What Are the Different Types of Heart Failure Medications?

Heart failure is a disorder of cardiac insufficiency. It generally manifests as reduced or impaired myocardial contractile function, leading to reduced cardiac output and reduced blood supply to the body's tissues for oxygen and metabolism, leading to heart failure. Heart failure treatment drugs can generally be divided into cardiac glycosides (positive inositol drugs), non-cardiac glycosides (such as ACE inhibitors, angiotensin II receptor antagonist ARB, receptor blockers, diuretics and calcium Channel blockers) ^[1] .

Anti-heart failure drugs I. Main targets of anti-heart failure drugs

As of 2015, anti-heart failure drugs have been developed for at least 285 targets worldwide. The following table shows the more studied targets ^[2] .

target	Mechanism
Angiotensin converting enzyme	Angiotensin converting enzyme inhibitor
Phosphodiesterase	Phosphodiesterase inhibitor
Endothelin receptor	Endothelin receptor antagonist
Adrenaline receptor	Alpha and beta adrenergic receptor antagonists
Adrenaline receptor	2, 1 adrenergic receptor agonist
Angiotensin II receptor	Angiotensin II receptor antagonist
Calcium channel	Calcium channel blocker

At present, a large number of targets have been discovered and used for the development of anti-heart failure drugs. Among them, angiotensin-converting enzyme, phosphodiesterase, and endothelin receptor are common anti-heart failure small molecule drug targets. For these types of targets, there are drugs that are already on the market and drugs that are currently in clinical research. Angiotensin-converting enzyme inhibitors mainly act on renin, which can reduce the production of angiotensin II by inhibiting angiotensin-converting enzyme in renin, and block angiotensinogen cleavage into angiotensin I, which can be significant and durable Decreased plasma renin activity, lowered the levels of angiotensin I and angiotensin II, and dilated blood vessels. Phosphodiesterase inhibitors are positive inotropic drugs and have vasodilatory effects. Endothelin is a polypeptide consisting of 21 amino acids, which is the strongest vasoconstrictor and pressurizing substance currently known. Endothelin produced by cardiomyocytes and vascular smooth muscle cells can increase the contractility of myocardium and vascular smooth muscle, while the endothelin system causes myocardial remodeling through excessive secretion of endothelin and upregulation of its receptor expression, which leads to heart failure, and therefore heart failure Treatment of animals with long-term endothelin receptor antagonists can significantly improve their survival.

Anti-heart failure drugs II. Treatment principles of anti-heart failure drugs

1. Use positive inotropic drugs to enhance the contractility of the heart muscle;

2. Apply diuretic drugs to reduce water and sodium retention and reduce the preload of the heart;

3. Application of vasodilator drugs to reduce the afterload of the heart;

4. Inhibit excessive activation of the neuro-endocrine system and inhibit myocardial remodeling ^[3] .

Anti-heart failure drugs III. Common anti-heart failure drugs

- Anti-heart failure drugs (a) renin-angiotensin system inhibitor

Angiotensin I converting enzyme (ACE) inhibitors and angiotensin II receptor (AT1) antagonists:
ACE inhibitors can inhibit the conversion of Ang to Ang in the systemic circulation and local tissues, reduce the content of Ang in blood and tissues, thereby reducing the vasoconstrictive effect of Ang, ACE inhibitors can also inhibit the degradation of bradykinin, and make the blood slow. Increased kinin content, bradykinin can promote the production of NO and PGI2, play the role of NO and PGI2 to expand blood vessels, reduce the role of cardiac afterload.
ACE inhibitors can reduce aldosterone production, reduce sodium and water retention, reduce preload of the heart; inhibit myocardial and vascular remodeling; reduce systemic vascular resistance, increase cardiac output, improve cardiac diastolic function, reduce renal vascular resistance, and increase renal blood flow ; Reduce sympathetic nerve activity. ACE inhibitors have beneficial effects on people with heart failure at all stages, which can eliminate or alleviate the symptoms of heart failure, improve exercise endurance, improve quality of life, prevent and reverse myocardial hypertrophy, reduce mortality, and delay early heart disease without symptoms. The progress of dysfunction delays the onset of heart failure. Therefore, it has been widely used in clinical treatment with diuretics as a first-line drug for the treatment of heart failure, especially for diastolic heart failure. The effect is significantly better than the traditional drug digoxin.
Angiotensin II receptor (AT1) antagonists can directly block the binding of Ang II and its receptors, exerting an antagonistic effect. The effect of this class of drugs on heart failure is similar to that of ACE inhibitors, with less adverse reactions, does not affect bradykinin metabolism, and is not likely to cause cough and angioedema. It is often used as a substitute for patients with intolerance to ACE inhibitors. ^3] .

