Isosorbide Dinitrate or Hydralazine HCl: A Comprehensive Overview

Overview:

Isosorbide dinitrate/Hydralazine HCl belongs to a class of vasodilators that are used to treat heart failure. In June 2005, the Food and Drug Administration (FDA) licensed a fixed-dose combination of Isosorbide dinitrate/Hydralazine to treat heart failure in black patients. The findings of the African American Heart Failure Trial (A-HeFT) showed that combination therapy reduced mortality and hospitalization rates in black patients with heart failure. In 2006, the Heart Failure Society of America recognized this combination therapy as the preferred method of care in heart failure therapy in black patients.

Drug Group:

Isosorbide dinitrate/Hydralazine HCl is a fixed-dose combination of two vasodilators that relaxes and expands the heart's muscles to treat angina and other cardiac disorders.

Available Dosage Forms and Strengths:

Isosorbide dinitrate/Hydralazine HCl (20 mg Isosorbide dinitrate and 37.5 mg (milligram) Hydralazine hydrochloride) is available as an orange, biconvex, roughly eight mm in diameter, scored, film-coated tablet and debossed with "20" on one side over the score and "N" on the other side.

For Patients

What Is Heart Failure?

Heart failure, also known as congestive heart failure, is a medical condition in which the heart fails to deliver enough blood to meet the needs of the entire body, either due to inadequate blood flow or insufficient heart function.

How Does Isosorbide Dinitrate or Hydralazine HCl Work?

Isosorbide dinitrate/Hydralazine HCl is a fixed-dose combination of the drugs Isosorbide dinitrate and Hydralazine. Isosorbide dinitrate belongs to a class of medications known as nitrates, which relax the heart's muscles and open the heart's veins and arteries to allow blood to circulate freely to all parts of the body. It may be utilized to alleviate angina and other heart problems caused by a shortage of oxygen and blood. Hydralazine belongs to a class of medications known as vasodilators, which assist in reducing blood pressure by relaxing and expanding the heart's muscles. These drugs help to relieve the symptoms of heart failure.

What Is the Dosage of Isosorbide Dinitrate or Hydralazine HCl?

The following is the suggested dose of Isosorbide dinitrate/Hydralazine HCl for the treatment of heart failure:

• Hydralazine 37.5 mg (Milligram) - Isosorbide dinitrate 20 mg orally three times a day as an initial dose.

• Hydralazine 75 mg - Isosorbide dinitrate 40 mg orally three times per day is the maximum dose.

It is necessary to note that the dosage may differ in accordance with the patient's individual characteristics and responses to therapy.

How Effective Is Isosorbide Dinitrate or Hydralazine HCl?

In clinical studies and practical applications, the efficacy of Isosorbide dinitrate and Hydralazine HCl in heart failure has been examined. The combination medication of Hydralazine and Isosorbide dinitrate has been shown in clinical trials to minimize morbidity and mortality in black individuals with heart failure and low ejection fraction. The African-American Heart Failure Trial (A-HeFT) reported that this combination treatment reduced the mortality rate in black patients with heart failure. As a result, the American College of Cardiology, American Heart Association, and the Heart Failure Society of America listed Hydralazine-Isosorbide dinitrate (H-ISDN) as a class I recommendation for black patients with heart failure with a low ejection fraction in their guidelines.

However, in clinical practice, the efficacy of Isosorbide dinitrate or Hydralazine HCl may vary. A study that looked at the usage and effects of Isosorbide dinitrate and Hydralazine HCl therapy in elderly patients hospitalized with heart failure and a low ejection fraction revealed that starting Isosorbide Dinitrate/Hydralazine HCl therapy at hospital discharge was unusual, and adherence to therapy was low. The study found no significant differences in outcomes between patients treated with Isosorbide dinitrate/Hydralazine HCl and those who were not treated at the time of discharge.

What Are the Things to Inform the Doctor Before Taking the Drug?

Here are some essential things to inform the doctor before starting Isosorbide dinitrate/Hydralazine HCl treatment:

1. If patients are allergic to Hydralazine, Isosorbide dinitrate, Isosorbide mononitrate, or Nitroglycerin, do not take Isosorbide dinitrate/Hydralazine HCl.

