Cardio Drugs_2024.pdf

PHARMACOLOGY OF CARDIOVASCULAR DRUGS Outline Cardiovascular- Renal Drugs Vasodilators/Anti- Lipid-Lowering Antihypert...

PHARMACOLOGY OF CARDIOVASCULAR DRUGS Outline Cardiovascular- Renal Drugs Vasodilators/Anti- Lipid-Lowering Antihypertensives Heart Failure Anti-arrhythmias Diuretics anginal Drugs Drugs  DRUGS ACTING ON THE Antihypertensive CARDIOVASCULAR SYSTEM Drugs Hypertension Most common cardiovascular disease 60-80% of both men and women will develop hypertension by age 80 Usually asymptomatic until overt end-organ damage is imminent or has already occurred The diagnosis of hypertension depends on measurement of blood pressure and not on symptoms reported by the patient Causes of Hypertension 1. Genetic Predisposition 2. Environmental Risk Factors Overweight and Obesity Sodium and Potassium Intake Sedentary lifestyle Alcohol Primary vs. Secondary Hypertension PRIMARY HYPERTENSION No specific cause of the hypertension could be found Also referred to as essential hypertension SECONDARY HYPERTENSION Hypertension due to a specific etiology (e.g. due to Cushing’s disease, pheochromocytoma) 2017 ACC/AHA Guidelines on Hypertension BP = CO x PVR Hypertensive Urgency vs. Hypertensive Emergency HYPERTENSIVE EMERGENCY HYPERTENSIVE URGENCY Severe elevations in BP (>180/120 Severe elevations in BP (>180/120 mmHg) associated with evidence mmHg) associated WITHOUT acute of new or worsening target organ or impending change in target damage organ damage or dysfunction Target organ damage = hypertensive encephalopathy, ICH, acute ischemic Usually, these patients have withdrawn stroke, acute MI, acute LV failure with from or noncompliant with pulmonary edema, unstable angina, antihypertensive therapy and do not have dissecting aortic aneurysm, acute renal clinical or laboratory evidence of target failure, eclampsia organ damage Hypertensive Urgency vs. Hypertensive Emergency HYPERTENSIVE EMERGENCY HYPERTENSIVE URGENCY Treatment: Treatment: Admission to an intensive care unit is Reinstitution/intensification of recommended for continuous antihypertensive drug therapy monitoring of BP and target organ Treatment of anxiety, if applicable damage and for parenteral administration of an appropriate NO INDICATION FOR: agent Referral to ER Immediate BP reduction in the ER Confinement Insights from the 2017 ACC/AHA Guidelines on Hypertension When to Start Pharmacologic Treatment? According to JNC 8 Guidelines: In the general population, pharmacologic treatment should be initiated when blood pressure is 150/90 mm Hg or higher in adults 60 years and older, or 140/90 mm Hg or higher in adults younger than 60 years. In patients with hypertension and diabetes, pharmacologic treatment should be initiated when blood pressure is 140/90 mm Hg or higher, regardless of age. Initial antihypertensive treatment should include a thiazide diuretic, calcium channel blocker, ACE inhibitor, or ARB in the general nonblack population or a thiazide diuretic or calcium channel blocker in the general black population. If the target blood pressure is not reached within one month after initiating therapy, the dosage of the initial medication should be increased, or a second medication should be added. JNC 8 Guidelines, as cited by the American Academy of Family Physicianshttps://www.aafp.org/afp/2014/1001/p503.html Insights from the 2020 CPG for Hypertension for Filipinos Basic Pharmacology of Antihypertensive Agents DIURETICS Lower blood pressure by depleting the body of sodium and reducing blood volume and perhaps by other mechanisms SYMPATHOPLEGIC Lower blood pressure by reducing peripheral vascular resistance, inhibiting cardiac AGENTS function, and increasing venous pooling in capacitance vessels. (The latter two effects reduce cardiac output.) DIRECT Reduce blood pressure by relaxing vascular smooth muscle, thus dilating resistance VASODILATORS vessels and—to varying degrees—increasing capacitance as well AGENTS THAT BLOCK Reduce blood pressure by peripheral vascular resistance and (potentially) blood PRODUCTION/ACTION volume. OF ANGIOTENSIN  DIURETICS Antihypertensive (with indications for hypertension) Drugs Diuretics Lower blood pressure primarily by depleting body sodium stores Reduce blood pressure by reducing blood volume and cardiac output Effective in lowering blood pressure by 10–15 mm Hg in most patients Often provide adequate treatment for mild or moderate essential hypertension. Thiazide Diuretics Inhibit NaCl transport by blocking the Na+/Cl- transporter, predominantly in the PCT Enhance Ca2+ absorption Rarely