Ke Li

Uses

Ke Li is used for:

• Heart failure
• Atrial fibrillation with an uncontrolled ventricular rate
• Acute left ventricular failure
• Chronic left ventricular failure and congestive heart failure, especially when caused by hypertensive valvular (especially mitral valvular) disease or ischaemic heart disease.

Ke Li is also used to associated treatment for these conditions: Chronic Atrial Fibrillation, Heart failure, mild, Heart failure, moderate, Mild to moderate heart failure, Myocardial contractility, Rate Control

How Ke Li works

Ke Li exerts hemodynamic, electrophysiologic, and neurohormonal effects on the cardiovascular system. It reversibly inhibits the Na-K ATPase enzyme, leading to various beneficial effects. The Na-K ATPase enzyme functions to maintain the intracellular environment by regulating the entry and exit of sodium, potassium, and calcium (indirectly). Na-K ATPase is also known as the sodium pump. The inhibition of the sodium pump by digoxin increases intracellular sodium and increases the calcium level in the myocardial cells, causing an increased contractile force of the heart. This improves the left ventricular ejection fraction (EF), an important measure of cardiac function.

Ke Li also stimulates the parasympathetic nervous system via the vagus nerve leading to sinoatrial (SA) and atrioventricular (AV) node effects, decreasing the heart rate. Part of the pathophysiology of heart failure includes neurohormonal activation, leading to an increase in norepinephrine. Ke Li helps to decrease norepinephrine levels through activation of the parasympathetic nervous system.

Dosage

Ke Li dosage

For rapid action: 1 to 1.5 mg in divided doses over 24 hours

For less urgent digitalisation: 0.25 to 0.5 mg daily(higher dose may be divided); Maintenance: 0.0625 to 0.5 mg daily (higher dose may be divided) accordingly to renal function and in atrial fibrilation on heart rate response;

Usual dose: 0.125 to 0.25 mg daily (lower dose my be appropriate in elderly).

Side Effects

Usually associated with excessive dosage include anorexia, nausea, vomiting, diarrhoea, abdominal pain, visual disturbance, headache, fatigue, drowsiness, confusion, delirium, hallucination, depression, arrhythmia, heart block, intestinal ischaemia, gynaecomastia on long term use, thrombocytopenia reported.

Toxicity

Oral TDLO (human female): 100 ug/kg, Oral TDLO (human male): 75 ug/kg, Oral LD50 (rat): 28270 ug/kg

Ke Li toxicity can occur in cases of supratherapeutic dose ingestion or as a result of chronic overexposure. Ke Li toxicity may be manifested by symptoms of nausea, vomiting, visual changes, in addition to arrhythmia. Older age, lower body weight, and decreased renal function or electrolyte abnormalities lead to an increased risk of digoxin toxicity.

Precaution

Cardiac dysrhythmias, hypokalaemia, hypertension, IHD, hypercalcaemia, hypomagnesaemia, electroconversion, chronic cor pulmonale, aortic valve disease, acute myocarditis, congestive cardiomyopathies, constrictive pericarditis, heart block, elderly, renal impairment, abnormalities in thyroid function; pregnancy. IV digoxin can only be given to patients who have not received cardiac glycosides in the preceding 2 wk.

Interaction

Effectiveness reduced by phenytoin, neomycin, sulphasalazine, kaolin, pectin, antacids and in patients receiving radiotherapy. Metoclopramide may alter the absorption of solid dosage forms of digoxin. Blood levels increased by calcium channel blockers, spironolactone, quinidine and calcium salts.

Potentially Fatal: Electrolyte imbalances such as hypokalaemia and hypomagnesemia (e.g. admin of potassium-losing diuretics, corticosteroids) can increase the risk of cardiac toxicity.

Food Interaction

• Avoid multivalent ions. Calcium and aluminum containing products (including kaolin-pectin) may interfere with absorption) and digoxin administration must be separated by several hours.
• Avoid potassium-containing products. They may cause arrhythmias when given with digoxin.
• Avoid St. John's Wort. This drug can decrease digoxin levels.
• Do not take with bran and high fiber foods. Separate administration of bran and high fiber foods from medication by at least 2 hours.

[Minor] Administration of digoxin with a high-fiber meal has been shown to decrease its bioavailability by almost 20%.

Fiber can sequester up to 45% of the drug when given orally.

Patients should be advised to maintain a regular diet without significant fluctuation in fiber intake while digoxin is being titrated.

Grapefruit juice may modestly increase the plasma concentrations of digoxin.

The mechanism is increased absorption of digoxin due to mild inhibition of intestinal P-glycoprotein by certain compounds present in grapefruits.

In 12 healthy volunteers, administration of grapefruit juice with and 30 minutes before, as well as 3.5, 7.5, and 11.5 hours after a single digoxin dose (0.5 mg) increased the mean area under the plasma concentration-time curve (AUC) of digoxin by just 9% compared to administration with water.

Moreover, P-glycoprotein genetic polymorphism does not appear to influence the magnitude of the effects of grapefruit juice on digoxin.

