Pharmacological Management of Congestive Heart Failure - Research Paper Example

?Pharmacological Management of Congestive Heart Failure Using Captopril and Its Therapeutic Implications This paper ventured to describe andcritically examine the pharmacological management of congestive heart failure (CHF) using Captropril an angiotensin-converting enzyme (ACE) inhibitor class of anti-hypertensive drugs. The discussion proper is divided in three sub-sections which focus on: congestive heart failure; pharmacological management of CHF; and Captropil and its pharmacological properties, adverse reactions and some statistics. The literature revealed that CHF results from changes in the structure and function of the heart. The readings also showed that the pharmacological management of CHF may be typified into first line and second line agents. The first line agents consist mainly of ACE-I, diuretics and beta blockers, while the second line agents consists of digoxin and hydralazine-isosorbide dinitrate. Captropil belongs to the second line of pharmacological agents. Use of Captropil had been found to enhance cardiac performance, among others. However, ACE inhibitors like Captropil sometimes causes in amigo-edema, painful tongue ulcers, and alveoli is to name a few. The implications of these and the rest of the findings are discussed in the conclusion. Discussion Congestive heart failure Congestive heart failure (CHF) is defined as an inability of the heart in supplying normal oxygen and nutrient demands to the body. CHF can be caused by a number of diseases which: (1) weaken the cardiac muscle; (2) harden the cardiac muscle; and (3) increase tissue oxygen demand beyond the capacity of the heart. This condition occurs primarily on elderly patients (Kaufman et al., 2008). Congestive heart failure commonly results from a dysfunctional heart muscle or myocardial dysfunction. CHF may also result from changes in the structure and function of the heart medically termed as progressive cardiac remodeling (Medifocus, 2011). The heart muscle enables it to pump blood to facilitate metabolism for the various tissues of the body. When the heart muscles do not function normally, blood flow through the heart and the entire body proceeds slower than normal. This causes increased pressure in the heart. The body responds to the decrease in the heart’s pumping capacity by the so-called compensatory mechanisms so that cardiac function can be maintained, such as the renin-angiotensin-aldosterone system and the sympathetic nervous system (Medifocus, 2011).         The compensatory mechanisms can be activated for a period of months or years. During the time that these compensatory systems are functioning, no evident symptoms of heart failure are presented and the patient is regarded as asymptomatic (Medifocus, 2011). Heart disease classified as asymptomatic is one in which the patient does not experience undue fatigue, dyspnea, palpitations and chest pain during ordinary activities (Capezuti, Siegler, & Mezey, 2008).         It should, however, be made very clear at this point that the functioning of the aforementioned compensatory systems will cause further damage to the heart in the long run, and consequently affect the circulation of the blood in the body. Such damage is caused by the changes brought about by process of structural remodeling where the heart may enlarge, the cardiac walls may thicken or become thinner and further decrease in the pumping capacity of the heart. One or a combination of these changes further weakens the heart and causes the pumping to be less effective until the patient eventually develops symptomatic heart failure (Medifocus, 2011). How CHF manifests itself depends on the type of stress the heart is being subjected to, in addition to which ventricle is affected. For example, disease affecting the left ventricle causes pulmonary edema. Meanwhile, disease affecting the right ventricle is more likely to cause edema to the lower limbs and other parts of the body. Moreover, CHF can affect the flow of blood to other organs. For example, inadequate blood flow to the kidneys could result to sodium loss and water secretion leading to edema. Left untreated, CHF could affect every organ in the body (Kaufman et al., 2008). Pharmacological management of CHF Traditional treatment of chronic heart failure included the use of digoxin and diuretics. In the 1980s the concept of pre-load and after-load gave rise to the use of vasodilators which help reduce mortality rates. The use of angiotensin-converting enzyme inhibitors further reduced mortality rates among CHF patients. Combined with beta-blockers and diuretics, ACE-I drugs have become the backbone of CHF treatments. Though new drugs are being introduced, none have shown long-term beneficial effects which are currently being offered by ACE-I (Van Veldhuisen & Van Gilst, 2003). Pharmacological management of CHF covers first and