causes hypercalcemia, but may mask hypocalcemia due to other causes (e.g. in hyperparathyroidism, carcinoma, sarcoidosis) Sometimes useful in the prevention of calcium-containing kidney stones caused by hypercalciuria and modestly reduce the risk of osteoporotic fractures. Prototype drug: Hydrochlorothiazide (HCTZ) Others: Chlorthalidone (only thiazide diuretic that can be given parenterally) Thiazide Diuretics INDICATIONS hypertension heart failure nephrolithiasis due to idiopathic hypercalciuria nephrogenic diabetes insipidus Thiazide Diuretics TOXICITY Hyperchloremic metabolic acidosis Impaired carbohydrate tolerance Hyperglycemia in patients who are overtly diabetic or mildly abnormal glucose tolerance tests. Usually seen at higher doses of HCTZ (>50 mg/d). Due to both impaired pancreatic release of insulin and diminished tissue utilization of glucose. Hyperlipidemia 5–15% increase in total serum cholesterol and low-density lipoproteins (LDLs). Hyponatremia Impaired uric acid metabolism and gout Potassium-Sparing Diuretics prevent K+ secretion by antagonizing the effects of aldosterone in collecting tubules most useful in states of mineralocorticoid excess or hyperaldosteronism (also called aldosteronism), due either to primary hypersecretion (Conn’s syndrome, ectopic adrenocorticotropic hormone production) or secondary hyperaldosteronism (evoked by heart failure, hepatic cirrhosis, nephrotic syndrome, or other conditions associated with diminished effective intravascular volume) MOA: Antagonism of mineralocorticoid (aldosterone receptors): Spironolactone, Eplerenone Inhibition of Na+ influx channels in the luminal membrane: Amiloride, triamterene Others: Ularitide, Nesiritide (IV form only) Potassium-Sparing Diuretics SPIRONOLACTONE Competitive antagonist to aldosterone Binds with high affinity and potently inhibits the androgen receptor, which is an important source of side effects in males (gynecomastia and decreased libido) Potassium-Sparing Diuretics EPLERENONE Spironolactone analog with much greater selectivity for the mineralocorticoid receptor less active on androgen and progesterone receptors than spironolactone, and therefore, eplerenone has considerably fewer adverse effects May slow the progression of albuminuria in diabetic patients and may reduce myocardial perfusion defects after myocardial infarction Potassium-Sparing Diuretics AMILORIDE direct inhibitors of Na+ influx in the CCT Used in Liddle’s syndrome nephrogenic diabetes insipidus Liddle’s syndrome rare autosomal dominant disorder that results in activation of sodium channels in the cortical collecting ducts, causing increased sodium reabsorption and potassium secretion by the kidneys Potassium-Sparing Diuretics TOXICITY Hyperkalemia Hyperchloremic metabolic acidosis Gynecomastia Acute renal failure (in triamterene with indomethacin) Kidney stones (triamterene)  DRUGS THAT ALTER SYMPATHETIC NERVOUS ANTIHYPERTENSIVES SYSTEM FUNCTION DRUGS THAT ALTER SYMPATHETIC NERVOUS SYSTEM FUNCTION All of the agents that lower blood pressure by altering sympathetic function can elicit compensatory effects through mechanisms that are not dependent on adrenergic nerves. The antihypertensive effect of any of these agents used alone may be limited by retention of sodium by the kidney and expansion of blood volume Thus, sympathoplegic antihypertensive drugs are most effective when used concomitantly with a diuretic CENTRALLY ACTING SYMPATHOPLEGICS: Clonidine, Methyldopa ADRENERGIC NEURON-BLOCKING AGENTS: Guanethidine, Reserpine ADRENORECEPTOR ANTAGONISTS: Beta-blocks, Alpha1 Blockers CENTRALLY ACTING SYMPATHOPLEGIC DRUGS reduce sympathetic outflow from vasomotor centers in the brain stem but allow these centers to retain or even increase their sensitivity to baroreceptor control E.g. Methyldopa, clonidine CENTRALLY ACTING SYMPATHOPLEGIC DRUGS METHYLDOPA analog of l-dopa and is converted to α-methyldopamine and α- methylnorepinephrine antihypertensive action appears to be due to stimulation of central α adrenoceptors by α- ethylnorepinephrine or α-methyldopamine lowers blood pressure chiefly by reducing peripheral vascular resistance, with a variable reduction in heart rate and cardiac output used primarily for hypertension during pregnancy Most common adverse effect: Sedation Other AEs: Lactation (with prolactin secretion); positive Coomb’s test (for autoimmune hemolytic anemia) CENTRALLY ACTING SYMPATHOPLEGIC DRUGS CLONIDINE Commonly used sublingually in hypertensive urgency Reduction of cardiac output due to decreased heart rate and relaxation of