By: Neal Shah

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Part I:              Preface.

Part II:             Brief review of cardiac electrophysiology.

Part III:           Ivabradine as a novel I_f blocker for the use of stable angina.

Part IV:           On the horizon: trimetazidine.

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PREFACE

When viewed anatomically, the heart may seem like a simple organ.  However, the electrophysiological aspects of the heart are somewhat complex.  As 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.  As 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.  I have had a significant interest in cardiac physiology since my first course in Anatomy and Physiology years ago.  In addition, I have read several books and papers dealing with the electrophysiological conductive system of the heart.  I hope that readers of this article are familiar with the basics of cardiac conduction and terminology.  If 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.

There are at least five different types of calcium channels in human physiology: L-, N-, P/Q-, R-, and T-type channels.^1,2  These voltage-gated channels are distributed throughout the body.  N-type calcium channels in the nervous system are inhibited by drugs such as ziconotide (Prialt®), gabapentin (Neurontin®), and pregabalin (Lyrica®).³  These medications are used for intrathecal anesthesia or neuropathic pain.³  T-and-L-type calcium channels are discussed in Part II, and are targets in the treatment of absence (petit mal) seizures⁴ and cardiovascular diseases, respectively.  P/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

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).  Since multiple calcium channel subtypes are present throughout the body, does verapamil exert its effects by blocking a single subtype of calcium channel?  Or does it block multiple calcium channels?  The answer may surprise you, as it did me.  Its mechanism for causing bradycardia is different from ivabradine, which is discussed in Part III.

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ELECTRICAL CONDUCTION AND EKG OF THE SINOATRIAL NODE

The sinoatrial (SA) node is commonly referred to as the “pacemaker” because, under normal physiological conditions, it has the most rapid rate of depolarization, and, thus, determines the heart rate.  The SA node depolarizes rapidly because it possesses an interesting property: the pacemaker potential.⁶  The pacemaker potential allows the SA node to spontaneously depolarize due to a lack of stable resting membrane potential, thereby expressing autorhythmicity.  This is due to the combination of the “funny channel” (I_f), and T-type Ca channels.  The L-type channels also control SA depolarization, overall pacemaker activity, and excitation-contracting coupling in cardiac, smooth, and skeletal muscles.⁷  Figures 1 and 2 (both in PDF) show the SA node’s electrical channel components.  Figure 3 (in PDF) correlates SA node and EKG readings when negative chronotropy is induced.⁸

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.  From 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—that is, verapamil is an L-type calcium channel blocker.  Verapamil 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 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.  A 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’s 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.

This brings us to the I_f, otherwise known as the “funny” channel.  I_f is an inward Na⁺/K⁺ current, activated by hyperpolarization of the membrane potential of the SA node.¹¹  The I_f 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 I_f is also inhibited by beta-adrenergic antagonists (such as propranolol or metoprolol), and this may contribute to their bradycardic effects.¹²

Angina is a cardiovascular disease where the heart’s supply of oxygen cannot meet the oxygen demand of the heart.  The goal of treatment is to restore the imbalance between oxygen supply and demand.  Mitigation of angina can occur by decreasing heart rate, contractility, or increasing oxygen supply.  Traditionally, angina has been pharmaceutically treated by use of nitrates, non-DHP CCBs, and beta blockers.¹³ 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  Therefore, it would be beneficial to have a specific I_f channel inhibitor – and ivabradine is currently the only drug to have this effect.

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IVABRADINE

Ivabradine (Procoralan®, Servier) is a selective I_f channel inhibitor.^11,12,15-18  It was internationally approved in 2005 for the treatment of stable angina, and is not currently available in the United States (US).  Ivabradine inhibits the SA node’s I_f current and induces negative chronotropy.  Since ivabradine is selective for the I_f, it avoids the non-cardiac side effects of agents that can also block the I_f, like beta blockers.  This 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  Unlike beta blockers, ivabradine selectively reduces heart rate without altering myocardial contractility, cardiac conduction, or coronary vascular tone.¹⁷

Interestingly, ivabradine’s neutral inotropic effects were not initially seen in animal experiments.  Ivabradine was shown to have positive inotropic activity, stemming from its bradycardic activity.  A parallel can be drawn between ivabradine and digoxin in this sense, as they both decrease heart rate yet increase ventricular ejection.  These 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  Unfortunately, ivabradine is not a true replacement for digoxin.

