Isosorbide dinitrate + Hydralazine hydrochloride

Isosorbide dinitrate + Hydralazine hydrochloride is an antihypertensive agent belonging to the Vasodilator class.

Peak plasma concentrations of the two active metabolites, isosorbide-2-mononitrate, and isosorbide-5-mononitrate, were 98 and 364 ng/mL/65 kg, respectively, at about 2 hours. Hydralazine hydrochloride: After intravenous administration of hydralazine in a dose of 0.3 mg/kg, the steady-state volume of distribution in patients with congestive heart failure was 2.2 L/kg. Isosorbide dinitrate: The volume of distribution of isosorbide dinitrate is 2 to 4 L/kg. About 28% of circulating isosorbide dinitrate is protein bound. Under steady-state conditions, isosorbide dinitrate accumulates significantly in muscle (pectoral) and vein (saphenous) wall relative to simultaneous plasma concentrations. Hydralazine is metabolized by acetylation, ring oxidation and conjugation with endogenous compounds including pyruvic acid. The major identified metabolite of hydralazine excreted in urine is acetylhydrazinophthalazinone. Isosorbide dinitrate undergoes extensive first-pass metabolism in the liver and is cleared at a rate of 2 to 4 L/minute with a serum half-life of about 1 hour. Isosorbide dinitrate’s clearance is primarily by denitration to the 2-mononitrate (15 to 25%) and the 5-mononitrate (75 to 85%). Both metabolites have biological activity, especially the 5-mononitrate which has an overall half-life of about 5 hours. The 5-mononitrate is cleared by denitration to isosorbide, glucuronidation to the 5-mononitrate glucuronides, and by denitration/hydration to sorbitol. The 2-mononitrate appears to participate in the same metabolic pathways with a half-life of about 2 hours. Hydralazine: Metabolism is the main route for the elimination of hydralazine. Negligible amounts of unchanged hydralazine are excreted in urine. Isosorbide dinitrate: Most isosorbide dinitrate is eliminated renally as conjugated metabolites.

Isosorbide dinitrate + Hydralazine hydrochloride shows common side effects like Headache, dizziness, lightheadedness, nausea, and flushing.

Isosorbide dinitrate + Hydralazine hydrochloride is available in the form of Oral Tablet.

Isosorbide dinitrate + Hydralazine hydrochloride is available in India, US, China, Japan, Singapore, Canada, and Australia.

Isosorbide dinitrate + Hydralazine hydrochloride belonging to the Vasodilator, acts as an antihypertensive agent.

Hydralazine: Direct vasodilation of arterioles (with little effect on veins) resulting in decreased systemic resistance.

Isosorbide Dinitrate: Stimulation of intracellular cyclic-GMP results in vascular smooth muscle relaxation of both arterial and venous vasculature with more prominent effects on the veins. Primarily reduces cardiac oxygen demand by decreasing preload (left ventricular end-diastolic pressure); may modestly reduce afterload. Additionally, coronary artery dilation improves collateral flow to ischemic regions.

The Data of onset of action of Isosorbide dinitrate + Hydralazine hydrochloride is about 5-30 minutes.

The Tmax of Isosorbide dinitrate + Hydralazine hydrochloride is found to be 1 hour (both agents).

The Data of duration of Action of Isosorbide dinitrate + Hydralazine hydrochloride is approximately 8 hours.

Isosorbide dinitrate + Hydralazine hydrochloride is available in the form Oral Tablet.

Isosorbide dinitrate + Hydralazine hydrochloride Tablet is taken orally, usually 3 times daily.

Isosorbide dinitrate + Hydralazine hydrochloride combination medicine used for the treatment of congestive heart failure. Isosorbide dinitrate + Hydralazine hydrochloride combination is not recommended for use in patients less than 18 years of age.

Isosorbide dinitrate + Hydralazine hydrochloride is an antihypertensive agent belonging to the Vasodilator class.

Hydralazine: Direct vasodilation of arterioles (with little effect on veins) resulting in decreased systemic resistance.

