Why Nitrates Tolerance Still Problem?

Despite undeniable benefit in relieving acute angina, the clinical use of organic nitrates is complicated by the development of tolerance to their pharmacologic effects.

Nitrate tolerance is characterized by: 

1-loss of hemodynamic and antianginal effects after repeated dosing;

2-higher and higher doses are needed to obtain the same physiologic effect.

3-Tolerance to intravenous, topical, and transdermal nitrates can develop in as little as 24 hours.

4- The use of the long-acting oral nitrates, isosorbide dinitrate and isosorbide mononitrate, also results in clinically significant nitrate tolerance in as little as 1 week, depending on the dosing schedule used.^[1]

In clinical research, tolerance to nitrates typically manifests as:

 a significantly decreased time to angina symptoms in treadmill testing after repeated dosing as compared with initial dosing.^[1] 

Potential mechanisms of nitrate tolerance include:

1-    the production of free radicals, which reduces the biotransformation of organic nitrates to nitric oxide (NO), and

^2-       depletion of sulfhydryl groups involved in the conversion of nitrates to NO.

^3-        In addition, counterregulatory mechanisms including volume expansion via sodium and water retention may also be involved.^[2-4]

Nitrate-Free Intervals to Avoid Nitrate Tolerance

Intermittent dosing of organic nitrates to provide a nitrate-free interval has been the preferred approach to nitrate tolerance for 2 decades.^[4,5] While intermittent dosing may preserve the hemodynamic effects of organic nitrates, it has many disadvantages.

Disadvantages of Intermittent dosing of organic nitrates

1-potentially confusing dosing schedules and

2- inconvenience to the patient,

3-the nitrate-free periods may be associated with worsening endothelial dysfunction and rebound ischemia, with increased frequency and intensity of ischemic events

Nicorandil prevents endothelial dysfunction

In diabetic patients, morbidity and mortality rise due to diabetic vascular complications such as atherosclerosis, retinopathy and nephropathy, triggered by endothelial dysfunction.

 Glycaemic control agents, statins and renin-angiotensin system inhibitors ameliorate endothelial dysfunction [59], thereby improving prognosis.

In this study of diabetic rats, nicorandil protected against endothelial dysfunction through inhibition of ROS production without glycaemic control.

 This result may suggest that nicorandil can improve the prognosis of patients with ischemic heart disease and diabetic complications through not only the pharmacological preconditioning effect, but also an endothelial protective effect. In fact,

the IONA [60] and J-CAD [61] studies demonstrated nicorandil to improve the prognosis of patients with ischemic heart disease and diabetes.

Source

Nicorandil Sustained Release Formulation

The present investigation revealed that Tamarindus kernals mucilage and guar gum, Ethyl cellulose and
HPMC appears to be suitable for use as a release retarding agents in the formulation of sustained release
matrix tablets because of its good swelling, good flow and suitability for matrix formulation.
From the dissolution study, it was concluded that Tamarindus kernals mucilage can be used as an excipient for
making sustained release matrix tablets of Nicorandil.
Nicorandil Sustained Release Formulation

A Meta-Analysis of the Effect of K-ATP Channel Opener ( Nicorandil )on the Prognosis of Coronary Heart Diseases

K-Channel Opener ( Nicorandil ) showed not only angina symptoms relieve but also significance positive outcomes in terms of:
- Reduction of :
 -The incidence of major adverse cardiac events including
1- Occurrence of cardiac deaths
2- Unplanned hospital admission for cardiac chest pain 
3-Congestive heart failure were significantly reduced compared with the control group. 
Source

BRIDGE study published: Cangrelor suited for important antiplatelet niche

Boston, MA - The BRIDGE study, showing that the intravenous P2Y12 receptor antagonist cangrelor (the Medicines Company) could represent an effective bridging therapy for patients taking thienopyridine antiplatelet agents such as clopidogrel who are scheduled for surgery, has been published in the January 18, 2012 issue of the Journal of the American Medical Association.

See the study athttp://www.theheart.org/article/1341135.do?utm_campaign=newsletter&utm_medium=email&utm_source=20120118_EN_Heartwire

Different K+ Channels Are Involved in Relaxation of Arterial and Venous Graft Induced by Nicorandil.

J Cardiovasc Pharmacol. 2011 Dec;58(6):602-608.


ABSTRACT: The drug nicorandil is a vasodilator approved for the treatment of angina. In addition to its well-known effect on the opening of ATP-sensitive K (KATP) channels, nicorandil-induced vasorelaxation also involves the opening of Ca-activated K channels. The aim of this study was to investigate the effects of nicorandil on the isolated human internal mammary artery (HIMA) and the human saphenous vein (HSV) and to define the contribution of different K channel subtypes in the nicorandil action on these arterial and venous grafts. Our results show that nicorandil induced a concentration-dependent relaxation of HSV and HIMA rings precontracted by phenylephrine. Glibenclamide, a selective KATP channels inhibitor, partially inhibited the response to nicorandil in both HSV and HIMA. Iberiotoxin, a most selective blocker of large-conductance Ca-activated K (BKCa) channels, partly antagonized relaxation of HIMA. A nonselective blocker of voltage-gated K channels, 4-aminopyridine caused partial inhibition of the nicorandil-induced relaxation of HSV but did not antagonize relaxation of HIMA induced by nicorandil. Margatoxin, a potent inhibitor of KV1.3 channels, did not abolish the effect of nicorandil on HSV and HIMA. Our results showed that nicorandil induced strong endothelium-independent relaxation of HSV and HIMA contracted by phenylephrine. It seems that KATP and 4-aminopyridine-sensitive K channels located in the smooth muscle of HSV mediated relaxation induced by nicorandil. In addition, KATP and BKCa channels are probably involved in the nicorandil action on HIMA.


Source PubMedhttp://www.ncbi.nlm.nih.gov/pubmed/22146404

Evaluation of the Protective Effects of Nicorandil

Pretreatment with nicorandil can reduce the infarct size, ameliorate micro vascular perfusion and preserve left ventricular systolic function in canine heart model of 3 hours ischemia followed by 2 hours reperfusion. And 24 hours after pretreatment with nicorandil, it can provide significant cardio protective effects on canine myocardium. All these effects can be blocked with glibencamide. http://www.res-medical.com/clinical-medicine/26702