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Digoxin Toxicity

Digoxin Toxicity. RCH Grand Rounds Andrei Karpov PGY-1, FRCPC Program. It’s an old, old drug. Cardiac Glycosides have long been used to treat “dropsy” or edematous state in addition to a variety of other ailments... Digitalis is mentioned in writings as early as 1250s

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Digoxin Toxicity

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  1. Digoxin Toxicity RCH Grand Rounds Andrei Karpov PGY-1, FRCPC Program

  2. It’s an old, old drug • Cardiac Glycosides have long been used to treat “dropsy” or edematous state in addition to a variety of other ailments... • Digitalis is mentioned in writings as early as 1250s • Ancient Egyptians reference medicinal uses of foxglove • Ancient Romans and Syrians used Squill or sea onion

  3. Natural sources • Balkan Foxglove plant Digitalis lanata • Digitalis • Digitalis purpurea • Digitoxin

  4. Adoption into medicine • In 1785, Sir William Withering, an English physician and botanist, described the use of the foxglove plant, Digitalis purpurea, for treatment of heart failure

  5. Early Problems • 1797 – Benjamin Rush wrote “I suspect the cases in which [digitalis preparations] were useful to have been either so few or doubtful and that the cases that they had done harm were so much more numerous and unequivocal as justly to banish them from the Materia Medica.”

  6. Very popular in the 1870s to early 1900s

  7. Problems through the 1960s-70s • Most common ADR in medical practice • 15% of all in-patients were taking digoxin • 20-30% of these patients would have signs of toxicity Beller GA, Smith TW, Abelmann WH, Haber E, Hood Jr WB: Digitalis intoxication. A prospective clinical study with serum level correlations.  N Engl J Med  1971; 284(18):989-997.

  8. Vincent Van Gogh’s “Yellow Period” • Chronically toxic? http://en.wikipedia.org/wiki/Vincent_van_Gogh

  9. Still a problem?.... Do I really need to know this??? • DPIC statistics (1) • Approximately 23,000 patients on digoxin in BC • In 2010 DPIC was consulted on 55 cases of chronic digoxin toxicity (51 over the age of 65 years • 47 required Digibind • US poison control statistics for 2008 (2) • 2632 cases • 17 deaths • ADR reporting statistics for 2005-2010 (3), • 5156 annual ED visits • >3/4 hospitalized • Still comes up on the Royal College exams/ sim scenarios (4) (1) http://dpic.org/article/professional/chronic-digoxin-toxicity-elderly-british-columbians (2)Bronstein AC, et al. 2008 annual report of the Amer-ican Association of Poison Control Centers’ National Poison Data System (NPDS). Clin Toxicol 2009;47(10):911–1084. (3)See I, Shehab N, Kegler SR, Laskar SR, Budnitz DS.Circ Heart Fail. 2014 Jan;7(1):28-34. (4) FR Resident – Personal disclosure

  10. Cardiac glycosides • Ouabain • Acokanthera, Strophanthus gratus • Oleander • Lilly of the Valley • Cardioactive steroids found in toads belonging to the Bufonidae family • Lovestone • Chan Su • Kyushin

  11. Therapeutic use of Digoxin • Increase ionotropy to improve cardiac output in CHF • Decrease AV node conduction in A. Fib to slow down ventricular rate • Class 1 indication HR control in A. Fib + CHF • Narrow therapeutic index (0.5 -0.9 ng/mL) http://www.uptodate.com/contents/digoxin-drug-information?source=see_link&utdPopup=true

  12. Na+ 2K+ ATP 3Na+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ ATP Ca2+ SR VG Ca Channel Ca2+

  13. Effects on myocytes • Increases intracellular Na, and extracellular K • Increases the Na gradients acting on the Ca/Na exchanger interfering with the extrusion of cytoplasmic Ca • This equals to higher intracellular Ca, so more Ca is re-sequestered into the SR • Increasing the amount of Ca released from the SR during the next contraction... Increasing the strength of the contraction

