Andrei Karpov PGY1 FRCPC Program Digoxin Toxicity Its an old old drug Cardiac Glycosides have long been used to treat dropsy or edematous state in addition to a variety of other ailments ID: 264952
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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 SuKyushinSlide11Slide12
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 relationshipsSlide34Slide35
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 commonSlide45Slide46Slide47
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