- ACRONYMS AND DEFINITIONS
- ACS - Acute coronary syndrome (myocardial infarction or unstable angina)
- AHA/ACC - American Heart Assoc / American College of Cardiology
- ANA - Antinuclear antibodies
- BP - Blood pressure
- EF - Ejection Fraction
- EKG - Electrocardiogram
- HCTZ - Hydrochlorothiazide
- Nitrates - collective term for nitroglycerin, isosorbide mononitrate, and isosorbide dinitrate
- NTG - Nitroglycerin
- NYHA - New York Heart Association heart failure classification
- RCT - Randomized controlled trial
- DRUGS IN CLASS
- Vasodilators (arterial and venous)
- Quick-acting
- Nitroglycerin sublingual powder (GoNitro™)
- Nitroglycerin spray (Nitromist®, Nitrolingual®)
- Nitroglycerin tablets (Nitrostat®)
- Long-acting
- Isosorbide Mononitrate (Imdur®, Ismo®, Monoket®)
- Isosorbide Dinitrate (Isordil®)
- Nitroglycerin patch (Nitro-Dur®, Minitran®)
- Nitroglycerin ointment (Nitro-Bid®)
- Vasodilators (arterial)
- Hydralazine (Apresoline®)
- Minoxidil (Loniten®)
- Combination products
- BiDil® (Isosorbide dinitrate + hydralazine)
- MECHANISM OF ACTION
- The vascular system
- The vascular system consists of arteries, veins, and capillaries
- Arteries carry blood away from the heart and deliver it to the various tissues and organs
- Veins return blood from the organs and tissues back to the heart
- Blood pressure is a measure of resistance to blood flow in the arteries
- Nitrates (nitroglycerin, isosorbide mononitrate, and isosorbide dinitrate)
- Nitrates dilate arteries and veins
- Arterial dilation reduces resistance to blood flow (lowers blood pressure)
- Venous dilation allows the veins to hold more blood thus decreasing the amount of blood returned to the heart
- Decreasing blood return to the heart, decreases the amount of work the heart must do and can help relieve congestion
- Hydralazine and minoxidil
- Hydralazine and minoxidil primarily dilate arteries
- Dilating arteries lowers blood pressure
- FDA-APPROVED INDICATIONS
- BiDil®
- Treatment of heart failure in self-identified black patients
- Hydralazine
- Hypertension
- Nitrostat®, Nitromist®, Nitrolingual®
- Acute relief of an attack or acute prophylaxis of angina pectoris due to coronary artery disease
- Imdur®, Ismo®, Monoket®
- Prevention of angina pectoris due to coronary artery disease. Not for an acute episode.
- Isordil®
- Prevention of angina pectoris due to coronary artery disease. Not for an acute episode.
- Minoxidil
- Treatment of hypertension that is symptomatic or associated with target organ damage and is not manageable with maximum therapeutic doses of a diuretic plus two other antihypertensive drugs
- Nitro-Bid®
- Prevention of angina pectoris due to coronary artery disease. Not for an acute episode.
- Nitro-Dur®, Minitran®
- Prevention of angina pectoris due to coronary artery disease. Not for an acute episode.
- HYPERTENSION
- Minoxidil
- Minoxidil has a profound blood pressure-lowering effect, but its side effects are significant. Because of this, it is typically reserved as a fourth- or fifth-line agent to treat resistant hypertension.
- Minoxidil is an older medication and there are no well-done studies that have evaluated its effects on hypertension. We pooled results from 3 small studies that were of suboptimal design.
- In 3 small studies, minoxidil had the following effects on blood pressure:
- SBP reduction: 23 - 29 mmHg
- DBP reduction: 12 - 24 mmHg
- The average baseline blood pressure in the studies was 167/107
- Dosing ranged from 15 - 80 mg/day [3,4,33]
- Hydralazine
- Hydralazine is an older drug and there a no well-done, placebo-controlled trials that have evaluated its effects in hypertension [39]
- We found one small randomized controlled trial (N=232) that compared hydralazine to prazosin in men with hypertension who were not controlled on HCTZ. The hydralazine group was treated with an average dose of 116 mg/day for 6 months. At the end of the study, the average reduction from baseline in BP for the hydralazine group was 5.1/8.2 mmhg. [PMID 7023744]
- Professional recommendations
- See hypertension guidelines for a review of recommended therapies and treatment goals from various professional organizations
- Summary
- Minoxidil is a powerful blood pressure-lowering agent, but its pronounced side effects limit its use. It is typically prescribed as a last resort in patients who have difficult to treat hypertension that has not responded to a combination of 3 or 4 other medications.
