THE POISON OF THE

FOXGLOVE

Dr Anshul Deshraj
Cardiology SHO
Thurs 29th August 2013
DIGOXIN TOXICITY-OVERVIEW

 What is Digoxin?
 Uses and pharmacology of Digoxin
 Practical points in using Digoxin
 Digoxin Toxicity
 Treatment of Digoxin Toxicity
 Summary
DIGOXIN

 Cardiac glycoside extracted from Digitalis Purpurea

(Foxglove)
 Known as a poison in the middle ages
 Powerful emetic
 The leaves of the plant were used in trials

by Sir Withering for treatment of various

ailments
HISTORY OF DIGOXIN
 Used by women in the 1700s to treat “dropsy”
 Fluid within the interstitium
 Modern day Pulmonary Oedema

 Originally discovered by Sir William Withering

 Sir William Withering was a botanist and physician working
in Birmingham from 1779
 Explained his experience with the use of Digoxin in his book
An Account of the Foxglove and Some of its Medical Uses:
with Practical Remarks on Dropsy, and Other Diseases
BASIC PHARMACOLOGY
 Cardiac glycoside along with digitoxin, digitalis and ouabain
 Reversible inhibition of sodium-potassium ATPase
 This causes an increase in intracellular sodium and decrease in
intracellular potassium
 The increase in sodium causes an increase in intracellular calcium
leading to stronger myocardial contraction (positive ionotrope)
 Blocks AV node and reduces heart rate by augmenting vagal
activity
 In toxicity, both mechanisms can result in fatal arrhythmias
USES

 Atrial Fibrillation
 Slows ventricular rate by increasing vagal tone
 This inhibits AV Node

 Heart Failure and systolic dysfunction

 Used primarily to control symptoms in combination with other drug
therapy
 SOB
 Fatigue

 Suggestion of improvement in mortality when within therapeutic

range
PRACTICAL APPLICATION OF
DIGOXIN’S USE
 Rapid Loading
 Total dose .75g-1.5g (IV) or 1-1.5g PO
 Total:10mcg/kg (lean body weight)
 Cautions: Hypokalaemia, hypomagnesaemia,
hypercalcaemia, hypoxic or hypothyroid are MORE sensitive
to digoxin
 Maintenance Dosing
 For AF
 125mcg-250mcg
 For Heart Failure
 62.5mcg-125mcg
PRACTICAL USES
 Dose Adjustment
 Low body weight (<45 kg then 50% of loading dose)
 Renal impairment (1/3-1/2 of dose in severe renal
dysfunction-Calculation based on lean body weight and
creatinine clearance)
 Elderly
 Interactions with other medications
 Verapamil and amiodarone can increase digoxin levels
 Cholestyramine and antacids reduce levels

 Diuretics can cause digoxin toxicity

 Tetracycline and erythromycin can alter/increase levels

DIGOXIN LEVELS

 Narrow therapeutic window (1.5-3mcg/L indicates toxicity)

 Therapeutic
range 0.5-1mcg/L in heart failure
 At RSCH Levels<2 are considered suggestive of toxicity

 Timing of collection
 Taken optimally 12 hours post dose but each hospital has own
criteria
 Atleast 6 hours post dose at RSCH for chronic digoxin toxicity
 Anytime for Acute Toxicity but ideally >6 hours

 In CKD/Haemodialysis-12-24 hours post dose

MONITORING OF DIGOXIN

 Monitoring recommended for those patients who use Digoxin

for Heart failure
 Checking Digoxin levels in AF ONLY if toxicity is suspected
 To check levels if electrolyte derangement and until correction
of electrolytes achieved
APPROACH TO ASSESSMENT OF
TOXICITY
 History and Examination
 Intercurrent Illness (AKI, MI, Sepsis)
 Recent introduction of new medications
 Symptoms of Toxicity
 Acute Ingestion

 Asymptomatic initially followed by GI symptoms,

confusion, weakness
 Chronic Toxicity:

 Insiduous over days/months. GI Symptoms,

altered mental state, confusion, lethargy, visual

changes (change in colour vision, scotomas,
blindness)
INVESTIGATIONS
 Laboratory
 Electrolytes in particular K, Mg and Ca
 In Acute Toxicity, hyperkalaemia is most important
 Inhibition of Na-K ATPase increases levels of K

 Correlates with mortality

 RenalFunction
 Digoxin levels
 BUT even if levels within normal range, DOESN’T mean
patients don’t have toxicity
ECG
 Serial ECGs as can produce range of arrythmias

 Premature Ventricular Contractions most common

 Bradycardia
 Atrial Tachyarrhythmias with AV Block
 Junctional Rhythms
 VT/VF
 Ventricular arrhythmias more common in chronic digoxin
toxicity
 First, second and third degree AV blocks

 Note: Digitalis Effect seen in Chronic Digoxin use not

toxicity
DIGITALIS EFFECT
TREATMENT
 If mild symptoms, withdrawal of Digoxin alone is
sufficient
 Can be managed in the community
 If cardiac involvement/instability
 Admission to hospital
 Correction of electrolyte abnormalities/acid-base
balance/treatment of underlying cause
 Stop medications that can precipitate/worsen toxicity
 Digoxin specific antibody fragments used first line
 If not available, then management of heart block with
atropine and temporary pacing
TREATMENT-FAB FRAGMENTS
 Made from immunoglobulin fragments from sheep
immunised with DDMA
 Binds to Digoxin inhibiting their action on Na-K Atpase

 Half Life 15-20 hours (if

normal renal function)
 Improvement within a few hrs
DIGIFAB

 In one study 85-90% patients made a full recovery or improved

in clinical state
 Indications
 Lifethreatening arrhythmias
 Renal Failure
 Reduced GCS
 Hyperkalaemia

 Interpret repeat digoxin levels after use of Digibind with

caution
 Base further use of digibind on clinical judgement rather than
levels
DOSAGE

 Each vial of 40mg od DigiFab binds 500mcg of

Digoxin
 The amount of DigiFab used based on the
quantity of Digoxin used
 If large, unknown, can have upto 20 vials

 For those in Acute distress but have been on

Digoxin for a significant period of time, can
have 6 vials
OTHER MANAGEMENT OPTIONS
 Activated Charcoal used within 1-2 hours of ingestion
 Treat Hyperkalaemia with Digibind
 Cancause hypokalaemia if used in combination with K
lowering agents
DIGOXIN TOXICITY IN RENAL FAILURE
 No need for dose alteration of Digibind
 Eliminationof Digibind and Digoxin both prolonged
 Monitored for atleast 72 hours

 Treat cause of Renal Failure

 Hydration
 Stopping medications causing renal dysfunction
 Dialysis NOT a treatment
SUMMARY
 Digoxin is a well known and effective drug used very
widely
 It can lead to toxicity in multiple scenarios

 If Acute Toxicity is suspected, treatment should be

administered without waiting for levels which may or
may not be accurate
 ECG monitoring is imperative

 Correction of electrolyte disturbance should be key in

treatment
 DigiFab is an efficacious treatment

 Routine monitoring for AF is not recommended unless

other reasons to monitor (Renal Failure)
THANK YOU
REFERENCES
 http://www.rsc.org/chemistryworld/2013/05/foxglove-dig
oxin-digitalis-podcast
 http://en.wikipedia.org/wiki/William_Withering
 http://en.wikipedia.org/wiki/Digoxin
 http://www.gutenberg.org/files/24886/24886-h/images/fro
ntispiece.jpg
 http://www.patient.co.uk/doctor/digoxin-and-the-cardiac-
glycosides
 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2399830/p
df/postmedj00053-0008.pdf
 Digoxin specific antibody fragments (Digibind) in
digoxin toxicity BMJ 2009;339:b2884
 http://en.wikipedia.org/wiki/Digoxin_Immune_Fab
