Congestive heart failure happens when the heart is unable to pump sufficient oxygen to the body in order to meet its needs (Kulick et al. 2007, Drug Digest 2007). It can be caused by diseases, which weaken or stiffen the heart muscles or increase oxygen demand by any tissue in the body beyond what the heart can deliver. The right and left atria or upper chambers, which pump blood, can be weakened by a systolic dysfunction, such as a heart attack or myocarditis, an infection. The right and left ventricles or lower chambers are involved in relaxing the heart muscles. They can be affected by diastolic dysfunction, such as hemochromatosis, which stiffens the heart muscles. A high demand for oxygen may be due to conditions like hyperthyroidism and result in high-output heart failure (Kulick et al., Drug Digest).
Many disease processes can cause congestive heart failure by decreasing the heart’s pumping efficiency (Kulick et al. 2007, Drug Digest 2007). In the U.S., the most common causes are coronary artery disease, high blood pressure or hypertension, chronic alcohol abuse, and disordered heart valves. Fatigue is an early symptom of congestive heat failure. The ability to exercise may also decrease. This may not be immediately felt because the person may unknowingly reduce his activities to adjust to the sense of limitation. An overload of fluid in the body creates swelling or edema of the ankles and legs or abdomen or in the lungs, which causes shortness of breath. This shortness of breath often occurs during exercise or when lying down flat. This can awaken the person at night and gasp for air and not fall asleep unless sitting up. The overload of fluid can increase urination. Accumulated fluid in the liver and intestines can also cause nausea and abdominal pain and reduce the appetite (Kulick et al., Drug Digest).
Coronary artery disease, valvular heart disease, diabetes and high blood pressure increase the risk of developing the condition (Drug Digest 2007). Other factors are age, gender, family history, cigarette smoking, high blood pressure, diabetes, alcohol abuse, coronary artery disease, chronic kidney disease, atrial fibrillation, high cholesterol, asthma or chronic obstructive pulmonary disease and race. Older people tend to develop the condition more than younger people. Men are likelier to develop coronary disease than women before age 60 or 70. Family history predisposes one to have it. African-Americans have been found to develop heart failure than Caucasian-Americans (Drug Digest).
Treatments
Lifestyle Modifications
Treatment for congestive heart failure consists of lifestyle modifications and medications (Kulick et al. 2007, Drug Digest 2007). Lifestyle modifications include the restriction of salt and fluid intake to offset the tendency of the body to accumulate fluid in the lungs and surrounding tissues. In most cases, intake is limited to 2 grams of sodium a day. Diuretics are prescribed to rid the body of excess fluids, at the same time, limiting the total fluid intake to 2 quarts from all sources. The patient is advised to monitor his or her body weight as an indicator of improvement or worsening of the condition. Aerobic exercise or any regular exercise can maintain overall functional capacity, enhance quality of life and even improve survival. And potentially reversible factors should be specifically addressed. Inadequate blood flow to the heart muscle, for example, can be treated by coronary artery surgery or catheter procedures. Other reversible factors, such as severe valvular disease and uncontrolled high blood pressure due to chronic or long-standing alcoholism, can also be directly resolved to reverse the condition.(Kulick et al., Drug Digest).
Medications
Medications for congestive heart failure include diuretics, beta-blockers, Digitalis or Digoxin, and ACE inhibitors (Kulick et al. 2007, Drug Digest 2007). Diuretics help keep fluid from accumulating in the lungs and other tissues. They promote the flow and elimination of fluid through the kidneys. They relieve symptoms like shortness of breath and leg swelling but have not shown to contribute to long-term survival. Beta-blockers are agents, which have shown to improve heart function and survival in congestive heart failure patients already taking Ace inhibitors, according to recent studies (Drug Digest, Kulick).
Digitalis
Digitalis is used to treat heart conditions. It works directly on the heart muscle by strengthening and regulating the heartbeat (MedicineNet 2007). Its brand name is Crystodigin. It must be taken exactly as prescribed and this is at the same time every day. It may be taken with food or milk in order to prevent or avoid stomach irritation. It should not be stopped suddenly without first consulting the doctor. Suddenly stopping the medication may make some conditions worse. Diarrhea, loss of appetite, drowsiness, headache, muscle weakness and fatigue may be experienced as the body adjusts to it. It should be used with caution if the patient has a history of liver or kidney disease, lung disease, thyroid disorders, or rheumatic fever (MedicineNet).
