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Dr. Sanjib Das VI. Cardiac Glycosides and Congestive Heart Failure A. Learning objectives What are the causes and major hemodynamic effects of congestive heart failure? How does congestive heart failure alter activity of the sympathetic nervous and renin-angiotensin systems? How are the 4 main factors affecting cardiac performance altered during congestive heart failure? 1. Digoxin Know for digoxin: (a) absorption, (b) distribution, (c) metabolism, and (d) excretion? What is the basic mechanism of action (or sequence of events) responsible for their positive inotropic effects? What are their major effects on the heart (i.e., on contractility, conduction, membrane potentials, tissue electrolytes, vagal tone, and ECG)? Digoxin----contd Why does its effect on (a) stroke volume, (b) heart rate, (c) cardiac output, and (d) vascular tone differ in normal versus failing hearts? What are their vascular, renal, gastrointestinal, and CNS effects? Mechanisms by which quinidine may affect responsiveness to digitalis. Mechanism of beneficial effects of digoxin in treatment of atrial fibrillation. Toxic effects and treatment of digoxin overdose. 2. Other positive inotropic drugs How does Inamrinone or milrinone increase myocardial contractility? What advantages do the bipyridines have over digoxin in the treatment of congestive heart failure? What advantages do the selective ß1-adrenergic agonists have over digoxin in the treatment of congestive heart failure? Rationale for using angiotensin converting enzyme inhibitors in the treatment of congestive heart failure. Incidence of Congestive Heart Failure (CHF) CHF results when the heart can no longer supply oxygenated blood adequately to peripheral tissues during stress or even at rest The heart is unable to pump blood at a rate sufficient to satisfy the needs of the metabolizing tissues Incidence of Congestive Heart Failure (CHF) CHF is primarily a disease of aging: 75% of existing and new cases occur in individuals over 65 years. CHF prevalence increases with age: • From < 1% at 50-59 years • Doubling with every decade • To reach almost 10% by age 80-89 Among survivors, quality of life is adversely affected by: • Progressive fatigue, • Shortness of breath • Functional disability Poor long-term prognosis even with appropriate treatment • 5-year survival of 38% in men and 57% in women • 30-50% of CHF patients with severe symptoms die within one year Mortality can be reduced by drug treatment Two main types of CHF Type of CHF “High-output" “Low-output" Main causes Hyperthyroidism anemia arteriovenous shunts thiamine deficiency (beriberi) Coronary artery disease hypertension myocardial infarction persistent arrhythmias rheumatic heart disease general cardiomyopathy Heart work conditions Healthy heart exhausted by working too hard Heart unable to pump enough blood to meet tissue needs Cardiac output High as the heart works hard to keep up with greatly increased body demands Low because the heart is unable to keep up with the tissue metabolic demands Inotropic drug response Poor or none Good, usually improves NBME Pathogenesis of Low output CHF A typical case The Problem 70 years old man 2 months Hx of : Progressive dyspnea on exertion Past 2 weeks he observed: PND + 3 pillow orthopnea Swollen feet > a week Swelling of his abdomen known case of hypertension for 10 years> not compliant O/E: Breathlessness at rest JVP raised 12 cm Pulse=110/min BP= 190/110 mmHg Apex beat at 6th left intercostal space 2 cm outside the mid-clavicular line. Heart sounds= 1st, 2nd, 3rd Crepitations in both lung bases Tender Palpable liver 4 cm below costal margin Peripheral oedema & minimal ascites CXR: large heart, opacities in both lung bases Hemodynamic Characteristics of CHF [A] Subnormal cardiac output causing decreased exercise tolerance with rapid muscular fatigue, tachycardia, pulmonary edema, and cardiomegaly [B] Myocardial hypertrophy to maintain cardiac performance increased myocardial muscle mass and muscle wall thickness [C] Neurohumoral reflex compensation arises from increased activity of sympathetic nerves, and renin-angiotensin-aldosterone system Chronic Congestive Heart Failure EVOLUTION OF CLINICAL STAGES NORMAL Asymptomatic LV Dysfunction No symptoms