CPC #7 A Dilemma on Orchid Island

1. CPC #7A Dilemma on Orchid Island Bridging the Gap. Where Clinical and Basic Sciences Meet Frank T. Schwender, MD Fellow, Cardiovascular Diseases Karl T. Weber, MD Professor of Medicine

2. The Cast of Characters Sy Lavin, a 66-year-old retired realtor from Chicago, recently married to 31-year-old Joyce Barnes. Sy has a cardiac arrest. Paramedics find torsades (200 bpm) on Sy’s ECG with prolonged QT interval and prominent U waves. Intravenous MgSO4 restores sinus rhythm. Sy has no PMH other than elevated cholesterol and allergic rhinitis for which he takes an antihistamine. Sy and son Stuart had a recent argument.

3. The Cast of Characters Joyce Barnes, Sy’s new bride, recommends grapefruit juice (GFJ) at breakfast and with afternoon cocktails to reduce Sy’s cholesterol and decaffeinated coffee to prevent sleeplessness.

4. The Cast of Characters Phillipe Ogden, Joyce’s chiropractor, recommends a licorice-based herbal tea to reduce salt and water loss that accompany exercise-related sweating in the warm Florida climate and which could account for Joyce and Sy’s muscle cramps.

5. The Cast of Characters Hiram Salker, a pharmacist, who fills Sy’s prescription for an H1 histamine receptor blocker. He also recommends licorice candies from the Netherlands, the licorice-based herbal tea and GFJ to reduce Sy’s cholesterol.

6. The Cast of Characters Stuart Lavin, Sy’s son, who has financial difficulties that prompt him to request a loan from his father. He and Sy have a heated argument shortly before Sy’s arrest.

7. “Go rest, young man,” Sy told him, gritting his teeth. “Take a walk on the beach. I need time to think. And try to be civil when our guests arrive later this afternoon.” Sy flopped into his favorite soft recliner and gave out a heavy sigh. Joyce, noting his brooding mood, looked to provide comfort. “Sy, I’ll prepare our afternoon screwdrivers now, yours with a double dose of vodka.” “Thank you. That sounds good,” he replied. “When are our guests arriving?”

8. “It’s 4:00 p.m. now. We’ll gather together poolside around 6:00. I’ve called Fig Leaf’s to cater the whole affair. Nothing for you to worry about, my dear.” But worry he did. He had to clear his mind. Stuart was in desperate need. How could he turn his back on his only child? The vodka provided much needed sleep to clear his mind and find a possible solution to the dilemma. He awoke at 5:43 p.m., freshened up and quickly took his medication in anticipation of tonight’s outdoor dose of pollen.

9. Fortunately, guests were fashionably late. They included Mike and Sally Calhoun, a recently retired law enforcement officer and his wife from New York City, whom Sy and Joyce had met at the marina; Gopal and Geeta Shankar, a cardiologist and his wife who lived next door; and David and Michelle Davis, lawyers in Vero Beach who helped manage the Lavin estate. All were standing around the pool engaged in polite conversation with Joyce and Stuart as Sy approached with an iced pitcher of screwdrivers.

10. Without warning, he went down in a heap, not 10 feet from his guests. Gopal sprang into action. Finding no pulse, he began manual chest compressions. Mike effortlessly joined in to provide ventilation. Geeta used their cellular phone to immediately alert fire rescue, who arrived minutes later. Paramedics maintained cardiopulmonary resuscitation (CPR), established intravenous access and applied ECG leads.

11. Gopal found torsades de pointes on Sy’s ECG, a form of ventricular tachycardia with QRS complexes appearing at a rate of 200 bpm and of changing amplitude that twisted around the isoelectric line. He immediately applied electrical shock to the chest that successfully restored sinus rhythm.

12. There was no ECG evidence of acute myocardial infarction, but the QT interval was markedly prolonged and there were prominent U waves. Gopal gave intravenous magnesium sulfate. Sy’s blood pressure recovered and spontaneous ventilation returned, but he was too groggy to communicate effectively. “Joyce,” asked Gopal, “is your husband taking any medications?” “Only an antihistamine,” she responded tearfully. “He’s been well otherwise. Will he be okay?”

13. “We’ll take him to the hospital for observation. You can ride with us in the ambulance. And I will need more information. Sy’s chaotic heart rhythm that accounted for this cardiac arrest and his abnormal ECG are puzzlesome,” said a serious Gopal as the ambulance drove off. Was this attempted murder? If so, by whom and how?

15. A Dilemma on Orchid Island Was this attempted murder? If so, by whom and how?

16. Potential suspects and motives • Joyce (wife)-could inherit lots of money, but would loose husband • Phillipe Ogden, a chiropractor, who massages Joyce professionally and recommends licorice-based herbal tea. He may become personal masseuse of widow Joyce

17. Potential suspects and motives • Hiram Salker, pharmacist, recommends licorice candies in addition to herbal tea and recommends plenty of grapefruit juice to lower Sy’s cholesterol. He also dispenses H-1 histamine receptor blocker for Sy’s allergies. He has shown an interest in Joyce’s leg cramps and knows what to do about it. • Stuart, Sy’s son, does not dispense anything except Sy’s money.

18. Sy’s road to Torsades • Sy has been taking large amounts of licorice. • 40 cases of licorice-induced hypokalemia have been reported in the English literature. (Sy has not read them) • Glycyrrhizic acid causing hypokalemia through its inhibition of the renal enzyme 11(beta)-hydroxysteroid dehydrogenase, which is responsible for renal conversion of cortisol to locally inactive cortisone. This leads to cortisol-mediated activation of renal mineralocorticoid receptors, resulting in a state of apparent mineralocorticoid excess, which includes K+ wasting.

19. Poor Sy • Hypokalemia is caused by renal or extrarenal loss of potassium or by an acute shift of potassium into cells. A daily dose of GA exceeding 100 mg produces side effects in sensitive individuals; 400 mg produces adverse affects in most individuals

20. The “Good” grapefruit juice from Hiram • Grapefruit juice (GFJ) has been shown to increase the bioavailibility of Terfenadine, a nonsedating H1-blocker by inhibition of Cytochrome P450 • H1 blockers, particularly terfenadine, increase the QT interval by blocking the the rapidly activating component of the delayed rectifier.

21. Torsade des pointes and the Long QT syndrome • In the past decade, the single most common cause of the withdrawal of drugs in the US has been QT prolongation associated with polymorphic ventricular tachycardia or torsade des pointes. • Nine structurally unrelated drugs were marketed in the US and have been removed from the market for their risk of cardiac toxicity.

22. Torsade des pointes • First described in 1966 in an elderly woman with heart block, torsade des pointes is often translated as a twisting of the points and refers to the beat-to-beat changes in QRS axis. • Torsade de pointes has been described in the setting of heart block, congenital long-QT syndrome or in association with drug therapy.

23. Risk factors for torsade des pointes • Female gender, hypokalemia, bradycardia, CHF, digitalis, rapid infusion of a QT prolonging drug such as baseline QT-prolongation, subclinical long QT syndrome, severe hypomagnesemia

24. Drugs causing torsade des pointes • Antiarrhythmics class 1 & 3, bepridil, cisapride, antiemetics, antipsychotics, methadone, antiinfective agents-erythromycin, sparfloxacine, pentamidine,

25. Was it attempted murder, and how, and by whom? • Hiram dispenses licorice causing severe hypokalemia and grapefruit juice, which through Cytochrome P450 inhibition increases the bioavailibility of certain H1-antihistaminics leading to a prolonged QT interval and predisposing to torsade des pointes

26. Answer: Gopal sat at the nurses’ station in the CCU, reviewing the information at hand. Sy, a 66-year-old male, would likely have coronary artery disease and be at risk of sudden cardiac death. But torsades with prolonged QT interval? This had him flummoxed. He knew the appearance of torsades was associated with congenital or acquired prolongation of ventricular repolarization.

27. Prolonged QT interval accompanies certain medications, including “antiarrhythmic” agents such as quinidine and procainamide, and electrolyte disturbances such as hypokalemia. Serum electrolyte levels were pending. The prominent U wave was suggestive of hypokalemia. But why K+ loss when Joyce denied Sy had recently experienced diarrhea or vomiting? Increased urinary excretion? Sy was not on a diuretic. Serum K+ proved to be 3.4 meq/L and was corrected. He must be receiving something that promotes urinary K+ excretion, thought Gopal. I’d better talk to his wife some more.

28. “Joyce, Sy is stable and regaining full consciousness. The arrhythmia has not reappeared. I need to ask several questions, please.” “Certainly, I’m so pleased he’s improving. Sy has never had a heart attack, that we know of, or a history of high blood pressure.” “He’s losing K+. Probably through his kidneys, perhaps his sweat, likely both. I need to find out why. Does Sy exercise regularly? Has he had leg cramps of late?”

29. “As a matter of fact, both Sy and I experienced leg cramps, although mine are a more chronic problem. We thought it was related to our daily workouts. And come to think of it, these cramps appeared since we began taking herbal tea with licorice. It’s called Victory Garden. We also like licorice candy from Holland.”

30. Licorice. This was an important clue to K+ loss, thought Gopal. But the marked prolongation of the QT interval? There had to be something more than hypokalemia. “Has Sy been dieting?” “No. We are careful with our diet, but no store-bought supplements or fads you read about in the papers. To help reduce our cholesterol we take grapefruit juice (GFJ) twice a day. Would that matter?” asked a puzzled Joyce.

31. “I don’t believe so.” Citrus fruit and torsades? “It seems unlikely,” remarked Gopal. “But let me check into it. And tell me the name of the antihistamine Sy is taking.” “It’s called terfenadine.”

