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DRUGS ACTING ON CARDIOVASCULAR SYSTEM
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Myocardial ischemia 6.5–16.5 million patients with stable angina1,2
Coronary artery disease Hypertension Hypertrophic cardiomyopathy Valvular heart disease 6.5–16.5 million patients with stable angina1,2 ≥ $1.9 billion in direct costs3 Myocardial ischemia: Significant clinical burden In summary, chronic ischemia (angina) imposes a significant clinical and economic burden. As the following slides demonstrate, it also imposes a significant burden on quality of life.
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Ischemia is related to myocardial O2 supply and demand
Heart rate Diastolic time Spasm Contractility Oxygen demand Oxygen supply Coronary blood flow Wall tension Collaterals Systolic pressure Volume Ischemia is related to myocardial O2 supply and demand Myocardial ischemia is related to the balance of oxygen supply and demand. Oxygen supply/demand imbalance can occur in a number of ways. Coronary blood flow is modulated by both stenotic plaques and vascular reactivity. Ischemia
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Classification of Ischemic Heart Disease
Chronic coronary artery disease (stable angina) Acute coronary syndromes -Unstable Angina -Myocardial infarction
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Myocardial ischemia: Sites of action of anti-ischemic medication
Development of ischemia Consequences of ischemia ↑ O2 Demand Heart rate Blood pressure Preload Contractility ↓ O2 Supply Ca2+ overload Electrical instability Myocardial dysfunction (↓systolic function/ ↑diastolic stiffness) Ischemia Ranolazine Traditional anti-ischemic medications: β-blockers Nitrates Ca2+ blockers Myocardial ischemia: Sites of action of anti-ischemic medication Ranolazine, in contrast to older antianginal medications, appears to work downstream of the ischemic insult, complementing traditional medications’ mechanism of action.
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New mechanistic approaches to myocardial ischemia
Rho kinase inhibition (fasudil) Metabolic modulation (trimetazidine) Preconditioning (nicorandil) Sinus node inhibition (ivabradine) Late Na+ current inhibition (ranolazine) New mechanistic approaches to myocardial ischemia Advances in understanding of myocardial ischemia have prompted evaluation of a number of new antianginal strategies, including: Rho kinase inhibition with fasudil Metabolic modulation, particularly inhibition of fatty acid oxidation in myocytes, with trimetazidine Ischemic preconditioning with nicorandil Sinus node inhibition with ivabradine Late Na+ current inhibition with ranolazine
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Rho kinase inhibition: Fasudil
Rho kinase triggers vasoconstriction through accumulation of phosphorylated myosin Ca2+ Ca2+ Agonist Receptor PLC PIP2 Rho Rho kinase VOC ROC IP3 Fasudil Rho kinase inhibition: Fasudil SR Ca2+ Myosin The role of Ca2+ in activating myosin light chain kinase (MLCK) and phosphorylating myosin to cause contraction is well known. Dephosphorylation by myosin phosphatase causes subsequent dilation. More recently, the involvement of Rho kinase has been identified. In the absence of increases in intracellular Ca2+, Rho (a member of the Ras superfamily of small G proteins) activates Rho kinase, which in turn deactivates myosin phosphatase. This causes accumulation of phosphorylated myosin. Other abbreviations used in the figure: IP3 = inositol triphosphate PIP2 = phosphatidylinositol biphosphate PLC = phospholipase C ROC = receptor-operated channel SR = sarcoplasmic reticulum VOC = voltage-operated channel MLCK Myosin phosphatase Ca2+ Myosin-P Calmodulin
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Metabolic modulation (pFOX): Trimetazidine
