Section III Circulation system

Overview of Cardiovascular Diseases 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 vessels：Coronary vascular diseases Dysfunction of cerebral vessels：Cerebral ischemia, hemorrhage Dysfunction of pulmonary vessels：Pulmonary hypertension Dysfunction of peripheral vessels: Peripheral vascular disorder Arteriosclerosis

Overview of Cardiovascular Drugs Classification based on target organs/tissues Heart：Heart failures, arrhythmias, cardiac ischemia, over-load of the heart Vessels：Vasodilatation, vasoconstriction, arteriosclerosis Classification based on the mechanisms Ion channels：Ca2+, Na+, K+ channels Receptors：Adrenoreceptors, AT1 receptors, etc. Enzymes：ACEI, Na+-K+-ATPase, HMG-CoA reductase Others：Diuretics

Chapter 6 Cardiovascular Drugs Part 1 Drugs affecting ion channels in CVS

Modes of solute transmembrane transport ion channel Modes of solute transmembrane transport

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

Ion transmembrane transport

Gating mechanisms of ion channels Chemically gated Ligand-gated Chemically gated Phospharylation-gated: G protein / second massagers Gating mechanisms of ion channels Voltage-gated Mechanosensitive

A. General properties of ion channels in CVS Voltage-gated ion channels Na+ channels Ca2+ channels K+ channels

General structure of ion channels Structure of -subunit filter voltage sensor General structure of ion channels Structure of -subunit

Na+ Channels K+ Channels Ca2+ 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

Ligand-gated ion channels

G protein/cyclic nucleotide-gated ion channels cyclic AMP  subunit of G protein

B. Drugs affecting ion channels in CVS Calcium channel blockers 1. Intracellular free Ca2+ (1) Ca2+ inward flow Voltage-gated： L, T, N, P, Q, R types Chemically gated: NMDA receptor (2) Release of stored Ca2+ IP3 receptor

Calcium channels

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.

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

Binding sites of antagonists on L-type calcium channels dihydropyridines verapamil Binding sites of antagonists on L-type calcium channels

B. Calcium channel blockers 3. Classification of calcium channel blockers Calcium channel blockers: The drugs which selectively act on voltage-gated calcium channels and block influx of Ca2+ Selective calcium channel blockers Dihydropyridines (二氢吡啶类): nifedipine 硝苯地平 nimoldipine 尼莫地平 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 艹 艹

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

B. Calcium channel blockers 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, urine tract, uterus

Mechanism of calcium channel blocker on myocardial and vascular smooth muscle

B. Calcium channel blockers (3) Anti-atherosclerosis Alleviating Ca2+ overload Inhibiting proliferation of smooth muscle cells and protein production of arterial matrix Inhibiting lipid peroxidation Decreasing cholesterol level (4) Hemodynamic effects Improving membrane stability of erythrocytes Inhibiting platelet aggregation

B. Calcium channel blockers (5) Others Kidney: increasing 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: verapamil Inactivated: diltiazem Resting: nifedipine (2) Open frequency-dependency Frequency-dependent: verapamil, diltiazem Frequency-independent: nifedipine

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

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

B. Calcium channel blockers (3) Hypertension nifedipine; 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, subarachnoid hemorrhage (5) Others peripheral vascular spasmodic disease, arteriosclerosis etc.

B. Calcium channel blockers 7. Adverse effects peripheral edema: nifedipine > verapamil > diltiazem symptoms of sympathetic excitation (heart rate increase): nifedipine reduced heart rate: verapamil, diltiazem 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 Selectively acting on cerebral vasculature 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

Diltiazem 地尔硫卓 B. Calcium channel blockers 艹 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 openers nicorandil (尼可地尔), pinacidil (吡那地尔), cromakalim (克罗卡林) Effects are similar to calcium channel blockers

B. Drugs affecting ion channels in CVS Sodium channel blockers Local anesthetics Antiarrythmic drugs (class I)