capacitance vessels, as well as a reduction in peripheral vascular resistance should not be given to patients who are at risk for mental depression and should be withdrawn if depression occurs during therapy Concomitant treatment with tricyclic antidepressants may block the antihypertensive effect of clonidine. Withdrawal of clonidine after protracted use, particularly with high dosages (more than 1 mg/d), can result in life-threatening hypertensive crisis mediated by increased sympathetic nervous activity. ADRENERGIC NEURON-BLOCKING AGENTS lower blood pressure by preventing normal physiologic release of norepinephrine from postganglionic sympathetic neurons GUANETHIDINE rarely used. produces all of the toxicities expected from “pharmacologic sympathectomy,” including marked postural hypotension, diarrhea, and impaired ejaculation RESERPINE alkaloid extracted from the roots of an Indian plant,, Rauwolfia serpentine; produceS sedation,lassitude, nightmares, and severe mental depression; BETA-ADRENOCEPTOR-BLOCKING AGENTS occupy β receptors and competitively reduce receptor occupancy by catecholamines and other β agonists Should not be discontinued abruptly; some patients experience a withdrawal syndrome, manifested by nervousness, tachycardia, increased intensity of angina, and increase of blood pressure. PROPRANOLOL the first β blocker shown to be effective in hypertension and ischemic heart disease largely replaced by cardioselective β blockers such as metoprolol and atenolol. BETA-ADRENOCEPTOR-BLOCKING AGENTS METOPROLOL, ATENOLOL Cardioselective beta blockers; although cardioselectivity is not complete, metoprolol causes less bronchial constriction than propranolol relatively short half-life; Atenolol is reported to be less effective than metoprolol in preventing the complications of hypertension BETA-ADRENOCEPTOR-BLOCKING AGENTS LABETALOL, CARVEDILOL, NEBIVOLOL have both β-blocking and vasodilating effects Nebivolol: has highly selective β1-blocking effects, while the l-isomer causes vasodilation; vasodilating effect may be due to an increase in endothelial release of nitric oxide via induction of endothelial nitric oxide synthase Carvedilol: reduces mortality in patients with heart failure and is therefore particularly useful in patients with both heart failure and hypertension Labetalol: useful in treating the hypertension of pheochromocytoma and hypertensive emergencies (given as IV bolus) BETA-ADRENOCEPTOR-BLOCKING AGENTS ESMOLOL β1-selective blocker that is rapidly metabolized via hydrolysis by red blood cell esterases short half-life (9–10 minutes) and is administered by intravenous infusion used for management of intraoperative and postoperative hypertension, and sometimes for hypertensive emergencies, particularly when hypertension is associated with tachycardia or when there is concern about toxicity such as aggravation of severe heart failure ALPHA1-ADRENOCEPTOR-BLOCKING AGENTS PRASOZIN, TERASOZIN, DOXAZOSIN Selective blocking of α1 receptors in arterioles and venules produce less reflex tachycardia when lowering blood pressure than do nonselective α antagonists such as phentolamine Alpha1-receptor selectivity allows norepinephrine to exert unopposed negative feedback (mediated by presynaptic α2 receptors) on its own release used primarily in men with concurrent hypertension and benign prostatic hyperplasia PHENTOLAMINE, PHENOXYBENZAMINE Non-selective; used in the diagnosis and treatment of pheochromocytoma VASODILATORS VASODILATORS HYDRALAZINE Dilates arterioles; usually given in pregnant womren with pre-eclampsia/eclampsia via IV route MINOXIDIL very efficacious orally active vasodilator. The effect esults from the opening of potassium channels in smooth muscle membranes by minoxidil sulfate, the active metabolite Used topically as hair grower SODIUM NITROPRUSSIDE powerful parenterally administered vasodilator that is used in treating hypertensive emergencies as well as severe heart failure rapidly lowers blood pressure; effects disappear within 1–10 minutes after discontinuation solution is sensitive to light; given via infusion pump VASODILATORS FENOLDOPAM Peripheral arteriolar dilator used for hypertensiveemergencies and postoperative hypertension It acts primarily as an agonist of dopamine D1 receptors, resulting in dilation of peripheral arteries and natriuresis VASODILATORS HYDRALAZINE Dilates arterioles; usually given in pregnant womren with pre-eclampsia/eclampsia via IV route MINOXIDIL very efficacious orally active vasodilator. The effect esults from the opening of potassium channels in