Myocytes O2 requirement of glucose pathway is lower than FFA pathway During ischemia, oxidized FFA levels rise, blunting the glucose pathway Free Fatty Acid Glucose Acyl-CoA Pyruvate β-oxidation Trimetazidine Acetyl-CoA Metabolic modulation (pFOX): Trimetazidine The free fatty acid oxidation hypothesis arose out of advances in understanding of myocardial metabolic pathways. Myocardial cells derive their energy via fatty acid and glucose metabolism. During ischemia the fatty acid pathway predominates. However, this pathway requires more oxygen than the glucose pathway.1 Theoretically, inhibition of fatty acid oxidation should promote a shift towards the more oxygen-efficient glucose pathway. Lopaschuk et al and Stanley have reported experimental data showing that the antianginal trimetazidine is an inhibitor of partial fatty acid oxidation (pFOX). However, MacInnes et al did not observe any inhibition with trimetazidine in other experimental models. Thus, inhibition of fatty acid oxidation as a major antianginal mechanism for trimetazidine remains to be definitively established. Energy for contraction pFOX = partial fatty acid oxidation FFA = free fatty acid Chaitman BR, Skettino SL, Parker JO, Hanley P, Meluzin J, Kuch J, et al, for the MARISA Investigators. Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina. J Am Coll Cardiol. 2004;43:
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Metabolic modulation (pFOX) and ranolazine
Clinical trials showed ranolazine SR 500–1000 mg bid (~2–6 µmol/L) reduced angina Experimental studies demonstrated that ranolazine 100 µmol/L achieved only 12% pFOX inhibition Ranolazine does not inhibit pFOX at clinically relevant doses Inhibition of fatty acid oxidation does not appear to be a major antianginal mechanism for ranolazine Metabolic modulation (pFOX) and ranolazine MacInnnes et al reported experimental data demonstrating that ranolazine partially inhibits fatty acid oxidation in a dose-dependent manner. At a concentration of 100 µmol/L, they observed 12% inhibition of oxidation. This concentration is substantially greater than the concentration achieved in humans at currently recommended doses (~2–6μmol/L). Thus, inhibition of fatty acid oxidation is not a major antianginal mechanism for ranolazine. An alternative mechanism has been proposed and will be discussed in later slides.
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Preconditioning: Nicorandil
Activation of ATP-sensitive K+ channels Ischemic preconditioning Dilation of coronary resistance arterioles O N HN O NO2 Preconditioning: Nicorandil Nitrate-associated effects Vasodilation of coronary epicardial arteries Nicorandil possesses a nitrate moiety and, therefore, produces hemodynamic effects similar to those of long-acting nitrates. It activates cyclic GMP (cGMP), dilates capacitance vessels, and decreases preload. Nicorandil is also capable of opening ATP-sensitive K+ (KATP) channels. These channels are involved in dilation of coronary resistance arterioles, which decreases afterload, and are also thought to mimic ischemic preconditioning, a potential cardioprotective effect. IONA Study Group. Lancet. 2002;359: Rahman N et al. AAPS J. 2004;6:e34.
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Sinus node inhibition: Ivabradine
If current is an inward Na+/K+ current that activates pacemaker cells of the SA node Ivabradine Selectively blocks If in a current-dependent fashion Reduces slope of diastolic depolarization, slowing HR Control Ivabradine 0.3 µM 40 20 Time (seconds) 0.5 –20 –40 –60 Sinus node inhibition: Ivabradine Potential (mV) Ivabradine selectively targets the Na+/K+ current (If current) in pacemaker cells of the sinoatrial node. Channels that carry the If current are unique to the sinoatrial node, although ion channels in the retina have a similar structure and are probably the source of mild, transient visual disturbances in some patients taking If blockers.1 Tardif J-C, Ford I, Tendera M, Bourassa MG, Fox K, for the INITIATIVE Investigators. Efficacy of ivabradine, a new selective If inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J. 2005;26:
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Late Na+ current inhibition: Ranolazine
Myocardial ischemia Late INa Ranolazine Na+ Overload Ca2+ Overload Late Na+ current inhibition: Ranolazine Mechanical dysfunction LV diastolic tension Contractility Electrical dysfunction Arrhythmias Myocardial ischemia is associated with ↑ Na+ entry into cardiac cells. ↑ Na+ activates the Na+/Ca2+ exchanger, causing efflux of Na+ and influx of Ca2+. ↑ Ca2+ (Ca2+ overload) may cause electrical and mechanical dysfunction. ↑ Late INa is an important contributor to the Na+-dependent Ca2+ overload. If the late Na+ current is an important contributor to myocardial ischemia through Ca2+ overload, then inhibition of this current with ranolazine will blunt the adverse effects of ischemia.
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Myocardial ischemia causes enhanced late INa
Sodium Current Late Peak Ischemia Sodium Current Late Na+ Peak Impaired Inactivation Myocardial ischemia causes enhanced late INa Na+ influx is controlled by a number of channels. The current flowing through voltage-gated Na+ channels is responsible for the upstroke of the action potential. Activation of these channels permits Na+ entry, with inactivation occurring a few milliseconds after. The channels remain closed and nonconducting throughout the plateau phase of the action potential. However, a small proportion of channels either do not close or close and then reopen. These channels allow a sustained current of Na+ to enter. This current is referred to as the late Na+ current to distinguish it from the peak current. Emerging data indicate that a number of pathologic diseases or conditions may be associated with a prolongation of the late Na+ current. Among these pathologic diseases is myocardial ischemia. Accumulation of Na+ secondary to enhanced late INa leads to activation of the reverse mode of the Na+/Ca2+ exchanger, with subsequent efflux of excess Na+ and influx of Ca2+. Eventually, Ca2+ overload of the cell results. Na+ Adapted from Belardinelli L et al. Eur Heart J Suppl. 2006;(8 suppl A):A10-13. Belardinelli L et al. Eur Heart J Suppl. 2004;6(suppl I):I3-7.
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Na+/Ca2+ overload and ischemia
Myocardial ischemia Intramural small vessel compression ( O2 supply) O2 demand Late Na+ current Na+ overload Diastolic wall tension (stiffness) Na+/Ca2+ overload and ischemia It is proposed that Na+-related Ca2+ overload mediates a vicious cycle of ischemia begetting more ischemia. Ca2+ overload may result in increased left ventricular diastolic tension. As a result, myocardial O2 consumption increases and intramural small vessels are compressed, causing increased O2 demand and decreased O2 supply, respectively. Positive feedback during ischemia increases the imbalance between myocardial oxygen supply and demand. Ca2+ overload
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Ranolazine: Key concepts
Ischemia is associated with ↑ Na+ entry into cardiac cells – Na+ efflux in recovery by Na+/Ca2+ exchange results in ↑ cellular [Ca2+]i and eventual Ca2+ overload – Ca2+ overload may cause electrical and mechanical dysfunction ↑ Late INa is an important contributor to the [Na+]i - dependent Ca2+ overload Ranolazine reduces late INa Ranolazine: Key concepts In summary, experimental data suggest that inhibition of the late Na+ current blunts the adverse effects of ischemia. Belardinelli L et al. Eur Heart J Suppl. 2006;8(suppl A):A Belardinelli L et al. Eur Heart J Suppl. 2004;(6 suppl I):I3-7.
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Angina Pectoris Clinical Syndrome Episodes of Chest Pain
Deficit in Myocardial Oxygen Most often caused by atherosclerotic plaques
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Antianginal Agents Nitrates Beta blockers: previously discussed
Calcium channel blockers: previously discussed
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Antianginal Agents Decrease Myocardial Demand for Oxygen
Increase Blood Supply to Myocardium
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Nitrates: Mechanism of Action
Dilate all blood vessels, primarily venous circulation, but slight arterial vasodilatation Venodilation is a result of relaxation of smooth muscle surrounding veins Potent dilating effect directly on coronary arteries!!!!!!
