Modern Concept of Mechanism of Pharma Dynamic Action ACE Inhibitor - Essay Example

Modern Concept of Mechanism of Pharma Dynamic Action ACE Inhibitor This paper analyses the Pharma dynamic action of the ACE inhibitor drugs. The paper specifically focuses on the history and discoveries, the mechanisms through which they work their beneficial and side effects relating to patients who receive the drug’s prescriptions. Introduction These ACE inhibitor drugs also known as angiotensin-converting enzyme inhibitors are pharmaceutical drugs often used to treat congestive heart failure and hypertension. Currently, there exist 11 approved ACE inhibitors for therapeutic use in the US and across the world. These groups of drugs have been widely subclassified into three groups, and this is dependent on their chemical compositions: i) Sulfhydryl-containing inhibitors; in the inhibitors under this category include the captopril and zofenopril. ii) Dicarboxylate-containing inhibitors; these have the largest number of inhibitors which include enalapril, ramipril, quinapril, Perindopril, lisinopril, benazepril, imidapril, trandolapril and cilazapril. iii) Phosphinate-containing inhibitors; this group contains Fosinopril as its only member Apart from the three sub-classifications above, there exists also naturally occurring ACE inhibitors which include: a) Casokinins and lactokinins; these refers to breakdowns products of casein and whey which occur naturally after the ingestion of milk products, particularly cultured milk. b) The lactotripeptides Val-pro-pro and Ile-pro-pro often produced by the probiotic Lactobacillus helveticus and/or derived from casein. The enzyme in question is a zinc-containing enzyme which substitutes dipeptide units from peptide substrate and is usually the one responsible for converting the decapeptide prohormone angiotensin I to angiotensin II. This enzyme belongs to the class of zinc proteases which require zinc and chloride to be activated and results to an increase in blood pressure through this conversion and by degrading bradykinin (Thomson 24). These drugs have been discovered to cause a relaxation in blood vessels and a reduction in blood volume which normally leads to lower blood pressure and a decrease in oxygen demand by the heart. They often react to inhibit angiotensin-converting enzyme. Angiotensin is an important component of the rennin-angiotensin aldosterone system. History and discovery of the drugs The initial stage of the development of these drugs was the discovery of angiotensin-converting enzyme in plasma by a scientist Leornard T. Skeggs in 1956. Then in 1965, a scientist by the name, Sergio Henrique Ferreira discovered a bradykinin-potentiating factor (BPF) existing in the venom of bothrops jararaca, a pit viper in South America. He reported that the viper’s venom had in it factors that potentiated the activity of bradykinin. With the isolated BPF, he then went to JohnVane’s laboratory to conduct further researches. During this period, there was a general belief that the conversion of the inactive angiotensin I in the human system to the active angiotensin II took place in the plasma. However, it was later shown by Kevin K. F. and John R. Vane in 1967, that this conversion in the plasma was too slow to account for the conversion of the angiotensin I to angiotensin II in the human system. Further revelations indicated that the rapid conversion occurred through the passage of the angiotensin I through the pulmonary circulation. Both bradykinin and angiotensin disappear in the pulmonary circulation. Bradykinin in particular is inactivated and completely disappears in a solo pass through the pulmonary circulation. Angiotensin I also disappears as it is converted to angiotensin II, which passes through the lungs without a loss. In 1970, using the BPF brought by Ferreira, the original thought that the inactivation of the bradykinin and the subsequent conversion of the Angiotensin I was dissipated. It was shown that this conversion was inhibited as it passed through the pulmonary circulation using the BPF by Vane and Ng. BPF became the lead compound for the further developments of new antihypertensive agents. It represented a member of the peptides family, and its potent action was linked to the inhibition of bradykinin by ACE. Its molecular analysis resulted into a nonapeptide BPF teprotide that gave the compound its ACE inhibition potency. This compound also showed beneficial effects to patients with heart failures. At the time though, it was not associated with a substantial clinical utility because of majorly its peptide nature and the corresponding lack of activity when administered orally. Knowledge of the substance structure-activity relationships that was needed for inhibition of ACE was later advanced in the early 1970s. Peptide analogues were used in the analysis of the structure of ACE through carboxypeptidase A as a model by David Cushman, Miguel Ondetti and other colleagues. The researchers made use of the knowledge of the substrate binding specifications. In addition, they highlighted the background idea of the similarity in properties of the ACE and that of the pancreatic carboxypeptidase. As a result, they came up with a hypothetical model of the enzyme active site. The findings by these scientists later led the development of captopril, and this was the first active ACE inhibitor that was administered orally