Pharmacology of the cardiovascular system

1. Pharmacology of the cardiovascular system 浙江大学医学院药理学系 张世红 shzhang713@zju.edu.cn

2. Drugs Affecting Ion Channels in the Cardiovascular System 1. Ion channels in the cardiovascular system 2. Drugs affecting ion channels in the cardiovascular system

3. Currents involved in action potentials in purkinje cells

4. Ion channels in the cardiovascular system Main characteristics of ion channels: • Permeation • Selectivity • Gating • Voltage-gated channels • Ligand-gated channels • Mechanosensitive channels • Non-gated background/leak channel

5. Ion channels in the cardiovascular system 1. Voltage-gated sodium (Na), calcium (Ca), potassium (K) channels (1) Structures

6. A typical structure of voltage-gated ion channel (exception for K+ channels)

7. Ion channels in the cardiovascular system (2) Voltage-gated sodium channels • Functions: phase 0 depolarization; phase 4 automatic depolarization • Deficiency of change from activated state to inactivated state causes arrhythmias

8. Ion channels in the cardiovascular system (3) Voltage-gated calcium channels • Functions: • muscle contraction • neurotransmitter release • automaticity and conductivity of slow response automatic cells

9. Ion channels in the cardiovascular system (3) Voltage-gated calcium channels • Origin and elimination of intracellular calcium: • extracellular calcium influx • calcium store release • calcium pump and Na+-Ca2+ exchange • L, T, N, P, Q, R, and ligand-gated types. • Primary types in cardiovascular system are L- and T- type

10. Ion channels in the cardiovascular system (4) Voltage-gated potassium channels • Functions: • resting potential • action potential duration • heart rate (affecting maximal repolarization potential and phase 4 spontaneous depolarization rate)

11. Ion channels in the cardiovascular system (4) Voltage-gated potassium channels • Classification a Transient outward K channel (Ito): Ito1 and Ito2, contribute to phase 1 b Delayed rectifier K channel (Ik): slowly activating component (Iks): phase 2 rapidly activating component (Ikr): phase 3 ultrarapidly activating component (Ikur): atrium repolarization c Inward rectifier K channel (Ik1): phase 3 and 4

12. Ion channels in the cardiovascular system (5) Pacemaker channel ( If) • Exist in autonomic cells (sinoatrial node, atrioventricular node, purkinje system ) • Activated when membrane hyperpolarized • Inward current because of Na+/K+/Ca2+ permeation • Regulated by neurotransmitter and intracellular cAMP level (phosphorylation of channel protein )

13. Ion channels in the cardiovascular system 2. Ligand-gated ion channels (1) Muscarinic K channel (Ik(Ach)): Acetylcholine M2 receptor Ik(Ach) opened hyperpolarization

14. Ion channels in the cardiovascular system 2. Ligand-gated ion channels (2) ATP-sensitive K channel (Ik(ATP)) : APD is shortened and cellular excitability is decreased at the presence of ischemia, hypoxia and decreased metabolism.

15. Drugs affecting ion channels in the cardiovascular system 1. Sodium channel blockers • local anesthetics • AEDs • anti-arrhythmic drugs: classⅠ

16. Drugs affecting ion channels in the cardiovascular system 2. Potassium channel blockers (PCBs) Selective blockers: Apamin (蜂毒明肽, Ca-activated) Sulfonylurea (磺酰脲类, ATP-sensitive) CTX (北非蝎毒素, Ito) New Class III anti-arrhythmic agents (Ikr) Non-selective blockers: TEA (tetraethylammonium, 四乙铵) 4-AP (4-aminopyridine, 4-氨基吡啶)

17. Drugs affecting ion channels in the cardiovascular system 3. Potassium channel openers (PCOs) A Mechanism:activate ATP-sensitive Kchannel (diazoxide二氮嗪, nicorandil尼可地尔, pinacidil吡那地尔, minoxidil米诺地尔, cromakalim克罗卡林) to dilate arteries B Therapeutic uses: Anti-hypertension Anti-angina and myocardial infarction Congestive heart failure

