By: Neal Shah<\/p>\n
–<\/p>\n
Part I:\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Preface.<\/p>\n
Part II:\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Brief review of cardiac electrophysiology.<\/p>\n
Part III:\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Ivabradine as a novel If<\/sub> blocker for the use of stable angina.<\/p>\n Part IV:\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 On the horizon: trimetazidine.<\/p>\n –<\/b><\/p>\n PREFACE<\/b><\/p>\n When viewed anatomically, the heart may seem like a simple organ. \u00a0However, the electrophysiological aspects of the heart are somewhat complex. \u00a0As pharmacists, in part, we not only need to understand how drugs exert their actions in pathological settings, but also how they can interfere with normal physiological functions to create adverse effects. \u00a0As researchers, we always strive to discover new pathways that have the potential to revolutionize current therapies or rekindle interests in old pathways to discover new effects. \u00a0I have had a significant interest in cardiac physiology since my first course in Anatomy and Physiology years ago.\u00a0 In addition, I have read several books and papers dealing with the electrophysiological conductive system of the heart. \u00a0I hope that readers of this article are familiar with the basics of cardiac conduction and terminology. \u00a0If not, I have provided a small review of pacemaker and ventricular electrical activity below, as the drug discussed in Part III does not work by a commonly-known pathway.<\/p>\n There are at least five different types of calcium channels in human physiology: L-, N-, P\/Q-, R-, and T-type channels.1,2<\/sup> \u00a0These voltage-gated channels are distributed throughout the body. \u00a0N-type calcium channels in the nervous system are inhibited by drugs such as ziconotide (Prialt\u00ae), gabapentin (Neurontin\u00ae), and pregabalin (Lyrica\u00ae).3<\/sup>\u00a0 These medications are used for intrathecal anesthesia or neuropathic pain.3<\/sup> \u00a0T-and-L-type calcium channels are discussed in Part II, and are targets in the treatment of absence (petit mal) seizures4<\/sup> and cardiovascular diseases, respectively. \u00a0P\/Q-type channels are located in the Purkinje cells of the cerebellum, and R-type channels are likewise located in the brain and cerebellum, but will not be discussed here.5<\/sup><\/p>\n Verapamil is a calcium channel blocker (CCB) that causes negative inotropy (a decrease in the force of contraction) and negative chronotropy (a decrease in heart rate). \u00a0Since multiple calcium channel subtypes are present throughout the body, does verapamil exert its effects by blocking a single subtype of calcium channel?\u00a0 Or does it block multiple calcium channels?\u00a0 The answer may surprise you, as it did me. \u00a0Its mechanism for causing bradycardia is different from ivabradine, which is discussed in Part III.<\/p>\n –<\/b><\/p>\n ELECTRICAL CONDUCTION AND EKG OF THE SINOATRIAL NODE <\/b><\/p>\n The sinoatrial (SA) node is commonly referred to as the \u201cpacemaker\u201d because, under normal physiological conditions, it has the most rapid rate of depolarization, and, thus, determines the heart rate. \u00a0The SA node depolarizes rapidly because it possesses an interesting property: the pacemaker potential.6<\/sup> \u00a0The pacemaker potential allows the SA node to spontaneously depolarize due to a lack of stable resting membrane potential, thereby expressing autorhythmicity. \u00a0This is due to the combination of the \u201cfunny channel\u201d (If<\/sub>), and T-type Ca channels. \u00a0The L-type channels also control SA depolarization, overall pacemaker activity, and excitation-contracting coupling in cardiac, smooth, and skeletal muscles.7<\/sup> \u00a0Figures 1 and 2 (both in PDF) show the SA node\u2019s electrical channel components. \u00a0Figure 3 (in PDF) correlates SA node and EKG readings when negative chronotropy is induced.8<\/sup><\/p>\n It is interesting to note that the T-type calcium channel is involved in the pacemaker potential, whereas the L-type is involved in rapid depolarization activity. \u00a0From Figures 1 and 3 (both in PDF), we can infer that the L-type channel is most affected by traditional non-dihydropyridine (non-DHP) CCBs like verapamil\u2014that is, verapamil is an L-type calcium channel blocker. \u00a0Verapamil possesses T-type calcium channel blockade as well, but only a small fraction of its L-type channel blockade (and this inhibition does not contribute significantly to its negative chronotropy).9,10<\/sup> Negative inotropy is not shown graphically, but is presumed to occur since L-type calcium channels control cardiac muscle contractions, and their blockade would decrease such activity. \u00a0A potential target for drugs in the future should also focus on the T-type calcium channels in the heart, especially if molecular specificity against the brain\u2019s T-type channels can be found. But the T-type calcium channel only controls the latter portion of the pacemaker potential, where blockade may prove unimportant if the first part is not first controlled.<\/p>\n This brings us to the If<\/sub>, otherwise known as the \u201cfunny\u201d channel. \u00a0If<\/sub> is an inward Na+<\/sup>\/K+<\/sup> current, activated by hyperpolarization of the membrane potential of the SA node.11<\/sup> \u00a0The If<\/sub> channel dictates the slope of the pacemaker potential depolarization, and, thus, the rate at which the SA node fires action potentials. It is interesting to note that If<\/sub> is also inhibited by beta-adrenergic antagonists (such as propranolol or metoprolol), and this may contribute to their bradycardic effects.12<\/sup><\/p>\n Angina is a cardiovascular disease where the heart\u2019s supply of oxygen cannot meet the oxygen demand of the heart. \u00a0The goal of treatment is to restore the imbalance between oxygen supply and demand. \u00a0Mitigation of angina can occur by decreasing heart rate, contractility, or increasing oxygen supply. \u00a0Traditionally, angina has been pharmaceutically treated by use of nitrates, non-DHP CCBs, and beta blockers.13<\/sup> However, these drugs do not act solely on the SA node and have adverse cardiovascular and non-cardiovascular side effects (such as insomnia and constipation).14 <\/sup>\u00a0Therefore, it would be beneficial to have a specific If<\/sub> channel inhibitor – and ivabradine is currently the only drug to have this effect.