Digitalis toxicity.pptx

Brief overview regarding digitalis

1. Seminar on approach to management of digitalis toxicity Presentor: Dr. Tamagnsew (R1) Moderator: Dr. Nadia (R2) Advisor: Dr. Ashenafi (consultant)

2. Outlines Introduction Mechanism of action Pharmacokinetics Sign and symptoms Pathophysiology Factors that increase digoxin toxicity History and physical examination Diagnosis Management

3. Objective Define the nature of digitalis. Identify sources digitalis. List the indications for digoxin use. Identify sign and symptoms of digitalis toxicity. Describe initial management of digitalis toxicity.

4. Introduction Cardiac glycosides are often called digitalis or digitalis glycosides. Digitalis lantana is the source of digoxin, the only glycoside that is currently in use.

5. Cont.… Others like Digitoxin ( from digitalis purpurea) are no longer in the market. In addition to availability as pharmaceuticals, cardiac glycosides are also found in the skin of toads (bufotoxin).

6. Cont.. Similar cardioactive steroids are also found in Plants such as: Foxglove, Oleander, Red squill, and Lily of the valley .

7. MOA Directly inhibit Na+/K+ ATPase intracellular Na+ inhibits Na+/Ca2+ exchanger intracellular Ca2+ Ca2+ release from SR contractile force (positive inotropy ). Also digoxin vagal activity & SA & AV conduction heart rate.

8. Kinetics Both digoxin and digitoxin have a narrow therapeutic index and toxicity is common. Good oral absorption with oral bioavailability of 80%. It is eliminated primarily through the kidney. It has a has a half-life of 36-48 hours, longer in renal failure. Therapeutic levels of digoxin are 0.8-2.0ng/ml. The toxic level is above 2.5 ng/ml

9. Cont.. Digoxin has a large volume of distribution, being 6-10 L/kg in adults. Onset of action after PO administration occurs in 30-120 minutes. Onset of action with IV administration occurs in 5-30 minutes. The peak effect with PO dosing is 2-4 hours, and that with IV dosing is 5-30 minutes.

10. Sign and symptoms of digitalis toxicity Cardiovascular Palpitation Syncope Dyspnea Dysrhythmias Constitutional Weakness, fatigue Central nervous system Headache , confusion, Lethargy, Agitation, Hallucination, delirium, acute psychosis Neuropathic pain, seizure Visual Blurred or snowy vision Photophobia Yellow-green chromatopsia (also red, brown, blue) Transient amblyopia, diplopia, scotomas , blindness Gastrointestinal Nausea, Vomiting ,Abdominal pain, Diarrhea Electrolyte disturbances Hyperkalemia

11. Digoxin toxicity Acute toxicity Chronic toxicity Clinical history Intentional or accidental ingestion Typically elderly cardiac patients taking diuretics, may have renal insufficiency GI effects Nausea and vomiting, abdominal pain, anorexia Nausea, vomiting, diarrhea, Abdominal pan CNS effects Headache, dizziness, confusion, coma Fatigue, Weakness, Confusion , Delirium, and Coma are often prominent Cardiac effects Bradyarrhythmias or supraventricular tachyarrhythmias with atrioventricular block are common Almost any ventricular or supraventricular arrhythmias can occur; ventricular arrhythmias are common Electrolyte abnormalities Hyperkalemia Normal ,decreased or increased serum potassium, hypomagnesaemia Digoxin level Markedly elevated (if obtained within 6 hrs.) Minimally elevated or within “therapeutic” range

12. Dysrhythmias Associated with Digitalis Toxicity Nonspecific PVCs 1st, 2 nd , and 3 rd -degree AV block Sinus bradycardia Sinus tachycardia Atrial tachycardia Junctional (escape) rhythm AV dissociation Ventricular tachycardia Torsades de pointes Ventricular fibrillation Ventricular bigeminy and trigeminy