18. Drugs affecting ion channels in the cardiovascular system 4. Calcium channel blockers (CCBs) (1) Classification of CCBs: Class I: blocks L-type a：phenylalkylamines (苯烷胺类): verapamil (ver, 维拉帕米) b：benzothiazepines (苯硫䓬类): diltiazem (dil, 地尔硫䓬) c：dihydropyridines (二氢吡啶类): nifedipine (硝苯地平, nif) ，nimoldipine (尼莫地平)， amlodipine (氨氯地平) d：tetrandrine (粉防己碱)

19. Drugs affecting ion channels in the cardiovascular system 4. Calcium channel blockers (CCBs) (1) Classification of CCBs: Class II: blocks other types T type: mibefradil (米贝地尔), ethosuximide (乙琥胺) N type: phenytoin (苯妥英钠), conotoxins (芋螺毒素) P type: spider toxin Class III: non-selective agents prenylamine (普尼拉明)，flunarizine (氟桂利嗪)

20. Calcium channel blockers (CCBs) (2) Actions A Heart (ver, dil) - Negative inotropic action负性肌力作用: excitation-contraction discoupling; - Negative chronotropic and dromotropic action负性频率和传导作用: inhibit spontaneous depolarization in phase 4 and depolarization in phase 0 of slow response autonomic cells

21. CCBs (钙拮抗剂) (2) Actions B Smooth muscle (nif) - Vascular smooth muscle: relax the tone of artery, especially coronary and cerebral arteries; - Others: relax smooth muscle of bronchus, gastrointestinal tract, ureter输尿管, uterus子宫

22. CCBs (钙拮抗剂) 三种钙通道阻滞药心血管效应的比较

23. CCBs (钙拮抗剂) (2) Actions C Anti-atherosclerosis抗动脉粥样硬化 - Reduce Ca2+ overload - Inhibit proliferation增殖 of smooth muscle cells and protein production of arterial matrix - Inhibit lipid peroxidation脂质过氧化 - Decrease cholesterol胆固醇 level

24. CCBs (钙拮抗剂) (2) Actions D Erythrocytes红细胞 and platelets血小板 - Improve membrane stability of erythrocytes - Inhibit platelet activation E Kidney - Increase the blood flow of kidney

25. CCBs (钙拮抗剂) (3) Clinical uses : A Angina pectoris (心绞痛) B Arrhythmias (心律失常): ver, dil C Hypertension (高血压) D Cerebrovascular diseases (脑血管病): 尼莫地平 transient ischemia attack, cerebral thrombosis 脑血栓, and cerebral embolism脑栓塞 E Other diseases: peripheral vascular spasmodic disease, arteriosclerosis, migraine偏头痛

26. CCBs (钙拮抗剂) (4) Adverse effects: A Peripheral edema B Sympathetic excitation (nif) C Bradycardia (ver, dil) D Hypotension (nif) (5) Contraindications A Hypotension B Severe heart failure C Sinus bradycardia D Atrioventricular block

27. Antianginal drugs 抗心绞痛药物

28. Outline • Overview • Antianginal drugs -Organic nitrates - β-blockers - Calcium channel blockers • Combination of antianginal drugs

29. Overview:Angina pectoris 心绞痛 Frequency: in America, about 6.3 million people are estimated to experience angina. An estimated 350,000 new cases of angina occur every year. One million died of angina each year in China A comprehensive approach to diagnosis and to medical management of angina is an integral part of the daily responsibilities of physicians.

30. Symptoms: Sudden, uncomfortable pressure, fullness, squeezing or severe substernal pain, radiating to the left arm, shoulders, neck, etc.