- Hydralazine is not as potent as minoxidil, and it has significant side effects. It is not commonly used to treat hypertension.
- HEART FAILURE WITH REDUCED EJECTION FRACTION (HFrEF)
- Overview
- Hydralazine and isosorbide dinitrate are used in combination to treat heart failure with reduced ejection fraction. The V-HeFT I trial compared hydralazine/isosorbide to prazosin and placebo, while the V-HeFT II trial compared hydralazine/isosorbide to enalapril. A post hoc analysis of these 2 trials found that black patients had a better response to hydralazine/isosorbide than white patients. This finding led to the A-HeFT trial where hydralazine/isosorbide was compared to placebo in black patients only. All 3 trials are detailed below. [10]
- The V-HeFT trial enrolled 642 men with symptomatic heart failure (average ejection fraction 30%)
Main inclusion criteria
- Receiving diuretic and digoxin
- EF < 45% or evidence of enlarged heart on chest X-ray or ECHO
- Reduced exercise tolerance
Main exclusion criteria
- Myocardial infarction within 3 months
- Obstructive valvular disease or myocardial obstructive disease
- Taking long-acting nitrates, calcium channel blockers, beta blockers, or antihypertensives other than diuretics
Baseline characteristics
- Average age 58 years
- Previous myocardial infarction - 41%
- Average EF - 30%
- CAD - 44%
Patients were randomized to 1 of 3 groups:
- Group 1 (186 patients) - Hydralazine 75 mg + Isosorbide dinitrate 40 mg four times a day (average daily dose hydralazine/isosorbide 270 mg/136 mg)
- Group 2 (186 patients) - Prazosin 5 mg four times a day (average dose 18.6 mg/day)
- Group 3 (273 patients) - Placebo 4 times a day
- Study medications were started at half the target dose and doubled after 2 weeks if tolerated
Primary outcome: Overall mortality
Results
Duration: Average of 2.3 years | ||||
Outcome | Hyd/Iso | Prazosin | Placebo | Comparisons |
---|---|---|---|---|
Primary outcome | 38.7% | 49.7% | 44% | 1 vs 3 p=0.046 | 2 vs 3 p>0.05 |
Cumulative mortality at 2 years | 25.6% | ∼34% | 34.3% | 1 vs 2 or 3 p<0.05 |
Drug discontinuation | 22% | 27% | 22% | N/A |
Change in BP at 1 year (mmHg) | +0.6/-1 | -4.6/-2.7 | -0.3/-0.3 | N/A |
Findings: Our data suggest that the addition of hydralazine and isosorbide dinitrate to the therapeutic regimen of digoxin and diuretics in patients with chronic congestive heart failure can have a favorable effect on left ventricular function and mortality
- The V-HeFT II trial enrolled 804 men with heart failure
Main inclusion criteria
- Receiving diuretic and digoxin
- EF < 45% or evidence of enlarged heart on chest X-ray or ECHO
- Reduced exercise tolerance
Main exclusion criteria
- Myocardial infarction or heart surgery within 3 months
- Angina requiring treatment
- Obstructive valvular disease
- Obstructive lung disease
Baseline characteristics
- Average age 61 years
- Average EF - 29%
- Prior myocardial infarction - 47%
- Average BP - 125/78
- NYHA class: I - 6% | II - 51% | III - 42% | IV - 0.3%
Randomized treatment groups
- Group 1 (401 patients) - Hydralazine 75 mg + Isosorbide dinitrate 40 mg four times a day (average daily dose 199 mg/100 mg)
- Group 2 (403 patients) - Enalapril 10 mg twice a day (average dose 15 mg/day)
- Patients were instructed not to take nonstudy vasodilators or antihypertensive drugs
- There was a run-in phase of at least 4 weeks where all patients were placed on diuretic and digoxin and nonstudy drugs were discontinued