Compensated Normal exercise CHF Abnormal LV fxn No symptoms Decompensated Exercise CHF Abnormal LV fxn Symptoms Refractory Exercise CHF Abnormal LV fxn No symptoms Normal exercise Normal LV fxn Symptoms not controlled with treatment Vicious Spiral of Progression of Heart Failure Decreased cardiac output (CO) activates production of neurohormones (NE, norepinephrine; AII, angiotensin II; ET, endothelin), which cause vasoconstriction and increased afterload. This further reduces ejection fraction (EF) and CO, and the cycle repeats. The downward spiral is continued until a new steady state is reached in which CO is lower and afterload is higher than is optimal for normal activity. Circled points 1, 2, and B represent points on the ventricular function curves depicted On next slide. Relation of Left Ventricular (LV) Performance to Filling Pressure PATHOPHYSIOLOGY OF CARDIAC PERFORMANCE DETERMINANTS OF VENTRICULAR FUNCTION CONTRACTILITY PRELOAD AFTERLOAD STROKE VOLUME - Synergistic LV contraction - LV wall integrity - Valvular competence CARDIAC OUTPUT HEART RATE Main determinants of cardiac workload I. Preload: forces acting on venous side to affect myocardial contractility -As venous return increases More blood enters the heart Intraventricular pressure rises Ventricular muscle stretched Force of contraction increases -In CHF preload is elevated by: increases in blood volume and venous tone Treatment with venodilator drugs reduces preload by dilating peripheral veins to retain more blood and keep blood away from the heart Treatment with diuretics reduces preload by decreasing blood volume Salt restriction II. Afterload: arterial resistance against which the heart pumps blood is determined by aortic impedance and vascular resistance -In CHF afterload rises because of increases in sympathetic and renin-angiotensin activity which elevate peripheral resistance via arterial constriction -Treatment with arteriodilator drugs reduces afterload by decreasing peripheral resistance Main determinants of cardiac workload III. Myocardial contractility: inherent ability of cardiac muscles to shorten and develop force for pumping; contractility is reduced when myocardial muscle fibers do not function properly or become fewer as in myocardial infarction In CHF contractility is reduced because myocardial muscle fibers are stretched beyond their elastic limits as ventricles become dilated Contractility is increased by inotropic drugs but reduced by badrenergic blockers IV. Heart rate: determines cardiac output (i.e., CO = HR X SV) In CHF reflex tachycardia results from sympathetic overactivity due to baroreflex activation brought about by the reduction in cardiac output b-adrenergic blocking drugs reduce cardiac work by slowing the heart rate Goals of drug treatment during CHF CHF Effects GOAL OF THERAPY Increased preload due to: increased blood volume increased venous tone Reduce preload (unloading) Increased afterload due to: increased aortic impedance increased arterial constriction Reduce afterload (unloading) Arteriodilator Decreased contractility due Increase Inotropic drug to ventricular dilation contractility Reflex tachycardia Reduce energy expenditure NBME Drugs Used Diuretic Venodilator ß-adrenergic antagonist A C E/ A R B B. Drugs to be considered Inotropes – digoxin (1), inamrinone (2), dobutamine (3) ,dopamine (4) Diuretics – hydrochlorothiazide , furosemide (5) , amiloride, spironolactone ACE inhibitors – captopril (6) & other drugs with common ending with ‘pril’ AII receptor blockers – losartan (7) & other with common ending with ‘sartan’. Sympatholytics – propranolol, carvedilol (8),metoprolol (9) Vasodilators – glyceryl trinitrate (10), hydralazine (11), sodium nitroprusside (12) “Cornerstones” of CHF Drug Therapy ACE inhibitors and other vasodilators to reduce cardiac workload I. II. Diuretics to reduce preload by correcting salt and water retention Loop diuretics preferred because of their potency III. Digoxin to improve cardiac pumping and output Because of potential digoxin toxicity, a reasonable therapeutic approach is to start treatment using an ACE inhibitor alone and if the response is inadequate then add a loop diuretic and finally digoxin if needed. ACE Inhibitors in CHF ACE inhibitors will counteract the increased renin-angiotensin