Tolerance was first noted nearly 100 years ago in munitions workers, who suffered headache, fatigue, and orthostatic symptoms on returning to work after short holidays. Their symptoms resolved after hours to days of continued exposure.
Tolerance today is manifested by loss of efficacy in treating symptoms of angina or congestive heart failure with long-acting preparations used without a nitrate-free interval. Tolerance is also seen when increasing doses of intravenous nitroglycerin are needed over time to achieve a specific hemodynamic response or antianginal effect.
1A 64-year-old man with stable exertional angina has been doing well on isosorbide dinitrate, 20 mg twice daily. Recently, he increased his dose to four times daily, thinking âœmore is better.â Soon after, he noted worsening angina. Why might this occur?
This patient could have worsening angina secondary to progression of his coronary artery disease or it may be the development of nitrate tolerance. Studies in patients with stable angina have shown persistent antianginal effects when a nitrate-free interval of 10-12 hours is provided. Many patients experience an attenuation or complete loss of anti-anginal effects when long-acting agents are used three or four times daily. Similarly, long-acting nitroglycerin patches should be removed for 10-12 hours daily.
1Name some possible mechanisms of nitrate tolerance.
Sulfhydryl depletionâ”Inadequate generation of sulfhydryl groups necessary for transformation of organic nitrates to nitric oxide.
Chronic stimulation by nitric oxide causes desensitization of guanylate cyclase.
Activation of counter-regulatory neurohumoral mechanismsâ”Increased catecholamines, arginine vasopressin, plasma renin, aldosterone, and angiotensin II.
Increased intravascular volumeâ”Starting forces favor net movement of fluid from tissues into the vascular space when capillary pressure is reduced by vasodilation.