Primary outcome: Overall mortality at 2 years
Results
Duration: Average of 2.5 years | |||
Outcome | Hydralazine/Isosorbide | Enalapril | Comparisons |
---|---|---|---|
Primary outcome (overall mortality at 2 years) | 25% | 18% | p=0.016 |
Overall mortality at 5 years | 54% | 48% | p=0.08 |
Hospitalization for heart failure | 18.4% | 18.9% | p>0.05 |
Headache | 73% | 54% | p<0.05 |
Symptomatic hypotension | 20% | 28% | p<0.05 |
Change in BP at 13 weeks (mmHg) | 0/-1 | -5/-4 | N/A |
Findings: The similar two-year mortality in the hydralazine-isosorbide dinitrate arms in our previous Vasodilator-Heart Failure Trial (26 percent) and in the present trial (25 percent), as compared with that in the placebo arm in the previous trial, (34 percent) and the further survival benefit with enalapril in the present trial (18 percent) strengthen the conclusion that vasodilator therapy should be included in the standard treatment for heart failure. The different effects of the two regimens (enalapril and hydralazine-isosorbide dinitrate) on mortality and physiologic end points suggest that the profile of effects might be enhanced if the regimens were used in combination.
- The A-HeFT trial enrolled 1050 blacks with heart failure
Main inclusion criteria
- Self-identified as black
- NYHA class III or IV heart failure
- EF ≤ 35% or ≤ 45% with a left ventricular internal end-diastolic diameter of > 2.9 cm
- Receiving standard therapy for heart failure
Main exclusion criteria
- Myocardial infarction, ACS, stroke, PCI, or heart surgery within 3 months
- Hypertrophic or restrictive cardiomyopathy
- Uncontrolled hypertension
Baseline characteristics
- Average age 57 years
- Average EF - 24%
- Average BP - 126/76
- NYHA class: III - 96% | IV - 4%
- Heart failure etiology: Ischemic - 23% | Hypertensive - 39% | Idiopathic - 26% | Valvular - 3%
- Baseline meds: Diuretic - 89% | ACE/ARB - 87% | Beta blocker - 74% | Carvedilol - 56% | Spironolactone - 38%
Randomized treatment groups
- Group 1 (518 patients) - Hydralazine 37.5 mg + isosorbide dinitrate 20 mg 1-2 tabs three times a day (average daily dose 142 mg/76 mg)
- Group 2 (532 patients) - Placebo three times day
- Hydralazine/isosorbide was started at half the target dose and increased if tolerated
Primary outcome: Composite score made up of weighted values for death from any cause, first hospitalization for
heart failure (during 18 months of follow-up), and change in the quality of life (at 6 months). Score ranges from -6 to +2, and higher scores are better.
Results
Duration: After an average follow-up of 10 months, the trial was stopped early due to higher mortality in the placebo group | |||
Outcome | Hydralazine/Isosorbide | Placebo | Comparisons |
---|---|---|---|
Primary outcome | -0.1 | -0.5 | p=0.01 |
Overall mortality | 6.2% | 10.2% | p=0.02 |
Hospitalization for heart failure | 16.4% | 24.4% | p=0.001 |
Heart failure exacerbation | 8.7% | 12.8% | p=0.04 |
Headache | 47.5% | 19.2% | p<0.001 |
Dizziness | 29.3% | 12.3% | p<0.001 |
SBP change from baseline at 6 months (mmHg) | -1.9 | +1.2 | p=0.02 |
DBP change from baseline at 6 months (mmHg) | -2.4 | +0.8 | p<0.001 |
Findings: The addition of a fixed dose of isosorbide dinitrate plus hydralazine to standard therapy for heart failure including neurohormonal blockers is efficacious and increases survival among black patients with advanced heart failure.
