Digoxin toxicity awe

presentation on Digitalis Toxicity

1. DIGITALIS TOXICITY PREPARED AND PRESENTED BY Dr Nigat Endalamaw EMCCR Moderator:dr hymanot emcc senior

2. Out line Introduction Mechanism of action Pharmacokinetics Effect on specific organ system Toxicity level Drug interaction Work up Management

3. Introduction - cardiac glycosides are compounds which all posess steroid nucleus with unsaturated lactone at c17 position and at least one glycoside at c3 position. -organ system effect of cardiac glycosides …… increase inotropy in cardiac myocsites …… affects cells in vascular smooth muscle ……affect Autonomic nervous system.

4. Electrophysiologic effect mechanism -shorten atrial and ventricular repolarization by decreasing the refractory period and thus increasing automaticity. - increase vagal tone via action at the carotid body by reducing conduction through the sinoatrial and atrioventricular nodes. -In toxic concentrations can increase sympathetic tone.

5. …… contineud - Reduce plasma renin concentrations in patients with advanced heart failure resulting in peripheral vasodilation . -patients without heart failure digoxin can cause vasoconstriction. -Increased central vagal tone typically produces cardiac manifestations such as ……. bradydysrhythmias …… atrioventricular block.

6. ……..continued -Direct cellular effect …….. inhibiting the membrane sodium-potassium (Na+-K+) pump …… raising intracellular levels of sodium ……leading to an accumulation of intracellular calcium. …..results increases cardiac contractility. -Indirect effect ……enhancing vagal tone.

7. Therapeutic Uses of Digitalis Compounds A) Heart Failure ↑ inotropy ↑ ejection fraction ↓ preload ↓ pulmonary congestion/edema B) Arrhythmias ↓ AV nodal conduction ( parasympathomimetic effect) ↓ ventricular rate in atrial flutter and fibrillation

8. Cardiac glycosides are found naturally in Plants and animals. A. Cardenolides : 1. Digitalis purpurea – Digitoxin , Gitoxin and Gitalin 2. Digitalis lanata - Digitoxin , Gitoxin and Digoxin 3. Strophanthus gratus – Ouabin

9. ……….continued 4. Thevetia nerifolia – Thevetin 5. Convallaria majalis – Convallotoxin B. Bufadienolides : Bufo vulgris - Bufotoxin Digoxin - the only cardiac glycoside mostly used in current clinical practice around the world. -some times digitoxin is used in Europe -One of top toxins in the world because …… wide availability of digoxin ….. narrow therapeutic window.

10. Mechanism Of Action -Direct inhibition of membrane-bound Na+/K+ - ATPase which pumps (3 Na+ outside for 2 K+ inside the cell) -This is responsible for maintenance of resting membrane potential in most excitable cells. 

11.   ….continued - This leads to an increase intracellular sodium that gradually decrease in intracellular potassium. - In Cardiac fiber [Ca2+] is exchanged for extracellular sodium (3:1 ratio) by Na+/Ca+ exchanger transport system that is forced by the concentration gradient for these ions and the transmembrane potential.

12. ……Continued -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.

13. …… Continued -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 .

14. Pharmacokinetics - Therapeutic daily dose from 5-15mcg/kg. - bioavailability is 95%. -excreted by kideny 60-80% of the dose unchanged. -The onset of action …..oral in 30-120 minutes. …. intravenous in 5-30 minutes. -Half life is 1-3 days

15. …… continued - 1% of the total amount of digoxin in the body is in the serum. - about 30 % bound to plasma proteins.   - volume of distribution 6- 7L/kg which is large. -A dose less than 5 mg is rarely to cause toxicity. -A dose higher than 11 mg may be fatal. -In pediatrics 4 mg can cause toxicity.

16. Use of digoxin during pregnancy -Widely in the acute management and prophylaxis of ----fetal paroxysmal supraventricular tachycardia ---- in rate control of atrial fibrillation.   -It is a category C drug. -Increased digoxin dosage because of …….enhanced renal clearance ……expanded blood volume.

17. Toxic Effect of on specific organ system Cardiac: 1- Dysrrhythmia - Alterations in cardiac rate and rhythm occurring in digitalis toxicity may simulate almost every known type of dysrhythmia . -The most common dysrhythmia in digoxin toxicity is premature ventricular contractions. -Decrease AV conduction leading to ……… bradycardia …….. heart block (first, second, third).

