PHARMACOTHERAPY – I PHCY 310 University of Nizwa College of Pharmacy and Nursing School of Pharmacy PHARMACOTHERAPY – I PHCY 310 Lecture 3 Cardiovascular Disorders “Angina Pectoris” Dr. Sabin Thomas, M. Pharm. Ph. D. Assistant Professor in Pharmacy Practice School of Pharmacy University of Nizwa

Course Outcome Upon completion of this lecture the students will be able to Define angina pectoris and classify acute coronary syndrome (ACS), Describe clinical manifestations, risk factors and investigations for ischemic heart disease, Explain the coronary risk factor reduction treatment, and pharmacological treatment for angina pectoris, Describe the pharmacy implications for use of drugs like nitrates in treating Ischemic heart disease.

It is most often due to coronary atherosclerosis. Angina pectoris is a discomfort in the chest that results from reversible myocardial ischemia that produces disturbances in Myocardial function without causing myocardial necrosis. It is most often due to coronary atherosclerosis. Pathophysiology: Coronary arteries narrowing or obstruction results in increased oxygen demand in the face of a fixed oxygen supply. Myocardial Ischemia may be defined as lack of oxygen and decreased or no blood flow in the myocardium. Severe stenosis (greater than 70% block) may provoke ischemia and symptoms at rest.

Myocardial ischemia is caused by an imbalance between coronary blood flow (supply) and the metabolic needs of the myocardium (demand). It occurs when myocardial oxygen demand exceeds myocardial oxygen supply. Ischemic Heart Disease (IHD) may present as an Acute Coronary Syndrome (ACS), which includes Unstable angina and Non–ST-segment elevation (Non-STEMI) or ST-segment elevation myocardial infarction (STEMI) [MI]), Stable angina (exertional) Ischemia without symptoms (silent), Ischemia due to coronary artery vasospasm (variant or Prinzmetal angina).

Clinical Presentation: Sensation of chest pain (radiates to the neck, left jaw, shoulder, and arm), nausea, vomiting, and diaphoresis. The pain lasts from 30 sec. to 30 minutes, and relief occurs with rest or sublingual nitrates. Symptoms are often provoked by exertion (e.g., walking, climbing stairs), emotional stress, and exposure to cold weather. Many episodes of ischemia do not cause symptoms of angina (silent ischemia).

Risk Factors Major risk factors that can be altered Dyslipidemia high total & low-density lipoprotein cholesterol low high-density lipoprotein cholesterol high triglycerides Smoking Glycemic control in DM Hypertension Therapeutic lifestyle changes exercise, weight reduction, reduced dietary cholesterol reduction in inflammation may play an important role Drug Induced Cocaine, Ergot alkaloids, Beta agonists (Increased HR), Oral contraceptives/estrogen replacements, Cytotoxics

Unalterable risk factors: gender age family history environmental influences climate, air pollution, trace metals in drinking water diabetes mellitus Alterable risk factors: smoking hypertension hyperlipidemia obesity, sedentary lifestyle hyperuricemia psychosocial factors (stress) medications

Magnetic Resonance Imaging (MRI) and CT (Non-invasive) Alternatives Investigations 1. Clinical History Location, precipitating factors and alleviating factors. Modifiable risk factors for CAD. 2. Physical examination to assess for: Resting ECG (ST-segment depression, T-wave inversion & ST elevation in Prinzmetal angina). Stress test (treadmill, bicycle exercise, or pharmacologic- using drugs such as dobutamine, adenosine, or dipyridamole). 3. Laboratory tests: Lipid profile Fasting blood glucose Hemoglobin if anemia is suspected Coronary Angiography (Invasive)-Gold Standard (Radiocontrast dye is injected into the coronary arteries and the coronary artery anatomy is visualized) Magnetic Resonance Imaging (MRI) and CT (Non-invasive) Alternatives

Treatment of stable angina According to ACC/AHA guidelines, standard treatment should include ABCDE methods for chronic stable angina. Aspirin and Antianginal Therapy β-blockers and Blood pressure control Cholesterol management and Cigarette cessation Dietary improvements and Diabetes control Education and Exercise

Coronary Risk Factor Reduction Treatment Coronary Risk Factor Reduction Smoking cessation: Intense efforts should be made to encourage smoking cessation to prevent development or worsening of CAD. Hypertension management: Blood pressure reduction reduces myocardial oxygen demand and benefits patients with angina. Lipid lowering: LDL-lowering therapy with HMG-CoA reductase inhibitors should be initiated in all patients with established coronary artery disease. Antiplatelet therapy: All patients without contraindications having angina or clinical or laboratory evidence of ischemic heart disease receive aspirin (75–325 mg/day) therapy indefinitely. Ticlopidine has been associated with serious adverse events, including neutropenia that limits its use in clinical practice. Clopidogrel is the agent of choice for patients with an absolute contraindication to aspirin therapy.

Pharmacologic therapy: Cardiac rehabilitation: Exercise training reduces cardiovascular mortality, improves functional capacity, and attenuates (lessens) myocardial ischemia, reduces other coronary risk factors like obesity, hypertension and diabetes. Exercise has a beneficial conditioning effect on skeletal and cardiac muscle and decrease oxygen demand. It also favorably affects fat and carbohydrate metabolism, which may aid in the reduction of cardiovascular risk Pharmacologic therapy: A- Drugs that Decrease the Risk of Cardiovascular Death, Myocardial Infarction or Stroke. All patients with angina pectoris due to CAD should be treated with an ACE inhibitor and an antiplatelet agent. All patients with a non-fasting total cholesterol level ≥ 3.5 mmol/L should receive statin therapy.

