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M5 - Angina

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Ranolazine is a novel anti-anginal drug that selectively inhibits the late inward sodium current in cardiac cells, reducing calcium overload during ischemia. It improves exercise tolerance and reduces angina symptoms and nitroglycerin use when added to standard anti-anginal therapies. Clinical trials demonstrate ranolazine's efficacy in reducing angina frequency and improving exercise performance without affecting heart rate or blood pressure. When added to amlodipine, ranolazine further reduced angina and nitroglycerin use.

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ANGINA: Basic Understanding Angina pectoris is the medical term for chest pain or discomfort due to coronary heart disease. Angina is a symptom of a condition called myocardial ischemia. It occurs when the heart muscle (myocardium) doesn't get as much blood (hence as much oxygen) as it needs. Etiological Factors: Coronary artery disease: One or more of the heart's arteries (blood vessels that supply blood to the heart muscle) is narrowed or blocked due to atherosclerosis of coronary artery [Most common cause]. Angina also can occur in people with o Valvular heart disease (disease related to valves of heart) o Hypertrophic cardiomyopathy (this is an enlarged heart due to disease) or o Uncontrolled high blood pressure. Risk Factors: High blood pressure Diabetes Unhealthy cholesterol levels Smoking Lack of exercise Obesity Too much salt in diet Excessive use of alcohol Family history of CAD or stroke
Being male Being a postmenopausal woman Age - Men >45 and for women >55 Provoking Factors: An angina attack may be provoked / stimulated by Extremes in emotion (being very angry or upset), Eating a large meal or eating it very quickly, Doing more exercise than usual, Being exposed to extremes in temperature (too hot or too cold), or Smoking. Pathophysiology: Myocardial ischemia that leads to angina can result from: 1. A reduction of coronary blood flow caused by fixed and/or dynamic coronary artery stenosis, 2. Abnormal constriction or deficient relaxation of coronary microcirculation (i.e., resistance vessels), or 3. Reduced oxygen-carrying capacity of the blood Atherosclerosis is the most common cause of coronary artery stenosis and, hence, angina pectoris.
Types of Angina Stable angina (Typical angina): Stable angina is the most common type. It occurs when the heart is working harder than usual. Chest pain results because of physical and emotional Exertion. The pain usually goes away in a few minutes after taking rest or nitrates. Typical angina is uncomfortable pressure, fullness, squeezing or pain in the center of the chest. The discomfort also may be felt in the neck, jaw, shoulder, back or arm. Unstable angina (Crescendo angina): It is more serious condition and may be a sign that a heart attack could happen soon. It is caused by transient formation and dissolution of a blood clot (thrombosis) within a coronary artery. Unstable angina is an acute coronary syndrome and should be treated as an emergency.
Unstable angina tends to happen more often in older adults. It has at least one of these three features: o It occurs at rest / during sleep (or with minimal exertion), usually lasting for 30 minutes. o It is severe and of new onset (i.e., within the prior 46 weeks). o It occurs with a crescendo pattern (i.e., distinctly more severe, prolonged, or frequent than before). They're at increased risk for: o Acute myocardial infarction (heart attack). o Severe cardiac arrhythmias. These may include ventricular tachycardia and fibrillation. o Cardiac arrest leading to sudden death. Vasospastic angina (Variant angina): It occurs because of coronary spasm. It is also called as Prinzmetals angina It usually occurs spontaneously, and unlike typical angina, it nearly always occurs when a person is at rest. It doesn't follow physical exertion or emotional stress, either. Attacks can be very painful and usually occur between midnight and 8 a.m. About two-thirds of people with it have severe coronary atherosclerosis in at least one major vessel. The spasm usually occurs very close to the blockage. Diagnostic Tests Electrocardiogram (ECG): Detects and records hearts electrical activity; this is a painless procedure and does not take very long. Stress test (Treadmill test): During exercise at increasing rates of exertion (generally by running on a treadmill); an ECG will monitor the entire time so that the doctor can see what changes occur in heart rhythm. Stress echocardiogram can show normal or abnormal movement in the heart muscle during exercise.
