Organic nitrates are well established in the treatment of a wide variety of cardiovascular disorders, most notably angina pectoris and congestive heart failure. However, attenuation of, or tolerance to, haemodynamic and anti-ischaemic effects may occur with all long-acting nitrate formulations. In the majority of patients continuous administration of long acting nitrates tends to promote the development of attenuation, while intermittent administration avoids it. Likewise, higher-doses appear to induce attenuation to a greater degree than lower doses. Attenuation of haemodynamic effects and exercise tolerance in heart failure patients, and of clinical end-points in angina patients, appears to be less than attenuation of exercise testing end-points in angina patients. While the use of intermittent therapy avoids the development of attenuation, it may expose the patient to an as yet undefined risk of silent and/or symptomatic anginal episodes occurring during the nitrate-free interval. Likewise, the role of concomitant therapy in avoiding this potential risk remains to be defined. Means of avoiding attenuation may include the coadministration of sulfhydryl donors such as N-acetylcysteine. Alternatively, angiotension-converting enzyme (ACE) inhibitors such as captopril may block renin-angiotensin system-induced reflex sympathetic stimulation. Attenuation may occur to a greater or lesser degree in individual patients. The proportion of attenuators vs non-attenuators remains to be defined, as does a means of identifying such patients prospectively by clinical and/or laboratory parameters. Conflicting results among smaller studies may reflect variable proportions of attenuators vs non-attenuators. However, conflicting results among larger studies may reflect differences in patient selection criteria, such as selecting patients with positive and reproducible stress tests and little in the way of spontaneously occurring angina versus selecting patients with positive but variable stress tests and frequent episodes of spontaneously induced angina. The former group may reflect pure fixed coronary artery disease with little in the way of vasospasm, or change in vasomotor tone, while the latter group may reflect greater variability in vasomotor tone and/or more in the way of plaque instability. The clinical efficacy of long acting nitrates might therefore be expected to be greatest in those patients with larger numbers of spontaneously occurring angina episodes. Recent data suggest that nitrates may have important direct effects on coronary vessels including dilating eccentric coronary stenoses, dilating intercoronary collateral channels and having greater dilating effects on more diseased segments as opposed to less diseased coronary segments.(ABSTRACT TRUNCATED AT 400 WORDS)

Nitrate tolerance. A review of the evidence.

Nitroglycerin (glyceryl trinitrate) has been used for many years via the sublingual route for treating acute anginal attacks. In recent years transdermal delivery of nitroglycerin has gained popularity for prophylaxis against angina. However, nitrate tolerance appears to be a therapeutic problem with all long-acting nitrates regardless of delivery mechanism, and it occurs in most patients with stable angina treated with continuous 24-hour application of nitroglycerin patches. Since continuous 24-hour plasma concentrations of nitroglycerin do not appear to be desirable, alternative approaches to therapy are needed. A simple method to minimise tolerance with transdermal nitroglycerin patches is to remove the patch at bedtime and reapply a new patch in the morning. Such intermittent therapy allows a patch-free period during the night, when most patients experience few angina attacks, but optimises nitrate sensitivity during the daytime. However, the place of intermittent nitroglycerin patch therapy in the treatment of stable angina needs clarification with further study, particularly comparisons with other long-acting forms of nitrates. There are insufficient data to recommend the use of transdermal nitroglycerin patches in the treatment of patients with unstable angina or congestive heart failure. In conclusion, transdermal nitroglycerin patches offer a convenient and cosmetically acceptable dosage form which has potential use in stable angina if administered as an intermittent regimen providing a patch-free period each night.

Transdermal nitroglycerin (glyceryl trinitrate). A review of its pharmacology and therapeutic use.

The various potential mechanisms contributing to nitrate tolerance are discussed. Pharmacokinetic alterations of the organic nitrate in the systemic circulation do not readily reflect pharmacologic tolerance. Neurohormonal changes do accompany continuous nitrate therapy, but the causative factor of tolerance, if it exists, has not been identified. Vascular metabolism of organic nitrates is impaired during in vitro nitrate tolerance, but it is still uncertain whether reduction in intracellular sulfhydryl availability is the operative mechanism. Vascular cyclic GMP production may be reduced during tolerance, but this change may not parallel that observed in vascular relaxation.