Fiber-rich foods can reduce the absorption of digoxin, so doctors advise patients to take it a few hours before or after eating such foods (MedicineNet 2007). Difficulty in breathing and swelling in the lower legs and ankles indicate too low a dose. But a doctor should be consulted before changing a dose. Patients who will undergo surgery or dental surgery should inform the surgeon or dentist that they are taking the drug. Pregnant women are prescribed this medication only when needed. Digoxin is excreted in breast milk. Digoxin also interacts with a number of other drugs. Doctors advise that these drugs be taken at least 2 hours after taking digoxin to prevent interactions or interference of their actions. Overdose of digoxin can also occur. Symptoms include visual changes, loss of appetite, nausea, vomiting, diarrhea, dizziness, weakness and irregular heartbeat (MedicineNet).
Digitalis is a steroid, which can have a specific and powerful action on cardiac muscles in animals (May 1996). It has been in use as treatment of heart conditions since it was discovered in 1775 by William Withering, an affluent Scottish doctor. In 1775, he could cure a patient with a very bad heart condition. This patient went instead to see a gypsy who gave him a secret herbal remedy, which improved his condition a lot. Dr. Withering fervently looked for that gypsy. When he finally found her and bargained with her, she presented him with a whole range of concoctions. The main ingredient was purple foxglobe or digitalis purpurea. This extract enjoys vast popularity since the dark ages as a poison for criminal offenders undergoing “trial by ordeal” in the Middle Ages. It was also used to treat wounds the dropsy. Withering synthesized the digitalis plant extracts, got successful results and introduced it officially in 1785. That original purple foxglove or digitalis purpurea is now used as a treatment to control heartbeat. The mechanism intensifies heart muscle contracts but reduces the rate. It works at a low dosage of only 0.3 mg. Digitalis purpurea contains many cardiac glucosides and saponins, which differ from locality to locality and with the season, its potency and quality also differ. Withering recommended that it be diluted and given repeatedly in small doses until the desired outcome occurred. Today, digitalis preparations from digitalis leaves are synthesized with the use of re-crystallization methods. They are then carefully standardized by bio-assay. The dilution or hydrolysis of digitalis creates three major aglycones or genins. All of these contain an alpha, beta-unsaturated lactone ring. The hyrdroxyl group and the unsaturated lactone are important elements to its action as a drug (May).
Withering may not have realized how useful his original digitalis drug has been to stimulate the heart muscle. Today, Digitalis drugs are used to treat congestive heart failure and irregular heartbeat (Flanigan 2001). They make the heart stronger and function more efficiently. As a result, blood circulation improves and swelling of the hands and ankles is relieved. These symptoms are common in those with heart disorders. Digitalis drugs or digitalis glycosides are prescribed medicines under the generic name digitoxin and digoxin. The recommended dosage differs for every patient. Only the exact amount prescribed should be taken. During treatment, the patient’s blood levels are monitored. Then the doctor changes the doses as he sees fit. Patients should, therefore, not change the dose on their own (Flanigan).
Patients taking digitalis drugs should learn to take their own pulse and do so regularly while under treatment (Flanigan 2001). Changes in pulse rate, rhythm or force could indicate side effects. But patients should not discontinue the drug without the permission of their doctors. They should avoid overdose. Taking overdoses is a serious and frequent concern in taking digitalis drugs. Signs of overdose include loss of appetite, nausea, vomiting, pain in the lower stomach, diarrhea, extreme fatigue and weakness, extremely slow or irregular heartbeat, blurring or other changes in vision, drowsiness, confusion or depression, headache, and fainting. Anyone who is taking digitalis drugs should inform health care professional in charge before undergoing any surgical or dental procedures or receiving emergency treatment. Any reactions to the drugs or other allergens should be reported before patients start taking digitalis again. Pregnant or breastfeeding women, older patients and other patients with certain medical problems are advised to first consult their doctors before using the drugs. These medical problems are heart disease, heart rhythm problems, severe lung disease, kidney disease, liver disease, and thyroid disease (Flanigan).