- AHA recommendations
- Summary
- In the A-HeFT trial, hydralazine/isosorbide therapy improved survival in black patients with NYHA class III - IV heart failure. The hydralazine/isosorbide group achieved a lower blood pressure, and this may have contributed to its efficacy. The majority of patients in the trial were receiving standard heart failure therapy with an ACE inhibitor/ARB and beta blocker. The two V-HeFT trials were performed before ACE inhibitors and beta blockers became standard treatment.
- ANGINA (CHEST PAIN)
- Overview
- Acute angina (nitroglycerin)
- Nitroglycerin has been used for more than 100 years to treat episodes of acute cardiac chest pain
- It is used almost universally in patients who are experiencing a heart attack (see heart attack below)
- It is also used intermittently in patients with a history of chronic, recurrent episodes of chest pain
- Because it acts quickly (within minutes) and is eliminated quickly (within 5-10 minutes), it is not practical to dose nitroglycerin on a regular basis
- Chronic angina (isosorbide dinitrate, isosorbide mononitrate, nitroglycerin patch, nitroglycerin ointment)
- Isosorbide dinitrate and isosorbide mononitrate are long-acting nitrates that can be used to prevent chronic angina
- Tolerance to the effects of nitrates develops quickly (in less than 24 hours), therefore other agents (beta blockers, calcium channel blockers) that prevent angina are often preferred
- A meta-analysis that evaluated the effects of different drugs in angina is detailed below
- STUDY
- A JAMA meta-analysis evaluated trials that compared isosorbide dinitrate (or mononitrate) to calcium channel blockers or beta blockers in the treatment of stable angina
- When nitrates were compared to calcium channel blockers, the following results were seen:
- There was no significant difference in angina episodes per week
- There was no significant difference in nitroglycerin use per week
- There was no significant difference in exercise tolerance
- When nitrates were compared to beta blockers, the following results were seen:
- There was no significant difference in cardiac outcomes (death or heart attack)
- There was no significant difference in angina episodes per week
- There was a trend towards less nitroglycerin use in the beta blocker group when compared to the nitrate group (p=0.08) [15]
- AHA recommendations
- The AHA 2012 CAD guidelines recommend beta blockers as the first-line agent for the treatment of chronic angina
- If beta blockers are contraindicated or not tolerated, then calcium channel blockers (dihydropyridines and nondihydropyridines) or long-acting nitrates should be used
- If initial beta blocker therapy does not control symptoms, then a calcium channel blocker or long-acting nitrate should be added to beta blocker therapy [35]
- Summary
- Beta blockers are the preferred first-line agent in chronic angina because they improve heart failure outcomes
- Calcium channel blockers and long-acting nitrates are also effective
- Nifedipine and diltiazem should be used with caution in patients with heart failure because they may worsen outcomes. Amlodipine has been shown to be safe in heart failure.
- Nitroglycerin sublingual tablets and sprays are appropriate to treat episodic, acute episodes of angina
- HEART ATTACK
- Overview
- Quick-acting nitroglycerin (spray, tablets, intravenous) is widely used in patients experiencing a heart attack
- Nitroglycerin helps relieve the chest pain associated with a heart attack, and it also helps decrease the workload on the heart through venous dilation
- The effects of nitrates on clinical outcomes was evaluated in the ISIS trial detailed below
- The ISIS-4 trial enrolled 58,050 patients who presented to the ER with suspected myocardial infarction
Main inclusion criteria
- Presenting to the ER with suspected myocardial infarction
- Onset of symptoms within 24 hours
Main exclusion criteria
- Indication for, or contraindication to study medications
- Cardiogenic shock
- Severe hypotension
- Fluid depletion
Baseline characteristics
- STEMI - 79%
- Previous myocardial infarction - 17%
- Symptomatic heart failure - 14%
- Nonstudy IV nitrate - 47%
Randomized treatment groups
- Patients were randomized in a 2 X 2 X 2 factorial design
- Group 1 (29,028 patients): Captopril (target dose 50 mg twice a day) or Placebo for 1 month
- Group 2 (29,018 patients) Isosorbide mononitrate (target dose 60 mg once daily) or Placebo for 1 month
- Group 3 (29,011 patients) Magnesium sulfate IV 8 mmol bolus followed by 72 mmol over 24 hours
Primary outcome: Overall mortality at 5 weeks
Results
Duration: 5 weeks | |||
Outcome | Drug | Corresponding placebo group | Comparisons |
---|---|---|---|
Primary outcome (captopril) | 7.19% | 7.69% | p=0.02 |
Primary outcome (isosorbide) | 7.34% | 7.54% | p>0.05 |
Primary outcome (magnesium) | 7.64% | 7.24% | p>0.05 |
|
Findings: Because of its size, ISIS-4 provides reliable evidence about the effects of adding each of these three treatments to established treatments for acute Ml. Intravenous
magnesium was ineffective, and although oral nitrate therapy appeared safe it did not produce a clear reduction in 1-month mortality.