system (RAS) activity that occurs during CHF Factors that increase RAS activity in CHF include: (A) Reduced renal perfusion activating renal baroreceptors NBME (B) Increased sympathetic activity stimulating ß1-adrenergic receptors on the JG apparatus (C) Antihypertensive drugs that stimulate renin secretion: Diuretics by decreasing delivery of Na+ to the macula densa Vasodilators by reducing renal perfusion pressure Drugs that specifically counteract the increased RAS activity are ACE inhibitors and angiotensin II antagonists which diminish cardiac workload by: • Decreasing afterload - reduce angiotensin-vasoconstriction • Decreasing preload - reduce aldosterone release and fluid volume Effective ACE inhibitors include: captopril, enalapril, lisinopril, ramipril, and quinapril Chronic ACE inhibitor therapy can reduce CHF mortality by 28-40% Angiotensin (AT1) antagonists act through the same mechanisms and may also prove as effective for CHF treatment Angiotensin Receptor Antagonists Candesartan, eprosartan, irvesartan, losartan, olmisartan, telmisartan, or valsartan Two types of angiotensin II receptors are: AT1 and AT2 • AT1 receptors predominate in vascular smooth muscle and cause most of the known actions of angiotensin II • All currently available AT II antagonists act by selectively blocking AT1 without affecting AT2 receptors NBME Two important differences from ACE inhibitors: [1] More specific than ACE inhibitors because AT II antagonists do not affect bradykinin metabolism they do not cause coughing or angioneurotic edema), and [2] More complete inhibition of angiotensin action because enzymes other than ACE than can generate angiotensin II (i.e., ACE inhibitors will only reduce angiotensin II formation by ACE while AT II antagonists will block all angiotensin effects regardless of how angiotensin is formed, not only through ACE but also through other enzymes) Except for the absence of coughing or angioneurotic edema, adverse effects are like those produced by ACE inhibition including: hyperkalemia and reduced renal function NBME Other Vasodilators for CHF Sodium nitroprusside is infused intravenously in acute decompensated CHF as long as cerebral and renal perfusion can be maintained despite the reduction in systemic BP It is a balanced vasodilator that dilates both veins and arteries to reduce both preload and afterload The most common adverse effect is excessive hypotension Organic nitrates like nitroglycerin or isosorbide dinitrate given orally dilate veins more than arteries thus lowering preload more than afterload; however, tolerance precludes their long-term use Calcium-channel antagonists (CCA) like nifedipine block slow calcium channels to reduce intracellular calcium, relax arteriolar smooth muscles, and produce vasodilation • • • By contrast, verapamil and diltiazem inhibit cardiac contraction, SA node impulse generation, and AV node conduction Verapamil and diltiazem should not be used for treatment of CHF because their cardiac effects may worsen CHF symptoms and increase mortality Dihydropyridines markedly enhance periperal edema which worsens CHF Amlodipine not as bad as others, but still should be stopped as CHF progresses ß-adrenergic antagonists for CHF b-adrenergic blockers produce a negative inotropic effect which could worsen ventricular function and be potentially harmful in CHF NBME • Despite this, many clinical studies show that long-term treatment with b-adrenergic blockers improves symptoms of CHF by slowing heart rate and contraction velocity to improve: Cardiac output Exercise tolerance Ventricular function • Exact mechanisms to explain the beneficial effects of b-adrenergic blockade remain uncertain but may include: Decreased heart rate and cardiac work Attenuation of responses to high catecholamine concentrations Up-regulation of b-adrenergic receptors Reduced myocardial remodeling • Those shown to be effective include: Bisoprolol Metoprolol Carvedilol DIURETICS in CHF Diuretics act to reduce extracellular fluid volume and thereby reduce preload Chronic diuretic treatment is used only for CHF patients with advanced disease and symptoms First-choice drugs are loop diuretics furosemide, NBME bumetanide, and torsemide; reserve ethacrynic acid only for patients allergic to sulfonamides Thiazides are