Pharmacologic Treatment of Cardiac Arrhythmias

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Pharmacologic Treatment of Cardiac Arrhythmias



Glycosides and Tannins

Submitted by:
GUEVARRA, Josel Aldrin C.
Submitted to:
BIAGTAN, Mary Grace; RPh


Digoxin Use Linked to Mortality in End-Stage Renal Disease
News Author: Laurie Barclay, MD
CME Author: Charles P. Vega, MD
Faculty and Disclosures
CME Released: 06/25/2010; Valid for credit through 06/25/2011

June 25, 2010 — Digoxin use is linked to mortality in patients with end-stage renal disease, according
to the results of a retrospective cohort study reported online June 24 in the Journal of the American
Society of Nephrology.

"We were surprised to find that digoxin use increased death risk in dialysis patients, especially
in patients on higher doses," said lead author Kevin E. Chan, MD, MSci, from Fresenius Medical Care
North America in Waltham, Massachusetts, in a news release. "Although digoxin has been prescribed
by doctors for over 200 years, widespread monitoring studies have not been conducted to examine
the penetration, effectiveness, and safety of the drug among patients on dialysis."
To reduce the potential for confounding by indication, the investigators used covariate- and propensity
score–adjusted Cox models to evaluate the association between digoxin prescription and survival
duration in a cohort of 120,864 patients receiving incident hemodialysis enrolled from more than 1800
clinics across North America and observed for up to 4 years. Digoxin was prescribed to 4% of the

Digoxin use was associated with a 28% increased mortality risk (hazard ratio [HR] 1.28; 95%
confidence interval [CI], 1.25 - 1.31). Increase in serum digoxin level was also a significant predictor
of death, with an HR of 1.19 per ng/mL increase (95% CI, 1.05 - 1.35). Patients with lower predialysis

serum potassium levels had the strongest association of increased mortality with digoxin level (HR,
2.53 [P = .01] for potassium level < 4.3 mEq/L vs HR, 0.86 [P = .35] for potassium level > 4.6 mEq/L).
"[D]igoxin use among patients who are on hemodialysis associates with increased mortality,
especially among those with low predialysis K [potassium]," the study authors write.

Limitations of this study include retrospective observational design, use of clinical surveillance
data, potential unmeasured confounders, and information bias from misclassification.

"Further research is needed to outline how and if digoxin can be safely prescribed in patients
on hemodialysis," Dr. Chan said, suggesting that therapeutic options other than digoxin be considered
for heart disease in patients starting dialysis. "For patients who remain on digoxin, vigilant monitoring
of digoxin and potassium blood levels can minimize the drug's possible side effects."
The study authors have disclosed no relevant financial relationships. J Am Soc Nephrol.
Published online June 24, 2010.

Digoxin is frequently prescribed for the management of congestive heart failure and atrial
fibrillation, as it works as both a positive inotrope and a negative chronotrope. It accomplishes these
actions through increasing intracellular levels of sodium and calcium in the cardiac myocyte via
inhibition of the Na+/K+-ATPase pump.

Both digoxin and potassium compete for this same myocyte-binding site, meaning that
hypokalemia can potentiate digoxin toxicity (whereas hyperkalemia can decrease the effectiveness of
digoxin). This relationship between potassium and the action of digoxin could be particularly
problematic for patients receiving dialysis, for whom potassium levels fluctuate significantly at

approximately the time of dialysis. The current study examines patient outcomes among individuals
receiving digoxin during hemodialysis.


Patients included in the study were receiving hemodialysis in one of more than 1800
centers in North America. Researchers compared patients who had received digoxin 90
days after beginning renal replacement therapy vs those patients who had not received

The main study outcome was mortality, which was recorded after 90 days of receipt of renal
replacement therapy. This result was adjusted to account for multiple demographic,
laboratory, and disease data. Researchers also accounted for digoxin dosages and serum
levels of digoxin in their analyses.

Among 120,864 patients receiving hemodialysis, 4549 were digoxin users. The median
prescribed dosage of digoxin was 62.5 µg/day. The average patient received a blood test to
check serum digoxin levels 2.7 times during the first 90 days of dialysis.

The median serum level of digoxin was 1.0 ng/mL. Interestingly, there was no relationship
between the serum digoxin level and the prescribed digoxin dosage.

