Action And Clinical Pharmacology: Although the precise mechanism of action of hydralazine is not fully understood, the major effects are on the cardiovascular system. Hydralazine apparently lowers blood pressure by exerting a peripheral vasodilating effect through a direct relaxation of vascular smooth muscle. Hydralazine, by altering cellular calcium metabolism, interferes with the calcium movements within the vascular smooth muscle that are responsible for initiating or maintaining the contractile state.
The peripheral vasodilating effect of hydralazine results in decreased arterial blood pressure (diastolic more than systolic); decreased peripheral vascular resistance; and an increased heart rate, stroke volume, and cardiac output. The vasodilating effect is much greater on arterioles than on veins and vascular resistance decreases more in the coronary, cerebral, splanchnic and renal circulations than in skin and muscle.
Hydralazine usually increases renin activity in plasma presumably as a result of increased secretion of renin by the renal juxtaglomerular cells in response to reflex sympathetic discharge. This increase in renin activity leads to the production of angiotensin II, which then causes stimulation of aldosterone and consequent sodium reabsorption and fluid retention.
Sodium retention and excessive sympathetic stimulation of the heart caused by hydralazine may be precluded by coadministration of a thiazide diuretic and a beta-blocker. Beta-adrenergic blocking drugs and hydralazine are complementary in their pharmacologic effects, a beta-adrenergic blocking agent minimizes hydralazine-induced increases in cardiac rate and ouput, and hydralazine prevents the reflex increase in peripheral resistance induced by beta-blockers.
Pharmacokinetics: Hydralazine is rapidly and fairly completely absorbed after oral administration. In the plasma only small amounts of the free drug can be traced, the bulk circulating in conjugated form, i.e., pyruvic acid hydrazone. Peak serum concentrations are reached within 1 to 2 hours after a dose.
Plasma levels of hydralazine vary widely among individuals. Orally administered hydralazine undergoes extensive, saturable first-pass metabolism (systemic availability: 26 to 55%), this first-pass effect being dependent on the individual’s acetylator status. In response to the same oral dose, slow-acetylators show higher apparent plasma hydralazine levels than rapid acetylators and require lower doses to maintain control of blood pressure.
After i.v. administration of hydralazine no first-pass effect occurs; acetylator status therefore has no influence on the plasma levels.
Hydralazine is widely distributed in the body. The apparent volume of distribution of hydralazine is approximately 50% body weight. Binding to plasma proteins (chiefly albumin) is 88 to 90%.
Hydralazine crosses the placental barrier and is excreted in the breast milk.
The pattern of the metabolites depends on the subject’s acetylator and presumably hydroxylator status. The main metabolite, NAc-HPZ (N-acetyl-hydrazine-phthalazinone), was found to be the relevant indicator for the drug-related phenotype.
The plasma half-life generally ranges between 1.7 and 3.0 hours in most subjects, but in rapid acetylators it is shorter, averaging 45 minutes.
Hydralazine and its metabolites are rapidly excreted by the kidney and 80% of the oral dose appears in the urine within 48 hours. The bulk of hydralazine excreted is in the form of acetylated and hydroxylated metabolites, some of which are conjugated with glucuronic acid; 2 to 14% is excreted as apparent hydralazine.
Indications And Clinical Uses: Oral: Essential hypertension. Hydralazine is used in conjunction with other antihypertensives such as beta-blockers and diuretics.
Parenteral: Severe hypertension when the drug cannot be given orally or when there is an urgent need to lower blood pressure (e.g., toxemia of pregnancy).
Contra-Indications: Hypersensitivity to hydralazine or other hydrazinophthalazine derivatives. Idiopathic systemic lupus erythematosus (SLE) and related diseases. Severe tachycardia and heart failure with a high cardiac output (e.g., in thyrotoxicosis). Myocardial insufficiency due to mechanical obstruction (e.g., in the presence of aortic or mitral stenosis or constrictive pericarditis). Isolated right-ventricular heart failure due to pulmonary hypertension (cor pulmonale). Acute dissecting aneurysm of the aorta. Coronary artery disease.
Manufacturers’ Warnings In Clinical States: Hydralazine may provoke in a few patients a clinical picture simulating SLE including glomerulonephritis. In its mild form this syndrome is reminiscent of rheumatoid arthritis (arthralgia, sometimes associated with fever and skin rash). When fully developed a syndrome resembling disseminated lupus erythematosus occurs.
Should this SLE-like syndrome develop, treatment should be discontinued immediately. Symptoms and signs usually regress when the drug is discontinued but residua have been detected many years later. Long-term treatment with adreno-corticosteroids may be necessary.
