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RCH Grand Rounds

Andrei Karpov. PGY-1, FRCPC Program. 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... .

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RCH Grand Rounds






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Slide1

RCH Grand Rounds

Andrei KarpovPGY-1, FRCPC Program

Digoxin ToxicitySlide2

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 1250sAncient Egyptians reference medicinal uses of foxgloveAncient Romans and Syrians used Squill or sea onionSlide3

Natural sources

Balkan Foxglove plant Digitalis lanata

Digitalis

Digitalis purpurea

DigitoxinSlide4

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 failureSlide5

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.”Slide6

Very popular in the 1870s to early 1900sSlide7

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 toxicityBeller 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.Slide8

Vincent Van Gogh’s “Yellow Period”

Chronically toxic?

http://en.wikipedia.org/wiki/Vincent_van_GoghSlide9

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 years47 required Digibind US poison control statistics for 2008 (2)2632 cases

17 deathsADR 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 Slide10

Cardiac glycosides

OuabainAcokanthera, Strophanthus gratusOleanderLilly of the ValleyCardioactive steroids found in toads belonging to the Bufonidae familyLovestoneChan SuKyushinSlide11
Slide12

Therapeutic use of Digoxin

Increase ionotropy to improve cardiac output in CHFDecrease AV node conduction in A. Fib to slow down ventricular rateClass 1 indication HR control in A. Fib + CHFNarrow therapeutic index (0.5 -0.9 ng/mL)

http://www.uptodate.com/contents/digoxin-drug-information?source=see_link&utdPopup=trueSlide13

SR

VG Ca Channel

Ca

2+

Ca

2+

Ca

2+

Ca

2+

Ca

2+

Ca

2+

Ca

2+

Ca

2+

Ca

2+

Ca

2+

Ca

2+

Ca

2+

Ca

2+

Ca

2+

Ca

2+

Ca

2+

Ca

2+

Ca

2+

Ca

2+

ATP

ATP

3Na

+

2K

+

Na

+

Ca

2+Slide14

Effects on myocytes

Increases intracellular Na, and extracellular KIncreases the Na gradients acting on the Ca/Na exchanger interfering with the extrusion of cytoplasmic CaThis equals to higher intracellular Ca, so more Ca is re-sequestered into the SRIncreasing the amount of Ca released from the SR during the next contraction... Increasing the strength of the contractionSlide15

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 nodeSlide16

Effects on the Purkinje fibers

Decreases resting potentialDecreases action potential durationEnhances automaticity by increasing phase 4 repolarization....Twitchy PukinjeSlide17

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 arrhythmiasThese effects are augmented by hypokalemia and hypomagnesemiaSlide18

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 pointesBi-directional V-Tach

Rosen’s Emergency Medicine 4e, Chapter 152, page 1983 Box 152-1Slide19

Classic EKG changes

Prolonged PRJ point depressionST depression in a “reverse check mark” appearanceU wave/ biphasic T wave

http://lifeinthefastlane.com/ecg-library/digoxin-effect/

Dale Dubin, Rapid Interpretation of EKG’s Slide20

Pharmacokinetics & Pharmacodynamics

DigoxinOrally/IV absorbed

Bioavailability ranges from 60–80%

Vd

is 5–10 L/kg

T1/2 is 30-50 hours

Renally excreted25% Protein boundprimarily 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=1~150Slide21

I’m not a pharmacist, do I care?

Large Vd, large molecule size, and significant protein binding makes it a poor candidate for hemodyalisisLong t1/2 suggest that temporizing measures such as atropine, antidysrhythmics, and pacing might not be as effective in toxicity as DigiFabEnterohepatic recirculation for digitoxin suggests a possible role for MDACSlide22

Factors associated with increased toxicity

Drug interactions... ManySympathomimetics

Beta-blockers

CCB’s

TCAs

Quinidine

AmiodaroneErythromycinRenal disease

ElectrolytesHypokalemia

,

hyperkalemia

Hypomagnesemia

Hypothyroidism

Elderly woman

Low BMISlide23

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 interactionSlide24

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, 391Slide25

Acute overdose

NauseaVomiting Abdominal painHyperkalemiaCardiac arrhythmias (bradycardias, AV blocks)Usually in younger patients (intentional OD, med error)Slide26

Chronic toxicity

NauseaAnorexiaabdominal pain

Weakness

Cardiac arrhythmias

(Ventricular more common)

Mental status changes

are common in the elderly and include confusion, depression, hallucinations, and psychosis.Visual disturbancesBlurry vision, yellow-green chromopsia, scotomas, diplopia

Hypokalemia

and

hypomagnesemia

Higher mortality with LL50 being 6ng/

mLSlide27

Diagnosis and management

Important to establish timing of last dosePeak level after 1.5-2 hrs post ingestionSteady state achieved 6-8 hours after dose/ ODGet a levelCall DPIC Give DigiFabSlide28

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 hoursSide effects/ Adverse reactions

Allergic reactions (<1%)Hypokalemia

Worsening of CHF

Rapid

A.FibSlide29

DigiFab

Indications:Serum K above 5Unstable 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)Slide30

DigiFab

DosingCall DPICEmpiric (hx of ingestion and unstable dysrhythmia) : 10 vials/ 30 mins, 4-6 vials for chronic toxicityCardiac arrest: 20 vialsKnown dose : 1 vial binds 0.5 mg Digoxin (2 x mg of Dig)

Known level (steady state): package insert based on levelSlide31

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 5.6Call DPIC and administer DigiFabPesky 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 MedicineSlide32

Something to do while you’re waiting for the DigiFab

to start working?Hypo K (usually chronic toxicity)Replace to 3.5Hyper K (usually acute.... Sometimes chronic)Dextrose, insulin, ventolin, ?Bicarb, ???Kayexalate

?Calcium

Magnesium

Replace if low

Caution in renal failureSlide33

Stone Heart

What is a stone heart?Animal study from 1927Series of 5 case reports dating back to 1933 with questionable temporal relationshipsSlide34
Slide35

Atropine

Severe BradycardiaAdvanced AV blocks...while you’re getting the pacing pads onSlide36

Pacing

Transcutaneous pacing firstTransvenous next... But watch out for irritable myocardiumSlide37

Cardioversion

May be used in unstable tachydysrhythmiasUse low energy settings (25-50 J) as per Rosen’s Slide38

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 effectRifmapinSlide39

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 conductionNarrow therapeutic index with non-specific symptoms in toxicityCheck the pharmanet!Can present with almost any arrhythmia (Increased automaticity and blocking of AV node)Slide40

Treatment Summary

Call DPICDigiFabIndications (K, unstable, ?level)

Dosing (by steady state level/ empiric)

MDAC

Within the first 2 hours post ingestion

Hyper K

?CaCorrect MagnesiumAtropinePacing (careful of

venticular arrhythmias) Cardioversion (low energy)

Lidocaine

?

RifampinSlide41

The End!Slide42

Treatment with PLEXSlide43

Kanji S and MacLean R; Cardiac Glycoside Toxicity : More Than 200 Years and CountingSlide44

Pediatric Dig

Can tolerate higher doses of digoxinSx : vomiting, somnolence, obtundationBlocks and bradycardias more commonSlide45
Slide46
Slide47

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 Slide48

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 arrhythmiasSlide49

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=1~150Slide50

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 Slide51

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