Management options: Life style modification: Adopt a Heart-Healthy Diet Maintaining a healthy weight and eating a healthy diet that is low in fat and salt will reduce your risk of heart attack and stroke. Stop Smoking Maintain an Ideal Body Weight Excess weight contributes strongly to the critical risk factors for heart disease, such as diabetes and high blood pressure. A regular exercise program will also help patient to maintain ideal body weight. Avoid stress Anti-anginal drugs: Angina pectoris can be treated with drugs that affect the blood supply to the heart muscle or the heart's demand for oxygen or both. Drugs that affect the blood supply are coronary vasodilators; they cause blood vessels to relax. When this happens, the opening inside the vessels (the lumen) gets bigger. Then blood flow improves, letting more oxygen and nutrients reach the heart muscle. Traditional anti-anginal Nitrates Calcium channel blockers 硫 blockers Newer anti-anginal drugs: Ranolazine
Other medications: Anti platelet drugs: e.g. aspirin, clopidogrel Long acting nitrates: e.g. isosorbide di-nitrates and mono-nitrates Angiotensin converting enzyme inhibitors: e.g. enalapril, ramipril Statin: Atorvastatin, rosuvastatin Nitrates: Nitroglycerin is the drug most often used. It mainly relaxes the veins and relaxes the coronary arteries a little. By relaxing the veins, it reduces the amount of blood that returns to the heart and eases the heart's workload. By relaxing the coronary arteries, it increases the heart's blood supply. Calcium channel blockers: Calcium channel blockers, also called calcium antagonists, relax and widen blood vessels by affecting the muscle cells in the arterial walls. This increases blood flow in heart, reducing or preventing angina. Calcium channel blockers also slow pulse and reduce the workload on your heart. CCBs in effort angina: Common to the effects of all types of CCBs is the inhibition of the L-type calcium channels, occurring at relatively low concentrations. Hence coronary vasodilatation is a major common property. CCBs in unstable angina: CCBs of dihydropyridine group should not be used without concurrent 硫 blockade because of risk of reflex adrenergic activation CCBs in vasospastic angina: All CCBs are effective. Among those specifically licensed are verapamil and amlodipine.
硫 blockers: Beta blockers work by blocking the effects of the hormone epinephrine, also known as adrenaline. As a result, heart beats more slowly and with less force, reducing blood pressure and reducing the workload on heart. Beta blockers also help blood vessels relax and open up to improve blood flow, which reduces or prevents angina. Need of new anti-anginal drugs Pharmacotherapy for the management of chronic stable angina has not changed much in the past 10-20 years. Although the use of revascularization has increased, beta-blockers, calcium channel blockers, and long-acting nitrates are still widely used in the management of patients with chronic stable angina. Most patients have relative intolerances to maximum doses of traditional antianginal agents like -blockers, non-dihydropyridine (verapamil and diltiazem) calcium channel blockers (CCBs), and nitrates. -blockers and many CCBs have similar depressive hemodynamic and electrophysiological effects. Despite the demonstrated effectiveness of these agents, a number of patients do not achieve the American College of Cardiology-American Heart Association goal of freedom from exertional angina attacks. Therefore anti-anginal drugs without these limitations are needed. Advances in understanding of myocardial ischemia have prompted evaluation of a number of new anti-anginal strategies. For the first time in more than a decade, a new agent, ranolazine, is available to assist in controlling exertional angina. RANOPILL (Ranolazine 500 mg Extended release tablets)
Ranolazine is a novel anti-anginal drug, approved for management of stable chronic angina. The drug was approved first time in the world in early 2006 for patients who remain symptomatic while on standard anti-anginal therapy. It has a unique mechanism of selective inhibition of the late INa current in cardiac cells. The anti-anginal and anti-ischemic activity of ranolazine occurs without affecting heart rate and blood pressure to a clinically significant extent. The proposed mechanism of action is inhibition of the late inward sodium current (INa) in cardiac cells. Voltage gated sodium channels play a fundamental role in the propagation of action potentials in the myocardium. During the plateau phase of the action potential, a small proportion of Na+ channels either do not close, or close and then reopen. So, the "late sodium current" (INa) is a sustained component of the fast Na+ current of cardiac myocytes and neurons. This late Na+ channel opening permits a sustained Na+ current to enter myocytes during systole. Common cardiac & neurological conditions are associated with abnormal (I Na) enhancement, which may contribute to the pathogenesis of both electrical and contractile dysfunction. For this reason, (INa) has become an appealing pharmacological target, with a potentially broad range of therapeutic indications. During ischemia, this enhanced late intracellular Na+ stimulates Na+/Ca2+ exchanger causing
