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CARDIAC GLYCOSIDES & OTHER DRUGS USED IN HEART FAILURE Refresh Your Memory! Cardiac Output (CO): The volume of blood pumped by each ventricle each minute Cardiac Output= heart rate X stroke volume Stroke Volume (SV): The volume of blood pumped out of each ventricle with each contraction or beat of the heart. Stroke volume = end-diastolic volume – end-systolic volume End-diastolic volume (EDV): the volume of blood in the ventricle at the end of diastole when filling is complete End-systolic volume (ESV): the volume of blood in the ventricle at the end of systole when emptying is complete Ejection Fraction (EF): Stroke Volume End-diastolic volume Definition of HF (HEART FAILURE) HF occurs when CO is inadequate to provide the oxygen needed by the body 5-year mortality rate ~50% The most common cause of HF in the USA is CAD In systolic failure, the mechanical pumping action (contractility) & the ejection fraction of the heart ↓ In diastolic failure, stiffening & loss of adequate relaxation plays a major role in ↓ CO & ejection fraction may be normal. Therapies used in HF Control of Normal Cardiac Contractility The vigor of contraction of the heart muscle is determined by several processes that lead to the movement of actin and myosin filaments in the cardiac sarcomere The contrcation of the heart (during systole) results from: Ca+2 interacts with actin-tropnintropomyosin system Actin-myosin interaction (Activator) From the Sarcoplasmic Reticulum (SR) + trigger calcium that enters the cell during the plateau of AP Contraction Control of Normal Cardiac Contractility Sites for drug action ß-agonists cause ↑ in “trigger” Ca influx through an action on L-type Ca channels. Conversely, CCBs ↓ this influx & ↓ contractility. Na-Ca exchanger uses Na gradient to move Ca against its concentration gradient from the cytoplasm to the extracellular space. Na+/K+ ATPase, by removing intracellular Na, is the major determinant of Na concentration in the cell. The Na influx through voltage-gated channels, which occurs as a normal part of almost all cardiac APs, is another determinant. Na+/K+ ATPase appears to be the primary target of cardiac glycosides Pathophysiology of Cardiac Performance 1. 2. 3. 4. Cardiac performance is a function of four primary factors: Preload Afterload Contractility of the heart Heart Rate Preload Preload: determines the ventricular enddiastolic pressure and volume = “atrial pressure” In normal hearts Preload Increase end-diastolic fibre length Increase Force of contraction In HF this response is reduced or even reversed Preload LV function curve (any measure of LV performance (e.g. SV, SW) + LV filing pressure. Preload In HF, preload increases because of: - increased blood volume and - increased venous tone if preload > 20-25 mmHg pulmonary congestion Treatments that reduces preload: 1. Salt restriction & diuretics >>> to reduce the high filling pressure 2. Vasodilators (e.g. nitroglycerine) >>> redistributing the blood away from the chest into peripheral veins Afterload The resistance against which the heart must pump blood; Represented by: aortic impedance and SVR E.g: increased arterial pressure and obstruction to outflow (e.g. aortic stenosis) In HF, SVR will increase, because: 1. Circulating cathcolamines 2. + RAS (angiotensin II is a vasoconstrictor) Treatments: drugs that will reduce arteriolar tone Contractility of the heart Determined largely by the intrinsic strength and integrity of muscle cells Force of heart contraction is decreased by: 1. ischemic heart disease (MI, chronic severe ischemia) 2. specific disorders affecting the heart muscle such as HTN and myocarditis 3. disorders of heart muscle of unknown cause (e.g. idiopathic) Heart Rate is a major determinant of CO. in HF, compensatory sympathetic activation of β-adrenoceptors comes into play to maintain CO Pathophysiology