<\/p>\n –<\/b><\/p>\n IVABRADINE<\/b><\/p>\n Ivabradine (Procoralan\u00ae, Servier) is a selective If<\/sub> channel inhibitor.11,12,15-18<\/sup>\u00a0 It was internationally approved in 2005 for the treatment of stable angina, and is not currently available in the United States (US).\u00a0 Ivabradine inhibits the SA node\u2019s If<\/sub> current and induces negative chronotropy. \u00a0Since ivabradine is selective for the If<\/sub>, it avoids the non-cardiac side effects of agents that can also block the If<\/sub>, like beta blockers. \u00a0This is crucial in patients who cannot tolerate beta blocker therapy, such as those with uncontrolled asthmatic or peripheral vascular disease, or those who are sensitive to fatigue, depression, and sexual dysfunction.16<\/sup> \u00a0Unlike beta blockers, ivabradine selectively reduces heart rate without altering myocardial contractility, cardiac conduction, or coronary vascular tone.17<\/sup><\/p>\n Interestingly, ivabradine\u2019s neutral inotropic effects were not initially seen in animal experiments. \u00a0Ivabradine was shown to have positive inotropic activity, stemming from its bradycardic activity. \u00a0A parallel can be drawn between ivabradine and digoxin in this sense, as they both decrease heart rate yet increase ventricular ejection. \u00a0These positive inotropic effects were converted to negative inotropic effects in the additional presence of the verapamil, proving that calcium was the mediator for the effects.15<\/sup> \u00a0Unfortunately, ivabradine is not a true replacement for digoxin.<\/p>\n The INITIATIVE trial was a large multicenter trial in which 939 patients with stable angina were randomized to ivabradine or atenolol. \u00a0Ivabradine, at doses of 5 and 7.5 mg twice daily, was shown to be at least as effective as atenolol 50 and 100 mg once daily, respectively.16<\/sup> \u00a0In another study, 120 patients were randomized to receive either ivabradine 15 mg or metoprolol 50 mg directly before coronary computed tomographic angiography. \u00a0It was shown that although heart rate was greatly decreased compared to metoprolol, neither the systolic or the diastolic blood pressures were significantly affected.19<\/sup> \u00a0A smaller trial compared the effects of ivabradine and bisoprolol on exercise tolerance. \u00a0Initially, both groups had a decreased resting heart rate; however, patients on ivabradine (but not those on bisoprolol) overcame exercise induced fatigue and tolerance.20<\/sup><\/p>\n It is possible that ivabradine may be used in patients that are intolerant of (or refractory to) beta adrenergic receptor antagonists or CCBs. \u00a0For example, ivabradine normalized the heart rate of a patient presenting with heart failure induced by acute right ventricular pacing with a concomitant COPD exacerbation.21 \u00a0<\/sup>It was reported that a hospitalized, 75-year old female presenting with severe acute angina and tachycardia did not respond to both IV diltiazem and propranolol.\u00a0 However, ivabradine (used off label in this emergency situation), upon titration from 2.5 mg twice a day to 5 mg twice a day, significantly reduced the heart rate and allowed the patient to be discharged one week later. \u00a0Even after three months, this patient remained asymptomatic.22<\/sup><\/p>\n The BEAUTIFUL trial indicated that ivabradine may also possess beneficial cardiac effects. \u00a0Ivabradine, at either 5 mg or 7.5 mg twice a day produced a slight increase in the left ventricular (LV) ejection fraction. \u00a0This was believed to have resulted from reversing detrimental LV remodeling in patients with CAD and LV systolic dysfunction.23<\/sup> \u00a0In the biggest trial of ivabradine to date (the SHIFT trial), ivabradine (in 793 out of an initial 3268 patients, 24.2%) produced a lowered heart rate with fewer adverse side effects.24<\/sup> \u00a0The most common side effect was symptomatic bradycardia. \u00a0Visual side effects, presenting as increased light sensitivity, were also reported, but these were transient.25<\/sup><\/p>\n Clinical trials are being conducted to determine if ivabradine can be used for other indications. \u00a0One recent trial focused on using ivabradine in multi-organ dysfunction syndrome (MODS), where beta blockers have been shown to be efficacious but problematic, as they produced negative inotropism.26<\/sup><\/p>\n –<\/b><\/p>\n ON THE HORIZON: TRIMETAZIDINE<\/b><\/p>\n Data from clinical trials suggest that ivabradine is efficacious in treating angina. \u00a0Another drug that has been available outside the US is trimetazidine (Vastarel MR\u00ae, Servier), which acts as a partial fatty oxidase (PFOX) inhibitor, forcing the heart to utilize glucose.27<\/sup> \u00a0A similar mechanism was previously suggested for ranolazine (Ranexa\u00ae, Gilead), before it was known that it produced late sodium inhibition mechanism. \u00a0However, a number of case reports indicated that trimetazidine produces extrapyramidal symptoms, which disappeared upon treatment discontinuation. \u00a0This is likely due to the antagonism of striatal D2<\/sub> dopaminergic receptors, as this compound is a phenothiazine derivative (like the D2<\/sub> antagonist, chlorpromazine).28<\/sup><\/p>\n SOURCES<\/b><\/span><\/p>\n