What is the recommended use of NTG (Nitroglycerin) and IMDUR (Isosorbide Mononitrate) for angina management?

Use of Nitroglycerin and IMDUR in Angina Management

For acute angina relief, use sublingual nitroglycerin 0.3-0.6 mg every 5 minutes for up to 3 doses, and call 911 if symptoms persist after the first dose or worsen; for chronic angina prophylaxis, use IMDUR (isosorbide mononitrate) 20 mg twice daily (7 hours apart) or 60-240 mg once daily extended-release, avoiding continuous 24-hour nitrate coverage to prevent tolerance. 1

Acute Angina Management with Sublingual NTG

Immediate Use Protocol

• Take 1 sublingual NTG tablet (0.3-0.6 mg) at the first sign of chest discomfort 2
• If symptoms are unimproved or worsening after 5 minutes, call 911 immediately 1
• For patients with chronic stable angina whose symptoms significantly improve after 1 dose, repeat every 5 minutes for maximum of 3 doses total 1
• If pain persists after 3 tablets in 15 minutes, or if pain is different than usual, seek emergency care immediately 2

Prophylactic Use

• Take sublingual NTG 5-10 minutes before activities that typically trigger angina 2
• Patient should sit when taking NTG to avoid falls from lightheadedness 2

Critical Safety Contraindications

• Absolute contraindication: Do not use within 24 hours of sildenafil or 48 hours of tadalafil due to risk of profound hypotension, MI, and death 1, 3, 4
• Avoid if systolic BP <90 mmHg or >30 mmHg below baseline 1
• Avoid with marked bradycardia or tachycardia 1
• Use extreme caution in right ventricular infarction (preload-dependent) 1

Intravenous NTG for Refractory Angina

Initiation and Titration

• Start at 10 mcg/min and increase by 10 mcg/min every 3-5 minutes until symptom relief or blood pressure response 1, 3, 4
• If no response at 20 mcg/min, use larger increments of 10-20 mcg/min 1, 3
• Stop titrating once symptoms resolve—no need to continue for blood pressure effect alone 3
• Commonly used ceiling is 200 mcg/min, though doses of 300-400 mcg/min have been safely used for 2-4 weeks 1, 3

Blood Pressure Targets

• Maintain systolic BP ≥110 mmHg in normotensive patients 3, 4
• In hypertensive patients, do not reduce mean arterial pressure by >25% 3

Transition Strategy

• Convert IV NTG to oral/topical nitrates within 24 hours once patient is symptom-free for 12-24 hours 1, 3
• Gradually taper IV NTG rather than abrupt cessation to avoid rebound ischemia 1
• It is inappropriate to continue IV NTG in patients free of ischemic signs/symptoms 1

Long-Acting Nitrates: IMDUR (Isosorbide Mononitrate)

Dosing Regimens to Avoid Tolerance

The critical principle is providing a nitrate-free interval of 10-14 hours daily to prevent tolerance 1

Immediate-Release Isosorbide Mononitrate

• 20 mg twice daily with asymmetric dosing (e.g., 7 AM and 2 PM)—7 hours apart 1
• This provides antianginal coverage during waking hours while allowing overnight nitrate-free interval 5

Extended-Release Isosorbide Mononitrate (IMDUR)

• 60-240 mg once daily in the morning 1
• Provides sustained daytime antianginal effect without 24-hour coverage 5
• Does not produce tolerance or zero-hour effect (deterioration before morning dose) 5

Why Tolerance Matters

• Tolerance develops after 24 hours of continuous nitrate therapy and is dose/duration dependent 1, 3
• Continuous dosing (qid, tid, or symmetric bid) produces marked tolerance and loss of antianginal effect 5
• Tolerance can eliminate responsiveness even to sublingual NTG (cross-tolerance) 6, 7
• Asymmetric dosing regimens with nitrate-free intervals maintain efficacy during long-term use 5

Alternative Long-Acting Nitrate: Isosorbide Dinitrate

If IMDUR Not Available

• Isosorbide dinitrate 30 mg three times daily (7 AM, 1 PM, 6 PM) provides 6 hours of coverage but develops partial tolerance 5
• Asymmetric bid dosing (7 AM and noon) may sustain effect but is less well-studied 5
• Standard doses: 5-80 mg 2-3 times daily or 40 mg slow-release 1-2 times daily 1

Common Pitfalls to Avoid

Tolerance Development

• Never prescribe nitrates for continuous 24-hour coverage—this guarantees tolerance 1, 7, 5
• Transdermal NTG patches are ineffective at 24 hours even at maximal doses due to rapid tolerance 8
• If using transdermal NTG, apply for only 12 hours daily (0.2-0.8 mg/h), then remove for 12-hour nitrate-free interval 1

Sublingual NTG Storage and Potency

• Keep in original glass container, tightly capped after each use 2
• Burning/tingling sensation is NOT a reliable indicator of potency 2

Rebound Ischemia

• Some patients experience increased angina frequency during nitrate-free intervals 1, 2
• Industrial workers with chronic high-dose nitrate exposure have experienced MI and sudden death upon abrupt withdrawal 2, 7
• Gradual dose reduction is advisable when discontinuing IV NTG 1

Evidence Limitations

• No randomized controlled trials demonstrate mortality benefit from nitrates in UA/NSTEMI 1
• Large trials (ISIS-4, GISSI-3) showed no mortality reduction with routine nitrate use in MI 1
• Rationale for nitrate use is based on pathophysiological principles and uncontrolled clinical observations 1
• Nitrates are considered third-line therapy for stable angina due to tolerance issues 6

Clinical Decision Algorithm

For acute symptoms:

1. Sublingual NTG 0.3-0.6 mg → if no improvement in 5 min → call 911 1, 2
2. If refractory to 3 sublingual doses → IV NTG starting at 10 mcg/min 1, 3

For chronic prophylaxis:

1. First-line: Beta-blockers or calcium channel blockers (not nitrates) 6
2. If additional antianginal needed: IMDUR 60-120 mg once daily AM 1, 5
3. Ensure 10-14 hour nitrate-free interval (typically overnight) 1, 5
4. Sublingual NTG as needed for breakthrough symptoms 2