What Are Cardiac Glycosides?
Glycosides, or glycosides and glycosides, are a class of organic compounds whose molecules are composed of an alcohol group or alcohol-like group (ligand, aglycon, or aglycon) combined with a variable number of sugar molecules. If the ligand contains a sterol nucleus (steroidal nucleus), the carbon atom at position 17 is connected to an unsaturated lactone ring, and the carbon atom at position 3 is connected to a sugar molecule. This glycoside is known as a cardiac glycoside. Left. Cardiac glycoside is a class of drugs with selective cardiac action, also known as cardiac glycoside or cardiac glycoside. Clinically, it is mainly used to treat chronic cardiac insufficiency, and in addition, it can treat some arrhythmias, especially supraventricular arrhythmias.
- Glycosides, or glycosides and glycosides, are a class of organic compounds whose molecules are composed of an alcohol group or alcohol-like group (ligand, aglycon, or aglycon) combined with a variable number of sugar molecules. If the ligand contains a sterol nucleus (steroidal nucleus), the carbon atom at position 17 is connected to an unsaturated lactone ring, and the carbon atom at position 3 is connected to the sugar molecule. Left. Cardiac glycoside is a class of drugs with selective cardiac action, also known as cardiac glycoside or cardiac glycoside. Clinically, it is mainly used to treat chronic cardiac insufficiency, and in addition, it can treat some arrhythmias, especially supraventricular arrhythmias.
Cardiac glycosides
- English name: cardiac glucoside
- heart
- Clinically it is mainly used to treat cardiac insufficiency. Digitalis, digoxin, deacetyllanolin C, and poisonous trilobatin K are commonly used in clinical practice. They have similar pharmacodynamic characteristics, but there are differences in pharmacokinetics and intensity of action. Classification of how fast and how long it lasts.
Cardiac glycoside drug distribution
- Cardiac glycosides are distributed only in angiosperms.
- Foxglove Digitalis
- 2. Type B cardiac glycosides: mainly distributed in Liliaceae (Squill) and Ranunculaceae (Iron Chopsticks).
- Hundreds of cardiac glycosides have been discovered from various plants so far, but only 20 to 30 species have been used and have been used clinically, and only 6 or 7 species are commonly used. The cardiac glycosides found in the world are mainly distributed in hundreds of plants in more than 17 families and 70-80 genera.
- Cardiac glycoside-containing traditional Chinese medicines are usually dominated by leaves, followed by seeds and roots, and fewer stems.
- For example, digitonin contained in foxglove digitalis has the highest leaf and stipule content, followed by calyx and perianth, and the least stem. The leaf content was highest in the early flowering period, and gradually decreased from the late flowering to the fruiting period. The content of cardiac glycoside is proportional to chloroplast, and the formation of cardiac glycoside is related to chloroplast. Digitalis is harvested in the early flowering period, especially when the chloroplast is rich, which is of great significance for increasing the content of cardiac glycosides.
Cardiac glycoside drug identification
- Keller-Kiliani (KK) reaction
- Reagents are ferric chloride, glacial acetic acid, concentrated sulfuric acid
- Color rendering: the acetic acid layer is blue or blue-green
- Scope of application : Free or hydrolyzable 2-deoxysugar
- Identification process: Take 1mg of sample, dissolve with 5ml of glacial acetic acid, add 1 drop of 20% ferric chloride aqueous solution, tilt the test tube after mixing, slowly add 5ml concentrated sulfuric acid along the tube wall, and observe the interface and the color of the acetic acid layer There is -deoxysugar, and the acetic acid layer is blue. The color of the interface is gradually diffused to the lower layer due to the effect of concentrated sulfuric acid on the aglycones. The color development varies with the position and number of aglycon hydroxyl groups and double bonds. Different, can be red, green, yellow, etc., but after a long time due to carbonization, all turned dark.
