Drugs affecting the Cardiovascular System (Tutorial) Therapeutic Classes • Antianginal • Antiarrhythmic • Antihypertensive • Cardioinhibitory • Cardiostimulatory • Diuretics • Pressor • Thrombolytic • Vasoconstrictor • Vasodilator Clinical Disorders • Angina • Arrythmias • Edema • Heart Failure • Hypertension • Hypotension • Myocardial Infarction Drug Mechanism Classes • Adenosine receptor agonist • Aldosterone receptor antagonists • Alpha-agonists • Alpha-blockers • Angiotensin-converting enzyme (ACE inhibitors) • Angiotensin Receptor blockers (ARBs) • Beta agonists • Beta blockers • Calcium-channel blockers • Centrally acting sympatholytics • Direct-acting vasodilators • Diuretics (loop,thiazide,potassium-sparing) • Endothelin receptor antagonists • Fibrinolytics • Ganglionic blockers • Muscarinic receptor antagonists • Cardiac glycosides • Natriuretic peptides • nitrodilators • Phosphodiesterase inhibitors • Potassium channel blockers • Potassium channel openers • Renin inhibitors • Sodium channel blockers • Sodium channel blockers (late sodium currents) • Sympathomimetics • Thrombolytics (fibrinolytics) • Vasopressin analogs • Antianginal Drugs • Therapeutic use & rationale • Redn in O2 supply/demand ratio • Improve this ratio • Increase blood flow – increases O2 delivery & supply • Decrease O2 demand – decrease myocardial O2 consumption • Prevent vasospasm & clot formation • Classes of Drugs Used to Treat Angina • Vasodialtors – dilate arteries & veins - Calcium channel blockers - Nitrodilators • Cardioinhibitory drugs – reduce heart rate & contractility - Beta blockers - Calcium channel blockers • Late soudium current blockers - Ranolazine • Anti-thrombotic drugs – prevent thrombus formation - Anticoagulants - Anti-platelet drugs • Calcium channel blockers (CCBs) MoA • Block calcium entry into cells of vascular sm, cardiac myocytes, cardiac nodal tissue • Cause vascular sm relaxation= vasodilation = decrease myocardial force generation = decrease heart rate = decreases conduction velocity in the heart Indications • Hypertension • Angina • Arrythmias • Classes of Calcium-Channel Blockers Dihydropyridines - Amlodipine - Felodipine - Isradipine - Nicardipine - Nifedipine - Nimodipine - Nitrendipine • smooth muscle selective • Mainly used to reduce systemic vascular resistance & arterial pressure • Mainly used to rx hypertension • Can lead to reflex cardiac stimulation (tachycardia & increased ionotropy) = increase myocardial O2 demand Non-dihydropyridines • Phynylalkylamine – verapamil - reduces myocardial oxygen demand - reverses coronary vasospasm and arrhythmias. • Benzothiazepine - Diltiazem - Cardiac depressant properties - Vasodilator actions - Reduces arterial pressure without the reflex cardiac stimulation caused by dihydropyridines. Side effects • Flushing • Headache • Excessive hypotension • Edema • Reflex tachycardia • Antiarrhythmic Drugs • Goal = to restore normal rhythm & conduction • Antiarrhythmic drugs are used to: • decrease or increase conduction velocity • alter the excitability of cardiac cells by changing the duration of the effective refractory period • suppress abnormal automaticity • Antiarrhythmic Drug Classes • Class I – Sodium channel blockers • Class II – Beta blockers • Class II – Potassium Channel blockers • Class IV – calcium channel blockers • Miscellaneous – adenosine, electrolyte supplements (mg & K salts), cardiac glycosides, atropine (muscarinic receptor antagonist) Condition Drug Comments Other underlying causes may need Sinus tachycardia Class II, IV treatment Class IA, IC, II, III, IV Ventricular rate control is important Atrial fibrillation/flutter digitalis goal; anticoagulation required adenosine Paroxysmal supraventricular Class IA, IC, II, III, IV tachycardia adenosine AV block atropine Acute reversal Ventricular tachycardia Class I, II, III Class II, IV PVCs are often benign and not Premature ventricular complexes Mg++ salts treated Class IB Digitalis toxicity Mg++ salts; KCl • Antihypertensive Drugs • Rationale for Pharmacologic Treatment of Hypertension - Reduce cardiac output 1) reduce blood volume - reduces central venous pressure and cardiac output 2) reduce systemic vascular resistance –dilate systemic vasculature 3) reduce cardiac output by depressing heart rate and stroke volume - • Drugs Used to Treat Hypertension Diuretics - thiazide diuretics - Loop diuretics - Potassium sparing diuretics Vasodilators • Alpha blockers • Angiotensin Converting Enzyme Inhibitors (ACE Inhibitors) • Angiotensin Receptor Blockers (ARBs) • Calcium-channel blockers • Direct acting arterial dilators • Ganglionic blockers • Nitrodilators • Potassium-channel openers • Renin inhibitors Cardio-inhibitory Drugs • Beta blockers • Calcium channel blockers Centrally Acting sympatholytics • Mechanisms of diuretic drugs • Diuretic drugs increase urine output by the kidney = promote diuresis • altering how the kidney handles sodium • If the kidney excretes more sodium, then water excretion will also increase • Most diuretics inhibit the reabsorption of sodium at different segments of the renal tubular system Loop diuretics • inhibit the sodium-potassium-chloride co- transporter in the thick ascending limb • This transporter normally reabsorbs about 25% of the sodium load • inhibition of this pump can lead to a significant increase in the distal tubular concentration of sodium - reduced hypertonicity of the surrounding interstitium, and - less water reabsorption in the collecting duct = increased water loss = diuresis = increased sodium loss = natriuresis • Loop diuretics act on the thick ascending limb, which handles a significant fraction of sodium re-absorption • loop diuretics are very powerful diuretics. • These drugs also induce renal synthesis of prostaglandins, which contributes to their renal action including the increase in renal blood flow and redistribution of renal cortical blood flow. Thiazide diuretics • the most commonly used diuretic, inhibit the sodium-chloride transporter in the distal tubule. • this transporter normally only reabsorbs about 5% of filtered sodium • these diuretics are less efficacious than loop diuretics in producing diuresis and natriuresis. • But are sufficiently powerful to satisfy most therapeutic needs requiring a diuretic. • Their mechanism depends on renal prostaglandin production. • loop and thiazide diuretics increase increases potassium loss (potentially causing hypokalemia) because the increase in distal tubular sodium concentration stimulates the aldosterone-sensitive sodium pump to increase sodium re-absorption in exchange for potassium and hydrogen ion, which are lost to the urine. • Potassium-sparing Diuretics. • do not act directly on sodium transport • Some drugs in this class antagonize the actions of aldosterone (aldosterone receptor antagonists) • more sodium (and water) to pass into the collecting duct and be excreted in the urine. • They are called K+-sparing diuretics because they do not produce hypokalemia like the loop and thiazide diuretics • often used in conjunction with thiazide or loop diuretics to help prevent hypokalemia Carbonic anhydrase inhibitors • inhibit the transport of bicarbonate out of the proximal convoluted tubule into the interstitium • leads to less sodium re-absorption • greater sodium, bicarbonate and water loss in the urine • the weakest of the diuretics and seldom used in cardiovascular disease. • Their main use is in the treatment of glaucoma. Cardiovascular effects of diuretics • decrease blood volume and venous pressure • decreased cardiac filling (preload) • decreased ventricular stroke volume • Venodilation • Reduced systemic vascular resistance (long term use) THERAPEUTIC USES OF DIURETICS • Hypertension • Heart Failure – reduces pulmonary & systemic congestion & edema • Most patients in heart failure are prescribed Loop diuretics- are more effective in unloading sodium and water than thiazide diuretics. • In mild heart failure, a thiazide diuretic may be used. • Potassium-sparing, aldosterone-blocking diuretics (e.g., spironolactone) are being used increasingly in heart failure. Class Specific Drugs Comments Thiazide chlorothiazide thiazide-like in chlorthalidone action, not structure hydrochlorothiazide prototypical drug; hydroflumethiazide thiazide-like in indapamide action, not structure methyclothiazide thiazide-like in metolazone action, not structure polythiazide Loop bumetanide ethacrynic acid furosemide torsemide distal tubule Na+- K+-sparing amiloride channel inhibitor aldosterone receptor antagonist; fewer side eplerenone effects than spironolactone aldosterone receptor spironolactone antagonist; side effect: gynecomastia distal tubule Na+- triamterene channel inhibitor prototypical drug; not used in treating CA inhibitors acetazolamide hypertension or heart failure not used in treating dichlorphenamide hypertension or heart failure not used in treating methazolamide hypertension or heart failure • Adverse Side Effects and Contraindications • Cardioinhibitory Drugs • Cardioinhibitory drugs depress cardiac function by decreasing heart rate (chronotropy) and myocardial contractility (inotropy), which decreases cardiac output and arterial pressure • These cardiac changes reduce the work of the heart and myocardial oxygen consumption • The mechanisms of action of these drugs also lead to depressed electrical conduction(dromotropy) within the heart. • Some of these drugs may also impair relaxation (lusitropy). Therapeutic Uses of Cardioinhibitory Drugs • Hypertension • Angina • Arrhythmias • Heart failure