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HydrALAZINE


Pronunciation

 (hye DRAL a zeen)


Synonyms

 Apresoline [DSC]; Hydralazine Hydrochloride


Generic Available

 Yes


Canadian Brand Names

 Apo-Hydralazine®; Apresoline®; Novo-Hylazin; Nu-Hydral


Use

 Management of moderate to severe hypertension, congestive heart failure, hypertension secondary to pre-eclampsia/eclampsia; treatment of primary pulmonary hypertension


Pregnancy Risk Factor

 C


Pregnancy Implications

 Crosses the placenta. One report of fetal arrhythmia; transient neonatal thrombocytopenia and fetal distress reported following late 3rd trimester use. A large amount of clinical experience with the use of this drug for management of hypertension during pregnancy is available. Available evidence suggests safe use during pregnancy.


Lactation

 Enters breast milk/compatible


Contraindications

 Hypersensitivity to hydralazine or any component of the formulation; mitral valve rheumatic heart disease


Warnings/Precautions

 May cause a drug-induced lupus-like syndrome (more likely on larger doses, longer duration). Adjust dose in severe renal dysfunction. Use with caution in CAD (increase in tachycardia may increase myocardial oxygen demand). Use with caution in pulmonary hypertension (may cause hypotension). Patients may be poorly compliant because of frequent dosing.

Monitor blood pressure closely following I.V. administration. Response may be delayed and unpredictable in some patients. Titrate cautiously to response. Hydralazine-induced fluid and sodium retention may require addition or increased dosage of a diuretics.


Adverse Reactions

 Frequency not defined.

Cardiovascular: Tachycardia, angina pectoris, orthostatic hypotension (rare), dizziness (rare), paradoxical hypertension, peripheral edema, vascular collapse (rare), flushing

Central nervous system: Increased intracranial pressure (I.V., in patient with pre-existing increased intracranial pressure), fever (rare), chills (rare), anxiety*, disorientation*, depression*, coma*

Dermatologic: Rash (rare), urticaria (rash), pruritus (rash)

Gastrointestinal: Anorexia, nausea, vomiting, diarrhea, constipation, adynamic ileus

Genitourinary: Difficulty in micturition, impotence

Hematologic: Hemolytic anemia (rare), eosinophilia (rare), decreased hemoglobin concentration (rare), reduced erythrocyte count (rare), leukopenia (rare), agranulocytosis (rare), thrombocytopenia (rare)

Neuromuscular & skeletal: Rheumatoid arthritis, muscle cramps, weakness, tremor, peripheral neuritis (rare)

Ocular: Lacrimation, conjunctivitis

Respiratory: Nasal congestion, dyspnea

Miscellaneous: Drug-induced lupus-like syndrome (dose related; fever, arthralgia, splenomegaly, lymphadenopathy, asthenia, myalgia, malaise, pleuritic chest pain, edema, positive ANA, positive LE cells, maculopapular facial rash, positive direct Coombs' test, pericarditis, pericardial tamponade), diaphoresis

*Seen in uremic patients and severe hypertension where rapidly escalating doses may have caused hypotension leading to these effects.


Overdosage/Toxicology

 Symptoms of overdose include hypotension, tachycardia, and shock. Treatment is supportive and symptomatic.


Drug Interactions

 Inhibits CYP3A4 (weak)

Beta-blockers (metoprolol, propranolol) serum concentrations and pharmacologic effects may be increased. Monitor cardiovascular status.

Propranolol increases hydralazine's serum concentrations. Acebutolol, atenolol, and nadolol (low hepatic clearance or no first-pass metabolism) are unlikely to be affected.

NSAIDs may decrease the hemodynamic effects of hydralazine; avoid use if possible or closely monitor cardiovascular status.


Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (may increase CNS depression).

Food: Food enhances bioavailability of hydralazine.

Herb/Nutraceutical: Avoid dong quai if using for hypertension (has estrogenic activity). Avoid ephedra, yohimbe, ginseng (may worsen hypertension). Avoid garlic (may have increased antihypertensive effect).


Stability

 Intact ampuls/vials of hydralazine should not be stored under refrigeration because of possible precipitation or crystallization. Hydralazine should be diluted in NS for IVPB administration due to decreased stability in D5W. Stability of IVPB solution in NS is 4 days at room temperature.