of HF may involve the right ventricle, the left ventricle or both, but the majority of patients with HF have symptoms due to an impairment of left ventricular function. may range from the predominantly diastolic dysfunction of a normal-sized chamber with normal emptying but impaired filling to the predominantly systolic dysfunction (EF<45%) of a markedly dilated chamber with reduced wall motion but preserved filling. Pathophysiology of HF Ventricular Dysfunction Diastolic “inadequate relaxation to permit normal filling” CO Systolic “ inadequate force generation to eject blood normally” CO EF normal Often due to hypertrophy or stiffening of the myocardium EF (< 45%) Typical for Acute failure, e.g. MI Doesn’t respond optimally to +ve inotropic agents Rarely, “high output” HF occurs Pathophysiology of HF 1. 2. 3. 4. biventricular dysfunction LV failure usually occurs first Isolated right-sided failure is usually associated with stenosis or spasm of the pulmonary artery, for example: Idiopathic or secondary pulmonary arterial HTN Collagen vascular disorders, sarcoidosis, fibrosis Drug-induced pulomonary HTN (heroin, methylphenidate, fenfluramine, dexfenfluramine) COPD Signs & symptoms (S&Ss) Weakness, Fatigue, Confusion decreased exercise tolerance (DOE) shortness of breath (SOB) Paroxysmal Nocturnal Dyspnea (PND) Cough Orthopnea (2-3 pillows) Reflex tachycardia peripheral and pulmonary edema cardiomegaly Compensatory Mechanisms (1) Sympathetic outflow , parasympathetic outflow This will cause: tachycardia, contractility, vasoconstriction Initially beneficial: force, preload and HR CO Later: Arteriolar tone will afterload, CO, EF, and renal perfusion Compensatory Mechanisms (2) Angiotensin II production Vasoconstriction May cause direct damage to cardiac myocytes ( fibrosis and vascular and myocardial hypertrophy + Aldosterone Myocardial fibrosis K+, Mg+ loss Cardiac Arrhythmia Na+ and water retention 1. afterload 2. (remodelling (of heart and vessels) Compensatory Mechanisms (3) Myocardial Hypertrophy <<The most important intrinsic compensatory mechanism>> - The increase in muscle mass helps to maintain cardiac performance in the face of adverse effects such as pressure or volume overload, loss of functional tissue (e.g. MI) or decrease in the contractility. However, after initial beneficial effect: - ischemic changes - impairment of diastolic filling - alteration of ventricular geometry Compensatory Mechanisms Basic Pharmacology of Drugs Used in Heart Failure Cardiac Glycosides Digitalis purpurea = “foxglove plant” Digitalis Lanata “white foxglove” Digoxin is the prototype influence Pharmacokinetics essential for activity Cardiac Glycosides Solubility is not pH dependent (WHY?) Because they lack an easily ionisable group Pharmacokinetics: Digoxin: well absorped P.O. Because of narrow therapeutic index, even minor variations in bioavaliability can cause toxicity or loss of effect T1/2= 36-40 hrs Enterohepatic cycling contributes for long t1/2 of digitoxin Cardiac Glycosides Pharmacodynamics: Mechanical Effects Electrical Effects At molecular level, all cardiac glycosides inhibit Na+/K+ ATPase; “sodium pump” Different isoforms in different tissues; & subunits Different affinities of cardiac glycosides ↑free Ca+2 in vicinity of contractile proteins during systole intensity of interaction intensity of contraction Mainly by: 1. Intracellular Na + & 2. Expulsion of Ca +2 by Na + -Ca +2 exchanger Proposed: 3. Facilitation of Ca +2 entry through Na + and Ca +2 voltage gated channels & 4. Ca+2 release from SR Cardiac Glycosides Mechanical Effects Cardiac Glycosides Direct Electrical Effects Autonomic Direct Effects (in absence of toxicity): - early brief prolongation of action potential followed by shortening of plateau phase ( K+ conductance because of Ca+2 in cells) → atrial and ventricular refractoriness if toxic dose: 1. ↓resting membrane potential (becomes