Nitrates are powerful vasodilators used to treat angina by improving blood flow and reducing the heart's workload. They work by donating nitric oxide, which relaxes smooth muscle in blood vessels, leading to decreased oxygen demand and increased oxygen supply to the heart.

These medications come in various forms, from fast-acting sublingual tablets to long-lasting patches. While effective, nitrates can cause side effects like headaches and low blood pressure. Proper patient education on usage and potential interactions is crucial for safe and effective treatment.

Nitrates

Mechanisms of nitrates for angina

• Nitrates act as vasodilators by relaxing smooth muscle in blood vessels
  • Venodilation primarily dilates veins, reducing preload and venous return to the heart, which decreases cardiac workload and oxygen demand (coronary sinus)
  • Arteriolar dilation also occurs, reducing afterload and systemic vascular resistance, improving cardiac output and reducing cardiac workload (coronary arteries)
• Nitrates donate nitric oxide (NO) which activates guanylate cyclase in vascular smooth muscle cells
  • Guanylate cyclase increases cyclic guanosine monophosphate (cGMP) levels
  • Elevated cGMP decreases intracellular calcium, causing vasodilation
• Coronary vasodilation dilates coronary arteries, improving blood flow to ischemic myocardium, increasing oxygen supply to heart muscle and alleviating angina symptoms
• Nitrates improve endothelial function, enhancing the overall vascular response

Hemodynamic effects and myocardial oxygen balance

• Nitrates reduce myocardial oxygen demand through various mechanisms:
  • Decreased preload and afterload
  • Improved coronary blood flow
  • Reduced wall tension
• These effects help alleviate ischemia in patients with coronary artery disease
• Organic nitrates (e.g., nitroglycerin, isosorbide dinitrate) are the primary agents used for these hemodynamic benefits

Comparison of nitrate medication forms

• Sublingual nitroglycerin (NTG)
  • Onset 1-3 minutes
  • Duration 20-30 minutes
  • Used for acute angina episodes or prophylactically before activities that may trigger angina (exercise)
• Nitroglycerin spray
  • Onset 1-3 minutes
  • Duration 20-30 minutes
  • Similar to sublingual NTG but may be easier to administer for some patients (elderly)
• Transdermal nitroglycerin patch
  • Onset 30-60 minutes
  • Duration 8-12 hours
  • Provides sustained nitrate therapy for chronic angina management
  • Requires patch-free interval of 10-12 hours daily to prevent tolerance
• Isosorbide dinitrate (ISDN)
  • Onset 15-30 minutes
  • Duration 4-6 hours
  • Oral formulation for chronic angina management (extended-release)
• Isosorbide mononitrate (ISMN)
  • Onset 30-60 minutes
  • Duration 6-8 hours
  • Oral formulation with longer duration of action compared to ISDN (once-daily dosing)

Adverse effects of nitrate therapy

• Headache is the most common side effect due to vasodilation
• Hypotension from excessive vasodilation may cause significant blood pressure drop
• Orthostatic hypotension is a sudden drop in blood pressure upon standing
• Reflex tachycardia occurs as a compensatory response to hypotension
• Flushing of the skin results from peripheral vasodilation
• Dizziness or lightheadedness is related to hypotension
• Nitrate tolerance may develop with continuous use, reducing therapeutic efficacy
• Drug interactions:
  • Phosphodiesterase-5 (PDE-5) inhibitors (sildenafil, tadalafil) concomitant use can cause severe hypotension and is contraindicated
  • Antihypertensives (beta-blockers, calcium channel blockers) may have additive hypotensive effects; monitor blood pressure closely
  • Alcohol may potentiate the hypotensive effects of nitrates

Patient education for nitrate use

• Instruct patients on proper administration technique for their specific nitrate formulation
  • Sublingual NTG: place under the tongue and allow to dissolve; do not swallow
  • Nitroglycerin spray: spray onto or under the tongue; do not inhale
  • Transdermal patch: apply to clean, dry, hairless skin; rotate application sites (chest, upper arm)
• Advise patients to sit or lie down when taking short-acting nitrates to prevent falls due to hypotension
• Encourage patients to keep a log of angina episodes and nitrate use to share with healthcare provider
• Educate patients on common side effects and when to seek medical attention
  • Inform that headache is common and may indicate the medication is working
  • Advise to report severe or persistent side effects to their healthcare provider
• Stress the importance of adhering to prescribed dosing schedule and patch-free intervals for transdermal nitrates to prevent tolerance
• Instruct patients to avoid PDE-5 inhibitors and limit alcohol consumption while taking nitrates
• Advise patients to inform all healthcare providers about their nitrate use before starting new medications or undergoing procedures (surgery)