Drugs acting on circulation system and blood / blood- forming organs

Cardiovascular System

Overview of Cardiovascular System §Common Cardiac Diseases §Abnormal contractility ： Heart failures §Abnormal rhythms ： Arrhythmias §Abnormal blood supply ： Ischemic heart diseases §Myocardial disorders §Common vascular diseases §Abnormal systematic resistance ： Hypertension §Dysfunction of coronary vessles ： Coronary vascular diseases §Dysfunction of cerebral vessles ： Cerebral ischemia, hemorrhage §Dysfunction of pulmonary vessles ： Pulmonary hypertension §Dysfunction of peripheral vessles: P eripheral vascular disorder §Arteriosclerosis

Overview of Cardiovascular Drugs §Classification based on target organs §Heart ： Heart failures, arrhythmias, cardiac ischemia, over-load of the heart §Vessels ： Vasodilatation, vasoconstriction, arteriosclerosis §Classification based on the mechanisms §Ion channels ： Ca 2+, Na +, K + channels §Receptors ： Adrenoceptors, AT receptors, etc. §Enzymes ： ACEI 、 Na + -K + -ATPase 、 HMG-CoA reductase §Others ： Diuretics

Drugs affecting ion channels in CVS

A. General properties of ion channels in CVS §Properties of ion channels §Permeation §Selectivity §Gating voltage-gated § chemically gated: ligand-gated § cyclic nucleotide -gated § mechanosensitive § nongated background / leak channels

Ion transmembrane transport

Gating mechanisms of ion channels

A. General properties of ion channels in CVS §Voltage-gated ion channels §Na + channels §Ca 2+ channels §K + channels

Structure of α-subunit Voltagesensor

Na + Channels K + Channels Ca 2+ Channels

General structures of ion channels

A. General properties of ion channels in CVS §Functional regulation of voltage-gated ion channels § Activation (open) § Inactivation (close)

Gating modes of ion channels

A. General properties of ion channels in CVS §Ligand-gated ion channels

B. Drugs affecting ion channels in CVS Calcium channel blockers §1. Intracellular free Ca 2+ §(1) Ca 2+ inward flow Voltage-gated ： L, T, N, P, Q, R types § Voltage-gated ： L, T, N, P, Q, R types Chemically gated: NMDA receptor § Chemically gated: NMDA receptor §(2) Release of stored Ca 2+ IP 3 receptor § IP 3 receptor

§Box Voltage-gated calcium channels §L-type calcium channels §Activated at － 10 mV, inactivated at － 60 ～－ 90 mV; §Long lasting opening; §Distributed in myocardial and vascular tissues §T-type calcium channels §Activated at － 70 mV, inactivated at － 100 ～－ 60 mV; §Transient opening; §Distributed mainly in heart conduction system (S-A node), arterial walls, etc.

§2. Structures and functions of voltage-gated calcium channels 5 subunits § 5 subunits §  1 subunit is a more important structure § 4 domains, 6TM in each domain § S4: voltage sensor, ， S6: site of drug binding B. Calcium channel blockers

§3. Classification of calcium channel blockers §Selective calcium channel blockers §Dihydropyridines ( 二氢吡啶类 ): nifedipine 硝苯地平 nimoldipine 尼莫地平 nimoldipine 尼莫地平 amlodipine 氨氯地平 Phenylalkylamines ( 苯烷胺类 ): verapamil 维拉帕米 amlodipine 氨氯地平 Phenylalkylamines ( 苯烷胺类 ): verapamil 维拉帕米 §Benzothiazepines ( 苯硫卓类 ): diltiazem 地尔硫卓 §Non-selective calcium channel blockers B. Calcium channel blockers

Verapamil维拉帕米 Nifedipine硝苯地平Diltiazem地尔硫卓

§4. Pharmacological effects §(1) Cardiac effects §A. Negative inotropic effect ： excitation- contraction discoupling §B. Negative chronotropic and slowing conduction action: phase 4 of spontaneous depolarization and phase 0 of depolarization of slow response autonomic cells §C. Protective effect on cardiac ischemia B. Calcium channel blockers