Cardiac glycoside drug classification
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Cardiac glycoside action mechanism
- The mechanism of positive inotropic effect of digoxin and other cardiac glycosides is mainly inhibition of cell membrane-bound Na, K-ATPase, resulting in an increase in free Ca2 + concentration in myocardial cells. [1] Currently, Na, K-ATPase is a specific receptor for cardiac glycosides, which is a dimer composed of and subunits. The alpha subunit is a catalytic subunit that runs through the inside and outside of the membrane and has a molecular weight of 112,000. The beta subunit is a glycoprotein with a molecular weight of about 35,000, which may be related to the stability of the alpha subunit. Cardiac glycoside binds to Na, K-ATPase, inhibits the activity of the enzyme, and inhibits Na and K ion transport. As a result, the intracellular Na gradually increases and K gradually decreases. Cardiotonin's mechanism of action: After blocking the Na, K-ATPase, the intracellular sodium ion concentration increases. Through the Na-Ca exchange system on the cell membrane, instead of intracellular Ca2 and extracellular Na exchange, but Intracellular Na exchanges with extracellular Ca to increase intracellular Ca concentration.
- In vivo process
- Those who take it orally are mainly absorbed in the intestine, and very little in the stomach. The absorption of digoxigenin is the most complete and constant, and digoxin is slightly worse. In general, fast-acting and transient cardiac glycosides are poorly soluble and poorly absorbed in the intestine. These drugs are often injected. After cardiac glycoside enters the blood, it has a certain degree of binding to serum proteins. Digitalis is mainly metabolized and transformed in the liver. Its metabolites and unchanged original form are also excreted from the bile. These substances are absorbed in the intestine to form an enterohepatic cycle. Therefore, digitalis The strongest accumulation and the most lasting effect. Fast-acting cardiac glycosides such as digoxin are mainly excreted from the kidney in its original form, so its excretion is affected by renal function.
- Cardiac glycosides do not have a special affinity for the heart muscle. Cardiac glycosides distributed in the heart are far less than those distributed in the liver and skeletal muscle, but the myocardium has a particularly high sensitivity to cardiac glycosides. Cardiac glycosides are distributed in the retina. The absorption of digitalis is complete and it is not affected by renal function, so its concentration in blood is relatively constant. Digoxin absorption is incomplete, and there are large individual differences, and it is more affected by renal function. Therefore, the concentration in blood can vary by several times. Therefore, the determination of digoxin blood concentration is affected by various factors, and the specific clinical situation should be combined when determining the diagnosis of poisoning.
Cardiac Pharmacological Action
Cardiac glycoside enhances myocardial contractility
- That is, positive inotropic effect.
- Cardiac glycosides have a direct effect on strengthening myocardial contractility. This effect is particularly pronounced in failing hearts and is selective. When the therapeutic dose has no obvious effect on other tissues and organs, it can already strengthen the myocardial contractility. Experiments have shown that the effects of enhancing myocardial contractility can be observed both in whole animals and in non-innervated chicken embryo hearts or papillary muscles. Moreover, this cardiotonic effect is not canceled by -receptor blockers, indicating that it has nothing to do with sympathetic neurotransmitters and their receptors, and the cardiotonic effect is direct.
- Positive muscle strength is manifested by the increase in the maximum tension and the maximum shortening rate of myocardial contraction, which makes the heart contract strong and agile. It shows the increase in the maximum rate of left ventricular pressure increase, and the time required to reach a certain level of maximum tension decreases. With the same load, the cardiac stroke work increased significantly. Cardiac glycosides have a positive inotropic effect on the heart of normal people and patients with heart failure, but only increase the stroke volume of patients with heart failure; because cardiac glycosides also have the effect of constricting blood vessels and increasing peripheral resistance in normal people, it does not increase Stroke volume. Cardiac glycosides in patients with heart failure reflexively reduce sympathetic nerve activity without increasing peripheral resistance.
