DIGOXIN
Chemistry - A cardiac glycoside, digoxin occurs as bitter tasting, clear to white crystals or as white, crystalline powder. It is practically insoluble in water, slightly soluble in diluted alcohol, and veryslightly soluble in 40% propylene glycol solution. Above 235°C it melts with decomposition.
The commercial injection consists of a 40% propylene glycol, 10% alcohol solution having a pHof 6.6-7.4.
At pH's from 5-8, digoxin is stable, but in solutions with a pH of less than 3, it is hydrolyzed.
The injectable product is compatible with most commercially available IV solutions, includinglactated Ringer's, D5W, and normal saline. To prevent the possibility of precipitation occurring, one manufacturer (Glaxo Wellcome) recommends that the injection be diluted by a volume at least4 times with either sterile water, D5W, or normal saline. Digoxin injection has been demonstrated tobe compatible with bretylium tosylate, cimetidine HCl, lidocaine HCl, and verapamil HCl.
Digoxin is incompatible with dobutamine HCl, acids and alkalies. The manufacturer does notrecommend mixing digoxin injection with other medications. Compatibility is dependent uponfactors such as pH, concentration, temperature, diluents used and it is suggested to consult specialized references for more specific information.
The digitalis glycosides also have several electrocardiac effects, including: decreased conductionvelocity through the AV node, and prolonged effective refractory period (ERP). They may alsoincrease the PR interval, decrease the QT interval and cause ST segment depression.
The exact mechanism of action of these agents have not been fully described, but their ability toincrease the availability of Ca++ to myocardial fibers and to inhibit Na+-K+-ATPase with resultantincreased intracellular Na+ and reduced K+ probably largely explain their actions.
For additional information, it is suggested to refer to a pharmacology text.
The drug is distributed widely throughout the body with highest levels found in kidneys, heart, intestine, stomach, liver and skeletal muscle. Lowest concentrations are found in the brain and theplasma. At therapeutic levels, approximately 20-30% of the drug is bound to plasma proteins.
Because only small amounts are found in fat, obese patients may receive too high dosages if dosingis based on total body weight versus lean body weight.
Digoxin is metabolized slightly, but the primary method of elimination is renal excretion both byglomerular filtration and tubular secretion. As a result, dosage adjustments must be made in patientswith significant renal disease. Values reported for the elimination half-life of digoxin in dogs havebeen highly variable, with values reported from 14.4-56 hours. Elimination half-lives reported inother species include: Cats»33.3±9.5 hrs; Sheep»7.15 hrs.; Horses»16.9 - 23.2 hrs.; and Cattle»7.8 hrs.
Contraindications/Precautions - Digitalis cardioglycosides are contraindicated in patients withventricular fibrillation or in digitalis intoxication. They should be used with extreme caution inpatients with glomerulonephritis and heart failure or with idiopathic hypertrophic subaortic stenosis(IHSS). They should be used with caution in patients with severe pulmonary disease, hypoxia, acutemyocarditis, myxedema, or acute myocardial infarction, frequent ventricular premature contractions, ventricular tachycardias, chronic constrictive pericarditis or incomplete AV block. They may be usedin patients with stable, complete AV block or severe bradycardia with heart failure if the block wasnot caused by the cardiac glycoside.
When used to treat atrial fibrillation or flutter prior to administration with an antiarrhythmic agentthat has anticholinergic activity (e.g., quinidine, procainamide, disopyramide), digitalis glycosideswill reduce, but not eliminate the increased ventricular rates that may be produced by those agents.
Since digitalis glycosides may cause increased vagal tone, they should be used with caution inpatients with increased carotid sinus sensitivity.
Elective cardioversion of patients with atrial fibrillation should be postponed until digitalis glycosides have been withheld for 1-2 days, and should not be attempted in patients with signs ofdigitalis toxicity.
Because digoxin is principally eliminated by the kidneys, it should be used with caution and serumlevels monitored in patients with renal disease. Animals that are hypernatremic, hypokalemic, hypercalcemic, hyper- or hypothyroid may require smaller dosages; monitor carefully.
The veterinary elixir is available in two separate concentrations, do not confuse the two.