increased cytosolic calcium (Ca 2+). Increased Ca 2+ in turn affects electrical and contractile dysfunction. Sustained contraction of ischemic tissue during diastole increases myocardial oxygen consumption and compresses intramural small vessels, thus reducing nutritive blood flow and exacerbating ischemia. Thus Na+ - mediated Ca 2+ overload mediates a vicious cycle of ischemia. Myocardial ischemia produces a cascade of complex ionic exchanges that can result in Intracellular acidosis, Excess cytosolic Ca2+ , Myocardial cellular dysfunction, and if sustained, Cell injury & death. Ranolazine reduces calcium overload in the ischemic myocyte through inhibition of the late sodium current (INa). Thus it preserves ionic homeostasis and reduces ischemia-induced contractile dysfunction. Ranolazine is a partial fatty acid oxidation inhibitor which shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation. Since the oxidation of glucose requires less oxygen than the oxidation of fatty acids, ranolazine can help maintain myocardial function in times of ischemia. (Recent Patents Cardiovasc Drug Discov. 2007 Jan;2(1):35-39) Dosage: Initiate ranolazine dosing at 500 mg twice daily and increase to 1000 mg twice daily, as needed, based on clinical symptoms. It can be taken with or without meals. Swallow tablets whole; do not crush, break, or chew. The maximum recommended daily dose is 1000 mg twice daily. Side effects & contraindications: Side-effects: Dizziness, constipation, nausea, and the potential for prolongation of the QTc interval. Contraindications: Ranolazine is contraindicated in patients with preexisting QTc prolongation, who have hepatic or renal impairment, or who are already taking drugs that prolong the QTc, or are potent CYP3 inhibitors.
Clinical trials: Efficacy & safety The efficacy & safety of ranolazine has been evaluated in randomized, double- blind, multi-centric trials: the MARISA, CARISA, ERICA, and MERLIN & ROLE. MARISA Trial (Chaitman BR, Skettino SL, Parker JO, et al. MARISA Investigators. 2004b. Antiischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina. J Am Coll Cardiol, 43:137582) The MARISA (Monotherapy Assessment of Ranolazine in Stable Angina) was conducted to establish the anti-anginal and anti-ischemic effects of ranolazine. Ranolazine 500, 1000, or 1500 mg given twice daily was compared with placebo in a 4-week trial in 191 patients with exertional angina. Other anti-anginal drugs were discontinued during the trial except for nitrates. An exercise test was conducted at trough (12 hours after dose) and peak (4 hours after dose) at the end of each treatment week. All 3 doses resulted in a significant increase in exercise duration at trough compared with placebo (P<0.005) in a dose- dependent fashion. Conclusion: Ranolazine had negligible effects on heart rate and blood pressure. Thus it significantly increased exercise performance throughout its dosing interval at all doses studied. CARISA Trial The CARISA (Combination assessment of Ranolazine In Stable Angina) study tested 823 patients with chronic angina on once-daily atenolol (50 mg), once-daily diltiazem (180mg), or once-daily amlodipine (5 mg). Exercise tests were performed 2, 6, and 12 weeks after randomization at trough and 2 and 12 weeks at peak. The results showed that, compared with placebo, ranolazine significantly increased symptom-limited exercise duration.
The improvement was sustained over the 12 weeks of therapy, indicating lack of tolerance over this time interval. The mean number of weekly angina attacks and nitroglycerin use over the 12 weeks of treatment with ranolazine was significantly reduced in a dose- dependent fashion ERICA Trial (Stone PH, Gratsiansky NA, Blokhin A, et al. ERICA Investigators. 2006. Antianginal Effi cacy of Ranolazine When Added to Treatment with Amlodipine. The ERICA (Effi cacy of Ranolazine in Chronic Angina) Trial. J Am Coll Cardiol, 48:56675.) The Efficacy of Ranolazine in Chronic Angina (ERICA) trial investigated 565 patients with persisting anginal symptoms despite maximum recommended doses of amlodipine (10 mg) to receive twice daily 1000 mg of ranolazine or placebo. At baseline, the mean number of angina attacks was 5.5 per week, and mean nitroglycerin use was 4.3 tablets or sprays per week; 45% of patients were taking concomitant long-acting nitrates. During the 6-week treatment phase, the mean number of angina episodes per week decreased to 3.2 in the placebo group and 2.8 in the ranolazine group (P<0.028). Mean nitroglycerin use per week decreased to 2.6 in the placebo group and 2.0 in the ranolazine group (P<0.014) without a significant change in heart rate or blood pressure. The magnitude of symptomatic improvement was greater in patients with more angina attacks per week at baseline. Ranolazine significantly reduced frequency of angina and nitroglycerine consumption when added to conventional anti-anginal medication. MERLIN TIMI 36 Trial (Morrow DA, Scirica BM, Karwatowska-Prokopczuk E, et al. 2007a. Effects of ranolazine on recurrent cardiovascular events in patients with nonst-elevation acute coronary syndromes. The MERLIN-TIMI 36 Randomized Trial. JAMA, 297:177583.)