18. …..continued - AV junctional block of varying degrees with increased ventricular automaticity. -manifestations of toxicity occur in 30-40% of patients with recognized digoxin toxicity.

19. ………continued -increase automaticity leading to several types of tachyarrhythmias . -When conduction and normal pacemaker are both depressed ectopic pacemakers take over producing …. atrial tachycardia …ventricular tachycardia .

20. Nonspecific ECG findings of toxicity include : - Premature ventricular contractions -First-second- and third-degree AV block -Sinus bradycardia -Sinus tachycardia - Sinoatrial block or arrest

21. …. continued - Atrial fibrillation with slower ventricular response - Atrial tachycardia - Junctional (escape) rhythm -AV dissociation -Ventricular bigeminy and trigeminy -Ventricular tachycardia - Torsade de pointes -Ventricular fibrillation

22. -Four ECG findings are seen with therapeutic levels of digoxin and are not indicators of toxicity. -They are: …….. T-wave flattening or inversion …….. QT-interval shortening ……..a “scooped” appearance of the ST segment with ST-segment depression ……..an increase in U-wave amplitude.

23. More specific not pathognomonic ECG findings include : - Atrial fibrillation with a slow regular ventricular rate ( ie , AV dissociation) - Nonparoxysmal junctional tachycardia (rate greater than 100 bpm - Atrial tachycardia with block ( atrial rate usually 150-200 bpm ) - ventricular tachycardia

24. 2) CNS and renal - can cause inadequate tissue perfusion with resultant CNS and renal complications such as : -Hypoxic seizures and -Acute tubular necrosis. 3- Hyperkalemia - is the major electrolytic complication in acute massive digitoxin poisoning due to inhibition of sodium-potassium ATPase .

25. ….continued - H yperkalmemia slows AV conduction adding to digoxin toxicity. - Hypokalemia is seen with chronic toxicity. 4- GIT manifestations: cause abdominal pain, nausea and vomiting where it increases vagal stimulation and activates chemoreceptor trigger zone.

26. 5- Visual disturbance : - colored vision (yellow and green patches), Scotomata , diplopia . -A patient with normal digoxin levels (0.5-2 ng / mL ) can have cardiotoxicity in case of ……. renal insufficiency ……..severe hypokalemia

27. ….. continued -Conditions which precipitate digoxin chronic toxicity are:  ----Deteriorating renal function -----dehydration -----electrolyte disturbances ----- drug interactions

28. Digoxin drug Interaction - Drugs interaction that cause chronic digoxin toxicity include :   - Amiloride - May reduce the inotropic response to digoxin - Amiodarone - Reduces renal and nonrenal clearance and have additive effects on the heart rate. -Benzodiazepines ( alprazolam , diazepam) - Have been associated with isolated reports of digoxin toxicity.

29. …… continued -Beta-blockers ( propranolol , metoprolol , atenolol ) - May have additive effects on the heart rate. carvedilol may increase digoxin blood levels in addition to potentiating its effects on the heart rate. -Calcium channel blockers - Diltiazem and verapamil increase serum digoxin levels. -not all calcium channel blockers share this effect.

30. … .continued -Cyclosporine - May increase digoxin levels, possibly due to reduced renal excretion -Erythromycin, clarithromycin , and tetracyclines - May increase digoxin levels Propafenone - Increases digoxin level.

31. ….continued - Quinidine - Increases digoxin level. - Hydroxychloroquine and quinine - may also affect levels. - Propylthiouracil - May increase digoxin levels by reducing thyroid hormone levels.

32. …..continued - Spironolactone - may directly increase digoxin levels and may alter renal excretion. -Hydrochlorothiazide Furosemide and other loop diuretics - Amphotericin B - May precipitate hypokalemia and subsequent digoxin toxicity - Succinylcholine - Increased risk of dysrhythmias has been reported.

