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Treatment of congestive heart failure Overview of congestive heart failure Congestive heart failure (CHF) is a condition in which the heart is unable to pump sufficient blood to meet the needs of body. CHF can be increased workload imposed on the heart. CHF is accompanied by abnormal increases in blood volume and interstitial fluid; the heart, veins, and capillaries are therefore generally dilated with blood. Hence the term “congestive(充血性)” heart failure, since the symptoms include pulmonary congestion with life heart failure, and peripheral edema with right heart failure. Underlying causes of CHF include arteriosclerotic heart disease, hypertensive heart disease, valvular heart disease(心瓣 膜病), dilated cardiomyopathy(扩张性心肌病), and congenital heart disease(先天性心脏病). Left systolic dysfunction secondary to coronaryartery disease is the most common cause of heart failure. Heart Failure Final common pathway for many cardiovascular diseases whose natural history results in symptomatic or asymptomatic left ventricular dysfunction Cardinal manifestations of heart failure include dyspnea, fatigue and fluid retention Risk of death is 5-10% annually in patients with mild symptoms and increases to as high as 30-40% annually in patients with advanced disease Main causes Coronary artery disease Hypertension Valvular heart disease (心瓣膜病) Cardiomyopathy (心肌病) Cor pulmonale Compensatory changes in heart failure Activation of SNS Activation of RAS Increased heart rate Release of ADH Release of atrial natriuretic peptide心钠素 Chamber enlargement 心室腔扩大 Myocardial hypertrophy 心室肥厚 Classification of heart failure Class I: No limitation of physical activity Class II: Slight limitation of physical activity Class III: Marked limitation of physical activity Class IV: Unable to carry out physical activity without discomfort New classification of heart failure Stage A: Asymptomatic with no heart damage but have risk factors for heart failure Stage B: Asymptomatic but have signs of structural heart damage Stage C: Have symptoms and heart damage Stage D: End stage disease ACC/AHA guidelines, 2001 CHF的病理生理过程及可能治疗的环节 心功能障碍 正性肌力药 收缩功能 舒张功能 改善舒张功能药 输出量 心率 长期病情 血管收缩 阻抗 顺应性 后负荷 心肌1受体 神经激素 RAA CA 心缩 力 顺应 性 抗RAA系统药 减后负荷药 血管肥厚、重构 恢复心血管病理形态的药 受体阻断药 钠水潴留 利尿药 心肌肥大、重构 血容量 前负荷 静脉淤血 减前负荷药 Strategy of treatment of CHF The therapeutic goal for CHF is to increase cardiac output. 1) Inotropic agents that increase the strength of contraction of cardiac muscle 2) PDEI (phosphodiesterase inhibitors) agents that increase cAMP to induce systoles and vasodilatation 3) Calcium sensitizers extracellular fluid volume 4) adrenergic agonist 5) adrenergic antagonist 6) Vasodilators: Calcium channel blocker 7) Decreasing RAS activity: ACEI and AT1 antagonist 8) Diuretic agents Treatment of congestive heart failure Classification 1 Positive inotropic drugs Cardiac glycosides β-adrenergic agonists (New dopamine receptor agonist) phosphodiesterase inhibitors Calcium sensitizers 2 Diuretics 3 Vasodilators Calcium channel blocker Nitryl-vasodilators Hydralazine 4 RAAS inhibitors: antiotensin converting enzyme inhibitor and AT1 antagonist 5 β-receptor blocker Classification1 Positive inotropic drugs Cardiac glycosides/强心苷类 structure-activity relationship A cardiac glycoside molecule consists of an aglycone苷元 or genin配基, which possesses the same pharmacologic activity as the whole molecule combined chemically with one or more sugars. Cardiac glycosides Aglycones Digitoxin = H at 12 C Digoxin = OH at 12 C 苷元 CH3 3A O C18 H31O9 CH3 12 17 D C OH B H