- ACRONYMS AND DEFINITIONS
- AHA/ACC - American Heart Assoc / American College of Cardiology
- ER - Extended-release
- IR - Immediate-release
- NTG - Nitroglycerin
- SL - Sublingual
Hydralazine (Apresoline®)
Dosage forms
Tablet
- 10 mg
- 25 mg
- 50 mg
- 100 mg
Dosing
Hypertension
- Starting: 40 - 100 mg/day given in 3 - 4 divided doses
- Maintenance: 100 - 200 mg/day given in 3 - 4 divided doses
- Max: 300 mg/day
- Increase dose at an interval of 3 - 5 days
- Food increases absorption. Take consistently either with or without food. [2,3]
Heart failure
- In the V-HeFT I and II trials, hydralazine was dosed 37.5 mg four times a day for 2 weeks, then 75 mg four times a day
- In the A-HeFT trial, hydralazine was initially dosed 37.5 mg three times a day, then increased to 75 mg three times a day if tolerated
- Food increases absorption. Take consistently either with or without food. [2,3]
Kidney disease
- 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. [9]
Liver disease
- Hydralazine undergoes extensive liver metabolism. The effects of hepatic impairment on hydralazine have not been studied. Use caution.
Generic / Price
- YES/$Minoxidil (Loniten®)
Dosage forms
Tablet
- 2.5 mg
- 10 mg
Topical
Dosing
Hypertension
- Starting: 5 mg once daily
- Maintenance: 10 - 40 mg/day
- Max: 100 mg/day
- May be given in 1 or 2 divided doses
- Increase dose at intervals of 3 days
- It is recommended that minoxidil be taken with a diuretic and beta blocker (see minoxidil side effects)
- May take without regard to food
Hair loss (off-label)
- Dosing: 0.25 - 5 mg once daily
- See low-dose oral minoxidil for hair loss
- May take without regard to food
Kidney disease
- Minoxidil can exacerbate fluid retention in kidney disease. Start with lower doses and titrate slowly.
Liver disease
- Minoxidil can exacerbate fluid retention in liver disease. Start with lower doses and titrate slowly.
Generic / Price
- YES/$Nitroglycerin aerosol spray (Nitromist®)
Dosage forms
Aerosol
- 0.4 mg/spray
- Comes in 4.1g (90 sprays) and 8.5g (230 sprays) bottle
Dosing
Acute angina (chest pain)
- 1 - 2 sprays on or under the tongue at the onset of pain. May repeat in 5 minutes if needed.
- No more than 3 sprays are recommended within a 15-minute period
- See quick-acting nitroglycerin dosing
- May take without regard to food
Prevention of angina
- 1 spray 5 - 10 minutes prior to engaging in activity
- May take without regard to food
Kidney disease
- No dose adjustment is necessary in kidney disease
Liver disease
- Nitroglycerin undergoes metabolism in the liver and at sites outside of the liver. It has not been studied in liver disease.
Generic / Price
- NO/$$$$Other
- Do not shake container
- Spray onto or under the tongue
- Prime bottle with 10 sprays initially. It will remain primed for 6 weeks. May be re-primed with 2 sprays if not used within 6 weeks.
- Do not rinse mouth for 5 - 10 minutes following spray
Nitroglycerin SL powder (GoNitro™)
Dosage forms
Sublingual powder
- 400 mcg per packet
- Comes in box with 12, 36, or 96 packets
Dosing
Acute angina (chest pain)
- Administer one or two packets (400 mcg of NTG) under the tongue at the onset of an attack
- One additional packet may be administered every five minutes as needed
- No more than three packets are recommended within a 15-minute period
- See quick-acting nitroglycerin dosing
Prevention of angina
- 1 packet 5 - 10 minutes prior to engaging in activity
Kidney disease
- No dose adjustment is necessary in kidney disease
Liver disease
- Nitroglycerin undergoes metabolism in the liver and at sites outside of the liver. It has not been studied in liver disease.
Generic / Price
- NO/$$$$Other
- Administer at rest, ideally in the sitting position
- To administer, empty the contents of a packet under the tongue, close mouth and breath normally. Allow powder to dissolve without swallowing.
