L8 Agents used in Heart Failure and Cardiac Arrhythmias

一、Heart Failure

Results from any structural or functional abnormality that impairs the ability of the ventricle to eject blood (Systolic Heart Failure) or to fill with blood (Diastolic Heart Failure)

Systolic failure: reduced mechanical pumping action (contractility)and reduced ejection fraction: failure in excitation-contraction coupling

Diastolic failure: stiffening and loss of adequate relaxation results in reduced filling and cardiac output

Final common pathway for many cardiovascular diseases whose natural history results in symptomatic or asymptomatic left ventricular dysfunction (less blood coming out of heart)

Cardinal manifestations of heart failure include dyspnea (呼吸困难) , fatigue and pulmonary edema

Risk of death is 5-10% annually in patients with mild symptoms and increases to as high as 30-40% annually in patients with advanced disease

Overview of congestive heart failure

Congestive heart failure (CHF) is a condition in which the heart is unable to pump sufficient blood to meet the needs of body.

CHF can be caused by increased workload imposed on the heart.

CHF is accompanied by abnormal increases in blood volume and interstitial fluid; the heart, veins, and capillaries are therefore generally dilated with blood.

symptoms include pulmonary congestion with left heart failure, and peripheral edema with right heart failure.

Underlying causes of CHF include arteriosclerotic heart disease, hypertensive heart disease, valvular heart disease(心瓣膜病), dilated cardiomyopathy(扩张性心肌病), and congenital heart disease(先天性心脏病)

The Vicious Cycle of Heart Failure

NE: Norepinephrine;
AII: Angiotensisn II
ET: Endothelin;
Therefore, targeting the SNS and RAS,together with vasodilators, will help to treat HF

Compensatory changes in heart failure

Activation of Sympathetic Nerve System

Activation of Renin-Angiotensin System

Increased heart rate

Release of Aldosterone Hormone (vaso-constriction)

Release of atrial natriuretic peptide 心钠素

Chamber enlargement 心室腔扩大

Myocardial hypertrophy 心室肥厚

二、Cardiac Contractility

Control of normal cardiac contractility

Sensitivity of contractile proteins to calcium
Amount of calcium released from SR
Amount of calcium stored in SR
Amount of trigger calcium entering cell
Activity of sodium-calcium antiporter 6.Activity of Na+/K+-ATPase

Strategy of treatment of CHF

The therapeutic goal for CHF is to increase cardiac output

Inotropic agents that increase the strength of contraction of cardiac muscle
PDEI (phosphodiesterase inhibitors) agents that increase cAMP to induce systoles and vasodilatation
Calcium sensitizers extracellular fluid volume
β adrenergic agonist
β adrenergic antagonist
Vasodilators: Calcium channel blocker
Decreasing RAS activity: ACEI and AT1 antagonist
Diuretic agents

Treatment of congestive heart failure

1. Positive inotropic drugs

Cardiac glycosides
β-adrenergic agonists (New dopamine receptor agonist)
phosphodiesterase inhibitors
Calcium sensitizers

Cardiac glycosides/强心苷类

An inotrope is an agent that alters the force or energy of muscular contractions. Negatively inotropic agents weaken the force of muscular contractions. Positively inotropic agents increase the strength of muscular contraction

prevent calcium efflux

The Unsaturated lactone（不饱和内酯环）Convey cardiotonic activity
The steroid nucleus（甾核）Convey the pharmacological activity
The Sugars- 3 mols. of digitoxose (3分子洋地黄毒糖) Modulate potency and pharmacokinetic distribution

(1) Machanism of cardiac glycoside on positive inotropic action

Inhibiting Na+-K+-ATPase in therapeutic dose:
Increasing of calcium inward and induce the releasing of calcium from sarcoplasmic reticulum

(2) Pharmacologic action

Action of cardiac glycosides on the heart

Positive inotropic action：Increasing contractility of cardiac muscle in heart failure.
- characteristic:
  - myocardiac quick contraction↓
    - rate of force ↑
    - time to peak tension ↓
- Effect of positive inotropic act
  - cardiac output is increased
  - compensatory sympathetic tone is reduced
  - cardiac preload and afterload is decreased
  - heart rate is reduced
  - myocardiac fiber tone and oxygen consumption is decreased
Negative chronotropic (heart-rate change) action
- Continuous effect of positive inotropic action → increased cardiac output, heart rate is decreased (due to dereased sympathetic tone)
- Chronotropic drugs may change the heart rate and rhythm by affecting the electrical conduction system of the heart and the nerves that influence it, such as by changing the rhythm produced by the sinoatrial node. Positive chronotropes increase heart rate; negative chronotropes decrease heart rate.
- The CO is determined by heart rate and muscle contraction strength

(3) Clinical uses

Cardiac glycosides are given for CHF

，
- Best ：go with atrial fibrillation
- Better：hypertension congenital heart disease