O Unsaturated lactone 不饱和内酯环 Convey cardiotonic activity O steroid nucleus 甾核 Sugars- 3 mols. of digitoxose 3分子洋地黄毒糖 Modulate potency and pharmacokinetic distribution Convey the pharmacological activity 1. The relationship between structure and effects CH3 C3 A O C18 H31O9 B CH3 C 12 17 D C O C14 OH O H The Indispensable parts of activity The number of -OH and glycose will decide water-solubility and lipid-solubility 活性基团activity :C17 不饱和内酯环Unsaturated lactone 、C14羟基OH、C3 洋地黄毒糖digitoxose 脂溶性lipid-solubility: C3 洋地黄毒糖;水溶性water-solubility :C12及其他位点的羟基数 Classification of cardiac glycosides 1. grade 1: in plant, cedilanide 2. grade 2: extract of digitalis Digitoxin(洋地黄毒苷), Digoxin(地高辛), Deslanoside (旋花毛地黄苷), Strophanthin K (毒毛旋花子苷K) 3.地高辛和洋地黄毒苷C3位均联结3个洋地黄毒糖, 地高辛C12位多一个羟基,毒毛花苷K的甾核上有多 个羟基,所以脂溶性:洋地黄毒苷>地高辛>毒毛 花苷K。 Process of drug through body Drug Absorption Protein- Heptoe Biotran Kidney T1/2 rate (%) binding nteral- sformat excretion (%) circulati ion (%) (%) on (%) digitoxin 90~100 97 27 30~70 10 5~7 day digoxin 60~85 <30 6.8 5~10 60~90 33~36 h Cedilanide 20~40 5 Few Quite few 90~100 33 h 5 Few 0 90~100 12~19 h Strophanthin 2~5 K Pharmacologic action I. Action of cardiac glycosides on the heart 1.Positive inotropic action:Increasing contractility of cardiac muscle in heart failure. (1) characteristic: A.myocardiac quick contraction, Q-T period↓ ①rate of force ↑ ②time to peak tension ↓ B. no increase oxygen consumption: the increase in output is not accompanied by an equivalent increase in oxygen consumption Factors of oxygen consumption: 1)Myocardia contractility 2)Heart rate 3)Myocadiac fiber length and tone Factors affect consumption of oxygen I. The force of cardiac contraction II. Heart rate III. Volume of ventricular C. Effect of positive inotropic act ① cardiac output is increased ② compensatory sympathetic tone is reduced ③ cardiac preload and afterload is decreased ④ heart rate is reduced ⑤ myocardiac fiber tone and oxygen consumption is decreased ⑥ increasing stroke volume causes a decrease in end-systolic volume (2) Machanism of cardiac glycoside on positive inotropic action A. Inhibiting Na+-K+-ATPase in therapeutic dose: B. Increasing of calcium inward and induce the releasing of calcium from sarcoplasmic reticulum ( internal stores, by CICR) Mechanism of pharmacological act Na+-K+-ATPase is a recetor of glycoside ↓ glycoside → α ↓ ↓ β Structure changes ↓ Enzyme activity ↓ ↓ Na+↑, K+↓ in cell ↓ Ca2+Na+exchange↓ in cell) → Na+ i Na+-K+-ATPase is the receptor of cardiac glycosides , so cardiac glycosides act by inhibiting the membrane Na+-K+ATPase pump → Na+ i →by Na+/Ca 2+exchanger → Ca2+ i↑ Bidirectional exchange ① Na+ enter ↓ → Ca2+ ↓ outer ② Na+ outer ↑→Ca2+ ↑ enter → Ca 2+ i↑ Sarcoplasmic reticulum Ca2+ -induced Ca2+ release Sarcoplasmic reticulum release Ca 2+ Enhance the increased cytosolic calcium concentration 2.Negative chronotropic action A. Continuous effect of positive inotropic action decreasing sinus rate heart rate is decreased B. Increasing sensibility of myocardia to vagus nerve (increasing of potassium outward and resting potential, reducing of automaticity). Heart rate is decreased, Atropine can antagonize (block) 3. Affects of glycosides to conductive tissues A. Increasing conduction of the atrial muscle fibers, because increasing excitation of vagus nerve (increasing of potassium outward). Increasing resting potential. Elevating rate of phase-0 depolarization. Acceleration rate of depolarization phase-0 and atrial fibers conduction. B. Slowing (depress) conduction at the atrioventricular (A-V) node (inhibiting Na-K-ATPase, reducing resting potential), and increase effctive refractory period atrial fibrillation, atrial flutter, paroxymal (and) or supraventricular tachycardia C. Increasing automaticity of Purkinjie fibres: toxicity Mechanism of toxicity act A. B. If Na+-K+-ATPase was inhibited more than 30%, cardiac glycosides would induce toxicity by the overload of intercellular free calcium concentration in myocardiac. (decreasing inotropic action) If intercellular potassium concentration was lower level, cardiac glycosides would easily induce toxicity in myocardiac. (arrhythmia) 4. Affects of cardiac glycasides to ECG (electrocardiography) A. Therapeutic dose: T-wave can become low, flat, isoelectric or inverted S-T segment falls below the isoelectric line P-R interval is lengthened, which is associated with slower or delayed A-V conduction Q-T interval is shortened, ERP and APD is shortened in Purkenje fibers B. Higher dose: arrhythmias The affects on ECG T wave It is characterized by an descend ST segment on the ECG P-R Q-T P-P II. Action of cardiac glycosides on neural and hormone Directly inhibit or reflected decrease sympathetic activity • Exciting increase the vagal activity • Inhibit RAAS system, promote the excrete of ANP • cause arrhythmias (toxic doses) II. Action of cardiac glycosides on vascular and kidney • Vasoconstriction, increase in peripheral vascular resistance • Diuretic,increase the blood flow through kidney and inhibit Na+-K+-ATPase → Na+ decreased re-absorb Clinical uses 1. Cardiac glycosides are given for CHF Effects: Best go with atrial fibrillation Better hypertension congenital heart disease not good anaemia lack of vitamin B1 not useful pericarditis 心包炎 2. Some kinds of arrhythmias Atrial fibrillation Atrial flutter Supraventricular Tachycardia Toxic effects 1. Responses of stomach-intestines : Anorexia 厌食, nausea,vomiting , Abdominal pain and diarrhoea 2. CNS: visual disturbaces 3. Arrhythmia: 1) Tachycardia 2)AV block 3)Bradycardia <60 beat/min Prophylaxis and treatment of the toxicity • Clear the signal of toxic and the indication of withdraw • Inspect the concentration of digoxin (3ng/ml), digitoxin(45ng/ml) • If necessary ,potassium supplements and antiarrhythmic drugs ( phenytoin ,lidocaine,atropine )administered • For severe intoxication ,antibodies specific to cardiac glycosides are available Method of administration • Classical :whole effect dose quick or slow (have use digoxin within two weeks) The suitable dose to the patients • Maintain :4~5 t ½ Digoxin 0.25mg/day , 6~7 day ( t ½ 33~36 hours) Classification1 Positive inotropic drugs -Adrenoceptor agonists They are used intravenously in CHF emergencies Example of -Adrenoceptor agonists : Dobutamine (多巴酚丁胺) • Exciting β1 Adrenoceptor → positive inotropic action →the volume of output↑ • Exciting β2 Adrenoceptor→dilate the vascular → afterload↓ have benefits within short time Classification1 Positive inotropic drugs Phosphodiesterase-Ⅲ inhibitors Inodilator / inodilating drugs Inhibiting the activity of PDE Ⅲ → cAMP↑→ causes an increase in myocardial contractility and vasodilatation →total peripheral resistance →cardiac output ↑ Examples: Armirinone(氨力农): Inhibits the excess product of NO, TNF and affects the neurohormone, anti-the forming of thrombus milrinone(米力农): stronger 20 time vesnarinone(维司力农): myocardial contract element’s the sensitivity to calcium Classification1 Positive inotropic drugs Calcium sensitizers Pimobendan 匹莫苯: Inhibit PDE Ⅲ ; increase TnC’s sensitivity to calcium Tn troponin—肌钙蛋白;myosin-肌球蛋白;tropomyosin-原 ;Actin 肌动蛋白 