2. Tell the doctor if patients have any of the following conditions to ensure Isosorbide dinitrate/Hydralazine HCl is safe for the patients:

• Lupus (an autoimmune illness that arises when the tissues and organs of the body are attacked by its own immune system).

• Low blood pressure.

• Pulmonary arterial hypertension (a type of excessive blood pressure that affects the lungs’ arteries and the right side of the heart).

3. It is unknown whether Isosorbide dinitrate/Hydralazine HCl will cause harm to an unborn child. If patients are pregnant or want to become pregnant, inform the doctor.

4. It is unknown whether Hydralazine and Isosorbide dinitrate enter breast milk or are harmful to breastfeeding infants. If patients are breast-feeding a baby, inform the doctor.

How Is Isosorbide Dinitrate or Hydralazine HCl Administered?

• Take this medication orally three times per day, as instructed by the doctor.

• The dosage is determined by the patient's medical condition as well as the responses to treatment. The doctor could initially begin with a low dose and then gradually raise it. Follow the doctor's advice properly.

• Take the medicine on a consistent schedule. Do not take the medicine more frequently than prescribed.

• Do not discontinue the drug unless advised by the doctor or a health care expert. Some conditions may worsen if the medicine is abruptly discontinued. The dose has to be reduced gradually.

How Is Isosorbide Dinitrate or Hydralazine HCl Administered?

Isosorbide dinitrate/Hydralazine HCl should be started with one Isosorbide dinitrate/Hydralazine HCl tablet three times per day. If tolerated, increase to a maximum of two pills three times daily.

Despite Isosorbide Dinitrate/Hydralazine HCl titration being done three to five days quickly, some patients may develop side effects and require more time to reach their maximum tolerable dose. If unacceptable side effects develop, the dosage can be reduced to one-half of Isosorbide dinitrate/Hydralazine HCl tablet three times a day. As soon as the negative effects have subsided, efforts should be made to titrate.

What Are the Side Effects of Isosorbide Dinitrate/Hydralazine HCl?

If patients experience the following, they should seek emergency medical attention.

• Hives (allergic reaction).

• Difficulty breathing.

• Swelling of the face, lips, tongue, or neck.

This medicine might produce headaches, especially when first used. As patients continue to take the medication, their headaches may get less intense. Do not discontinue Isosorbide dinitrate/Hydralazine HCl. Before taking any headache medicine, consult the doctor.

If patients develop any of the following symptoms, contact the doctor right away:

• A light-headed sensation, as if people might pass out.

• Tingling or numbness in the extremities.

• Joint ache or swelling.

• Fever, chest discomfort, and general malaise.

• Rapid heart rate.

• More severe than usual shortness of breath.

• Heart attack symptoms such as sweating, chest discomfort or pressure, pain radiating to the jaw or shoulder, and nausea.

Some side effects are more prevalent in elderly people.

The following are some of the most common adverse effects of Isosorbide Dinitrate/Hydralazine HCl:

• Headache.

• Dizziness.

Missed Dose:

If patients forget to take a dose, take it as soon as possible. If the next dose is approaching, take only that dose. Do not take extra doses.

Overdose:

The overdose symptoms include the following.

• Warmth.

• Confusion.

• Dizziness.

• Headache.

• Rapid heartbeats.

• Chest discomfort.

These overdose symptoms require emergency medical assistance or call the Poison Help Line.

Storage:

• Keep away from children's reach.

• Place at room temperature between 15 and 30 degrees Celsius (59 and 86 degrees Fahrenheit). Light should be avoided. The container should be tightly shut. Discard any unused medicine after its expiration.

For Doctors:

Indications:

Isosorbide dinitrate/ Hydralazine hydrochloride is indicated for the therapeutic management of heart failure as a supplement to standard therapy in self-declared black patients to extend survival, delay hospitalization for heart failure, and enhance patient-reported functional status.

• Limitations of Use: There is not much experience regarding New York Heart Association (NYHA) class IV heart failure patients.