in 1975. Captopril was then later approved by the US Food and Drug Administration in 1981. Researchers later sought to find and come up with compounds that did not contain the sulfhydryl group of captopril. The development led to the establishment of the ground for further discoveries, and within two years, other nonsulfhydryl-containing ACE inhibitors like the enalapril was introduced into the market. The enalapril though was noted to be poor in oral bioavailability despite its excellent intravenous (IV) activity. Eight other dicarboxylate ACE inhibitors have been approved and marketed for therapeutic use apart from others like spirapril. This imminent search for ACE inhibitors that did not contain the sulfhydryl group also led to the investigation and introduction of phosphorous containing compounds like the Fosinopril inhibitor. The evolution of these different drugs has led to the enhancement of their binding and potency. In addition, it has created varied differences in absorption and onset of action. Most importantly, it has led to plasma protein binding, elimination, duration of action among other aspects of these ACE inhibition drug types. The Japanese created the first milk-based ACE inhibitor in 1991. The Milk-based Ace inhibitor was created in the form of a fermented milk drink, where they used specific cultures to isolate the tripeptide isoleucine-proline (IPP) from the milk protein. Another milk tripeptide, similar to the chemical structure of IPP known as Valine-proline-proline (VPP) was also isolated in the process. Both of these have often been referred to as lactotripeptides, and their blood-lowering pressure effect in the human blood confirmed in 1996. Different proportion of the two inhibitors is however required to produce similar effects in the human blood, IPP being the more active of the two lactotripeptides. After the trials, the use of these inhibitors has spread too many other different countries. All of these compounds have been reported effectively to help in the conversion of angiotensin I to angiotensin II and are both known to have the same therapeutic and physiologic impacts. They were initially approved to treat patients with high blood pressure and could be used either alone or in combination with other drugs. They were later found beneficial in the treatment of some other cardiovascular and renal complications, especially when applied with other forms of medications, and these complications included: a) Cardiac failure b) Acute myocardial infraction c) Renal complications of diabetic nephropathy Other types and class of cardiovascular drugs that have also been used to prevent the effects of angiotensin II on the body successfully are the angiotensin II receptor antagonists. These drugs possess several common features with the ACE inhibitors and are usually preferred for patients who are intolerant to the effects initiated by the use of the ACE inhibitors (Galon 42). The Mechanism of action The ACE inhibitors help reduces the effects of the renin-angiotensin system by inhibiting the conversion of angiotensin I to angiotensin II. This rennin-angiotensin system is as illustrated below: This system plays a very vital role through undertaking unrelated set of mechanisms for the control of the blood volume, pressure and its salt homeostasis electrolytic composition. It could also have a critical function in the name of pathogenesis of the various aspects of the metabolic syndrome (Thomson 68). From the diagram of the system, it is evident that the ACE inhibitors do not interfere directly with the other components of the rennin-angiotensin system apart from this inhibition effect. It however causes effects that cause the attenuation in the angiotensin II concentration. A normal body system usually has a way of maintaining the blood pressure. This mechanism is initiated normally by the production of a protein called renin, a proteolytic enzyme which controls the physiological functions of other organs, by the kidney cells, juxtaglomerular apparatus. The production of renin is usually guided by the nervous system and is salt sensitive, normally secreted in a direct proportionality to sodium excretion by the kidneys. It is worth noting that the secretion of renin leads to the production of another protein angiotensin. This protein signals the adrenal gland to produce the aldosterone hormone. This regulatory system of the body is normally activated in response to a fall in the blood pressure. However, in certain circumstances the system is activated when there is an imbalance in the salt-water body; decrease in blood volume or in the sodium content in the distal tubule of the kidney. This is in addition to when the kidney is stimulated by the sympathetic nervous system. In these circumstances, the kidney produces the renin which usually acts as an enzyme cutting off all but the first ten amino acids remains of angiotensinogen. This is known as the angiotensin I. The angiotensin-converting enzyme then further removes two residues leading to the conversion of the angiotensin I to angiotensin II. The process is usually found in the pulmonary circulation and the endothelium of several blood vessels. As a result, the condition of increased amount of salt and water in the body which eventually results to increased blood pressures arises (Puzyn, Tomasz, Jerzy and Mark 89). The effect of the ACE inhibitors would be essentially to block