Classification 2 Diuretics Diuretics inhibit sodium and water retention, →reduce the volume of blood, →venous pressure and the thus cardiac preload are reduced↓, increasing the efficiency of the heart as a pump→ cardiac output ↑, so reduce oedema due to heart failure Heart failure • Low-grade : Thiazides hydrochlorothiazide 氢氯噻嗪 • Higher-grade : Acute left heart failure loop diuretics --- furosemide 呋塞米(速尿) Spironolacton 螺内酯 (anti-aldosterone ,keep potassium and diuretics) Classification 3 Vasodilators Antiotensin converting enzyme inhibitor (ACEI) and AT1 antagonist Calcium channel blocker Nitryl-vasodilators Hydralazine ACEI and AT blocker bradykinin aldosterone Classification 3 Vasodilators Angiotensin-converting-enzyme inhibitor (ACEI ) Captopril Enalapril Methanism of anti-CHF: 1) Humour: Inhibit ACE→angiotensin Ⅱ and aldosterone levels↓, reduce sodium retention, increase bradykinin levels , ANP、 NO、PGI2↑, reduce the release of NA ET and renew the expression of βreceptor 2) This therefore causes vasodilatation (include coronary artery) →reduction in peripheral resistance→ increase the cardiac output, Increase the blood flow of kidney so Improve the function of kidney 3) Prevent the remodel of the heart AT1 antiagonists Losartan (氯沙坦) The function just like ACEⅠ It dosen’t influence bradykinin levels Clinical utilize: • CHF • Protection of kidney Calcium-channel blockers Amlodipine 氨氯地平 Vessel Dilate artery Dilate the coronary Alleviate the LV Wall Tension Others --- Vasodilators mechanism Dilatation of the veins→ decreases preload Dilatation of the artery→ decreases afterload Decrease the oxygen demand of the heart Nitrate esters: nitroglycerin , nitroprusside sodium 硝普纳 Hydralazine Prazosin 肼屈嗪 哌唑嗪 direct dilate the vascular ɑ- receptor blocker Classification 4 receptor blocker Carvedilol 卡维地洛 labetalol 拉贝洛尔 Bisoprolol 比索洛尔 Carvedilol 卡维地洛 mechanism • Anti RAAS system • Anti-arrthymias • Anti-myocardial ischemia Cardiomyopathy 心肌病 Thanks ! Good Luck! 二 other action of cardiac gylcosides 1. Nerve system Toxic concentration:enhancing sympathetic activity increasing sympathetic impulse of preganglial and afterganglial fibers, can cause atrial fibrillation and ventricular tachycardia. Therapeutic dose: increasing parasympathetic center in brain stem excitation------slowing rate of heart,inhibiting conduction 2. Effect of cardiac glycosides to kidney ①increasing renal blood flow and filtering rate of glomerulus ②competitive antagonism with aldosterone in proximal tubule Clinical uses 1. Congestive heart failure *Depends in part on the cause of the failure *Depends in part on the severity of cardiac damage A. The best therapeutic effect is the chronic, low-output form Such as: heart failure with atrial fibrillation an rapid heart rate B. The better therapy is heart failure caused by hypertension, heart disease caused by coronary atherosclerosis Valvular stenosis(瓣膜狭窄) Rheumatic valvulitis(风湿性瓣膜炎) C. No better Thyrotoxicosis(甲状腺中毒症) Thyroidism(甲状腺功能亢进) Serious anemia Vitamin B deficiency Advanced valvular stenosis D. No use pulmonocardiac disease activity carditis serious myocardia injured (1) Activity rheumatic (2) other forms of infectious or toxic myocarditis , pulmonocardiac disease (3) advanced cardiomyopathy心肌病 (4) badly damaged hearts cardiopericarditis 心包炎 E. Acute heart failure Use strophanthin K iv. } cedilanide 2. Atrial fibrillantion Atrial rate :400~650/min ↓ Ventricular rate ↑ ↓ Circulative blood flow ↓ ↓ Heart failure Cardiac gylcosides ↓ ventricular rate ↓ (atrial fibrillation) ↓ Circulative blood flow volume ↑ ↓ (relive) sysptoms of heart failure •In atrial fibrillation, the same vagomimetic action helps control ventricular rate, thereby improving ventricular filling and increasing cardiac output. •Slowing conduction in A-V node,increasing concealed conduction(隐匿性传导),slowing ventricular rate. Concealed conduction The impulses arriving at the AV node are rapid and random in time. Most of these impulses either fail to enter the AV node because it is refractory or propagate only partway through it and give rise to the phenomenon of concealed conduction. 3. Atrial flutter atrial rate : 320~360 beats/min, rapid and regular In atrial flutter, the depressant effect of the drug on atrioventricular conduction will help control an excessively high ventricular rate. The effects of the drug on the atrial musculature may convert flutter to fibrillation, with a further decrease in ventricular rate Therapeutic action: (1)Increasing block and ERP in atrioventricular (AV) node heart rate decrease (ventricular rate) (2) Shortening ERP of atrium (convert) atrial flutter →atrial fibrillation (3) After withdrawal cardiac glycosides, sinus rhythm may return, ERP increase (prolong ERP of shortened ERP in atrium) (4) Quinidine may convert atrial flutter to sinus rhythm , but may increase the risk of cardiac glycosides toxicity. 3. Paroxysmal supraventricular tachycardia Increasing function of vagal nerve Enhance vagal activity Decrease excitation of atrium No use: supraventricular tachycardia caused by glycosides------intoxication Toxicity of cardiac glycosides 1. Gastrointestinal and centre nerve systom occasions sickness , vomiting , purging泄泻 , giddiness眩晕 , confused vision , green vision or yellow vision , anorexia厌食 , nausea , diarrhea , abdominal discomfort or pain , headache , fatigue the drugs may stimulate the chemoreceptor of trigger zone (CTZ) in the area postrema of the medulla(延髓极后区,化学感受区) 2. Toxic effects on the heart (1)Tachycardiac rhythm abnormalities (arrhythmia) Atrioventricular (AV) node Artial Ventricular } fibrillation Tachycardia death Bigeminy 二联律 , trigeminy三联律 machanism Severe inhibiting Na+-K+-ATPase ↓ Depletion of K+ in cell ↓ Resting potential or Change small maximal diastolic potential (negative value) } ↓ (1)Automaticity easy to depolarization (2) Delaying after depolarization↑迟后 (2) AV block ★ the development of AV block is due in part to the vagal effect of glycosides +-K+-ATPase is strongly depressed Na ★ Resting potential↓ ↓ Phase 0 depolarization rate ↓ ↓ Conduction slows (3)Sinus bradycardia Sinus atrial node is depressed ↓ Automaticity ↓ Prevention of cardiac intoxication 1.Intoxication symptoms and signs Gastrointestinal effects Neurological effects Drug concentration in blood can be measured 2. Pathological situations Ion pH of blood Oxygen deficiency Age Drug interaction Treatment of cardiac glycosides introxication 1. Administration K+ , orally or iv 2. Administration of phenytoin treats severe tachycardiac rhythm abnormalities ventricular tachycardia bigeminy二联律 recovering activity of enzyme Lidocaine : ventricular tachycardia Ventricular fibrillation Atropine: Sinus bradycardia AV conduction block } severe Administration 1 Digitalization Slow approach to “ digitalization” Is the safest dosing technique. Rapid approach to “digitalization” can be achieved quickly with a large loading dose (divided into three or four portions and given over 24~36 hours) followed by maintenance dose 2 Maintenance doses 3 Therapeutic method of Digoxin t1/2 36 hours 0.25 mg/day 4~6 t1/2 (6~7 days) to approach steady-state level (Css) Thanks