Some kinds of arrhythmias (abnormal heart rate)

Atrial fibrillation
Atrial flutter
Supraventricular Tachycardia

β-Adrenoceptor agonists

They are used intravenously in CHF emergencies

Example of β-Adrenoceptor agonists :

Dobutamine (多巴酚丁胺)

Exciting β1 Adrenoceptor → positive inotropic action →the volume of output↑
Exciting β2 Adrenoceptor→dilate the vascular → afterload↓

have benefits within short time

Phosphodiesterase-Ⅲ inhibitors

Inodilator / inodilating drugs

Inhibiting the activity of PDE Ⅲ → cAMP↑→ causes an increase in myocardial contractility and vasodilatation →total peripheral resistance ↓ →cardiac output ↑

Examples:

Armirinone（氨力农）: Inhibits the excess product of NO, TNF and affects the neurohormone, anti-the forming of thrombus
milrinone（米力农）: stronger 20 time
vesnarinone（维司力农）: myocardial contract element’s
the sensitivity to calcium ↑

Calcium sensitizers

Pimobendan 匹莫苯:

Inhibit PDE Ⅲ ; increase TnC’s sensitivity to calcium

Tn troponin—肌钙蛋白；myosin－肌球蛋白；tropomyosin－原；Actin 肌动蛋白

2. Diuretics

Diuretics inhibit sodium and water retention, →reduce the volume of blood, →venous pressure and the thus cardiac preload are reduced↓, increasing the efficiency of the heart as a pump→ cardiac output ↑, so reduce oedema due to heart failure

Heart failure

Low-grade : Thiazides hydrochlorothiazide 氢氯噻嗪
Higher-grade : Acute left heart failure
loop diuretics — furosemide 呋塞米（速尿）
Spironolacton 螺内酯
- （anti-aldosterone ,keep potassium and diuretics)

3. Vasodilators

Calcium channel blocker
Nitryl-vasodilators
Hydralazine

Angiotensin-converting-enzyme inhibitor (ACEI )

Example: Captopril Enalapril

Methanism of anti-CHF:

Humour: Inhibit ACE→angiotensin Ⅱ and aldosterone levels↓, reduce sodium retention, increase bradykinin levels , ANP、 NO、PGI2↑, reduce the release of NA ET and renew the expression of βreceptor
This therefore causes vasodilatation (include coronary artery) →reduction in peripheral resistance→ increase the cardiac output, Increase the blood flow of kidney so Improve the function of kidney
Prevent the remodel of the heart

vesodilation → reduce preload

AT1 antiagonists

Losartan （氯沙坦）

The function just like ACEⅠ

Clinical utilize:

CHF (Congestive heart failure)
Protection of kidneys

Calcium-channel blockers

Amlodipine 氨氯地平

Blood Vessel Targeting
Dilate artery
Dilate the coronary
Alleviate the LV Wall Tension

Others –Vasodilators: for phrephoiral

for heart failure patients, the pre and afterload should be both low by using drugs low afterload: prevent CO to decrease

mechanism: Finally Decrease the oxygen demand of the heart

Dilatation of the veins→ decreases preload
Dilatation of the artery→ decreases afterloads

Examples:

Nitrate esters: nitroglycerin , nitroprusside sodium 硝普纳
Hydralazine 肼屈嗪 direct dilate the vascular
Prazosin 哌唑嗪 ɑ-receptor blocker

4. RAAS inhibitors

antiotensin converting enzyme inhibitor and AT1 antagonist

Combine drugs to treat heart failure to increase CO and induce vessel dilation at the same time, to prevent entering into the vicious cycle

The same as combining drugs to treat HTN: inducing vessel dilation while decreasing CO

三、Agents used in Cardiac Arrhythmias

Definition of arrhythmia: irregular heart beat

Arrhythmias and disrhythmias are the same thing. Cardiac arrhythmia is an abnormality of the heart rhythm

Bradycardia – heart rate slow (<60 beats/min) 心动过缓
Tachycardia – heart rate fast (>100 beats/min) 心动过速

Arrhythmias is common

50% of anesthetized patients
80% of myocardial infarction patients

Can cause diziness, loss of consciousness, or death

Categories of arrhythmias

ECG

ECG is the body surface manifestion of the depolarization and repolarization waves of the heart

P: Atrial depolarization (Site of origin of the electrical impulse)

QRS: ventricle depolarization

T: ventricle repolarization

PR interval: a measure of conduction time from atrium to ventricle

QRS: the time required for all of the ventricular cells to be activated (the intraventricular conduction time)

QT: the duration of the ventricular action potential

1. Cardiac Electrophysiology

To understand the action and classification of the antiarrhythmic drugs, it is first necessary to understand the ionic movements that underlie the cardiac membrane potential