Knowledge objectives for Cardiovascular Pharmacology Angiotensin Converting Enzyme ACE Inhibitors As a result of this lecture the student will be able to Describe the general mechanism by which peptide hormones such as bradykinin and angiotensin are generated and degraded Discuss the advantages and disadvantages of developing drugs to affect critical steps in peptide hormone metabolic pathways Recall the mechanisms by which ACE inhibitors decrease blood pressure and reduce complications of cardiovascular disease and diabetes Describe the side effects that limit the usefulness of these drugs Drugs ACE Inhibitors captopril lisinopril enalapril prodrug enalaprilat active form benazepril fosinopril moexipril perindopril quinapril ramipril trandolapril RELATED losartan and other sartans Angiotensin receptor antagonist Aliskiren renin inhibitor CALCIUM ANTAGONISTS Review mechanisms for regulation of intracellular calcium concentration import compartmentalization sequestering etc Know the major types of voltage dependent Ca 2 channels L type long lasting T type transient and N P type Ca antagonists selectively interact with L type channels in vessels and heart 1 As a result of vascular selectivity Ca antagonists increase coronary perfusion that leads to improved oxygen supply They also decrease peripheral vessel resistance that leads to decrease in blood pressure Together these effects result in improved heart performance Know the major cardiovascular pathologies treated by Ca antagonists Know that verapamil and diltiazem have selectivity to sino atrial node and can be used in treatment of supraventricular dysrhytmia New calcium antagonists have selectivity toward T type calcium channels They do not have negative inotropism they do not have sympathetic activation They can reduce heart rate they are highly selective towards coronary vessels they have minimal side effects DIURETICS Focus on the following points Definition of diuretics and the purposes of diuretic therapy Please remember the table of different types of diuretics types examples sites and mechanisms of action Several diuretics are sulfonamide derivatives Major clinical indications of each types of diuretics particularly those explained by their mechanism of action Side effects of each types of diuretics related to their mechanisms of action Particularly pay attention to the distortion of water and electrolyte balance Carbonic anhydrase inhibitors inhibit carbonate reabsorption and proton excretion Osmotic diuretics inhibit reabsorption of water by osmotic force It also expand volume of extracellular compartment and may increase heart burden Loop diuretics inhibit the Na K 2Cl symport in thick ascending limb of loop of Henle There are two types of loop diuretics example furosemide and ethacrynic acid Loop diuretics inhibit reabsorption of most ions in the tubular fluid The difference between loop diuretics and thiazide diuretics Thiazide use and mechanism of action Difference between potassium sparing diuretics and other diuretics Different types of potassium sparing diuretics and their use Drug interaction between diuretics and between diuretics and other drugs DRUG TREATMENT OF HEART FAILURE Understand the three major therapeutic issues in CHF Volume control cardiac contractility hypertrophic remodeling Volume Control diuretics ace inhibitors natriuretic peptide 2 Know the key role of angiotensin Why is control of volume and afterload one key to controlling symptoms of CHF Cardiac Contractility Positive Inotropic agents used in conjunction with diuretic agents ACE inhibitors vasodilators increase cardiac output at constant preload and heart rate increase intrinsic contractility of heart Why is enhancement of cardiac contractility one key to controlling symptoms of CHF Cardiac glycosides increase cardiac contractility by direct action on cardiomyocyte Na K ionic pump is receptor for cardiac glycoside digoxin and digitoxin are commonly used glycosides antiarrhythmic action against supraventricular arrhythmia slowing of A V conduction negative dromotropic effect negative chronotropic action due to reflex bradycardia vagal effect indications for use in low output heart failure particularly when atrial arrhythmias are present digitalis toxicity ventricular tachyarrhythmias gastrointestinal upset CNS symptoms such as dizziness convulsion Sympathetic agonists Dobutamine beta1 beta2 PDE phosphodiesterase inhibitors amrinone milrinone Vasodilators Proven mortality Reduction beta blockers ACE inhibitors spironolactone ANTIARRHYTHMIC AGENTS 3 Know the four classes of antiarrhythmic drugs Note that side effects of overdoses of these drugs is often arrhythmia Group I Na channel blockers Useful for treatment of ventricular tachyarrhythmia and occasionally atrial tachyarhythmia Group II Beta adrenoceptor blockers Useful against supraventricular tachyarrhythmias Group III Action potential prolonging agents Used against ventricular arrythmias due to reentry circuits Bretyllium is a chemical defibrillator Group IV Calcium channel blockers Highly effective in treatment of supraventricular tachyarrhythmias ANTIANGINAL AGENTS These substances are for symptomatic treatment of angina Know the three basic mechanisms of anti anginal drugs Nitrates and nitrites Nitroglycerin and related substances restore oxygen supply demand balance through redistribution of coronary flow reductions in preload afterload and total peripheral resistance Beta blockers reduce cardiac contractility and heart rate by antagonizing beta effects of endogenous catecholamines thus resulting in diminished myocardial oxygen consumption Calcium channel blockers reduce afterload and thereby decrease oxygen demand of the heart ANTIHYPERTENSIVE DRUGS Know classification of antihypertensive drugs AHDs based on their mechanisms Think about how blood pressure BP is maintained BP cardiac output CO x peripheral vascular resistance PVR Therefore the anatomical sites of action for these drugs are heart kidney blood vessels and part of the brain Why diuretics have been used as first line AHDs How are they further divided into 3 groups based on mechanisms of action Know why they are useful when combined with several other AHDs agonists and blockers Know the difference between 1 and 2 adrenergic receptors What are the sites of actions Know how centrally acting AHDs work and what are the common adverse effects 4 Know the basic mechanism of peripherally acting AHDs is to block one or more
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