Digoxin Toxicity This Presentation Is Intended for Health Care Practitioners in the United Kingdom Only

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Digoxin Toxicity This presentation is intended for health care practitioners in the United Kingdom only. Cardioactive Steroids also known as cardiac glycosides

Digitalis: Plant Digoxin is the most derived cardioactive commonly prescribed steroid form of digitalis

Digitoxin is being Digitoxin is also studied as an anti- available in the U.K. cancer agent for various tumour types

Giardina EG, Sylvia L. Up to Date, Rose BD (ED), Waltham, MA, 2012.

BTG Confidential Not For Distribution 3 Cardioactive Steroids: Sources

Many plants contain cardioactive steroids

Digitalis purpurea (foxglove), Nerium oleander (oleander), Convallaria majalis (lily of the valley), Drimia maritima (red squill)

Toxicity may result from use of herbal products or teas derived Bufo marinus toad – from such plants or direct ingestion dried secretions are a of the plant itself supposed aphrodisiac and contain a cardioactive steroid

Giardina EG, Sylvia L. Up to Date, Rose BD (ED), Waltham, MA, 2012.

BTG Confidential Not For Distribution 4 Digoxin: Therapeutic Role Formulations Injection Oral Solution Tablets (IV; rarely used IM)

Mechanism of Action

Inhibits the ion transfer system known as sodium-potassium ATPase

Digoxin

BTG Confidential Not For Distribution 5 Giardina EG, Sylvia L. Up to Date, Rose BD (ED), Waltham, MA, 2012 Middlekauff HR. Int Med 1998; 37: 112-122. Digoxin: Therapeutic Role Formulations Injection Oral Solution Tablets (IV; rarely used IM)

Mechanism of Action

Inhibits the ion transfer system known as sodium-potassium ATPase

This transport system moves Na+ Many cells including cardiac cells ions out of the cell and potassium have this transport system ions into the cell

As the Na+ concentration inside An increase in Ca+2 inside the Increased inotropy causes the cell increases, so does cell increases contractility of the smooth muscle contraction the Ca+2 concentration cell (inotropy) and vasoconstriction inside the cell

May be a benefit in heart failure secondary to neurohumoral effects Decreases heart rate via other (decrease in sympathetic activity) mechanism not well understood rather than its inotropic effects

Giardina EG, Sylvia L. Up to Date, Rose BD (ED), Waltham, MA, 2012 Middlekauff HR. Int Med 1998; 37: 112-122.

BTG Confidential Not For Distribution 6 Digoxin: Therapeutic Role

Disease states used in:

Atrial fibrillation

Heart failure

Supraventricular tachycardia

Used in adults and paediatrics

Giardina EG, Sylvia L. Up to Date, Rose BD (ED), Waltham, MA, 2012.

BTG Confidential Not For Distribution 7 Digoxin: Kinetics

Volume of Time to peak Protein Binding Half Life Distribution (serum)

6-7 L/kg 25% Age, Renal, and Oral: 1-3 hours cardiac function dependent Distribution phase: 6-8 hours Approximately 38 Hours (parent Steady state: drug) 7-10 Days

Giardina EG, Sylvia L. Up to Date, Rose BD (ED), Waltham, MA, 2012.

BTG Confidential Not For Distribution 8 Risk Factors for Digoxin Toxicity

Kidney Injury: digoxin is primarily eliminated by the kidneys

Age: elderly are more likely to have decreased renal function and taking potentially interacting concomitant medications

Electrolyte Imbalance: increases sensitivity to digoxin effects

Fluid Status: fluid loss or poor fluid intake can lead to electrolyte imbalances

BTG Confidential Not For Distribution 9 Digoxin: Causes of Toxicity

Hypokalemia Hypercalcemia Hypomagnesemia

Results in increased Enhances Can sensitize the digoxin binding digitalis-induced heart to increasing its inotropy leading to digitalis-induced therapeutic and toxic possible Ca+2 arrhythmias effects. overload and (includes any increased arrhythmia except susceptibility to supraventricular digitalis-induced tachydysrhythmias). arrhythmias.

Hack JM, Lewin NA. Cardioactive Steroids. Goldfrank’s Toxicologic Emergencies, 8th edition. 971-982.

BTG Confidential Not For Distribution 10 Digoxin: Causes of Toxicity

Drug interactions: many commonly used drugs interact with digoxin

Via decreased renal clearance of digoxin (class of drugs/examples)

calcium channel blockers: (Nondihydropyridine): verapamil, diltiazem

NSAIDs: ibuprofen, naproxen sodium

Giardina EG, Sylvia L. Up to Date, Rose BD (ED), Waltham, MA, 2012. Gomes T , Mamdani MM, Juurlink DN. Clin Pharm & Therap 2009; 86: 383-386.