- Cardiac glycoside does not increase or even reduce myocardial oxygen consumption in the heart of a failed and enlarged heart when it strengthens myocardial contractility, but it can increase myocardial oxygen consumption in a normal heart. In patients with heart failure, due to the enlargement of the heart, the increase of the ventricular wall tension, and the compensatory heart rate increase, the myocardial oxygen consumption increases. After the application of cardiac glycoside, the increase of myocardial contractility can increase myocardial oxygen consumption, but it can also make the ventricles Complete emptying, improved circulation, reduced venous pressure, etc., which reduces the volume of the heart that expands during heart failure, reduces ventricular tension, and also slows the heart rate. These two effects reduce myocardial oxygen consumption and improve the heart's Work efficiency. For a normal heart, because the cardiac contractility is strengthened, there is no significant effect on the ventricular wall tension, and the heart rate is only slightly reduced, so the total oxygen consumption is increased.
Cardiac glycosides slow heart rate
- That is, negative frequency effects.
- In chronic cardiac insufficiency, due to insufficient stroke output, the compensatory heart rate is accelerated through the reflex regulation of carotid sinus and aortic arch baroreceptors. When the heart rate accelerates beyond a certain limit, the diastolic period is too short, the return blood volume decreases, and the cardiac output decreases instead. At the same time, the heart rate is too fast and the coronary arteries are oppressed for a long time. Coronary artery flow is reduced, which is not conducive to the blood supply to the heart muscle. Cardiotonin can slow the heart rate. It has long been thought that its negative frequency effect is the result of increased cardiac contractility, increased cardiac output, and increased reflexivity of the vagus nerve. At present, experiments have shown that a significant heart rate slowdown has been seen before the occurrence of positive inotropic effects. Digoxin is believed to have the effect of enhancing vagus nerve activity and inhibiting sympathetic nerve activity. Negative frequency effects are very beneficial for patients with heart failure.
Effect of cardiac glycoside on myocardial electrical
- (1) At low doses, conductive cardiac glycosides increase the Ca2 + influx due to the effect of strengthening the vagus nerve. Atrioventricular node deceleration is extremely slowed, and atrioventricular conduction velocity is slowed. At higher doses, due to the inhibition of Na +, K + -ATPase, which causes K + loss in cardiomyocytes, reduces the maximum diastolic potential, and slows atrioventricular conduction.
- (2) The autologous therapeutic amount of cardiac glycoside has little direct effect on the autonomy of the sinoatrial node and the atrial conduction tissue, and indirectly reduces the autonomy by strengthening the vagus nerve activity; the poisoning amount directly inhibits Purkinje fiber cell membranes Na +, K + -ATPase, make the cell lose K +, increase autonomy, and easily lead to ventricular premature beats.
- (3) Effective refractory period Cardiotonin accelerates K + efflux and accelerates atrial muscle repolarization, thereby shortening effective refractory period. For ventricular muscle and Purkinje fibers, Na +, K + -ATPase is inhibited to maximize The diastolic potential is reduced, and the effective refractory period is shortened. The atrioventricular node is mainly affected by vagal nerve excitement, and the effective refractory period is prolonged.
Cardiotonin
- Drugs for treating cardiac insufficiency are called cardiotonics, the most important of which are cardiotonin and non-glycoside cardiotonics (such as epinephrine, ephedrine, etc.), which have the function of enhancing cardiac output. Camphor and some of its derivatives, heptyl alcohol, myo-inositol phosphate alcohol, decenol, etc. also have cardiac function. Certain vasodilators (such as aminophylline, nitroprusside, nitroglycerin, and -adrenergic antagonists) are effective for some types of heart failure. Some beta-adrenergic stimulants are expected to be used as cardiotonics. As the saying goes, central stimulants are often called "heart-strengthening drugs", and injections of these drugs are called "heart-strengthening drugs", which is incorrect.
