Long-Acting Nitrates for Angina Management
Long-acting nitrates should be reserved as add-on therapy for angina not adequately controlled by β-blockers and calcium channel blockers, as they provide purely symptomatic relief without mortality or morbidity benefit. 1, 2, 3
Role in Angina Treatment Hierarchy
Long-acting nitrates are third-line agents for angina management, not first-line therapy 1, 2:
- Optimize β-blockers first (especially in patients with prior MI), along with aspirin 75 mg daily and statin therapy for prognostic benefit 4, 3
- Add calcium channel blockers if β-blockers are insufficient or contraindicated 1
- Add long-acting nitrates only when angina remains uncontrolled despite adequate doses of β-blockers and CCBs 1
Critical Limitation
Nitrates provide no mortality reduction or MI prevention—they are purely symptomatic therapy 2, 4, 3. This distinguishes them from β-blockers, ACE inhibitors, and antiplatelet agents that improve prognosis.
Choice Between ISMN and ISDN
Isosorbide mononitrate (ISMN) is preferred over isosorbide dinitrate (ISDN) for long-term prophylaxis 3:
ISMN Advantages:
- Once-daily dosing (60-240 mg) improves compliance 2, 3
- More predictable pharmacokinetics and superior patient adherence 3
- Duration of action: 12-24 hours 2
- FDA-approved for prevention of angina pectoris 5
ISDN Characteristics:
- Requires 2-3 times daily dosing (5-80 mg per dose) with asymmetric schedules (e.g., 7 AM and noon) 2, 3
- FDA-approved for prevention of angina pectoris 6
- More frequent dosing leads to poorer compliance 7
Mandatory Nitrate-Free Interval
A 10-12 hour nitrate-free interval is absolutely required to prevent tolerance development 2, 4, 3:
- Tolerance develops after 24 hours of continuous therapy 4, 8
- Without a nitrate-free interval, complete loss of anti-ischemic effects occurs 8
- Once-daily morning dosing naturally provides overnight nitrate-free periods 2, 3, 8
- This strategy maintains efficacy during daytime hours when angina is most likely 2, 9
Evidence of Tolerance:
Studies with ISDN or ISMN dosed ≥3 times daily demonstrate clinically relevant tolerance 8. However, once-daily high-dose sustained-release formulations prevent tolerance development 8, 9, 10.
Absolute Contraindications
Never use nitrates with phosphodiesterase-5 inhibitors 1, 2, 3:
- Contraindicated within 24 hours of sildenafil or 48 hours of tadalafil 2, 3
- Risk of profound hypotension, MI, and death 2
Other Contraindications:
- Severe hypotension 3
- Marked bradycardia or tachycardia 3
- Right ventricular infarction 3
- Angle-closure glaucoma 3
- Severe anemia 3
- Cirrhotic patients >50 years (ISMN specifically—increased mortality risk) 3
Common Side Effects and Management
Dose-dependent headache is the most common adverse effect 2, 4:
- Usually mild to moderate 9
- Improves with continued therapy 9, 7
- Rarely requires discontinuation 9
- Headache frequency increases with ISDN but decreases with continued ISMN use 7
Other Side Effects:
- Postural hypotension, especially with overdosing 4
- Reflexogenic tachycardia with excessive dosing can cause "paradoxical" angina 4
- Patients should sit during first use to prevent postural hypotension 4
Critical Distinction: Not for Acute Angina
Long-acting nitrates (ISMN/ISDN) are NOT for acute angina attacks 4, 5, 6:
- Onset of action is not sufficiently rapid for aborting acute episodes 5, 6
- Use sublingual nitroglycerin (GTN) 0.3-0.6 mg or spray (0.4 mg) for acute relief 4, 3
- GTN acts within 1-7 minutes 4
- An angina attack not responding to short-acting nitroglycerin should be regarded as possible MI 4
Practical Dosing Algorithm
For Chronic Angina Prevention:
ISMN (preferred):
- Start with 60 mg once daily in the morning 2
- Titrate up to 120-240 mg once daily if needed for symptom control 2, 10
- Provides sustained daytime effect without tolerance 2
ISDN (alternative):
- Dose 5-80 mg, 2-3 times daily with asymmetric timing 2, 3
- Example: 7 AM and noon dosing 3
- Ensures 10-12 hour nitrate-free interval overnight 3
Monitoring Effectiveness:
Short-acting nitrate consumption serves as a useful measure of treatment effectiveness—decreasing use indicates successful angina control 4.
Special Considerations
Abrupt Discontinuation:
Abrupt discontinuation during long-term therapy may exacerbate anginal symptoms 9. Taper if discontinuing after prolonged use.
No Rebound Phenomenon:
There is no evidence of rebound worsening of ischemia 24 hours after ISMN administration at the end of the dosing interval 9, 10.
Hypertension:
Hypertension does not impact the use of long-acting nitrates for angina prevention 1. However, nitrates have not been shown to be useful for managing hypertension itself 1.