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Nitrates: Therapeutic Uses
Relax Smooth Muscle Produce Vasodilatation Decrease Preload Decrease Workload Decrease Afterload
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4) Antianginal Drugs Organic Nitrates Used to treat or prevent angina
Mechanism: Nitrates are converted to NO in vascular smooth muscle NO activates guanylate cyclase Increase formation of cGMP so that the intracellular calcium levels decrease Vasodilation
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Name Amyl nitrate Onset 10 Sec Duration 10 min Route Inhalation Glyceral trinitrate 1-2 min 15-30 min Sublingual Isosorbide mononitrate 1 hr 12 hrs Isosorbide dinitrate 30 min Erythrityl tetranitrate 15 min 3 hrs Oral Penterythrityl tetranitrate 6 hrs
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4) Antianginal Drugs(Cont’d)
Relieves anginal pain by relaxing smooth muscles in the blood vessels (vasodilation) by several mechanisms Dilate veins Dilate coronary arteries Dilate arterioles Most widely used nitrate is nitroglycerin (Glyceryl trinitrate) Since it is highly lipid soluble, it can be administered by sublingual and transdermal route, as well as oral and intravenous routes
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4) Antianginal Drugs (Cont’d)
Nitrate preparations and dosage Drug and dosage form Route Dosage Glyceryl Trinitrate Sublingual tablet 500mcg Sublingual 1 tablet under the tongue immediately as required Spray 0.4mg/dose Spray 1-2 doses under tongue Capsule 2.5mg (Retard) Oral 1-2 capsules 2-3 times a day
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4) Antianginal Drugs (Cont’d)
Drug and dosage form Route Dosage Glyceryl Trinitrate (Cont’d) Transdermal patches 5mg / 10mg Transdermal 1 patch every 24 hours Isosorbide Mononitrate Tablet 20mg Oral 20mg bd to tid / 40mg bd Tablet 60mg (controlled release) 30-120mg in the morning Capsule 50mg (sustained release) 1-2 capsules in the morning
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4) Antianginal Drugs (Cont’d)
Drug and dosage form Route Dosage Isosorbide Dinitrate Tablet 10mg Oral 30-240mg in divided doses Tablet 40mg (sustained release) 20-40mg every 12 hours Capsule 20mg (sustained release) 1 capsule bd or tid
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4) Antianginal Drugs (Cont’d)
Tolerance Tolerance to nitrate induced vasodilation can develop rapidly This may be due to depletion of sulfhydryl (S-H) groups in the vascular smooth muscle. These groups are needed to convert nitrate to NO
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4) Antianginal Drugs (Cont’d)
Adverse Effects Headache Orthostatic hypotension Symptoms include light headedness and dizziness Reflex tachycardia
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Older antianginal drugs: Pathophysiologic effects
O2 Supply O2 Demand Coronary blood flow Heart rate Arterial pressure Venous return Myocardial contractility Drug class β-blockers DHP CCBs Non-DHP CCBs Long-acting nitrates * / Older antianginal drugs: Pathophysiologic effects Beta-blockers work primarily by decreasing myocardial oxygen consumption through reductions in heart rate, blood pressure, and myocardial contractility. Both dihydropyridine (DHP) and non-DHP classes of calcium antagonists increase blood flow, but non-DHP agents decrease or regulate heart rate, producing beneficial effects. In contrast, some DHP agents increase heart rate. Beta-blockers and many CCBs have similar depressive effects on BP, heart rate, and atrioventricular conduction. Nitrates improve components of myocardial oxygen supply and demand through their potent vasodilatory effect. Many patients have relative intolerance to full doses of beta-blockers, calcium antagonists, and nitrates. Boden WE et al. Clin Cardiol. 2001;24: Gibbons RJ et al. ACC/AHA 2002 guidelines. Kerins DM et al. In: Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 10th ed. CCB = calcium channel blocker DHP = dihydropyridine *Except amlodipine
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Older antianginal drugs: Clinical conditions that may limit use
Drug class β-blockers Nitrates Calcium channel blockers† Asthma Severe bradycardia AV block Severe depression Raynaud’s syndrome Sick sinus syndrome Severe aortic stenosis Hypertrophic obstructive cardiomyopathy Erectile dysfunction* Bradycardia Heart failure Left ventricular dysfunction Sinus node dysfunction Older antianginal drugs: Clinical conditions that may limit use Advancing age is associated with a higher prevalence of comorbidities. Dosing of antianginal therapies becomes more limited in elderly patients, in whom sick sinus syndrome and sinus node dysfunction are common. Although these agents have been used to treat myocardial ischemia for decades, they can have major limiting factors across all patient populations. *Treated with PDE5 inhibitors †Nondihydropyridine CCBs Gibbons RJ et al. ACC/AHA 2002 guidelines.
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