R C H G R A N D R O U N D SA N D R EI KA R P OV

P G Y- 1 , F R C P C P R O G R A M

Digoxin Toxicity

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

Natural sources

Balkan Foxglove plant Digitalis lanata Digitalis

Digitalis purpurea Digitoxin

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

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.”

Very popular in the 1870s to early 1900s

Problems through the 1960s-70s

Most common ADR in medical practice15% of all in-patients were taking digoxin20-30% 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.

Vincent Van Gogh’s “Yellow Period”

Chronically toxic?

http://en.wikipedia.org/wiki/Vincent_van_Gogh

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

Cardiac glycosides

Ouabain Acokanthera, Strophanthus gratus

OleanderLilly of the ValleyCardioactive steroids found in toads

belonging to the Bufonidae family Lovestone Chan Su Kyushin

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

SRVG Ca Channel

Ca2+

Ca2+

Ca2+

Ca2+

Ca2+Ca2+

Ca2+

Ca2+

Ca2+

Ca2+

Ca2+

Ca2+

Ca2+

Ca2+

Ca2+

Ca2+

Ca2+

Ca2+Ca2+

ATP

ATP 3Na+

2K+ Na+

Ca2+

Effects on myocytes

Increases intracellular Na, and extracellular KIncreases 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

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

Effects on the Purkinje fibers

Decreases resting potentialDecreases action potential durationEnhances automaticity by increasing phase 4

repolarization

....Twitchy Pukinje

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

Question #1 - One is not like the others

Which arrhythmia isn’t seen in Digoxin toxicity?

(A) PVC’s(B) Junctional tachycardia(C) A.Fib with RVR(D) Torsades de pointes(E) Bi-directional V-Tach

Rosen’s Emergency Medicine 4e, Chapter 152, page 1983 Box 152-1

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

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

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

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

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

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

Acute overdose

NauseaVomiting Abdominal painHyperkalemiaCardiac arrhythmias (bradycardias, AV

blocks)

Usually in younger patients (intentional OD, med error)

Chronic toxicity

NauseaAnorexiaabdominal painWeaknessCardiac 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 hypomagnesemiaHigher mortality with LL50 being 6ng/mL

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 levelCall DPIC Give DigiFab

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

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)

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

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?A. Call DPIC, and check the expiry date on your DigiFab vialsB. Administer more DigiFab and re-check a level againC. Check to make sure the patient’s symptoms are resolving and not worry

about the levelD. Tell your R1 to switch into psych... Or Internal Medicine

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

Stone Heart

What is a stone heart? Animal study from 1927 Series of 5 case reports dating

back to 1933 with questionable temporal relationships

Atropine

Severe BradycardiaAdvanced AV blocks

...while you’re getting the pacing pads on

Pacing

Transcutaneous pacing firstTransvenous next... But watch out for

irritable myocardium

Cardioversion

May be used in unstable tachydysrhythmiasUse low energy settings (25-50 J) as per

Rosen’s

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

Take home points!

Cardiac Glycosides are everywhere!... Not reallyNa/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)

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

The End!

Treatment with PLEX

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

Pediatric Dig

Can tolerate higher doses of digoxinSx : vomiting, somnolence, obtundationBlocks and bradycardias more common

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

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

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 supraventricular tachyarrhythmias 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

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

PK / PD 2

While mechanistically equivalent, these drugs have several different pharmacologic properties. Digitoxin is absorbed more readily and has a smaller volume of distribution, a longer half-life, and greater protein binding. In addition, digitoxin is hepatically cleared while digoxin is cleared renally.Both digoxin and digitoxin have a narrow therapeutic index and toxicity is common