ACE Inhibitors in Congestive Cardiac Failure - Essay Example

The utilization of ACE inhibitors in Congestive Cardiac Failure Renin -angiotensin - aldosterone system This is an endocrine system to regulate the osmolarity in the body. Renin is synthesized and secreted in the arteriolar component of, juxtaglomerular apparatus (JG Apparatus), formed by the anatomical and physiological association of cells in the walls of afferent renal arteriole and distal convoluted tubules. This system controls the release of aldosterone through a negative feedback loop (ACE Inhibitors 2006). Whenever there is disturbance in the perfusion pressure in downward direction (hemorrhage, hypotension and reduction in extracellular volume due to sodium deletion), rennin is released to respond to this situation. Renin release is followed by conversion of hepatic angiotensinogen to angiotensin I which is subsequently converted to angiotensinogen II by the enzyme angiotensin converting enzyme (ACE). ACE is found in high concentrations in the pulmonary circulation, systemic vasculature and kidney. Angiotensinogen in turn carries out two important independent actions to bring the hemostasis back to normal: the direct vasoconstrictve effect to improve the blood pressure and stimulation of adrenal cortex to secrete aldosterone which results in sodium retention and potassium excretion. Aldosterone also responds to adrenocorticotrpic hormone (ACTH) and potassium excess for its release. The aldosterone action for sodium resorption by the distal convoluted involves the mineralocorticoid receptor (MR); the induction of the basolateral sodium-potassium ATPase pump and the apical sodium channel (Stewart pp1-10) (Weber 2001). Figure 1: Renin-angiotensin-aldosterone system Source: (Whitehead 1999) Congestive cardiac failure is the condition when heart is unable to carry out its normal function of pumping blood to supply oxygen and nutrients to different parts of the body including vital organs, in other words there is an insufficient cardiac out to meet the demand of the body. Human body, initially, responses to this pathology by the expansion of the intravascular volume. The renin-angiotensin-aldosterone system comes into action to bring back the perfusion pressure and then maintain it. Renin stimulation increases the level of angiotensinogen II in the blood, which in turn increases the peripheral resistance to improve blood pressure and thus perfusion of the tissue. Secondly, it also stimulates the adrenal cortex to secrete aldosterone. Some other major stimuli, like angiotensinogen act to increase the secretion of aldosterone, which include: elevated potassium levels in exchange for sodium excretion and plasma corticotrophin level which increases in the congestive cardiac failure on long term basis. These two stimuli are very strong and eventually result in high levels of aldosterone in the circulation (Weber 2001) (Peterson 2002). Another factor which keeps aldosterone in very high concentration in the circulation is its decreased degradation in the liver because of reduced perfusion of liver in congestive cardiac failure. This reduction causes many fold increase in aldosterone level. So increase in angiotensinogen II due to overactivity of the renin-angiotensin-aldosterone system results in the resorption of sodium from the proximal nephron and aldosterone release increases the resorption from the distal nephron. This also results in decreased serum level of potassium and magnesium. As body respond to the congestive cardiac failure on long-term basis so these changes in the renin-angiotensin-aldosterone system may result in remodeling of various tissues in the body (Weber 2001). There are some morphological changes which occur as a result of the remodeling of various tissues. In response to increased aldosterone secretions, Na+ /K+-ATPase activity increases to maintain the osmolarity between extracellular and intracellular compartments. Some morphologic changes also occur resulting in perivascular, atrial and ventricular fibrosis. Thus may be due to increase in aldosterone for a longer duration (Weber 2001). Angiotensin Converting Enzyme Inhibitors (ACEI) These are the group of pharmaceuticals used as agent of choice for management of heart failure (Howland 2006) (Andreoli pp.66-67). They have been classified based on the side group attached to the main molecule, as (ACE Inhibitors 2006): 1. Sulhydryl-containg ACEI Captopril 2. Dicarboxylate-containing ACEI Enalapril Ramipril Quinapril Perindopril Lisinopril 3. Phosphonate-containnig ACEI Fosinopril Level of drug action ACEI through, inhibition of angiotensin converting enzyme, decrease the level of angiotensinogen II in the circulation and in turn reduce the circulating levels of aldosterone. These two inhibitory effects that results low level of angiotensinogen and aldosterone, eventually lead to (Howland 2006)(ACE Inhibitors 2006): reduction in the vascular resistance reduction in venous tone reduction in blood pressure increase in cardiac output Apart from these effects, ACEI also reduces the increased levels of epinephrine secreted due to angiotensin II