The frequency of these untoward effects increases with dosage and duration of exposure to the drug and is higher in slow than in fast acetylators. When treated with the same dosage, slow acetylators have higher serum concentrations than fast acetylators. The lowest effective dosage should therefore be used for maintenance therapy. If 100 mg daily fails to elicit an adequate clinical effect, the patient’s acetylator status should be evaluated.
Slow acetylators and women run a greater risk of developing this SLE-like syndrome. In such cases dosage should be kept below 100 mg daily and the patients carefully monitored for clinical signs and symptoms suggestive of this syndrome.
Complete blood counts, examination of LE cell preparations, antinuclear antibody titre determinations and urine analysis are indicated before and periodically (e.g., every 6 months) during prolonged therapy with hydralazine even though the patient is asymptomatic. These tests are also indicated if the patient develops arthralgia, fever, chest pain, continued malaise or other unexplained signs or symptoms. If the test results are abnormal, treatment should be discontinued.
Antinuclear antibody may be found in the blood of as many as 50% of patients receiving hydralazine who remain asymptomatic. A positive antinuclear antibody titre requires that the physician carefully weigh the implications of the test results against the benefits to be derived from antihypertensive therapy with hydralazine. Microhematuria and/or proteinuria, in particular together with positive titres of antinuclear antibodies, may be initial signs of immune-complex glomerulonephritis associated with the SLE-like syndrome.
The chronotropic and inotropic effects of hydralazine increase myocardial oxygen requirements. It can cause ECG changes of myocardial ischemia, and in patients with coronary artery disease may precipitate angina pectoris or congestive heart failure. Hydralazine has been implicated in the production of myocardial infarction.
Hydralazine must therefore be used with caution in patients with suspected coronary artery disease. It should be given in combination with a beta-blocker or other suitable sympatholytic agents. The beta-blocker medication should be commenced a few days before the start of treatment with hydralazine.
Patients who have survived a myocardial infarction should not receive hydralazine until postinfarction stabilization has been achieved.
The hyperdynamic circulation caused by hydralazine may accentuate specific cardiovascular inadequacies (e.g., hydralazine may increase pulmonary artery pressure in patients with mitral valvular disease).
Pregnancy: Animal studies indicate that high doses of hydralazine are teratogenic in mice, possibly in rabbits, but not in rats. Teratogenic effects observed were cleft palate and malformation of facial and cranial bones. There are no adequate and well-controlled studies in pregnant women. Although clinical experience does not include any positive evidence of adverse effects on the human fetus, hydralazine should be used during pregnancy only if the benefit clearly justifies the potential risk to the fetus.
Precautions: Postural hypotension may result from hydralazine, but is less common than with ganglionic blocking agents. The drug should be used with caution in patients with cerebral vascular disease since abrupt decreases in blood pressure should be avoided in these patients.
Occupational Hazards: A pronounced lowering of the blood pressure may adversely affect the patient’s reactions (e.g., as in driving or operating machinery).
In hypertensive patients with normal kidneys who are treated with hydralazine, there is evidence of increased renal blood flow and a maintenance of glomerular filtration rate. In some instances, improved renal function has been noted where control values were below normal prior to hydralazine administration. However, as with any antihypertensive agent, hydralazine should be used with caution in patients with advanced renal damage.
In patients with renal impairment, serum levels of hydralazine increased as compared to those in patients with normal renal function, therefore the dose or the dosing interval has to be adapted according to the clinical response, in order to avoid accumulation of the apparent active substance.
In patients with hepatic dysfunction, serum levels of hydralazine increased as compared to those in patients with normal hepatic function, therefore the dose or the dosing interval has to be adapted according to the clinical response, in order to avoid accumulation of the apparent active substance.
Peripheral neuritis, evidenced by paresthesias, numbness and tingling in the extremities has been observed. Published evidence suggests an antipyridoxine effect and the addition of pyridoxine to the regimen if symptoms develop.
Blood dyscrasias consisting of reduction in hemoglobin and red cell count, leukopenia, agranulocytosis and purpura have been reported. Periodic blood counts are advised during therapy. If such abnormalities develop, therapy should be discontinued.
Tumorigenicity and Mutagenicity: Hydralazine in chronic toxicity studies has been shown to increase the incidence of some tumors in aging rodents. A mutagenic potential was observed in some but not all mutagenicity tests. The extent to which these findings indicate a risk to man is uncertain. While long-term clinical observations have not suggested that human cancer is associated with hydralazine use, epidemiologic studies have so far been insufficient to arrive at any conclusion.
Lactation: Hydralazine passes into breast milk. Alternatives to hydralazine should be considered in nursing mothers.
Geriatrics: The elderly may be more sensitive to the hypotensive effects. In addition the risk of hydralazine-induced hypothermia may be increased in elderly patients.
