Digoxin toxicity

Introduction

One of top toxins in the world becauseof the wide availability of digoxin and anarrow therapeutic window.

Digitalis is a plant-derived cardiacglycoside commonly used in the treatmentof congestive heart failure (CHF), atrialfibrillation, and reentrant supraventriculartachycardia.

Digoxin-specific fragment antigen-binding(Fab) antibody has contributedsignificantly to the improved morbidityand mortality of toxic patients

Mechanism Of Action

The positive inotropic effect of digitalis hasthe following component:

Direct inhibition of membrane-boundNa+/K+ -ATPase, which pumps 3 Na+

outside the cell in exchange with 2 K+

inside the cell which is responsible formaintenance of resting membranepotential (RMP) in most excitable cells.

This leads to an increase intracellularsodium gradually, and a gradual, smalldecrease in intracellular potassium.

Cardiac fiber [Ca2+] is exchanged forextracellular sodium (3:1 ratio) by byNa+/Ca+ exchanger transport system thatis driven by the concentration gradient forthese ions and the transmembranepotential; increase in [Na+]i is relatedcrucially to the positive inotropic effect ofdigitalis.

Facilitation of Ca+ entry through thevoltage gated Ca+ channels of themembrane. That is associated withincrease in slow inward calcium currentduring the plateau of action potential.

They exert negative chronotropic effectthrough vagal and extravagal stimulation.

They decrease AV conduction throughdirect action on the myocardium and vagalstimulation.

They increase heart automaticity inoverdose only leading to pulse bigeminusand pulse trigeminus.

Digoxin pharmacokinetics The therapeutic daily dose of digoxin

ranges from 5-15mcg/kg.

its bioavailability is 95%.

The kidney excretes 60-80% of thedigoxin dose unchanged.

The onset of action by oral administrationoccurs in 30-120 minutes

the onset of action with intravenousadministration occurs in 5-30 minutes.

Only 1% of the total amount of digoxin inthe body is in the serum; of that amountabout 30 % bound to plasma proteins.

Large volume of distribution about 8L.

A dose less than 5 mg is rarely to causetoxicity, however a dose higher than 11 mgmay be fatal

In pediatrics a dose higher than 4 mg cancause toxicity.

During pregnancy Digoxin is used widely inthe acute management and prophylaxis offetal paroxysmal supraventricular tachycardia,as well as in rate control of atrial fibrillation. It

is a category C drug. Increased digoxindosage may be necessary duringpregnancy because of enhanced renalclearance and expanded blood volume.

Pathophysiology 1. Cardiac: Dysrrhythmia

Alterations in cardiac rate and rhythmoccurring in digitalis toxicity may simulatealmost every known type of dysrhythmia.

- Decrease AV conduction leading tobradycardia and heart block (first, second,third).

Indeed, AV junctional block of varyingdegrees, alone or with increasedventricular automaticity, are the mostcommon manifestations of digoxintoxicity, occurring in 30-40% of patientswith recognized digoxin toxicity.

- Increase automaticity leading to severaltypes of tachyarrhythmias.

When conduction and the normal pacemakerare both depressed, ectopic pacemakers maytake over, producing atrial and ventriculartachycardia.

2- Arrhythmias can cause inadequate tissueperfusion, with resultant central nervoussystem (CNS) and renal mplications suchas the following:

Hypoxic seizures

Acute tubular necrosis

3- Hyperkalemia is the major electrolyticcomplication in acute, massive digitoxinpoisoning. In addition hyperkalmemia slowsAV conduction adding to digoxin toxicity.

Hypokalemia is seen with chronic toxicity.

4- GIT manifestations:

nausea, vomiting, abdominal pain, anorexia

Digitalis preparation cause nausea andvomiting where it increases vagalstimulation and activates chemoreceptortrigger zone.

5- Visual disturbance: colored vision (yellowand green patches), Scotomata, diplopia.

Clinical digoxin toxicity represents a complexinteraction between digoxin and variouselectrolyte and renal abnormalities.

A patient with normal digoxin levels (0.5-2ng/mL) but renal insufficiency or severehypokalemia may have more seriouscardiotoxicity than a patient with highdigoxin levels and no renal or electrolytedisturbances.

The most common precipitating cause ofdigitalis intoxication is depletion of potassiumstores, which occurs often in patients withheart failure as a result of diuretic therapyand secondary hyperaldosteronism.

Deteriorating renal function, dehydration,electrolyte disturbances, or druginteractions usually precipitate chronictoxicity.

Acute overdose or accidental exposure toplants containing cardiac glycosides maycause acute toxicity.

Erroneous dosing, especially in infantsreceiving parenteral digoxin, is a frequentcause of digoxin toxicity and is usuallyassociated with high mortality.