Cardiac effects may be seen before other extra-cardiac symptoms and may include almost everytype of cardiac arrhythmia described with a resultant worsening of heart failure symptoms. Morecommon arrhythmias or ECG changes seen, include complete or incomplete heart block, bigeminy,
ST segment changes, paroxysmal ventricular or atrial tachycardias with block, and multifocalpremature ventricular contractions. Because these effects can also be caused by worsening heartdisease, it may be difficult to determine if they are a result of the disease process or of digitalisintoxication. If in doubt, monitor serum levels or stop digoxin therapy temporarily.
Extracardiac symptoms most commonly seen in veterinary medicine include mild GI upset, anorexia, weight loss and diarrhea. Vomiting has been associated with IV injections and should notcause anxiety nor alarm. Ocular and neurologic effects are routinely seen in humans, but are notprevalent in animals or are not detected.
Overdosage - Symptoms of chronic toxicity are discussed above. In dogs the acute toxic dose after IV administration has been reported to be 0.177 mg/kg.
Treatment of chronic digoxin toxicity is dictated by the severity of the signs and symptoms associated with it. Many patients will do well after temporarily stopping the drug and reevaluating the dosage regimen.
If an acute ingestion has recently occurred and no present cardiotoxic or neurologic signs (coma, seizures, etc.) have been manifested, emptying the stomach may be indicated followed with activatedcharcoal administration. Because digoxin can be slowly absorbed and there is some enterohepaticrecirculation of the drug, repeated charcoal administration may be beneficial even if the ingestionoccurred well before treatment. Anion-exchange resins such as colestipol or cholestyramine havealso been suggested to reduce the absorption and enterohepatic circulation of digoxin and digitoxin, but are not readily available in most veterinary practices. These agents may be of more benefit toadsorb less polar compounds such as digitoxin.
Dependent on the type of cardiotoxicity, supportive and symptomatic therapy should be implemented. Serum electrolyte concentrations, drug level if available on a "stat" basis, arterial blood gases if available, and continuous ECG monitoring should be instituted. Acid-base, hypoxia, and fluid and electrolyte imbalances should be corrected. The use of potassium in normokalemic patients is very controversial and should only be attempted with constant monitoring and clinicalexpertise.
The use of specific antiarrhythmic agents in treating life-threatening digitalis-induced arrhythmiasmay be necessary. Phenytoin, lidocaine, and propranolol are most commonly employed for thesearrhythmias. Atropine may be used to treat sinus bradycardia, SA arrest, or 2nd or 3rd degree AVblock.
Digoxin immune Fab is a promising treatment for digoxin or digitoxin life-threatening toxicity. Itis produced from specific digoxin antibodies from sheep and will bind directly to the drug, inactivating it. It is extremely expensive however and veterinary experience with it is extremelylimited.
The following agents may either increase the serum level, decrease the elimination rate, or enhancethe toxic effects of digoxin: diazepam, quinidine, anticholinergics, succinylcholine, verapamil, tetracycline and erythromycin.
Patients on digoxin that receive thyroid replacement therapy may need their digoxin dosageadjusted.
Penicillamine may decrease serum levels of digoxin independent of route of digoxin dosing.
Drugs that can affect electrolyte balance can alter the efficacy or enhance the toxic effects ofdigoxin. Diuretics (furosemide, thiazides) may predispose the patient to digitalis toxicity. Otherdrugs which can deplete body potassium (amphotericin B, glucocorticoids, ACTH, laxatives, sodium polystyrene sulfonate) or decrease extracellular potassium (glucagon, high dose IVdextrose, dextrose/insulin infusions) may also predispose patients to toxic effects of digitalisdrugs. Spironolactone may enhance or decrease the toxic effects of digoxin.
Refer to specialized references for more information.
The commercial injection consists of a 40% propylene glycol, 10% alcohol solution having a pHof 6.6-7.4.
Storage, Stability, Compatibility
Digoxin tablets, capsules, elixir and injection should be storedat room temperature (15-30°C) and protected from light.At pH's from 5-8, digoxin is stable, but in solutions with a pH of less than 3, it is hydrolyzed.
The injectable product is compatible with most commercially available IV solutions, includinglactated Ringer's, D5W, and normal saline. To prevent the possibility of precipitation occurring, one manufacturer (Glaxo Wellcome) recommends that the injection be diluted by a volume at least4 times with either sterile water, D5W, or normal saline. Digoxin injection has been demonstrated tobe compatible with bretylium tosylate, cimetidine HCl, lidocaine HCl, and verapamil HCl.