smooth muscle membranes by minoxidil sulfate, the active metabolite Used topically as hair grower SODIUM NITROPRUSSIDE powerful parenterally administered vasodilator that is used in treating hypertensive emergencies as well as severe heart failure rapidly lowers blood pressure; effects disappear within 1–10 minutes after discontinuation solution is sensitive to light; given via infusion pump Most serious toxicity is accumulation of cyanide VASODILATORS: Calcium Channel Blockers CALCIUM CHANNEL BLOCKERS Reduce PVR and BP, on top of antianginal and antiarrhythmic effects Reduces BP by inhibiting calcium influx into smooth muscle cells Dihydropyridines more selective as vasodilators and have less cardiac depressant Amlodipine, felodipine, isradipine, nicardipine, nifedipine, nisoldipine Non-dihydropridines Verapamil (greatest depressant effect on the heart) Diltiazem VASODILATORS: Calcium Channel Blockers CALCIUM CHANNEL BLOCKERS Reduce PVR and BP, on top of antianginal and antiarrhythmic effects Reduces BP by inhibiting calcium influx into smooth muscle cells Dihydropyridines more selective as vasodilators and have less cardiac depressant Amlodipine, felodipine, isradipine, nicardipine, nifedipine, nisoldipine Non-dihydropridines Verapamil (greatest depressant effect on the heart) Diltiazem INHIBITORS OF ANGIOTENSIN ANTIHYPERTENSIVES ACE Inhibitors ARBs ANGIOTENSIN-CONVERTING ENZYME (ACE) INHIBITORS Inhibit the converting enzyme peptidyl dipeptidase that hydrolyzes angiotensin I to angiotensin II and (under the name plasma kininase) inactivates bradykinin, a potent vasodilator that works at least in part by stimulating release of nitric oxide and prostacyclin Useful in treating patients with chronic kidney disease because they diminish proteinuria and stabilize renal function (even in the absence of lowering of blood pressure) Useful In the treatment of heart failure and as treatment after myocardial Infarction Evidence suggest ACEi reduce the incidence of diabetes in patients with high cardiovascular risk e.g. Captopril, enalapril, benazepril, fosinopril, moexipril, perindopril, quinapril, ramipril, trandolapril ANGIOTENSIN-CONVERTING ENZYME (ACE) INHIBITORS TOXICITY Severe hypotension (in hypovolemic patients) Acute renal failure (in px with bilateral renal artery stenosis) Dry cough, angioedema (secondary to bradykinin and substance P) Hyperkalemia (if given with potassium supplements or K-sparing diuretics) ANGIOTENSIN RECEPTOR BLOCKING AGENTS (ARBs) blockers of the angiotensin II type 1 (AT1) receptor no effect on bradykinin metabolism; more selective blockers of angiotensin effects than ACE inhibitors potential for more complete inhibition of angiotensin action compared with ACE inhibitors provide benefits similar to those of ACE inhibitors in patients with heart failure and chronic kidney disease ACE inhibitors and angiotensin receptor blockers or aliskiren, which had once been considered useful for more complete inhibition of the renin-angiotensin system, are not recommended due to toxicity e.g. Losartan, valsartan, azilsartan, candesartan, eprosartan, irbesartan, olmesartan, and telmisartan  JNC 8 Hypertension Treatment Algorithm  Vasodilators and Drugs DRUGS ACTING ON THE CARDIOVASCULAR SYSTEM Used in the Treatment of Angina Pectoris Angina Pectoris chest pain caused by accumulation of metabolites resulting from myocardial ischemia primary cause of angina pectoris is an imbalance between the oxygen requirement of the heart and the oxygen supplied to it via the coronary vessels imbalance between oxygen delivery and myocardial oxygen demand can be corrected by decreasing oxygen demand or by increasing delivery (by increasing coronary flow) Classic/Effort/Stable Angina vs. Vasospastic/Variant/Prinzmetal Angina vs. Unstable Angina Drugs Used in the Treatment of Angina 1. Nitrates and nitrites 2. Calcium channel blockers 3. Beta-blockers Nitrates and Nitrites Prototype: Nitroglycerin Others: Isosorbide mononitrate, Isosorbide dinitrate, Pentaerythritol tetranitrate (PETN), Amyl nitrite NITROGLYCERIN Classically used in the manufacture of dynamite Low oral bioavailability; usually given sublingually to avoid first-pass effect but duration of effect is short (15-30 mins) May be administered by buccal and transdermal PETN Used orally as long acting nitrate Nitrates and Nitrites AMYL NITRITE Volatile liquids, in ampules which can be crushed by fingers enclosed in a cloth covering. Obsolete! Nitrates and Nitrites EFFECTS ON ORGAN SYSTEMS Relaxation of vascular smooth muscles (arteries and veins) Relaxation of