Cardiovascular Cardiovascular pharmacologypharmacology

Chapter 32 Antianginal drugsChapter 32 Antianginal drugs

China Medical University

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 .

The heart as pump

Left anterior descending

CoronaryBlood Flow

Oxygen Supply

Oxygen Demand

Systolic BP

LV Volume

Contractility

Heart Rate

LV Wall Tension

Arrhythmias

Ischemia

LV Dysfunction Chest Pain

pathology

Causes of angina

• Coronary atherosclerosis

• Coronary artery spasm

• Transient platelet aggregation and coronary thrombosis

• Endothelial injury causing the accumulation of vasoconstrictor substances.

• Coronary vasoconstriction following adrenergic stimulation

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 .

Classification of angina :Classification of angina :

• 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)

Classifications of treatment medicine

Nitrate esters CH2

CH2

CH

O NO2

O NO2

O NO2

Nitroglycerin 硝酸甘油

CH2 CH CH CH CH CH2

O NO2

O NO2

O

O

CH2 CH CH CH CH CH2

O NO2

O H

O

O

Isosorbide Dinitrate硝酸异山梨酯

Isosorbide -5-Mononitrate5’- 单硝酸异山梨酯

Nitroglycerin 硝酸甘油

Dilatation of the coronary arteries increases blood flow and oxygen delivery to the myocardium.

Pharmacological Function:CH2

CH

CH2

O NO2

O NO2

O NO2

Dilatation of the veins and artery decreases preload and afterload thus the oxygen demand of the heart

Increase the heart rate

Nitroglycerin are 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.

Mechanism of action:

active

Ca2+ inner cell

VSM dilation

NO

cGMP dependent PK-PKG

SMC or EC （ GC ）

cGMP

Nitrate esters

active

Inhibit platelet aggregation and adhesion

Nitroglycerin is administered sublingually , and can be given by intravenous infusion or from patches.

Nitroglycerin is given for the prophylaxis预防 and treatment of angina － Stable angina

Route of administration:

Indication:

The side effects of nitroglycerin include postural hypotension, tachycardia, headache ,flushing and dizziness.

To avoid nitrate tolerance, a drug-free period of approximately 8 hours is needed.

Adverse effects ：

Therapeutic notes:

-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

Pharmacological Function:

-blockers-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

2) Improve the myocardial metabolism 3) Increases blood flow and oxygen of The ischemia region4) Promote the oxygen release from the Hb

Inhibit platelet aggregation

Clinical utilization:

• 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

To

Contraindications and notes

• Related to heart:

Bradycardia, hypotention, AV block, and CHF

• Asthmatic 哮喘

•β1 receptor up-regulation

So slowly reduce the doses

Calcium-channel blockers

Verapamil

Diltiazem

Nifedipine

Examples of calcium-channel blockers include

block L-type calcium channels, thereby reducing calcium entry into cardiac and vascular cells

block L-type calcium channels in vascular cells,

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

Pharmacological Function:

Coronary vascular dilatation promote the opening of side branch Inhibit platelet aggregation

Increase the supply of blood

Protect the ischemic myocardial

Treatment of angina Variant angina

Verapamil is given for

Clinical uses

supraventricular arrhythmias

othersDipyridamole 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

Nicorandil increase the cGMP ， active the channel of potassium ,dilate the coronary vessels

conjunction use

Nitrate esters + Calcium-channel blockersAmlodipine 氨氯地平 络活喜

-receptor blocker ＋ Calcium-channel blockers

Nitrate esters+ -receptor blocker

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

Factor Nitrate esters-receptor blocker

Calcium-channel blockers

Wall Tenson 室壁张力 ↓ ± ↓

LV volume心室容量 ↓ ↑ ±

Ventricularpressure 心室压力

↓ ↓ ↓

rate 心 率 ↑ ↓ ±

contractility 收缩性 ↑ ↓ ±

心内膜 / 心外膜 blood ratio 血流比率

↑ ↑ ↑

the flow of side branch 侧枝血流 ↑ → ↑

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