Digoxin toxicity

toxicology

1. Digoxin toxicity

2. Introduction One of top toxins in the world because of the wide availability of digoxin and a narrow therapeutic window. Digitalis is a plant-derived cardiac glycoside commonly used in the treatment of congestive heart failure (CHF), atrial fibrillation, and reentrant supraventricular tachycardia. Digoxin -specific fragment antigen-binding ( Fab ) antibody has contributed significantly to the improved morbidity and mortality of toxic patients

3. Mechanism Of Action The positive inotropic effect of digitalis has the following component: Direct inhibition of membrane-bound Na + /K + - ATPase , which pumps 3 Na + outside the cell in exchange with 2 K + inside the cell which is responsible for maintenance of resting membrane potential (RMP) in most excitable cells. This leads to an increase intracellular sodium gradually, and a gradual, small decrease in intracellular potassium.

4. Cardiac fiber [Ca 2+ ] is exchanged for extracellular sodium (3:1 ratio) by by Na + /Ca + exchanger transport system that is driven by the concentration gradient for these ions and the transmembrane potential; increase in [Na + ] i is related crucially to the positive inotropic effect of digitalis. Facilitation of Ca + entry through the voltage gated Ca + channels of the membrane. That is associated with increase in slow inward calcium current during the plateau of action potential.

5. They exert negative chronotropic effect through vagal and extravagal stimulation.   They decrease AV conduction through direct action on the myocardium and vagal stimulation .   They increase heart automaticity in overdose only leading to pulse bigeminus and pulse trigeminus .

6. Digoxin pharmacokinetics The therapeutic daily dose of digoxin ranges from 5-15mcg/kg. its bioavailability is 95%. The kidney excretes 60-80% of the digoxin dose unchanged. The onset of action by oral administration occurs in 30-120 minutes the onset of action with intravenous administration occurs in 5-30 minutes. Only 1% of the total amount of digoxin in the body is in the serum; of that amount about 30 % bound to plasma proteins.

7. Large volume of distribution about 8L. A dose less than 5 mg is rarely to cause toxicity, however a dose higher than 11 mg may be fatal In pediatrics a dose higher than 4 mg can cause toxicity. During pregnancy Digoxin is used widely in the acute management and prophylaxis of fetal paroxysmal supraventricular tachycardia, as well as in rate control of atrial fibrillation. It is a category C drug. Increased digoxin dosage may be necessary during pregnancy because of enhanced renal clearance and expanded blood volume.

8. Pathophysiology 1. Cardiac: Dysrrhythmia Alterations in cardiac rate and rhythm occurring in digitalis toxicity may simulate almost every known type of dysrhythmia .  - Decrease AV conduction leading to bradycardia and heart block (first, second, third). Indeed, AV junctional block of varying degrees, alone or with increased ventricular automaticity, are the most common manifestations of digoxin toxicity, occurring in 30-40% of patients with recognized digoxin toxicity.

9. Increase automaticity leading to several types of tachyarrhythmias . When conduction and the normal pacemaker are both depressed, ectopic pacemakers may take over, producing atrial and ventricular tachycardia. 2- Arrhythmias can cause inadequate tissue perfusion, with resultant central nervous system (CNS) and renal mplications such as the following: Hypoxic seizures Acute tubular necrosis

10. 3- Hyperkalemia is the major electrolytic complication in acute, massive digitoxin poisoning. In addition hyperkalmemia slows AV conduction adding to digoxin toxicity. Hypokalemia is seen with chronic toxicity. 4- GIT manifestations: nausea , vomiting, abdominal pain, anorexia Digitalis preparation cause nausea and vomiting where it increases vagal stimulation and activates chemoreceptor trigger zone. 5- Visual disturbance: colored vision (yellow and green patches), Scotomata , diplopia .  

11. Clinical digoxin toxicity represents a complex interaction between digoxin and various electrolyte and renal abnormalities. A patient with normal digoxin levels (0.5-2 ng / mL ) but renal insufficiency or severe hypokalemia may have more serious cardiotoxicity than a patient with high digoxin levels and no renal or electrolyte disturbances. The most common precipitating cause of digitalis intoxication is depletion of potassium stores, which occurs often in patients with heart failure as a result of diuretic therapy and secondary hyperaldosteronism .

