Antianginal Drugs PDF

Antianginal Drugs  Introduction Atherosclerotic disease of the coronary arteries = Coronary Artery Disease (CAD) = Ischemic Heart disease (IHD) Most common cause of mortality worldwide Atherosclerotic lesions obstruct blood flow leading to an imbalance between myocardi...

Antianginal Drugs  Introduction Atherosclerotic disease of the coronary arteries = Coronary Artery Disease (CAD) = Ischemic Heart disease (IHD) Most common cause of mortality worldwide Atherosclerotic lesions obstruct blood flow leading to an imbalance between myocardial O2 supply and the myocardium tissue demand  Characteristics of angina pectoris: Typical symptoms: - Sudden, severe, chest pain that may radiate to the neck, jaw, back and arms - Sometimes with dyspnea Atypical symptoms: - Indigestion, nausea and vomiting - Sometimes diaphoresis Ø Note: Transient, self-limiting stable angina don’t result in cell death, but acute coronary syndrome or chronic ischemia cause HF, arrhythmias and sudden death  Management of angina Guideline-directed medical therapy Lifestyle modification: smoking cessation, physical activity, weight management Management of modifiable risk factors: HTN, DM, dyslipidemia  Types of Angina Stable angina = effort-induced angina = classic angina = typical angina Unstable angina Prinzmetal = varient = vasospastic = rest angina Stable angina = effort-induced angina = classic angina = typical angina Most common angina Typical symptoms: - Short-lasting burning, heavy or squeezing feeling in the chest Atypical symptoms: - Extreme fatigue - Diaphoresis - Nausea - Sometimes no symptoms (silent angina) Stable angina = effort-induced angina = classic angina = typical angina Ø Atypical symptoms are more common in: - Diabetic patients - Elderly - Women Ø When the pattern of chest pain and the amount of effort required to trigger chest pain do not vary over time, the angina is named “stable angina” Stable angina = effort-induced angina = classic angina = typical angina Ø Pathogenesis: - Atherosclerosis causes a fixed obstruction of a coronary artery, so that the blood supply cannot increase upon increased demand, resulting in ischemia. Ø Trigger: - Physical activity - Emotional stress or excitement Ø Normally relieves by rest or nitroglycerin  Unstable angina Chest pain occurs with increased frequency, duration and intensity, with progressively less effort Rest angina longer than 20 min New onset-angina Any increasing angina  Unstable angina Symptoms not relieved by rest or nitroglycerin Requires hospitalization Can quickly progress to MI and death  Acute coronary syndrome Emergency state Due to rupture of atherosclerotic plaque Followed by platelet aggregation and thrombosis of a coronary artery Results in partial or complete coronary artery occlusion Can result in cardiac muscle necrosis (MI) Prinzmetal, varient, vasospastic, rest angina Uncommon pattern of episodic angina Occurs at rest Due to coronary artery spasm Patients may have also significant coronary atherosclerosis The attacks are unrelated to physical activity, heart rate, or blood pressure Respond promptly to coronary vasodilators (nitroglycerin and CCB)  Classes of antianginal drugs β-blockers Calcium channel blockers (CCBs) Organic nitrates Sodium channel blockers Rational of drug use: These agents help to balance the cardiac oxygen supply and demand, by affecting blood pressure, veous return, heart rate and contractility  β-blockers Benefits of β-blockers: - Reduce O2 demand at exertion and rest - Reduce both frequency and severity of angina attacks - Increase exercise duration and tolerance in patients with stable angina - Reduce the risk of death and MI for patients with prior MI - Improve mortality for patients with HTN and HF  β-blockers With the exception of vasospastic angina, β-blockers are recommended as initial therapy for all patients unless contraindicated β-blockers are ineffective and can even worsen vasospastic angina β-blockers with intrinsic sympathomimetic activity (Pindolol) should be avoided. β-blockers should be avoided in patients with severe bradycardia Nonselective β-blockers should be avoided for patients with asthma  β-blockers Should be used with caution (require monitoring) for patients with - Diabetes mellitus - Peripheral vascular disease - Chronic obstructive pulmonary disease (COPD)  Calcium channel blockers (CCBs) Types - Dihydropyridine CCBs: Amlodipine, Nifedipine - Nondihydropyridine CCBs: Verapamil, Diltiazem Protect the tissues by preventing calcium entrance into cardiac