Digoxin toxicity

Digoxin toxicity can occur through a number of different mechanisms:

Acute

Overdose after suicide attempt
Medication dosing error
Malicious intent (homicidal poisoning).

Chronic

Chronic digoxin over-medication
Decreased renal clearance due to renal insufficiency or drugs[7][8][9][10][11]
Displacement of digoxin from protein-binding sites[7][8][10]
Conditions that increase susceptibility to digoxin (electrolyte abnormalities, e.g., hypokalaemia, hypomagnesaemia, hypercalcaemia)[12][13]
Increased gastrointestinal absorption (caused by antibacterial therapy, or by drug-induced P-glycoprotein inhibition)[14][15][16]
- Digoxin is largely dependent on P-glycoprotein for elimination. Thus, medications that inhibit P-glycoprotein may increase digoxin levels and potentially cause toxicity. Clinically significant medications in this category include verapamil, diltiazem, amiodarone, quinidine, ketoconazole, itraconazole, vinblastine, doxorubicin, and erythromycin. These substances may also inhibit cytochrome 3A4.[17] Others include clarithromycin, ciclosporin, propafenone, and spironolactone.

Digoxin inhibits Na+/K+ ATPase on the membrane of myocardial cells and cardiac conducting tissue. This increases cytosolic Ca, which increases inotropy.

Therapeutically, digoxin increases automaticity and shortens the repolarisation intervals of the atria and ventricles. There is a concurrent decrease in depolarisation and conduction through the sinoatrial and atrioventricular (AV) nodes respectively. These changes are reflected on the ECG by a decrease in ventricular response rate PR-interval prolongation, QT-interval shortening, and ST-segment and T-wave forces opposite the direction of the major QRS forces (scooped ST segment). This results in the characteristic digitalis effect.[18][Figure caption and citation for the preceding image starts]: ECG showing digoxin effect [Citation ends].

In overdose, digoxin produces two major effects that correlate with its therapeutic action:

Slowed conduction by increasing block at the AV node
Increased automatic triggered electrical activity in atrial muscle, the AV junction, the His-Purkinje system, and the ventricular muscle (increased automaticity).

Digoxin toxicity can also cause hyperkalaemia, which increases the risk of dysrhythmias. Toxicity depends on intra-cellular levels and does not correlate well with serum levels. Non-cardiac adverse effects may also be mediated by inhibition of Na+/K+ ATPase in other tissues.[19] Abnormal sodium, potassium, or magnesium levels and acidosis increase toxicity by further depressing the Na+/K+ ATPase pump.

Acute toxicity: patients who take a digoxin overdose when they are not prescribed digoxin themselves (i.e., patients who take an accidental or intentional overdose when not already prescribed digoxin for an existing condition).

Acute on chronic toxicity: patients who are prescribed digoxin for an existing condition and take a digoxin overdose. Acute overdose in patients on regular therapy is expected to be more toxic than in patients who are not already taking therapeutic digoxin.

Chronic toxicity: patients who present with digoxin toxicity because of drug accumulation (commonly due to renal failure) without having taken an overdose.

Pathophysiology

Classification