Although side effects of digitalis drugs are rare, patients are urged to consult reactions such as skin rash, hives or other troublesome symptoms (May 2006). Signs of overdose should be observed and also reported promptly. Digitalis drugs may also interact with other medicines and side effects can develop. They may increase the risk of heart rhythm disorders when taken with other heart medicines, amphetamines or diet medicines. Taking calcium channel blockers may increase digitalis level and lead to overdose. Diuretics, which reduce the amount of potassium in the body, may increase the side effects of digitalis medicines. Anti-diarrhea or cholesterol medicines and high-fiber foods can prevent the absorption of digitalis drugs. Digitalis drugs should be taken and high-fiber foods eaten several hours before taking any drugs, which interact with them (May).
Digitalis can also be toxic or poisonous. Reports say that in the U.S., approximately.4% of all hospital admissions, 1.1% of outpatients using digoxin and 10-18% of home patients develop toxicity (Schreiber et al. 2006, Perez 2001). Globally, toxicity has been reported in 2.1% of inpatients on the drug and 0.3% of all hospital admissions. Usual morbidity at 4.6-10% rises to 50% if the digoxin is taken at doses higher than 6 mg/mL. Mortality is variable. Older persons are more affected than younger ones and adults, more than children. Advanced age of 80 or more is a risk factor to both morbidity and mortality. The overall incidence has, however, been lowered on account of certain factors. These include increased awareness of drug reactions by doctors, patients and the general public; reduced use of digoxin in treating heart failure and arrhythmias and the use or radio-immunoassays to monitor drug levels (Perez, Schreiber et al.).
Physicians first recognized and studied digoxin toxicity in 1785 (Schreiber et al. 2006). The effect of digoxin results from the inhibition of the sodium-potassion adenosine triphosphatase pmp. The role of calcium and sodium and the loss of intracellular potassium increases the force of muscular contraction of the heart. This bring about the net positive inotropic effect of digoxin. Digoxin also increases the automaticity of Purkinje fibers but slows down conduction. Dysrhythmias sometimes occur with an increase in automaticity, resulting in a decrease in conduction. Cardiac glycoside toxicity from plants, is rare but quite deadly (Schreiber et al.).
Digitalis toxicity is considered a complication of digitalis therapy or incorrect ingestion of digitalis (Perez 2001). It can result from high levels of the drug in the body or the body’s decreased tolerance to the drug. Toxicity can result from a single exposure or long-standing overmedication. It may also occur even with normal levels of the drug but due to interaction with certain other drugs. Patients with heart failure are prescribed with diuretics along with digitalis to eliminate excess body fluid. But some diuretics can lead to loss of potassium, which increases the risk of digitalis toxicity. Digitalis toxicity may also develop from reduced levels of magnesium in the body. Kidney problems may likewise increase the risk of digitalis toxicity (Perez).
Digitalis toxicity is diagnosed through an ECG, taking of the heart rate, the serum level, and blood chemistry, which reveals the potassium and magnesium levels (Perez 2001). Recent cases of digitalis toxicity are treated with gastric lavage and charcoal intake. Introduction of digoxin-specific antibodies may be resorted to in severe or emergency cases. Hemodialysis reduces digitalis levels in the body. Complications of digitalis toxicity include arrhythmias, lethal arrhythmias, and heart failure. It can be prevented by regular monitoring of digitalis levels through blood chemistries. Doctors prescribe potassium supplements when digitalis and diuretics are simultaneously taken (Perez).
Angiotension-Converting Enzyme or ACE Inhibitors
ACE inhibitors help relax blood vessels by preventing an enzyme from producing angiotensin II (Mayo Clinic Staff 2006). Angiotensin Ii is a substance, which narrows blood vessels. Narrowing can result in high blood pressure and force the heart to work harder. There are many ACE inhibitorsavailable for different conditions. Examples are benazepril, enalapril, and lisinopril. ACE inhibitors prevent, treat or improve the symptoms of high blood pressure, coronary artery disease, heart failure, diabetes, some chronic kidney diseases, heart attacks, scleroderma and migraines. Known side effects of ACE inhibitors are dry cough, increased blood-potassium level, rash, dizziness, lightheadedness, changes in taste and decreased appetite. Pregnant women or those planning to become pregnant have been cautioned about ACE inhibitors. They have been linked to birth defects (Mayo Clinic Staff).
By inhibiting angiotensin, ACE inhibitors widen blood vessels and thus increase the amount of blood pumped and reduce blood pressure (Weiss 2007). They are prescribed not only to regulate high blood pressure but also for heart attack prevention. A national survey reported that 2.7 million childbearing women received prescriptions for an ACE inhibitor. There were 150 million prescriptions in 2005 alone (Weiss).