second-line agents. For first-line treatment: (1) ACE-I is recommended for all patients with systolic heart failure unless contraindicated or not tolerated (2) ACE-I dosage should be increased based on levels considered beneficial on major trials; (3) diuretics should be utilized in fluid-overloaded patients; (4) beta-blockers are recommended to patients with systolic heart failure who remain mildly to moderately symptomatic, unless contraindicated or not tolerated; (5) beta-blockers are also recommended for patients with advanced CHF; (6) aldosterone receptor blockers with spironolactone is recommended in cases where ACE-I and diuretics fail to alleviate symptoms; and (7) angiotensin II receptor antagonists may be utilized as an alternative for patients who do not tolerate ACE-I treatments (Krum, Jelinek, Stewart, Sindone, Atherton & Hawkes, 2006). Guidelines for second-line treatments include: (1) digoxin may be utilized for the relief of symptoms for patients with advanced CHF; and (2) hydralazine-isosorbide dinitrate should only be used as a last resort for patients who do not tolerate ACE-I and angiotensin receptor antagonists or when the used of such drugs is contraindicated (Krum, Jelinek, Stewart, Sindone, Atherton & Hawkes, 2006). Captopril Captopril belongs to the angiotensin-converting enzyme (ACE) inhibitor class of anti-hypertensive drugs. It is the first ACE inhibitor developed for oral administration. The drug regulates hypertension by facilitating the relaxation of blood vessels (Hochadel, 2006). As a vasodilator, the administration of Captopril helps improve cardiac performance by reducing systemic vascular resistance and left ventricular filling pressure. The improvements on preload and afterload are made possible by the inhibition of the angiotensin-converting enzyme or ACE. ACE is a vasoconstrictor and stimulant of aldosterone production and release. Captopril inhibits the conversion angiotensin I into angiotensin II, reduces urinary aldosterone concentrations, and increases plasma renin activity (Romankiewicz, Brogden, Heel, Speight & Avery, 1983). Adverse reactions. Sabroe and Black (1997) observed the effects of ACE-I on patients being treated for hypertension and chronic heart failure and determined the following: (1) angio-edema occurs in 0.1% to 0.7% of patients; (2) 60% of angio-edema occurrences manifested on the first week of treatment; (3) effects vary from mild to fatal. The authors recommended discontinuing ACE-I treatments when symptoms appear and consider the use of drugs from a different class. In addition, ACE-I should be avoided by patients with hereditary or acquired CI esterase inhibitor deficiency. Izraili and Hall’s (1992) review on the link between angio-edema and ACE-I therapy show that angio-edema occurred to 0.1% to 0.2% of patients, mostly manifesting within hours up to 1 week after start of therapy. Patients experiencing angio-edema upon receiving ACE-I therapy are treated for symptoms and shifted to an alternate anti-hypertensive drug. Mahmood, Zaka, Sander and Khan (2011) conducted a retrospective study on patients suffering from congestive heart failure to examine the effects of ACE-I treatments. Captopril was used to treat 32.5% of the patients. Analysis of history, clinical examination, and laboratory results show that 90% of patients did not experience any side effects from taking ACE-I. The remaining patients experienced mild hypotension which was effectively addressed through dose adjustment. The authors concluded that the use of ACE-I drugs such as captopril should be reinforced with dose management and therapeutic drug monitoring to address any side effects. However, the authors also expressed their concern regarding outpatient compliance since reduced compliance by the patient will more likely increase mortality rates. Another side effect of captopril therapy is the development of painful tongue ulcers. A case study performed by Nichols, Maslowski, Ikram and Espiner (1981) on a 75-year old patient with congestive heart failure developed ulcers in the lateral margins of the tongue on the third month of treatment. Prior to the ulcers appearing, the patient also experienced a significant loss of taste at the third week of treatment. The patient was re-admitted to the hospital and the captopril treatment was stopped. The ulcers healed after 2 weeks. Due to the deterioration of the patient’s cardiac status captopril treatment was resumed. However, the ulcers reappeared after 2 to 3 weeks, first on the tongue, then on the glans penis. The ulcers promptly disappeared after 2 weeks of stopping the captopril treatment. Side effects. Respiratory side effects of captopril use include alveolitis associated with eosinophilia and lymphocytic pulmonary infiltrate. Side effects on sensory systems include dysgeusia. Meanwhile, hematologic effects include bone marrow suppression, neutropenia, agranulocytosis, toxic epidermal necrolysis, fever, malaise, rash, orthostatic hypotension, diffuse erythroderma, autoimmune thrombocytopenia, pancytopenia. Additional side effects include sialadenitis, pancreatitis, acute renal insufficiency, tubular necrosis, and lupus-like syndrome. (Aronson, 2009). Captopril and renal function. Berger et al. (2006) conducted a retrospective analysis of the Minnesota Heart Survey to determine the link between the use of ACE-I and ARB on 30-day and 1-year mortality rates. Results were further classified in accordance to glomerular filtration rate or GFR. Analysis of the survey results revealed that patients with coexistent heart failure and severely impaired renal failure are less likely to receive ACE-I or ARB while hospitalized, compared to patients with congestive heart failure (CHF) and normal renal function. Moreover, impaired renal function has been associated with increased mortality rates. Furthermore, results have shown that the use of ACE-I or ARB lowered mortality rates for both 30-day and 1-year periods. The authors suggested the used of ACE-I and ARB on patients with CHF, regardless of current renal function to help reduce mortality rates. However, further research should be conducted for CHF patients undergoing hemodialysis treatments.         Packer, Lee, Medina and Yushak (1986) evaluated the effects of renal function in the effectiveness of ACE inhibitors in patients with severe chronic heart failure by measuring hemodynamic and clinical responses to captopril. Subjects were grouped according to renal function: (1) normal; (2) mild to moderate renal impairment; and (3) severe renal impairment. Results of the study show improvement in cardiac index and stroke volume index, as well as reduced left ventricular filling pressure, mean arterial pressure, and systemic vascular resistance. Moreover, patients with normal renal function benefited more from the captopril treatment compared to patients with renal impairment. Also, adverse reactions were more evident on patients with impaired renal function in comparison to patients with normal renal function. The authors concluded that renal function before treatment has a significant role in determining the efficacy and safety of captopril treatments in patients with severe chronic heart failure. Use with other drugs. Dickstein and Kjekshus (2002) conducted a double-blinded randomized controlled trial on 5,477 patients with myocardial infarction to evaluate the effectiveness of treatments using losartan, captopril, and combination of both. Results of the study showed a non-significant difference in mortality rates on the losartan group at 18%, compared to the captopril group at 16%. However, losartan was found to be more tolerated by patients. The authors suggested that ACE inhibitors should remain as an option for first-line treatments. Meanwhile the use of losartan for cases where patients are ACE inhibitor-tolerant should also be explored. These findings confirm the findings of an earlier study by Pitt et al. (1997) on a comparative study on the use of angiotestin II receptor blockade drugs (losartan) and angiotestin-converting-enzyme inhibitors (captopril). Results indicate lower mortality rates for patients under ARB therapy compared to patients using ACE-I. In addition, losartan was better tolerated by patients in comparison to captopril. Additional confirmatory studies by Pitt et al. (2000) have yielded the same results. However, mortality rates between treatment groups did not reveal any significant difference. Pfeffer et al. (2003) evaluated the effectiveness of captopril, valsartan, and combination treatments in patients with myocardial infarction through a double-bind trial. Results of the study show that valsartan is as effective as captopril. In addition, captopril is less expensive and causes lesser hypotension and renal problems. It was also noted that the combination treatment of valsartan and captopril caused the most adverse reactions and did not show any indication of improved effectiveness. Krymyly et al. (2000) evaluated the effects of captopril on serum digoxin levels in patients with congestive heart failure undergoing digoxin therapy through measurement of serum digoxin levels before and after administration of captopril. Pre and post administration measurements show that captopril caused a significant increase in serum digoxin concentration. In addition, none of the patients show evidence of digoxin toxicity. The authors suggested that captopril help increase serum digoxin concentrations in patients with congestive heart failure. Some statistics. Pilote, Abrahamowicz, Eisenberg, Humphries, Behlouli, and Tu (2008) evaluated several ACE inhibitors to assess benefits in survival and readmission rates of patients with congestive heart failure. A total of eight ACE-I drugs were evaluated: (1) ramipril; (2) lisinopril; (3) fosinopril; (4) quinapril; (5) enelapril; (6) captopril; (7) perindopril; and (8) cilizapril. Each drug was analyzed based on mortality rate using a time-dependent model. Results of the analysis show highest mortality rates for captopril compared to other ACE inhibitors used in the study. It was suggested that physicians take into consideration of a 10 to 15% increase in mortality if captopril is to be utilized for treatment.            