Digoxin toxicity

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1. Digitalis toxicity By:   Amr Mohamed Abdelmonem Elsharkawy   Critical Care Resident Physician   Alexandria Main University hospital

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. Cardiac muscle action potential

4. Normal depolarization of the cardiac myocyte begins with the opening of the fast sodium channels. The resulting increase in intracellular sodium, and subsequent change in the resting membrane potential, opens voltage-gated calcium channels. The initial influx of calcium induces further release of calcium from the sarcoplasmic reticulum , which results in muscle contraction . Sodium is then removed from the cell by, among several mechanisms, the sodium-potassium ATPase . Some calcium is removed from the cell by the sodium-calcium antiporter .

5. Mechanism Of Action The positive inotropic effect of digitalis has the following component: Direct inhibition of membrane-bound Na + /K + - ATPase , which normally 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.

6. Increased amounts of Ca 2+ also leads to increased storage of calcium in the  sarcoplasmic reticulum , causing a corresponding increase in the release of calcium during each action potential. This leads to increased contractility of the heart ( inotropic effect).

7. - 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 by shortening the refractory period of atria and venticles

8. Pathophysiology 1. Cardiac: arrh ythmia Alterations in cardiac rate and rhythm occurring in digitalis toxicity may simulate almost every known type of ar rhythmia .  - 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 digoxin poisoning. In addition hyperkalmemia slows AV conduction adding to digoxin toxicity. Hypokalemia is seen with chronic toxicity.

11. 4- GIT manifestations: nausea, vomiting, abdominal pain, anorexia vagal stimulation>> Chemoreceptor trigger zone 5- Visual disturbance: colored vision (yellow and green patches), Scotomata , diplopia .  

12. Digoxin pharmacokinetics The onset of action by oral administration occurs in 30-120 minutes the onset of action with intravenous administration occurs in 5-30 minutes . its bioavailability is 95%. Only 1% of the total amount of digoxin in the body is in the serum; of that amount about 30 % bound to plasma proteins . Large volume of distribution about 8L.

13. The kidney excretes 60-80% of the digoxin dose unchanged. 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 . Because of  digoxin's large volume of distribution and molecular weight, extracorporeal removal is not beneficial . Neither hemoperfusion nor hemodialysis have been shown to be helpful in the management of digoxin toxicity.

14. CLINICAL FEATURES AND DIAGNOSIS  of toxicity: History: Determine the agent, amount taken, time of ingestion, and any coingestants whenever possible. - Determine also if the patient normally takes digitalis or if it was someone else's prescription. - Ask about symptoms suggesting an acute illness. - Inquire carefully about gastrointestinal, cardiac, and neurologic manifestations, including visual disturbances. - Inquire also about symptoms that suggest hypoperfusion , such as confusion and abdominal pain, which may stem from mesenteric ischemia.

15. Circumstances of toxicity 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. Acute , non therapeutic overdose—unintentional, suicidal, or homicidal—can cause toxicity

16. LABORATORY AND ECG EVALUATION: (1) Serum  digoxin   concentration: With acute toxicity,  ideally , blood samples should be collected four hours after an intravenous dose or six hours after an oral dose in order to account for drug distribution and obtain an accurate measurement.

17. (2) Serum potassium concentration: - Hyperkalemia is correlated with mortality in acute intoxication. - All patients with an initial potassium level greater than 5.5 have poor prognosis. As regards chronic toxicity, the most common precipitating cause of digitalis intoxication is hypokalemia which occurs often in patients with heart failure as a result of diuretic therapy. (3) Creatinine and BUN to assess renal function : Renal dysfunction is also commonly encountered in the setting of chronic  digoxin   toxicity and is often what precipitates the rise in the digoxin level. (4) Serial electrocardiograms:

18. ECG shows any type of arrhythmia

19. Hyperkalemia

20. Managment A- B - C 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

21. GI Decontamination and Enhanced Elimination The administration of   activated charcoal   (AC) or  cholestyramine   for gastrointestinal decontamination should be viewed as adjunctive and  not  primary therapy in patients with digitalis poisoning . Patients suspected of having an acute digitalis intoxication who present to the emergency department within one to two hours of ingestion may benefit from the administration of AC. Cardiac glycosides undergo some degree of enterohepatic or enteroenteric recirculation and are adsorbed to  activated charcoal  . AC or multi-dose AC (MDAC) are recommended for digitalis toxicity .

22. Management of arrhythmia: - In case of tachycardia: give lidocaine or phenytoin (No effect on AV conduction). - Life-threatening ventricular arrhythmias are treated according to the algorithms of advanced cardiac life support (ACLS). - In case of bradycardia : give atropine. - Correct electrolyte disturbances - In case of hyperkalemia : give EDTA and give insulin + glucose to shift K + intracellularly But Ca gluconate is contraindicated However, hyperkalemia itself does not cause death, and treatment with potassium-lowering agents does  not reduce mortality.

23. Indications of Antidotal therapy with antibody ( Fab ) fragments - Fab fragments should be given in all cases of severe digitalis poisoning. - Life-threatening arrhythmia ( eg , ventricular tachycardia; ventricular fibrillation; asystole ; complete heart block; Mobitz II heart block; symptomatic bradycardia ) -Evidence of end-organ dysfunction ( eg , renal failure, altered mental status) Hyperkalemia (serum potassium >5 to 5.5  meq /L) serum digoxin concentration is greater than 10  ng / mL   at steady state in acute ingestions, or greater than 4  ng / mL   in chronic ingestions an adult ingests more than 10 mg or a child more than 4 mg acutely.