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Section III

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

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Section III

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  1. Section III Circulation system

  2. 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

  3. 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

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

  5. ion channel Modes of solute transmembrane transport

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

  7. Ion transmembrane transport

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

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

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

  11. Na+ Channels K+ Channels Ca2+ Channels

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

  13. Gating modes of ion channels

  14. Ligand-gated ion channels

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

  16. B. Drugs affecting ion channels in CVSCalcium 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

  17. Calcium channels

  18. BoxVoltage-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.

  19. 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

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

  21. 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

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

  23. 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

  24. 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

  25. Mechanism of calcium channel blocker on myocardial and vascular smooth muscle

  26. 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

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

  28. 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

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

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

  31. B.Calcium channel blockers (3) Hypertension • nifedipine; verapamil, diltiazem • Complicated withcoronary heart disease, myocardial ischemia, peripheral vascular diseases, bronchial asthma, chronic obstructive pulmonary diseases, etc.

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

  33. 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)

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

  35. 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.

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

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

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

  39. B.Calcium channel blockers

  40. B. Drugs affecting ion channels in CVSPotassium 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

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

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