Pharmacological Aspects of Isosorbide Dinitrate/Hydralazine HCl

• Pharmacodynamics: The reason for the beneficial therapeutic properties of Isosorbide dinitrate and Hydralazine Hydrochloride tablets is unknown. In a short trial of individuals with chronic heart failure given single doses of Hydralazine 75 mg, Isosorbide dinitrate 20 mg, and the combination, the combination resulted in a statistically significant reduction in pulmonary capillary wedge pressure when compared to Hydralazine alone. However, the combination had no larger effect on cardiac output, renal blood flow, or limb blood flow than Hydralazine alone. There has been no investigation into the hemodynamic effects of multiple dosages.

• Mechanism of Action: Isosorbide dinitrate is a vasodilator that relaxes vascular smooth muscle by producing nitric oxide and activating guanylyl cyclase in the arteries and veins. After 24 hours of continuous medication, clinical trials have demonstrated that active medicines are no more beneficial than placebo. Attempts to get over nitrate tolerance through dose escalation have been unsuccessful, and responsiveness to nitrates is restored only after nitrates have been gone for several hours. Nitrate tolerance may also be reduced by Hydralazine hydrochloride, a selective dilator of arterial smooth muscle.

• Half-Life in Adults: Hydralazine had a half-life of four hours, while Isosorbide dinitrate had a half-life of two hours.

Pharmacokinetics:

The pharmacokinetics are as follows:

Absorption: In healthy adults, the bioavailability of Hydralazine and Isosorbide dinitrate tablets was investigated. Peak plasma concentrations of Hydralazine and Isosorbide dinitrate were attained in one hour after a 75-mg oral dosage. The effect of diet on their bioavailability is unknown at the moment. The mean absolute bioavailability of a single oral dose in individuals with heart failure ranges from ten to twenty-six percent. Isosorbide dinitrate absorption is practically complete, with a bioavailability of approximately twenty-five percent on average. Serum concentrations peak approximately one hour after intake.

Distribution:

• Hydralazine Hydrochloride: In congestive heart failure patients, the steady-state volume of distribution was 2.2 L/kg (liters per kilogram) after the intravenous injection of Hydralazine at a dose of 0.3 mg/kg (milligrams per kilogram).
• Isosorbide Dinitrate: Isosorbide dinitrate has a volume of distribution of two to four L/kg. The protein binds roughly twenty-eight percent of the circulating Isosorbide dinitrate. Isosorbide dinitrate accumulates extensively in pectoral muscle and saphenous vein walls under steady-state conditions compared to concomitant plasma concentrations.

Metabolism: Hydralazine is broken down by acetylation, ring oxidation, and conjugation with endogenous molecules such as pyruvic acid. The acetylator phenotype influences bioavailability, with about fifty percent of patients being fast acetylators. Hydralazine, Pyruvate hydrazone, and Methyltriazolophthalazine are the major circulating metabolites, with Hydralazine being the most pharmacologically active. Acetylhydrazinophthalazinone is the most common metabolite discharged in urine. Isosorbide dinitrate undergoes significant first-pass metabolism in the liver, with a serum half-life of about one hour and a clearance rate of two to four L/minute. Both metabolites are biologically active, with a half-life of roughly five hours for 5-mononitrate.

Excretion:

• Hydralazine: Metabolism is the primary route of Hydralazine disposal, with only trace amounts excreted in urine.
• Isosorbide Dinitrate: The majority of Isosorbide dinitrate is removed renally as conjugated metabolites.

Clinical Studies:

Two placebo-controlled clinical trials in individuals with mild to severe heart failure comparing Isosorbide dinitrate/Hydralazine HCl to a combination of Isosorbide dinitrate and Hydralazine hydrochloride found barely any difference in mortality between the two treatment groups. In black individuals, however, there was a trend toward preferring Hydralazine and Isosorbide dinitrate. In the other trial, Isosorbide dinitrate/Hydralazine HCl was found to be superior to enalapril in terms of mortality, but there was little variance in survival in the black group. The study was terminated early since there was a significant reduction in all-cause mortality and a 39 percent reduction in the likelihood of initial hospitalization for heart failure.

Contraindications of Isosorbide Dinitrate/Hydralazine HCl

• Isosorbide dinitrate/Hydralazine HCl is not recommended for people with a history of allergies to organic nitrates.