less negative) (because of inhibition of Na pump, less –ve inside cell) 2. Oscillatory depolarising afterpotential will evoke (because of overloading intracellular Ca+2 and oscillating ion conc.) If < threshold If threshold Cardiac Glycosides- Toxicity If threshold A new action potential will be produced premature beat “ectopic beat”, if in ventricle bigeminy in ECG (ST depression and inverted T wave) If < threshold Afterpotentials will interfere with the normal conduction because of further reduction of resting potential Cardiac Glycosides- Toxicity If toxicity deteriorates Self-sustaining arrhythmia “tachycardia” If allowed to progress Fibrillation (if in ventricle) Fatal Digitalis-induced bigeminy Cardiac Glycosides Electrical Effects: (Continued) 2. Autonomic Effects Parasympathetic •At therapeutic levels; parasympathetic effects predominates • Atropine-blockable effects: slow HR • cholinomimetic effects useful in treatment of certain arrhythmias Sympathetic If toxic levels: sympathetic outflow will These effects not essential for typical toxicity Types of digitalis-induced arrhythmias: atrioventricular junctional rhythm, premature ventricular depolarizations, bigeminal rhythm, second-degree atrioventricular blockade. virtually every variety of arrhythmia. Cardiac Glycosides Effects on other organs - Less affinity, because of different isoforms GIT: most common site of toxicty outside heart: N & V, anorexia, diarrhea direct effects on GIT & affects CNS + CTZ - CNS: - vagal + CTZ - - less often, disorientation, hallucination (elderly) - - visual disturbances (aberrations of color perceptions) - - agitation, convulsion - Gynecomastia: rare Digitalis interactions with electrolytes Careful evaluation of serum electrolytes in patients on digitalis: K+: (1) competes with digoxin on binding to Na+/K+ ATPase (2) abnormal cardiac automaticity is inhibited by hyperkalemia Ca+2: facilitates toxic actions of digoxin by accelerating overloading of intracellular Ca +2 stores Mg+2: Opposite effects of Ca +2 Summary: K+, Mg+2 and Ca+2 will increase risk of digoxin toxicity Treatment of digitalis toxicity If mild: manifested only by GIT and visual disturbances etc lower dose only If moderate/arrhythmia: - serum ~, K+ and ECG monitored - correct electrolyte status (K+, Mg+2, Ca+2) if abnormal - If PVB or brief runs of bigeminy - If arrhythmia is serious: Withdrawal of digoxin Oral K+ supplements I.V. K+ supplemets If severe (suicidal OD): Antiarrhytnmatic drug (e.g. Lidocaine) 1. Insertion of temporary cardiac pacemaker catheter 2. Digitalis AB (digoxin immune fab) Treatment of digitalis toxicity In case of severe digitalis toxicity: antiarrhythmic drugs can lead to cardiac arrest because automaticity is already depressed No need for K+ supplements in this case, as it will be already elevated because of loss from skeletal muscle cells and tissues OTHER +VE INOTROPIC DRUGS Phosphodiesterase inhibitors e.g. Bipyridines (Inamrinone, milrinone), Bipyridines: 1. selective inhibition of isozyme-3 (cardiac & smooth muscles)→↑cAMP & cGMP ↑contractiliy vasodilation 2.↑ Influx of Ca+2 3. Influence SR: ↑ intracellular Ca+2 movement ↑CO ↓LVFP ↓ PVR Phosphodiesterase inhibitors Inamrinone + milrinone (continued) Available only parenterally (can be given P.O.) t1/2= 3-6 hours, (10-40% excreted in urine) Given only for short term use Used only in acute HF or for an exacerbation of chronic HF Not used for long term because of TOXICITY Phosphodiesterase inhibitors Inamrinone Milrinone 1. Severe N&V Thrombocytopenia Liver Toxicity 1. Arrhythmia mortality (sometimes) 2. 