Acute, nontherapeutic overdose—unintentional, suicidal, or homicidal—cancause toxicity

Drug Interaction Some medications directly increase

digoxin plasma levels; other medicationsalter renal excretion or induce electrolyteabnormalities. Drugs that have beenreported to cause digoxin toxicity includethe following:

Amiloride

Amiodarone - Reduces renal clearance ofdigoxin and may have additive effects onthe heart rate

Benzodiazepines (alprazolam, diazepam) -

Beta blockers May have additive effects onthe heart rate

Calcium channel blockers - Diltiazem andverapamil increase serum digoxin levels;not all calcium channel blockers share thiseffect.

Cyclosporine, Erythromycin,clarithromycin, and tetracyclines,Propafenone

Quinidine - Increases digoxin levelsubstantially

Propylthiouracil,Indomethacin,

Spironolactone, Hydrochlorothiazide,Furosemide and other loop diuretics,Triamterene

Amphotericin B - May precipitatehypokalemia and subsequent digoxintoxicity

Herb/nutraceutical - Avoid ephedra (riskof cardiac stimulation); avoid naturallicorice (causes sodium and waterretention and increases potassium loss)

Increase patient awareness about thesymptoms of digitalis toxicity.

In addition, educate patients about druginteractions and about maintainingadequate hydration.

Work up

Prognosis in digitalis toxicity is poor withincreasing age and associated comorbidconditions. Morbidity and mortality ratesincrease if the patient has a dysrhythmia,advanced AV block, or other significantECG abnormality.

The lethal dose of most glycosides isapproximately 5-10 times the minimaleffective dose and only about twice thedose that leads to minor toxicmanifestations.

Usually arrhythmia, and hyperkalemiasuggestive of acute toxicity (usually commonin young indidiuals, bradryarythmias are morecommon)

- Visual disturbances and hypokalemia inchronic toxicity (usually in old patients ondigoxin treatment, all types of arrhythmiamore commonly tachyarrhythmias)

The plasma digoxin level can be used tomonitor compliance and toxicity and can beused as a guide to the appropriate dosing ofmedication (TDM).

Therapeutic digoxin levels vary; the lower limitranges from 0.6-1.3 ng/mL, while the upperlimit generally is agreed to be 2.6 ng/mL.

False-negative assay results may occur inthe setting of acute ingestion of nondigoxincardiac glycosides, such as foxglove andoleander, even in the setting of profoundclinical toxicity.

Initial potassium levels are better correlatedwith the prognosis than either ECG changesor the initial serum digoxin level. In onemonitor, all patients with an initial potassiumlevel greater than 5.5 died

Measure Na+, K+, Cl-, CO2-, Mg++, Ca++,blood urea nitrogen (BUN), and creatininelevels.

Long-term digoxin users often havehypomagnesemia secondary to diureticusage. Intracellular magnesium depletionmay occur in long-term diuretic usedespite a normal serum magnesium level.Importantly, magnesium is a cofactor ofthe Na+/K+ -ATPase pump, and alterationsof its concentration will affect the pump'sactions.

ECG shows any of the following

Atrial fibrillation with slow, regular ventricular rate

Atrial tachycardia with block (atrialrate usually 150-200 bpm)

Bidirectional ventricular tachycardia

Inverted T wave

Peaked T wave (hyperkalemia)

Torsade de pointes

Managment

hydration with IV fluids, oxygenation andsupport of ventilatory function,discontinuation of the drug, and,sometimes, the correction of electrolyteimbalances.

Fab antibody fragments are extremelyeffective in the treatment of severe, acutedigitalis toxicity

Management of arrhythmia:

– In case of tachycardia: give lidocaine orphenytoin (No effect on AV conduction).

– In case of bradycardia: give atropine.

– In case of hyperkalemia: give EDTA andgive insulin + glucose to shift K+

intracellularly.

- Ca gluconate is contraindicated becauseof Ca, Ca contraindicated)

Correction of electrolyte disturbances ashypo and hyper kalemia

Correct hypomagnesemia in cases oftachycardia. Give 1-2 g Mg sulfate evenwith normal Mg levels it also may act asan indirect antagonist of digoxin at thesupraphysiologic level.

Temporary pacing is an alternative forpatients with nodal blocks before anyother medical interventions areattempted.

Electrocardioversion is not recommendedexcept with specific cases

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 beenrecommended to decrease the incidenceof AV block or bradycardia as a result ofincreased vagal tone caused by gastriclavage.

To break enterohepatic circulation, usebinding resins, such as cholestyramine.

Induced emesis with ipecac syrup - Notrecommended, because of the increasedvagal effect

Whole-bowel irrigation - May be useful,but clinical data are lacking

Forced diuresis - Not recommended,because it has not been shown to increaserenal excretion and can worsen electrolyteabnormalities

Dialysis - Has been shown to produce onlysmall-added clearances unless severehyprekalemia