Compatibility

 Stable in dextran 6% in dextrose, dextran 6% in NS, D5LR, D5 1 /4NS, D5 1 /2NS, D5NS, D10W, LR, 1 /2NS, NS; not stable in D5W

Y-site administration: Compatible: Heparin, hydrocortisone sodium succinate, potassium chloride, verapamil, vitamin B complex with C. Incompatible: Aminophylline, ampicillin, diazoxide, furosemide. Variable (consult detailed reference): Nitroglycerin

Compatibility when admixed: Compatible: Dobutamine. Incompatible: Aminophylline, ampicillin, chlorothiazide, edetate calcium disodium, ethacrynate, hydrocortisone sodium succinate, mephentermine, methohexital, nitroglycerin, phenobarbital, verapamil


Mechanism of Action

 Direct vasodilation of arterioles (with little effect on veins) with decreased systemic resistance


Pharmacodynamics/Kinetics

Onset of action: Oral: 20-30 minutes; I.V.: 5-20 minutes

Duration: Oral: Up to 8 hours; I.V.: 1-4 hours; Note: May vary depending on acetylator status of patient

Distribution: Crosses placenta; enters breast milk

Protein binding: 85% to 90%

Metabolism: Hepatically acetylated; extensive first-pass effect (oral)

Bioavailability: 30% to 50%; increased with food

Half-life elimination: Normal renal function: 2-8 hours; End-stage renal disease: 7-16 hours

Excretion: Urine (14% as unchanged drug)


Dosage

Children:

Oral: Initial: 0.75-1 mg/kg/day in 2-4 divided doses; increase over 3-4 weeks to maximum of 7.5 mg/kg/day in 2-4 divided doses; maximum daily dose: 200 mg/day

I.M., I.V.: 0.1-0.2 mg/kg/dose (not to exceed 20 mg) every 4-6 hours as needed, up to 1.7-3.5 mg/kg/day in 4-6 divided doses

Adults:

Oral: Hypertension:

Initial dose: 10 mg 4 times/day for first 2-4 days; increase to 25 mg 4 times/day for the balance of the first week

Increase by 10-25 mg/dose gradually to 50 mg 4 times/day (maximum: 300 mg/day); usual dose range (JNC 7): 25-100 mg/day in 2 divided doses

Oral: Congestive heart failure:

Initial dose: 10-25 mg 3-4 times/day

Adjustment: Dosage must be adjusted based on individual response

Target dose: 75 mg 4 times/day in combination with isosorbide dinitrate (40 mg 4 times/day)

Range: Typically 200-600 mg daily in 2-4 divided doses; dosages as high as 3 g/day have been used in some patients for symptomatic and hemodynamic improvement. Hydralazine 75 mg 4 times/day combined with isosorbide dinitrate 40 mg 4 times/day were shown in clinical trials to provide a mortality benefit in the treatment of CHF. Higher doses may be used for symptomatic and hemodynamic improvement following optimization of standard therapy.

I.M., I.V.:

Hypertension: Initial: 10-20 mg/dose every 4-6 hours as needed, may increase to 40 mg/dose; change to oral therapy as soon as possible.

Pre-eclampsia/eclampsia: 5 mg/dose then 5-10 mg every 20-30 minutes as needed.

Elderly: Oral: Initial: 10 mg 2-3 times/day; increase by 10-25 mg/day every 2-5 days.

Dosing interval in renal impairment:

Clcr 10-50 mL/minute: Administer every 8 hours.

Clcr<10 mL/minute: Administer every 8-16 hours in fast acetylators and every 12-24 hours in slow acetylators.

Hemodialysis: Supplemental dose is not necessary.

Peritoneal dialysis: Supplemental dose is not necessary.


Administration

 Inject over 1 minute. Hypotensive effect may be delayed and unpredictable in some patients.


Monitoring Parameters

 Blood pressure (monitor closely with I.V. use), standing and sitting/supine, heart rate, ANA titer


Dietary Considerations

 Administer with meals.


Patient Education

 Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. Take as directed, with meals. Avoid alcohol. This medication does not replace other antihypertensive interventions; follow prescriber's instructions for diet and lifestyle changes. Weigh daily at the same time, in the same clothes for the first 2 weeks and weekly thereafter. Report weight gain >5 lb/week, swelling of feet or ankles. May cause dizziness or weakness (change position slowly when rising from sitting or lying position, climbing stairs, and avoid driving or activities requiring alertness until response to drug is known); nausea or vomiting (small, frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); impotence (reversible); diarrhea (boiled milk, buttermilk, or yogurt may help); or constipation (increased exercise, fluids, fruit, or fiber may help). Report chest pain, rapid heartbeat, or palpitations; flu-like symptoms; respiratory difficulty; skin rash; numbness and tingling of extremities; muscle cramps, weakness, or tremors; or unresolved GI problems. Pregnancy precaution: Inform prescriber if you are or intend to become pregnant


Nursing Implications

 Aid with ambulation, rising may cause orthostasis


Anesthesia and Critical Care Concerns/Other Considerations

 May be combined with isosorbide dinitrate for the treatment of heart failure. It is considered to be safe for the management of blood pressure during pregnancy.