§(2) Effects on smooth muscles A. Vascular smooth muscle: relaxing the arterial smooth muscles, especially coronary artery §B. Others ： smooth muscle of bronchus, gastrointestinal tract, ureter, uterus B. Calcium channel blockers

§(3) Anti-atherosclerosis § Alleviating Ca 2+ overload § Inhibit proliferation of smooth muscle cells and protein production of arterial matrix § Inhibit lipid peroxidation § Decrease cholesterol level §(4) Hemodynamic effects Improving membrane stability of erythrocytes § Improving membrane stability of erythrocytes Inhibiting platelet aggregation § Inhibiting platelet aggregation B. Calcium channel blockers

§(5) Others Kidney: Increase the blood flow of kidney § Kidney: Increase the blood flow of kidney § Endocrine: inhibiting the release of ACTH, TSH, insulin, etc. B. Calcium channel blockers

§5. Action modes §(1) actions on different functional states § § Activated （ 0 phase ） : verapamil § Inactivated （ 1~3 phases ） : diltiazem § Resting （ 4 phase ） : nifedipine B. Calcium channel blockers

verapamil diltiazem nifedipine Resting (closed) Activated (open) Inactivated (closed)

verapamil diltiazem nifedipine

§(2) Open frequency-dependency §Verapamil, diltiazem: frequency-dependent §Nifedipine: frequency-independent B. Calcium channel blockers

§6. Clinical uses §(1) Angina pectoris §Variant angina: §Variant angina: nifedipine §Stable angina: §Stable angina: verapamil, diltiazem §Unstable angina: §Unstable angina: verapamil, diltiazem, § nifedipine +  receptor blockers B. Calcium channel blockers

(2) Arrhythmias supraventricular tachycardia arrhythmias induced by triggered activity following after-depolarization arrhythmias induced by triggered activity following after-depolarization － verapamil, diltiazem － verapamil, diltiazem B. Calcium channel blockers

(3) Hypertension §Severe: nifedipine §Mild to moderate: verapamil, diltiazem §Complicated with coronary heart disease, myocardial ischemia, peripheral vascular diseases, bronchial asthma, chronic obstructive pulmonary diseases, etc. B. Calcium channel blockers

§(4) Cerebrovascular diseases transient ischemic attack, cerebral thrombosis cerebral thrombosis subarachnoid hemorrhage subarachnoid hemorrhage (5) Others peripheral vascular spasmodic disease arteriosclerosis arteriosclerosis etc. etc. B. Calcium channel blockers

§7. Adverse effects peripheral edema: nifedipine > verapamil > diltiazem symptoms of sympathetic excitation (heart rate increase): nifedipine symptoms of sympathetic excitation (heart rate increase): nifedipine heart rate reduced: verapamil, diltiazem heart rate reduced: verapamil, diltiazem hypotension: nifedipine hypotension: nifedipine §Contraindications ： hypotension (nifedipine); severe heart failure, sinus bradycardia, atrioventricular block (verapamil, diltiazem) B. Calcium channel blockers

§8. Special agents Nifedipine 硝苯地平 B. Calcium channel blockers

§(1) Pharmacological effects §Vessels: vasodilatation, hypotension, increase of cardiac output §Heart: reflex increase of heart rate, weak direct inhibiting effects §(2) Clinical uses §Angina pectoris ； hypertension ； peripheral vascular diseases; etc. §Slow releasing forms: adverse effects  ; action duration  §(3) Adverse effects §Hypotension; tachycardia; edema; headache, flushing, etc. B. Calcium channel blockers

Nimodipine 尼莫地平 Selectively acting on cerebral vasculature B. Calcium channel blockers

Verapamil 维拉帕米 Potent efficacy on the heart, and weak on the vessels B. Calcium channel blockers

Diltiazem 地尔硫卓 Potent efficacy on the heart and the vessels B. Calcium channel blockers

B. Drugs affecting ion channels in CVS Potassium channel modulators Potassium channel blockers Sulfonylureas: for treatment of diabetes Drugs under research Potassium channel openners Effects are similar to calcium channel blockers