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 6 Cardiovascular Drugs
Part 1 Drugs affecting ion channels in CVS

5. Modes of solute transmembrane transport
ion channel
Modes of solute transmembrane transport

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

7. Ion transmembrane
transport

8. 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

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

10. General structure of ion channels Structure of -subunit
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 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

17. Calcium channels

18. 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.

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. Binding sites of antagonists on L-type calcium channels
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. 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

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 with coronary 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 Selectively acting on cerebral vasculature
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. Diltiazem 地尔硫卓 B. Calcium channel blockers艹
Potent efficacy on the heart and the vessels

39. B. Calcium channel blockers

40. 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

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