Isosorbide Dinitrate: Stimulation of intracellular cyclic-GMP results in vascular smooth muscle relaxation of both arterial and venous vasculature with more prominent effects on the veins. Primarily reduces cardiac oxygen demand by decreasing preload (left ventricular end-diastolic pressure); may modestly reduce afterload. Additionally, coronary artery dilation improves collateral flow to ischemic regions.

• Beneficiary of Isosorbide dinitrate + Hydralazine hydrochloride

Isosorbide dinitrate + Hydralazine hydrochloride is indicated for the treatment of heart failure as an adjunct to standard therapy in self-identified black patients to improve survival, to prolong time to hospitalization for heart failure, and to improve patient-reported functional status.

Isosorbide dinitrate + Hydralazine hydrochloride is approved for use in the following clinical indications

• Treatment of Heart Failure in Self-identified Black Patients

Isosorbide dinitrate + Hydralazine hydrochloride is indicated for the treatment of heart failure as an adjunct to standard therapy in self-identified black patients to improve survival, to prolong time to hospitalization for heart failure, and to improve patient-reported functional status.

• Treatment of Heart Failure in Self-identified Black Patients

Oral: Initial: One tablet (containing 20 mg of isosorbide dinitrate and 37.5 mg of hydralazine) 3 times daily; titrate dose as tolerated in 2 to 4 weeks to a target dose of 2 tablets (containing a total of 40 mg of isosorbide dinitrate and 75 mg of hydralazine) 3 times daily.

Isosorbide dinitrate + Hydralazine hydrochloride is available in various strengths as 37.5 mg-20 mg.

Isosorbide dinitrate + Hydralazine hydrochloride is contraindicated in patients with

• Drug-induced lupus-like syndrome

Hydralazine may cause a drug-induced lupus-like syndrome (more likely on larger doses, longer duration).

• Fluid/sodium retention

Hydralazine-induced fluid and sodium retention may require addition or increased dosage of diuretics.

• Hypotension/bradycardia

Severe hypotension can occur; paradoxical bradycardia and increased angina pectoris can accompany hypotension. Use with caution in volume or salt depletion and/or moderate hypotension; use with extreme caution with inferior wall MI and suspected right ventricular infarctions. Symptomatic hypotension, particularly with upright posture, may occur with even small doses.

• Intracranial pressure increased

Nitrates may precipitate or aggravate increased intracranial pressure and subsequently may worsen clinical outcomes in patients with neurologic injury (eg, intracranial hemorrhage, traumatic brain injury).

• Peripheral neuritis

Hydralazine has been associated with peripheral neuritis (e.g., paresthesia, numbness, and tingling), possibly due to an antipyridoxine effect. Pyridoxine therapy should be initiated with onset of such symptoms.

• Hypotension

Symptomatic hypotension, particularly with upright posture, may occur with even small doses of Isosorbide dinitrate + Hydralazine hydrochloride. Hypotension is most likely to occur in patients who have been volume or salt depleted; correct prior to initiation of Isosorbide dinitrate + Hydralazine hydrochloride.

• Systemic Lupus Erythematosus

Hydralazine hydrochloride has been reported to cause a drug-induced systemic lupus erythematosus (SLE) syndrome. Symptoms and signs usually regress when hydralazine hydrochloride is discontinued.

• Worsening Is chemic heart disease

Hydralazine hydrochloride can cause tachycardia and hypotension potentially leading to myocardial ischemia and angina, particularly in patients with hypertrophic cardiomyopathy.

• Peripheral Neuritis

Hydralazine hydrochloride has been associated with peripheral neuritis, evidenced by paresthesia, numbness, and tingling, which may be related to an antipyridoxine effect. Pyridoxine should be added to Isosorbide dinitrate + Hydralazine hydrochloride therapy if such symptoms develop.

Consumption of alcohol during treatment with Isosorbide dinitrate + Hydralazine hydrochloride combination medicine may increase the risk of severe side effects.