• Isosorbide dinitrate/Hydralazine HCl should not be used in patients using PDE-5 inhibitors such as Avanafil, Sildenafil, Tadalafil, or Vardenafil. Concurrent usage can result in severe hypotension, syncope, and myocardial ischemia.

• Isosorbide dinitrate/Hydralazine HCl should not be used in patients who are taking soluble guanylate cyclase (sGC) stimulants. Concurrent usage can result in hypotension.

Warnings and Precautions:

The warnings and precautions associated are as follows:

• Hypotension: Even low dosages of Isosorbide dinitrate/Hydralazine HCl can cause symptomatic hypotension, especially in an upright position. Patients who have been deprived of volume or sodium are more likely to develop hypotension; rectify before starting Isosorbide dinitrate/Hydralazine HCl.

• Systemic Lupus Erythematosus: Hydralazine hydrochloride has been linked to drug-induced systemic lupus erythematosus (SLE). When Hydralazine hydrochloride is stopped, symptoms and signs frequently return.

• Severe Ischemic Heart Disease: In patients with hypertrophic cardiomyopathy, Hydralazine hydrochloride can produce tachycardia and hypotension, potentially leading to myocardial ischemia and angina.

• Peripheral Neuritis: Hydralazine hydrochloride has been linked to peripheral neuritis, which manifests as paresthesia, numbness, and tingling and may be due to an antipyridoxine action. If such symptoms occur, Pyridoxine should be added to Isosorbide dinitrate/Hydralazine HCl medication.

Drug Interactions

• PDE5 inhibitors (Phosphodiesterase-5 inhibitors) such as Avanafil, Sildenafil, Vardenafil, and Tadalafil are known to stimulate the hypotensive effects of organic nitrates.

• Isosorbide Dinitrate/Hydralazine HCl should not be used in patients who are using a soluble guanylate cyclase (sGC) stimulant. Concurrent usage may result in severe hypotension, syncope, or myocardial ischemia.

Specific Considerations:

• Pregnancy: Isosorbide dinitrate/Hydralazine HCl, an antihypertensive medication, has not been investigated in pregnant women due to the risk of embryotoxicity and teratogenicity. Another antihypertensive medication, Hydralazine hydrochloride, has been linked to increased maternal hypotension, placental abruption, cesarean sections, oliguria, deleterious effects on fetal heart rate, and poorer Apgar scores. During 15 pregnancies, 13 individuals with long-standing hypertension were given a combination of Propranolol and Hydralazine hydrochloride, resulting in 14 live births and one stillbirth. Hydralazine hydrochloride and its metabolites were discovered in maternal and umbilical plasma using a non-selective assay in pregnant women treated with the drug. In pregnant women, Isosorbide dinitrate is prescribed to manage acute and sub-chronic hypertension; however, there have been no trials evaluating its effects in a chronic regimen on pregnant women and fetuses. This drug falls under FDA pregnancy category C.

• Lactation: It is unclear whether Hydralazine or Isosorbide dinitrate is excreted in human milk.

• Pediatric Use: Isosorbide dinitrate/Hydralazine HCl's safety and effectiveness in children have not been established.

• Geriatric Use: Isosorbide dinitrate/Hydralazine HCl clinical trials did not include a considerable number of patients beyond the age of 65 and up to assess whether older patients respond differently than younger subjects. Other clinical studies have found no variations in responsiveness between older and younger patients. Overall, the dose for an elderly patient should begin at the low end of the dosing range, reflecting the higher prevalence of reduced hepatic and renal function, as well as concomitant disease or other pharmacological regimens. It is possible that Isosorbide dinitrate, its active metabolites, and Hydralazine will be slowly removed in older patients.

• Renal Impairment: There have been no investigations of Isosorbide Dinitrate/Hydralazine HCl in renal impairment. There is no need to change the dose of hydralazine or Isosorbide dinitrate. Hydralazine's dialysis ability has not been determined. Dialysis is ineffective for eliminating Isosorbide dinitrate or its metabolite, Isosorbide-5-mononitrate, from the human body.

• Liver Impairment: It has not been studied whether hepatic impairment affects the pharmacokinetics of Hydralazine alone. Isosorbide dinitrate in cirrhotic patients has higher amounts.