stimulation. On other hand, increased levels of bradykinin appears in the circulation mediated by this pathway, which also helps reducing peripheral resistance by vasodilatation. There is increasing evidence that ACEI are used rarely when indicated and they are used in low doses. There is a need to increase the frequency of prescribing ACEI where it is indicated and also to increase the dose to get its desirable results (Rocca 1999) (Campbell 2000). Pharmacokinetics It has been observed that all ACEI are absorbed incompletely after taking the medicines orally; although, the absorption is adequate. As food interferes with the absorption of the drug therefore, it is recommended that this drug should be taken empty stomach. Most of the ACEI are prodrug, captopril being an exception, and for their activation they are required to be acted upon by the liver enzymes through hydrolysis. Plasma half-life of active compounds vary ranging from 2-12 hours but the duration of their effect of inhibition is longer (Howland 2006). Ramipril Ramipril is an ACEI belongs to the second group of ACEI, with Dicarboxylate side chain. This is the drug, which is newer in its approval from the FDA. Administration The drug shows variation in different individuals when taken as IV and oral ramipril or IV ramiprilat. Generally, around 35% of the oral dose is absorbed; out of absorbed quantity, 75% of the ramipril is metabolized in the liver. Through liver metabolism 25% is then converted to systemic ramiprilat on the other hand 100% is converted to systemic ramiprilat when is it metabolized in the kidney. Irrespective of the organ for metabolism, the prime action of inhibition continued for 24 hours following 2.5 mg oral dose (Shoemaker 2006). Mechanism of action Like other ACEI, ramipril interferes with the conversion of angiotensinogen I to angiotensinogen II through the inhibition of the conversion enzyme. This way the drug reduces the increase in blood pressure and improves perfusion pressure (Ramipril 2005). Site of action Through its major action of inhibition ramipril improves the morbidity status of a broad range of high-risk patients who are unaware of having low ejection fraction. These improvements are: reduction in the death rate, reduction in myocardial infarction and reduction in the stroke (HOPE 2000) (Ramipril 2005). Ramipril have been observed to improve the health of postmenopausal women who are at high risk of cardiovascular events, like: established coronary, cerebrovascular and peripheral arterial diseases, those with diabetes and additional risk factors. The drug could reduce the risk of major vascular events, CV deaths, stroke and the worsening angina. At the same time it has been shown in a study that ACEI was better than other drugs -blockers or antiplatelet drugs (Lonna 2002). Clinical effects Table showing the various effects of ACEI on different parts of the body(ACE Inhibitors 2006)(Ramipril 2005)(Side effects 2004) Systems Good effects Bad effects (drugs.com) Immunological response Allergic reactions CNS Reduction in stroke Mild dizziness, light headed ness Psychiatric problems Mood elevation Anxiety, depression CVS Reduces the blood pressure and improves tissue perfusion Irregular heartbeat Lungs Difficulty breathing Endocrinology Reduces the progress of diabetic nephropathy General Dry, persistent, tickling cough GIT Nausea, vomiting and diarrhea Musculoskeletal system Unusual fatigue, weakness Pharmacogenetics Use in other physiological/medical problems (Drug information 2005) (Vasodilators) a) Pregnancy: ACEI use especially, during 2nd and 3rd trimester may result in low blood pressure, which may lead to severe renal failure, very high potassium and eventually death of the fetus. b) Lactation: some of the ACEI, benazepril, captpril, enalapril, and fosinopril, pass into breast milk while others do not. It is better to avoid drug in the lactational period, as no evidence is available that it does not cause any harm. c) Diabetes mellitus: the levels of potassium may increase and insulin effect may increase in controlling the disease d) Heart or blood vessels problems or low sodium diet: in these conditions further lowering blood pressure by ACEI may worsen the situation e) Kidney/liver diseases: inhibitory effect of the ACEI may prolong because of slow elimination of the drug by these diseased organs. f) Kidney transplant: increased risk of kidney disease caused by ACEI. g) Systemic Lupus Erythematosus (SLE): increased risk of blood problems caused by ACEI Interactions (Side effects 2004)(Vasodilators)(Drug information 2005) a) Alcohol/diuretics/-1blocker: some diuretics synergise the hyperkalemic effect of ACEI, while effect on blood pressure may also increase in the above conditions leading to hypotension. b) NSAIDs/estrogens/sympathomimetics: the blood pressure lowering effect of ACEI is reduced c) Potassium containing medicines/supplements: potassium imbalance d) Salt substitutes/low-salt milk: concomitant use of these compounds wit ACEI may result in very high serum potassium level to interfere with the normal rhythm of heart. 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