B - Drugs that Decrease or Prevent Angina 1. ß blockers: ß-blockers are the 1st line therapy of chronic angina. They reduce oxygen demand by reducing HR, contractility, and BP. β-Blockers should be initiated at lowest doses, with titration according to symptom and to maintain resting heart rate between 50 and 60 beats per minute. β-Blockers should be used with caution in combination with agents that depress AV conduction (e.g., digoxin, verapamil, and diltiazem) to avoid bradycardia and heart block. 2. Nitrates: Organic nitrates are prodrugs and must be converted to nitric oxide that reacts further with sulfhydryl groups to form S-nitrosothiols thereby activating cGMP in smooth muscle. Short-acting nitrates: Sublingual tablet and spray nitroglycerin are first-line treatment to lessen the acute anginal attacks because of rapid absorption.

Counseling a patient on Sublingual Nitroglycerin use: The seated position is generally preferred when using nitroglycerin since the drug may cause dizziness. Acute events, place the dose (spray or tablet) under the tongue, and not swallow the tablet. If the pain is not relieved within 5 minutes, the process may be repeated until a total of three doses have been given (15 minutes), after which time the patient should contact their physician, or be transported to an emergency room. Keep nitroglycerin tablets in the original glass container and close the cap tightly after use. When the bottle is opened the patient should remove the cotton plug and discard it. Discard after 8 weeks of opening (Chemical degradation). Nitroglycerin should not be used within 24 hours of taking sildenafil or vardenafil or within 48 hours of taking tadalafil because of the potential for life-threatening hypotension.

Nitrate Products Product Onset (min) Duration Initial Dose Nitroglycerin   IV   Sublingual/lingual   Oral   Ointment   Patch   1 – 2 1 – 3 40 20 – 60 40 – 60 3 – 5 min 30 – 60 min 3 – 6 h 2 – 8 h > 8 h 5 mcg/min 0.3 mg 2.5 – 9 mg tid 0.5 – 1 in 1 patch Erythritol tetranitrate 5 – 30 4 – 6 h 5 – 10 mg tid Pentaerythritol tetranitrate 30 4 – 8 h 10 – 20 mg tid Isosorbide dinitrate   Sublingual/chewable 2 – 5 20 – 40 1 – 2 h 2.5 – 5 mg tid 5 – 20 mg tid Isosorbide mononitrate 30 – 60 6 – 8 h 20 mg daily, bida a Product dependent 14 DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition: http://www.accesspharmacy.com

Why to use only combinations with other antianginal drugs? Long acting nitrates: If angina attacks are frequent (> once daily), long acting nitrates are used for prophylaxis of angina symptoms (in combination with ß-blocker or calcium channel blockers). Nitrate Tolerance: A decreased pharmacological response on continuous (round-the-clock) or frequent administration of nitrates. (depletion of sulfhydryl donors impairing the intracellular formation of nitric oxide and S-nitrosothiols, resulting in decreased formation of cGMP) To avoid nitrate tolerance, we should allow a daily nitrate-free interval of at least 8 to 12 hours. Eg., isosorbide dinitrate can be dosed on awakening and again 7 hours later. Why to use only combinations with other antianginal drugs? To provide 24-hour protection from ischemia by: 1. Covering the nitrate free period. 2. Overcoming reflex tachycardia which may occur due to nitrate-induced venodilation.

3. Calcium channel blockers: CCBs reduce myocardial oxygen demand by lowering both wall tension and cardiac contractility. CCBs increase myocardial oxygen supply by dilating coronary arteries, thus increasing coronary blood flow and relieving vasospasm. The nondihydropyridine CCBs verapamil and diltiazem further decrease myocardial oxygen demand by lowering heart rate. Therefore, verapamil and diltiazem are more preferred than dihydropyridine CCBs. Patients for CCBs: 1. Patients with intolerance to ß-blockers. 2. Coexisting conduction system disorders (excluding the use of verapamil or diltiazem). 3. Prinzmetal’s angina. 4. Ventricular dysfunction (amlodipine is the agent of choice, while verapamil or diltiazem should be avoided if Ejection Fraction<35%).

Treatment of variant angina pectoris All patients should be first treated for acute attacks. The main therapy is sublingual nitroglycerin or ISDN. Also IV nitroglycerin can be used. Nitrate free period not advised during sleep (ideal during day time) because most episodes are during night or morning hours. CCBs are as effective as nitrates and can also be considered 1st line therapy of variant angina. Combination of nitrates and CCBs can also be considered. Patient should be maintained on prophylactic therapy for 6-12 months. Aggravating factors as alcohol, cocaine, or cigarette smoking should be stopped. Beta blockers should not be used as they exacerbate coronary vasospasm.

Revascularization Therapy Treatment Summary Questions to Answer Revascularization Therapy Method of administration of various Nitrate products like Sublingual tablets, Buccal tablets, Ointments and Patches Reference: Richard A. Helms, David J. Quan, Eric T. Herfindal, Dick R.Gourley. Textbook of Therapeutics. Drug and Disease Management. 8th Edition. Lippincott Williams and Wilkins.