Hydralazine

Hydralazine

20mg/ml

Solution for Injection (IM/IV)

Drug Category: Direct Vasodilator

Description:

A clear colorless solution to pale yellow solution in USP.

Pharmacokinetics:

Hydralazine given orally is rapidly absorbed from the gastrointestinal tract but undergoes considerable first pass metabolism by acetylation in the gastrointestinal mucosa and liver. The rate of metabolism is genetically determined and depends upon the acetylator status of the individual. The bioavailability of hydralazine has been reported to be about 35% in slow acetylators and less in fast acetylators; thus plasma concentrations after a given dose are higher in slow acetylators. Peak plasma concentrations have been reported to occur after about one hour. Hydralazine is chiefly present in plasma as hydrazone conjugate with pyruvic acid. Plasma protein binding is about 90%. The drug is widely distributed, notably into arterial walls. Systemic metabolism in the liver is by hydroxylation of the ring system and conjugation with glucuronic acid; most sources suggest that N-acetylation is not of major importance in systemic clearance and that therefore acetylator status does not affect elimination. Hydralazine is excreted mainly in urine as metabolites. The apparent average half-life for hydralazine has been reported to vary from about 45 minutes to about 8 hours, with a number of sources giving the average as about 2 to 4 hours. Some of the variation may be due to problems with analytical procedures. The half-life is prolonged in renal impairment and may be up to 16 hours in patients with a creatinine clearance of less than 20 ml/minute. Hydralazine crosses the placenta and is distributed into breast milk.

Indications:

Hydralazine is used for the treatment of hypertension usually with a beta blocker and a thiazide diuretic. It is also used with isosorbide dinitrate in the management of heart failure.

Dosage and Administration

In hypertensive crises, hydralazine hydrochloride is given in doses of 5 to 10 mg by slow intravenous injection, repeated if necessary after 20 to 30 minutes. Alternatively, it may be given by continuous intravenous infusion in an initial dose of 200 to 300 micrograms per minute. The usual maintenance dose range is 50 to 150 micrograms per minute. Hydralazine hydrochloride can be also given by intramuscular injection.

Adverse Effects:

Adverse effects are common with hydralazine, particularly tachycardia, palpitations, angina pectoris, sever headache, and gastrointestinal disturbances such as anorexia, nausea, vomiting, and diarrhea. These adverse effects, and flushing, dizziness, and nasal congestion, which occur less often, may be seen at the start of treatment, especially if the dose is increased quickly. They generally subside with continued treatment. Other less common adverse effects include orthostatic hypotension, fluid retention with edema and weight gain, conjunctivitis, lachrymation, tremor, and muscle cramps. Hydralazine may deplete pyridoxine in the body, and can produce peripheral neuropathy with numbness and tingling of the extremities. Occasionally, hepatotoxicity, blood dyscrasia, hemolytic anemia, difficulty in urinating, glomerulonephritis, constipation, paralytic ileus, depression, and anxiety occur. Hypersensitivity reactions including fever, chills, pruritus, and rashes have been reported, and eosinophilia may occur. Antinuclear antibodies may develop after prolonged use of large doses, and a condition resembling Systemic Lupus Erythematosus may occur. The incidence is greater in slow acetylators, patients with renal impairment, women, and patients taking more than 100mg of hydralazine daily. The symptoms usually disappear when the drug is withdrawn; some patients may require treatment with corticosteroids. Acute overdosage may produce hypotension, tachycardia, myocardial ischemia, arrhythmias, shock and coma.

Carcinogenicity. Although earlier reports suggested that hydralazine might be carcinogenic, there was no evidence from a survey of 1978 patients with lung or colorectal carcer and 6807 controls that there was an increased risk o these neoplasms.

Effects on the blood. Three cases of thrombocytopenia were reported in neonates whose mothers had been treated with hydralazine for some months before deliver. The thrombocytopenia and bleeding was transient with full recovery occurring within a few weeks. No adverse effects were noticed in the mothers.

Effects on the cardiovascular system. Paradoxical sever hypertension developed after oral or intramuscular hydralazine on 3 occasions in a patient with renal artery stenosis.

Effects on the kidney. Rapidly progressive glomerulonephritis with focal and segmental lesions, usually accompanied by necrosis and crescents formation, has been reported in patients given hydralazine. The condition is reported to be associated with the presence of antinuclear antibodies and slow acetylator status, factors associated with the development of hydralazine induced lupus erythematosus. However, renal involvement is much less common in drug-induced lupus, and in a report of 15 such cases men and women and fast and slow acetylators were equally affected. In addition the criteria for Systemic Lupus Erythematosus were not usually fulfilled in these patients and it was suggested withdrawal of hydralazine generally results in some improvement in renal function but complete recovery is uncommon; sever cases may require immunosuppressive therapy.

Effects on the skin. Pruritus and skin rashes have been reported with hydralazine use. A 59-year-old woman who had been taking hydralazine 2t5mg three times daily for 6 months developed sysmtoms of Sweet's syndrome (erythematosus plaques and nodules and hemorrhagic blisters). Symptoms began to subside on withdrawal of the drug but recurred on rechallenge. The condition resolved on discontinuation of hydralazine and treatment with prednisolone.