BTG Confidential Not For Distribution 11 Digoxin: Causes of Toxicity

Drug interactions: many commonly used drugs interact with digoxin Via decreased serum potassium levels (loop and thiazide diuretics):

furosemide

hydrochlorthiazide

Giardina EG, Sylvia L. Up to Date, Rose BD (ED), Waltham, MA, 2012. Gomes T , Mamdani MM, Juurlink DN. Clin Pharm & Therap 2009; 86: 383-386.

BTG Confidential Not For Distribution 12 Digoxin: Causes of Toxicity

Drug interactions: many commonly used drugs interact with digoxin Via altering the mechanism of digoxin excretion (and hence elimination) via renal or intestinal p-glycoprotein activity

verapamil diltiazem quinidine amiodarone

Giardina EG, Sylvia L. Up to Date, Rose BD (ED), Waltham, MA, 2012. Gomes T , Mamdani MM, Juurlink DN. Clin Pharm & Therap 2009; 86: 383-386.

BTG Confidential Not For Distribution 13 Digoxin: Causes of Toxicity

Increased Serum Levels

Amiodarone Indomethacin Quinidine Benzodiazepines Itraconazole Quinine Bepridil Macrolides Spironolactone Cyclosporine Propafenone Tetracyclines Diphenoxylate Propantheline Verapamil

Decreased Serum Levels

Oral aminglycosides Metoclopramide Al+/Mg+ containing antacids Neomycin Antineoplastics Penicillamine Activated charcoal Rifampin Cholestyramine St. John’s wort Colestipol Sulfasalazine Kaoline / pectin

BTG Confidential Not For Distribution 14 Digoxin: Causes of Toxicity

Enhanced Pharmacodynamic Effects

Beta-blockers Succinylcholine Calcium Sympathomimetics Verapamil Diuretics Diltiazem

Antagonize Pharmacodynamic Effects

Thyroid hormones

BTG Confidential Not For Distribution 15 Digoxin: Toxicity

Signs/symptoms of acute toxicity

Gastrointestinal Neurological

nausea, vomiting, abdominal pain weakness, confusion

Electrolyte Cardiac

hyperkalemia bradycardia, heart block, (> 5.5 mEq/L is a poor prognostic several types of arrhythmias sign)

BTG Confidential Not For Distribution 16 Digoxin: Toxicity

Signs/symptoms of chronic toxicity

Gastrointestinal Neurological

Patients may have more subtle signs confusion, drowsiness, of acute digoxin toxicity (nausea, headache, hallucinations anorexia)

Visual

sensitivity to light, yellow halos around lights, blurred vision

Schaeffer TH, Mlynarchek SL, Stanford CF. JAOA 2010; 110: 587-592

BTG Confidential Not For Distribution 17 Digoxin: Laboratory Analyses Interpreting laboratory values in the digoxin poisoned patient

Hyperkalemia: > 5.5 mEq/L in the acutely poisoned digoxin patient

Poor prognostic sign in acute toxicity. Antidote warranted when > 5 mEq/L. May be seen in chronic toxicity but not as serious.

Hypokalemia: can predispose the patient to further dysrhythmias and should be corrected with close monitoring to avoid hyperkalemia

Hack JM, Lewin NA. Cardioactive Steroids. Goldfrank’s Toxicologic Emergencies, 8th edition. 971-982.

BTG Confidential Not For Distribution 18 Digoxin: Laboratory Analyses Interpreting laboratory values in the digoxin poisoned patient

Hypomagnesemia may cause refractory hypokalemia

Magnesium is contraindicated in:

Bradycardia Heart block

Pre-existing Decreased renal function hypermagnesemia or failure

Hack JM, Lewin NA. Cardioactive Steroids. Goldfrank’s Toxicologic Emergencies, 8th edition. 971-982.

BTG Confidential Not For Distribution 19 Digoxin: Laboratory Analyses

Digoxin levels in the poisoned patient

Obtaining an immediate digoxin level in an acutely poisoned patient will not reflect the peak serum level as the distribution phase of digoxin is long. An initial 4-6 hour post-ingestion level is appropriate.

Useful following administration of Free digoxin digoxin-specific Fab fragments

Serum concentrations predict cardiac concentrations Total digoxin Fab fragments of digoxin-specific antibodies will cause a rise in total digoxin levels (as Fab bound digoxin is also being measured)

BTG Confidential Not For Distribution 20 Diagnosis of Digoxin Toxicity What is needed?