Cardiovascular Considerations

 May be combined with isosorbide dinitrate for the treatment of heart failure. This combination has shown to decrease cardiovascular morbidity and mortality in patients with heart failure. The combination of hydralazine and isosorbide dinitrate should be considered in ACE inhibitor intolerant patients or in patients who develop symptoms regardless of maximal ACE inhibitor therapy. One disadvantage of combination therapy includes the need for multidosing.

For the management of hypertension, hydralazine may be used alone or in combination with other agents. It is considered to be safe for the management of blood pressure during pregnancy.


Dental Health: Effects on Dental Treatment

 No significant effects or complications reported


Dental Health: Vasoconstrictor/Local Anesthetic Precautions

 No information available to require special precautions


Mental Health: Effects on Mental Status

 May cause drowsiness


Mental Health: Effects on Psychiatric Treatment

 Concurrent use with MAO inhibitors may result in significant decrease in blood pressure; use cautiously


Dosage Forms

Injection, solution, as hydrochloride: 20 mg/mL (1 mL)

Tablet, as hydrochloride: 10 mg, 25 mg, 50 mg, 100 mg


Extemporaneously Prepared

 An oral solution (20 mg/5 mL) has been made from 20 mL of the hydralazine injection (20 mg/mL), 8 mL of propylene glycol and purified water USP qs ad 100 mL; expected stability: 30 days if refrigerated

A flavored syrup (1.25 mg/mL) has been made using seventy-five hydralazine hydrochloride 50 mg tablets, dissolved in 250 mL of distilled water with 2250 g of Lycasin® (75% w/w maltitol syrup vehicle); edetate disodium 3 g and sodium saccharin 3 g dissolved in 50 mL distilled water was added; solution was preserved with 30 mL of a solution containing methylparaben 10% (w/v) and propylparaben 2% (w/v) in propylene glycol; flavored with 3 mL orange flavoring; qs ad to 3 L with distilled water and then pH adjusted to pH of 3.7 using glacial acetic acid; measured stability was 5 days at room temperature (25°C); less than 2% loss of hydralazine occurred at 2 weeks when syrup was stored at 5°C

Alexander KS, Pudipeddi M, and Parker GA, "Stability of Hydralazine Hydrochloride Syrup Compounded From Tablets," Am J Hosp Pharm , 1993, 50(4):683-6.

Nahata MC and Hipple TF, Pediatric Drug Formulations , 2nd ed, Cincinnati, OH: Harvey Whitney Books Co, 1992.


References

Chobanian AV, Bakris GL, Black HR, et al, "The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 Report," JAMA , 2003, 289(19):2560-71.

"Consensus Recommendations for the Management of Chronic Heart Failure. On Behalf of the Membership of the Advisory Council to Improve Outcomes Nationwide in Heart Failure," Am J Cardiol , 1999, 83(2A):1A-38A.

Erstad BL and Barletta JF, "Treatment of Hypertension in the Perioperative Patient," Ann Pharmacother , 2000, 34(1):66-79.

Hunt SA, Baker DW, Chin MH, et al, "ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult: Executive Summary. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure)," J Am Coll Cardiol , 2001, 38(7):2101-13.


International Brand Names

 Alphapress® (AU, IL); Apo-Hydralazine® (CA, SG); Apresolina® (BR); Apresoline® (AU, CA, GB, HK, IE, NL, NZ, TH, ZA); Apresolin® (NO, SE); Cesoline Y® (TH); Hidral® (AR); Hidralazina Clorhidrato® (CL); Hidralazina L.CH.® (CL); Hydralazine® (CY); Hydrapres® (AR, CR, DO, ES, GT, PA, SV); Hydrapress® (JP); Hyperphen® (ZA); Nepresol® (BR); Novo-Hylazin (CA); Nu-Hydral (CA); Rolab-Hydralazine HCl® (ZA)


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