Ranolazine has been tested in a large acute coronary syndrome trial to determine its impact on death and recurrent ischemic events. The Metabolic Efficiency with Ranolazine for Less Ischemia in NonST-Elevation Acute Coronary Syndrome (MERLIN TIMI 36) study is a large (6000 patients) multinational end-point driven trial of patients with an acute coronary syndrome follow every 4 months and an exercise study conducted 8 months after randomization Ranolazine showed a significant reduction in HbA1c at 4 months compared with placebo (p = 0.001). Diabetic patients treated with ranolazine showed a significant decline in HbA1c from 7.5% to 6.8% ( p < 0.001). Further, diabetic patients were more likely to achieve an HbA1c <7% at 4 months when treated with ranolazine vs placebo (59% vs 49%, p < 0.001). Also, ranolazine-treated diabetic patients showed less worsening of hyperglycemia by 1 year of follow-up (14.2% vs 20.6%, p < 0.001). Interestingly, in diabetes-free patients at baseline (baseline HbA1c of <6%), ranolazine showed reduced incidence of new increase in HbA1c 6% (p = 0.003) ROLE Trial (Long Term Safety & Tolerability) (Chaitman BR, Pepine CJ, Parker JO, et al. 2004a. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial. JAMA, 291:30916.) In The Ranolazine Open Label Experience (ROLE) program, 2.8-year mean follow-up was done for 746 chronic angina patients on ranolazine. The most common adverse effects reported were dizziness (11.8%) and constipation (10.9%). These complaints led to discontinuation in 0.9% and 0.5% of patients, respectively. No subjects were withdrawn for QTc prolongation and no torsades de pointe was reported.
Further, the presence of diabetes status was not correlated with increased adverse event-related discontinuation of ranolazine. Syncope and postural hypotension can occur with ranolazine, likely due to alpha- adrenergic receptor blockage at very high doses of up to 2000 mg. It is avoidable by the usual practice of initiating ranolazine with the lowest available dose and carefully titrating upward based on both efficacy and tolerability. UNIQUE SELLING POINTS Ranolazine is a relatively selective inhibitor of the late I Na (late sodium) current & has effects on several other cardiac ion currents like late ICa,L, IKr) Ranolazine, in contrast to older antianginal medications, works downstream of the ischemic insult It complements the action of traditional anti-anginal medications Ranolazine is useful in patients who have not achieved an adequate response with other antianginal medications It can be used in combination with amlodipine, -blockers, or nitrates. It exerts anti-anginal effects without causing significant bradycardia and/or lowering systemic blood pressure. It helps maintain myocardial function in times of ischemia because it is a partial inhibitor of fatty acids. It is well suited for patients with lower blood pressure or heart rate, in whom the upward titration of anti-anginal medications with important hemodynamic effects may not be well tolerated. It is safe therapy in refractory angina with an advantage of decreased angina frequency, increased exercise tolerance, and no deleterious effects on hemodynamics. It has a favorable effect on HbA1C levels in diabetic patients.
Procedures used to treat angina: Invasive techniques that improve the heart and the heart's blood supply may be used. One of these is PTCA (percutaneous transluminal coronary angioplasty). It's also known as PCI (Percutaneous coronary intervention), balloon dilation or balloon angioplasty. In it, a thin, flexible plastic tube (catheter) with a balloon is inserted into an artery and advanced to the blockage. Then the balloon is inflated, squeezing open the fatty plaque deposit. Then the balloon is deflated and the catheter is withdrawn. Often a stent is also placed to hold the artery open. Coronary artery bypass graft surgery is also used. In it, a blood vessel is used to route blood around the blocked part of the artery, forming a kind of detour.