smooth muscles in the bronchi, GIT and GUT Improvement of erectile function (sildenafil, alprostadil) Decreased platelet aggregation (NO from nitroglycerin stimulates increase in cGMP, resulting in decreased platelet aggregation) Reading assignment: Nitrites in the management of cyanide poisoning Nitrates and Nitrites TOXICITY Acute AEs: orthostatic hypotension, tachycardia, and throbbing headache NITRATES may be used safely in increased IOP (glaucoma) NITRATES are CONTRAINDICATED if ICP is elevated! Tolerance may develop (cysteine supplementation may partially reverse this) CALCIUM CHANNEL BLOCKERS CALCIUM CHANNEL BLOCKERS EFFECTS ON ORGAN SYSTEMS 1. Relaxation of vascular smooth muscles (dihydropyridines have a greater ratio of vascular smooth muscle effects relative to cardiac effects than do diltiazem and verapamil) 2. Decreased impulse generation in SA and AV node CALCIUM CHANNEL BLOCKERS TOXICITY serious cardiac depression, including bradycardia, atrioventricular block, cardiac arrest, and heart failure dihydropyridines+ACEi = increased risk for cardiac events in patients with HTN/DM Verapamil: Markedly affects SA and AV nodes BETA-BLOCKERS first-line drugs in chronic effort angina Beneficial effects due to decreased heart rate, blood pressure, and contractility, which decrease myocardial oxygen requirements decrease mortality of patients with heart failure or recent myocardial infarction and improve survival and prevent stroke in patients with hypertension AEs: increase in end-diastolic volume and an increase in ejection time, fatigue, impaired exercise tolerance, insomnia, unpleasant dreams, worsening of claudication, and erectile dysfunction CONTRAINDICATIONS: asthma and other bronchospastic conditions, severe bradycardia, atrioventricular blockade, bradycardia-tachycardia syndrome, and severe unstable left ventricular failure. BETA-BLOCKERS AEs: increase in end-diastolic volume and an increase in ejection time, fatigue, impaired exercise tolerance, insomnia, unpleasant dreams, worsening of claudication, and erectile dysfunction CONTRAINDICATIONS: asthma and other bronchospastic conditions, severe bradycardia, atrioventricular blockade, bradycardia-tachycardia syndrome, and severe unstable left ventricular failure. NEWER ANTIANGINAL DRUGS RANOLAZINE Reduces a late sodium current (INa) that facilitates calcium entry via the sodium-calcium exchange, which reduces diastolic tension, cardiac contractility, and work TRIMETAZIDINE pFOX inhibitor partially inhibits the fatty acid oxidation pathway in myocardium Shifts metabolism to oxidation of fatty acids in ischemic myocardium, which leads to the increased oxygen requirement per unit of ATP produced IVABRADINE reduce cardiac rate by inhibiting the hyperpolarization-activated sodium channel in the sinoatrial node PERIPHERAL ARTERY DISEASE & INTERMITTENT CLAUDICATION ASPIRIN/CLOPIDOGREL prevents clotting in the regions of plaque CILOSTAZOL phosphodiesterase type 3 (PDE3) inhibitor, may have selective antiplatelet and vasodilating effects shown to increase exercise tolerance in patients with severe claudication  DRUGS ACTING ON THE Drugs Used in Heart CARDIOVASCULAR SYSTEM Failure HEART FAILURE cardiac output is inadequate to provide the oxygen needed by the body may be systolic failure or diastolic failure Low-output HF vs. High-output HF manifests as tachycardia, decreased exercise tolerance, shortness of breath, and cardiomegaly, peripheral and pulmonary edema, decreased exercise tolerance with rapid muscular fatigue GOALS of TREATMENT reducing symptoms and slowing progression as much as possible during relatively stable periods Managing acute episodes of decompensated failure HEART FAILURE DIGOXIN Digitalis is the name of the genus of plants that provide most of the medically useful cardiac glycosides PROTOTYPE: DIGOXIN (from Digitalis lanata, white foxglove plant) Half-life: 36-40 hrs in normal patients MOA: inhibit Na+/K+-ATPase, the membrane-bound transporter often called the sodium pump extremely narrow therapeutic window and may not decrease mortality in chronic heart failure. DIGOXIN THEREPEUTIC EFFECTS increases contraction of the cardiac sarcomere by increasing the free calcium concentration in the vicinity of the contractile proteins during systole ADVERSE EFFECTS ECG changes: atrioventricular junctional rhythm, premature ventricular depolarizations, bigeminal rhythm, ventricular tachycardia, second-degree atrioventricular blockade DIGOXIN ADVERSE EFFECTS affect all excitable tissues, including smooth muscle and the CNS gastrointestinal tract is