- Do not rinse or spit for 5 minutes after dosing
Nitroglycerin SL tablet (Nitrostat®)
Dosage forms
Sublingual tablet
- 0.3 mg
- 0.4 mg
- 0.6 mg
- Comes in bottle with 25 tablets
Dosing
Acute angina (chest pain)
- 1 tablet every 5 minutes up to a total of 3 tablets
- See quick-acting nitroglycerin dosing
- May take without regard to food
Prevention of angina
- 1 tablet 5 - 10 minutes prior to engaging in activity
- May take without regard to food
Kidney disease
- No dose adjustment is necessary in kidney disease
Liver disease
- Nitroglycerin undergoes metabolism in the liver and at sites outside of the liver. It has not been studied in liver disease.
Generic / Price
- YES/$Other
- Store in original container with cap screwed on tightly
- Drug will lose potency when exposed to light and air
Nitroglycerin spray (Nitrolingual®)
Dosage forms
Spray
- 0.4 mg/spray
- Comes in 4.9g (60 sprays) and 12g (200 sprays) bottle
Dosing
Acute angina (chest pain)
- 1 - 2 sprays onto or under the tongue at the onset of pain. May repeat in 5 minutes if needed.
- No more than 3 sprays are recommended within a 15-minute period
- See quick-acting nitroglycerin dosing
- May take without regard to food
Prevention of angina
- 1 spray 5 - 10 minutes prior to engaging in activity
- May take without regard to food
Kidney disease
- No dose adjustment is necessary in kidney disease
Liver disease
- Nitroglycerin undergoes metabolism in the liver and at sites outside of the liver. It has not been studied in liver disease.
Generic / Price
- YES/$$Other
- Do not shake container
- Spray onto or under the tongue
- Avoid swallowing immediately after spray
- Prime bottle with 5 sprays. It will remain primed for 6 weeks.
- Do not rinse mouth for 5 - 10 minutes following spray
Isosorbide dinitrate IR (Isordil®)
Dosage forms
Tablet
- 5 mg
- 10 mg
- 20 mg
- 30 mg
- 40 mg
Dosing
Prevention of angina
- Starting: 5 - 20 mg two to three times a day
- Maintenance: 10 - 40 mg two to three times a day
- Max: 160 mg/day
- Daily dose free interval of at least 14 hours is advised to minimize tolerance
- May take without regard to food
Heart failure
- In the V-HeFT I and II trials, isosorbide dinitrate was dosed 20 mg four times a day for 2 weeks, then 40 mg four times a day
- In the A-HeFT trial, isosorbide dinitrate was initially dosed 20 mg three times a day, then increased to 40 mg three times a day if tolerated
- May take without regard to food
Kidney disease
- No dose adjustment is necessary in kidney disease
Liver disease
- Isosorbide dinitrate undergoes extensive first-pass metabolism in the liver and considerable extrahepatic metabolism. It has not been studied in liver disease. Use caution.
Generic / Price
- YES/$ (#90 tablets)Isosorbide mononitrate IR | Monoket® | ISMO®
Dosage forms
Tablet, immediate-release
- 10 mg
- 20 mg
Dosing
Prevention of angina
- Dosing: 20 mg twice a day with the doses given 7 hours apart
- Max: 40 mg/day
- A starting dose of 5 mg twice a day may be appropriate in smaller patients. This dose should be increased to 10 mg by the second or third day of therapy.
- Tablets are scored
- May take without regard to food
Kidney disease
- No dose adjustment is necessary in kidney disease
Liver disease
- No dose adjustment is necessary in liver disease
Generic / Price
- YES/$Isosorbide mononitrate ER (IMDUR®)
Dosage forms
Tablet, extended-release
- 30 mg
- 60 mg
- 120 mg
Dosing
Prevention of angina
- Starting: 30 - 60 mg once daily
- Maintenance: 60 - 120 mg once daily
- Max: 240 mg/day
- Take dose in morning
- Tablets should not be chewed or crushed
- May take without regard to food
Kidney disease
- No dose adjustment is necessary in kidney disease
Liver disease
- No dose adjustment is necessary in liver disease
Generic / Price
- YES/$Nitroglycerin ointment (Nitro-bid®)
Dosage forms
Ointment
- 2% ointment
- Comes in 30 g and 60 g tube
- Comes in box of 48 one gram foilpacs (one pack is equivalent to one inch of ointment)
Dosing
Prevention of angina
- Starting: Apply 1/2 inch over area of truncal skin in morning and 6 hours later
- Max: 2 inches per dose
- Typically applied to chest. Do not rub into the skin. Coverage of an area approximately the size of the dose-measuring applicator (3 1/2" by 2 1/4") should be sufficient to obtain the desired clinical effects. A larger area may be used. Tape applicator in place.