33. Work up in digoxin toxicity -Morbidity and mortality rates in digoxin toxicity increase if the patient has …… Dysrhythmia …..advanced AV block ….. other significant ECG abnormality ….. comorbid condition …..Advanced age

34. .Investigations -plasma digoxin level -serum electrolyte -Electrocardiography -Renal function test -liver function test - toxicologic screen -chest x-ray -echocardiography -cardiac biomarkers

35. …. .continued - The lethal dose of most glycosides is 5-10 times the minimal effective dose . -only about twice the dose that leads to minor toxic manifestations . -suggestive of acute toxicity in young ….. bradyarythmias ….. hyperkalemia .

36.   ….continued - Suggestive of chronic toxicity in old age ……Visual disturbances …. Hypokalemia ….. 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 .

37. …… continued -Therapeutic digoxin levels vary: …. lower limit from 0.6-1.3 ng / mL …. upper limit agreed to be 2.6 ng / mL.   -Initial potassium levels are better correlated with the prognosis. - all patients with an initial potassium level greater than 5.5 died. -Measure Na+, K+, Mg++, Ca++, blood urea nitrogen (BUN), and creatinine levels.

38. …….. continued -conditions which affect serum magneseium level are: ……..Long-term digoxin users ……..long-term diuretic users -Importantly magnesium is a cofactor of the Na+/K+ - ATPase pump and alterations of its concentration will affect the pump's actions .

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

40. Approach to digoxin toxicity - The clinical manifestations digoxin toxicity are the same across all these age groups. (infants, children, and adults)    - Treatment of digoxin toxicity should be guided by ……the patient’s signs and symptoms …..the specific toxic effects …..not necessarily by digoxin levels alone. 

41. Therapeutic options includes: -supportive care - Digoxin Fab fragments - cardioversion and Cardiac pacing - Antiarrhythmic drugs -GI decontamination and enhance elimination -gastric lavage and induce emesis and whole bowl irregation and forced diuresis -binding resins - Hemodialysis for severe acute toxicity.

42. prehospital care includes: - Administration of oxygen -cardiac monitoring -establishment of IV access -and transport are usually requiered

43. Supportive care includes : - Hydration with IV fluids -oxygenation -support of ventilatory function -discontinuation of the drug -correction of electrolyte imbalances.

44. General and specific principles of management of toxicity - Assessment of the severity of the toxicity and its etiology . -Consideration of factors that influence treatment include: …..age and ECG changes …..medical history and renal insuffieciency ….. chronicity of intoxication …..existing heart disease

45. ….. continued -Continuous hemodynamic assessment, including 12-lead electrocardiogram and cardiac monitoring. -Prompt measurement of electrolyte levels and of serum creatinine and digoxin levels  . -intensive care unit admission.

46. Binding resins - cholestyramine –drug may bind enterohepatically -recycled digoxin and digitoxin . - more appropriately used for treatment of chronic toxicity in patients with renal insufficiency.

47. GI Decontamination and Enhanced Elimination: - The first-line treatment for acute ingestion is repeated dosing of activated charcoal to reduce absorption and interrupt enterohepatic circulation. -1 gram/kg PO can be considered in an awake alert cooperative patient who presents within 1 h of ingestion.

48. Gastric lavage - increases vagal tone and may precipitate or worsen arrhythmias. -Consider pretreatment with atropine if gastric lavage is performed. -Treatment with digitalis Fab antibody usually renders gastric lavage unnecessary.

49. -Induced emesis with ipecac syrup - is not recommended because of the increased vagal effect. - Whole-bowel irrigation - may be useful if clinical data are lacking. - Forced diuresis - is not recommended because it can worsen electrolyte abnormalities. - Dialysis - has been shown to produce only small additional clearance.

50. Treatment of Electrolyte Imbalance - Correct hyperkalemia , hypokalemia , and hypomagnesemia . -Correction of electrolyte imbalances may reverse dysrhythmias . Digoxin Immune Fab Therapy - Digoxin immune Fab is an immunoglobulin fragment that binds with digoxin . - first-line treatment for significant dysrhythmias (severe bradyarrhythmia , second- or third-degree heart block, ventricular tachycardia or fibrillation) from sever acute digitalis toxicity. 

51. - Digoxin -specific antibody fragments: IV bolus 5–10 vials if amount of digoxin ingested is unknown.