the most common site of digitalis toxicity outside the heart (anorexia, nausea, vomiting, and diarrhea) hyperkalemia reduces the enzyme-inhibiting actions of cardiac glycosides, whereas hypokalemia facilitates these actions Hypercalcemia increases the risk of a digitalis-induced arrhythmia BIPYRIDINES MILRINONE inhibits phosphodiesterase isozyme 3 (PDE-3) increase myocardial contractility by increasing inward calcium flux in the heart during the action potential may also alter the intracellular movements of calcium by influencing the SR BETA-AGONISTS DOBUTAMINE increases cardiac output together with a decrease in ventricular filling pressure potential for producing angina or arrhythmias in patients with coronary artery disease is significant DRUGS WITHOUT POSITIVE INOTROPIC EFFECTS USED IN HEART FAILURE Diuretics (spironolactone, eplerenone) ACEi (Captopril reduces PVR and afterload, reduce salt and water retention, reduce long-term remodeling) Vasodilators (Nesiritide) Beta blockers (reduce mortality in patients with stable severe HF, except bucindolol)  DRUGS ACTING ON THE Drugs Used in CARDIOVASCULAR SYSTEM Cardiac Arrhythmias Arrhythmias caused by abnormal pacemaker activity or abnormal impulse propagation Class Mechanism/Features Class 1 Sodium channel blockade Class 1a Prolong APD Class 1b Shorten APD Class 1c Minimal effect on APD Class 2 Sympatholytic (Beta-blockers) Class 3 Prolongs the APD; bloc the rapid component of the delayed rectifier potassium current IKr Class 4 Blockade of cardiac calcium channel current (CCBs) Class 1: Sodium channel-blocking drugs Class 1A: PROCAINAMIDE effective against most atrial and ventricular Arrhythmias but many clinicians attempt to avoid long-term therapy because of the requirement for frequent dosing and the common occurrence of lupus-related effects Slows the upstroke of the action potential, slows conduction, and prolongs the QRS, duration of the ECG; can cause hypotension AEs: excessive AP prolongation, torsade de pointes, syncope, arthralgia/arthritis resembling SLE Class 1: Sodium channel-blocking drugs Class 1A: PROCAINAMIDE effective against most atrial and ventricular Arrhythmias but many clinicians attempt to avoid long-term therapy because of the requirement for frequent dosing and the common occurrence of lupus-related effects Slows the upstroke of the action potential, slows conduction, and prolongs the QRS, duration of the ECG; can cause hypotension AEs: excessive AP prolongation, torsade de pointes, syncope, arthralgia/arthritis resembling SLE Class 1: Sodium channel-blocking drugs Class 1A: QUINIDINE Similar actions to procainamide Rarely used because of adverse effects AEs: Cinchonism (headache, dizziness, tinnitus) at toxic concentrations Class 1A: DISOPYRAMIDE Similar actions to procainamide and quinidine but with marked antimuscarinic effects Rarely used because of adverse effects AEs: urinary retention, dry mouth, blurred vision, constipation, and worsening of preexisting glaucoma. Class 1: Sodium channel-blocking drugs Class 1B: LIDOCAINE agent of choice for termination of ventricular tachycardia and prevention of ventricular fibrillation after cardioversion in the setting of acute ischemia low incidence of toxicity and a high degree of effectiveness in arrhythmias associated with acute myocardial infarction blocks activated and inactivated sodium channels with rapid kinetics READING ASSIGNMENT: Mexiletine, Flecainide, Propafenone, Moricizine Class 2: Beta-Adrenoreceptor Blocking Agents PROPRANOLOL (and other beta blockers) antiarrhythmic properties by virtue of their β-receptor-blocking action and direct membrane effects can prevent recurrent infarction and sudden death in patients recovering from acute myocardial infarction ESMOLOL Used for intraoperative and other acute arrhythmias Class 3: Drugs that Prolong Action Potentials AMIODARONE for oral and intravenous use to treat serious ventricular arrhythmias effective in the treatment of supraventricular arrhythmias such as atrial fibrillation very extensively used for a wide variety of arrhythmias causes peripheral vasodilation; may produce symptomatic bradycardia and heart block in patients with preexisting sinus or AV node disease dose-related pulmonary toxicity (fibrosis) is the most important adverse effect Other AEs: Abnormal liver function tests, gray-blue skin discoloration, visual disturbances Reading Assignment: Dronedarone, Sotalol Class 4: Calcium channel blockers Verapamil and diltiazem have antiarrhythmic effects Dihydhydropyridine CCBs do not share antiarrhythmic efficacy and