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 very slightly 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 pH of 6.6-7.4.
Storage/Stability/Compatibility - Digoxin tablets, capsules, elixir and injection should be stored at 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, including lactated 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 least 4 times with either sterile water, D5W, or normal saline. Digoxin injection has been demonstrated to be compatible with bretylium tosylate, cimetidine HCl, lidocaine HCl, and verapamil HCl.
Digoxin is incompatible with dobutamine HCl, acids and alkalies. The manufacturer does not recommend mixing digoxin injection with other medications. Compatibility is dependent upon factors such as pH, concentration, temperature, diluents used and it is suggested to consult specialized references for more specific information.
Pharmacology - The pharmacology of the digitalis glycosides have been extensively studied, but a thorough discussion is beyond the scope of this reference. Suffice it to say that digitalis glycosides cause the following effects in patients with a failing heart: increased myocardial contractility (inotropism) with increased cardiac output; increased diuresis with reduction of edema secondary to a decrease in sympathetic tone; reduction in heart size, heart rate, blood volume, and pulmonary and venous pressures; and (usually) no net change in myocardial oxygen demand.
The digitalis glycosides also have several electrocardiac effects, including: decreased conduction velocity through the AV node, and prolonged effective refractory period (ERP). They may also increase 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 to increase the availability of Ca++ to myocardial fibers and to inhibit Na+-K+-ATPase with resultant increased 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 - Absorption following oral administration occurs in the small intestine and is variable 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 minutes after oral elixir, and at about 90 minutes after oral tablet administration. In patients receiving an initial 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 the plasma. 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 dosing is based on total body weight versus lean body weight.
Digoxin is metabolized slightly, but the primary method of elimination is renal excretion both by glomerular filtration and tubular secretion. As a result, dosage adjustments must be made in patients with significant renal disease. Values reported for the elimination half-life of digoxin in dogs have been highly variable, with values reported from 14.4-56 hours. Elimination half-lives reported in other 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 with ventricular fibrillation or in digitalis intoxication. They should be used with extreme caution in patients 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, acute myocarditis, myxedema, or acute myocardial infarction, frequent ventricular premature contractions, ventricular tachycardias, chronic constrictive pericarditis or incomplete AV block. They may be used in patients with stable, complete AV block or severe bradycardia with heart failure if the block was not caused by the cardiac glycoside.
When used to treat atrial fibrillation or flutter prior to administration with an antiarrhythmic agent that has anticholinergic activity (e.g., quinidine, procainamide, disopyramide), digitalis glycosides will 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 in patients 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 of digitalis toxicity.
Because digoxin is principally eliminated by the kidneys, it should be used with caution and serum levels 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 toxic serum levels and are categorized into cardiac and extracardiac signs and symptoms. There are species differences with regard to the sensitivity to digoxin’s toxic effects also. Cats are relatively sensitive 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 every type of cardiac arrhythmia described with a resultant worsening of heart failure symptoms. More common arrhythmias or ECG changes seen, include complete or incomplete heart block, bigeminy, ST segment changes, paroxysmal ventricular or atrial tachycardias with block, and multifocal premature ventricular contractions. Because these effects can also be caused by worsening heart disease, it may be difficult to determine if they are a result of the disease process or of digitalis intoxication. 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 not cause anxiety nor alarm. Ocular and neurologic effects are routinely seen in humans, but are not prevalent 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 activated charcoal administration. Because digoxin can be slowly absorbed and there is some enterohepatic recirculation of the drug, repeated charcoal administration may be beneficial even if the ingestion occurred well before treatment. Anion-exchange resins such as colestipol or cholestyramine have also 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 to adsorb 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 clinical expertise.
The use of specific antiarrhythmic agents in treating life-threatening digitalis-induced arrhythmias may be necessary. Phenytoin, lidocaine, and propranolol are most commonly employed for these arrhythmias. Atropine may be used to treat sinus bradycardia, SA arrest, or 2nd or 3rd degree AV block.
Digoxin immune Fab is a promising treatment for digoxin or digitoxin life-threatening toxicity. It is 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 extremely limited.