weaker diuretics used only for mild CHF Concurrent treatment with any vasodilator may reduce renal blood flow and thus inhibit diuretic efficacy INOTROPIC DRUGS: Digoxin Originally obtained from digitalis (foxglove) plants or toad skin (protective venom) Previous uses included: • Diuretic and rat poison by ancient Romans • Arrow poison by some African tribes • Draft evaders during WW II to simulate heart disease Are therefore potentially toxic so beware of digitalis toxicity! Until the late 90’s digitalis was among most commonly prescribed drugs in the US and given to 17-27% of all hospital admissions Digoxin, the only glycoside now used in th US, is used mainly for treatment of CHF and of atrial fibrillation INOTROPIC DRUGS: Digoxin Chemical structure of digoxin has two parts: • Aglycone or genin is responsible for all biological activity • 3 molecules of sugar (digitoxose) influence pharmacokinetics including absorption, half-life, and metabolism Two other digitalis glycosides that are still referred to are: • Digitoxin - no longer available in the US • Ouabain - used experimentally DIGOXIN: Cardiac Effects Most important cardiac effects are mechanical and electrophysiological Mechanical effects are on: • Myocardial contractility (stroke volume) is always increased in both normal and failing hearts; also known as positive inotropy which is most important for treatment of CHF • Mechanism of inotropic action begins with: Inhibition of Na+/K+ATPase (aka: digitalis receptor) Intracellular increase in Na+ and decrease in K+ Decreased expulsion of intracellular Ca2+ Increased intracellular Ca2+ Increased actin-myosin interaction by intracellular Ca2+ Increased force of myocardial contraction DIGOXIN Inotropic Effect 1) Digoxin inhibits Na+/K+ATPase to decrease extrusion of Na+ and increase it intracellularly 2) Increased intracellular Na+ inhibits the Na+/Ca2+ exchanger to decrease extrusion of Ca2+ and increase it intracellularly 3) Trigger Ca2+ taken SR followed by large Ca2+ release 4) More Ca2+ is released via the ryanodine receptor (RyR) and available to increase contraction DIGOXIN: Cardiac Effects Because potassium and digoxin inhibit each others binding to Na+/K+ATPase receptor, potassium counteracts digoxin toxicity and reduces abnormal cardiac automaticity By contrast, calcium increases digoxin toxicity Digoxin toxicity should therefore be treated with potassium but never, never with calcium Heart rate is decreased • In failing hearts bradycardia is due to decreased sympathetic tone • In untreated CHF sympathetic activity is already high but upon treatment with digoxin, contractility and cardiac output will be increased thus removing the stimulus for the increased sympathetic tone Cardiac output increased by digoxin in CHF because of the increased contractility • Increased cardiac output will remove the stimulus for sympathetic overactivity so that the ensuing reduction in sympathetic tone will cause: Venodilation = reduced preload Arteriodilation = reduced afterload Hence, cardiac output improves not only because of direct cardiac stimulation but also because of venous and arterial dilation due to decreased sympathetic tone DIGOXIN: Cardiac Effects NBME Electrical effects result from two actions that are dose-dependent: • Direct action on myocardial cells (↓ of Na+/K+ATPase → Na+/Ca+ entrapment inside cell→ Tachyarrhythmogenic activity • Indirect action by parasympathetic stimulation (due to ↓ of Na+/K+ATPase of Neuronal cells→nodal tissue depolarization→ ↓ SA & AV nodal activity→ Bradyarrhythmic activity) • Indirect action of sympathetic stimulation (due to ↓ of Na+/K+ATPase of Neuronal cells→only ventricular tissue depolarization→ Tachyarrhythmogenic activity) Therapeutic doses decrease automaticity, prolong refractory period, and slow AV node conduction In failing hearts digoxin produces bradycardia by decreasing sympathetic tone • By increasing contractility, digoxin will increase cardiac output and thereby remove the stimulus for the elevated sympathetic tone in CHF Toxic doses can cause arrhythmias by increasing sympathetic activity and automaticity to form ectopic foci • Slowed conduction may cause sinus bradycardia or heart block • May produce almost every variety of arrhythmia Based on the reduction in conduction velocity