  14. Effects on SA and AV node • Directly and indirectly increases vagal activity at therapeutic levels • At toxic levels, this blocks the generation of impulses at the SA node, and blocks the conduction of impulses through the AV node

  15. Effects on the Purkinje fibers • Decreases resting potential • Decreases action potential duration • Enhances automaticity by increasing phase 4 repolarization • ....Twitchy Pukinje

  16. Adverse Effects - Myocytes • Excessive intracellular calcium may cause delayed after-depolarizations, which may in turn lead to premature contractions and trigger arrhythmias • Shorter repolarization decreases the refractory period of the myocardium, thereby increasing automaticity and the risk for arrhythmias • These effects are augmented by hypokalemia and hypomagnesemia

  17. Question #1 - One is not like the others • Which arrhythmia isn’t seen in Digoxin toxicity? • PVC’s • Junctional tachycardia • A.Fib with RVR • Torsades de pointes • Bi-directional V-Tach Rosen’s Emergency Medicine 4e, Chapter 152, page 1983 Box 152-1

  18. Classic EKG changes • Prolonged PR • J point depression • ST depression in a “reverse check mark” appearance • U wave/ biphasic T wave http://lifeinthefastlane.com/ecg-library/digoxin-effect/ Dale Dubin, Rapid Interpretation of EKG’s

  19. Pharmacokinetics & Pharmacodynamics • Digoxin • Orally/IV absorbed • Bioavailability ranges from 60–80% • Vd is 5–10 L/kg • T1/2 is 30-50 hours • Renally excreted • 25% Protein bound • primarily excreted in urine unchanged with some hepatic metabolism (CYP 450 3A) • Digitoxin • Orally/IV absorbed • >90% bioavailability • Vd is 0.5 L/Kg • T1/2 5-8 days (enterohepatic recirculation) • 95% protein bound • Hepatically metabolized with enterohepatic recirculation • No longer prescribed http://www.uptodate.com/contents/digoxin-drug-information?source=search_result&search=digoxin&selectedTitle=1~150

  20. I’m not a pharmacist, do I care? • Large Vd, large molecule size, and significant protein binding makes it a poor candidate for hemodyalisis • Long t1/2 suggest that temporizing measures such as atropine, antidysrhythmics, and pacing might not be as effective in toxicity as DigiFab • Enterohepatic recirculation for digitoxin suggests a possible role for MDAC

  21. Factors associated with increased toxicity • Drug interactions... Many • Sympathomimetics • Beta-blockers • CCB’s • TCAs • Quinidine • Amiodarone • Erythromycin • Renal disease • Electrolytes • Hypokalemia, hyperkalemia • Hypomagnesemia • Hypothyroidism • Elderly woman • Low BMI

  22. The 3 most common scenarios resulting in cardiac glycoside toxicity • (1) Intentional or accidental acute ingestion leading to acute toxicity • (2) Systemic accumulation secondary to hepatic or renal dysfunction • (3) Systemic accumulation secondary to a drug interaction

  23. How much is too much? • Acute ingestion of as little as 1 mg of Digoxin in a child or 3 mg of Digoxin in an adult • A few leaves of oleander or foxglove.... • Generally, children appear to be more resistant than adults to the cardiotoxic effects of cardiac glycosides Lange Poisoning & Drug Overdose 6e, Chapter 69, 391

  24. Acute overdose • Nausea • Vomiting • Abdominal pain • Hyperkalemia • Cardiac arrhythmias (bradycardias, AV blocks) • Usually in younger patients (intentional OD, med error)

  25. Chronic toxicity • Nausea • Anorexia • abdominal pain • Weakness • Cardiac arrhythmias (Ventricular more common) • Mental status changes are common in the elderly and include confusion, depression, hallucinations, and psychosis. • Visual disturbances • Blurry vision, yellow-green chromopsia, scotomas, diplopia • Hypokalemia and hypomagnesemia • Higher mortality with LL50 being 6ng/mL