Brooksby, Robinson, Segal, Klinger, Pitt and Cowley (1999) performed an ELITE substudy to evaluate the effects of captopril and losartan in QT dispersion. QT dispersion is identified as a predictor of sudden death in elderly patients with heart failure. Analysis of the data collected from the ELITE study show an increase in QT dispersion among patients taking captopril. In contrast, patients taking losartan did not exhibit any increase in QT dispersion. Mougenot, Bos, Mediani, and Lechat (2005) investigated the cardiovascular and renal impact of the addition of diuretics (furosemide) in captopril treatments in terms of survival rate. Experiments on rats indicate an improvement on diuresis, natriuresis, and left ventricular fractional shortening for the captopril+furosemide treatment group. In addition, rats in the captopril+furosemide group had higher heart rates, lower systolic and diastolic blood pressure, reduced body and heart rate, and increased plasma rennin activity and angiotensin-I levels. These effects contributed to an increased survival rate in treated rats. These observations were also evident on human subjects as revealed in an earlier study by Dzau and Hollenberg (1984) on the effects of captopril and furosemide treatments on patients with severe heart failure. The combination of captopril and furosemide resulted to improved natriuresis, weight loss, and correction of hyponatremia. Conclusion Evidence was found as to the efficacy of the use of ACE inhibitors in the reduction of mortality rate among CHF patients, especially when used in combination with beta-blockers and diuretics. Hence, the so called ACE-I drugs of which Captropil is one, have become the backbone of CHF treatments. Van Veldhuisen and Van Gilst (2003), among others have attested to the long-term beneficial effects which are currently being offered by ACE-I. In general, Captropil improves cardiac performance, reduces vascular resistance and left ventricle filling pressure, reduces urinary aldosterone concentrations and increases the activity of plasma renin. There is, however, a long list of disadvantages of the use of ACE-I like Captropil. This includes angio-edema, mild hypotension, painful tongue ulcers, loss of taste, alveolitis, dysgeusia, bone marrow suppression, and neutropenia, agranulocytosis, toxic epidermal necrolysis, fever, malaise, rash, orthostatic hypotension, diffuse erythroderma, autoimmune thrombocytopenia, pancytopenia, sialadenitis, pancreatitis, acute renal insufficiency, tubular necrosis, and lupus-like syndrome. Comparative studies of the efficacy of Captropil versus other drugs revealed no significant differences in the mortality rate of patients being treated with Captropil and Losartan, although patients were more tolerant with Losartan (Dickstein & Kjekshus, 2002; Pitt et al., 1997). Pfeffer et al. (2003) found that Captropil and Valsartan are just about as effective, but that patients can economize with Captropil. Moreover, Captropil was found to cause less hypotension and renal problems. Most importantly, combined treatment with Captropil and Valsartan should not be administered to patients in consideration of adverse reactions and absence of effectiveness compared to use of one or the other. Extreme care should be taken in prescribing Captropil, a rather old drug because among the other ACE-I drugs, the highest mortality rate was registered among patients with Captropil. Captropil was also found to cause a higher QT dispersion, which causes sudden death among patients with CHF, than Losartan. In view of the findings of the paper, it may be concluded that Captropil is still effective in the pharmacological management of congestive heart failure. However, in recognition of its adverse effects including higher mortality and increased risk of sudden death from CHF, it is being recommended that: (1) if Captropil is to be used in the management of CHF, combine treatment with furosemide, a diuretic; (2) switch to angiotensin receptor blockers (ARBs) or the sartans; or (3) aim for the newer second line drugs. References Aronson, J. K. (2009). Meyler’s side effects of cardiovascular drugs. San Diego, CA: Elsevier. Berger, A. K., Duval, S., Manske, C., Vazquez, G., Barber, C., Miller, L. & Luepker, R. V. (2006). Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in patients with congestive heart failure and chronic kidney disease. 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The pharmacological management of heart failure: Too many treatments? European Journal of Heart Failure, 5(1), 5-8. Read More