12. Deteriorating renal function, dehydration, electrolyte disturbances, or drug interactions usually precipitate chronic toxicity. Acute overdose or accidental exposure to plants containing cardiac glycosides may cause acute toxicity. Erroneous dosing, especially in infants receiving parenteral digoxin , is a frequent cause of digoxin toxicity and is usually associated with high mortality. Acute, nontherapeutic overdose—unintentional, suicidal, or homicidal—can cause toxicity

13. Drug Interaction Some medications directly increase digoxin plasma levels; other medications alter renal excretion or induce electrolyte abnormalities. Drugs that have been reported to cause digoxin toxicity include the following: Amiloride Amiodarone - Reduces renal clearance of digoxin and may have additive effects on the heart rate Benzodiazepines ( alprazolam , diazepam) -

14. Beta blockers May have additive effects on the heart rate Calcium channel blockers - Diltiazem and verapamil increase serum digoxin levels; not all calcium channel blockers share this effect. Cyclosporine, Erythromycin, clarithromycin , and tetracyclines , Propafenone Quinidine - Increases digoxin level substantially Propylthiouracil,Indomethacin ,

15. Spironolactone , Hydrochlorothiazide, Furosemide and other loop diuretics, Triamterene Amphotericin B - May precipitate hypokalemia and subsequent digoxin toxicity Herb/ nutraceutical - Avoid ephedra (risk of cardiac stimulation); avoid natural licorice (causes sodium and water retention and increases potassium loss) Increase patient awareness about the symptoms of digitalis toxicity. In addition, educate patients about drug interactions and about maintaining adequate hydration.

16. Work up Prognosis in digitalis toxicity is poor with increasing age and associated comorbid conditions. Morbidity and mortality rates increase if the patient has a dysrhythmia , advanced AV block, or other significant ECG abnormality. The lethal dose of most glycosides is approximately 5-10 times the minimal effective dose and only about twice the dose that leads to minor toxic manifestations.

17. Usually arrhythmia, and hyperkalemia suggestive of acute toxicity (usually common in young indidiuals , bradryarythmias are more common) - Visual disturbances and hypokalemia in chronic toxicity (usually in old patients on digoxin treatment, all types of arrhythmia more commonly tachyarrhythmias ) The plasma digoxin level can be used to monitor compliance and toxicity and can be used as a guide to the appropriate dosing of medication (TDM). Therapeutic digoxin levels vary; the lower limit ranges from 0.6-1.3 ng / mL , while the upper limit generally is agreed to be 2.6 ng / mL.

18. False-negative assay results may occur in the setting of acute ingestion of nondigoxin cardiac glycosides, such as foxglove and oleander, even in the setting of profound clinical toxicity. Initial potassium levels are better correlated with the prognosis than either ECG changes or the initial serum digoxin level. In one monitor, all patients with an initial potassium level greater than 5.5 died

19. Measure Na + , K + , Cl - , CO 2- , Mg ++ , Ca ++ , blood urea nitrogen (BUN), and creatinine levels. Long-term digoxin users often have hypomagnesemia secondary to diuretic usage. Intracellular magnesium depletion may occur in long-term diuretic use despite a normal serum magnesium level. Importantly, magnesium is a cofactor of the Na + /K + - ATPase pump, and alterations of its concentration will affect the pump's actions.

20. ECG shows any of the following Atrial fibrillation with slow, regular ventricular rate Atrial tachycardia with block ( atrial rate usually 150-200 bpm ) Bidirectional ventricular tachycardia Inverted T wave Peaked T wave ( hyperkalemia ) Torsade de pointes

21. Managment hydration with IV fluids, oxygenation and support of ventilatory function, discontinuation of the drug, and, sometimes, the correction of electrolyte imbalances. Fab antibody fragments are extremely effective in the treatment of severe, acute digitalis toxicity

22. Management of arrhythmia: In case of tachycardia: give lidocaine or phenytoin (No effect on AV conduction).   In case of bradycardia : give atropine.   In case of hyperkalemia : give EDTA and give insulin + glucose to shift K + intracellularly .   - Ca gluconate is contraindicated because of Ca, Ca contraindicated)  

23. Correction of electrolyte disturbances as hypo and hyper kalemia Correct hypomagnesemia in cases of tachycardia. Give 1-2 g Mg sulfate even with normal Mg levels it also may act as an indirect antagonist of digoxin at the supraphysiologic level. Temporary pacing is an alternative for patients with nodal blocks before any other medical interventions are attempted. Electrocardioversion is not recommended except with specific cases

24. GI Decontamination and Enhanced Elimination The first-line treatment for acute ingestion is gastric lavage with repeated dosing of activated charcoal to reduce absorption and interrupt enterohepatic circulation. It is most effective if ingestion has occurred within 6-8 hours. Pretreatment with atropine has been recommended to decrease the incidence of AV block or bradycardia as a result of increased vagal tone caused by gastric lavage .

25. To break enterohepatic circulation, use binding resins, such as cholestyramine . Induced emesis with ipecac syrup - Not recommended, because of the increased vagal effect Whole-bowel irrigation - May be useful, but clinical data are lacking Forced diuresis - Not recommended, because it has not been shown to increase renal excretion and can worsen electrolyte abnormalities Dialysis - Has been shown to produce only small-added clearances unless severe hyprekalemia