《CHFlecture药理》PPT课件

1、Overview of congestive heart failureCongestive 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

2、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 di

3、sease, 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. Treatment of congestive heart failure1医学PPTHeart FailureFina

4、l common pathway for many cardiovascular diseases whose natural history results in symptomatic or asymptomatic left ventricular dysfunctionCardinal manifestations of heart failure include dyspnea, fatigue and fluid retentionRisk of death is 5-10% annually in patients with mild symptoms and increases

5、 to as high as 30-40% annually in patients with advanced disease2医学PPTMain causesCoronary artery diseaseHypertensionValvular heart disease (心瓣膜病) Cardiomyopathy (心肌病)Cor pulmonale3医学PPTCompensatory changes in heart failureActivation of SNSActivation of RASIncreased heart rateRelease of ADHRelease of

6、 atrial natriuretic peptide心钠素Chamber enlargement 心室腔扩大Myocardial hypertrophy 心室肥厚4医学PPTClassification of heart failureClass I: No limitation of physical activityClass II: Slight limitation of physical activityClass III: Marked limitation of physical activityClass IV: Unable to carry out physical ac

7、tivity without discomfort5医学PPTNew classification of heart failureStage A: Asymptomatic with no heart damage but have risk factors for heart failureStage B: Asymptomatic but have signs of structural heart damageStage C: Have symptoms and heart damageStage D: End stage diseaseACC/AHA guidelines, 2001

8、6医学PPT心功能障碍收缩功能舒张功能输出量神经激素心肌1受体RAACA心缩力顺应性 心肌肥大、重构 钠水潴留血容量静脉淤血血管收缩阻抗顺应性后负荷血管肥厚、重构 前负荷抗RAA系统药改善舒张功能药正性肌力药受体阻断药利尿药减前负荷药减后负荷药恢复心血管病理形态的药 CHF的病理生理过程及可能治疗的环节长期病情心率7医学PPTStrategy of treatment of CHFThe therapeutic goal for CHF is to increase cardiac output. Inotropic agents that increase the strength of c

9、ontraction of cardiac musclePDEI (phosphodiesterase inhibitors) agents that increase cAMP to induce systoles and vasodilatationCalcium sensitizers extracellular fluid volumeb adrenergic agonistb adrenergic antagonistVasodilators: Calcium channel blocker Decreasing RAS activity: ACEI and AT1 antagoni

10、st Diuretic agents8医学PPTTreatment of congestive heart failureClassification1 Positive inotropic drugsCardiac glycosides-adrenergic agonists (New dopamine receptor agonist)phosphodiesterase inhibitors Calcium sensitizers2 Diuretics3 VasodilatorsCalcium channel blocker Nitryl-vasodilatorsHydralazine4

11、RAAS inhibitors: antiotensin converting enzyme inhibitor and AT1 antagonist5 -receptor blocker9医学PPTClassification1 Positive inotropic drugsCardiac 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 pharmacologi

12、c activity as the whole molecule combined chemically with one or more sugars.10医学PPTCardiac glycosidesOOOHCH3CH3HOC18 H31O912ACBD173DigitoxinDigoxin= H at 12 C= OH at 12 CSugars- 3 mols. of digitoxose 3分子洋地黄毒糖Aglycones苷元Unsaturated lactone不饱和内酯环steroid nucleus甾核Convey the pharmacological activityCon

13、vey cardiotonic activityModulate potency and pharmacokinetic distribution11医学PPTOOOHCH3CH3HOC18 H31O912ACBD173 1. The relationship between structure and effectsThe Indispensable parts of activityC14CCThe number of -OH and glycose will decide water-solubility and lipid-solubility活性基团activity ：C17 不饱和

14、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12医学PPTClassification of cardiac glycosides1. 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

15、.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。13医学PPTProcess of drug through bodyDrugAbsorption rate (%)Protein-binding (%)Heptoenteral-circulation (%)Biotransformation (%)Kidney excretion (%)T1/2digitoxin90100972730701057 daydigoxin6085306.851060903336 hCedilanide20405Few

16、Quite few9010033 hStrophanthin K255Few 0901001219 h14医学PPTPharmacologic actionI. Action of cardiac glycosides on the heartPositive inotropic action：Increasing contractility of cardiac muscle in heart failure. (1) characteristic:myocardiac quick contraction, Q-T period rate of force time to peak tens