52. Indications for immunotherapy with digoxin Fab fragment include : - ingestion of massive quantities of digitalis (in children 4 mg and adults 10 mg). - Hyperkalemia (serum potassium level greater than 5 mEq /L). -Altered mental status attributed to digoxin toxicity. -Rapidly progressive signs and symptoms of toxicity -For patients with rate-related ischemia or hemodynamic instability.

53. …….. continued Management of digoxin toxicity dysrhythmias depending on : -Presence or absence of hemodynamic instability -Nature of the dysrhythmia -Presence or absence of electrolyte disturbances -Preferences of toxicology and/or cardiology consultants.

54. …… continued  -Early in acute intoxication, depression of sinoatrial or AV nodal function may be reversed by atropine. -Subsequent manifestations are the result of direct and vagomimetic actions of the drug on the heart and are not reversed by atropine.

55. Ectopic rhythms due to digoxin toxicity are due to -enhanced automaticity -reentry -both and may include: - Nonparoxysmal junctional tachycardia - Extrasystole -Premature ventricular contractions -Ventricular flutter and fibrillation - Atrial flutter and fibrillation - ventricular tachycardia

56. …… .continued - Bidirectional ventricular tachycardia is particularly characteristic of severe digitalis toxicity and results from ---------alterations in intraventricular conduction ----- -- junctional tachycardia with aberrant intraventricular conduction ----------or rarerly alternating ventricular pacemakers.

57. The following features may also be seen in digoxin toxicity: - Depression of the atrial pacemakers resulting in -SA arrest -SA block -AV block -Sinus exit block resulting from depression of normal conduction - Nonparoxysmal atrial tachycardia with block Cardiac arrest -CPR with current advanced cardiac life support protocols .

58. …… continued -In hemodynamically stable patients ……. bradyarrhythmias and …….. supraventricular arrhythmias can be treated with observation and supportive care. -Short-acting beta blockers ( eg , esmolol ) are helpful for supraventricular tachyarrhythmias with rapid ventricular rates.

59. …….. continued - Esmolol may precipitate advanced or complete atrioventricular block in patients with sinoatrial or AV node depression. - Hemodynamically stable PVCs, bigeminy , or trigeminy may require only observation. -If they are hemodynamically unstable lidocaine may be effective. 

60. - Phenytoin has been shown to dissociate the inotropic and dysrhythmic action of digitalis. - phenytoin suppress digitalis-induced tachydysrhythmias without diminishing the contractile effects. -Atropine is indicated for hemodynamically unstable bradyarrhythmic patients. - lidocaine is indicated for ventricular tachycardia.

61. ……….. continued - Lidocaine dose - given in boluses of 100 mg and begin a maintenance infusion at 1-4 mg/min. - Phenytoin has been administered in boluses of 100 mg every 5-10 minutes, up to a loading dose of 15 mg/kg.

62. ……… .continued -Magnesium sulfate 2 g IV over 5 minutes to terminate Torsade de pointes in digoxin -toxic patients with and without overt cardiac disease. -After the initial bolus a maintenance infusion at 1-2 g/h is initiated. -Monitor magnesium levels approximately every 2 hours. -The therapeutic goal is a level between 4 and 5 mEq /L.  -Magnesium is contraindicated in the setting of bradycardia or AV block and should be used cautiously in patients with renal failure.

63. Electrical cardioversion and pacing - Cardioversion for severe dysrhythmias due to digitalis is hazardous. -it can precipitate ventricular fibrillation and asystole . - if the patient is hemodynamically unstable and has a wide, complex tachycardia and if fascicular tachycardia has been ruled out, cardioversion will need to be used early.

64. Hospital Admission criteria in digoxin toxicity: - New cardiac dysrhythmias -Severe bradyarrhythmias -Advanced AV block -Acute prolongation of the QRS interval -Severe electrolyte abnormalities, especially hypokalemia or hyperkalemia -Dehydration -inability to care for self -Suicidal ideation

65. (ICU) admission criteria in digoxin toxicity include the following: - Hemodynamic instability -Refractory dysrhythmias - Hyperkalemia -Renal failure

66. REFERENCE - Tintinallis 8 th edition -UP to date 21.6 -MEDSCAPE -SLIDESHARE -Gold frank toxicology emergency

67. ?Thank you