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(2/28) Schlemmer Lecture: Pharmacology of Drugs used to treat Angina Coronary Artery Disease (CAD): Also known as ASCVD, Coronary Heart Disease (CHD), and Ischemic HD - Epidemiology: 1 in 3 adults has a variation of cardiovascular disease, >13mil have CAD and ~9mil have Angina o #1 cause of death, higher in AA. The greater the number of vessels occluded à worse outcome - Pathophysiology: Fatty streaks can be considered normal, essentially all adults have them. However, when plaques build up, they can become obstructive atherosclerotic plaques. Associated inflammatory processes further promote occlusion, and although often clinically silent, severe occlusions may require bypass surgery - Complications: Angina pectoris, MI, HF, Ventricular arrhythmias, Death Angina: Term for chest pain or discomfort attributed to Coronary artery disease (CAD) - Sx: Pressure, squeezing, pain in the center of the heart ~ sternum/left side of chest - Cx: Pain results from acidic metabolites stimulating myocardial pain nerve-endings. The accumulation of metabolites secondary to myocardial ischemia will effectively decreasing oxygen supply to the extent that the demands of myocardial oxygen balance are not met. - Electric: The ST segment connects the QRS complex to the T wave, and represents the ventricular repolarization phase. Normally, it is flat. - Stable Angina: Inducible by moderate effort. Coronary artery functions on reduced capacity, quickly relieved by rest or nitroglycerin - Unstable Angina: Also referred to as acute coronary syndrome, this type of angina may be provoked even when resting. Atherosclerotic plaques rupture, clotting to form a plug, blocking flow to the heart muscle. Unstable angina should be treated as a medical emergency - Prinzmetal’s Angina: An unstable variation of angina whereby spasms cause reductions in blood flow. This may occur in or in absence of atherosclerotic disease. It is also referred to as Vasospastic angina Treatment of Angina - The aim of treatment dictates the style of treatment. To impart long-term prevention, we must stop the progression of atherosclerosis, made possible inhibiting platelet activation, fibrinolytic activities, and inflammatory abnormalities. Sometimes, to relieve or avert the onset of pain, we require significant lifestyle changes and potentially even surgery. Surgery includes, angioplasty, stents, and coronary bypass. o Short-term goals: Reduce or prevent angina symptoms that impair quality of life o Long-term goals: Prevent MI, arrhythmias, HF, and extend the patient’s life. - Nitrate Therapy: Nitrates are the classic prototype drugs used for short-term relief of Angina o à Reduce myocardial O 2 demand o Sublingual and Translingual formulations are used to terminate acute angina and as acute prophylaxis o Ointments and Patches are used for sustained protection against angina attacks throughout the day - b-Blocker Therapy: The mainstay therapy for Chronic stable angina o à Reduce myocardial O 2 demand Nitrates: Nitroglycerin - MoA: Upon entering the vascular smooth muscle, Nitroglycerin dissociates off Nitric Oxide (NO) which activates guanylyl cyclase. Guanylyl cyclase increases cGMP formation which dephosphorylates myosin light chains à Vascular smooth muscle relaxes o Predominantly act at the venous capacitance vessels and large coronary arteries to induce relaxation - Standard Dose: Dilation of systemic veins, causing blood to pool within veins (Ývenous capacitance), and decreasing venous return to the heart. This reduces the workload of the heart, reducing myocardial O 2 demand. o Coronary/Epicardial Arteries: Will be relaxed. This reduces spasm of variant angina and increases coronary perfusion thereby aiding oxygen delivery. - Higher Doses:, Arteriolar resistance begins to decrease, further reducing the workload of the heart due to lack of an afterload resistance. Extensive venous pooling continues, and overall blood pressure will decrease. - AE: High doses may trigger the baroreceptor reflex, producing reflex tachycardia and dizzy spells. This may frighten the patient, so it is worth counseling them on – it is safe and to be expected. Additionally: o Headaches (cerebral vasodilation), Cutaneous flushing (arterial dilation of face), postural hypotension - ContraX: Nitrates should not be used in combination with other nitrates. A PDE-5 inhibitor, sildenafil (Viagra) increases cGMP thereby potentiating nitrate activity. Due to the risk of life-threatening hypotension, drugs for sexual-activity should not be used. Try some meditation therapy or something instead o Viagra: Avoid nitrate therapy for 24 hours following most recent Viagra/Levitra dosing o Cialis: Avoid nitrate therapy for 36 hours following most recent Cialis dosing (longer duration of action) - Metabolism/PK: Nitrates have very low oral bioavailability (<10-20%) due to both chemistry and a significant first-pass effect by nitrate reductase in the liver. As a result, sublingual dosing is preferred as it avoids first-pass
