Digoxin toxicity is caused by digoxin, a plant-derived cardiac glycoside used to treat heart conditions. It has a narrow therapeutic window, so toxicity can easily occur. Common signs of toxicity include arrhythmias such as heart block or tachycardia. Management involves discontinuing digoxin, treating arrhythmias, correcting electrolyte imbalances, and using digoxin antibody fragments for severe toxicity. Factors like renal impairment, hypokalemia, and drug interactions can precipitate or worsen digoxin toxicity.

1. Digoxin toxicity

2. Introduction
 One of top toxins in the world because
of the wide availability of digoxin and a
narrow therapeutic window.
 Digitalis is a plant-derived cardiac
glycoside commonly used in the treatment
of congestive heart failure (CHF), atrial
fibrillation, and reentrant supraventricular
tachycardia.
 Digoxin-specific fragment antigen-binding
(Fab) antibody has contributed
significantly to the improved morbidity
and mortality of toxic patients

3. Mechanism Of Action
The positive inotropic effect of digitalis has
the following component:
 Direct inhibition of membrane-bound
Na+/K+ -ATPase, which pumps 3 Na+
outside the cell in exchange with 2 K+
inside the cell which is responsible for
maintenance of resting membrane
potential (RMP) in most excitable cells.
 This leads to an increase intracellular
sodium gradually, and a gradual, small
decrease in intracellular potassium.

4.  Cardiac fiber [Ca2+] is exchanged for
extracellular sodium (3:1 ratio) by by
Na+/Ca+ exchanger transport system that
is driven by the concentration gradient for
these ions and the transmembrane
potential; increase in [Na+]i is related
crucially to the positive inotropic effect of
digitalis.
 Facilitation of Ca+ entry through the
voltage gated Ca+ channels of the
membrane. That is associated with
increase in slow inward calcium current
during the plateau of action potential.

5.  They exert negative chronotropic effect
through vagal and extravagal stimulation.
 They decrease AV conduction through
direct action on the myocardium and vagal
stimulation.
 They increase heart automaticity in
overdose only leading to pulse bigeminus
and pulse trigeminus.

7. Digoxin pharmacokinetics
 The therapeutic daily dose of digoxin
ranges from 5-15mcg/kg.
 its bioavailability is 95%.
 The kidney excretes 60-80% of the
digoxin dose unchanged.
 The onset of action by oral administration
occurs in 30-120 minutes
 the onset of action with intravenous
administration occurs in 5-30 minutes.
 Only 1% of the total amount of digoxin in
the body is in the serum; of that amount
about 30 % bound to plasma proteins.

8.  Large volume of distribution about 8L.
 A dose less than 5 mg is rarely to cause
toxicity, however a dose higher than 11 mg
may be fatal
 In pediatrics a dose higher than 4 mg can
cause toxicity.
 During pregnancy Digoxin is used widely in
the acute management and prophylaxis of
fetal paroxysmal supraventricular tachycardia,
as well as in rate control of atrial fibrillation. It
is a category C drug. Increased digoxin
dosage may be necessary during
pregnancy because of enhanced renal
clearance and expanded blood volume.

9. Pathophysiology
 1. Cardiac: Dysrrhythmia
 Alterations in cardiac rate and rhythm
occurring in digitalis toxicity may simulate
almost every known type of dysrhythmia.
- Decrease AV conduction leading to
bradycardia and heart block (first, second,
third).
Indeed, AV junctional block of varying
degrees, alone or with increased
ventricular automaticity, are the most
common manifestations of digoxin
toxicity, occurring in 30-40% of patients
with recognized digoxin toxicity.

10. - Increase automaticity leading to several
types of tachyarrhythmias.
When conduction and the normal pacemaker
are both depressed, ectopic pacemakers may
take over, producing atrial and ventricular
tachycardia.
2- Arrhythmias can cause inadequate tissue
perfusion, with resultant central nervous
system (CNS) and renal mplications such
as the following:
 Hypoxic seizures
 Acute tubular necrosis

11.  3- Hyperkalemia is the major electrolytic
complication in acute, massive digitoxin
poisoning. In addition hyperkalmemia slows
AV conduction adding to digoxin toxicity.
 Hypokalemia is seen with chronic toxicity.
 4- GIT manifestations:
nausea, vomiting, abdominal pain, anorexia
Digitalis preparation cause nausea and
vomiting where it increases vagal
stimulation and activates chemoreceptor
trigger zone.
 5- Visual disturbance: colored vision (yellow
and green patches), Scotomata, diplopia.


13. Clinical digoxin toxicity represents a complex
interaction between digoxin and various
electrolyte and renal abnormalities.
 A patient with normal digoxin levels (0.5-2
ng/mL) but renal insufficiency or severe
hypokalemia may have more serious
cardiotoxicity than a patient with high
digoxin levels and no renal or electrolyte
disturbances.
 The most common precipitating cause of
digitalis intoxication is depletion of potassium
stores, which occurs often in patients with
heart failure as a result of diuretic therapy
and secondary hyperaldosteronism.