- AHA recommendations
- The AHA 2011 NSTEMI-Unstable angina guidelines state that patients with ongoing chest pain should receive up to 3 doses of sublingual nitroglycerin after which IV nitroglycerin may be started if chest pain persists. IV nitroglycerin is indicated in the first 48 hours for persistent decreased blood flow to the heart, heart failure, or hypertension. Nitrates should not be given to patients with any of the following: SBP < 90 (or ≥ 30 below baseline), bradycardia (< 50 bpm), tachycardia (> 100 bpm), absence of symptomatic heart failure, treatment with a phosphodiesterase inhibitor for ED within 24 h of sildenafil or 48 h of tadalafil, right ventricular infarction [22]
- The AHA 2013 STEMI guidelines state that nitrates may help relieve the symptoms of ischemia, but they do not attenuate myocardial injury unless vasospasm plays a significant role [36]
- Summary
- Nitroglycerin is used almost universally in acute heart attacks because it relieves chest pain and helps decrease the workload on the heart
- There is no evidence that nitrates improve survival or other important outcomes in ACS
- SIDE EFFECTS | Hydralazine
- Headache
- Headache is a common complaint with hydralazine
- The frequency is not well-defined
- Gastrointestinal side effects
- Gastrointestinal side effects including nausea, vomiting, and diarrhea are common with hydralazine
- The frequency is not well-defined
- Rapid heart rate (tachycardia)
- When hydralazine dilates the arteries, the heart reacts by increasing its rate
- This reaction is called "reflex tachycardia"
- The frequency is not well-defined
- Palpitations
- Palpitations are common with hydralazine
- The frequency is not well-defined
- Dizziness / lightheadedness
- Dizziness and lightheadedness can occur with hydralazine
- The frequency is not well-defined
- Drug-induced lupus
- Overview
- Lupus erythematosus is an autoimmune disease that can lead to joint inflammation and organ damage
- Hydralazine can cause a lupus erythematosus-like syndrome to develop in some individuals
- When drugs cause lupus, it is often referred to as "drug-induced lupus"
- Incidence
- A study in the British Medical Journal followed 281 patients taking hydralazine for hypertension
- Patients were monitored for the development of drug-induced lupus, and the following was observed:
- The overall incidence of drug-induced lupus was 6.7% at 3 years of therapy
- Drug-induced lupus was diagnosed at an average of 24 months after therapy was started (earliest 9 months)
- The incidence was higher for higher doses of hydralazine (100 mg/day - 5.4%, 200 mg/day - 10.4%)
- Women had a higher incidence than men ( 11.6% for women overall vs 2.8% for men) [18]
- Symptoms
- Joint pain and swelling
- Muscle pain
- Fever
- Rash
- Weight loss
- Blood abnormalities (anemia, low white count, low platelets) [18,30,31]
- Diagnosis of drug-induced lupus is based on clinical symptoms and the following lab tests:
- A positive ANA (antinuclear antibody) test - typically present in drug-induced lupus - about 50% of patients taking hydralazine will develop a positive ANA test
- ANA pattern is often homogenous in drug-induced lupus
- Anti-histone antibodies are positive in up to 95% of patients
- Anti-ssDNA (single stranded DNA) antibodies are often present
- anti-dsDNA (double stranded DNA) antibodies are rare
- Complement levels are typically normal in drug-induced lupus [18,30,31]
- Treatment
- Symptoms typically resolve once hydralazine is stopped
- In severe cases, steroids may be used
- Summary
- Hydralazine-induced lupus can be a significant problem, particularly in women and people taking higher doses
- The manufacturer recommends that a blood cell count and ANA titer be performed before therapy and "periodically" thereafter in prolonged therapy
- Because the ANA titer can turn positive in 50% of patients taking hydralazine, checking ANA titers periodically may be of little utility
- A more prudent approach is to check an ANA titer and blood cell count before therapy to establish a baseline, and then repeat the tests if symptoms occur
- Patients should be maintained on the lowest dose of hydralazine that is effective
- SIDE EFFECTS | Minoxidil
- Fluid retention
- The vasodilatory effects of minoxidil can stimulate fluid and sodium retention. The incidence of minoxidil-induced lower extremity edema is not well-defined, but a concomitant loop diuretic, and possibly sodium restriction, is typically required to prevent fluid retention. Use caution in conditions marked by fluid overload (e.g. heart failure, liver failure, kidney disease).