may precipitate arrhythmias VERAPAMIL blocks both activated and inactivated L-type calcium channels causes peripheral vasodilation, which may be beneficial in hypertension and peripheral vasospastic disorders Used in the treatment of SVT; may reduce the ventricular rate in atrial fibrillation and flutter but only rarely converts atrial flutter and fibrillation to sinus rhythm MISCELLANEOUS ANTIARRHYTHMIC DRUGS IVABRADINE Selective blocker of If. It slows pacemaker activity by decreasing diastolic depolarization of sinus node cells. It is an open channel blocker that shows use-dependent block Unlike other heart rate-lowering agents such as β blockers, it reduces heart rate without affecting myocardial contratility, ventricular repolarization, or intracardiac conduction AE: Visual disturbances (attributable to the block of the If channels in the retina) MISCELLANEOUS ANTIARRHYTHMIC DRUGS Reading assignment: Adenosine Vernakalant Ranolazine Magnesium Potassium  DRUGS ACTING ON THE CARDIOVASCULAR SYSTEM Diuretics Diuretics 1. Carbonic anhydrase inhibitors 2. Sodium glucose cotransporter 2 (SGLT2) inhibitors 3. Loop diuretics 4. Thiazides 5. Potassium sparing diuretics 6. Aquaretics Osmotic diuretics ADH agonists ADH antagonists Carbonic anhydrase inhibitors Prototype: Acetazolamide Carbonic anhydrase is present in many nephron sites, but the predominant location of this enzyme is the epithelial cells of the PCT, where it catalyzes the dehydration of H2CO3 to CO2 at the luminal membrane and rehydration of CO2 to H2CO3 in the cytoplasm as previously described. By blocking carbonic anhydrase, inhibitors blunt NaHCO3 reabsorption and cause diuresis. Carbonic anhydrase inhibitors USES: Glaucoma (dorzolamide, brinzolamide) Urinary alkalinization Metabolic alkalosis Acute mountain sickness TOXICITY: Hyperchloremic metabolic acidosis Renal stones Renal potassium wasting LOOP DIURETICS Loop diuretics seletively inhibit NaCl reabsorption (NKCC2) in the TAL the loop diuretics reduce the reabsorption of NaCl and also diminish the lumen-positive potential that comes from K+ recycling PROTOTYPE: Furosemide, ethacrynic acid USES: Hyperkalemia Acute renal failure Anion overdose (toxic ingestions of fluoride, bromide, iodide) LOOP DIURETICS TOXICITY: Hypokalemia Hypokalemic metabolic acidosis Ototoxicity Hyperuricemia Hypomagnesemia OSMOTIC DIURETICS MANNITOL Osmotic diuretics have their major effect in the proximal tubule and the descending limb of Henle’s loop. Through osmotic effects, they also oppose the action of ADH in the collecting tubule Used to reduce intracranial pressure/intraocular pressure and to promote prompt removal of renal toxins Toxicity: Extracellular volume expansion Dehydration, hyperkalemia, hypernatremia, hyponatremia (in severe renal impairment) Acute renal failure ADH Agonists VASOPRESSIN, DESMOPRESSIN Used in the treatment of central diabetes insipidus ADH Antagonists (reading assignment) CONIVAPTAN, TOLVAPTAN Uses: SIADH Autosomal dominant polycystic kidney disease Toxicity: Nephrogenic diabetes insipidus Renal failure Dry mouth, thirst  DRUGS ACTING ON THE CARDIOVASCULAR SYSTEM Lipid-Lowering Drugs Atherosclerosis leading cause of death for both genders in the USA and other Western countries What is ASCVD? Atherosclerotic Cardiovascular Disease Inclusion Criteria for Clinical ASCVD Acute coronary syndromes History of MI Stable/unstable angina Coronary or other arterial revascularization Stroke Transient ischemic attack Peripheral arterial disease HMG-CoA Reductase Inhibitors “Statins”: Lovastatin, atorvastatin, fluvastatin, pravastatin, simvastatin, rosuvastatin, and pitavastatin Inhibit the rate-limiting enzyme of cholesterol synthesis Primarily lower LDL-C, but also lower TC, TG, and increase HDL-C induce an increase in high-affinity LDL receptors; increases both the fractional catabolic rate of LDL and the liver’s extraction of LDL precursors Because cholesterol synthesis occurs predominantly at night, reductase inhibitors—except atorvastatin, rosuvastatin, and pitavastatin—should be given in the evening Pleiotropic Effects of Statins Decreased vascular inflammation Promotes plaque stabilization and prevents plaque rupture Decreases incidence of cardiovascular events Decreases platelet aggregation Statin AEs Myalgias Elevations of ALT Increased FPG by 5-7 mg/dL → risk for new-onset diabetes Rhabdomyolysis Intensity of Statins Grundy SM, Stone NJ, Bailey AL, et al. (2018). 2018 ACC/AHA/AACVPR/AAPA/ABC/ACPM/ADA/AGS/ APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol2018;Nov 10:[Epub ahead of print].  