Mechanisms of nitrate action and vascular tolerance

Critically ill patients commonly show a decrease in hemoglobin concentration during their stay in the intensive care unit. The purpose of the present study was to evaluate whether nonbleeding patients with acute coronary syndrome (ACS) show a similar decrease of hemoglobin, and thereby furnish reference values and analyze possible mechanisms. In this retrospective, descriptive study, the charts of all patients with ACS hospitalized between January 2004 and September 2005 were screened with regard to patient characteristics, time course of hemoglobin, as well as clinical parameters, concomitant drug therapy, and fluid balances. One hundred three nonbleeding patients with ACS were analyzed. They showed an average hemoglobin decrease of 1.27 +/- 1.00 g/dl (p <0.001). The decrease in hemoglobin level was observed during the first 12 to 24 hours; thereafter the hemoglobin concentration remained stable. We found a correlation among decrease of hemoglobin, parameters of stress, such as hypertension (p = 0.019), tachycardia (p = 0.004), pain (p = 0.043), and white blood cells (p = 0.021), as well as the intravenous administration of nitroglycerin (p = 0.004). In conclusion, during the first 24 hours in the intensive care unit the hemoglobin concentration of nonbleeding patients with ACS regularly decreases at 1.27 +/- 1.00 g/dl. Any further decrease in hemoglobin level beyond these values should entail early active search of the bleeding source. We hypothesize that this decrease is due to normalization of the previous stress-induced hemoconcentration and "internal hemodilution" by nitroglycerin.

/pdf/time-course-of-hemoglobin-concentrations-in-the-intensive-6w2yugdnon.pdf

Time Course of Hemoglobin Concentrations in the Intensive Care Unit in Nonbleeding Patients With Acute Coronary Syndrome

Based on Capillary Gate Theory and Tissue Repair Theory, this paper describes the "Stress Repair Mechanism" (SRM) that maintains and repairs vertebrate tissues. It accounts for most of the mysterious manifestations of allostasis that remain unexplained by Hypothalamic-Pituitary-Axis (HPA) hormones and thereby enables the Universal Theory of Medicine predicted by Hans Selye. SRM activity explains hemodynamic physiology, capillary hemostasis, infarction, Korotkoff sounds, blood pressure, hypertension, diabetes, allostasis, allostatic load, anesthesia, analgesia, atherosclerosis, apoptosis, malignancy, eclampsia, sepsis, Multi-System Organ Failure (MSOF), the surgical stress syndrome, the fight or flight response, and numerous other manifestations of physiology and pathology. SRM function comprises the autonomic nervous system, the vascular endothelium, and the dynamic enzymatic interaction of blood-borne hepatic Factors VII, VIIIC, IX and X that produces thrombin, soluble fibrin and insoluble fibrin, whose combined effects account for all SRM manifestations. The vascular endothelium is a diaphanous neuroendocrine organ that lines all blood vessels and is the sole constituent of capillary walls. It secretes tissue factor into extravascular tissues, and insulates those tissues from the hepatic enzymes, so that tissue disruption exposes tissue factor to the enzymatic interaction and activates tissue repair. The vascular endothelium also releases nitric oxide and von Willebrand Factor into blood in accord with autonomic balance to regulate the enzymatic interaction to govern tissue perfusion and organ function. Therefore, continuously fluctuating combinations of nervous stimuli that affect autonomic balance and forces that disrupt tissues determine SRM activity.

http://stressmechanism.com/virtualoffice_files/CHDDT-10-2-Coleman.pdf

A stress repair mechanism that maintains vertebrate structure during stress.

Transdermal nitroglycerin (Nitroderm TTS 5) and a placebo were applied to 10 healthy male volunteers for 10 days. Before the first application and 6, 24, 48, 96, and 240 h thereafter, the viscosity of plasma and whole blood was measured and the packed-cell volume determined. During nitroglycerin application, the viscosity of plasma and whole blood was significantly diminished, and after 10 days it averaged 5% below the initial value. The greater the initial viscosity, the more marked was the druginduced reduction: in 5 subjects with plasma and whole-blood viscosities near the lower limit of the normal range, there was only a temporary decrease and the values reverted to their initial levels after 4 days; in the other 5 subjects, whose whole-blood viscosities were near the upper limit of the normal range, a 10% reduction was still demonstrable after 10 days. In those subjects all values measured throughout the 10-day observation period were significantly below the initial values. The haematocrit readings followed the same pattern as the alterations in viscosity. It can be assumed, therefore, that the decrease in viscosity induced by nitroglycerin results from “internal haemodilution”. The clinical relevance of the changes observed is discussed. The improvement in the rheological properties of the blood may contribute to the anti-anginal effect of Nitroderm TTS.

P. Moser

Papers

Effect of nitroglycerin on blood rheology in healthy subjects