31. Leading Sources of Disease Burden* • Ischemic Heart Disease • Unipolar Major Depression • Cardiovascular Disease • Alcohol Use • Traffic Accidents • Lung and Other Cancers • Dementia and Neurodegenerative Disorders *Based on DALY’s (Disability Adjusted Life Years, WHO) which measure lost years of healthy life due to premature death or disability

32. 胆固醇 http://www.who.int/healthinfo/global_burden_disease/GlobalHealthRisks_report_full.pdf

33. Classification of angina pectoris: • Stable angina pectoris • Unstable angina pectoris initial onset type accelerated type spontaneous type angina at rest Variant angina pectoris • Mixed angina pectoris Effort angina Caused by atherosclerosis plaque and/or thrombus formation Caused by spontaneous spasm of coronary arteries

34. Extreme weather Strong emotion Excessive exercise Excessive food intake Excessive smoking • Stable and unstable angina pectoris usually occur on following conditions • Variant angina: usually occur when a person is at rest between midnight and 8am

35. How does angina pectoris happen? Demand of the myocardium for oxygen 动脉粥样硬化斑块和血栓形成 Normal Ischemia 冠脉痉挛 Oxygen delivery to the myocardium by the coronary circulation

36. Factors disturb the balance between oxygen demand and delivery • Demand • Preload (venous return ) • Afterload (arteriolar resistance) • Heart rate • Delivery • Atherosclerosis plaque • Thrombus • Spasm of coronary arteries

37. Strategies for angina treatment Decrease the oxygen demand and/or increase the delivery BY - Dilating arteries, especially coronary arteries, including relieving spasm and opening collateral circulation - Dilating veins - Cardiac inhibition: decrease HR, contractility, tensility of myocardium - Antiatherosclerosis and prevention of thrombosis

38. Antianginal drugs • Organic nitrates • -receptor blockers • Calcium channel blockers • Other drugs (ACEIs, nicorandil尼可地尔, molsidomine吗多明)

39. Organic nitrates （硝酸酯类） Nitroglycerin（硝酸甘油） Isosorbide dinitrate（硝酸异山梨酯，消心痛） Isosorbide mononitrates（单硝酸异山梨酯） • Actions • Dilate vessels: • - Dilate veins and arteries, decrease pre/after-load and cardiac oxygen demand • - Dilate coronary arteries, epicardial vessels and open collateral circulation, redistribute blood to ischemic area • - Decrease LVFP, increase blood to subendocardial area • Protect myocardial cells against ischemic injury • Anticoagulation of platelets

40. Organic nitrates CAD: coronal artery disease

42. Time to peak effect Duration of action 2 min Sublingual 25 min 15 min Sublingual 1 hour Organic nitrates Pharmacokinetics 硝酸甘油 Nitroglycerin 硝酸异山梨酯 Isosorbide dinitrate

43. Organic nitrates Clinical uses • Angina pectoris • Acute myocardial infarction • Chronic heart failure • Acute respiratory failure and pulmonary arterial hypertension

44. Organic nitrates Adverse effects • Symptoms due to vasodilation: headache, tachycardia, postural hypotension, increase in intraocular and/or intracranial pressure, and facial flushing • Allergy • Methaemoglobinaemia (高铁血红蛋白血症，at very high doses)

45. Organic nitrates Tolerance • Easily induced by repeated uses • Minimized by • - provision of daily “nitrate-free interval” • - supplement of –SH (food, drugs), Vc Drug interactions • Antihypertensive drugs • Alcohol, Viagra and similar drugs

46. Story time Something’s Gotta Give

47. β-blockers Propranolol Metoprolol Atenolol 普萘洛尔 美托洛尔 阿替洛尔 Actions - Inhibit cardiac contractility, decrease O2 demand - Increase blood supply to ischemic area: perfusion time , vascular tone in normal tissues  - Improve myocardial metabolism (FFA )

48. β-blockers Clinical uses: - stable and unstable angina pectoris, especially associated with hypertension or arrhythmias, even with myocardial infarction. - NOT used for variant angina. Notices: Start from small doses Withdraw gradually (rebound phenomenon) Better when combined with nitroglycerin Cardiac depression

49. Calcium channel blockers, CCBs Actions contributing to anti-anginal effect : - Decrease myocardial oxygen consumption - Increase myocardial blood supply: dilate coronary vessels, open collateral circulation - Protect ischemic myocardial cellsby inhibiting Ca2+ overload - Inhibit coagulation of platelets

50. Calcium channel blockers, CCBs Clinical uses: - Stable and unstable angina: ver, dil, nif+  blockers - Variant angina: nif, dil, ver