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

Drugs Affecting Ion Channels in the Cardiovascular System

Currents involved in action potentials in purkinje cells

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

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

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

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

Ion channels in the cardiovascular system (3) Voltage-gated calcium channels Functions: muscle contraction neurotransmitter release automaticity and conductivity of slow response automatical cells 房室结的传导性取决于动作电位0期去极速度和幅度以及临近部位膜的兴奋性。

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

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) 窦房结的自律性：K通道影响最大复极电位水平和4期自动除极速度（与Ik的进行性衰减有关）

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 胞内钙浓度过高时，瞬时外向钾电流2钙依赖性开放，缩短动作电位时程，减少钙内流。 整流：当膜电位处在钾的电－化学平衡电位（ E K ）时，净跨膜钾流为零。当膜电位负于 E K 时， K + 内流；而当膜电位正于 E K 时， K + 外流。 通过内流和外流的调整将细胞静息膜电位控制在EK左右。因为膜电位往往高于静息电位，整流钾通道往往产生外向电流。Ikr/Ik1具有内向整流特性，去极化时外流小，超极化时的内向通透性大于去极化时的外向通透性。

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 ) 乙酰胆碱和去甲肾上腺素可以影响If（内向电流）大小，cAMP增加，If增强。 窦房结的If成分比较复杂，包括钾、钙、钠通道的参与。浦氏纤维的If主要是钠内流

Ion channels in the cardiovascular system 2. Ligand-gated ion channels (1) Muscarinic K channel (Ik(Ach)): Acetylcholine M2 receptor Ik(Ach) opened 窦房结起搏减慢，房室传导减慢 hyperpolarization

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. 复极加速，缩短动作电位时程有利于降低心脏收缩性，减少需氧量，但也容易导致缺血性心律失常。

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

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)

Drugs affecting ion channels in the cardiovascular system 3. Potassium channel openers (PCOs) A Mechanism: activate ATP-sensitive K channel (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

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) 粉防己碱双苄基异喹啉

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)

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

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

CCBs (钙拮抗剂) 三种钙通道阻滞药心血管效应的比较 负性肌力 负性频率 冠脉扩张 外周血管扩张 维拉帕米 + ++ +++ 地尔硫䓬 硝苯地平 -

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

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 红细胞内钙离子浓度与红细胞膜的脆性相关，浓度高容易发生溶血

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): nif 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

CCBs (钙拮抗剂) (4) Adverse effects: (5) Contraindications 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

Antianginal drugs 抗心绞痛药物

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

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.

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

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

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

Caused by atherosclerosis plaque and thrombus formation Classification of angina pectoris: Stable angina pectoris Unstable angina pectoris initial onset type accelerated type spontaneous type Variant/Prinzmetal’s angina pectoris Caused by atherosclerosis plaque and thrombus formation Caused by spontaneous spasm of coronary arteries

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

Oxygen delivery to the myocardium by the coronary circulation How does angina pectoris happen? Demand of the myocardium for oxygen Normal Ischemia Oxygen delivery to the myocardium by the coronary circulation

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

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

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

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

Organic nitrates CAD: coronal artery disease

Organic nitrates Mechanisms of action cGMP [Ca2+]i Vascular smooth muscle relaxation Anticoagulation of platelets Dephosphorylation of myosin light chain GC activated NO Nitrates (prodrug)

Organic nitrates Pharmacokinetics 硝酸甘油 Nitroglycerin 硝酸异山梨酯 Time to peak effect Duration of action 2 min 25 min Sublingual 硝酸甘油 Nitroglycerin 15 min 1 hour Sublingual 性质不稳定，遇光、热、空气易分解，首关消除明显 硝酸异山梨酯 Isosorbide dinitrate

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

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)

Organic nitrates Tolerance Drug interactions Easily induced by repeated uses Minimized by - provision of daily “nitrate-free interval” - supplement of –SH (food, drugs), Vc Drug interactions 万艾可(Viagra)、希爱力(Cialis)和艾力达(Levitra)：PDE5（在阴茎海绵体中高表达）抑制剂 Antihypertensive drugs Alcohol, Viagra and similar drugs

Story time Something’s Gotta Give

Propranolol Metoprolol Atenolol 普萘洛尔 美托洛尔 阿替洛尔 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 ) 抑制脂肪分解酶活性，减少FFA

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

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 cells by inhibiting Ca2+ overload - Inhibit coagulation of platelets

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

Calcium channel blockers, CCBs Adverse effects: - peripheral edema - sympathetic excitation (nif) - cardiac inhibition (ver, dil) - hypotension (nif) Contraindications: - hypotension - severe heart failure - sinus bradycardia - atrioventricular block

Combination of anti-anginal drugs 作用 硝酸酯类 受体阻断药 CCBs 硝苯地平 维拉帕米 硝酸酯类+ 受体阻断药 动脉压    心率  心肌收缩力 不变或降低 射血时间 不变 左室舒张末压 - Caution: Hypotension, low cardiac perfusion, bradycardia, A-V block

(ACEIs, β blocker, CCBs, Diuretics)