- Rapid heart rate (tachycardia)
- Minoxidil-induced vasodilation can cause a reflex tachycardia. Concomitant beta blocker therapy can help to prevent this.
- Cardiac chest pain (angina)
- Minoxidil-induced tachycardia may exacerbate angina. Concomitant beta blocker therapy can help to prevent this.
- Hair growth (hypertrichosis)
- Minoxidil stimulates hair growth through an unknown mechanism in up to 80% of patients. Increased growth typically appears 3 - 6 weeks after starting therapy, with the eyebrows, forehead, cheekbone area, and extremities commonly affected. Enhanced growth typically ceases within 1 - 6 months of discontinuation.
- Pericarditis / Pericardial effusion
- Pericarditis and pericardial effusion, occasionally with tamponade, have been reported in 3% of minoxidil-treated patients not on dialysis. In most cases, patients had marked fluid retention from another condition (e.g. renal failure, heart failure, connective tissue disease), but in some instances, no potential cause of effusion was present. If patients develop symptoms of pericardial effusion (e.g. dyspnea, chest pain), prompt echocardiographic evaluation should be performed.
- ECG changes
- Up to 60% of patients treated with minoxidil have T-wave inversion on their ECG. This effect usually disappears over time or with drug discontinuation. The significance of these changes is unknown, but they have not been associated with signs of cardiac damage (e.g. chest pain, enzyme elevations).
- Lab changes
- Minoxidil-induced fluid retention can cause a transient decrease in hemoglobin and hematocrit (hemodilution). An initial fall of 7% is typical before returning to baseline values.
- Transient increases in serum creatinine (average of 6%) and BUN have been observed that return to baseline with continued treatment
- Alkaline phosphatase may increase without other signs of bone or liver disease
- SIDE EFFECTS | Nitrates
- Headache
- Headache is reported in up to 60% of nitrate users
- Hypotension
- Nitrates dilate blood vessels, and this can lead to hypotension. Symptoms of hypotension include lightheadedness, dizziness, and syncope. Hypotension induced by nitroglycerin may be accompanied by paradoxical bradycardia, which can increase angina.