Digoxin is incompatible with dobutamine HCl, acids and alkalies. The manufacturer does notrecommend mixing digoxin injection with other medications. Compatibility is dependent uponfactors such as pH, concentration, temperature, diluents used and it is suggested to consult specialized references for more specific information.
Pharmacology - DIGOXIN
The pharmacology of the digitalis glycosides have been extensively studied, but athorough discussion is beyond the scope of this reference. Suffice it to say that digitalis glycosidescause the following effects in patients with a failing heart: increased myocardial contractility(inotropism) with increased cardiac output; increased diuresis with reduction of edema secondary toa decrease in sympathetic tone; reduction in heart size, heart rate, blood volume, and pulmonary andvenous pressures; and (usually) no net change in myocardial oxygen demand.The digitalis glycosides also have several electrocardiac effects, including: decreased conductionvelocity through the AV node, and prolonged effective refractory period (ERP). They may alsoincrease the PR interval, decrease the QT interval and cause ST segment depression.
The exact mechanism of action of these agents have not been fully described, but their ability toincrease the availability of Ca++ to myocardial fibers and to inhibit Na+-K+-ATPase with resultantincreased intracellular Na+ and reduced K+ probably largely explain their actions.
For additional information, it is suggested to refer to a pharmacology text.
Uses, Indications
The veterinary indications for digitalis glycosides include treatment of congestive heart failure, atrial fibrillation or flutter, and supraventricular tachycardias.Pharmacokinetics - DIGOXIN
Absorption following oral administration occurs in the small intestine and isvariable dependent upon the oral dosage form used (see Dosage Forms below). Food may delay, but does not alter the extent of absorption. Peak serum levels generally occur within 45-60 minutesafter oral elixir, and at about 90 minutes after oral tablet administration. In patients receiving aninitial oral dose of digoxin, peak effects may occur in 6-8 hours after the dose.The drug is distributed widely throughout the body with highest levels found in kidneys, heart, intestine, stomach, liver and skeletal muscle. Lowest concentrations are found in the brain and theplasma. At therapeutic levels, approximately 20-30% of the drug is bound to plasma proteins.
Because only small amounts are found in fat, obese patients may receive too high dosages if dosingis based on total body weight versus lean body weight.
Digoxin is metabolized slightly, but the primary method of elimination is renal excretion both byglomerular filtration and tubular secretion. As a result, dosage adjustments must be made in patientswith significant renal disease. Values reported for the elimination half-life of digoxin in dogs havebeen highly variable, with values reported from 14.4-56 hours. Elimination half-lives reported inother species include: Cats»33.3±9.5 hrs; Sheep»7.15 hrs.; Horses»16.9 - 23.2 hrs.; and Cattle»7.8 hrs.
Contraindications/Precautions - Digitalis cardioglycosides are contraindicated in patients withventricular fibrillation or in digitalis intoxication. They should be used with extreme caution inpatients with glomerulonephritis and heart failure or with idiopathic hypertrophic subaortic stenosis(IHSS). They should be used with caution in patients with severe pulmonary disease, hypoxia, acutemyocarditis, myxedema, or acute myocardial infarction, frequent ventricular premature contractions, ventricular tachycardias, chronic constrictive pericarditis or incomplete AV block. They may be usedin patients with stable, complete AV block or severe bradycardia with heart failure if the block wasnot caused by the cardiac glycoside.
When used to treat atrial fibrillation or flutter prior to administration with an antiarrhythmic agentthat has anticholinergic activity (e.g., quinidine, procainamide, disopyramide), digitalis glycosideswill reduce, but not eliminate the increased ventricular rates that may be produced by those agents.
Since digitalis glycosides may cause increased vagal tone, they should be used with caution inpatients with increased carotid sinus sensitivity.
Elective cardioversion of patients with atrial fibrillation should be postponed until digitalis glycosides have been withheld for 1-2 days, and should not be attempted in patients with signs ofdigitalis toxicity.
Because digoxin is principally eliminated by the kidneys, it should be used with caution and serumlevels monitored in patients with renal disease. Animals that are hypernatremic, hypokalemic, hypercalcemic, hyper- or hypothyroid may require smaller dosages; monitor carefully.
The veterinary elixir is available in two separate concentrations, do not confuse the two.