Patients receiving digoxin tended to be older, have higher levels of comorbidity, and higher
overall medication use.

After full adjustment, the HR for death associated with the use of digoxin was significant at

Each 1-ng/mL increase in the serum digoxin level increased the risk for mortality by 19%
after covariate and propensity score adjustment.

A low average predialysis serum potassium level predicted a higher risk for death
associated with higher serum digoxin levels. Digoxin was also associated with a higher risk
for death among patients with good vs poor status of physical function.

Digoxin works as a positive inotrope and a negative chronotrope. Hyperkalemia could
reduce the efficacy of digoxin, whereas hypokalemia may promote digoxin toxicity.

The current study suggests that the use of digoxin is associated with a higher risk for
mortality among patients receiving hemodialysis. Higher serum levels of digoxin were
associated with a higher risk for mortality, particularly when the average predialysis serum
potassium level was low.

o Guo X, Gallagher MM, Yap YG, Harries M, Malik M, Camm J. Does digoxin affect the
outcome of DC cardioversion in humans? Program and abstracts of the American
College of Cardiology 50th Annual Scientific Session; March 18-21, 2001; Orlando,
o Greenstein RS, Merz J, Fay W, et al. Time required to achieve therapeutic
anticoagulation with warfarin prior to cardioversion for atrial fibrillation. Program and
abstracts of the American College of Cardiology 50th Annual Scientific Session; March
18-21, 2001; Orlando, Florida.
o Yamamoto K, Kozhevnikov DO, Robotis D, Restivo M, El-Sherif N. Mechanism of
enhanced susceptibility of hypertrophied heart to acquired torsade de pointes
arrhythmias. Program and abstracts of the American College of Cardiology 50th Annual
Scientific Session; March 18-21, 2001; Orlando, Florida.
o Gbadebo TD, Trimble RW, Roden DM, Anderson ME. A novel index of ventricular
repolarization predicts initiation of torsade de pointes. Program and abstracts of the
American College of Cardiology 50th Annual Scientific Session; March 18-21, 2001;
Orlando, Florida.
o Unnikrishnan D, Varshneya N, Lucariello R, Dutcher JP, Wiernik PH, Chlaramida S.
Torsade de pointes associated with arsenic trioxide treatment for hematological
malignancies. Program and abstracts of the American College of Cardiology 50th
Annual Scientific Session; March 18-21, 2001; Orlando, Florida.
o Kowey PR, Zhang Q, Garavaglia S, et al. Detecting population-level protective benefits
of potassium replacement in diuretic users. Program and abstracts of the American
College of Cardiology 50th Annual Scientific Session; March 18-21, 2001; Orlando,
o Schmidt G, Barhel P, Schneider R, Schomig A, Camm J, Malik M. EMIAT Substudy:
Prediction of the efficacy of amiodarone by heart rate turbulence Program and abstracts
of the American College of Cardiology 50th Annual Scientific Session; March 18-21,
2001; Orlando, Florida.
o Thompson TD, Mahoney EM, Veledar E, Weintraub WS. Marginal cost-effectiveness of
amiodarone targeted to high risk patients undergoing open heart surgery. Program and
abstracts of the American College of Cardiology 50th Annual Scientific Session; March
18-21, 2001; Orlando, Florida.
o Alegria J, Gersh B, Scott C, Hodge D, Hammill S, Sen W. Recurrent syncope following
beta-blocker therapy vs. conservative management in patients with vasovagal syncope.
Program and abstracts of the 50th Annual American College of Cardiology Scientific
Session; March 18-21, 2001; Orlando, Florida.

New Strategy Aims to Reduce Agricultural Ammonia
ScienceDaily (May 22, 2011) — As concerns about air pollution from large dairies and other
concentrated animal feeding operations (CAFOs) continue to mount, scientists are reporting a
practice that could cut emissions of an exceptionally abundant agricultural gas -- ammonia -- by up to
In the May-June 2011 issue of theJournal of Environmental Quality, a team led by Mark
Powell, a soil scientist with the USDA Agricultural Research Service's U.S. Dairy Forage Research
Center in Madison, WI, describes how natural plant compounds, known as tannins, can reduce both
the amount of nitrogen cows excrete in urine, and the action of a microbial enzyme in manure that
converts the nitrogen into ammonia on the barn floor.

