Partial occlusion / early recanalization / rich collaterals leads to NSTEMI (non-ST elevation MI) Total occlusion of infarct related artery leads to ST elevation (STEMI) and subsequent evolution of Q waves
shift ATP production from fatty acid to more oxygen efficient carbohydrate oxidation by stimulating glucose oxidation during the elevated plasma free fatty acid levels associated with myocardial ischemia
Basis of pFOX 1. Myocardial ischemia is associated with sudden increase in fatty acid levels resulting in enhanced oxidation of long chain fatty acids 2. Oxidation of fatty acids needs more ATPs and also an increased oxygen demand for their breakdown than oxidation of carbohydrates 3. Moreover this may lead to accumulation of free fatty acids and lactic acid increasing the acidosis and affecting heart performance. 4. These mechanisms have harmful effects on the contractility and efficiency of the heart. 5. Treatment must aim to shift myocardial substrate utilisation to glucose metabolism as this will then provide benefits to ischemic patients. 6. This is achieved by drugs which suppress fatty acid oxidation. Trimetazidine Ranolazine
Ranolazine blocks late inward sodium currents in cardiomyocytes
By blocking late inward sodium currents, there is reduction in calcium overload and diastolic wall stress-
This, in turn, reduces diastolic stiffness and improves myocardial perfusion.
This, along with pFOX, contributes to superior anti-anginal efficacy of ranolazine.
Ranolazine - summary Ischaemia ↑ Late I Na Na + Overload Diastolic relaxation failure (Increased diastolic tension) Extravascular compression Ca ++ Overload Ranolazine: Inhibits the late inward Na current Ranolazine prevents the diastolic stiffness and thereby preserves myocardial blood flow Intramural small vessel compression ( ↓ O2 supply) and ↑ O2 demand
Digoxin [Coadministration of Ranolazine and digoxin increases the plasma concentrations of digoxin by approx. 1.5-fold];
Tricyclic antidepressants & some antipsychotics
Ranolazine prolongs the QT-interval. Hence, it is contradicted in patients with prolonged QT-intervals.
Ranolazine – the studies MARISA = Monotherapy Assessment of Ranolazine In Stable Angina CARISA = Combination Assessment of Ranolazine In Stable Angina ERICA = Evaluation of Ranolazine in Chronic Angina MERLIN-TIMI = Metabolic Efficiency with Ranolazine for Less Ischemia in Non ST elevation acute coronary syndromes
Despite the current use of drugs for CAD like beta blockers, CCBs, nitrates, and satisfying response to current treatments, patients still continue to get recurring pain = chronic angina or refractory angina.
These anginal patients have 2 abnormalities which are not effectively controlled by current antianginals / revascularization therapies:
Such ischaemia of diastolic stiffness-induced angina, occuring due to the late sodium inward entry; is prevented by ranolazine as it blocks late inward sodium entry and thus helps to avoid diastolic stifness.
In the European Union, the drug remains indicated for stable angina as an add-on therapy when symptoms aren't controlled with first-line agents.
Basis for such change
As seen in the MERLIN-TIMI 36 trial and in clinical practice, patients with ischemia and angina can be at increased risk for arrhythmias and also often have diabetes. Considering its mechanism of action, established cardiovascular safety, and observed reductions in arrhythmias and [glycosylated hemoglobin], ranolazine now becomes an even more important drug in the treatment of chronic angina.
Cardioplegia is the temporary cessation of cardiac activity.
Results suggest that addition of ranolazine during hyperkalemic ischemic cardioplegic arrest is beneficial and provides further protection against contracture.
Ranolazine as an Adjunct to Cardioplegia: A Potential New Therapeutic Application by Hyosook Hwang, PhD et al. Heart Institute, Good Samaritan Hospital, Los Angeles, California, Journal of Cardiovascular Pharmacology and Therapeutics, Vol. 14, No. 2, 125-133 (2009)
Results suggest that ranolazine was effective in reducing myocardial infarct size, the mechanism by which it did this was independent of improving perfusion during either ischemia or reperfusion, suggesting that ranolazine's effect of reducing infarct size involves alternative mechanisms. .
The Antianginal Agent, Ranolazine, Reduces Myocardial Infarct Size but Does Not Alter Anatomic No-Reflow or Regional Myocardial Blood Flow in Ischemia/Reperfusion iby Sharon L. Hale, BS et al, Heart Institute, Good Samaritan Hospital and the Division of Cardiovascular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, firstname.lastname@example.org, Journal of Cardiovascular Pharmacology and Therapeutics, Vol. 13, No. 3, 226-232 (2008)
Results from MERLIN-TIMI and other studies suggest that ranolazine was effective in reducing HbA1c.
Even in CARISA, though ranolazine did not appear to significantly lower fasting glucose levels in diabetic patients, there was a statistically significant reduction of HbA1c.
Ranolazine’s effect on HbA1c levels may be speculated by its action on cell membrane or its metabolic action; but could possibly be due to a ranolazine-induced decrease in anginal symptoms leading to increased physical activity, with a resultant increase in insulin sensitivity.
Nicorandil acts by relaxing the smooth muscle of the blood vessels, especially those of the venous system. It does this by 2 ways-
Firstly, by activating K+ channels, and
Secondly, by donating nitric oxide to activate the enzyme guanylate cyclase. Guanylate cyclase activation leads to both arterial and venous vasodilatation. Although it can dilate the coronary vessels, it dilates the venous system, instead, thus reducing preload and the work of the heart.
Peri-anal, ileal and peri-stomal ulceration is a side effect limiting its use.
Ivabradine acts on the If ion current, which is highly expressed in the sinoatrial node. (f is for "funny", so called because it had unusual properties compared with other current systems known at the time of its discovery)
It is one of the most important ionic currents for regulating activity in the SA node.
Ivabradine selectively inhibits the pacemaker If current in a dose-dependent manner.
It has been shown to be non-inferior to the beta-blocker atenolol for this indication 3 and amlodipine.
Apart from angina, it is also being used off-label in the treatment of inappropriate sinus tachycardia.
Reduction in heart rate with ivabradine does not improve cardiac outcomes in all patients with stable coronary artery disease and left-ventricular systolic dysfunction, but could be used to reduce the incidence of coronary artery disease outcomes in a subgroup of patients who have heart rates of 70 bpm or greater .
The Lancet, Volume 372, Issue 9641, Pages 807 - 816, 6 September 2008, Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL).