THE BIG IMPACT OF SMALL CHANGES IN NARROW THERAPEUTIC INDEX DRUGS

ABSTRACT

CASE An 84-year-old woman with atrial fibrillation on Digoxin presented with acute onset of confusion associated with a week history of abdominal pain, vomiting, and poor fluid intake. A few days prior, Amiodarone was added to her drug regimen which included Lasix. Additionally, she received the COVID-19 booster vaccine which led to a viral-like syndrome resulting in dehydration. The patient was afebrile, normotensive, but bradycardic. EKG showed a prolonged PR interval and scooped ST segments. Labs showed hyperkalemia, pre-renal acute kidney injury (AKI), and a Digoxin level of 4.3 ng/mL (therapeutic range 0.8-2.0 ng/mL). Digoxin and Lasix were held and Digoxin antidote, Digibind, was administered with normalizing heart rate, potassium, and clinical improvement. IMPACT/DISCUSSION: Digoxin is used to slow conduction in atrial fibrillation and increase cardiac contractility in heart failure. It inhibits the membrane sodium-potassium-adenosine triphosphatase pump (Na/K ATPase), resulting in increased cytosolic calcium and subsequent cardiac contractility and automaticity. In turn, this can also cause premature ventricular contractions and tachycardia. In the carotid sinus, increased baroreceptor firing and subsequent increased vagal tone occurs which can cause bradycardia, atrioventricular blocks, hypotension, and GI symptoms. In skeletal muscle, hyperkalemia can result due to the abundance of Na/K ATPase pumps. Digoxin has a narrow therapeutic index with serum levels easily affected by many commonly prescribed drugs by way of decreasing renal clearance, inhibiting P-glycoprotein, and inducing secondary electrolyte disturbances. That said, drug dosing should be individualized with close monitoring to avoid potentially life-threatening effects that may result with even mildly increased digoxin levels. Acute toxicity manifests as non-specific GI, and neurologic symptoms (confusion, lethargy, visual changes), hyperkalemia, and brady or tachy-arrhythmias. Treatment is with digoxin specific fragment antigen binding (Fab) antibody, Digibind, which binds digoxin, inactivating it within 6-8 hours. Postadministration, digoxin serum testing cannot distinguish free verse bound drug;therefore, drug levels remain elevated for days to weeks until the FabDigoxin complex is excreted. In the case above, the viral-like-syndrome after the booster vaccine with subsequent AKI secondary to dehydration likely precipitated Digoxin toxicity. Accompanying drug interactions of diuretics causing dehydration and hypokalemia, P-glycoprotein inhibitors (Amiodarone, Verapamil, Diltiazem, Quinidine), and ACE inhibitors can further worsen renal clearance and culminate in Digoxin toxicity. CONCLUSION: Given Digoxin's narrow therapeutic index, small clinical changes such as post COVID-19 vaccine flu-like symptoms, dehydration, and medication changes can manifest drug toxicity. Therefore, attentive monitoring of accompanying comorbidities and drug interactions is imperative at preventing catastrophic toxic effects.