13. Cont.. More Specific but Not Pathognomonic Atrial fibrillation with slow, regular ventricular rate ( AV dissociation ) Nonparoxysmal junctional tachycardia (rate 70-130 beats/min) Atrial tachycardia with block (atrial rate usually 150-200 beats/min ) Bidirectional ventricular tachycardia

14. Factors that Increased Risk of Digitalis Toxicity Renal insufficiency Congestive heart failure Hypothyroidism Electrolyte imbalance : Hypokalemia, Hypomagnesaemia, Hypercalcemia Alkalosis Acidosis

15. Drugs that are associated with digoxin toxicity Diuretics Amiodarone Beta blocker Calcium channel blockers Macrolide antibiotics Ketoconazole

16. History Determine the agent Amount taken Time of ingestion Any coingestants whenever possible Determine also if the patient normally takes digitalis or if it was someone else's prescription Obtain a thorough medication history to determine if any recent additions or dosing changes were made

17. Physical examination Assess patient's airway ,breathing , and circulation Assess the patient's vital signs. Look for evidence of hypoperfusion and end organ dysfunction.

18. Diagnosis Digoxin toxicity can occur with a single ingestion of 1 to 2 milligrams in an adult . Fatalities have been reported following an acute ingestion of 10 milligrams in an adult and 4 milligrams in a child.

19. Electrocardiogram Almost any cardiac dysrhythmia may be observed in digoxin toxicity . The most common arrhythmias in digoxin toxicity are PVCs and Bradyarrhythmias. Ventricular dysrhythmias occur more frequently in chronic than in acute poisonings.

20. ECG findings therapeutic levels T-wave changes (such as flattening/inversion/Biphasic T waves), QT-interval shortening, “Scooped” or “ S alvador Dali sagging ” ST segment depression, and Increased U-wave amplitude

21. ECG finding at toxic level Frequent PVCs ( the most common abnormality), including ventricular bigeminy and trigeminy. Sinus bradycardia Slow Atrial Fibrillation Any type of AV block ( 1 st degree,2 nd degree & 3 rd degree) Ventricular tachycardia, including polymorphic and bidirectional VT

22. Laboratory Serum digoxin concentration Serum electrolyte level Creatinine and BUN to assess renal function RBS Acetaminophen and salicylate levels, to rule out these common coingestants Pregnancy test in women of childbearing age

23. Cont.… Generally accepted therapeutic digoxin levels are 0.5 to 2.0 ng/ml. With corresponding toxic levels above 2.5 ng/ml. Ideally, blood samples should be collected 4 hours after an IV dose or 6 hours after PO dose.

24. Cont.… Serum digoxin level is likely to be falsely elevated If the sample is obtained soon after administration or ingestion. Endogenous digoxin -like substances have been identified in: Pregnant women, Newborns, Subarachnoid hemorrhage, Liver disease, and renal failure

25. Cont.…. Naturally occurring cardiac glycosides from Plants and animals may cross-react with digoxin assays.

26. Treatment General supportive care Treatment of specific complications of toxicity, Prevention of further drug absorption, Enhancement of drug elimination, Antidote administration when indicated Safe disposition

27. GI Decontamination The initial treatment should be directed toward prevention of further GI absorption . Gastric lavage??? Patients who present to the ED within 1 to 2 hours of ingestion may benefit from the administration of AC.

28. Cont.. The standard dose is 1 g/kg (maximum 50 g ). Cholestyramine may interrupt enterohepatic recirculation.

29. Antidotal therapy with antibody (Fab) fragments DigiFab binds digoxin thus reducing free digoxin levels, thereby reducing cardio-toxic effects. There are at least three approaches

30. Cont.. Indications for digoxin-Fab Life-threatening arrhythmia Evidence of end-organ dysfunction ( eg , renal failure, altered mental status) Hyperkalemia (serum potassium >5 to 5.5) Cardiac arrest

31. cont.. Some toxicologists give fab fragments if: The serum digoxin concentration is > 10 ng/ml in acute ingestions, or A child more than 4 mg acutely. Serum digoxin level > 15ng/ml or >= 10 ng/ml 6 hours after post ingestion, regardless of clinical effect.

32. The first is empirical therapy A patient has a history of digitalis ingestion, consistent symptoms, and life-threatening dysrhythmias. Empiric therapy for acute poisoning 10-20 vials for adult/pediatric Empiric therapy for chronic poisoning Adult: 3-6 vials children: 1-2 vials

33. The second approach uses a simple calculation When the ingested dose is known with reasonable certainty. 1 vial of DigiFab contains 38 mg or 40 mg, respectively, of Fab fragments, which bind 0.5 mg of digoxin or digitoxin

34. The third approach Base the dosage on the steady-state serum digoxin or digitoxin level after 6 to 8 hours

35. Cont.. Following the acute ingestion of an unknown amount of digitalis, empiric treatment consists of 10 vials of digoxin Fab fragments for adults or 5 vials for children . 1 vial binds approximately 0.5 mg of digoxin.

36. Cont.… In chronic toxicity a hemodynamically stable patient without clear life threatening arrhythmias is to administer half of the dose calculated by level . If instability develops, the remainder of the full calculated dose can be administered. 1 to 3 vials (40 to 120 milligrams) of digoxin-Fab are often adequate in reversing chronic toxicity.

37. Cont.… Fab fragments should be given over 30 minutes in all patients except those in cardiac arrest or in whom arrest is imminent .

38. Cont.… A full neutralizing dose of digoxin-Fab is based on an estimation of the total-body load of digoxin, which can be calculated from either the dose ingested or a steady-state serum digoxin level.

39. Cont.… Calculation of Digoxin-Specific Antibody Fragment (Fab) Full Neutralizing Dose Based on Ingested Dose of Digoxin or Digitoxin Digoxin body load (milligrams) = 0.8 × suspected ingested amount (milligrams). One vial (about 40 milligrams) of digoxin-Fab neutralizes 0.5 milligram of digoxin ingested Based on Steady-State Digoxin Concentration Number of vials = serum digoxin concentration (ng/mL) x patient weight (kg)/100

40. Sample calculation of digifab based on ingested dose of digoxin Case 1: A toxic-appearing 40-year-old woman has ingested fifty (50) 0.25-mg digoxin tablets. How much is digoxin body loading? and how much is dose of digoxin Fab fragments in vials?

41. Answer Body load = amount ingested x 0.8 (BA of digoxin tablets) = 12.5mg × 0.8 = 10mg Dose of digoxin Fab fragments (in vials) = 10mg ÷ 0.5mg per vial = 20 vials

42. Sample calculation of digifab based on steady-state digoxin concentration Case 2: A toxic-appearing 4-year-old child weighing 20 kg has a digoxin level of 16 ng/mL 8 hours after ingestion of an unknown number of digoxin tablets. How much is dose of digoxin Fab fragments in vials?

43. Answer Dose (in number of vials )= (serum digoxin concentration × weight in kg) /100 =16 x 20 /100 = approximately vials

44. Bradyarrhythmias Digibind is the definitive treatment. Atropine Pacing

45. Tachyarrhythmias Digibind is the definitive treatment MgSO4 as an adjunctive measures Phenytoin Lidocaine Often refractory to cardiovesion

46. Hyperkalemia Insulin and glucose , bicarbonates Calcium is traditionally contra-indicated due the risk of precipitating a “ stone heart”.

47. Cont.… The initial serum potassium concentration may in fact be a better predictor of mortality than the initial digoxin concentration.

48. Cont.. In a study of 91 patients with acute digoxin poisoning, nearly 50% of the patients with serum K+ 5.0 and 5.5 meq/L died. No patients with a K+ < 5.0 meq/L died, and all 10 patients with serum K+ > 5.5 meq/L perished.

49. Hypokalemia I n chronic toxicity, which may be exacerbated by hypokalemia, maintenance of the serum potassium level to at least 3.5 to 4 mEq/L .

50. References

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