ISOSORBIDE DINITRATE AND HYDRALAZINE HYDROCHLORIDE
Clinical safety rating: safe
Phosphodiesterase inhibitors (eg sildenafil) can cause severe hypotension Can cause tolerance with continuous use and severe headaches.
Isosorbide dinitrate is a vasodilator that relaxes vascular smooth muscle via nitric oxide-mediated increases in cyclic guanosine monophosphate (cGMP), leading to venodilation and reduced preload. Hydralazine is a direct arteriolar vasodilator that reduces afterload. Combination therapy improves cardiac output in heart failure.
| Metabolism | Isosorbide dinitrate undergoes denitration to isosorbide mononitrates and further metabolism by aldehyde dehydrogenase, with some glucuronidation. Hydralazine is metabolized by N-acetyltransferase (NAT2) and cytochrome P450 enzymes. |
| Excretion | Isosorbide dinitrate: primarily renal (urine) as metabolites, ~80% excreted renally; hydralazine: extensively metabolized, ~85% excreted renally as metabolites, 10% as unchanged drug in urine, minor biliary/fecal elimination. |
| Half-life | Isosorbide dinitrate: terminal half-life 5-6 hours for active metabolites (isosorbide-5-mononitrate); hydralazine: terminal half-life 2-8 hours (increases with renal impairment), clinically relevant for dosing interval. |
| Protein binding | Isosorbide dinitrate: ~30% bound to plasma proteins; hydralazine: ~87% bound to plasma proteins (albumin and alpha-1 acid glycoprotein). |
| Volume of Distribution | Isosorbide dinitrate: Vd 2-4 L/kg (extensive tissue distribution); hydralazine: Vd 1.5-3 L/kg (distributes into vascular smooth muscle). |
| Bioavailability | Oral: isosorbide dinitrate ~20-30% (extensive first-pass metabolism); hydralazine ~30-50% (affected by acetylator phenotype; slow acetylators have higher bioavailability). |
| Onset of Action | Oral: isosorbide dinitrate onset 15-30 min; hydralazine onset 20-60 min. |
| Duration of Action | Oral: isosorbide dinitrate duration 4-6 hours; hydralazine duration 2-6 hours (depends on acetylator status). |
Isosorbide dinitrate 20 mg plus hydralazine hydrochloride 37.5 mg (1 tablet) orally three times daily; may titrate to target dose of isosorbide dinitrate 40 mg plus hydralazine hydrochloride 75 mg (2 tablets) three times daily as tolerated.
| Dosage form | TABLET |
| Renal impairment | CrCl <30 mL/min: Use with caution; no specific dose adjustment guidelines available. Monitor for hypotension and fluid retention. |
| Liver impairment | Child-Pugh Class A or B: No adjustment required. Child-Pugh Class C: Consider starting at lower doses (e.g., isosorbide dinitrate 10 mg/hydralazine 25 mg) and titrate cautiously due to reduced clearance of hydralazine. |
| Pediatric use | Safety and efficacy not established in pediatric patients; no specific dosing recommendations available. |
| Geriatric use | Start at lower doses (e.g., isosorbide dinitrate 10 mg/hydralazine 25 mg) and titrate slowly due to increased risk of hypotension and orthostatic effects; monitor renal function. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Phosphodiesterase inhibitors (eg sildenafil) can cause severe hypotension Can cause tolerance with continuous use and severe headaches.
| FDA category | Animal |
| Breastfeeding | Isosorbide dinitrate: Excreted in breast milk; amount not quantified; insufficient data for M/P ratio. Hydralazine: Excreted in breast milk; M/P ratio approximately 1.0. Use with caution due to potential for adverse effects in nursing infant (including hypotension). |
| Teratogenic Risk |
■ FDA Black Box Warning
None.
| Common Effects | Headache |
| Serious Effects |
["Concomitant use with phosphodiesterase-5 inhibitors (e.g., sildenafil, tadalafil, vardenafil)","Severe hypotension (systolic blood pressure < 90 mmHg)","Hypersensitivity to isosorbide dinitrate or hydralazine","Acute myocardial infarction with low filling pressures"]
| Precautions | ["Hypotension","Worsening angina or myocardial infarction with abrupt discontinuation","Use with phosphodiesterase-5 inhibitors (e.g., sildenafil) is contraindicated due to severe hypotension","Hepatic impairment may require dose adjustment","Monitor for lupus-like syndrome and peripheral neuritis with hydralazine","Slow acetylator phenotype increases risk of drug-induced lupus"] |
| Food/Dietary |
Loading safety data…
| Isosorbide dinitrate: No adequate human studies; animal studies not reported. Hydralazine: Crosses placenta; associated with maternal hypotension and fetal distress if used near term. First trimester: No evidence of major malformations in humans. Second/third trimester: Risk of fetal tachycardia, meconium staining, and neonatal thrombocytopenia (hydralazine). |
| Fetal Monitoring | Maternal: Blood pressure, heart rate, signs of hypotension, fluid balance. Fetal: Heart rate monitoring during labor (risk of fetal distress with hydralazine-induced maternal hypotension). |
| Fertility Effects | No human data on fertility effects. Hydralazine shown to impair fertility in animal studies at high doses (reduced conception rates). |
| Avoid high-fat meals, as they can reduce absorption of hydralazine. Alcohol may exacerbate hypotension. No known interaction with grapefruit juice. |
| Clinical Pearls | Fixed-dose combination of isosorbide dinitrate (nitrate) and hydralazine (direct vasodilator). FDA-approved specifically for African Americans with NYHA class III-IV heart failure as an adjunct to standard therapy (ACE inhibitors, beta-blockers, diuretics). Avoid in patients with severe renal impairment (CrCl <30 mL/min) or lupus. Titrate to target dose: 2 tablets (37.5 mg hydralazine/20 mg isosorbide dinitrate) three times daily. Monitor for hypotension, syncope, and fluid retention. Can cause drug-induced lupus with hydralazine; check antinuclear antibody titer if symptoms develop. Nitrate tolerance may occur with sustained use; use lowest effective dose and avoid long-acting nitrates. |
| Patient Advice | Take this medication exactly as prescribed, usually three times a day. · Do not stop suddenly without talking to your doctor; it may worsen heart failure. · Stand up slowly to avoid dizziness from low blood pressure. · Avoid taking sildenafil (Viagra), tadalafil (Cialis), or vardenafil (Levitra) while on this drug. · Report symptoms like joint pain, rash, fever, or lupus-like symptoms immediately. · This combination is specifically approved for Black patients with heart failure. |