- Effective for about 7 hours
- A 10 - 12 hour nitrate-free interval per day is recommended to prevent tolerance
Kidney disease
- No dose adjustment is necessary in kidney disease
Liver disease
- Nitroglycerin undergoes metabolism in the liver and at sites outside of the liver. It has not been studied in liver disease.
Generic / Price
- Tube - NO/$
- Foilpac (#48) - NO/$$
Nitroglycerin patch | Nitro-Dur® | Minitran®
Dosage forms
Patch
- 0.1 mg/hr
- 0.2 mg/hr
- 0.3 mg/hr
- 0.4 mg/hr
- 0.6 mg/hr
- 0.8 mg/hr
- Comes in carton with 30 patches
Dosing
Prevention of angina
- Starting: 0.2 - 0.4 mg/hr patch applied for 12 - 14 hours a day
- Max: 0.8 mg/hr patch
- A 10 - 12 hour patch-free interval per day is recommended to prevent tolerance
- Apply to reasonably hair-free site. Typically applied to trunk. Avoid extremities below the knee or elbow, skin folds, scar tissue, burned or irritated areas. May shower with patch on.
- After removing patch, skin may feel warm and appear red. This is normal.
Kidney disease
- No dose adjustment is necessary in kidney disease
Liver disease
- Nitroglycerin undergoes metabolism in the liver and at sites outside of the liver. It has not been studied in liver disease.
Generic / Price
- 0.1, 0.2, 0.4, 0.6 mg/hr - YES/$
- 0.3, 0.8 mg/hr - NO/$$$$
Bidil® (hydralazine + isosorbide dinitrate)
Dosage forms
Tablet
- Isosorbide dinitrate - Hydralazine
- 20 mg - 37.5 mg
Dosing
Heart failure in black patients
- Starting: 1 tablet three times a day
- Target: 2 tablets three times a day
- Max: 2 tablets three times a day
- Titrate dose as tolerated
- See A-HeFT trial for more
- Effect of food on absorption is unknown
Generic / Price
- NO/$$$$Other
- Tablets are scored
- 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 |
- QUICK-ACTING NITROGLYCERIN DOSING
- AHA quick-acting nitroglycerin recommendations for angina
- Patients with chest pain should take 1 dose of quick-acting nitroglycerin
- If pain is not improved or worsening after 5 minutes, it is recommended that 9-1-1 be called, and further instructions should be taken from them
- If pain is significantly improved after 1 dose, then 2 more doses should be given five minutes apart (total of 3 doses), and 9-1-1 should be called if pain does not resolve completely [4]
- Kidney disease dosing
- 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. [9]
- 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 dosing
- 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.
- 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 [10]
- Heparin - IV nitroglycerin may decrease the effect of heparin [14, 15]
- 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 [11]
- 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. [12, 13]
- 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
- PRICE ($) INFO
Pricing legend
- $ = 0 - $50
- $$ = $51 - $100
- $$$ = $101 - $150
- $$$$ = > $150
- Pricing based on one month of therapy at standard dosing in an adult
- Pricing based on information from GoodRX.com®
- Pricing may vary by region and availability
- BIBLIOGRAPHY
- 1 - Manufacturer's Package Insert for each drug listed
- 2 - PMID 1706804
- 3 - PMID 1780961
- 4 - PMID 21444888
- 5 - PMID 7572574
- 6 - PMID 7942523
- 7 - PMID 2112878
- 8 - PMID 2121114
- 9 - BiDil prescribing information
- 10 - Nitroglycerin PI
- 11 - PMID 21444888
- 12 - PMID 7572574
- 13 - PMID 7942523
- 14 - PMID 2112878
- 15 - PMID 2121114