the conversion of angiotensin I to angiotensin II, by so doing it helps in the following: a) Increase the capacity of venous b) Reduce the amount of cardiac output, stroke work, cardiac index and volume. c) Lower arterial resistance d) reduced resistance kidneys blood resistance. e) Lead to increased excretion of sodium and urine (natriuresis) Other notable effects of the ACE inhibitors would be an increase of renin concentration in the blood resulting to increase in angiotensin I, decrease of both angiotensin II and aldosterone hormone. Bradykinin increases due to the less inactivation of the ACE. Without the introduction of the ACE inhibitors, production of angiotensin II would continue unabated This would act throughout the body to produce several cardiovascular, metabolic, endocrine, and behavioral affects most of which would include: a) A decrease in the renal protein kinase C b) Vasoconstriction also referred to as the narrowing of blood vessels, and vascular smooth muscle enlargement. These can potentially increase the blood pressure and cause hypertension. Constriction of the efferent arterioles of the kidney also induced by angiotensin II, also in most cases results into an increase in the perfusion pressure in the glomeruli. c) Results into the stimulation of the posterior pituitary to release antidiuretic hormone, ADH (vasopressin) which usually acts on the kidney increasing its water retention. If this hormone is produced in excess especially in heart failure, sodium ion level in the plasma could fall, and this could be a pointer to increased death risk in heart failure patients. d) Stimulation of the adrenal cortex to produce aldosterone hormone which usually acts on kidney tubules, causing chloride and sodium ions retention and excretion of potassium also takes place. This enables water retention is resulting to increased blood volumes thence an increasing in the pressure of the blood. The ACE inhibitors have been used in other several health applications in critical conditions including: i) Heart failure. The ACE inhibitors have been known to be of a huge benefit to heart failure patients by helping in lowering their blood pressures and preservation of serum potassium level. This is attributed to their effect on endothelial function. ACE inhibitors have been recommended for use by all heart failure patients there are certain contra-indications. Pharmacist should thus be actively involved in heart failure health care plans because most patients usually die because of neglect or under dosages. These inhibitors have also been identified to cause a central enhancement in the activity of parasympathetic nervous system in individuals who are healthy or in patients with heart failure complications. The action helps in the reduction of the prevalence of malignant cardiac arrhythmias, and the sudden death reduction revealed in large clinical trials. These inhibitors also function to help reduce the levels of plasma norepinephrine and its associated vasoconstriction effects experienced by heart failure patients by breaking the cycle of sympathetic and renin-angiotensin system activation. Enalapril, as an ACE inhibitor has also been proven to reduce cardiac cachexia in patients attacked by chronic heart failures (Foye William Thomas and David 76) ii) Post-MI: Most of these benefits associated with patients with a prior MI are based on preventing the deterioration of ventricular function. Most of these benefits are derived from the same mechanisms like that of the heart failure. These include preload reduction, potassium preservation and their effects on endothelial function. In addition, they help in the correction of the las-minogen activator inhibitor-1 activity, antigen levels and left ventricular modeling. Positive outcomes have been reported too on post-MI patients on the effects of ACE inhibitors on their cardiovascular mortality and morbidity. Timing of their dosages should also be taken into account though several researches have indicated that benefits have been derived in dosages taken within thirty-six hours or more than three days after having an MI. For those patients with chest pains, captopril, lisinopril or ramipril should be taken within 36 hours and continued for six weeks. Further treatment is recommended for those who experience continued left ventricular dysfunction after the six weeks. ii) Renal disease. Numerous trials have also reported the ACE effects in decreasing proteinuria in patients who are either affected by diabetes mellitus or not. The effects have been found to be entirely independent of these drugs effects on blood pressure. The ACE inhibitors have assisted in reducing proteinuria in patients suffering the renal disease without increasing the blood pressures. The inhibition of the conversion of angiotensin I to angiotensin II is also crucial in subverting the renal diseases as this helps in the protection of the kidneys from the adverse effects of angiotensin II. It is worth noting that these inhibitors should not be prescribed to patients higher levels of serum creatinine that exceeds 3 mg/dL. Higher levels of serum creatinine often inhibit results into an increase in the same which could result into further renal dysfunction (Vogel 66). iv) Hypertension. Further researches and involvement of the ACE inhibitors in hypertensive patients have yielded better results even for patients with type 1 diabetes mellitus