2018 ACC/AHA Guidelines: LIPID LOWERING THEREAPY FOR PATIENTS WITH DIABETES MELLITUS Grundy SM, Stone NJ, Bailey AL, et al. (2018). 2018 ACC/AHA/AACVPR/AAPA/ABC/ACPM/ADA/AGS/ APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol2018;Nov 10:[Epub ahead of print]. Baigent C, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366(9493):1267-78; N Engl J Med. 2017; Mar 12.  2018 ACC/AHA Guidelines: PRIMARY PREVENTION of ASCVD Grundy SM, Stone NJ, Bailey AL, et al. (2018). 2018 ACC/AHA/AACVPR/AAPA/ABC/ACPM/ADA/AGS/ APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol2018;Nov 10:[Epub ahead of print].  2018 ACC/AHA Guidelines: SECONDARY PREVENTION of ASCVD Grundy SM, Stone NJ, Bailey AL, et al. (2018). 2018 ACC/AHA/AACVPR/AAPA/ABC/ACPM/ADA/AGS/ APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol2018;Nov 10:[Epub ahead of print].  2018 ACC/AHA Guidelines: SEVERE HYPERCHOLESTEROLEMIA (LDL-C 190 mg/dL and above) Grundy SM, Stone NJ, Bailey AL, et al. (2018). 2018 ACC/AHA/AACVPR/AAPA/ABC/ACPM/ADA/AGS/ APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol2018;Nov 10:[Epub ahead of print]. NCEP-ATP III Classification of Lipid Levels US National Institutes of Health, National Heart, Lung and Blood Institute  2019 European Society of Cardiology- European Atherosclerosis Society Guidelines (ESC-EAS) GOALS FOR LDL-C TREATMENT The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). 2019 ESC/EAS Guidelines for the Management of Dyslipidaemias. European Heart Journal (2019) 00, 178 FIBRIC ACID DERIVATIVES (FIBRATES) Gemfibrozil, Fenofibrate, Bezafibrate MOA: function as ligands for the nuclear transcription receptor PPAR-α. They transcriptionally upregulate LPL, apo A-I, and apo A-II, and they downregulate apo C-III, an inhibitor of lipolysis useful drugs in hypertriglyceridemias in which VLDL predominate and in dysbetalipoproteinemia increase lipolysis of lipoprotein triglyceride via LPL -- reduced triglycerides VLDL decrease, in part as a result of decreased secretion by the liver Also reduce LDL-C in modest levels AE: rashes, gastrointestinal symptoms, myopathy, arrhythmias, hypokalemia, and high blood levels of aminotransferases or alkaline phosphatase, rhabdomyolysis (rare), increase in the risk of cholesterol gallstone NIACIN (Nicotinic Acid/Vit B3) decreases triglycerides and LDL levels, and Lp(a) in most patients, increases HDL-C significantly inhibits VLDL secretion, in turn decreasing production of LDL AE: cutaneous vasodilation and sensation of warmth (may take Aspirin or Naproxen 30 mins before taking niacin to blunt this effect) BILE ACID-BINDING RESINS COLESTIPOL, CHOLESTYRAMINE, COLESEVALAM bind bile acids in the intestinal lumen and prevent their reabsorption resulting in enhanced conversion of cholesterol to bile acids in liver via 7α- hydroxylation used in treatment of patients with primary hypercholesterolemia, producing approximately 20% reduction in LDL cholesterol in maximal dosage AE: constipation, bloating, steatorrhea, Vit K malabsorption EZETIMIBE inhibits intestinal absorption of phytosterols and cholesterol by targeting NPC1L1 verage reduction in LDL cholesterol with ezetimibe alone in patients with primary hypercholesterolemia is about 18%, with minimal increases in HDL cholesterol PCSK-9 Inhibitors EVOLUCUMAB, ALIROCUMAB Development of inhibitors of proprotein convertase subtilisin/ kexin type 9 (PCSK9) followed on the observation that loss of function mutations result in very low levels of LDL and no apparent morbidity LDL reductions of up to 70% at the highest doses have been achieved with these agents when administered subcutaneously every two weeks Use of these agents is restricted to patients who have familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease who require additional reduction of LDL Omega-3 Fatty Acids (Fish oil) Animal and human studies have identified the long-chain n-3 polyunsaturated fatty acids (n-3 PUFA), eicosapentaenoic acid (EPA, 20:5n-3), and docosahexaenoic acid (DHA, 22:6n-3) as major active constituents in fish/seafood and fish oil Fish oil preparations are available by prescription or as nutritional supplements and are generally derived from small pelagic fish used for fish feed or from formulations produced by algae. Prescription preparations vary in composition and dose The US Food and Drug Administration (FDA) has determined that cardiovascular risk reduction in selected patients with mild hypertriglyceridemia is an off-label indication for prescription preparations of n-3 PUFA. AE: nausea, fishy taste on burping Thank you!