Anti-heart failure drugs (two) anti-aldosterone drugs

The concentration of aldosterone in the blood increases, and a large amount of aldosterone causes the remodeling of the atrium, ventricle, and large blood vessels, which accelerates the deterioration of heart failure. In addition, it can prevent myocardial uptake of norepinephrine (NE), increase the free concentration of NE, induce coronary spasm and arrhythmia, and increase the possibility of ventricular arrhythmias and sudden death during heart failure.
Clinical studies have shown that on the basis of conventional treatment, the addition of spironolactone can significantly reduce the mortality of heart failure, prevent myocardial interstitial fibrosis during left ventricular hypertrophy, and improve hemodynamics and clinical symptoms. Combined with ACE inhibitors can reduce Ang II and aldosterone levels, which can further reduce the patient's mortality rate and reduce the incidence of ventricular arrhythmias. The effect is better.

Anti-heart failure drugs (three) diuretics

Diuretics play an important role in the treatment of heart failure and are still widely used as first-line drugs in the treatment of various heart failures.
Diuretics promote the excretion of Na + and H2O, reduce blood volume, reduce preload of the heart, and improve heart function; reduce venous pressure, eliminate or relieve venous congestion and the pulmonary edema and peripheral edema caused by it. It is especially applicable to those with heart failure accompanied by edema or obvious congestion.
For mild heart failure, thiazide diuretics alone can receive good results. For patients with moderate or severe heart failure or thiazine alone, the diuretics or thiazines and potassium retention diuretics can be used. Combination of drugs; for severe heart failure, acute episodes of chronic heart failure, acute pulmonary edema or systemic edema, thiazide drugs are often ineffective, and furosemide should be injected intravenously. Potassium-sparing diuretics have a weak effect, and they are often combined with other diuretics such as tincture diuretics, which can effectively antagonize the increase of aldosterone levels caused by RAAS activation, enhance the diuretic effect and prevent potassium loss, but also inhibit collagen proliferation and prevent fiber Into.
Large-dose diuretics can reduce effective circulating blood volume, reflex excitatory sympathetic nerves, aggravate insufficient tissue and organ perfusion, reduce renal blood flow, aggravate liver and kidney dysfunction, and lead to worsening heart failure. Disturbance of electrolyte balance caused by diuretics is one of the common causes of arrhythmia caused by heart failure, especially with cardiac glycosides and when used more easily. Attention should be paid to potassium supplementation or combined with potassium retention diuretics.

Anti-heart failure drugs (IV) -receptor blockers

Beta receptor blockers block cardiac beta receptors and antagonize the toxic effects of excessive catecholamines on the heart, improve myocardial remodeling, reduce renin release, inhibit RAAS, upregulate cardiac beta receptors to restore their signal transduction capabilities, and improve beta Receptor sensitivity to catecholamines. In addition, -receptor blockers have significant anti-myocardial ischemia and antiarrhythmic effects, and the latter is an important mechanism for reducing the mortality and sudden death of heart failure. Carvedilol has the effects of blocking 1 receptor and anti-oxidation, showing a comprehensive anti-sympathetic effect. Although the application of -blockers in heart failure may inhibit myocardial contractility and aggravate cardiac dysfunction, long-term application can improve the symptoms of heart failure and reduce mortality. It has been recommended as a conventional medication for chronic heart failure. The combined effect of -receptor blocker and ACE inhibitory agent is further increased. Beta receptor blockers are mainly used for dilated cardiomyopathy. For dilated cardiomyopathy and ischemic heart failure, long-term application can prevent the deterioration of clinical symptoms, improve cardiac function, reduce the incidence of sudden death and arrhythmia. It should be used with caution or disabled in patients with severe bradycardia, severe left ventricular dysfunction, obvious atrioventricular block, hypotension and bronchial asthma.