Children: Although there is some experience with the use of hydralazine in children, controlled clinical trials to establish safety and effectiveness in this age group have not been conducted.
Drug Interactions: Concomitant treatment with other vasodilators, calcium antagonists, ACE inhibitors, diuretics, antihypertensives, tricyclic antidepressants and major tranquilizers, as well as the consumption of alcohol, may potentiate the hypotensive effect of hydralazine.
Administration of hydralazine shortly before or after diazoxide may lead to marked hypotension. When potent antihypertensive drugs, such as diazoxide, are used in combination with hydralazine, patients should be continuously observed for several hours for any excessive fall in blood pressure.
Concurrent administration of hydralazine with beta-blockers subject to a strong first-pass effect (e.g., propranolol) may increase their bioavailability. Downward dosage adjustment of these drugs may be required when they are given concomitantly.
MAO inhibitors should be used with caution in patients receiving hydralazine.
Hydralazine may reduce the pressor responses to epinephrine.
Adverse Reactions: The most common adverse reactions are tachycardia, palpitation, anginal symptoms, flushing, headache, and gastrointestinal disturbances. These are more frequent at the start of treatment, especially if the dosage is raised rapidly. However, such reactions generally subside in the further course of treatment or following a reduction of dosage.
The most severe reactions are neuropathy, blood dyscrasias and an acute rheumatoid state resulting in a syndrome resembling disseminated lupus erythematosus (see Warnings and Precautions).
Cardiovascular: tachycardia, palpitation, flushing, hypotension, anginal symptoms, edema, heart failure, paradoxical pressor responses.
Central and Peripheral Nervous System: headache, dizziness, peripheral neuritis as evidenced by paresthesia numbness and tingling, polyneuritis, tremor, agitation, anorexia, anxiety, depression, hallucinations, disorientation, sleep disturbances.
Musculoskeletal: arthralgia, joint swelling, myalgia, muscle cramps.
Skin and Appendages: rash.
Urogenital: proteinuria, increased plasma creatinine, hematuria sometimes in association with glomerulonephritis, acute renal failure, urinary retention, difficulty in micturition.
Gastrointestinal: gastrointestinal disturbances, diarrhea, constipation, nausea, vomiting, jaundice, liver enlargement, abnormal liver function sometimes in association with hepatitis, paralytic ileus.
Blood: anemia, leukopenia, neutropenia, thrombocytopenia with or without purpura, hemolytic anemia, leukocytosis, lymphadenopathy, pancytopenia, splenomegaly, agranulocytosis, antinuclear antibodies.
Sense Organs: increased lacrimation, conjunctivitis, nasal congestion, blurred vision.
Hypersensitivity Reactions: SLE-like syndrome (see Warnings), chills, eosinophilia, hypersensitivity reactions such as pruritus, urticaria, vasculitis, hepatitis.
Respiratory: dyspnea, pleural pain.
Miscellaneous: fever, weight decrease, malaise, exophthalmos, decreased libido, pancreatitis. Hyperuricemia, hyperglycemia and hypokalemia have been reported.
Symptoms And Treatment Of Overdose: Symptoms: hypotension, tachycardia, headache, generalized skin flushing, sweating, nausea and dizziness. Myocardial ischemia with angina pectoris, cardiac arrhythmia, and profound shock can develop.
Further signs may include impairment of consciousness, vomiting, tremor, convulsions, oliguria and hypothermia.
Treatment: No known specific antidote.
Evacuate gastric contents by induction of emesis or gastric lavage, taking adequate precautions against aspiration and for protection of the airway. If general conditions permit, administer activated charcoal slurry and possibly an osmotic cathartic. These procedures may have to be omitted or carried out after cardiovascular status has been stabilized, since they might precipitate cardiac arrhythmias or increase the depth of shock.
Support of the cardiovascular system is of primary importance. Shock should be treated with volume expanders without resorting to use of vasopressors. The use of dopamine to elevate systolic blood pressure to 90 mmHg may be considered in an emergency. If a vasopressor is required, a type that is least likely to precipitate or aggravate cardiac arrhythmia should be used, and the ECG should be monitored while they are being administered. Digitalization may be necessary. Renal function must be monitored and supported as required.
No experience has been reported with extracorporeal or peritoneal dialysis.
Dosage And Administration: The dose must always be individualized and adjusted according to the patient’s blood pressure response.
Oral: Initially, one 10 mg tablet 4 times daily for the first 2 to 4 days. The dose is increased to 25 mg 4 times daily for the remainder of the first week. Dosage is then increased to 50 mg 4 times daily for the second and subsequent weeks of treatment.