Cardiac aglycone
- Ligands are the pharmacologically active part of cardiac glycosides. The effects of ligands on the myocardium are weak and short, but the intensity and persistence of their effects increase when they are combined with sugar. The sugar portion affects the pharmacokinetic properties of cardiac glycosides (absorption, half-life, metabolism, etc.). In China, cardiac glycosides have been proposed from more than 30 implants for clinical application. 3000 years ago, the ancient Egyptians knew a variety of medicinal plants containing cardiac glycosides. At the end of the 18th century, after the author of English physician and botanist W. Withering discussed digitalis, digitalis preparations were widely used. These drugs include digitalis leaf end, digitalis toxin, digoxin, geniposide C, deacetylanthocyanin C, etc., all of which are taken from purple digitonis and narrow-leaved digitonis of the genus Ginseng. Other cardiac glycosides, such as poisonous rotulin, are taken from the green oleander flower of the oleander family; yellow glycosides are obtained from the oleander family oleander, and scutellarin is obtained from the horns ; Lily of the valley toxin is taken from the lily family lily of the valley (junyingcao). Cardinal glycosides are also found in broom grass, apocynum, evergreen and oleander. A cardiac glycoside is also extracted from the skin glands of the toad, but its lactone ring is hexagonal. Cardiac glycosides are easy to store in dark and low pH conditions, and the expiration period is 1 to 5 years. Cardiac glycosides commonly used in clinical practice are digitalis and poisonous trilobatin. Cardiac glycoside is still one of the important drugs for the treatment of heart failure. However, the safety range of these preparations is very small, and there is not much difference between the amount of treatment and the amount of poisoning. Improper dosage can easily cause poisoning and even death. Work is now underway to change its structure to increase the width of the treatment.
Cardiac glycoside use classification
- Cardiac glycosides have different effects on symptomatic treatment of CHF caused by different causes.
- 1. It has a good effect on patients caused by valvular disease, hypertension, congenital heart disease, etc. by improving the myocardial contractility, reducing the load before and after the heart, and increasing the cardiac output.
- 2. The efficacy of CHF secondary to severe anemia, hyperthyroidism, and vitamin B1 deficiency is poor, because in these cases, myocardial energy production has been impaired, and cardiac glycosides cannot improve energy production. For pulmonary heart disease, severe myocardial injury, or active myocarditis such as CHF during rheumatism, cardiac glycosides are also ineffective, because myocardial hypoxia at this time not only has energy production disorders, but also is prone to cardiac glycoside poisoning. The dose is also limited and it is difficult to exert the effect.
- 3. For CHF caused by extra-cardiac mechanical factors, including severe mitral valve stenosis and constrictive pericarditis, cardiac glycosides have worse or even ineffective effects, because at this time the left ventricular diastolic filling is limited, the stroke volume is limited, and it is difficult Relieve symptoms.
Clinical application of cardioside
Cardiac glycoside chronic heart insufficiency
- Cardiac glycoside enhances myocardial contractility and increases cardiac output, thereby improving the blood supply of the arterial system; due to complete cardiac emptying and prolonged diastole, the amount of returning heart blood increases and venous pressure decreases, thereby relieving the symptoms of venous system congestion. The response of chronic cardiac insufficiency to cardiac glycosides depends on the state of myocardial function and the cause of heart failure, and there is a large gap in efficacy.
- (1) Cardiac glycosides have the best effect on cardiac insufficiency with atrial flutter and fibrillation.
- (2) Good effect on cardiac dysfunction caused by heart valve disease, congenital heart disease and heart overload (such as hypertension).
- (3) The effect of heart failure caused by hyperthyroidism, severe anemia, and vitamin B deficiency is poor, because these diseases are mainly caused by the energy production or storage of myocardial contraction, and it is difficult for cardiac glycosides to work.
- (4) It is also ineffective for cardiac insufficiency caused by pulmonary heart disease, active myocarditis, and severe myocardial damage, because in these cases, the myocardium is accompanied by severe hypoxia and energy production is impaired.
- (5) For heart failure caused by mechanical obstruction such as constrictive pericarditis, severe mitral stenosis, etc., cardiac glycosides have very poor or ineffective curative effects, because the main contradiction of these conditions is that ventricular diastole is limited, although cardiac contractility can be reduced. Increased, but the cardiac output is still small, can not improve the symptoms of heart failure, surgery should be performed.
- (6) For patients with acute heart failure or with pulmonary edema, it is advisable to use venus glycoside K or lanolin C for intravenous injection. After the condition is stable, switch to oral digoxin to maintain.