Drug Interactions - Many digoxin interactions are listed in human medicine, the following may be of 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 enhance the toxic effects of digoxin: diazepam, quinidine, anticholinergics, succinylcholine, verapamil, tetracycline and erythromycin. Patients on digoxin that receive thyroid replacement therapy may need their digoxin dosage adjusted. 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 of digoxin. Diuretics (furosemide, thiazides) may predispose the patient to digitalis toxicity. Other drugs which can deplete body potassium (amphotericin B, glucocorticoids, ACTH, laxatives, sodium polystyrene sulfonate) or decrease extracellular potassium (glucagon, high dose IV dextrose, dextrose/insulin infusions) may also predispose patients to toxic effects of digitalis drugs. Spironolactone may enhance or decrease the toxic effects of digoxin. Refer to specialized references for more information.
a) 0.022 mg/kg daily orally (maintenance) (McConnell and Hughey 1987)
b) 0.06 - 0.08 mg/kg PO q8h for 5-6 doses to digitalize, then 0.01 - 0.02 mg/kg PO maintenance. (Hilwig 1987)
Note: a case report of serious digoxin toxicity in a horse has been reported following 0.035 - 0.07 mg/kg/day for 5 days; digitalize with caution.
Monitoring Parameters -
1) Serum levels
Because of the significant interpatient pharmacokinetic variation seen with this drug and its narrow therapeutic index, it is strongly recommended to monitor serum levels to help guide therapy. Unless the patient received an initial loading dose, at least 6 days should pass after beginning therapy to monitor serum levels as to allow levels to approach steady-state. Suggested therapeutic serum levels in the dog are 0.9 - 3.0 ng/ml and 0.9 - 2.0 ng/ml in cat (Neff-Davis 1985). For other species, values from 0.5 - 2.0 ng/ml can be used as guidelines. Levels at the higher end of the suggested range may be necessary to treat some atrial arrhythmias, but may also result in higher incidences of adverse effects. Usually a trough level (just before next dose or at least 8 hours after last dose) is recommended.
3) Cardiac rate, ECG changes
4) Serum electrolytes
5) Clinical efficacy for CHF (improved perfusion, decreased edema, increased venous (or arterial) O2 levels).
Client Information - Contact veterinarian if animal displays changes in behavior, vomits, has diarrhea, lack of appetite, symptoms of colic (horses), becomes lethargic or depressed.
Dosage Forms/Preparations/FDA Approval Status/Withholding Times -
There are bioavailability differences between dosage forms and in tablets produced by different manufacturers. It is recommended that tablets be used from a manufacturer that the clinician has confidence in and that brands not be routinely interchanged. Should a change in dosage forms be desired, the following bioavailability differences can be used as guidelines in altering the dose: Intravenous = 100%, IM ≈ 80%, Oral tablets ≈ 60%, Oral elixir ≈ 75%, Oral capsules ≈ 90-100%. The bioavailability of digoxin in veterinary species has only been studied in a limited manner. One study in dogs yielded similar values as those above for oral tablets and elixir, but in horses only about 20% of an intragastric dose was bioavailable.
Digoxin Elixir 0.05 mg/ml 60 ml dropper bottle; Cardoxin® LS ( Evsco); (Rx)
Digoxin Elixir 0.15 mg/ml in 60 ml dropper bottle; i.Cardoxin® ;(Evsco); (Rx)
Digoxin tablets and elixir have been approved for veterinary use, but no species are listed in the indications. There are no drug residue data for meat or milk published and no meat or milk withdrawal times are available.
Digoxin for Injection 0.1 mg/ ml in 1 ml amps & 0.25 mg/ml in 2 ml amps, & 1 & 2 ml Tubex; Lanoxin® (Glaxo Wellcome), Digoxin® (Elkins-Sinn) and (Wyeth-Ayerst) (Rx)
Digoxin tablets 0.125 mg, 0.25 mg and 0.5 mg; Lanoxin® (Glaxo Wellcome), generic; (Rx)
Digoxin capsules 0.05 mg, 0.1 mg, 0.2 mg; Lanoxicaps® (Glaxo Wellcome); (Rx)
Digoxin Elixir Pediatric 0.05 mg/ml in 60 ml dropper bottle, 50 ml and UD 2.5 & 5 ml; Lanoxin® (Glaxo Wellcome); (Rx); generic (Rx)
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