3. (less likely to cause arrhythmia) 2. (less likely to cause bone marrow and liver toxicity) -adrenoceptor stimulants Dobutamine : selective 1- receptor agonist in cardiac cells. CO and ventricular filling pressure with some effect on HR not active P.O used for acute HF. Intermittent infusion for chronic HF Tachyphylaxis Careful in patients with CAD: tachycardia, ↑myocardial O2 consumption. Dopamine has also been used in acute heart failure and may be particularly helpful if there is a need to raise blood pressure Doses are Important! Dopamine Low dose (Renal Dose): 1-3 mcg/kg/minute: increase renal blood flow and urine output Intermediate dose (Cardiac Dose) 3-10 mcg/kg/minute: increase renal blood flow, heart rate, cardiac contractility and cardiac output (activates B1) High dose > 10 mcg/kg/min: alpha-adrenergic effects begin to predominate, vasoconstriction, increased BP DRUGS WITHOUT +VE INOTROPIC EFFECTS USED IN HF Diuretics If mild HF: Thiazide ~ moderate/severe: Loop ~ MOA: ↓salt & water retention→ ↓preload →↓edema & cardiac size Spirolonactone: ~aldosterone antagonist decreases the morbidity and mortality associated with HF (aldosterone may also cause myocardial and vascular fibrosis and baroreceptor dysfunction in addition to its renal effects). •If there is no oedema, 1st line treatment in HF. •Reduce morbidity and mortality and improve symptoms ACE-I SVR Long term remodeling of heart and vessels Salt and water retention Venous and arteriolar dilation Sympathetic stimulation Preload Bradykinin Afterload AngiotensinII- receptor antagonists Produce beneficial hemodynamic effects similar to those of ACE-I.. BUT: Large clinical trials suggest that they should only be used in patients who are intolerant of of ACE-I (e.g. because of cough, angioedema) Vasodilators 1. 2. Effective in Acute HF because they ↓preload or afterload or both. Some evidence that long term use of Hydralazine and isosorbide dinitrate can ↓damaging remodeling of the heart Recently, a synthetic form of the endogenous brain natriuretic peptide (BNP) has been approved for use in acute HF Vasodilators NEW A synthetic form of the endogenous peptide brain natriuretic peptide (BNP) is approved for use in acute cardiac failure Nesiritide (Natrecor ) ® MOA: 1. ↑cGMP in smooth muscles (stimulates Guanelyl cyclase) →↓venous and arteriolar tone 2. Causes diuresis V. short t1/2 = 18 minutes (why?) Because it it metabolised extensively by the NEP in the liver, kidney and lungs Measurement of endogenous BNP has recently been used as diagnostic test for patients with suspected HF Vasodilators NEW Bosentan (Tracleer®) competitive inhibitor of endothelin orally active Showed benefits in experimental animal models, but results in human trials have been disappointing This drug is approved for use in pulmonary hypertension Has significant teratogenic and hepatotoxic effects -blockers Used in chronic NOT acute HF (why?) In acute HF: RAS and sympathetic systems provide support for the circulation…while in chronic HF: they will cause vasoconstriction, volume expansion and progressive LV dysfunction Most patients with chronic HF respond favourably to - blockers in spite of the fact that these drugs can cause acute decompensation of cardiac function Decompensation: Failure of physiological compensation to some stimulus -blockers (MBC) Metoprolol, Bisoprolol and Carvedilol decrease mortality in patients with stable HF (stable severe HF) Not with bucindolol Full understanding of the beneficial effects in HF is lacking but suggested mechanisms: 1. attenuation of the adverse effects of the high concentration catechoamines (including apoptosis); 2. ↓Remodeling by inhibition of mitogenic activity of catecholamines; 3. upregulation of receptors; 4. HR diminish tachycardia Clinical Pharmacology of Drugs Used in Heart Failure Table 13-3. Steps in the treatment of chronic heart failure. 