Thus, the interaction is unlikely to be of clinical significance.

Ke Li Drug Interaction

Moderate: aspirin, aspirin, furosemide, furosemide, atorvastatin, atorvastatin, metoprolol, metoprolol, cholecalciferol, cholecalciferolUnknown: warfarin, warfarin, apixaban, apixaban, clopidogrel, clopidogrel, cyanocobalamin, cyanocobalamin, rivaroxaban, rivaroxaban

Ke Li Disease Interaction

Major: accessory AV pathway, bradyarrhythmia/AV block, hypercalcemia, hypocalcemia, hypokalemia/hypomagnesemia, preserved left ventricular ejection, renal dysfunction, vasoconstriction, ventricular arrhythmiaModerate: acute MI, hyperthyroidism, hypothyroidism, thiamine deficiency

Volume of Distribution

This drug is widely distributed in the body, and is known to cross the blood-brain barrier and the placenta. The apparent volume of distribution of digoxin is 475-500 L. A large portion of digoxin is distributed in the skeletal muscle followed by the heart and kidneys. It is important to note that the elderly population, generally having a decreased muscle mass, may show a lower volume of digoxin distribution.

Elimination Route

Ke Li is approximately 70-80% absorbed in the first part of the small bowel. The bioavailability of an oral dose varies from 50-90%, however, oral gelatinized capsules of digoxin are reported to have a bioavailability of 100%. Tmax, or the time to reach the maximum concentration of digoxin was measured to be 1.0 h in one clinical study of healthy patients taking 0.25 mg of digoxin with a placebo. Cmax, or maximum concentration, was 1.32 ± 0.18 ng/ml−1 in the same study, and AUC (area under the curve) was 12.5 ± 2.38 ng/ml−1. If digoxin is ingested after a meal, absorption is slowed but this does not change the total amount of absorbed drug. If digoxin is taken with meals that are in fiber, absorption may be decreased.

A note on gut bacteria

An oral dose of digoxin may be transformed into pharmacologically inactive products by bacteria in the colon. Studies have indicated that 10% of patients receiving digoxin tablets will experience the degradation of at least 40% of an ingested dose of digoxin by gut bacteria. Several antibiotics may increase the absorption of digoxin in these patients, due to the elimination of gut bacteria, which normally cause digoxin degradation.

A note on malabsorption

Patients with malabsorption due to a variety of causes may have a decreased ability to absorb digoxin. P-glycoprotein, located on cells in the intestine, may interfere with digoxin pharmacokinetics, as it is a substrate of this efflux transporter. P-glycoprotein can be induced by other drugs, therefore reducing the effects of digoxin by increasing its efflux in the intestine.

Half Life

Ke Li has a half-life of 1.5-2 days in healthy subjects. The half-life in patients who do not pass urine, usually due to renal failure, is prolonged to 3.5-5 days. Since most of the drug is distributed extravascularly, dialysis and exchange transfusion are not optimal methods for the removal of digoxin.

Clearance

The clearance of digoxin closely correlates to creatinine clearance, and does not depend on urinary flow. Individuals with renal impairment or failure may exhibit extensively prolonged half-lives. It is therefore important to titrate the dose accordingly and regularly monitor serum digoxin levels. One pharmacokinetic study measured the mean body clearance of intravenous digoxin to be 88 ± 44ml/min/l.73 m². Another study provided mean clearance values of 53 ml/min/1.73 m² in men aged 73-81 and 83 ml/min/1.73 m² in men aged 20-33 years old after an intravenous digoxin dose.

Elimination Route

The elimination of digoxin is proportional to the total dose, following first order kinetics. After intravenous (IV) administration to healthy subjects, 50-70% of the dose is measured excreted as unchanged digoxin in the urine. Approximately 25 to 28% of digoxin is eliminated outside of the kidney. Biliary excretion appears to be of much less importance than renal excretion.

Ke Li is not effectively removed from the body by dialysis, exchange transfusion, or during cardiopulmonary bypass because most of the drug is bound to extravascular tissues.

Pregnancy & Breastfeeding use

Use in pregnancy: Ke Li can be used.

Use in lactation: Ke Li is excreted in breast milk but in concentration below those found in plasma and therefore poses no hazard to the breast-feed infant.

Contraindication

Ventricular fibrillation and hypersensitivity to digoxin or other digitalis preparation.

Special Warning

Use in children & neonates: Ke Li can be used.

Use in elderly: Partly because of reduced renal function and partly because of their tissues are more sensitive to the effects of digitalis, the elderly require lower maintenance dose of digoxin than younger adults

Acute Overdose

Symptoms: Hyperkalaemia, cardiac arrhythmias and heart block.

Management: Treatment is symptomatic and supportive. Reduce absorption by gastric lavage if present within 30 min of ingestion. Do not induce vomiting or attempt passage of a gastric tube if presented >2 hr after ingestion or already has toxic manifestations, as this may induce an acute vagal episode and worsen digitalis-related arrhythmias. Activated charcoal is helpful in reducing drug absorption.

Storage Condition

Store at 25°C.

Innovators Monograph

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