in the AV node digoxin is used for pretreatment in atrial fibrillation before antiarrhythmic drugs are used • Antiarrhythmic drugs when given alone may cause paradoxical ventricular tachycardia which can be prevented by pretreatment digoxin which will slow the ventricular rate DIGOXIN: electrophysiological & ECG effects Site of action Electrophysiologic effect NBME ECG change A-V node Prolonged Refractory Period slowed conduction Prolonged P-R interval Ventricle Accelerated repolarization Shortened Q-T interval Ventricle Changes in phase 2 or 3, Depressed S-T segment or in direction of or inverted T wave repolarization DIGOXIN: other effects Two opposing vascular effects depending on myocardial status: Normal hearts - contract smooth muscle vasoconstriction Failing hearts - increase cardiac output remove the stimulus for sympathetic hyperactivity reduced sympathetic activity vasodilation Kidneys are affected only slightly, if at all; diuresis results from hemodynamic improvement caused by increased cardiac contractility increased cardiac output improved renal perfusion • Increased GFR is due to cardiac, rather than renal, actions • Digoxin causes diuresis only in edematous patients with CHF • No diuresis in normal subjects or other types of edema Gastrointestinal effects include: • Anorexia and diarrhea due to direct gastrointestinal irritation • Vomiting due to stimulation of the chemoreceptor trigger zone • Abdominal pain due to mesenteric arteriolar constriction DIGOXIN: common adverse effects NBME Narrow margin of safety and toxicity is common because the therapeutic dose is 5060% of the toxic dose and adverse effects often occur even with therapeutic doses; toxicity leads to discontinuing digoxin in 5-25% of patients Earliest signs of intoxication are gastrointestinal (↓ of Na+/K+ATPase ) • • • • Anorexia, nausea, vomiting, diarrhea, abdominal discomfort Copious salivation often accompanies the nausea Vomiting can be harmful as it requires great physical effort GI symptoms disappear a few days after discontinuing digoxin Most dangerous adverse effects are cardiac; can simulate almost all arrhythmias including sinus bradycardia, ectopic ventricular beats, AV block, and bigeminy • Cardiac toxicity may be lethal and necessitate stopping therapy • Most common cause of death is ventricular fibrillation • Always monitor adverse cardiac effects by routine measurements of ECG, and serum digoxin and potassium CNS adverse effects (↓ of Na+/K+ATPase) include headache, fatigue, malaise, drowsiness, trigeminal neuralgia, and mental symptoms • Disorientation and hallucinations often in the elderly • Color and visual disturbances occur occasionally Skin rashes, eosinophilia, and gynecomastia rarely Treatment of intoxication should include: discontinue digoxin administration; oral or intravenous potassium; lidocaine or phenytoin; and digoxin antibodies (digoxin immune fab) DIGOXIN: drug interactions Many drugs can influence digoxin toxicity and this is important because treatment of CHF often requires concurrent administration of digoxin with diuretics, quinidine, and other antiarrhythmic or cardiovascular drugs Pharmacokinetic interactions either: Digoxin toxicity enhance by: Decreasing digoxin renal clearance or volume of distribution as with quinidine, amiodarone, captopril, verapamil, diltiazem, cyclosporine Increasing digoxin GI absorption by erythromycin, omeprazole, etc Digoxin toxicity reduced by: Increasing digoxin renal clearance by thyroxine Decreasing digoxin GI absorption by cholestyramine, bran, etc DIGOXIN: drug interactions Many drugs can influence digoxin toxicity and this is important because treatment of CHF often requires concurrent administration of digoxin with diuretics, quinidine, and other antiarrhythmic or cardiovascular drugs Pharmacodynamic interactions that enhance toxicity include: • Kaliuretic diuretics which produce hypokalemia as when digoxin is used together with thiazide or loop diuretics for treatment of CHF • b-adrenergic antagonists which inhibit SA or AV node activity • Calcium-channel antagonists which inhibit contractility • Catecholamines may sensitize the myocardium to digoxin NBME Hypothyroidism also predisposes to intoxication by reducing renal clearance to elevate serum digoxin levels Elderly patients