Anti-heart failure drugs (5) Cardiotonin

Cardiac glycosides are a class of glycosides with cardiotonic effects. They have the same properties, and the side chains differ only in the pharmacokinetics. Cardiac glycoside inhibits the activity of the cardiac glycoside receptor Na + -K + -ATPase on the membrane of myocardial cells, which increases the amount of Na + in the cell and decreases the K + ions. Through the two-way exchange mechanism of Na + -Ca2 +, Ca2 + increases in the myocardial cells, exerting positive Sexual muscle effect. After cardiac dysfunction, cardiac output increased after cardiac glycoside application, reflexively stimulated the vagus nerve, increased myocardial sensitivity to the vagus nerve, the sinoatrial node and atrioventricular node were inhibited, the autonomy of the sinoatrial node decreased, and the heart rate decreased. Atrioventricular conduction slows. So bradycardia and conduction block caused by excessive cardiac glycoside can be counteracted by atropine. At high concentrations, cardiac glycosides can excessively inhibit Na + -K + -ATPase, cause cells to lose potassium, improve self-discipline, shorten ERP, and increase Ca2 + in cells can cause Ca2 + oscillations, depolarization early, and depolarization late; etc .; poisoning Cardiac glycosides can also enhance central sympathetic activity at doses. Therefore, various cardiac arrhythmias can occur during cardiac glycoside poisoning. Ventricular premature beats and ventricular tachycardia are more common.
A toxic dose of cardiac glycoside can excite vomiting and induce vomiting in the posterior polar region of the brain, and also excite the sympathetic nerve center, which significantly increases the sympathetic nerve impulses and causes tachyarrhythmias. Cardiac glycoside slowing heart rate and inhibiting atrioventricular conduction are also related to its excitement of the parasympathetic nerve center of the brainstem.
Cardiac glycoside can also reduce plasma renin activity in patients with heart failure, thereby reducing angiotensin and aldosterone content, and antagonize RAAS that is over-activated during cardiac insufficiency. Cardiac glycosides inhibit renal tubular Na + -K + -ATPase, improve heart function in patients with heart failure, increase renal blood flow and glomerular filtration rate, and exert diuretic effect.
Cardiac glycosides are now mostly used for systolic dysfunction, and patients with heart failure who have poor curative effects on diuretics, ACE inhibitors, -blockers, and atrial fibrillation, atrial flutter, and paroxysmal supraventricular Speeder.
Cardiac glycosides are the most serious and dangerous side effects of cardiac reactions, with about 50% of cases of various types of arrhythmias. Ventricular premature beats are the most common and the earliest, and can also occur in doublet, triplet, tachycardia, and even ventricular fibrillation. Potassium chloride is an effective drug for the treatment of tachyarrhythmia caused by cardiac glycoside poisoning. For severe arrhythmia, phenytoin sodium and lidocaine should also be used. Cardiac glycoside can cause atrioventricular block due to increasing vagus nerve excitability and high inhibition of Na + -K + -ATPase. At this time, K + should not be supplemented and can be treated with M receptor blocker atropine. Gastrointestinal reaction is the most common early symptom of poisoning with cardiac glycosides. Visual abnormalities are usually a precursor to cardiac glycosides poisoning and can be used as an indication of drug withdrawal.

Anti-heart failure medicine (6) other

Vasodilator drugs can quickly reduce the pre- and post-load of the heart to improve the symptoms of acute heart failure. Commonly used drugs are nitroglycerin, isosorbide nitrate, hydralazine, sodium nitroprusside, prazosin, and so on. A newly developed vasodilator, nesiritide, is a synthetic product of endogenous brain natriuretic peptide (BNP) prepared by genetic recombination technology. In addition to dilating arterial and venous blood vessels, it also has a diuretic effect. The competitive endothelin receptor blocker bosentan has also been put into clinical use, and the long-term effect on heart failure has not yet reached a final conclusion.
Non-glycoside positive inotropic drugs such as beta receptor agonists and phosphodiesterase inhibitors may increase the mortality of patients with heart failure, so they should not be used for conventional treatment.
Ca2 + channel antagonists are mainly used for heart failure in diastolic dysfunction.

Anti-heart failure drugs IV. Development of anti-heart failure drugs

As of May 10, 2015, a total of 73 heart failure treatment drugs have been launched in Japan, Brazil, Spain, Canada, the United States, Switzerland, the European Union, and China.

Some of the commercially available drugs for the treatment of heart failure have been developed by major European, American and Japanese companies, and the main targets for different types of drugs are also different. Most of these biotechnology drugs have been developed with tumor necrosis factor, angiotensin II ligand, endothelin as targets. The main targets of small molecule drugs are more concentrated on angiotensin II receptors, epinephrine receptors, potassium channels and so on. Judging from the technical source of the drug developed by the enterprise, many products of many original research companies have been transferred to other companies for development, and there are currently many companies conducting research and development on the same drug.

In China, the development of drugs for the treatment of heart failure is still in its infancy. Up to now, only the muscarinic receptor antagonist penehyclidine hydrochloride developed by Chengdu Lisite Pharmaceutical Co., Ltd. has been developed. The three drugs, the trypsin inhibitor ulinastatin and the recombinant human brain natriuretic peptides developed by Tibet Nuodikang Pharmaceutical Co., Ltd., have been marketed. The drugs developed by other companies and research institutes are currently in clinical research.

Anti-heart failure drugs V. Prospects of anti-heart failure drugs

As the population ages, the market demand for cardiovascular drugs will gradually increase. Central heart failure is an important and increasingly serious public health problem, and new therapeutic drugs are urgently needed. Globally, US $ 108 billion is spent on the treatment of heart failure diseases each year, with huge market potential.

With the development of clinical research on the treatment of heart failure and the development of medical technology, its drug therapy has changed from the past short-term pharmacology and hemodynamic direction to long-term repair therapy. The drug has changed from the previous diuretic, heart, and expansion Vascular conversion is mainly based on diuretics and drugs that inhibit myocardial remodeling and sympathy ^[4] , with digitalis as an adjuvant therapy. In clinical use, it should be used reasonably according to the condition of the patient to achieve the best therapeutic effect.