Lupus erythematosus. Lupus erythematosus is a well-documented adverse effects of hydralazine. Onset is typically delayed from 1 month to 5 years from the start of treatment, and the most common symptoms are arthralgia or arthritis, usually non-deforming, in up to 95% of patients, fever and myalgia in about 50%, and pleuropulmonary involvemnt, manifesting as pleurisy, pleural effusions, or pulmonary infiltrates in up to 30%. Renal involvement is reported to be less common than idiopathic Systemic Lupus Erythematosus and there is some uncertainty as to whether the glomerulonephritis sometimes seen in patients receiving hydralazine should be considered lupus nephritis (see Effects on the Kidneys). Nonetheless, a 20% incidence of renal involvement has been reported. Other complications and symptoms associated with lupus erythematosus in patients taking hydralazine include cutaneous ulceration, bilateral retinal vasculitis, reactive hypoglycemia (although the attribution is uncertain), life-threatening cardiac tamponade, and hoarseness and stridor secondary to vocal cord palsy, which progressed to respiratory arrest. Skin rashes are reported to be less prominent than with the idiopathic from of the disease. Fatalities have occurred, but appear to be rare. Estimates of the overall incidence of hydralazine-associated lupus erythematosus vary from about 1.2 to 5% or more. Th syndrome appear to occur only in patients who develop antinuclear antibodies while receiving hydralazine, but the incidence of positive antinuclear antibody tests is much higher than that of lupus, at up to 60%, so the presence of antinuclear antibodies alone is not diagnostic. There is a strong relationship with drug dose, acetylator status, and patient gender, the syndrome being more common in slow acetylators and women, and in patients receiving 100mg daily or more. Although it has been reported that hydralazine-associated lupus was more frequent in patients with HLA-DR4 antigen this was not confirmed by others and subsequent work has suggested that the association is rather with the non-expressing or null forms of the adjacent complement C4 in vitro and might exacerbate complement deficiency (which is known to be associated with idiopathic Systemic Lupus Erythematosus) in patients with an already low lever of C4 due to a null allele.

Overdosage and Treatment of Adverse Effects

Withdrawal of hydralazine or dosage reduction reverses many of the adverse effects. Peripheral neuropathy has been reported to be alleviated by pyridoxine. If overdose occurs the benefit of gastric decontamination is uncertain, but activated charcoal may be given, If the patient presents within 1 hour of ingestion. Symptomatic and supportive treatment, including plasma expanders for shock and a beta blocker for tachycardia, should be given as necessary. Hypotension may respond to placing the patient in the supine position with the feet raised. If possible, pressor drugs should be avoided. If a pressor is necessary, one should be chosen that will not cause tachycardia or exacerbate arrhythmias; adrenaline should not be used.

Precaution:
Hydralazine is contraindicated in patients with sever tachycardia, dissecting aortic aneurysm, heart failure with high output, cor pulmonale, or myocardial insufficiency due to mechanical obstruction, for example aortic or mitral stenosis or constrictive pericarditis. Hydralazine is also contraindicated in patients with idiopathic Systemic Lupus Erythematosus and related disorders. Hydralazine-induced vasodilation produces myocardial stimulation. It should therefore be used with caution in patients with ischemic heart disease since it can increase angina and it should not be given after myocardial infarction until the patient's condition has stabilized. Patients with suspected or confirmed ischemia heart disease should be given hydralazine under cover of a beta blocker, which should be started a few days before hydralazine, in order to prevent myocardial stimulation. If given to patients with heart failure they should be monitored for orthostatic hypotension and tachycardia during the initial stages of therapy, preferably in hospital. If treatment with hydralazine is to be stopped in patients with heart failure it should generally be withdrawn gradually. Hydralazine should be used with caution in patients with cerebrovascular disorders. The dose of hydralazine should be reduced or the dosage interval prolonged in patients with hepatic or renal impairment. Complete blood counts and antinuclear antibody determinations should be carried out about every 6 months during long term therapy. Urine analysis (for microhematuria and proteinuria) is also recommended. Hydralazine is teratogenic in some species of animals and should therefore be avoided during the first tow trimesters of pregnancy. Patients may experience impaired, especially at the start of therapy, and should not drive or operate machinery if affected.

Breastfeeding. Hydralazine is distributed into mild in small amounts (see Pregnancy) but no adverse effects have been seen in infants and the American Academy of Pediatrics therefore considers hydralazine to be usually compatible with breastfeeding.

Pregnancy. Hydralazine should be avoided during first two trimesters of pregnancy.

Drug Interactions:

The hypotensive effect on hydralazine may be enhanced by other drugs with hypotensive action. Severe hypotension may occur if hydralazine and diazoxide are given together. However, some interactions with an antihypertensive may be beneficial: thiazide diuretics also counteract the fluid retention caused by hydralazine, and beta-blockers diminish the cardiac accelerating effects.

Storage Condition

Store at temperatures not exceeding 25^oC. Protect from light and moisture. The injection should be discharge if any visible article appears.