms in hypertensive patients treated with hydralazine. J. Lab. Clin. Med. 76 114-125. 

There are some exceptions to the rule, namely structures VII through XI. All of these were active in animal tests but only 1-hydrazinoisoquinoline (VII) showed activity in man comparable to hydralazine. 

Pildralazine (65), when administered i.v. or orally, displays a high antihypertensive activity in conscious hypertensive animals (rats, dogs). The hypotensive effect, caused by oral doses of 0.1 mg/kg to 1 mg/kg, has been reported to last more than 24 h. The therapeutic index (LD50/ED25 rats oral administration) has been found to be 70-times higher than that of hydralazine due to both higher potency and reduced toxicity [197]. It has been concluded that (65), like hydralazine, acts on peripheral smooth muscle on specific receptors which are physiologically affected by ATP released from... 

In Spain, various 6-phenyl-5-aminomethyl-3-hydrazinopyridazines have been prepared and investigated [307]. The antihypertensive activity of compounds of type (75) has been found to exceed the activity of hydralazine. Similar activity has been observed with compound (76) [308]. The activity of the 4-piperazinopyridazine derivative (77) was found to equal that of hydralazine [309]. Also replacement of the phenylpiperazinomethyl substituent in compound (75) by a morpholinomethyl group was found to afford antihypertensive agents [310]. 

The N-acetyl-y-glutamyl pro-drug of the hydralazine-hke vasodilator CGP 18137 showed a higher renal-selective activity than the parent compound, CGP 18137. In contrast to the parent drug, the pro-drug caused a decrease in renal resistance without any effect on blood pressure [49]. 

Hydralazine is a vasodilating drug and inhibition of DNA methyltransferases in the range of 10-20 pM have been reported in vitro [83]. In addition, hypomethylation in cell culture has also been shovm [84]. Also the local anesthetic procaine [85] and its amide analog procainamide [84] have been identified as DNA methyltransferase inhibitors. Synthetic analogs of procaine have shown activity only around 500 pM [86] (Figure 8.10). 

Pharmacokinetics Hydralazine is rapidly absorbed after oral use. Half-life is 3 to 7 hours. Protein binding is 87%, and bioavailability is 30% to 50%. Plasma levels vary widely among individuals. Peak plasma concentrations occur 1 to 2 hours after ingestion duration of action is 6 to 12 hours. Hypotensive effects are seen 10 to 20 minutes after parenteral use and last 2 to 4 hours. Slow acetylators generally have higher plasma levels of hydralazine and require lower doses to maintain control of blood pressure. Hydralazine undergoes extensive hepatic metabolism it is excreted in the urine as active drug (12% to 14%) and metabolites. 

Isosorbide Dinitrate Hydralazine (BiDil) [Antianginal, Antihypertensive/Vasodilator, Nitrate] Uses HF in African Amer-icans improve survival functional status, prolong time between hospitalizations Action Relaxes vascular smooth muscle peripheral vasodilator Dose Initially 1 tab tid PO (if not tol ated reduce to 1/2 tab tid), titrate >3-5 d as tolerated Max 2 tabs tid Caution [C, /-] recent MI, syncope, hypovolemia, hypotension, hep impair Contra For children, concomitant use w/ PDE5 inhibitors (sildenafil) Disp Tabs SE HA, dizziness, orthostatic hypotension, sinusitis, GI distress, tach, paresthesia, amblyopia Interactions t Risk of severe hypotension W/ antihypertensives, ASA, CCBs, MAOIs, phenothiazides, sildenafil, tadalafil, vardenafil, EtOH X pressor response Wf i -1- effects W7 NSAIDs EMS Use ASA, antihypertensives and CCBs w/ caution, may t hypotension concurrent Viagra-type drug use can lead to profound hypotension concurrent EtOH use can t effects OD May cause N/V, profound hypotension, skin flushing, HA from ICP, bradycardia, confusion, and circulatory collapse activated charcoal may be effective, epi use is contraindicated... 

ACE-inhibition will cause a reduction of cardiac afterload and preload in patients with heart failure. In addition, the ACE-inhibitors exert a favourable effect on the neuro-endocrine activation process associated with chronic heart failure. They are more effective than classic vasodilators such as hydralazine and isosorbide, which do not influence these neuroendocrine mechanisms in a favourable manner. 

The vasodilation produced by hydralazine (Apresoline) depends in part on the presence of an intact blood vessel endothelium. This imphes 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. 

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 A-acetylation of hydralazine is an important metabolic pathway and depends on the activity of the enzyme A-acetyltransferase, genetically determined differences in the activity of this enzyme in certain individuals (known as slow acetylators) wih result in higher plasma levels of hydralazine therefore, the drug s therapeutic or toxic effects may be increased. 

Minoxidil (Loniten) is an orally effective vasodilator. It is more potent and longer acting than hydralazine and does not accumulate significantly in patients with renal insufficiency. It depends on in vivo metabolism by hepatic enzymes to produce an active metabolite, minoxidil sulfate. Minoxidil sulfate activates potassium channels, resulting in hyperpolarization of vascular smooth muscle and relaxation of the blood vessel. 

---