  26. Diagnosis and management • Important to establish timing of last dose • Peak level after 1.5-2 hrs post ingestion • Steady state achieved 6-8 hours after dose/ OD • Get a level • Call DPIC • Give DigiFab

  27. DigiFab • Digoxin specific fragment antigen-binding antibodies. • Derived from immunized sheep, Fc fragment cleaved • Dosed according to steady state levels, and weight • Average dose for most patients with chronic toxicity is 2-3 vials at $460.84/ vial • Median time for initial response is 19 minutes, complete resolution in hours • Renally excreted with a t1/2 of 15-20 hours • Side effects/ Adverse reactions • Allergic reactions (<1%) • Hypokalemia • Worsening of CHF • Rapid A.Fib

  28. DigiFab • Indications: • Serum K above 5 • Unstable dysrhytmias (VT, VF, advanced blocks...asystole) • End organ dysfunction in the setting of supratherapeutic digoxin level • ((Level >10 ng/mL in acute overdose / >4 ng/mL in chronic toxicity)

  29. DigiFab • Dosing • Call DPIC • Empiric (hx of ingestion and unstable dysrhythmia) : 10 vials/ 30 mins, 4-6 vials for chronic toxicity • Cardiac arrest: 20 vials • Known dose : 1 vial binds 0.5 mg Digoxin (2 x mg of Dig) • Known level (steady state): package insert based on level

  30. Question #2 • You pick up a chart of an elderly woman with T2DM, A.Fib, and CHF who is coming in with a Cc: “weak and dizzy” and is on 13 meds, one of them is Digoxin.... You get a level and an EKG, among other investigations • BP is 80/40, Digoxin level = 5 ng/mL (high), EKG shows junctional rate 80 with scooped “reverse check” sign ST segments, and a K level of 5.6 • Call DPIC and administer DigiFab • Pesky R1 gets another level 2 hours after the administration of DigiFab and it turns out to be 11 ng/mL !!! • What now? • Call DPIC, and check the expiry date on your DigiFab vials • Administer more DigiFab and re-check a level again • Check to make sure the patient’s symptoms are resolving and not worry about the level • Tell your R1 to switch into psych... Or Internal Medicine

  31. Something to do while you’re waiting for the DigiFab to start working? • Hypo K (usually chronic toxicity) • Replace to 3.5 • Hyper K (usually acute.... Sometimes chronic) • Dextrose, insulin, ventolin, ?Bicarb, ???Kayexalate • ?Calcium • Magnesium • Replace if low • Caution in renal failure

  32. Stone Heart • What is a stone heart? • Animal study from 1927 • Series of 5 case reports dating back to 1933 with questionable temporal relationships

  33. Atropine • Severe Bradycardia • Advanced AV blocks • ...while you’re getting the pacing pads on

  34. Pacing • Transcutaneous pacing first • Transvenous next... But watch out for irritable myocardium

  35. Cardioversion • May be used in unstable tachydysrhythmias • Use low energy settings (25-50 J) as per Rosen’s

  36. Still looking for more stuff to do? • Lidocaine (or other class 1 antiarrhythmic) • Indications: • Unstable tachydysrhythmias while DigiFab is unavailable or awaiting for it to take effect • Rifmapin

  37. Take home points! • Cardiac Glycosides are everywhere!... Not really • Na/K ATPase inhibitor, increases Ca (Ionotropy), making atrial and ventricles more irritable and slows down AVN conduction • Narrow therapeutic index with non-specific symptoms in toxicity • Check the pharmanet! • Can present with almost any arrhythmia (Increased automaticity and blocking of AV node)

  38. Treatment Summary • Call DPIC • DigiFab • Indications (K, unstable, ?level) • Dosing (by steady state level/ empiric) • MDAC • Within the first 2 hours post ingestion • Hyper K • ?Ca • Correct Magnesium • Atropine • Pacing (careful of venticular arrhythmias) • Cardioversion (low energy) • Lidocaine • ?Rifampin