are more susceptible to digoxin intoxication as their serum digoxin levels are elevated by hypochlorhydria or reduced renal clearance; infants usually require larger doses OTHER INOTROPES: PDE Inhibitors Phosphodiesterases (PDE) inactivate cAMP and cGMP, and unspecific PDE inhibitors like theophylline and aminophylline were once used as heart stimulants In the 80’s, specific PDE inhibitors which had inotropic and smooth muscle relaxing properties were discovered and widely tested but results have been equivocal Inamrinone (aka amrinone) and milrinone are given by injection but vesnarinone, is orally active All 3 inhibit type III phosphodiesterase which is present in cardiac and smooth muscles; they do not affect Na+/K+ATPase or adrenergic receptors They increase myocardial contractility by increasing cAMP and inward calcium flux in the heart • Also relax vascular smooth muscles to cause vasodilation Inamrinone and milrinone in long-term trials often produced intolerable adverse effects (arrhythmias, liver and bone marrow toxicity), had minimal long-term efficacy, and increased mortality in CHF patients Used only for short-term treatment in advanced heart failure OTHER INOTROPES: ß-Adrenergic & Dopaminergic Agonists Dopamine and ß1-adrenergic agonists like dobutamine (Dobutrex) are infused IV to increase myocardial contractility in acute CHF ß2-adrenergic agonists like albuterol or pirbuterol relax vascular smooth muscles and have been tested as vasodilators in CHF Most of these drugs are ineffective orally and are currently used only for acute failure or failure refractory to oral drugs Extra Credit Quiz Section A typical case The Problem 70 years old man 2 months Hx of : Progressive dyspnea on exertion Past 2 weeks he observed: PND + 3 pillow orthopnea Swollen feet > a week Swelling of his abdomen known case of hypertension for 10 years> not compliant O/E: Breathlessness at rest JVP raised 12 cm Pulse=110/min BP= 190/110 mmHg Apex beat at 6th left intercostal space 2 cm outside the mid-clavicular line. Heart sounds= 1st, 2nd, 3rd Crepitations in both lung bases Tender Palpable liver 4 cm below costal margin Peripheral oedema & minimal ascites CXR: large heart, opacities in both lung bases Treatment Objectives To relieve symptoms and improve quality of life To improve cardiac output To treat the precipitating cause To treat complications Non Pharmacological T/t • • • • • • Reduce salt intake Reduce weight in overweight and obese individuals Avoid alcohol Avoid smoking Encourage moderate exercise Bed rest in hospitalised patients Pharmacological T/t Initial therapy of mild heart failure (NYHA CLASS I-II) • Furosemide (frusemide), oral, Adults 40-80 mg daily Children 1-2 mg/kg daily • Lisinopril, oral, (only when blood pressure > 100/60 mmHg) Adults 2.5-20 mg daily • Or • Carvedilol, oral, Adults 3.125-12.5 mg 12 hourly (maximum 25 mg 12 hourly) • Or Pharmacological T/t • Bisoprolol, oral, Adults 1.25-10 mg daily • Initial therapy of moderate heart failure (NYHA CLASS III) • Furosemide (frusemide), oral, Adults 80-120 mg daily Children 2-4 mg/kg daily • · Lisinopril, oral, Adults 2.5-20 mg daily • Or Pharmacological T/t • Losartan, oral, Adults 25-50 mg daily • Spironolactone, oral, Adults 25-50 mg daily • In patients with fast atrial fibrillation • Digoxin, oral, Adults 250 micrograms 12 hourly for 24-48 hours, Then 250 micrograms once daily Elderly 125 micrograms 12 hourly for 24-48 hours, Then Pharmacological T/t Then 125 micrograms once daily Children 5 micrograms/kg 12 hourly Initial therapy of severe heart failure (NYHA CLASS IV) • Admit patient • Prop patient up in bed • Oxygen, by nasal cannula or face mask • Insert an intravenous cannula • Furosemide (Frusemide), IV, 40-80 mg, repeat after 30 minutes if necessary; Thereafter Pharmacological T/t • Furosemide (Frusemide), IV, 40-80 mg 12 hourly; • If patient improves, change to • Frusemide, oral, 40-80 mg, 12 hourly after 24- 48 hours of IV treatment • If patient does not improve, continue • Furosemide (Frusemide), IV, 40-80 mg, 12 hourly and give in addition • Morphine, IV, 5-10 mg slowly And • Metoclopramide, IV, • 10 mg to prevent vomiting Pharmacological T/t • • • • • • • • • • • If there is fast atrial fibrillation, Digoxin, oral, 250 micrograms 12 hourly for 24-48 