The INITIATIVE trial was a large multicenter trial in which 939 patients with stable angina were randomized to ivabradine or atenolol.  Ivabradine, 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  In another study, 120 patients were randomized to receive either ivabradine 15 mg or metoprolol 50 mg directly before coronary computed tomographic angiography.  It was shown that although heart rate was greatly decreased compared to metoprolol, neither the systolic or the diastolic blood pressures were significantly affected.¹⁹  A smaller trial compared the effects of ivabradine and bisoprolol on exercise tolerance.  Initially, both groups had a decreased resting heart rate; however, patients on ivabradine (but not those on bisoprolol) overcame exercise induced fatigue and tolerance.²⁰

It is possible that ivabradine may be used in patients that are intolerant of (or refractory to) beta adrenergic receptor antagonists or CCBs.  For 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  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.  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.  Even after three months, this patient remained asymptomatic.²²

The BEAUTIFUL trial indicated that ivabradine may also possess beneficial cardiac effects.  Ivabradine, at either 5 mg or 7.5 mg twice a day produced a slight increase in the left ventricular (LV) ejection fraction.  This was believed to have resulted from reversing detrimental LV remodeling in patients with CAD and LV systolic dysfunction.²³  In 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  The most common side effect was symptomatic bradycardia.  Visual side effects, presenting as increased light sensitivity, were also reported, but these were transient.²⁵

Clinical trials are being conducted to determine if ivabradine can be used for other indications.  One 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

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ON THE HORIZON: TRIMETAZIDINE

Data from clinical trials suggest that ivabradine is efficacious in treating angina.  Another drug that has been available outside the US is trimetazidine (Vastarel MR®, Servier), which acts as a partial fatty oxidase (PFOX) inhibitor, forcing the heart to utilize glucose.²⁷  A similar mechanism was previously suggested for ranolazine (Ranexa®, Gilead), before it was known that it produced late sodium inhibition mechanism.  However, a number of case reports indicated that trimetazidine produces extrapyramidal symptoms, which disappeared upon treatment discontinuation.  This is likely due to the antagonism of striatal D₂ dopaminergic receptors, as this compound is a phenothiazine derivative (like the D₂ antagonist, chlorpromazine).²⁸