History

Signs and symptoms

EKG

Digoxin levels

Electrolytes

BTG Confidential Not For Distribution 21 Diagnosis of Digoxin Toxicity What is needed?

History

Risk factors for digoxin toxicity including age of patient (for patients chronically using digoxin therapeutically)

Initiation or discontinuation of Any disease drugs that changes Altered renal potentially (such as thyroid function interact with disease) digoxin

Giardina EG, Sylvia L. Up to Date, Rose BD (ED), Waltham, MA, 2012.

BTG Confidential Not For Distribution 22 Diagnosis of Digoxin Toxicity What is needed?

Signs and Symptoms

Acute overdose:

Cardiac Signs: Central Nervous Electrolyte sinus bradycardia, Gastrointestinal: System: changes: second or third degree nausea, vomiting confusion, weakness, AV block. Any type of hyperkalemia lethargy dysrhythmia is possible

Hack JM, Lewin NA. Cardioactive Steroids. Goldfrank’s Toxicologic Emergencies, 8th edition. 971-982.

BTG Confidential Not For Distribution 23 Diagnosis of Digoxin Toxicity What is needed?

Signs and Symptoms

Chronic overdose (symptoms usually insidious in onset):

Electrolyte Central Nervous Visual: Cardiac Signs: changes: System: delirium, photophobia, bradydysrhythmias Gastrointestinal: hyperkalemia hallucinations, changes in color (often unresponsive anorexia, nausea, (sometimes confusion,, lethargy vision (such as to atropine) vomiting, weight loss hypokalemia (seizures are yellow halos around ventricular especially if diuretics possible but rare) lights) tachydysrhythmias are used)

Hack JM, Lewin NA. Cardioactive Steroids. Goldfrank’s Toxicologic Emergencies, 8th edition. 971-982.

BTG Confidential Not For Distribution 24 Diagnosis of Digoxin Toxicity What is needed?

EKG

Almost any arrhythmia or conduction abnormality may be seen with digitalis toxicity.

Hack JM, Lewin NA. Cardioactive Steroids. Goldfrank’s Toxicologic Emergencies, 8th edition. 971-982.

BTG Confidential Not For Distribution 25 Diagnosis of Digoxin Toxicity What is needed?

Digoxin levels

However, this can be misleading Therapeutic range of digoxin has in the acutely poisoned patient historically been 0.5 - 2.0 ng/mL Stat levels may not correlate with (although current medical practice the severity of the poisoning is evolving and some experts now especially in acute ingestions advocate target levels, < 1.0 Digoxin’s long distribution phase ng/mL) results in high serum levels for 6-12 hours prior to completed tissue distribution

Hack JM, Lewin NA. Cardioactive Steroids. Goldfrank’s Toxicologic Emergencies, 8th edition. 971-982.

BTG Confidential Not For Distribution 26 Diagnosis of Digoxin Toxicity What is needed?

Electrolytes

Hypercalcemia enhances Hypokalemia digitalis-induced Hypomagnesemia results in increased inotropy leading to can sensitize the digoxin binding possible Ca+2 heart to increasing its overload and digitalis-induced therapeutic and increased arrhythmias. toxic effects. susceptibility to digitalis-induced arrhythmias.

Hack JM, Lewin NA. Cardioactive Steroids. Goldfrank’s Toxicologic Emergencies, 8th edition. 971-982.

BTG Confidential Not For Distribution 27 Digoxin Toxicity: Available Treatments Decontamination/enhanced elimination

Enhanced elimination (dialysis, hemoperfusion) does For acute overdose: Activated not effectively remove charcoal can adsorb digoxin digoxin due to large volume in the gut of distribution and relatively high protein binding

Hack JM, Lewin NA. Cardioactive Steroids. Goldfrank’s Toxicologic Emergencies, 8th edition. 971-982.

BTG Confidential Not For Distribution 28 Digoxin Toxicity: Available Treatments

Available U.K. products: Fab fragments of DigiFab® digoxin-specific antibodies digoxin immune fab (ovine) Protherics UK Limited.

BTG Confidential Not For Distribution 29 DigiFab®: Indications

For the treatment of known (or strongly suspected) life-threatening digoxin toxicity associated with ventricular arrhythmias or bradyarrhythmias unresponsive to atropine where measures beyond withdrawal of digoxin and correction of serum electrolyte abnormalities are considered necessary.