Studies published in the New England Journal of Medicine found that ACE inhibitors could cause birth defects when taken in the first trimester of pregnancy (Weiss 2007, Hitti 2007). Earlier studies had already established the likelihood of birth defects during the second and third trimesters. The most common observed defects were those in the nervous system and in the heart. Associate professor of pediatrics William O. Cooper at the Vanderbilt University Schools of Medicine said that the action of ACE inhibitors on the angiotensin enzyme can interfere with the proper organ development of the fetus. The study gathered data on 29,507 infants born between 1995 and 2000. Of this number 856 were found to have birth defects with 203 showing more than one defect. Of the 18 exposed to the drug during the first trimester, roughly 7% were born with defects. These were defects in the heart, the muscles, the skeletal, gastrointestinal and central nervous systems (Weiss, Hitti).
The American College of Obstetrician and Gynecologists said that up to 5% of women already have high blood pressure before they become pregnant (Mayo Clinic Staff 2006, Hitti 2007). Diet and exercise are often sufficient to control the condition. In other cases, however, medication is needed and prescribed. They are advised to avoid ACE inhibitors and ARBs. Doctors will prescribe a safer medication with the lowest but effective dose. But these women who are already taking the medication are advised not to discontinue taking it or to adjust it (Mayo Clinic Staff, Hitti).
But on the whole, ACE inhibitors offer greater protection against coronary heart disease than angiotensin receptor blockers or ARBs (Science Daily 2007). This was the conclusion of a new research published in the Journal of Hypertension by the George Institute for International Health. ACE inhibitors and ARBs are among the drugs, which lower blood pressure. The research evaluated the benefits derived from these two drugs. It was found that ACE inhibitors reduced the risk of coronary heart disease 9% better than ARBs. The finding would be a valuable input for half a million people diagnosed with high blood pressure by their doctors each year. The results were obtained from data collected on more than 160,000 patients. These were important additional inputs to data already gathered by the Blood Pressure Lowering Treatment Tialists’ Collaboration. The group is known to have undertaken extensive research on the benefits of blood-pressure lowering drugs. It also found that aggressive treatment, which can bring blood pressure lower than target levels can provide even greater protection against stroke, coronary heart disease and other complications. The George Institute for International Health organized the Collaboration in 1995 to provide clinicians and policymakers with the best available evidence on the effects of various blood pressure drugs and medications (Science Daily).
Meanwhile, a study conducted found that ACE inhibitors do not lower the risk of cardiovascular death, heart attack or the need for bypass surgery or angioplasty (NHLBI 2004). It elaborated that many heart patients presently on modern therapy do not necessarily benefit from ACE inhibitors. This new study was funded by the National Heart, Lung and Blood Institute of the National Institutes of Health. Currently, the American Heart Association recommends the use of ACE inhibitors by all patients who have had a heart attack and coronary and other vascular diseases. Established clinical studies maintained that ACE inhibitors improve survival and reduce the risk of heart attack among those who sustain heart failure. Ace inhibitors have also shown to help prevent heart failure in those with moderate to severe ventricular dysfunction or lower chamber abnormalities. Acting Director Barbara Alving said that this new finding would significantly change clinical care of millions of Americans with heart disease. Heart disease is the single leading cause of death in the U.S., with more than 13 million adults diagnosed with a coronary heart disease. This puts them at risk for heart attack, sudden death, angina, heart failure and stroke (NHLBI).
PEACE was organized to test if ACE inhibitors offer added benefits to heart disease survivors but have coronary heart disease and have relatively good heart function (NHLBI 2004). The trial conducted by PEACE used 8,300 participants with these characteristics. They had normal or near normal left ventricular function with higher than 40% left ventricular ejection fraction. The average age of the participants was 64 and the study was conducted at 180 clinical sites in the U.S., Canada, Puerto Rico and Italy. All of them followed recommended treatments for heart disease. A follow-up after 4.8 years found that 22% of each group had died from cardiovascular disease, had a heart attack of needed revascularization. PEACE concluded from this trial that patients with coronary disease and normal or only slightly reduced heart function did not or do not benefit from ACE inhibitors. The data gathered can be used to assist physician in evaluating patients’ need for ACE inhibitors. PEACE was the last of three large clinical trials conducted worldwide (NHLBI).