14.  Deteriorating renal function, dehydration,
electrolyte disturbances, or drug
interactions usually precipitate chronic
toxicity.
 Acute overdose or accidental exposure to
plants containing cardiac glycosides may
cause acute toxicity.
 Erroneous dosing, especially in infants
receiving parenteral digoxin, is a frequent
cause of digoxin toxicity and is usually
associated with high mortality.
 Acute, nontherapeutic overdose—
unintentional, suicidal, or homicidal—can
cause toxicity

16. Drug Interaction
 Some medications directly increase
digoxin plasma levels; other medications
alter renal excretion or induce electrolyte
abnormalities. Drugs that have been
reported to cause digoxin toxicity include
the following:
 Amiloride
 Amiodarone - Reduces renal clearance of
digoxin and may have additive effects on
the heart rate
 Benzodiazepines (alprazolam, diazepam) -

17.  Beta blockers May have additive effects on
the heart rate
 Calcium channel blockers - Diltiazem and
verapamil increase serum digoxin levels;
not all calcium channel blockers share this
effect.
 Cyclosporine, Erythromycin,
clarithromycin, and tetracyclines,
Propafenone
 Quinidine - Increases digoxin level
substantially
 Propylthiouracil,Indomethacin,

18.  Spironolactone, Hydrochlorothiazide,
Furosemide and other loop diuretics,
Triamterene
 Amphotericin B - May precipitate
hypokalemia and subsequent digoxin
toxicity
 Herb/nutraceutical - Avoid ephedra (risk
of cardiac stimulation); avoid natural
licorice (causes sodium and water
retention and increases potassium loss)
 Increase patient awareness about the
symptoms of digitalis toxicity.
 In addition, educate patients about drug
interactions and about maintaining
adequate hydration.

19. Work up
 Prognosis in digitalis toxicity is poor with
increasing age and associated comorbid
conditions. Morbidity and mortality rates
increase if the patient has a dysrhythmia,
advanced AV block, or other significant
ECG abnormality.
 The lethal dose of most glycosides is
approximately 5-10 times the minimal
effective dose and only about twice the
dose that leads to minor toxic
manifestations.

21.  Usually arrhythmia, and hyperkalemia
suggestive of acute toxicity (usually common
in young indidiuals, bradryarythmias are more
common)
 - Visual disturbances and hypokalemia in
chronic toxicity (usually in old patients on
digoxin treatment, all types of arrhythmia
more commonly tachyarrhythmias)
 The plasma digoxin level can be used to
monitor compliance and toxicity and can be
used as a guide to the appropriate dosing of
medication (TDM).
 Therapeutic digoxin levels vary; the lower limit
ranges from 0.6-1.3 ng/mL, while the upper
limit generally is agreed to be 2.6 ng/mL.

22.  False-negative assay results may occur in
the setting of acute ingestion of nondigoxin
cardiac glycosides, such as foxglove and
oleander, even in the setting of profound
clinical toxicity.
 Initial potassium levels are better correlated
with the prognosis than either ECG changes
or the initial serum digoxin level. In one
monitor, all patients with an initial potassium
level greater than 5.5 died

23.  Measure Na+, K+, Cl-, CO2-, Mg++, Ca++,
blood urea nitrogen (BUN), and creatinine
levels.
 Long-term digoxin users often have
hypomagnesemia secondary to diuretic
usage. Intracellular magnesium depletion
may occur in long-term diuretic use
despite a normal serum magnesium level.
Importantly, magnesium is a cofactor of
the Na+/K+ -ATPase pump, and alterations
of its concentration will affect the pump's
actions.

26. ECG shows any of the following
 Atrial fibrillation with slow, regular
ventricular rate
 Atrial tachycardia with block (atrial
rate usually 150-200 bpm)
 Bidirectional ventricular tachycardia
 Inverted T wave
 Peaked T wave (hyperkalemia)
 Torsade de pointes

28. Managment
 hydration with IV fluids, oxygenation and
support of ventilatory function,
discontinuation of the drug, and,
sometimes, the correction of electrolyte
imbalances.
 Fab antibody fragments are extremely
effective in the treatment of severe, acute
digitalis toxicity

29.  Management of arrhythmia:
– In case of tachycardia: give lidocaine or
phenytoin (No effect on AV conduction).
– In case of bradycardia: give atropine.
– In case of hyperkalemia: give EDTA and
give insulin + glucose to shift K+
intracellularly.
- Ca gluconate is contraindicated because
of Ca, Ca contraindicated)


30.  Correction of electrolyte disturbances as
hypo and hyper kalemia
 Correct hypomagnesemia in cases of
tachycardia. Give 1-2 g Mg sulfate even
with normal Mg levels it also may act as
an indirect antagonist of digoxin at the
supraphysiologic level.
 Temporary pacing is an alternative for
patients with nodal blocks before any
other medical interventions are
attempted.
 Electrocardioversion is not recommended
except with specific cases

31. GI Decontamination and
Enhanced Elimination
 The first-line treatment for acute ingestion
is gastric lavage with repeated dosing of
activated charcoal to reduce absorption
and interrupt enterohepatic circulation. It
is most effective if ingestion has occurred
within 6-8 hours.
 Pretreatment with atropine has been
recommended to decrease the incidence
of AV block or bradycardia as a result of
increased vagal tone caused by gastric
lavage.

32.  To break enterohepatic circulation, use
binding resins, such as cholestyramine.
 Induced emesis with ipecac syrup - Not
recommended, because of the increased
vagal effect
 Whole-bowel irrigation - May be useful,
but clinical data are lacking
 Forced diuresis - Not recommended,
because it has not been shown to increase
renal excretion and can worsen electrolyte
abnormalities
 Dialysis - Has been shown to produce only
small-added clearances unless severe
hyprekalemia