  39. The End!

  40. Treatment with PLEX

  41. Kanji S and MacLean R; Cardiac Glycoside Toxicity : More Than 200 Years and Counting

  42. Pediatric Dig • Can tolerate higher doses of digoxin • Sx : vomiting, somnolence, obtundation • Blocks and bradycardias more common

  43. Pathophys • 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 [8]. 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. • Cardiac glycosides reversibly inhibit the sodium-potassium-ATPase, causing an increase in intracellular sodium and a decrease in intracellular potassium [1,5]. The increase in intracellular sodium prevents the sodium-calcium antiporter from expelling calcium from the myocyte, which increases intracellular calcium. The net increase in intracellular calcium augments inotropy [9,10]. Cardiac glycosides also increase vagal tone which results in decreased conduction through the sinoatrial and atrioventricular nodes

  44. Pathophys 2 • Excessive intracellular calcium may cause delayed after-depolarizations, which may in turn lead to premature contractions and trigger arrhythmias. Cardiac glycosides shorten repolarization of the atria and ventricles, decreasing the refractory period of the myocardium, thereby increasing automaticity and the risk for arrhythmias

  45. Indications for use • Atrial fibrillation: For the control of ventricular response rate in adults with chronic atrial fibrillation. • Heart failure: For the treatment of mild-to-moderate (or stage C as recommended by the ACCF/AHA) heart failure (HF) in adults; to increase myocardial contractility in pediatric patients with heart failure • Note: In treatment of atrial fibrillation (AF), use is not considered first-line unless AF coexistent with heart failure or in sedentary patients (Anderson, 2013). In the treatment of heart failure, digoxin should be considered for use only in HF with reduced ejection fraction (HFrEF) when symptoms remain despite guideline-directed medical therapy or as initial therapy in patients with severe symptoms yet to respond to guideline-directed medical therapy (Yancy, 2013). • Use - Unlabeled Fetal tachycardia with or without hydrops; to slow ventricular rate in supraventriculartachyarrhythmias such as supraventricular tachycardia (SVT) excluding atrioventricular reciprocating tachycardia (AVRT) • http://www.uptodate.com/contents/digoxin-drug-information?source=search_result&search=digoxin&selectedTitle=1~150

  46. Pharmacokinetics/ Pharmacodynamics • Onset of action: Heart rate control: Oral: 1-2 hours; I.V.: 5-60 minutes • Peak effect: Heart rate control: Oral: 2-8 hours; I.V.: 1-6 hours; Note: In patients with atrial fibrillation, median time to ventricular rate control in one study was 6 hours (range: 3-15 hours) (Siu, 2009) • Duration: Adults: 3-4 days • Absorption: By passive nonsaturable diffusion in the upper small intestine; food may delay, but does not affect extent of absorption • Distribution: • Normal renal function: 6-7 L/kg • Vd: Extensive to peripheral tissues, with a distinct distribution phase which lasts 6-8 hours; concentrates in heart, liver, kidney, skeletal muscle, and intestines. Heart/serum concentration is 70:1. Pharmacologic effects are delayed and do not correlate well with serum concentrations during distribution phase. • Hyperthyroidism: Increased Vd • Hyperkalemia, hyponatremia: Decreased digoxin distribution to heart and muscle • Hypokalemia: Increased digoxin distribution to heart and muscles • Pro • Half-life elimination (age, renal and cardiac function dependent): • Neonates: Premature: 61-170 hours; Full-term: 35-45 hours • Infants: 18-25 hours • Children: 18-36 hours • Adults: 36-48 hours • Adults, anephric: 3.5-5 days • Half-life elimination: Parent drug: 38 hours; Metabolites: Digoxigenin: 4 hours; Monodigitoxoside: 3-12 hours • Time to peak, serum: Oral: 1-3 hours • Excretion: Urine (50% to 70% as unchanged drug) • Protein binding: ~25%; in uremic patients, digoxin is displaced from plasma protein binding sites

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