Despite the findings, ACE inhibitors continue to be recommended by doctors to patients who have heart failure or ventricular dysfunction, according to PEACE project officer Yves Rosenberg (NHLBI 2004). NHLBI’s Framingham Heart Study said that roughly 22% of men and 46% of women who survive a heart attack would be disabled by heart failure within 6 years (NHLBI).
ACE inhibitors have been used for treating hypertension and congestive heart failure for more than two decades (Science Daily 2007). Multiple studies on thousands of patients have convincingly shown a significant improvement of symptoms, reduced or prevention of clinical deterioration and longer survival. They have also demonstrated efficacy in preventing the development of heart failure and heart attacks. Volumes of evidence are so strong in favor of ACE inhibitors as to be considered the standard treatment of heart failure. This is specifically for cases of weakness of heart muscles. Possible side effects include persistent and dry cough; low blood pressure; increased kidney dysfunction; and electrolyte imbalances. With proper monitoring, most of the patients put on this medication have been able to tolerate them without significant consequences. However, those who are unable to tolerate may resort to ARBS. ARBS act on the same hormonal pathway as do ACE inhibitors. ARBs instead inhibit the action of angiotensin II directly at the receptor site (Science Daily).
A study of one of the ARBs suggested a greater survival benefit among elderly patients suffering from congestive heart failure (Science Daily 2007). Another and bigger follow-up study, however, failed to prove the superiority of ARBs to ACE inhibitors. More studies are being undertaken on the use of these medications on congestive heart failure alone or in combination. Possible side effects of ARBS are similar to those of ACE inhibitors (Science Daily).
Still another study found that ARBs work better than ACE inhibitors for women suffering from heart failure (Law 2007). Men are likelier to die from heart failure than women. A review of the data presented during the 11th Annual Scientific Meeting of the Heart Failure Society of America, women with heart failure seen to fare better with ARBs than on ACE inhibitors. Data gathered from almost 20,000 men and women said that women had significantly lower mortality rates than women on ACE inhibitors. The reason was unclear. Both ARBs and ACE inhibitors are prescribed to control blood pressure. They both counteract the increased activity of the neuro-hormonal system in heart failure. And they both inhibit the enzyme angiotensin although through different mechanisms. The ARB mechanism appears to help women more, while the ACE inhibitor mechanism seems to favor non-hypertensive men more (Law).
The findings confirmed with those of previous studies (Law 2007). However, ACE inhibitors have remained the recommended and standard therapy for both men and women. Thus, the sponsor of the study recommended the use of ARBs in treating women with heart failure (Law).
Combining digitalis with ACE inhibitors and diuretics has shown to produce the best effects (Cayley et al. 2004). The combination will reduce hospitalization rates and improve clinical status in patients in normal sinus rhythm with left ventricular systolic dysfunction and symptoms of congestive heart failure with moderate or mild activity. The addition of digitalis to the therapies will, however, not decrease the risk of death. The benefit that can be derived from adding digitalis to therapies, which include ACE inhibitors, beta blockers and spironolactone, was unclear (Cayley et al.).
This was the conclusion of a review of a clinical scenario, involving a 63-year-old man with a history of congestive heart failure (Cayley et al. 2004). He also exhibited dyspnea with moderate exertion. His heartbeats were regular and he had edema in the legs (Cayley et al.).
Other experts also suggested a combination of ACE inhibitors and ARBs although it has not been well-defined and has remained controversial (Drug Digest 2007). Nonetheless, they recommended the use of other “vasodilators,” such as hydralazine and nitrate therapy for patients who cannot tolerate Ace inhibitors alone or ARBs alone. The hydralazine and nitrate combination has been considered a second-line therapy option. But it should not be used on patients who have not been treated previously with an ACE inhibitor. According to tests, a new drug called BiDil has improved survival among African-American patients with heart failure. BiDil combines hydralazine and isosorbide dinitrate in a single tablet (Drug Digest).
Some doctors recommended that digitalis be used only on patients who still have symptoms of heart failure after receiving treatment with an ACE inhibitor, diuretic and a beta blocker (Drug Digest 2007). Although digoxin has not convincingly shown to reduce death, it has demonstrated its worth in improving heart failure symptoms and patients’ quality of life. It was further suggested that patients on both diuretic and digitalis to supplement their potassium levels. Those experiencing severe heart failure may add another type of diuretic to their regimen. That regimen should consist of an ACE inhibitor, diuretic, beta-blockr and digoxin. Spironolactore is a potassium-sparing diuretic. It has demonstrated efficacy in reducing mortality in such patients. Spironolactone stops the action of aldosterone. Aldosterone is a hormone capable of exerting harmful effects on the heart muscle and peripheral blood vessels. It may improve fluid balance and also decrease the risk of heart failure progression. The use of spironolactone of patients with more severe forms of heart failure has shown to reduce hospitalization and death from heart failure. The safety and efficacy of spironolactone on patients with mild to moderate heart failure have remained unknown (Drug Digest).