Adverse Effects, Warnings
Adverse effects of digoxin are usually associated with high or toxicserum levels and are categorized into cardiac and extracardiac signs and symptoms. There arespecies differences with regard to the sensitivity to digoxin's toxic effects also. Cats are relativelysensitive to digoxin while dogs tend to be more tolerant of high serum levels.Cardiac effects may be seen before other extra-cardiac symptoms and may include almost everytype of cardiac arrhythmia described with a resultant worsening of heart failure symptoms. Morecommon arrhythmias or ECG changes seen, include complete or incomplete heart block, bigeminy,
ST segment changes, paroxysmal ventricular or atrial tachycardias with block, and multifocalpremature ventricular contractions. Because these effects can also be caused by worsening heartdisease, it may be difficult to determine if they are a result of the disease process or of digitalisintoxication. If in doubt, monitor serum levels or stop digoxin therapy temporarily.
Extracardiac symptoms most commonly seen in veterinary medicine include mild GI upset, anorexia, weight loss and diarrhea. Vomiting has been associated with IV injections and should notcause anxiety nor alarm. Ocular and neurologic effects are routinely seen in humans, but are notprevalent in animals or are not detected.
Overdosage - Symptoms of chronic toxicity are discussed above. In dogs the acute toxic dose after IV administration has been reported to be 0.177 mg/kg.
Treatment of chronic digoxin toxicity is dictated by the severity of the signs and symptoms associated with it. Many patients will do well after temporarily stopping the drug and reevaluating the dosage regimen.
If an acute ingestion has recently occurred and no present cardiotoxic or neurologic signs (coma, seizures, etc.) have been manifested, emptying the stomach may be indicated followed with activatedcharcoal administration. Because digoxin can be slowly absorbed and there is some enterohepaticrecirculation of the drug, repeated charcoal administration may be beneficial even if the ingestionoccurred well before treatment. Anion-exchange resins such as colestipol or cholestyramine havealso been suggested to reduce the absorption and enterohepatic circulation of digoxin and digitoxin, but are not readily available in most veterinary practices. These agents may be of more benefit toadsorb less polar compounds such as digitoxin.
Dependent on the type of cardiotoxicity, supportive and symptomatic therapy should be implemented. Serum electrolyte concentrations, drug level if available on a "stat" basis, arterial blood gases if available, and continuous ECG monitoring should be instituted. Acid-base, hypoxia, and fluid and electrolyte imbalances should be corrected. The use of potassium in normokalemic patients is very controversial and should only be attempted with constant monitoring and clinicalexpertise.
The use of specific antiarrhythmic agents in treating life-threatening digitalis-induced arrhythmiasmay be necessary. Phenytoin, lidocaine, and propranolol are most commonly employed for thesearrhythmias. Atropine may be used to treat sinus bradycardia, SA arrest, or 2nd or 3rd degree AVblock.
Digoxin immune Fab is a promising treatment for digoxin or digitoxin life-threatening toxicity. Itis produced from specific digoxin antibodies from sheep and will bind directly to the drug, inactivating it. It is extremely expensive however and veterinary experience with it is extremelylimited.
Drug Interactions
Many digoxin interactions are listed in human medicine, the following may beof importance in veterinary medicine: Antacids, cimetidine, metoclopramide, neomycin (oral), chemotherapy agents (e.g., cyclophosphamide, doxorubicin, vinca alkaloids, cytarabine)may decrease the amount of digoxin absorbed from the GI tract.The following agents may either increase the serum level, decrease the elimination rate, or enhancethe toxic effects of digoxin: diazepam, quinidine, anticholinergics, succinylcholine, verapamil, tetracycline and erythromycin.
Patients on digoxin that receive thyroid replacement therapy may need their digoxin dosageadjusted.
Penicillamine may decrease serum levels of digoxin independent of route of digoxin dosing.
Drugs that can affect electrolyte balance can alter the efficacy or enhance the toxic effects ofdigoxin. Diuretics (furosemide, thiazides) may predispose the patient to digitalis toxicity. Otherdrugs which can deplete body potassium (amphotericin B, glucocorticoids, ACTH, laxatives, sodium polystyrene sulfonate) or decrease extracellular potassium (glucagon, high dose IVdextrose, dextrose/insulin infusions) may also predispose patients to toxic effects of digitalisdrugs. Spironolactone may enhance or decrease the toxic effects of digoxin.
Refer to specialized references for more information.