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Common Adverse effects

• Chest pain, Headache, dizziness, Weakness.

Rare Adverse effects

• Hypotension, palpitations, ventricular tachycardia, tachycardia, Paresthesia, drowsiness, malaise, Alopecia, diaphoresis, Hyperglycemia, hyperlipidemia, hypercholesterolemia, Nausea, vomiting, cholecystitis, Angioedema, hypersensitivity reaction, Arthralgia, myalgia, tendinopathy, Amblyopia, Bronchitis, rhinitis, sinusitis.

• Phosphodiesterase Inhibitors

Isosorbide dinitrate + Hydralazine hydrochloride is contraindicated in patients who are using a selective inhibitor of cyclic guanosine monophosphate (cGMP)- specific phosphodiesterase type 5 (PDE5), PDE5 inhibitors such as avanafil, sildenafil, vardenafil, and tadalafil have been shown to potentiate the hypotensive effects of organic nitrates. Do not use Isosorbide dinitrate + Hydralazine hydrochloride in patients who are taking the soluble guanylate cyclase (sGC) stimulator riociguat. Concomitant use can cause hypotension.

The common side effects of Isosorbide dinitrate + Hydralazine hydrochloride include the following

Common

● Headache, dizziness, lightheadedness, nausea, and flushing.

Rare

● Rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing, severe tiredness, aching/swollen joints, rash on nose and cheeks, swollen glands, signs of kidney problems (such as change in the amount of urine, bloody/pink urine), signs of infection (such as sore throat that doesn't go away, fever, chills), easy bruising/bleeding, fainting, fast/irregular/pounding heartbeat.

• Pregnancy

Pregnancy Category C

There are no studies using Isosorbide dinitrate + Hydralazine hydrochloride in pregnant women. Isosorbide dinitrate has been shown to cause a dose-related increase in embryo-toxicity (excess mummified pups) in rabbits at 70 mg/kg (12 times the MRHD of Isosorbide dinitrate + Hydralazine hydrochloride on a body surface area basis). Hydralazine hydrochloride is teratogenic in mice at 66 mg/kg and possibly in rabbits at 33 mg/kg (2 and 3 times the MRHD of Isosorbide dinitrate + Hydralazine hydrochloride on a body surface area basis). There are no animal studies assessing the teratogenicity of Isosorbide dinitrate + Hydralazine hydrochloride. A meta-analysis of randomized controlled trials comparing hydralazine hydrochloride with other antihypertensive agents for severe hypertension in pregnancy found that hydralazine hydrochloride was associated with significantly more maternal hypotension, placental abruption, caesarean sections and oliguria, with more adverse effects on fetal heart rate and with lower Apgar scores. A combination of propranolol and hydralazine hydrochloride was administered to 13 patients with long-standing hypertension during 15 pregnancies. These pregnancies resulted in 14 live births and one unexplained stillbirth. The only neonatal complications were two cases of mild hypoglycemia. Hydralazine hydrochloride and its metabolites have been detected using a non-selective assay in maternal and umbilical plasma in patients treated with the drug during pregnancy. Isosorbide dinitrate has been used for effective acute and sub-chronic control of hypertension in pregnant women, but there are no studies using it in a chronic regimen and assessing its effects on pregnant women and/or the fetus.

• Nursing Mothers

No studies have been performed with Isosorbide dinitrate + Hydralazine hydrochloride. It is not known if either hydralazine or isosorbide dinitrate is excreted in human milk.

• Pediatric Use

The safety and effectiveness of Isosorbide dinitrate + Hydralazine hydrochloride in children have not been established.

• Geriatric Use

Clinical studies of Isosorbide dinitrate + Hydralazine hydrochloride did not include enough subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in response between elderly and younger patients. In general, dose selection for an elderly patient should start at the low end of the dosing range, reflecting the greater frequency of decreased hepatic and renal function, and of concomitant disease or other drug therapies. Isosorbide dinitrate, its active metabolites, and hydralazine may be eliminated more slowly in elderly patients.