The Food and Drug Administration recently approved the use of eplerenone as treatment for heart failure following a heart attack (Drug Digest 2007). Eplerenone is a selective aldosterone receptor blocker. Patients with documented heart failure preceding a heart attack may ask about eplerenone therapy. In other cases, surgery may be the better or best option. When the heart failure is due to diseased heart valves, for example, surgery alone can repair them. Otherwise, implanting an artificial heart valve may be helpful or necessary. Surgery also corrects congenital heart defects, which can in turn lead to heart failure. When a partial or complete blockage of the coronary arteries is the cause of heart failure a coronary bypass surgery or angioplasty must be performed. Heart transplants are also a last resort for severe heart failure on account of diseased heart muscle. The success rate of heart transplants has well improved, but the cost of the surgery and the shortage of appropriate donor organs make it a less practical option except as a very last resort (Drug Digest).
Bibliography
Cayley, William E., Jr. “Digitalis for Treatment of Congestive Heart Failure in Patients in Sinus Rhythm.” Cochrane for Clinicians. American Academy of Family Physicians, 2004
Drug Digest Team. “Heart Failure.” Drug Digest. DrugDigest.com: Express Scripts,
Inc., 2007
Flanigan, Nancy Ross-. Digitalis Drugs. Encyclopedia of Medicine: Encyclopedia of Medicine: Gale Encyclopedia of Medicine, 2001
Hitti, Miranda. ACE Inhibitors May Boost Birth Defects. WebMD Medical News:
WebMD, 2007. Retrieved on December 12, 2007 at http://women.webmd.com/news/20060607/ace-inhibitors-may-boost-birth-defects
Kulick, Daniel. Congestive Heart Failure. MedicineNet: MedicineNet, Inc., 2007.
Retrieved on December 12, 2007 at http://www.medicinenet.com/script/main/art.asp?articlekey-1930&pf=3&[age=1
Law, Bridget Murray. ARBs Outperform ACE Inhibitors in Women with Heart
Failure. Vol 4 #11-page 10. DOC News: American Diabetes Association, 2007
Mayo Clinic Staff. Angiotensin-Converting Enzymes (ACE) Inhibitors. Mayo Clinic:
Mayo Foundation for Medical Education and Research, 2006. Retrieved on December 12, 2007 at http://www.mayoclinic.com/health/ace-inhibitors/H100060
ACE Inhibitors: New Warning for Pregnant Women, June 9, 2006.
Retrieved on December 12, 2007 at http://www.cnn.com/HEALTH/library/DI/00068.html
May, Paul. Digitalis. Local Heroes: Cambridge Crystallographic Database, May
1996. Retrieved on December 12, 2007 at http://www.bris.ac.uk/Depts/Chemstry/MOTM/digitalis/digtalis.htm
MedicineNet. Generic Name: Digitalis Medicine – Oral. MedicineNet, Inc., 2007.
Retrieved on December 12, 2007 at http://www.medicinenet.com/digitalis_medicine-oral/article.html
NHLBI. ACE Inhibitors Not Needed for Many Heart Disease Patients, According to Study. NHI News: National Heart, Lung and Blood Institute, 2004. Retrieved on December 12, 2007 at http://www.nhlbi.nih.gov/new/press/04-11-08a.htm
Perez, Eric. Digitalis Toxicity. Medical Encyclopedia: National Institute for Health.
Retrieved on December 12, 2007 at http://www.nlm.nih.gov/medlineplus/ency/article/000165.htm
Schneiber, Donald, et al. Toxicity, Digitalis. Emergency Medicine: emedicine. 2006.
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News: Science Daily LLC. 2007
Weiss. Seeger. ACE Inhibitors. Lawyerseek: Seiger Weiss LLP, 2007. Retrieved on December 12, 2007 at http://www.lawyerseek.com/Practice/Pharmaceutical-Inquiry-C1ACE-Inhibitors-P136
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