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M5 - Angina

  • 1. ANGINA: Basic Understanding Angina pectoris is the medical term for chest pain or discomfort due to coronary heart disease. Angina is a symptom of a condition called myocardial ischemia. It occurs when the heart muscle (myocardium) doesn't get as much blood (hence as much oxygen) as it needs. Etiological Factors: Coronary artery disease: One or more of the heart's arteries (blood vessels that supply blood to the heart muscle) is narrowed or blocked due to atherosclerosis of coronary artery [Most common cause]. Angina also can occur in people with o Valvular heart disease (disease related to valves of heart) o Hypertrophic cardiomyopathy (this is an enlarged heart due to disease) or o Uncontrolled high blood pressure. Risk Factors: High blood pressure Diabetes Unhealthy cholesterol levels Smoking Lack of exercise Obesity Too much salt in diet Excessive use of alcohol Family history of CAD or stroke
  • 2. Being male Being a postmenopausal woman Age - Men >45 and for women >55 Provoking Factors: An angina attack may be provoked / stimulated by Extremes in emotion (being very angry or upset), Eating a large meal or eating it very quickly, Doing more exercise than usual, Being exposed to extremes in temperature (too hot or too cold), or Smoking. Pathophysiology: Myocardial ischemia that leads to angina can result from: 1. A reduction of coronary blood flow caused by fixed and/or dynamic coronary artery stenosis, 2. Abnormal constriction or deficient relaxation of coronary microcirculation (i.e., resistance vessels), or 3. Reduced oxygen-carrying capacity of the blood Atherosclerosis is the most common cause of coronary artery stenosis and, hence, angina pectoris.
  • 3. Types of Angina Stable angina (Typical angina): Stable angina is the most common type. It occurs when the heart is working harder than usual. Chest pain results because of physical and emotional Exertion. The pain usually goes away in a few minutes after taking rest or nitrates. Typical angina is uncomfortable pressure, fullness, squeezing or pain in the center of the chest. The discomfort also may be felt in the neck, jaw, shoulder, back or arm. Unstable angina (Crescendo angina): It is more serious condition and may be a sign that a heart attack could happen soon. It is caused by transient formation and dissolution of a blood clot (thrombosis) within a coronary artery. Unstable angina is an acute coronary syndrome and should be treated as an emergency.
  • 4. Unstable angina tends to happen more often in older adults. It has at least one of these three features: o It occurs at rest / during sleep (or with minimal exertion), usually lasting for 30 minutes. o It is severe and of new onset (i.e., within the prior 46 weeks). o It occurs with a crescendo pattern (i.e., distinctly more severe, prolonged, or frequent than before). They're at increased risk for: o Acute myocardial infarction (heart attack). o Severe cardiac arrhythmias. These may include ventricular tachycardia and fibrillation. o Cardiac arrest leading to sudden death. Vasospastic angina (Variant angina): It occurs because of coronary spasm. It is also called as Prinzmetals angina It usually occurs spontaneously, and unlike typical angina, it nearly always occurs when a person is at rest. It doesn't follow physical exertion or emotional stress, either. Attacks can be very painful and usually occur between midnight and 8 a.m. About two-thirds of people with it have severe coronary atherosclerosis in at least one major vessel. The spasm usually occurs very close to the blockage. Diagnostic Tests Electrocardiogram (ECG): Detects and records hearts electrical activity; this is a painless procedure and does not take very long. Stress test (Treadmill test): During exercise at increasing rates of exertion (generally by running on a treadmill); an ECG will monitor the entire time so that the doctor can see what changes occur in heart rhythm. Stress echocardiogram can show normal or abnormal movement in the heart muscle during exercise.
