ASCVD 2024 Fall 2024 PHAR 404 PDF

Atherosclerotic Cardiovascular Disease (ASCVD) Danielle Cruthirds, PhD PHAR 404 Fall 2024  ▪ Background and pathophysiology of ASCVD ▪ Agents used in treatment and prevention Outline  ▪ Describe the pathophysiology of ASCVD, including risk...

Atherosclerotic Cardiovascular Disease (ASCVD) Danielle Cruthirds, PhD PHAR 404 Fall 2024  ▪ Background and pathophysiology of ASCVD ▪ Agents used in treatment and prevention Outline  ▪ Describe the pathophysiology of ASCVD, including risk factors, symptoms and outcomes. Learning ▪ Describe the mechanism of action, adverse effects, contraindications and drug interactions of the agents Objectives used in the treatment and prevention of ASCVD.  ▪ Atherosclerosis is the pathological process in the coronary arteries, cerebral arteries, iliac and femoral arteries, and aorta that is responsible for coronary heart disease (CHD), stroke, and peripheral arterial disease ASCVD (PAD). ▪ Atherosclerosis: thickening or hardening of the arteries. It is caused by a buildup of plaque in the inner lining of an artery.  ▪ Arrhythmia ▪ Pain or pressure in upper body (chest or jaw) ▪ Shortness of breath ▪ Headache ASCVD ▪ Weakness in extremities Symptoms ▪ Leg pain when walking ▪ Fatigue  ▪ ACE inhibitors ▪ Aldosterone antagonists ▪ Calcium channel blockers ▪ Statins ▪ Anticoagulants Pharmacological ▪ Antiplatelets Treatment ▪ ▪ Beta blockers Nitrates Options ▪ Ranolazine ▪ Fibrinolytics  Nitrates and Miscellaneous Agents Used for Myocardial Ischemia  ▪ Background of Angina Pectoris ▪ Treatment Approaches Outline ▪ Classification of Angina Pectoris ▪ Pharmacologic Agents  ▪ Define angina pectoris, its symptoms, and classifications. ▪ Describe the relationship between myocardial oxygen demand and supply, and the factors that govern each. ▪ Describe the pharmacology and clinical application of organic nitrates in the treatment of angina pectoris. Learning ▪ Describe, mechanistically, the interaction between nitrates and phosphodiesterase inhibitors such as tadalafil. Objectives ▪ Describe the mechanism of action, major pharmacokinetic properties, major adverse effects, and therapeutic effects of the various nitrate agents. ▪ Describe how calcium channel blockers, beta-blockers and afterload reducers affect myocardial oxygen supply and demand, and the role these agents play in the treatment of angina.  ▪ “Chest pain” ▪ Clinical syndrome characterized by discomfort in the Angina Pectoris chest, jaw, shoulder, back, or arm. Angina pectoris is the primary symptom of ischemic heart disease (myocardial ischemia).  ▪ Myocardial ischemia results when the heart experiences __________________ to perform the work of pumping blood. When the heart experiences inadequate oxygen Myocardial supply, it becomes ischemic. Unlike other muscles in the body, the heart cannot simply “rest” or stop contracting Ischemia when blood supply is inadequate…it must continue to contract to pump blood to peripheral tissues. As a result, tissue damage occurs and painful stimuli are released from the tissue.  ▪ Pain signals are transmitted to the spinal cord and upwards to the cortex for interpretation. ▪ Because the neurons carrying the pain signals from the Symptoms of heart to the brain are in close proximity to other sensory Angina neurons, the pain signals from the heart may actually “cross paths” with another pain tract from a different part of the body…this is called “referred pain”.  ▪ Angina pectoris results “when the heart experiences insufficient blood flow (oxygen delivery) to perform the work of pumping blood”. Angina ▪ Another way of putting this is that angina pectoris will occur when myocardial oxygen ____________ exceeds myocardial oxygen _____________.  ▪ To treat angina pectoris, one can: Treatment 1. 2. Approaches 3.  ▪ What governs myocardial oxygen demand? ▪ It is directly related to the workload the heart is required to do. ▪ Oxygen demand increases when: Let’s think about ▪ Heart rate increases this ▪ Contractility increases ▪ Venous return increases ▪ The first two (heart rate and contractility) are straight forward, but what about venous return?  On your own revisit this mechanism!!! Frank Starling Mechanism As venous return increases, CO ___________. This _____oxygen demand. Angina occurs when oxygen _____________outweighs oxygen ___________.  HR contractility Venous return So… one way to treat angina is to decrease oxygen demand by: ▪ Decreasing ▪ Decreasing ▪ Decreasing ▪ What drugs do you already know that can do this?  ▪ The heart extracts about 70% of the oxygen from the blood (this is very high). To get more oxygen to the Heart, blood, myocardial tissue, blood flow must be ___________________. oxygen ▪ Therefore, coronary arterial blood flow controls myocardial oxygen supply.  ▪ Sometimes the coronary arteries are unable to supply adequate blood flow to meet the oxygen demands of the myocardial tissue. This can result from several causes: Heart, blood, 1. oxygen 2. 3. Angina Koda-Kimble & Young, 7th ed. Figs. 15-3,4, p15-4  So, how can we treat inadequate myocardial oxygen supply? 