SOURCES

1. http://pathman.smpdb.ca/pathways/SMP00375/pathway accessed November 16, 2011.
2. Yamakage M, Namiki A. Calcium channels – basic aspects of their structure, function and gene encoding; anesthetic action on the channels – a review. Can J Anesth, 49:2, 2002.
3. Pexton T, Moeller-Bertram T, Schilling JM, et al. Targeting voltage-gated calcium channels for the treatment of neuropathic pain: a review of drug development. Expert Opin Investig Drugs. 2011 Sep;20(9):1277-84.
4. Coulter DA, Huguenard JR, Prince DA. Characterization of ethosuximide reduction of low-threshold calcium current in thalamic neurons. Ann Neurol. 1989 Jun;25(6):582-93.
5. Hansen PB, Poulsen CB, Walter S, et al. Functional importance of L- and p/q-type voltage-gated calcium channels in human renal vasculature. Hypertension. 2011 Sep;58(3):464-70.
6. Martini FH, Nath JL. Fundamentals of Anatomy and Physiology, 8th edition. Benjamin Cummings, 2008.
7. Katz AM. Physiology of the Heart, 4th edition. Lippincott Williams & Wilkins, 2006.
8. Germann W, Stanfield C. Principles of Human Physiology, 2nd edition. Pearson Education, Benjamin Cunningham, 2005.
9. Bergson P, Lipkind G, Lee SP, et al. Verapamil Block of T-type Calcium Channels. Mol Pharm, 2010 Dec 13.
10. Katz AM. Calcium channel diversity in the cardiovascular system. J Am Coll Cardiol. 1996 Aug;28(2):522-9.
11. Thollon C, Vilaine JP. I(f) inhibition in cardiovascular diseases. Adv Pharmacol. 2010;59:53-92.
12. DiFrancesco D. The role of the funny current in pacemaker activity. Circ Res. 2010 Feb 19;106(3):434-46.
13. Gayet JL, Paganelli F, Cohen-Solal A. Update on the medical treatment of stable angina. Arch Cardiovasc Dis. 2011 Oct;104(10):536-44. Epub 2011 Oct 12.
14. DiFrancesco D, Borer JS. The funny current: cellular basis for the control of heart rate. Drugs. 2007;67 Suppl 2:15-24.
15. Boldt A, Gergs U, Pönicke K, et al. Inotropic effects of ivabradine in the mammalian heart. Pharmacology. 2010;86(5-6):249-58.
16. Diaz A, Tardif JC. Heart rate slowing versus other pharmacological antianginal strategies. Adv Cardiol. 2006;43:65-78.
17. Fox K. Selective and specific I(f) inhibition: new perspectives for the treatment of stable angina. Expert Opin Pharmacother. 2006 Jun;7(9):1211-20.
18. Prasad UK, Gray D, Purcell H. Review of the If selective channel inhibitor ivabradine in the treatment of chronic stable angina. Adv Ther. 2009 Feb;26(2):127-37. Epub 2009 Mar 2.
19. Pichler P, Pichler-Cetin E, Vertesich M, et al. Ivabradine Versus Metoprolol for Heart Rate Reduction Before Coronary Computed Tomography Angiography. Am J Cardiol. 2011 Oct 17.
20. Amosova E, Andrejev E, Zaderey I, et al. Efficacy of Ivabradine in Combination with Beta-Blocker Versus Uptitration of Beta-Blocker in Patients with Stable Angina. Cardiovasc Drugs Ther. 2011 Aug 10.
21. de Ruvo E, Sebastiani F, Sciarra L, et al. Usefulness Of Ivabradine To Treat “unexpected” Heart Failure Caused By “acute” Right Ventricular Pacing. Indian Pacing Electrophysiol J. 2011 Sep;11(5):149-52. Epub 2011 Oct 2.
22. Ripa C, Germano G, Caparra A, et al. Ivabradine use in refractory unstable angina: a case report. Int J Immunopathol Pharmacol. 2009 Jul-Sep;22(3):849-52.
23. Ceconi C, Freedman SB, Tardif JC, et al. Effect of heart rate reduction by ivabradine on left ventricular remodeling in the echocardiographic substudy of BEAUTIFUL. Int J Cardiol. 2011 Feb 3;146(3):408-14.
24. Swedberg K, Komajda M, Böhm M, et al.  Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet. 2010 Sep 11;376(9744):875-85.
25. Sulfi S, Timmis AD. Ivabradine – the first selective sinus node If channel inhibitor in the treatment of stable angina. Int J Clin Pract. 2006 February; 60(2): 222–228.
26. Nuding S, Ebelt H, Hoke RS, et al. Reducing elevated heart rate in patients with multiple organ dysfunction syndrome by the I (f) (funny channel current) inhibitor ivabradine : MODI (f)Y trial. Clin Res Cardiol. 2011 Oct;100(10):915-23.
27. Bucci M, Borra R, Någren K, et al.  Trimetazidine Reduces Endogenous Free Fatty Acid Oxidation and Improves Myocardial Efficiency in Obese Humans. Cardiovasc Ther. 2011 Jul 31.
28. Masmoudi K, Masson H, Gras V, et al. Extrapyramidal adverse drug reactions associated with trimetazidine: a series of 21 cases. Fundam Clin Pharmacol. 2011 Nov 2.

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