What is the “zero time effect” of nitrate drugs? Nitrate drugs, represented by nitroglycerin, are the oldest and most commonly used drugs to deal with angina pectoris, and have been used clinically for more than 130 years. Because of its reliable efficacy in the treatment of coronary heart disease and angina, it is still the most widely used class of drugs in the treatment of cardiovascular disease today, as new therapies continue to emerge. Nitrates are generally safe for clinical use, but sometimes there is a “zero hour effect” that can lead to an acute attack of angina and even sudden cardiac death. What is the “zero hour effect” of nitrate drugs? Usually, most patients use intermittent medication to prevent resistance to nitrates. However, it is said that this is a combination of advantages and disadvantages and is not suitable for the treatment of patients with unstable angina and severe cardiac insufficiency. The intermittent dosing method will reduce the concentration of nitrate drugs to the lowest level at this time, resulting in loss of efficacy, resulting in vasoconstriction, increased blood pressure, and increased myocardial ischemia, which will instead promote an acute attack of angina pectoris and even induce the risk of sudden death, because this phenomenon often occurs in the early morning hours, so it is called the “zero hour effect”. However, the “zero hour effect” can be avoided. In order to achieve effective pharmacological effects of nitrate drugs, there is a great deal of skill in their clinical use. There are three main types of nitrate drugs commonly used in clinical practice: isosorbide trinitrate (nitroglycerin), isosorbide dinitrate (e.g., cardiac pain, isoxsanguine) and isosorbide 5-mononitrate (e.g., long-acting isradine, clomid). Nitrate has a relaxing effect on vascular smooth muscle, which can improve hemodynamics, improve myocardial blood supply, and relieve and prevent angina attacks. At low doses it dilates veins, reducing venous return and decreasing cardiac preload. At moderate doses it dilates arteries (e.g. coronary arteries). At higher doses, it can lower blood pressure by diastaging peripheral resistance vessels and myocardial resistance vessels. According to the pharmacokinetics of nitrate drugs can be divided into fast-acting preparations and medium- and long-acting preparations, and different preparations and routes of administration are used according to different needs in clinical practice. Fast-acting preparations include: ① Sublingual preparations: nitroglycerin and cardiac pain are commonly used. ② Spray preparations: commonly used nitroglycerin oral spray and isosorbide dinitrate oral spray. (③) intravenous drug delivery preparations: commonly used nitroglycerin and isosorbide dinitrate. Fast-acting preparations are characterized by rapid onset of action, constant action and no hepatic first-pass metabolism. Second, the medium and long-acting preparations include: ① oral preparations, commonly used for cardiac pain and isosorbide 5-mononitrate, which is characterized by higher bioavailability and longer duration of action, suitable for long-term treatment of coronary heart disease and prevention of angina pectoris. ② patch, ointment preparations, commonly used nitroglycerin ointment, nitroglycerin patch, etc., transdermal administration, long duration of action, no hepatic first-pass metabolism. Avoid nitrate drug resistance and the “zero hour effect” method: Generally speaking, after a long period of continuous intravenous application, the use of patches or frequent use of nitrate formulations, nitrate resistance can occur within 24 ~ 48 hours. The clinical manifestations of nitrate resistance are: (1) decreased therapeutic effect with long-term administration of the same dose, and in order to achieve the same therapeutic effect, the dose must be increased; (2) decreased exercise tolerance and frequent angina attacks; (3) decreased angina threshold during the drug-free period. Although resistance to nitrates can develop, it is distinct from antibiotic resistance. This resistance has nothing to do with the type of drug or dosage form, but is closely related to the method of use and dosage. As long as the drug is not used continuously or by providing a nitrate blank interval, its resistance can be rapidly eliminated, thus restoring its therapeutic effect. To avoid nitrate resistance and the “zero hour effect”, the following methods can be used clinically: First, avoid high-dose administration and the use of extended-release agents without intervals. Maintain a drug-free period (or low concentration period) of 10 to 12 hours per day. Second, intermittent dosing, eccentric dosing or incremental dosing. The length and timing of intermittent periods should vary depending on the patient and the dosage form used. However, some patients cannot maintain the therapeutic effect during the drug-free period and may experience rebound phenomenon (“zero-hour effect”), so β-blockers or calcium antagonists can be added as appropriate. Third, choose daytime or nighttime drug delivery method. For patients with frequent daytime episodes of exertional angina, take the drug during the day and give a “nitrate-free” interval at night; for spontaneous angina attacks at night, use the opposite method of drug delivery; for those who are prone to angina in the early morning after waking up, it is advisable to take sublingual cardiac pain before waking up. Fourth, choose short-acting formulations. Long-acting formulations are more likely to produce drug resistance than short-acting formulations, while slow-release formulations and transdermal formulations are more likely to produce drug resistance. Therefore, in the application of nitrate for the treatment of angina pectoris, try to avoid the use of slow-release or transdermal dosage forms. Fifth, the combined use of drugs. Because the application of nitrate can lead to blood volume expansion, weakening the role of drugs, can be used in combination with diuretics to correct nitrate resistance; combined with captopril, can prevent nitrate resistance, captopril in addition to providing sulfhydryl groups, but also to counteract the activation of the renin-angiotensin-aldosterone system, play the role of anti-myocardial ischemia; with β-blockers, calcium antagonists, angiotensin II receptor antagonists The combination with β-blockers, calcium antagonists, angiotensin II receptor antagonists or statins can help prevent drug resistance; it can also be combined with traditional Chinese medicine such as compound salvia drops or quick-acting heart pills to prevent drug resistance and “zero time effect”. Sixth, master the contraindications of nitrate. Allergy to this type of drug, hypertrophic obstructive cardiomyopathy, severe aortic stenosis, hypotension (systolic blood pressure < 90 mmHg) and the application of sildenafil and other phosphodiesterase 5 inhibitors are contraindications to the application of nitrate. Finally, it should be noted that patients with coronary angina, if there is ineffective nitrate drug therapy, should not blindly take more or indiscriminately, should promptly go to the hospital to avoid delay in treatment. And for patients with acute coronary syndrome, unstable angina and severe cardiac insufficiency, they should be hospitalized.