- Methemoglobinemia
- Methemoglobinemia is a rare condition where hemoglobin is in the ferric state and unable to release oxygen to tissues. Nitrates have been found to induce methemoglobinemia in rare cases. [20]
- Rebound chest pain when stopping
- To reduce tolerance (see nitrate tolerance below), nitrates are often dosed so that there is a daily drug-free interval. Rebound chest pain and ischemia during the drug-free interval have been reported. The significance of this effect is unknown. [21]
- NITRATE TOLERANCE
- Overview
- One of the main issues that limits the usefulness of nitrates is the rapid development of tolerance to their effects
- Tolerance can develop within 24 hours of continuous nitrate use
- In order to limit the tolerance, a daily drug-free interval is recommended
- Dosing regimens to help limit nitrate tolerance
- Isosorbide mononitrate - an interval of 17 hours between the last dose of each day and the first dose of the next day
- Isosorbide dinitrate - an interval of 14 hours between the last dose of each day and the first dose of the next day
- Nitroglycerin ointment or patch - 10-12 hours with patch or ointment off each day [20, 28, 29]
- CONTRAINDICATIONS
- Nitrates (nitroglycerin, isosorbide mononitrate, isosorbide dinitrate)
- Concomitant phosphodiesterase type 5 inhibitor (Viagra®, Cialis®, etc.) - see drug interactions below
- Severe anemia
- Concomitant riociguat (Adempas®)
- Increased intracranial pressure
- Known hypersensitivity
- Early myocardial infarction (particularly right ventricular infarction)
- Circulatory failure and shock
- Hydralazine
- Mitral valve heart disease
- Known hypersensitivity
- Minoxidil
- Known hypersensitivity
- Pheochromocytoma - may stimulate secretion of catecholamines from the tumor through its antihypertensive action
- PRECAUTIONS
- Kidney disease
- Hydralazine
- Hydralazine has not been studied extensively in kidney disease. In one small study (N=49), severe kidney disease (CrCl 5 - 28 ml/min) did not affect hydralazine pharmacokinetics. Dose adjustments do not appear to be necessary in kidney disease. [32]
- Minoxidil
- Minoxidil can exacerbate fluid retention in kidney disease. Start with lower doses and titrate slowly.
- Nitroglycerin, Isosorbide dinitrate, Isosorbide mononitrate
- No dose adjustment is necessary in kidney disease
- Liver disease
- Hydralazine
- Hydralazine undergoes extensive liver metabolism. The effects of hepatic impairment on hydralazine have not been studied. Use caution.
- Isosorbide dinitrate
- Isosorbide dinitrate undergoes extensive first-pass metabolism in the liver and considerable extrahepatic metabolism. It has not been studied in liver disease. Use caution.
- Isosorbide mononitrate
- No dose adjustment is necessary in liver disease
- Minoxidil
- Minoxidil can exacerbate fluid retention in liver disease. Start with lower doses and titrate slowly.
- Nitroglycerin
- Nitroglycerin undergoes metabolism in the liver and at sites outside of the liver. It has not been studied in liver disease.
- Coronary artery disease (hydralazine and minoxidil)
- The reflex tachycardia (see side effects above) caused by hydralazine or minoxidil may exacerbate angina (cardiac chest pain) in patients with coronary artery disease
- Heart failure (minoxidil)
- Minoxidil-induced fluid retention can worsen heart failure. Use caution and adjust diuretics as needed.
- Hypertrophic cardiomyopathy (nitrates)
- Nitrates may aggravate the angina caused by hypertrophic cardiomyopathy
- Peripheral neuritis (hydralazine)
- Hydralazine hydrochloride has been associated with peripheral neuritis, evidenced by paresthesia, numbness, and tingling, which may be related to an anti-pyridoxine (vitamin B6) effect
- Pyridoxine (vitamin B6) should be added to hydralazine therapy if symptoms develop
- Mitral valve heart disease (hydralazine)
- Hydralazine may increase pulmonary artery pressure in patients with mitral valvular disease
- DRUG INTERACTIONS
- NOTE: The drug interactions presented here are NOT all-inclusive. Other interactions may exist. Drug interaction checkers provide the most efficient and practical way to check for interactions among multiple medications. A free interaction checker is available from Drugs.com (see Drugs.com interactions checker).
- Hydralazine
- MAO inhibitors - MAO inhibitors should be used with caution in patients receiving hydralazine
- Nitrates
- Alcohol - beverage alcohol may potentiate the blood pressure-lowering effect of nitrates
- Aspirin - aspirin has been shown to significantly increase blood levels of nitroglycerin. Vasodilatory and hemodynamic properties of nitroglycerin may be enhanced when taken with aspirin.
- Calcium channel blockers - marked symptomatic orthostatic hypotension has been reported when calcium channel blockers and organic nitrates were used in combination
- Dihydroergotamine (Migranal®) - nitrates may increase blood levels of dihydroergotamine and they should not be taken together [20]
- Heparin - IV nitroglycerin may decrease the effect of heparin [25, 26]
- Phosphodiesterase type 5 inhibitors (Viagra®, Cialis®, sildenafil, etc.) - phosphodiesterase type 5 inhibitors, which are commonly used to treat erectile dysfunction (ED), should not be taken with nitrates because severe hypotension may occur. Recommendations for intervals between dosing are provided below.
