Transcript CPC: Plumbism or Promiscuity?

Bridging the Gap. Where Clinical and Basic Sciences Meet
CPC #7
A Dilemma on Orchid Island
Frank T. Schwender, MD
Fellow, Cardiovascular Diseases
Karl T. Weber, MD
Professor of Medicine
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.
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.
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.
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.
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.
“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?”
“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.
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.
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.
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.
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?”
“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?
A Dilemma on Orchid Island
Was this attempted murder?
If so, by whom and how?
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
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.
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.
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
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.
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.
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-tobeat 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.
Risk factors for torsade des
pointes
• Female gender, hypokalemia, bradycardia,
CHF, digitalis, rapid infusion of a QT
prolonging drug such as baseline QTprolongation, subclinical long QT
syndrome, severe hypomagnesemia
Drugs causing torsade des
pointes
• Antiarrhythmics class 1 & 3, bepridil,
cisapride, antiemetics, antipsychotics,
methadone, antiinfective agentserythromycin, sparfloxacine, pentamidine,
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 H1antihistaminics leading to a prolonged QT
interval and predisposing to torsade des
pointes
Answer:
Gopal sat at the nurses’ station in
the CCU, reviewing the
information at hand. Sy, a 66year-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.
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.
“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?”
“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.”
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.
“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.”
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.
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.
“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.
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.
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?”
“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.
“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.
Terfenadine (T) is a secondgeneration 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.
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.
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.
Flavonoids also inhibit renal 11ßhydroxysteroid 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.
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.
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 computerdetected 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.