The U.S. EPA already monitors ammonia emissions from large animal operations under the
"Superfund" act, and in April a coalition of citizen groups petitioned the agency to begin regulating
ammonia under the Clean Air Act, as well. Besides its pungent smell, ammonia that volatilizes from
cattle manure is highly reactive in the atmosphere, forming particulates that travel long distances and
contribute to environmental problems such as acid rain, nutrient pollution, and smog.

Feeding tannins to cattle could not only help dairy farmers reduce these impacts and meet
regulatory standards, Powell says, but tannins could also boost nitrogen use efficiency in cows,
thereby decreasing the need for expensive protein supplements. Only 20 to 35% of feed nitrogen
ends up in milk on commercial dairy farms, with the remainder excreted about equally in manure and
urine as the compound, urea.
Urea is produced when nitrogen-rich proteins break down mainly in the cow rumen, forming ammonia
gas that's eventually converted to urea before being excreted. Tannins are thought to cut urea
production by somehow allowing more protein to escape digestion in the rumen and enter the cow
intestine, where it's used more efficiently to produce milk protein.

Tannins are perhaps best known for their role in leather tanning, but Powell began
investigating them in ruminant feed more than two decades ago in West Africa. In the communities
where he worked, tannin-rich shrubs were grown as windbreaks, and to amend the soil and feed
livestock. Tannins in the diets of cattle, sheep and goats are in fact well-studied in the tropics, where
vegetation tends to be naturally higher in the astringent plant chemicals, Powell explains. "But tannin
research, in terms of ruminant nutrition, is relatively new in temperate environments."

In the new study, Powell and dairy scientists from the University of Wisconsin-Madison fed
tannin extracts from red quebracho and chestnut trees to dairy cows that also received two
concentrations of crude protein: a low level of 15.5% protein, and a higher one of 16.8%. What they
found is that dietary tannin cut ammonia emissions from the cows' manure by an average of 30% at
the low protein level, 16% at the high level, or 23% overall. In other words, cows that consumed
tannin expelled significantly less urea, thus making less available for conversion to ammonia.

But a drop in urea production wasn't the only effect. To his surprise, Powell discovered that
tannins also appear to inhibit urease, the enzyme that converts urea to ammonia. Urease activity in
the feces of tannin-fed cows was significantly lower than in the feces of control animals, resulting in
an 11% drop in emitted ammonia -- or one-third of tannin's total impact on emissions at the high
protein level. And when the researchers applied tannin directly to manure on the barn floor (rather
than feeding it to cows), the effect was even greater: Ammonia emissions declined by nearly 20%.

The tannin sources investigated in the study are already approved for animal feed, and "the
levels we used amount to pennies per cow per day," Powell says, suggesting they could offer a costeffective means to cut ammonia losses from the barn floor, as well as from manure that's applied to
farm fields as fertilizer. Powell is now working with chemists to determine exactly which compounds in
the tannin mixtures produce the effect, with an eye toward manufacturing a synthetic substitute later
In the meantime, he has his sights on another important air pollutant that is prodigiously produced by
cows. "We have another experiment looking at higher doses of tannin in dairy cattle," he says. "We
want to see if it can reduce methane emissions."

J. M. Powell, M. J. Aguerre, M. A. Wattiaux. Tannin Extracts Abate Ammonia Emissions
from Simulated Dairy Barn Floors. Journal of Environment Quality, 2011; 40 (3): 907
DOI: 10.2134/jeq2010.0492


Voice of the Vine - December 1, 2011
New Research Busts Tannin Additions Myth, Sparks Trans-Pacific Collaboration

If you’re using tannin additions in your red winemaking process, you may well be wasting your
money, according to recently published research by Washington State University enologist Jim
Harbertson and Australian wine and grape researcher Mark Downey, a lead researcher at Victoria’s
Department of Primary Industries.
Harbertson, Downey and their colleagues analyzed commercially available tannin additives
and found them to be, at best, an unnecessary expense for red wines made from Washington-grown
Many winemaking manuals recommend adding tannins, though, in the belief that the additions
help bolster mouth feel and improve color in red wine. A red wine’s mouth feel is the result of a range
of chemicals causing astringency and is described with a variety of words ranging from “velvety” to