- The AHA/ACC makes the following statements about nitrates and ED medications:
- Nitrates should not be taken within 24 hours of sildenafil (Viagra®)
- Nitrates should not be taken within 48 hours of tadalafil (Cialis®)
- The suitable time for the administration of nitrates after vardenafil (Levitra®) has not been determined [22]
- Avanafil (Stendra®) - the avanafil PI states that when nitrate administration is deemed medically necessary in a life-threatening situation, at least 12 hours should elapse after the last dose of avanafil before nitrate administration is considered
- Riociguat (Adempas®) - DO NOT USE nitrates in patients who are taking riociguat because severe hypotension may occur. Riociguat stimulates soluble guanylate cyclase (sGC), an enzyme in the cardiopulmonary system and the receptor for nitric oxide.
- Tissue plasminogen activator (t-PA, Activase®, Alteplase®) - IV nitroglycerin has been shown to decrease the effectiveness and blood levels of t-PA. [23, 24]
- Metabolism and clearance
- Hydralazine (Apresoline®)
- CYP2D6 - weak inhibitor
- Isosorbide dinitrate (Isordil®)
- CYP3A4 - substrate
- Isosorbide mononitrate (ISMO®)
- CYP3A4 - substrate
- Minoxidil (Loniten®)
- Primarily metabolized by glucuronidation
- Nitroglycerin (Nitrostat®, etc.)
- Nitroglycerin is metabolized by a reductase enzyme in the liver
- Nitroglycerin also undergoes extrahepatic metabolism in red blood cells and vascular walls
- NITRATE PHARMACOKINETICS
Drug | Onset of action | Duration of effect |
---|---|---|
Nitroglycerin spray, tablet. powder | 1 - 3 minutes | around 25 minutes |
Isosorbide dinitrate | about 1 hour | up to 8 hours after one dose |
Isosorbide mononitrate | about 1 hour | up to 12 hours after one dose |
Nitroglycerin ointment | not rapid enough for acute angina | up to 12 hours |
Nitroglycerin patch | steady-state reached in 2 hours | up to 12 hours |
- DOSING
- LONG-TERM SAFETY
- Vasodilators have been used for many years
- They can have significant side effects, but are typically safe when prescribed appropriately
- BIBLIOGRAPHY
- 1 - Minoxidil PI
- 2 - Hydralazine PI
- 3 - PMID 6419809
- 4 - PMID 2141612
- 5 - PMID 8665975
- 6 - PMID 7023744
- 7 - PMID 20687078
- 8 - PMID 3520315
- 9 - PMID 2057035
- 10 - PMID 10496190
- 11 - PMID 15533851
- 12 - PMID 19324967
- 13 - PMID 7661937
- 14 - PMID 7910229
- 15 - PMID 10349897
- 16 - PMID 17502569
- 17 - PMID 19821384
- 18 - PMID 6432120
- 19 - PMID 16466117
- 20 - Nitroglycerin PI
- 21 - PMID 9316524
- 22 - PMID 21444888
- 23 - PMID 7572574
- 24 - PMID 7942523
- 25 - PMID 2112878
- 26 - PMID 2121114
- 27 - PMID 3671250
- 28 - Isosorbide mononitrate PI
- 29 - Isosorbide dinitrate PI
- 30 - PMID 21513360
- 31 - PMID 17153847
- 32 - BiDil PI
- 33 - PMID 4391708 - Minoxidil study
- 34 - PMID 23741058 - AHA 2013 HF GL
- 35 - PMID 23166211 - AHA 2012 CAD GL
- 36 - PMID 23247304 - AHA 2013 STEMI GL
- 37 - PMID 28455343 - PMID 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure
- 38 - PMID 29277252 - PMID 2017 ACC Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment: Answers to 10 Pivotal Issues About Heart Failure With Reduced Ejection Fraction
- 39 - PMID 22071816 - Hydralazine for essential hypertension, Cochrane review (2011)