and smooth muscle cells (of coronaries and peripheral arteries) All CCBs are arteriolar vasodilators (coronary and peripheral arteriols)  Calcium channel blockers (CCBs) Rational for the use of CCBs for exercise-induced angina: - CCBs reduce myocardial O2 consumption by decreasing vascular resistance and decreasing afterload Rational for the use of CCBs for vasospastic angina - Relaxation of coronary arteries  Dihydropyridine CCBs Dihydropyridines are effective for variant angina due to prominent vasodilation effect. Nifedipine is administered as extended-release oral formulation Note: short-acting Dihydropyridines should be avoided in CAD because of increased mortality after MI, and an increase of MI risk in HTN patients.  Nondihydropyridine CCBs Verapamil - Directly slows AV conduction, decrease heart rate, contractility, blood pressure and O2 demand - Has greater negative inotropic effects than Amlodipine, but weaker vasodilation. - Contraindicated in preexisting depressed cardiac function (HF) or AV conduction abnormalities.  Nondihydropyridine CCBs Diltiazem - Slows AV conduction - Decrease rate of SA node firing - Coronary artery vasodilator - Can relieve coronary artery spasm (useful for variant angina) - Contraindicated in preexisting depressed cardiac function (HF)  Organic nitrates They reduce myocardial O2 demand, followed by relief of symptoms Effective in: Stable, unstable and variant angina Mechanism of action: - It is converted intracellularly into Nitrite (NO 2-) ions and then into Nitric oxide (NO), which activates guanylate cyclase and increases cGMP production. - cGMP mediates the dephosphorylation of myosin light chain, causing relaxation of smooth muscles  Organic nitrates Nitrates cause vasodilation of: - Systemic arteries and veins (decrease afterload and preload), decrease O2 demand - Coronary vasculature (increase O2 supply to the myocardium)  Tolerance to Organic nitrates Tolerance to the action of nitrates develops rapidly, as the blood vesicles become desensitized to vasodilation Tolerance can be overcome by daily “nitrate-free intervals”: - Normally 10-12 hr at night because demand on the heart is decreased at that time - Nitroglycerin patches are worn for 12 hr and removed for 12 hr - Variant angina worsens early morning due to circadian catecholamine surges, therefore, nitrates-free intervals in these patients should be take in the late afternoon.  Pharmacokinetics of organic nitrates Differ in their onset of action and rate of elimination Onset of action for Nitroglycerin is around 1 min Onset of action for Isosorbid mononitrate is around 30 min Nitroglycerin (sublingual, buccal spray) is the drug of choice for the prompt relief of effort-induced angina  Pharmacokinetics of organic nitrates All patients suffering angina should have nitroglycerin on hand Nitroglycerin undergo extensive first pass metabolism, therefore administered sublingually or transdermally (patch or ointment) Isosorbid mononitrate has improved bioavailability, less first pass metabolism Isosorbid dinitrate undergo denitration into two mononitrates, both exert antianginal activity  Adverse effects of organic nitrates Postural hypotension Facial flushing Reflex tachycardia Phosphodiesterase type V inhibitors (e.g. Sildenafil) potentiate the actions of nitrates, so the combination is contraindicated. Sodium channel blocker (Ranolazine) During the plateau phase of action potential, a small fraction of sodium channels may not fully inactivate after opening. These channels may continue to open and close spontaneously throughout the plateau phase of the action potential at a time when sodium channels typically remain closed. The late openings of these channels allow a sustained/persistent current of sodium ions (referred to as late INa) to enter the myocardial cell throughout systole. late INa is increased in myocytes exposed to hypoxia Belardinelli et al., 2006 Sodium channel blocker (Ranolazine) An elevation of the intracellular sodium concentration leads to: - An increased exchange of intracellular sodium for extracellular calcium (i.e. activity of NCX in the reverse mode, with sodium exit and calcium entry) - A reduced exchange of intracellular calcium for extracellular sodium (i.e. activity of NCX in the forward mode, with calcium exit and sodium entry) - leads to intracellular calcium overload Belardinelli et al., 2006  Sodium channel blocker (Ranolazine) Ranolazine Ronalizine has also antiarrhythmic activity Adverse effect: prolong QT interval Belardinelli et al., 2006