1. Reduce workload of the heart a. Limit activity, put on bed rest b. Reduce weight c. Control hypertension 2. Restrict sodium intake 3. Restrict water (rarely required) 4. Give diuretics 5. Give ACE inhibitor or angiotensin receptor blocker 6. Give digitalis if systolic dysfunction with 3rd heart sound or atrial fibrillation is present 7. Give b blockers to patients with stable class II-IV heart failure 8. Give vasodilators 9. Cardiac resynchronization if wide QRS interval is present in normal sinus rhythm ACE-I & ARBs In patients with LV dysfunction but no edema, an ACE-I should be used first. ACE inhibitors cannot replace digoxin in patients already receiving that drug because ……. ACE inhibitors are also valuable in asymptomatic patients with ventricular dysfunction. By ↓ preload & afterload, these drugs appear to slow the rate of ventricular dilation → delay onset of clinical HF. → ACE inhibitors are beneficial in all subsets of patients, from those who are asymptomatic to those in severe chronic failure. Vasodilators Can be divided into 1,2,3 ACE-Is nonselective arteriolar & venous dilators. In patients with high filling pressures in whom the principal symptom is dyspnea, venous dilators such as long-acting nitrates will be most helpful in↓ filling pressures & the symptoms of pulmonary congestion. In patients in whom fatigue due to low LV output is a primary symptom, an arteriolar dilator such as hydralazine may be helpful in ↑ forward cardiac output. In severe chronic failure (both ↑ filling pressures & ↓ CO) dilation of both arterioles & veins is required Beta Blockers (BRBs) & Calcium Channel Blockers (CCBs) The rationale for BBs use is based on the hypothesis ….. However, such therapy must be initiated very cautiously at low doses, because……. After several months: slight ↑EF, ↓HR, ↓ symptoms. MBC: have been shown to reduce mortality. CCBs appear to have no role in the treatment of patients with HF. Their depressant effects on the heart may worsen HF. Digitalis Digoxin is indicated in patients with HF & atrial fibrillation (AFib). It is also most helpful in patients with a dilated heart & third heart sound. It is usually given after ACE inhibitors. When symptoms are mild, slow loading (digitalization) is safer and just as effective as the rapid method. Digitalis (cont’d) Toxic effects may occur before the therapeutic end point is detected If digitalis is being loaded slowly, simple omission of one dose & halving the maintenance dose will often bring the patient to the normal range Measurement of plasma digoxin levels is useful in patients who appear unusually resistant or sensitive; a level of 1 ng/mL or less is appropriate Although digitalis had a neutral effect on mortality (Digitalis Investigation Group, 1997), it ↓ hospitalization & deaths from progressive HF at the expense of ↑in sudden death. Digitalis (cont’d) Digitalis ↑ stroke work & cardiac output → eliminates the stimuli evoking ↑ sympathetic outflow, →↓ both HR & vascular tone. With ↓ end-diastolic fiber tension (the result of ↑ systolic ejection &↓ filling pressure), heart size & oxygen demand ↓. ↑ renal blood flow →↑ GFR & ↓ aldosteronedriven Na reabsorption → ↓ edema fluid → further reducing ventricular preload & the danger of pulmonary edema Digitalis Interactions risk for serious digitalis-induced cardiac arrhythmias if hypokalemia develops, as in diuretic therapy or diarrhea quinidine displaces digoxin from tissue binding sites (a minor effect) & depresses renal digoxin clearance (a major effect)→ ↑digoxin toxic effects antibiotics that alter GI flora may ↑ digoxin bioavailability in ~ 10% of patients. agents that release catecholamines may sensitize myocardium to digitalis-induced arrhythmias. Management of Acute Heart Failure Acute HF occurs frequently in patients with chronic HF; Those episodes are associated with: - exertion, emotion; - salt in diet; - non-compliance with medication; - metabolic demand (anaemia, fever etc). Management of Acute Heart Failure A particularly common and important cause of HF-with or without chronic HF- is myocardial infarction (MI) Patients with acute MI are best treated with emergency revascularization with either coronary angioplasty and a stent or a thrombolytic