  • 5. Management options: Life style modification: Adopt a Heart-Healthy Diet Maintaining a healthy weight and eating a healthy diet that is low in fat and salt will reduce your risk of heart attack and stroke. Stop Smoking Maintain an Ideal Body Weight Excess weight contributes strongly to the critical risk factors for heart disease, such as diabetes and high blood pressure. A regular exercise program will also help patient to maintain ideal body weight. Avoid stress Anti-anginal drugs: Angina pectoris can be treated with drugs that affect the blood supply to the heart muscle or the heart's demand for oxygen or both. Drugs that affect the blood supply are coronary vasodilators; they cause blood vessels to relax. When this happens, the opening inside the vessels (the lumen) gets bigger. Then blood flow improves, letting more oxygen and nutrients reach the heart muscle. Traditional anti-anginal Nitrates Calcium channel blockers 硫 blockers Newer anti-anginal drugs: Ranolazine
  • 6. Other medications: Anti platelet drugs: e.g. aspirin, clopidogrel Long acting nitrates: e.g. isosorbide di-nitrates and mono-nitrates Angiotensin converting enzyme inhibitors: e.g. enalapril, ramipril Statin: Atorvastatin, rosuvastatin Nitrates: Nitroglycerin is the drug most often used. It mainly relaxes the veins and relaxes the coronary arteries a little. By relaxing the veins, it reduces the amount of blood that returns to the heart and eases the heart's workload. By relaxing the coronary arteries, it increases the heart's blood supply. Calcium channel blockers: Calcium channel blockers, also called calcium antagonists, relax and widen blood vessels by affecting the muscle cells in the arterial walls. This increases blood flow in heart, reducing or preventing angina. Calcium channel blockers also slow pulse and reduce the workload on your heart. CCBs in effort angina: Common to the effects of all types of CCBs is the inhibition of the L-type calcium channels, occurring at relatively low concentrations. Hence coronary vasodilatation is a major common property. CCBs in unstable angina: CCBs of dihydropyridine group should not be used without concurrent 硫 blockade because of risk of reflex adrenergic activation CCBs in vasospastic angina: All CCBs are effective. Among those specifically licensed are verapamil and amlodipine.
  • 7. 硫 blockers: Beta blockers work by blocking the effects of the hormone epinephrine, also known as adrenaline. As a result, heart beats more slowly and with less force, reducing blood pressure and reducing the workload on heart. Beta blockers also help blood vessels relax and open up to improve blood flow, which reduces or prevents angina. Need of new anti-anginal drugs Pharmacotherapy for the management of chronic stable angina has not changed much in the past 10-20 years. Although the use of revascularization has increased, beta-blockers, calcium channel blockers, and long-acting nitrates are still widely used in the management of patients with chronic stable angina. Most patients have relative intolerances to maximum doses of traditional antianginal agents like -blockers, non-dihydropyridine (verapamil and diltiazem) calcium channel blockers (CCBs), and nitrates. -blockers and many CCBs have similar depressive hemodynamic and electrophysiological effects. Despite the demonstrated effectiveness of these agents, a number of patients do not achieve the American College of Cardiology-American Heart Association goal of freedom from exertional angina attacks. Therefore anti-anginal drugs without these limitations are needed. Advances in understanding of myocardial ischemia have prompted evaluation of a number of new anti-anginal strategies. For the first time in more than a decade, a new agent, ranolazine, is available to assist in controlling exertional angina. RANOPILL (Ranolazine 500 mg Extended release tablets)
  • 8. Ranolazine is a novel anti-anginal drug, approved for management of stable chronic angina. The drug was approved first time in the world in early 2006 for patients who remain symptomatic while on standard anti-anginal therapy. It has a unique mechanism of selective inhibition of the late INa current in cardiac cells. The anti-anginal and anti-ischemic activity of ranolazine occurs without affecting heart rate and blood pressure to a clinically significant extent. The proposed mechanism of action is inhibition of the late inward sodium current (INa) in cardiac cells. Voltage gated sodium channels play a fundamental role in the propagation of action potentials in the myocardium. During the plateau phase of the action potential, a small proportion of Na+ channels either do not close, or close and then reopen. So, the "late sodium current" (INa) is a sustained component of the fast Na+ current of cardiac myocytes and neurons. This late Na+ channel opening permits a sustained Na+ current to enter myocytes during systole. Common cardiac & neurological conditions are associated with abnormal (I Na) enhancement, which may contribute to the pathogenesis of both electrical and contractile dysfunction. For this reason, (INa) has become an appealing pharmacological target, with a potentially broad range of therapeutic indications. During ischemia, this enhanced late intracellular Na+ stimulates Na+/Ca2+ exchanger causing
