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Chapter 12

Chapter 12. Cardiovascular Drugs. Cardiovascular diseases.

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Chapter 12

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  1. Chapter 12 Cardiovascular Drugs

  2. Cardiovasculardiseases • Cardiovascular diseases include hypertension (高血压), hyperlipidemia (高血脂), angina (心绞痛), atherosclerosis (动脉粥样硬化), coronary diseases (冠心病), hypotension (低血压), cardiac arrhythmias (心率失常), heart failure (心力衰竭), and certain vascular disorders.

  3. Cardiovascular Drugs • Cardiovascular drugs effect on heart or vascular system to adjust the total output of heart blood by different action mechanism, or alter blood distribution in circulation system to improve, resume cordis (心脏的) and vascular function.

  4. Classification of cardiac drugs • Cardiac drugs include cardiac agents (强心药), antianginal drugs (抗心绞痛药), antiarrhythmic agents (抗心率失常药), antihypertensive agents (抗高血压药), hypolipidemic drugs (降血脂药).

  5. Section 1 Cardiac Agents • Cardiac Agents , also called inotropic agents (正性肌力药)，are applied for congestive heart failure to enhance the force of cardiac contraction.

  6. 充血性心力衰竭(Congestive heart failure，CHF） • CHF是由于心肌收缩力减弱引起心输出量明显不足而心脏血容量有所增加的疾病，导致血压升高和肾血流降低，严重时会发展成下肢水肿，肺水肿以及肾衰竭。 • CHF是一种常见病，它引起的死亡率一直在增加。因此，治疗CHF的药物是世界性热门课题。

  7. Drugs for CHF • Cardiac Agents • Vasodilators • Diuretics • Angiotensin-converting enzyme inhibitors (ACEI)

  8. The Sorts ofCardiac Agents • 1. Cardiac glycosides • 2. Phosphodiesterase inhibitors • 3. Calcium sensitizers • 4. βAdrenergic agonists

  9. 1. Cardiac glycosides (强心苷类) • Cardiac glycosides have applied for heart failure for more than hundred years. Today they are still important drugs to treated heart failure. • 强心苷类广泛存在于许多有毒的植动物体内（如洋地黄、蟾蜍毒等）。小剂量时有强心作用，但大剂量使心脏中毒停止跳动。 • 主要缺点：安全范围小，强度不够大，且具有吸收、消除途径及速度方面的缺点。

  10. Digoxin • (3β, 5β, 12β)-3-[(O-2,6-dideoxy-β–D-ribo-hexopyranosyl-(1 4)-O-2,6-dideoxy-β–D-ribo-hexopyranosyl-(1 4)-2,6-dideoxy-β–D-ribo-hexopyranosyl)oxy]-12,14-dihydroxy-–card-20(22)-enolide

  11. Digoxin in the body • Digoxin is absorbed and distributed in tissues rapidly. It is excreted in prototype by kidney. • Digoxin is used for acute and chronic heart failure and atrial fibrilation (心房纤颤) and atrial flutter (心房扑动）.

  12. cardiac glycosides in clinic • There are lots of cardiac glycosides in clinic, including digitoxin(洋地黄毒苷), digoxin (地高辛), lanatoside C (毛花苷C), β–strophanthin K (毛花苷K) and convallatoxin (铃兰毒苷).

  13. Digoxin (地高辛)

  14. Digitoxin（洋地黄毒苷）

  15. Lanatoside C (毛花苷C)

  16. β–strophanthin K (毛花苷 K)

  17. Convallatoxin (铃兰毒苷)

  18. 1）Chemistry of cardiac glycosides aglycone sugar moieties steroid nucleus α,β unsaturated lactone Cardiac glycosides 配糖基部分

  19. steroid nucleus • Stereo-structure of steroid nucleus cis- A/B , trans-B/C, cis-C/D.

  20. α,β unsaturated lactone • Five-member(plant): Cardenolide (卡烯内酯) • Six member(animal): Bufadienolide (蟾二烯羟酸内酯)

  21. Sugar moieties

  22. The function of chemical structure • Aglycone steroid nucleus which convey the pharmacological activity of these compounds. • An unsaturated lactone ring which conveys cardiotonic (强心的) activity. • Sugar moieties which modulate potency and pharmacokinetic distribution.

  23. 2）The Action Mechanism • Cardiac glycosides act by inhibiting the membrane Na+/K+ ATPase pump. This increases intracellular Na+ concentration, thus reducing the sodium gradient across the membrane and decreasing the amount of calcium pumped out of the cell by the Na+/Ca2+ exchanger during diastole(心脏舒张). • Consequently, the intracellular calcium concentration rises, thus increasing the force of cardiac contraction and maintaining normal blood pressure.

  24. Figure of the action mechanism

  25. 3) The SAR of cardiac glycosides • 1. C17β - α,β unsaturated lactone • 2. steroid nucleus ; • 3. C19-CH3; • 4. C14- β-OH; • 5. C3β-O-sugar.

  26. Figure of cardiac glycosides and Na+,K+/ATPase action

  27. Methyldigoxin toxicity

  28. 2. Phosphodiesterase inhibitor, PDEI • PDEI is a sort of new cardiac drugs having different action mechanism with cardiac glycosides. • Examples of PDEI include amrinone (氨力农) and milrinone (米力农). • These have been developed as a result of the many adverse effects and problems associated with cardiac glycosides. • There is no evidence that these improve the mortality.