The signs and symptoms of overdosage with Isosorbide dinitrate + Hydralazine hydrochloride are expected to be those of excessive pharmacologic effect, i.e., vasodilatation, reduced cardiac output and hypotension, and signs and symptoms include headache, confusion, tachycardia, and generalized skin flushing. Complications can include myocardial ischemia and subsequent myocardial infarction, cardiac arrhythmia, and profound shock. Syncope, coma and death may ensue without appropriate treatment.

Pharmacodynamic

The basis for the beneficial clinical effects of Isosorbide dinitrate + Hydralazine hydrochloride is not known. In a small study of patients with chronic heart failure administered single doses of hydralazine 75 mg, isosorbide dinitrate 20 mg, and the combination, the combination elicited a statistically significant decrease in pulmonary capillary wedge pressure compared to hydralazine alone. The increase in cardiac output, renal blood flow and limb blood flow with the combination, however, was not greater than with hydralazine alone. There is no study of hemodynamic effects following multiple dosing.

Pharmacokinetics

• Absorption

Following a single 75-mg oral dose of hydralazine plus 40 mg of isosorbide dinitrate to 19 healthy adults, peak plasma concentrations of hydralazine (88 ng/mL/65 kg) and isosorbide dinitrate (76 ng/mL/65 kg) were reached in 1 hour. The half-lives were about 4 hours for hydralazine and about 2 hours for isosorbide dinitrate. Peak plasma concentrations of the two active metabolites, isosorbide-2-mononitrate, and isosorbide-5-mononitrate, were 98 and 364 ng/mL/65 kg, respectively, at about 2 hours. No information is currently available regarding the effect of food on the bioavailability of hydralazine or isosorbide dinitrate from Isosorbide dinitrate + Hydralazine hydrochloride tablets.

• Distribution

Hydralazine hydrochloride: After intravenous administration of hydralazine in a dose of 0.3 mg/kg, the steady-state volume of distribution in patients with congestive heart failure was 2.2 L/kg. Isosorbide dinitrate: The volume of distribution of isosorbide dinitrate is 2 to 4 L/kg. About 28% of circulating isosorbide dinitrate is protein bound. Under steady-state conditions, isosorbide dinitrate accumulates significantly in muscle (pectoral) and vein (saphenous) wall relative to simultaneous plasma concentrations.

• Metabolism

Hydralazine is metabolized by acetylation, ring oxidation and conjugation with endogenous compounds including pyruvic acid. Acetylation occurs predominantly during the first pass after oral administration which explains the dependence of the absolute bioavailability on the acetylator phenotype. About 50% of patients are fast acetylators and have lower exposure. After oral administration of hydralazine, the major circulating metabolites are hydralazine pyruvate hydrazone and methyltriazolophthalazine. Hydralazine is the main pharmacologically active entity; hydralazine pyruvate hydrazone has only minimal hypotensive and tachycardic activity. The pharmacological activity of methyltriazolophthalazine has not been determined. The major identified metabolite of hydralazine excreted in urine is acetylhydrazinophthalazinone. Isosorbide dinitrate undergoes extensive first-pass metabolism in the liver and is cleared at a rate of 2 to 4 L/minute with a serum half-life of about 1 hour. Isosorbide dinitrate’s clearance is primarily by denitration to the 2-mononitrate (15 to 25%) and the 5-mononitrate (75 to 85%). Both metabolites have biological activity, especially the 5-mononitrate which has an overall half-life of about 5 hours. The 5-mononitrate is cleared by denitration to isosorbide, glucuronidation to the 5-mononitrate glucuronides, and by denitration/hydration to sorbitol. The 2-mononitrate appears to participate in the same metabolic pathways with a half-life of about 2 hours.

• Excretion

Hydralazine: Metabolism is the main route for the elimination of hydralazine. Negligible amounts of unchanged hydralazine are excreted in urine. Isosorbide dinitrate: Most isosorbide dinitrate is eliminated renally as conjugated metabolites.

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