17、ion 15医学PPTB. no increase oxygen consumption： the increase in output is not accompanied by an equivalent increase in oxygen consumptionFactors of oxygen consumption： 1）Myocardia contractility 2）Heart rate 3）Myocadiac fiber length and tone16医学PPTFactors affect consumption of oxygenThe force of cardia

18、c contractionHeart rateVolume of ventricular17医学PPTC. Effect of positive inotropic act cardiac output is increased compensatory sympathetic tone is reduced cardiac preload and afterload is decreased heart rate is reduced myocardiac fiber tone and oxygen consumption is decreased increasing stroke vol

19、ume causes a decrease in end-systolic volume18医学PPT(2) Machanism of cardiac glycoside on positive inotropic actionA. 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)19医学PPTglycosid

20、eStructure changesEnzyme activity Na+, K+ in cellCa2+Na+exchange in cell)Na+-K+-ATPase is a recetor of glycosideMechanism of pharmacological act20医学PPTNa+-K+-ATPase is the receptor of cardiac glycosides , so cardiac glycosides act by inhibiting the membrane Na+-K+-ATPase pump Na+ i Na+ i21医学PPT Bidi

21、rectional exchange Na+ enter Ca2+ outer Na+ outer Ca2+ enterby Na/Ca 2+exchanger Ca2+ i22医学PPTCa2+ -induced Ca2+ release Sarcoplasmic reticulum release Ca 2+Enhance the increased cytosolic calcium concentration Sarcoplasmic reticulum Ca 2+ i23医学PPT2.Negative chronotropic actionA. Continuous effect o

22、f positive inotropic action decreasing sinus rate heart rate is decreased24医学PPTHeart rate is decreased,Atropine can antagonize (block) B. Increasing sensibility of myocardia to vagus nerve (increasing of potassium outward and resting potential, reducing of automaticity).25医学PPT3. Affects of glycosi

23、des to conductive tissuesA. 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 conduct

24、ion.26医学PPTB. 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 tachycardiaC. Increasing automaticity of Purkinjie fibr

25、es： toxicity27医学PPTIf 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

26、induce toxicity in myocardiac. (arrhythmia)Mechanism of toxicity act28医学PPT4. Affects of cardiac glycasides to ECG (electrocardiography)A. Therapeutic dose:T-wave can become low, flat, isoelectric or invertedS-T segment falls below the isoelectric lineP-R interval is lengthened, which is associated

27、with slower or delayed A-V conductionQ-T interval is shortened, ERP and APD is shortened in Purkenje fibersB. Higher dose: arrhythmias29医学PPTThe affects on ECGT waveIt is characterized by an descend ST segment on the ECG P-R Q-T P-P30医学PPT Directly inhibit or reflected decrease sympathetic activity

28、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+-

29、ATPase Na decreased re-absorbnewII. Action of cardiac glycosides on neural and hormone31医学PPTClinical usesCardiac 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Some ki

30、nds of arrhythmias Atrial fibrillation Atrial flutter Supraventricular Tachycardia32医学PPTToxic effectsResponses of stomach-intestines : Anorexia 厌食, nausea，vomiting , Abdominal pain and diarrhoeaCNS: visual disturbacesArrhythmia: 1) Tachycardia 2)AV block 3)Bradycardia 60 beat/min33医学PPTProphylaxis

31、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 spec

32、ific to cardiac glycosides are available 34医学PPTMethod of administration Classical ：whole effect dose quick or slow (have use digoxin within two weeks) The suitable dose to the patients Maintain ：45 t Digoxin 0.25mg/day , 67 day ( t 3336 hours)35医学PPT Classification1 Positive inotropic drugs -Adreno

33、ceptor agonists They are used intravenously in CHF emergenciesExample of -Adrenoceptor agonists :Dobutamine (多巴酚丁胺) Exciting 1 Adrenoceptor positive inotropic action the volume of output Exciting 2 Adrenoceptordilate the vascular afterload have benefits within short time36医学PPTClassification1 Positi

34、ve inotropic drugs Phosphodiesterase- inhibitorsInodilator / inodilating drugsInhibiting the activity of PDE 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

35、 the neurohormone, anti-the forming of thrombus milrinone（米力农）: stronger 20 time vesnarinone（维司力农）: myocardial contract elements the sensitivity to calcium37医学PPTClassification1 Positive inotropic drugs Calcium sensitizersPimobendan 匹莫苯: Inhibit PDE ; increase TnCs sensitivity to calciumTn troponin肌