  • 9. increased cytosolic calcium (Ca 2+). Increased Ca 2+ in turn affects electrical and contractile dysfunction. Sustained contraction of ischemic tissue during diastole increases myocardial oxygen consumption and compresses intramural small vessels, thus reducing nutritive blood flow and exacerbating ischemia. Thus Na+ - mediated Ca 2+ overload mediates a vicious cycle of ischemia. Myocardial ischemia produces a cascade of complex ionic exchanges that can result in Intracellular acidosis, Excess cytosolic Ca2+ , Myocardial cellular dysfunction, and if sustained, Cell injury & death. Ranolazine reduces calcium overload in the ischemic myocyte through inhibition of the late sodium current (INa). Thus it preserves ionic homeostasis and reduces ischemia-induced contractile dysfunction. Ranolazine is a partial fatty acid oxidation inhibitor which shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation. Since the oxidation of glucose requires less oxygen than the oxidation of fatty acids, ranolazine can help maintain myocardial function in times of ischemia. (Recent Patents Cardiovasc Drug Discov. 2007 Jan;2(1):35-39) Dosage: Initiate ranolazine dosing at 500 mg twice daily and increase to 1000 mg twice daily, as needed, based on clinical symptoms. It can be taken with or without meals. Swallow tablets whole; do not crush, break, or chew. The maximum recommended daily dose is 1000 mg twice daily. Side effects & contraindications: Side-effects: Dizziness, constipation, nausea, and the potential for prolongation of the QTc interval. Contraindications: Ranolazine is contraindicated in patients with preexisting QTc prolongation, who have hepatic or renal impairment, or who are already taking drugs that prolong the QTc, or are potent CYP3 inhibitors.
  • 10. Clinical trials: Efficacy & safety The efficacy & safety of ranolazine has been evaluated in randomized, double- blind, multi-centric trials: the MARISA, CARISA, ERICA, and MERLIN & ROLE. MARISA Trial (Chaitman BR, Skettino SL, Parker JO, et al. MARISA Investigators. 2004b. Antiischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina. J Am Coll Cardiol, 43:137582) The MARISA (Monotherapy Assessment of Ranolazine in Stable Angina) was conducted to establish the anti-anginal and anti-ischemic effects of ranolazine. Ranolazine 500, 1000, or 1500 mg given twice daily was compared with placebo in a 4-week trial in 191 patients with exertional angina. Other anti-anginal drugs were discontinued during the trial except for nitrates. An exercise test was conducted at trough (12 hours after dose) and peak (4 hours after dose) at the end of each treatment week. All 3 doses resulted in a significant increase in exercise duration at trough compared with placebo (P<0.005) in a dose- dependent fashion. Conclusion: Ranolazine had negligible effects on heart rate and blood pressure. Thus it significantly increased exercise performance throughout its dosing interval at all doses studied. CARISA Trial The CARISA (Combination assessment of Ranolazine In Stable Angina) study tested 823 patients with chronic angina on once-daily atenolol (50 mg), once-daily diltiazem (180mg), or once-daily amlodipine (5 mg). Exercise tests were performed 2, 6, and 12 weeks after randomization at trough and 2 and 12 weeks at peak. The results showed that, compared with placebo, ranolazine significantly increased symptom-limited exercise duration.
  • 11. The improvement was sustained over the 12 weeks of therapy, indicating lack of tolerance over this time interval. The mean number of weekly angina attacks and nitroglycerin use over the 12 weeks of treatment with ranolazine was significantly reduced in a dose- dependent fashion ERICA Trial (Stone PH, Gratsiansky NA, Blokhin A, et al. ERICA Investigators. 2006. Antianginal Effi cacy of Ranolazine When Added to Treatment with Amlodipine. The ERICA (Effi cacy of Ranolazine in Chronic Angina) Trial. J Am Coll Cardiol, 48:56675.) The Efficacy of Ranolazine in Chronic Angina (ERICA) trial investigated 565 patients with persisting anginal symptoms despite maximum recommended doses of amlodipine (10 mg) to receive twice daily 1000 mg of ranolazine or placebo. At baseline, the mean number of angina attacks was 5.5 per week, and mean nitroglycerin use was 4.3 tablets or sprays per week; 45% of patients were taking concomitant long-acting nitrates. During the 6-week treatment phase, the mean number of angina episodes per week decreased to 3.2 in the placebo group and 2.8 in the ranolazine group (P<0.028). Mean nitroglycerin use per week decreased to 2.6 in the placebo group and 2.0 in the ranolazine group (P<0.014) without a significant change in heart rate or blood pressure. The magnitude of symptomatic improvement was greater in patients with more angina attacks per week at baseline. Ranolazine significantly reduced frequency of angina and nitroglycerine consumption when added to conventional anti-anginal medication. MERLIN TIMI 36 Trial (Morrow DA, Scirica BM, Karwatowska-Prokopczuk E, et al. 2007a. Effects of ranolazine on recurrent cardiovascular events in patients with nonst-elevation acute coronary syndromes. The MERLIN-TIMI 36 Randomized Trial. JAMA, 297:177583.)
