Chapter 32 Antianginal drugs

1. China Medical University Chapter 32 Antianginal drugs Cardiovascular pharmacology

2. Angina • Angina is a specific type of pain in the chest caused by inadequate blood flow through the blood vessels (coronary vessels) of the heart muscle (myocardium). • So coronary flow does not meet the metabolic needs of the heart, a radiating chest pain ---anginal pain –results .

3. The heart as pump Left anterior descending

4. pathology Contractility Coronary Blood Flow Oxygen Supply Oxygen Demand Heart Rate LV Wall Tension Systolic BP LV Volume Ischemia LV Dysfunction Arrhythmias Chest Pain

5. Coronary atherosclerosis • Coronary artery spasm • Transient platelet aggregation and coronary thrombosis • Endothelial injury causing the accumulation of vasoconstrictor substances. • Coronary vasoconstriction following adrenergic stimulation Causes of angina

9. Classification of angina : • Stable or classical angina is due to fixed stenosis 狭窄of the coronary arteries, and is brought on by exercise and stress. • Unstable angina can occur suddenly at rest, and becomes progressively worse, with a increase in the number and severity of attacks. • Variant angina occurs at rest, at the same time each day, and usually due to coronary artery spasm .

10. Classifications of treatment medicine • Nitrate esters : Nitroglycerin Isosorbide dinitrate (IDN) 硝酸异山梨酯 •  receptor blocker : Propranolol Atenolol Metoprolol • Calcium channel blockers: Verapamil Diltiazem Nifedipne Unstable angina is treated with: • Aspirin (reduces platelet aggregation)

11. Nitrate esters CH NO O 2 2 CH NO Nitroglycerin 硝酸甘油 O 2 CH NO O 2 2 O Isosorbide Dinitrate 硝酸异山梨酯 O NO 2 CH CH CH CH CH CH 2 2 Isosorbide -5-Mononitrate 5’-单硝酸异山梨酯 O NO 2 O O O NO 2 CH CH CH CH CH CH 2 2 O H O

12. Pharmacological Function: Nitroglycerin 硝酸甘油 • Dilatation of the veins and artery decreases preload and afterload thus the oxygen demand of the heart • Dilatation of the coronary arteries increases blood flow and oxygen delivery to the myocardium. Increase the heart rate

13. Mechanism of action: Nitrate esters Nitroglycerinare prodrugs, decomposing to form nitric oxide (NO), which activates guanylyl cyclase (GC) ,thereby increasing the levels of cyclic guanosine monophosphate (cGMP). Protein kinase G is activated and contractile proteins are phosphorylated. NO active SMC or EC（GC） cGMP active cGMP dependent PK-PKG Ca2+ inner cell VSM dilation Inhibit platelet aggregation and adhesion

15. Route of administration: Nitroglycerin is administered sublingually , and can be given by intravenous infusion orfrom patches. Indication: Nitroglycerinis given for the prophylaxis预防and treatment of angina－ Stable angina

16. Adverse effects： The side effects of nitroglycerin include postural hypotension, tachycardia, headache ,flushing and dizziness. Therapeutic notes: To avoid nitrate tolerance, a drug-free period of approximately 8 hours is needed.

17. -receptor blocker • Propranolol 普奈洛尔 • Pindolol 吲哚洛尔 • Timolol 噻吗洛尔 Metoprolol 美托洛尔 Atenolol 阿替洛尔

18. Pharmacological Function: -blockers block 1- adrenoreceptors in the heart. this causes a decrease in heart rate (slowing of phase 4) in systolic blood pressure in cardiac contractile activity and in myocardial oxygen demand. 1

19. 2) Improve the myocardial metabolism 3) Increases blood flow and oxygen of The ischemia region 4) Promote the oxygen release from the Hb Inhibit platelet aggregation

20. Clinical utilization: To • Stable or classical angina • (specially to patient who concurring the fast heart rate and hypertension ) • Unstable angina not suitable to Variant angina  receptor （一） α receptor will be predominate coronary artery spasm

21. Contraindications and notes • Related to heart: • Bradycardia, hypotention, AV block, and CHF • Asthmatic 哮喘 • β1 receptor up-regulation So slowly reduce the doses

22. Calcium-channel blockers Examples of calcium-channel blockers include Verapamil Diltiazem Nifedipine block L-type calcium channels, thereby reducing calcium entry into cardiac and vascular cells block L-type calcium channels in vascular cells,

23. Pharmacological Function: • This decrease in intracellular calcium →reduces cardiac contractility and causes vasodilatation, which results in several effects: • Reduced preload due to the reduced venous pressure; • Reduced afterload due to the reduced arteriolar pressure; Increased coronary blood flow; • Reduced cardioc contractility • decreased heart rate • anti-sympathetic activity reduced myocardial oxygen consumption

24. Coronary vascular dilatation promote the opening of side branch Inhibit platelet aggregation Increase the supply of blood Protect the ischemic myocardial Clinical uses Treatment of angina Variant angina Verapamil is given for supraventricular arrhythmias

25. others Dipyridamole 双嘧达莫 潘生丁 Nicorandil 尼可地尔 Dipyridamol causes inhibition of adenosine uptake, resulting in the accumulation of adenosine within the tissue. Adenosine is an endogenous vasodilator---the effect is pronounced on arterioles Nicorandilincrease the cGMP，active the channel of potassium ,dilate the coronary vessels

26. conjunction use Nitrate esters + Calcium-channel blockers Amlodipine 氨氯地平 络活喜 -receptor blocker ＋ Calcium-channel blockers Nitrate esters+ -receptor blocker

27. N- Nitrate esters B -β -receptor blocker Notes：↑= increase，↓=decrease，→= no change，↓↑= unsure

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