32. Gopal began with the Physicians’ Desk Reference (PDR) at the nurses’ station. Terfenadine indeed is implicated in QT prolongation and ventricular arrhythmias, including torsades, and sudden cardiac death. These rare complications are seen in association with increased terfenadine levels that accompany its concomitant administration with certain antibiotics, such as ketoconazole or itraconazole, clarithromycin, erythromycin or troleandomycin.

33. These drug interactions, however, were not at play in Sy’s case. Could GFJ be implicated? There was nothing in the PDR on this possibility. He would contact the pharmacist at Shrugg’s. Next he would conduct an online search of the pharmaceutical database, and if that failed, a search on the World-Wide Web for grapefruits and the heart.

34. “Hello, this is Dr. Gopal Shankar,” he said as he connected with Shrugg’s. “May I speak to the pharmacist please?” “Hiram Salker, pharmacist, speaking.” “Dr. Salker, Dr. Shankar here. I have an unusual question for you. Are you aware of any reports that would link consumption of GFJ with increased bioavailability of terfenadine?” “Why, no. Is there a problem? Is Mr. Lavin sick?” “There is no problem. Thank you for your help.” How did Hiram know I was calling about Sy Lavin? wondered Gopal.

35. Gopal’s computerized literature search indicated there now was an emerging body of evidence that linked GFJ with altered pharmacokinetics of dihydroperidine calcium channel blockers. Earlier in 1996, several reports identified enhanced bioavailability of terfenadine and QT prolongation with GFJ consumption. Additionally, GFJ has the potential, like licorice, to enhance urinary K+ excretion.

36. The next morning on rounds, Gopal went to the CCU. Sy had fully recovered and there was no recurrence of torsades or other ventricular arrhythmias. “Sy, do you know anyone who would wish you harm?”

37. “No. My son Stuart is a bit tempestuous, but he’s okay.” “Do you know Hiram Salker over at Shrugg’s?” “Why, yes I do. Why do you ask?” “Oh, good morning, Mrs. Lavin,” Gopal said as Joyce entered Sy’s room. “We were just talking about Hiram Salker. Do you know him?” “I do, indeed,” sighed Joyce. “Would Hiram have known that either or both of you were taking Victory Garden and that you favored GFJ twice a day?” “I don’t think so,” said Sy.

38. “That’s not correct, honey. I mentioned this to Hiram several weeks ago when I purchased the herbal tea. He proceeded to recommend the licorice candies to me.” “And when you purchased terfenadine for your allergies, Sy, did Hiram indicate there was a possible interaction with GFJ and that K+ wasting associated with the combination of licorice and GFJ could further predispose you to an irregular heartbeat?” “No, he did not.” “I believe I shall talk to the authorities,” said Gopal.

40. Terfenadine (T) is a second-generation selective H1 receptor antagonist with few central nervous system effects. It also is a potent antagonist of the delayed rectifier K+ current in cardiac myocytes. Elevated levels of T is the proposed mechanism for repolarization abnormalities, including QT prolongation, that predispose to ventricular tachycardia, including torsades.

41. T, a pro-drug, is biotransformed by cytochrome CYP3A4 in the liver. Inhibition of this step allows for accumulation of unmetabolized T. GFJ and its flavonoids (e.g., naringin), in particular, inhibit CYP3A4. The flavonoid composition of GFJ is enhanced when ripening fruit is exposed to freezing temperatures, and is at a peak during early development.

42. In producing GFJ, forceful mechanical compression increases the presence of compounds derived from fruit tissues high in naringin, as contrasted with GFJ obtained solely from juice vesicles by hand-squeezed fruit without pulp. Increments in the time to maximum concentration and area under the concentration-time curve of T, together with QT prolongation, are observed when T is coadministered with GFJ.

43. Flavonoids also inhibit renal 11ß-hydroxysteroid dehydrogenase, the guardian enzyme that preserves the specificity of the promiscuous steroid receptor for mineralocorticoids. This enzyme is inhibited by flavonoids and glycyrrhizic acid, the active principle of licorice. In combination, GFJ and large-dose licorice, derived in Sy’s case from two sources—herbal tea and imported candies known to have a high concentration of licorice—would permit more plentiful glucocorticoids to act as mineralocorticoids and predispose to hypokalemia and ventricular arrhythmias.

44. POSTSCRIPT The U.S. manufacturer of T has recently withdrawn this agent from the marketplace. The Food and Drug Administration (FDA) has requested that generic formulations of T likewise be withdrawn. In the UK, the Committee on Safety of Medicines has recommended that the status of T be changed to prescription only.

45. In 1996, the Michigan Court of Appeals ruled that a retail pharmacy may be held liable to a patient based on its commercial advertisement on computer-detected harmful drug interactions. In so doing, the pharmacy and its pharmacist each assumed a responsibility in monitoring a patient’s drug regimen. A failure to do so is actionable under the theories of negligence and fraud.