Cardiac arrhythmia
- Cardiac glycoside inhibits atrioventricular conduction and slows down the heart rate. It can be used to treat atrial fibrillation, atrial flutter and paroxysmal supraventricular tachycardia.
- (1) Atrial fibrillation, that is, weak and irregular fibrillation of atrial muscles, with a frequency of 400 to 600 times per minute, which mainly harms the occurrence of excessive atrial impulse in the hand to reach the ventricle via the conduction system, causing the ventricular frequency to be too fast and reduced Ventricular drainage function. Cardiac glycosides can slow atrioventricular conduction, prevent excessive impulses from passing from the atrium to the ventricles, and slow down the ventricular frequency. Improves ventricular pumping, but it does not eliminate atrial fibrillation in most patients.
- (2) Atrial flutter is a fast and regular atrial rhythm with 250 to 300 beats per minute. Although the frequency is less than that of atrial fibrillation, the impulse of atrial too fast is easily transmitted to the ventricle, causing the ventricular rate to be too fast. Cardiac glycosides can shorten the effective refractory period of the atrial, turning flutter into fibrillation, and the excitatory impulse during flutter is weaker than flutter, which is easily inhibited by cardiac glycosides to inhibit the atrioventricular conduction, so it can slow down the ventricular frequency. Cardiac glycosides are the most effective drugs for atrial flutter in the presence or absence of heart failure.
- (3) Paroxysmal supraventricular tachycardia is often effective for intravenous injection of cardiac glycosides, which may be to enhance the vagus nerve excitability and reduce the autonomy of atrial autonomic cells to terminate supraventricular tachycardia. However, cardiac glycosides are at risk of inducing ventricular fibrillation, so ventricular tachycardia is contraindicated.
Cardiac glycoside medication
- Cardiac glycosides are administered orally or intravenously. They are divided into two categories according to their speed:
- 1. Slow acting classes. Slow onset of action, slow metabolism and excretion in the body, and long duration of action. This class is all oral drugs, including digitalis leaf end, digitalis toxin and so on.
- 2. Fast acting class. The effect starts quickly, and the metabolism and excretion in the body are also fast, and the effect time is short. Applicable to acute heart failure and acute exacerbation of chronic heart failure. Intravenous or oral. This class of medicines includes digoxin, lanolin C, geniposide, carrageenin, lily of the valley, toxin, etc.
Cardiotonin adverse reactions and prevention
Cardioside adverse reactions
- 1. Gastrointestinal reactions: anorexia, nausea, vomiting, diarrhea, abdominal pain
- 2. Nervous system: headache, fatigue, dizziness, nightmares, blurred vision, and color vision disorders (yellow and green vision)
- 3. Cardiotoxicity: ventricular premature beats, atrioventricular nodularity, ventricular tachycardia, atrioventricular block, etc.
Prevention and treatment of cardiac glycoside poisoning
- First, according to the patient's body condition and whether they have used long-acting cardiac glycosides recently, the appropriate preparation, dosage and method of administration should be selected to reduce the chance of poisoning. The patient's response should be closely monitored during the medication, and the drug should be discontinued immediately if symptoms of poisoning occur. Cardiac tachycardia-induced arrhythmias are often effective in the treatment of potassium salts, and potassium salts have a significant inhibitory effect on the autonomy of ectopic pacing points. However, it should be noted that potassium ions can directly reduce heart rate and conduction speed, aggravate the conduction block caused by cardiac glycosides, and those with obvious atrioventricular block and bradycardia should not be used.
- Antiarrhythmic drugs such as phenytoin sodium and lidocaine are very effective against tachyarrhythmia caused by cardiac glycosides. They can reduce the autonomy of ectopic rhythm points without inhibiting atrioventricular conduction. Phenytoin can also improve atrioventricular Conduction is more applicable.
- Sinus bradycardia and conduction block caused by cardiac glycosides are treated with atropine. In addition, cholestyramine can bind to digoxigenin, block liver-gut circulation, and reduce poisoning. Digoxin antibody Fab fragments are injected intravenously, which can quickly bind to digoxin and relieve the inhibition of Na +, K + -ATPase by digoxin.