1. Dilate coronary arteries/prevent vasospasms Treating Angina 2. Reverse atherosclerosis 3. Prevent microthromboses  Overview of Myocardial Oxygen Supply and Demand  ▪ Three major classifications exist for angina pectoris: ▪ Stable angina (also called: “classical”, “typical”, or Classification of “angina on exertion”) Angina Pectoris ▪ Variant angina ▪ Unstable angina (UA; also called “angina at rest”)  ▪ Stable angina occurs in situations where myocardial workload (oxygen demand) is increased, such as exercise, emotional stress, etc. At rest, when the heart is performing minimal work, oxygen supply is sufficient. Stable Angina However, as oxygen demand increases, the coronary arteries are unable to dilate to allow increased blood (Exertional flow and oxygen delivery. Resting and/or sublingual NTG will usually result in the disappearance of symptoms. Angina) Stable angina is usually due to atherosclerotic narrowing of the coronary arteries. Typically, the amount of artery occlusion required for stable angina is approximately _____.  ▪ Organic Nitrates ▪ Organic nitrates are capable of denitration to release nitric oxide (NO). NO is an endogenous, potent Pharmacologic vaso_______ Agents ▪ The mechanism by which nitrates (via NO generation) cause vaso____________ is:  ▪ Organic nitrates undergo denitration to form NO. Being a gas, NO diffuses easily across the vascular smooth muscle cell membrane, binds to a heme moiety on an enzyme called soluble guanylyl cyclase (sGC), and activates the enzyme. sGC converts GTP into cyclic GMP Organic Nitrates (cGMP). cGMP results in dephosphorylation of the myosin LC, thereby leading to relaxation. ▪ Nitrates, via liberation of NO, cause relaxation of vascular smooth muscle cells.  ▪ Organic nitrates, in low doses, have a predominant effect on veins over arteries. Therefore, venous capacitance increases, venous return decreases, but there is little change in arterial blood pressure. ▪ In higher doses, organic nitrates will also affect the arteries, including the coronary arteries. This results in Organic Nitrates increased coronary artery blood flow. ▪ Thus, organic nitrates decrease myocardial oxygen demand (via venous dilation and decreased preload) and increase myocardial oxygen supply (via dilation of coronary arteries).  ▪ Organic nitrates are denitrated by a cellular enzyme called mitochondrial aldehyde dehydrogenase (mtALDH). After prolonged exposure to organic nitrates, mtALDH Drug tolerance becomes damaged and inactive. to nitrates ▪ ____________ bioactivation of the drug. ▪ Chronic nitrate therapy need a “nitrate-free” period  ▪ Non-symmetrical dosing intervals or by use of a long- acting preparation given once-daily (e.g. in the AM) that results in reduced plasma concentrations during the Achieving night, when anginal episodes are least likely to occur. nitrate free ▪ If using a sustained-release patch, the patch is usually removed at bedtime. period ▪ Tolerance usually occurs between ____ - ____ hours exposure.  ▪ Activity of organic nitrates involves the formation of cGMP. VSM cells contain enzymes that control the Nitrate-PDE amount of cGMP in the cell. inhibitor Drug ▪ Phosphodiesterases (PDE), metabolize cGMP to GMP, Interaction which is inactive. This is a very important concept with respect to drug interactions with PDE inhibitors.  ▪ What will happen to intracellular cGMP levels if a patient were to take an organic nitrate AND a PDE inhibitor? Nitrates and PDE5 inhibitors  ▪ Nitroglycerin ▪ Sublingual tablets and spray (bypass first-pass metabolism; ~30 minute duration) ▪ Transdermal ointment ▪ Transdermal patch ▪ Extended release capsule (not used much) ▪ IV Preparations ▪ Isosorbide dinitrate (ISDN; Isordil®) ▪ Oral and chewable tablets ▪ Longer acting than nitroglycerin ▪ Isosorbide mononitrate (ISMN; Ismo®, Imdur®) ▪ Oral tablets and capsules ▪ Longer acting than ISDN….may be given once daily  ▪ Extensive liver metabolism (first-pass effect) of dinitrate preparations ▪ Tolerance development (mtALDH inactivation) ▪ Absolute contraindication with PDE-5 inhibitors Special (Viagra, Levitra, Cialis) Considerations ▪ Sublingual preparations are extremely fast acting, but have a short duration of action ▪ Protect nitroglycerin preparations from light and air  ▪ Capable of blocking many ion channels in the heart and is actually very similar to ______________. ▪ “Add-on” therapy for angina patients who do not completely respond to beta blockers, CCB’s, or nitrates. Ranolazine ▪ Capable of blocking potassium channels, and may cause (Ranexa) a dose-dependent increase in the ___________ interval. ▪ Because it is metabolized by 3A4, and also a substrate for P-glycoprotein, it should be used cautiously with ____________________.  ▪ Describe the state of oxygen balance in angina pectoris. ▪ List the types of angina pectoris and characterize each. ▪ Explain the mechanism of action and physiological Sample effect of organic nitrates. Questions ▪ Why is the concomitant use of nitrates and PDE5 inhibitors contraindicated? ▪ Why do nitrates require a nitrate free period and how is this achieved? Fibrinolytics Promote conversion of plasminogen to plasmin which initiates fibrinolysis  ▪ Explain the role of fibrinolytics ▪ Describe the mechanism of action, major Learning pharmacokinetic properties, major adverse effects, and Objectives therapeutic effects of the various fibrinolytic agents.  ▪ Alteplase ▪ Reteplase Fibrinolytics ▪ Tenecteplase  Bleeding Bruising Nausea Adverse Effects Vomiting Orolingual angioedema  ▪ Potential interaction with other anticoagulants and Drug Interactions antiplatelets due to increased bleeding risk and ▪ Absolute and relative contraindications (will be Contraindications discussed in detail with Dr. Thomason)  ▪ When would you choose a fibrinolytic? ▪ Explain the mechanism of action of this medication class. Sample ▪ Compare and contrast the three fibrinolytics used in Questions treatment.