with proteinuria. Apart from helping to lower the blood pressure, the ACE inhibitors have shown beneficial impacts to patients with left ventricular hypertrophy. They are also devoid of the numerous metabolic defects associated with the other antihypertensive medications, which include but not limited to glucose intolerance, dyslipidemia and hyperinsulinemia (Arcangelo, Virginia and Andrew 54) The ACE inhibitors usually possess varied strengths with different dosages and should be adjusted about clinical response (Foye et al. 38). The table below gives the different dosages for hypertension for the different ACE inhibitors; Name Equivalent daily dose Start Usual Maximum Benazepril 10 mg 10 mg 20-40 mg 80mg Captopril 50 mg (25 mg bid) 12.5-25 mg bid-tid 25-40 mg bid-tid 450 mg/d Enalapril 5 mg 5 mg 10-40 mg 40 mg Fosinopril 10 mg 10 mg 20-40 mg 80 mg Lisinopril 10 mg 10 mg 10-40 mg 80 mg Moexipril 7.5 mg 7.5 mg 7.5-30 mg 30 mg Perindopril 4 mg 4 mg 4-8 mg 16 mg Quinapril 10 mg 10 mg 20-80 mg 80 mg Ramipril 2.5 mg 2.5 mg 2.5-20 mg 20 mg Trandolapril 2 mg 1 mg 2-4 mg 8 mg To be noted in the table: Bid = 2 times a day Tid = 3 times a day D= daily The people who work in this field include the pharmacists and the clinical medics. The pharmacists can adequately the advice on the dosages and the adherence to the drugs prescribed. In any operation concerning heart failure, cardiovascular complications and/or renal problems the presence of a clinical medic and a pharmacist is always recommended. Most of the patients succumb to these complications as a result of lack of prescription of these drugs or due to under dosages when prescribed. With the involvement of the pharmaceutical profession, most of these deaths and further complications can be subverted. Side Effects of the ACE drugs Notable side effects of the drugs have been discovered, and these include: 1) Dose-dependent hypotension; this is usually experienced by patients who have low serum sodium, created by either a decrease in its intake or diuretic usage. Relatively, recommendations should be done for lower starting doses for such patients. 2) The ACE also inhibitors cause a dry, persistent cough. This is associated with an increase in the levels of bradykinin or prostaglandins produced by the inhibitors. In addition, the condition can cause much unease in patients to the extent of discontinuation of their medication. Pharmacists may be in the best position to evaluate the existence of these adverse effects and provide for necessary mitigations. 3) The inhibitors could also result in the increased levels of bradykinin which is linked to a lot of after effects of the drug’s uptake (Black, Henry and William 34). These increased levels of this compound often lead to a dry cough condition, angioedema and rash and pain related to inflammation. 4) Causes hyperkalemia; this is also another side effect complication experienced by these patients who partake of these inhibitors. This effect is usually produced by the reduction in the release of aldosterone and is most common in patients who have renal dysfunction. Aldosterone is normally useful for increasing the excretion of potassium hence with a reduced amount released; potassium retention is increased. This complication could lead to a decrease in the velocity of impulse conduction in the muscles and the nerves leading to neuromuscular aftermaths. That is; nausea, diarrhea, paresthesia, weakness and/or cardiac dysfunction could be the resultant effect (Liang and Wei-Shuo, 67). 5) In pregnant women, these drugs have led to such effects as stillbirths, congenital malformations and neonatal deaths when used during all the trimesters. Some of these abnormalities i.e. intrauterine growth retardation, oligohydramnios, renal dysplasia and incomplete ossification of the skull have been noted in newborns that have been exposed to the effects of these drugs (Aronson, 40). Conclusion As much as these drugs have been considered beneficial to a range of patients’ complications, contra-indications should be recommended to some patients especially to those with; renal artery stenosis, hypersensitivity to the ACE inhibitors and those with the previous angioedema connected with ACE inhibitor therapy. Caution should also be adhered to when using these drugs in patients mostly with impaired renal function and hypovolemia Provision of counseling should also be given to these ACE prescribed patients especially by the pharmacists who encounter them more often. These patients should be guided on the benefits of therapy (Golan 56), the effects of the drugs and the importance of them adhering to their regimen. They should also be encouraged to undertake a follow-up monitoring scheme in order to bring out the best clinical outcomes of these drugs (Aronson, 40). Work cited Arcangelo, Virginia P, and Andrew M. Peterson. Pharmacotherapeutics for Advanced Practice: A Practical Approach. Philadelphia, PA [u.a.: Lippincott Williams & Wilkins, 2005. Print. Aronson, J K. Meylers Side Effects of Cardiovascular Drugs. Amsterdam: Elsevier, 2009. Internet resource. Black, Henry R, and William J. Elliott. Hypertension: A Companion to Braunwalds Heart Disease. Philadelphia, PA: Saunders Elsevier, 2007. 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Wilson and Gisvolds Textbook of Organic Medicinal and Pharmaceutical Chemistry. Baltimore, MD: Lippincott Williams & Wilkins, 2011. Print. Read More