hours, Then 250 micrograms once daily If there is cardiogenic shock, Dobutamine, IV, 2.5-10 micrograms/kg/minute Monitor urine output Encourage early ambulation Consider anticoagulation prophylaxis against venous thrombosis, Enoxaparin, subcutaneously, 40 mg daily Identify and treat (if possible) precipitating causes such as hypertension, myocardial infarction, anaemia or thyrotoxicosis Medicament Dr._______ Correspondence details Licence details Date Name of the patient Age,Sex,Occupation Correspondence details Rx ------------------------------------------------------------------------------------------------------------------Nonpharmacotherapeutical Intervention 1. 2. 3. Pharmacotherapeutical Intervention (S.No) (Dosage form).(Trade/Generic drug name)(dose) (Frequency) (Duration) (special instruction if any) 1. 2. 3. ---------------------------------------------------------------------------------------------------------Instruction to Pharmacist ---------------------------------------------------------------------------------------------------------Signature Now answer the following Qs.before you start practicing MCQs 1. Digoxin What is the basic mechanism of action (or sequence of events) responsible for their positive inotropic effects? What are their major effects on the heart (i.e., on contractility, conduction, membrane potentials, tissue electrolytes, vagal tone, and ECG)? Why does its effect on (a) stroke volume, (b) heart rate, (c) cardiac output, and (d) vascular tone differ in normal versus failing hearts? What are their vascular, renal, gastrointestinal, and CNS effects? Mechanisms by which quinidine may affect responsiveness to digitalis. Mechanism of beneficial effects of digoxin in treatment of atrial fibrillation. Toxic effects and treatment of digoxin overdose. 2. Other positive inotropic drugs How does Inamrinone or milrinone increase myocardial contractility? What advantages do the bipyridines have over digoxin in the treatment of congestive heart failure? What advantages do the selective ß1-adrenergic agonists have over digoxin in the treatment of congestive heart failure? Rationale for using angiotensin converting enzyme inhibitors in the treatment of congestive heart failure. In a 65-year-old man who has severe congestive heart failure with pulmonary edema, treatment with diuretics or venodilators would be beneficial because of which of following mechanisms? A) Decreased myocardial contractility B) Increased myocardial contractility C) Reflex tachycardia D) Reduced afterload ANS = E Diuretics and E) Reduced preload venodilators decrease preload In a 55-year-old man receiving digoxin for treatment of congestive heart failure, which of the following would be the earliest sign of digoxin intoxication? A) Visual disturbances B) Bigeminy C) Sinus bradycardia D) Trigeminal neuralgia E) Anorexia ANS = E GI toxicity occurs the earliest; Cardiac toxicity is most life-threatening Paradoxical benefit of beta blockers Drugs to be considered for heart failure Digitalis Bipyridines Diuretics β-adrenergic agonists Digoxin Inamrinone Milrinone Thiazide, Loop, and Potassiumsparing Dobutamine Dopamine (D1) Na/K ATPase I PDEI Digoxin Force CO HR PR Normal CHF Vasodilators and ACE inhibitors Adverse effects GI CNS Visual Cardiac A 65-year-old man with hypertension, managed for several years with medications, has recently gained about 25 pounds and complains of swollen feet and shortness of breath. Clinical findings include blood pressure of 170/100 mm Hg, pulse 100 bpm, ankle edema, dyspnea and cyanosis. Current medications, including hydrochlorothiazide, atenolol, and naproxen were discontinued. Which of the following combination of medications would be most appropriate for treating the current status of this patient? A. B. C. D. E. Digoxin + quinidine Digoxin + butoxamine Enalapril + furosemide Minoxidil + reserpine Prazosin + diltiazem Answer: C Never give calcium channel blockers in CHF Which of the following drugs may prolong life in a 65-year-old man with congestive heart failure in spite of its negative inotropic effect on cardiac contractility? A. B. C. D. E. Bumetanide Digoxin Dobutamine Enalapril Metoprolol Answer: E Beta blockers pose some risk in CHF because of negative inotropic effect >>> but overall have positive outcomes.