  • 12. Ranolazine has been tested in a large acute coronary syndrome trial to determine its impact on death and recurrent ischemic events. The Metabolic Efficiency with Ranolazine for Less Ischemia in NonST-Elevation Acute Coronary Syndrome (MERLIN TIMI 36) study is a large (6000 patients) multinational end-point driven trial of patients with an acute coronary syndrome follow every 4 months and an exercise study conducted 8 months after randomization Ranolazine showed a significant reduction in HbA1c at 4 months compared with placebo (p = 0.001). Diabetic patients treated with ranolazine showed a significant decline in HbA1c from 7.5% to 6.8% ( p < 0.001). Further, diabetic patients were more likely to achieve an HbA1c <7% at 4 months when treated with ranolazine vs placebo (59% vs 49%, p < 0.001). Also, ranolazine-treated diabetic patients showed less worsening of hyperglycemia by 1 year of follow-up (14.2% vs 20.6%, p < 0.001). Interestingly, in diabetes-free patients at baseline (baseline HbA1c of <6%), ranolazine showed reduced incidence of new increase in HbA1c 6% (p = 0.003) ROLE Trial (Long Term Safety & Tolerability) (Chaitman BR, Pepine CJ, Parker JO, et al. 2004a. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial. JAMA, 291:30916.) In The Ranolazine Open Label Experience (ROLE) program, 2.8-year mean follow-up was done for 746 chronic angina patients on ranolazine. The most common adverse effects reported were dizziness (11.8%) and constipation (10.9%). These complaints led to discontinuation in 0.9% and 0.5% of patients, respectively. No subjects were withdrawn for QTc prolongation and no torsades de pointe was reported.
  • 13. Further, the presence of diabetes status was not correlated with increased adverse event-related discontinuation of ranolazine. Syncope and postural hypotension can occur with ranolazine, likely due to alpha- adrenergic receptor blockage at very high doses of up to 2000 mg. It is avoidable by the usual practice of initiating ranolazine with the lowest available dose and carefully titrating upward based on both efficacy and tolerability. UNIQUE SELLING POINTS Ranolazine is a relatively selective inhibitor of the late I Na (late sodium) current & has effects on several other cardiac ion currents like late ICa,L, IKr) Ranolazine, in contrast to older antianginal medications, works downstream of the ischemic insult It complements the action of traditional anti-anginal medications Ranolazine is useful in patients who have not achieved an adequate response with other antianginal medications It can be used in combination with amlodipine, -blockers, or nitrates. It exerts anti-anginal effects without causing significant bradycardia and/or lowering systemic blood pressure. It helps maintain myocardial function in times of ischemia because it is a partial inhibitor of fatty acids. It is well suited for patients with lower blood pressure or heart rate, in whom the upward titration of anti-anginal medications with important hemodynamic effects may not be well tolerated. It is safe therapy in refractory angina with an advantage of decreased angina frequency, increased exercise tolerance, and no deleterious effects on hemodynamics. It has a favorable effect on HbA1C levels in diabetic patients.
  • 14. Procedures used to treat angina: Invasive techniques that improve the heart and the heart's blood supply may be used. One of these is PTCA (percutaneous transluminal coronary angioplasty). It's also known as PCI (Percutaneous coronary intervention), balloon dilation or balloon angioplasty. In it, a thin, flexible plastic tube (catheter) with a balloon is inserted into an artery and advanced to the blockage. Then the balloon is inflated, squeezing open the fatty plaque deposit. Then the balloon is deflated and the catheter is withdrawn. Often a stent is also placed to hold the artery open. Coronary artery bypass graft surgery is also used. In it, a blood vessel is used to route blood around the blocked part of the artery, forming a kind of detour.