36、钙蛋白；myosin肌球蛋白；tropomyosin原 ；Actin 肌动蛋白38医学PPTClassification 2 DiureticsDiuretics 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

37、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)39医学PPTAntiotensin converting enzyme inhibitor (ACEI) and AT1 antagonistCalcium channel b

38、locker Nitryl-vasodilatorsHydralazineClassification 3 Vasodilators40医学PPTbradykininaldosteroneACEI and AT blocker41医学PPTClassification 3 VasodilatorsAngiotensin-converting-enzyme inhibitor (ACEI )Captopril EnalaprilMethanism of anti-CHF:Humour: Inhibit ACEangiotensin and aldosterone levels, reduce s

39、odium retention, increase bradykinin levels , ANP、 NO、PGI2, reduce the release of NA ET and renew the expression of receptor This therefore causes vasodilatation (include coronary artery) reduction in peripheral resistance increase the cardiac output, Increase the blood flow of kidney so Improve the

40、 function of kidney3) Prevent the remodel of the heart 42医学PPTAT1 antiagonistsLosartan （氯沙坦）The function just like ACEIt dosent influence bradykinin levelsClinical utilize: CHF Protection of kidney43医学PPTCalcium-channel blockersAmlodipine 氨氯地平Dilate arteryDilate the coronaryAlleviate the LV Wall Ten

41、sionVessel44医学PPTDilatation of the veins decreases preload Dilatation of the artery decreases afterload Decrease the oxygen demand of the heartmechanismOthers - VasodilatorsNitrate esters: nitroglycerin , nitroprusside sodium 硝普纳Hydralazine 肼屈嗪 direct dilate the vascularPrazosin 哌唑嗪 - receptor block

42、er45医学PPTClassification 4 receptor blockerCarvedilol 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46医学PPT Thanks ！ Good Luck！47医学PPT 二 other action of cardiac gylcosides Nerve system Toxic concentration:enhancin

43、g sympathetic activity increasing sympathetic impulse of preganglial and afterganglial fibers, can cause atrial fibrillation and ventricular tachycardia.48医学PPTTherapeutic dose: increasing parasympathetic center in brain stem excitation-slowing rate of heart,inhibiting conduction49医学PPT2. Effect of

44、cardiac glycosides to kidneyincreasing renal blood flow and filtering rate of glomeruluscompetitive antagonism with aldosterone in proximal tubule50医学PPTClinical uses1. Congestive heart failure *Depends in part on the cause of the failure *Depends in part on the severity of cardiac damage51医学PPTA. T

45、he best therapeutic effect is the chronic, low-output formSuch as: heart failure with atrial fibrillation an rapid heart rate52医学PPTB. 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）53医学

46、PPTC. No better Thyrotoxicosis（甲状腺中毒症）Thyroidism（甲状腺功能亢进） Serious anemia Vitamin B deficiency Advanced valvular stenosis54医学PPTD. No use pulmonocardiac disease activity carditis serious myocardia injured Activity rheumatic other forms of infectious or toxic myocarditis , pulmonocardiac disease advan

47、ced cardiomyopathy心肌病 badly damaged hearts cardiopericarditis 心包炎55医学PPTE. Acute heart failureiv.Use strophanthin K cedilanide56医学PPT2. Atrial fibrillantionVentricular rate Atrial rate :400650/min Circulative blood flow Heart failure57医学PPTCardiac gylcosidesventricular rate (atrial fibrillation)Circ

48、ulative blood flow volume (relive) sysptoms of heart failure58医学PPTIn 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 ven

49、tricular rate.59医学PPTConcealed conductionThe 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.60医学PPT3. Atrial f

50、lutteratrial rate : 320360 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 de

51、crease in ventricular rate61医学PPTTherapeutic action:Increasing block and ERP in atrioventricular (AV) node heart rate decrease (ventricular rate)(2) Shortening ERP of atrium(convert) atrial flutter atrial fibrillation62医学PPT(3) After withdrawal cardiac glycosides, sinus rhythm may return, ERP increa

52、se (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. 63医学PPT3. Paroxysmal supraventricular tachycardiaIncreasing function of vagal nerveEnhance vagal activityDecrease excitation of atriumNo use

53、: supraventricular tachycardia caused by glycosides-intoxication64医学PPTToxicity of cardiac glycosides1. 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 chemo