For maintenance, adjust dosage to lowest effective levels. The incidence of toxic reactions, particularly the lupus erythematosus syndrome, is highest in the group of patients receiving large doses of hydralazine.
The usual effective maintenance daily dose ranges from 50 to 200 mg. However, the dose should not be increased above 100 mg/day without determining the acetylator phenotype.
After the titration period, some patients may be maintained on a twice daily schedule.
The influence of food on the bioavailability of hydralazine is uncertain. Contradictory results have been obtained.
Note: Geriatric patients may be more sensitive to the effects of the usual adult dose. Response should be monitored and the dosage adjusted accordingly to lowest effective levels.
In patients with renal impairment the dose or the dosing interval should be adapted according to the clinical response, in order to avoid accumulation of the apparent active substance.
In patients with hepatic dysfunction the dose or the dosing interval should be adapted according to the clinical response, in order to avoid accumulation of the apparent active substance.
Parenterally: Patients should be hospitalized. The parenteral administration of hydralazine should always be carried out cautiously and under strict medical supervision.
Blood pressure and heart rate should be checked frequently (every 5 minutes). Blood pressure levels may begin to fall within a few minutes after injection, with an average maximal decrease occurring in 10 to 80 minutes. A satisfactory response can be defined as a decrease in diastolic blood pressure to 90 to 100 mmHg.
The initial dose is 5 to 10 mg, administered by slow i.v. injection in order to avoid precipitous decreases in mean arterial pressure with a critical reduction in cerebral or utero-placental perfusion. In hypertensive crises other than pre-eclampsia/eclampsia, initial doses of up to 40 mg have been used. If necessary, the dose can be repeated after an interval of 20 to 30 minutes.
Apresoline may also be given by continuous i.v. infusion, beginning with a flow rate of 200 to 300 g/min. Maintenance flow rates must be determined individually and are usually within the range of 50 to 150 Âµg/min.
Patients with marked renal damage may require a lower dosage. In cases where there is a previously existing increased intra-cranial pressure, lowering the blood pressure may increase cerebral ischemia.
Most patients can be transferred to oral hydralazine within 24 to 48 hours.
The freshly prepared solution should be used immediately and any remainder discarded.
Direct Injection: Administer the reconstituted solution by slow i.v. injection. For ease of administration the reconstituted solution may be further diluted with physiological saline.
I.V. Infusion: For administration by i.v. infusion, freshly reconstituted hydralazine ampul(s) should be further diluted by the addition of physiological saline, 5% sorbitol solution or Ringer solution. Such admixtures should be used within 24 hours because of the risk of microbial contamination during preparation.
Glucose solution is not suitable for further dilution.
Dilution and Administration: Each mL reconstituted solution contains approximately 19.7 mg hydralazine HCl.
SuppliedSupplied: Ampuls: Each mL of sterile lyophilized solution contains: hydralazine HCl 20 mg. Alcohol-, bisulfite-, gluten-, lactose-, sodium-, parabens- and tartrazine-free. Ampuls of 1 mL, cartons of 10. Protect from heat (store below 30°C) and light.
Tablets: 10 mg: Each yellow, uncoated, biconvex, scored tablet, imprinted FA on one side and CIBA on the other, contains: hydralazine HCl 10 mg. Nonmedicinal ingredients: colloidal silicon dioxide, cornstarch, edetate disodium, FD&C Yellow No. 5, magnesium stearate, mannitol and talc. Energy: 0.54 kJ (0.13 kcal).
25 mg: Each blue, coated tablet, contains: hydralazine HCl 25 mg. Nonmedicinal ingredients: acacia, FD&C Blue No. 1, carnauba wax, cornstarch, gelatin, hydroxypropylmethylcellulose, lactose, magnesium stearate, polyethylene glycol, povidone, sucrose, talc, titanium dioxide and white ink. Energy: 2 kJ (0.48 kcal). Alcohol-, bisulfite-, gluten-, parabens- and tartrazine-free. Bottles of 100. Protect from heat (store below 30°C) and humidity.
50 mg: Each pink, coated tablet, contains: hydralazine HCl 50 mg. Nonmedicinal ingredients: acacia, carnauba wax, cornstarch, FD&C Red No. 3, gelatin, hydroxypropylmethylcellulose, lactose, magnesium stearate, polyethylene glycol, povidone, sucrose, talc, titanium dioxide and white ink. Energy: 1.67 kJ (0.4 kcal). Alcohol-, bisulfite-, gluten-, parabens- and tartrazine-free. Bottles of 100. Protect from heat (store below 30°C) and humidity. (Shown in Product Recognition Section)
APRESOLINE® Novartis Pharmaceuticals Hydralazine HCl Antihypertensive