“At the recommended dosage, these additives are, at most, giving a slight tweak to
astringency,” Harbertson said. “In higher doses, you get some aroma shifting and a negative impact
on sensory character. It made them earthy tasting, and turned the wine brown.”
Harbertson and Downey collaborated with renowned sensory scientist Hildegarde Heymann,
professor of enology at UC Davis, and her Italian post-doctoral student, Giuseppina Parpinello, to
conduct sensory analyses of Merlot and Cabernet Sauvignon wines made with tannin additions. “In a
collaboration with Chateau Ste. Michelle, we added commercial tannin products to both barrel-aging
Merlot and to Cabernet Sauvignon after pressing the grapes,” Harbertson said. “We used a range of
concentrations and a variety of commercially available additives to get a sense of what is going on
when these products are added to Washington wines.”
Harbertson explained that there is a crucial difference between taste (flavor, aroma) and
astringency, or mouth feel. “Mouth feel is a tactile sensation,” he said. “It’s basically the removal of the
lubricating proteins that naturally occur in the mouth. Aroma and flavor, in contrast, are receptorbased and are caused by our taste buds being stimulated by the flavor and aroma molecules in wine.
Astringency is thought to be a result of chemical precipitation in which tannin molecules bind the
lubricating proteins in the mouth, thus taking them out of action. That’s why some wines have a drying
or ‘spikey’ mouth feel, as the overabundance of tannins rob the mouth of its lubricants.”
Not only did the additives have a limited or negative impact on wine quality, analysis of the
products revealed them to be, at most, only 48 percent tannin. “On the low end, we found some
products to contain as little as 12 percent tannin,” Harbertson said. The products contain fillers that
enable the additives to go into solution more easily. Harbertson and Downey conducted the analysis
of the tannin additives.
“The bottom line for Washington red winemakers is this,” Harbertson said. “We have plenty of
naturally available tannins available in red grapes grown here. In an industry with tight margins and
dealing with global competition, we are suggesting that the extra expense of adding tannins is simply
Downey observed that “Tannins additives are one of the many tools available to winemakers in
Australia and have been used extensively by some producers without a clear understanding of their
impact. Some winemakers consider their addition essential, while for others it is more of an insurance
policy, but neither approach is based on science. Given that tannin additions are an added cost,

understanding their impact may result in cost-savings for producers. In the current economic climate,
this is of considerable interest.”
Harbertson speculated that tannin additions might control some problems faced by white wine
makers, such as protein haze or Botrytis. “But this idea has not been scientifically tested,” he pointed
Harbertson also mentioned that certain hybrid grape varieties, once grown in Europe for their
resistance to diseases and pests, don’t produce much tannin on their own, so an additive is needed.
However, most hybrids aren’t grown in Europe simply because they produce wine that is too acidic for
most consumers. Several hybrid varieties are still grown on the east coast of the U.S. and in Ontario,
Canada, where they are popular as constituents of the ice wines enjoyed in the region.
“This study shows us what happens when you add tannins at one end of the spectrum. What
we need to do is look at the other end: adding tannins to wines from low-tannin regions or fruit grown
in high volumes in a warm climate. Not all of these conditions are present in Washington or Victoria
(or convenient to our research programs) so it makes sense to work together,” said Downey.
Downey said that his and Harbertson’s research programs “are complementary rather than
competitive. The knowledge earned from scientific research doesn’t give you a competitive
advantage. Rather, it’s how growers and winemakers use that knowledge that gives you the
advantage. Working together actually achieves more for our respective industries. By collaborating
and sharing the load, the Washington industry gets more research outcomes for the same research
dollar invested and so do we.”

Indeed, Harbertson and Downey plan to continue their collaborative research. Among other
things, they will be investigating the effects of aging red wines in oak barrels. Like so much of their
work, both together and individually, the role of oak and oak’s contribution of tannins, in wine quality is
assumed but not well understood. Indeed, this and other questions have led the scientists’ respective
institutions to sign a formal agreement, allowing them to collaborate over the long term in ways that
would not otherwise be possible.

–Brian Clark

The paper discussed in this article, “Impact of exogenous tannin additions on wine chemistry and
wine sensory character,” will be published in the April, 2012 issue of the journal Food Chemistry.


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