  29. The Action Mechanism • Phosphodiesterase is responsible for the degradation of cAMP; Thus, inhibiting this enzyme raises cAMP levels and causes increase in myocardial (心肌) contractility and vasodilatation (血管舒张). • Cardiac output is increased, and pulmonarywedge pressure (肺压) and total peripheral resistant are reduced, without much change in heart rate or blood pressure.

  30. Figure of the Action Mechanism the force of cardiac contraction PDEI

  31. Phosphodiesterase, PDE • PDE has three types: PDE-Ⅰ, Ⅱ, Ⅲ. • PDE-Ⅰ,Ⅱ, which both have different subtypes, don’t have speciality on cAMP. • PDE－Ⅲ , which only has a subtype, possesses high speciality and affinity on cAMP.

  32. Amrinone (氨力农) Amrinone is the first PDEI drug in clinical use in 1978.

  33. Pharmacology of Amrinone • Amrinone is short acting and is administered intravenously. • It is given for severe acute heart failure that is resistant to other drugs. • It has several adverse effects. These include nausea and vomiting, arrhyth-mias, liver dsyfunction, abdominal pain, and hypersensitivity.

  34. Milrinone (米力农) • 化学名：1,6-二氢-2-甲基-6-氧-(3,4‘-双吡啶)-5-氰,又名米利酮。 • 1,6-dihydro-2-methyl-6-oxo-[3,4’-bipyridine]-5-carbonitrile, corotrope

  35. Pharmacology of Milrinone • Milrinone is long acting and is administered orally. • Milrinone has high speciality on PDE -Ⅲ. So it is 10～20 fold effective than amrinone. • Its adverse effects are less than amrinone, but it has potentarrhythmias possibility.

  36. Enoximone (依洛昔酮） • Enoximone is a potent selective inhibitor. • It is administered orally for a long period.

  37. 3. Calcium sensitizers (钙敏化剂) • 钙敏化剂是一类能增加肌纤维丝对Ca2+ 敏感性的药物，即能使生理浓度的游离Ca2+对心肌产生更大的张力。

  38. Isomazole(伊索马唑) • 能增加收缩蛋白对Ca2+ 敏感性，在不增加Ca2+浓度的情况下，提高心肌收缩力。

  39. 4. βAdrenergic Agonists • β受体激动剂主要是兴奋心脏的β1受体，产生心肌收缩的作用。但大多数肾上腺素能激动剂由于可加速心率和产生血管收缩作用，限制了治疗心衰的价值。 • Examples of βadrenergic agonists include dobatumine (多巴酚丁胺) and dopamine. They are used intravenously in CHF emergencies.

  40. Dobutamine (多巴酚丁胺) • Dobutamine is a selective agonist of cardiac β1receptor. • It is given for heart failure. But it is short acting, and no effective orally.

  41. Denopamine (地诺帕明） • Denopamine has distinct positive inotropic action when given orally and doesn’t increase heart rate.

  42. Section 2 Antianginal Drugs • Angina is the primary symptom of ischemic heart disease, characterized by a sudden, server pain originating in the chest, often radiating to the left shoulder and down the left arm. • Angina is the symptom of the coronary artery. • The latter is the supply route of blood carrying oxygen from the left ventricle to all heart tissues, including the ventricle themselves.

  43. Oxygen supplying • When the coronary artery becomesless efficient in supplying blood and oxygento the heart, the heart is said to be ischemic (short in oxygen). • Myocardial ischemia (心肌缺血) occurs when the oxygen is not efficient to meet the myocardial (心肌的) workload. • This can occur because of atherosclerotic narrowing of the coronary circulation (typical) or vasospasm (血管痉挛) of the coronary artery (variant).

  44. Oxygen requirements • The oxygen requirements of the myocardial tissues are related to the workload of the heart, which is, in part, a function of the heart rate, the systolic（心肌收缩的）pressure, and the peripheral resistance of the blood flow.

  45. Antianginal Drugs • Therapy of angina is directed mainly toward alleviating and preventing anginal attacks by dilating the coronary artery (increasing oxygen supply), veins (decreasing preload) and arteries (decreasing afterload ).

  46. Figure of Antianginal Drugs acting vasodilating, O2 preload heart rate afterload the force of cardiac contraction

  47. The class of Antianginal Drugs • 1. NO donor drugs • 2. Calcium antagonits (calcium channel blockers ) • 3.β-adrenergic antagonists (β-adrenergic blockers )

  48. (1) The Development of NO donor drugs • Organic nitrates have dominated the treatment of acute angina over 100 years after the antiaginal effect of amyl nitrite (亚硝酸异戊酯) was first observed in 1857. • Although the introduction of the calcium channel blockers and the β-adrenergic blockers as antianginal agents has expanded the physician’s therapeutic arsenal, organic nitrates are still the class of choice to treat acute anginal episode.

  49. Chemistry of nitrates • Organic nitrates are esters of simple organic alcohols or polyols with nitric acid.

  50. Nitrates in clinical use today

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