KAUNAS UNIVERSITY OF MEDICINE Department of Basic & Clinical Pharmacology
Trends in the use of Angiotensin converting enzyme inhibitors and Angiotensin II antagonists in Lithuania on 2005 – 2007 years
The author: Asta Dičkutė a student of Pharmacy faculty of Kaunas University of Medicine
Work supervisor: Lekt. Edmundas Kaduševičius
TABLE OF CONTENTS
Abbreviations...3
1. Introduction and novelty of the master work...4
2. Objective and tasks...8
3. The renin-angiotensin aldosterone system: physiological role and pharmacologic inhibition .. ...9
3.1 Components of the renin-angiotensin aldosterone system...9
3.2.Description and clasification of AT1 and AT2 receptors...11
3.3 Classical Endocrine Pathway of Angiotensin Biosynthesis………..…………...12
3.4 Tissue renin-angiotensin aldosterone system and Alternative Pathways of Angiotensin Biosynthesis………...13
3.5 Dysregulation of the renin-angiotensin aldosterone system in Cardiovascular Disorders…..…16
3.6 Renin-angiotensin aldosterone system inhibition. Early Preclinical Findings………17
3.7. Pharmacologic Intervention in the Renin-Angiotensin System Cascade………..….17
4. Angiotensin – converting enzyme inhibitors. History. Chemical structure. Pharmacokinetics....19
4.1 History……...………19
4.2 Chemical structure……….………..20
4.3 Pharmacokinetics of the ACE inhibitors………..………...23
5. Angiotensin II antagonists. History. Chemical structure. Pharmacokinetics…………..………..25
5.1 History……….………25
5.2 Chemical structure……….……….25
5.3 Pharmacokinetics of angiotensin II antagonists………..27
6. Head-to-head efficacy comparisons……….….29
ABBREVIATIONS
ACE-I - angiotensin-converting enzyme inhibitors ARA - angiotensin receptor antagonists
BP – blood pressure
BKR-2 - the bradykinin receptor type 2
CAGE - chymostatin-sensitive angiotensin generating enzyme CVD – cardiovascular diseases
EU - Europe Union
GFR - glomerular filtration rate HgbA1c - glycated hemoglobin IHD – isheamic heart diseases JG - juxtaglomerular cells LV – left ventricular
mRNA - messenger ribonucleic acid PGE-2 - prostaglandin E2
PGI-2 - prostaglandin I2 PRA - plasma renin activity
RAAS – the renin-angiotensin aldosterone system RAS – the renin–angiotensin system
RCT - randomized controlled trial UK - United Kingdom
1. INTRODUCTION AND NOVELTY OF THE MASTER WORK
Cardiovascular disease is one of the main causes of death in the world in 2005. Among the 58 million deaths in the world in 2005, noncommunicable diseases were estimated to account for 35 million. Sixteen million of the 35 million deaths occur in people aged under 70 years. The majority of deaths (80%) from noncommunicable diseases occur in low and middle income countries, where most of the world‘s population lives, and the rates are higher than in high income countries. Deaths from noncommunicable diseases occur at earlier ages in low and middle income countries than in high income countries.[1].
Among the noncommunicable diseases, cardiovascular diseases are the leading cause of death, responsible for 30% of all deaths – or about 17.5 million people – in 2005[1].
In addition to the high death toll, noncommunicable diseases cause disability. The most widely used summary measure of the burden of disease is disability-adjusted life years (DALYs), which combines years of healthy life lost to premature death with time spent in less than full health. Almost half of the global burden of disease is caused by noncommunicable diseases, compared with 13% by injuries and 39% by communicable diseases, maternal and perinatal conditions, and nutritional deficiencies combined. While the share of cardiovascular diseases, chronic respiratory diseases and cancer decreases, other noncommunicable diseases increase from 9% to 28%, primarily due to a larger share for mental disorders, and to a lesser extent due to impairments of the sense organs (sense and hearing) and musculoskeletal system (mainly arthritis). [1]
Cardiovascular diseases remain the major cause of death across Europe, and a major cause of morbidity and loss of quality of life. [2]
Every year more than 4 million Europeans die from diseases of the heart and blood vessels.
