Case History 2
December 6 and 7, 2004

A.J. is a 58-year-old male admitted with a chief complaint of increasing shortness of breath and an 8 kg weight gain. Two years before admission, he noted the onset of dyspnea on exertion after one flight of stairs, orthopnea and ankle edema. Since that time, his symptoms have progressed Three weeks before admission, he noted the onset of episodic bouts of paroxysmal nocturnal dyspnea and he has only been able to sleep in a sitting position. A.J. notes a productive cough, nocturia and mild, dependent edema.

Physical examination reveals a dyspneic, cyanotic, tachycardic male with the following: blood pressure 160/100 mm Hg, pulse 100 beats/minute, respiratory rate 28/minute. He is 5 feet 11inches tall and weighs 78 kg. His neck veins are distended. He is noted to have 3+ pitting edema of the extremities and sacral edema. Chest examination reveals bilateral inspiratory rales.

Admitting laboratory values include the following: hematocrit 41.1% (40-45); WBC count 5300/mm³ (5000-10000); sodium 132 mEq/L (136-144); potassium 3.2 mEq/L (3.5-5.3); chloride 90 mEq/L (96-106); bicarbonate 30 mEq/L (22-28); magnesium 1.2 mEq/L (1.7-2.7) uric acid 8 mg/dL (3.5-7); BUN 40 mg/dL (10-20); creatinine 0.8 mg/dL (0.5-1.2). The chest x-ray shows bilateral pleural effusions and cardiomegaly.

A.J. is put on 0.375 mg/day of digoxin and does well for the next six months until he noted the onset of palpitations which were diagnosed by ECG as atrial fibrillation. A digoxin level drawn at that time was 1.6 µg/L; but all other laboratory tests were normal.

He was begun on quinidine sulfate at a dose of 200 mg qid with rapid resolution of the atrial fibrillation. Four days later, during a follow-up clinic visit, he was noted to have bradycardia with a pulse rate of 50 beats/minute. He also complained of nausea, dizziness and weakness. His digoxin level was 2.9 µg/L.

This interaction is very common, occurring at a frequency of almost 100 percent. Early hypotheses focused on the displacement of digoxin from tissue binding sites by quinidine. The following experiments were performed in order to investigate the nature of the interaction of digoxin and quinidine.

Experiment 1: Aliquots of the sarcolemma fraction of lamb ventricular myocardium were incubated for 30 minute with tritiated ouabain and varying amount of unlabeled ouabain or quinidine chloride. The results are given in Figure 1.

Experiment 2: Healthy volunteers received single 1.0 mg doses of intravenous digoxin by 4-minute infusion on two occasions separated by at least 4 weeks. One digoxin administration served as the “control”, without concurrent quinidine. For the other digoxin dosage trial, subjects ingested quinidine (200 mg qid) for three days prior to digoxin dosage and continuing for 72 hours after digoxin administration. The sequence of the two trials was randomized. Figure 2 illustrates the results from one subject.

Experiment 3: Five patients who had atrial fibrillation and were on digoxin gave informed consent for this study. Digoxin doses were adjusted to maintain levels less than 1 nmol/L. Subjects were admitted to hospital and given a single i.v. dose of [³H]-digoxin (9 µg digoxin; 200 µCi). Tritium activity was analyzed in plasma and urine. Plasma digoxin levels were determined by radioimmunoassay. Two weeks after the digoxin alone study, subjects were started on quinidine sulfate (600 mg bid). After two days another i.v. dose of [³H]-digoxin was given and blood and urine samples were obtained as before. The results are summarized in Table 1.

* p<0.05 by paired Student’s t-test

Students should be able to discuss the following topics.

1. What are the indications for the use of digoxin? Did A.J. exhibit these?
2. What is the mechanism of action of the cardiac glycosides? What adverse effects are associated with their use?
3. What are the pharmacokinetic constants for digoxin and what is their clinical importance? Students should be prepared to calculate steady state levels for digoxin.
4. What are the indications for quinidine and what are its pharmacokinetic constants?
5. In the light of the experiments described here what is the explanation for the interaction between digoxin and quinidine? What other experiments might you want to perform?
6. Are there alternatives for quinidine when the patient is digitalized?
7. Digoxin interacts with many other drugs not necessarily by the same mechanism as quinidine. Discuss another digoxin-drug interaction that occurs by a different mechanism.