agent. Even with revascularization, acute HF may occur. Revascularization A stent Management of Acute Heart Failure Many of the signs and symptoms of acute and chronic HF are identical However, their therapies diverge (why?) Because of the: 1. The need for rapid response, 2. frequency and severity of pulmonary vascular congestion & 3. The need for more rapid recognition and evaluation of changing hemodynamic status in case of acute HF Subsets of patients following an MI Patients with acute CHF following an MI can be usefully characterised on the basis of 3 hemodynamic measurements: - arterial pressure - LVFP - Cardiac Index When filling pressure is greater than 15 mm Hg and stroke work index is less than 20 gm/m2, the mortality rate is high. Intermediate levels of these two variables imply a much better prognosis. Table 13-4. Therapeutic classification of subsets in acute myocardial infarction. Subset Systolic Arterial Pressure (mm Hg) Left Ventricular Filling Pressure (mm Hg) Cardiac Index 2 (L/min/m ) Therapy 1. Hypovolemia < 100 < 10 < 2.5 Volume replacement 2. Pulmonary congestion 100-150 > 20 > 2.5 Diuretics 3. Peripheral vasodilation < 100 10-20 > 2.5 None or vasoactive drugs 4. Power failure < 100 > 20 < 2.5 Vasodilators, inotropic drugs 5. Severe shock < 90 > 20 < 2.0 Vasoactive drugs, inotropic drugs, circulatory assist devices 6. Right ventricular infarct < 100 RVFP > 10 LVFP < 15 < 2.5 Volume replacement for LVFP, inotropic drugs. Avoid diuretics. 7. Mitral regurgitation, ventricular septal defect < 100 > 20 < 2.5 Vasodilators, inotropic drugs, circulatory assist, surgery 1.Hypovolemia ↓LV filling pressure, ↓ SV Because of diuretic fluid intake Treatment: volume replacement LVFP > 15 mL 2.Pulmonary Congestion Very large subset & represents other causes of HF Severe congestion + oedema Diuretics are used to ↓ intravascular volume: furosemide (IV): ~ + immediate ↑compliance of systemic veins → peripheral pooling →↓ L & R ventricular filling pressure 2.Pulmonary Congestion Morphine sulfate: clinically effective in management of acute pulmonary oedema - reduce pain due to infarction - MOA unknown: in pulmonary oedema Aminophylline: if bronchospasm is prominent bronchodilator + inotropic agent vasodilator 3. Peripheral Vasodilation Hypotensive & warm extremities Treatment: none is necessary as LVFP is normal and CO is satisfactory But if BP is : vasoactive agent (dopamine) to maintain arterial pressure at desired level Vasodilation 4. “Power Failure” 1. 2. Patients with: ↓arterial pressure ↑LVFP ↓Cardiac index Treatment goal: ↑ CO & ↓ LVFP without further ↓ in the arterial pressure Diuretics will ↓ LVFP but will not ↑ CO Combined venous/arteriolar dilator e.g. nitroprusside is extremely beneficial (MOA?) 4. “Power Failure” The main limitation of nitroprusside is that it may ↓arterial pressure. Rule of thumb: give nitroprusside only if systolic pressure is 90 mm Hg or higher The effects of nitroprusside depends on the LVFP 5. Severe shock Patients with: v low arterial pressure, v high LVFP and v low cardiac index Cardiogenic Shock Acute angioplasty, intra-aortic balloon pump X vasodilators (initially): worsen hypotension dopamine: ↑arterial pressure (titrate the dose) Then cautiously add nitroprusside (titrate dose) that will increase CO and decrease LVFP + inotropic drugs: Inamrinone, dobutamine 6. Right ventricular Infarction Hypotension: due to RV unable to deliver enough blood to LV to maintain CO Treatment Goal: to optimise LVFP ( ) 1. Volume infusion (despite elevated central venous pressure) Avoid diuretics (worsen hypotension and tachycardia) + inotropic drugs 2. 3. 7. Mitral regurgitation & ventricular septal defect Such patients are also found in other subsets, particularly shock Treatment: (1) surgery (most definitive) - give nitroprusside, to stabilise patients before surgery - circulatory assistance (maintain LVFP at 15 mL)