The prevalence of many cardiovascular diseases increases exponentially with ageing, especially coronary heart disease, heart failure, atria fibrillation, hypertension and aortic stenosis. This is a challenge for modern cardiology since all surveys show that management of elderly patients often differs from management in younger patients. Specific attention is needed for guideline development and adherence with respect to elderly. [2]
Figure 1. Population of Europe in 2004. [2]
There is an apparent west-east gradient with more elderly people in the Western countries. [2] This reflects the longer life-expectancy in Western countries, which is partly a result of the lower age-specific mortality from cardiovascular diseases. Cardiovascular disease is the main cause of death in most countries in Europe. At present (latest available data ≈ 2004), the average age standardised cardiovascular mortality ratio is 5.1 per 1,000 inhabitants for men, and 3.4 for women. [2]
CVD is the main cause of death before the age of 65 for men in 28 of the 49 countries of Europe for which we have mortality data and for women in 17 countries. In women, the countries where CVD is the main cause of death before the age of 65 are all Central and Eastern European countries. [3]
CVD is the main cause of death before the age of 65 for men in ten countries in the EU (Estonia, Finland, Greece, Ireland, Latvia, Lithuania, Poland, Slovakia, Sweden and the UK). [3]
Lithuania is ascribed to the states of high risk cardiovascular diseases by World Health Organisation and Europen Society of Cardiology. [4]
About 55 percent of all deaths and 25-50 percent of disablement and 15-20 percent of all medical consultations are because of cardiovascular diseases. Cardiovascular diseases are one of the main causes of death and disablement among middle aged and elder men and women in Lithuania. Mortality from cardiovascular diseases increased 16.6 percent since 2000 till 2005. [4]
Almost 89 percent of all deaths from cardiovascular diseases occur in people aged 60 years old and more. The biggest rate of mortality from cardiovascular diseases is in Alytus, Utena, Taurage districts in Lithuania in 2005. [4]
Almost 52 percent of all deaths (or 562 people of 1090.86 total deaths) are from cardiovascular diseases in Lithuania in 2006. [4]
Age adjusted death rates by cause of death, 2006 Deaths per 100 000 European standard population
Causes of death
Total 1090,86
Malignant neoplasms 195,45
Diseases of the circulatory system 562,05 External causes of death 149,77
Intentional self-harm 28,94
Table.1. Age adjusted death rates by cause of deaths in Lithuania in 2006 [4]
Among the cardiovascular diseases ischaemic heart diseases are the leading cause of death, responsible for 56 percent of all deaths – or about 13.7 thousand people – in 2006 in Lithuania. Almost 82 percent of all deaths from cardiovascular diseases occur in people aged 65 years and more. [4]
The morbidity of cardiovascular diseases increases between young and able-bodied population. [4]
The decrease of risk factors is one of the main components of the IHD medical treatment strategy. It is important to decrease risk factors for healthy people and patients with IHD symptoms (primary and secondary prevention of the disease). The other not less important component of secondary prevention is the treatment with medicine. It is set that people sick with IHD and using every of the main medicines (aspirin, BAB, AKF inhibitor or statin) have ¼ less isheamic heart attacks, people who use drugs combinations decrease heart attacks till ¾ ones. [5]
Although their antihypertensive efficacy as monotherapy is similar to other antihypertensive agents, they have the advantage of better tolerability, limited side effects and a favourable metabolic profile. When compared to other antihypertensive agents (diuretics, beta-adrenergic blockers and calcium antagonists) in large clinical trials, ACE-I and ARA provided no additional advantages regarding improvement in cardiovascular and total mortality. With the exception of the superiority of ARA in prevention of stroke, RAS inhibitors have no advantage over other agents in prevention of other cardiovascular morbid events, namely, heart failure (though ACE-I are superior to calcium antagonists), coronary heart disease and total cardiovascular events. However, there is the possibility that these agents have other benefits beyond blood pressure lowering. At equal degrees of blood pressure reduction, RAS inhibitors prevent or delay the development of diabetes mellitus and provide better end-organ protection, kidneys, blood vessels and the heart when compared with other antihypertensive agents. The combined use of ACE-I and ARA is particularly useful in organ protection. RAS inhibitors are specifically indicated in the treatment of hypertension in patients with impaired left ventricular systolic function, diabetes, proteinuria, impaired kidney function, myocardial infarction, multiple cardiovascular risk factors and possibly elderly patients. The main limitation of the ACE-I is cough and rarely angioedema. Elderly patients or those who are volume depleted or receiving large doses of diuretics or in heart failure are liable to develop hypotensive reaction and/or deterioration in kidney function. [13]
New methods for prevention and treatment of cardiovascular diseases have delayed the onset of clinical manifestations, have improved the immediate disease outcome, and have improved life expectancy. This has resulted in an increasing number of patients who survive a cardiovascular event, and who require subsequent medical or interventional therapy. The burden of cardiovascular disease has shifted from the middle aged to the elderly, and remains high. [2]
In Lithuania like in other EU countries expenses for drugs increase very fast compare with other sectors in health system. Lithuania predicted to spend 587.8 million on drugs and medical goods in 2007. In 2006 Medical expenses amounted to 507 mill. compared to 447 mill. in previous year. [11] Compensation expenses on cardiovascular drugs were 24.6% of all compensation expenses on drugs in 2005. [4]
Because of increased expenses on drugs various methods of regulation must be applied. A rational distribution of funds helps to decrease expenses on drugs. [10]
2. OBJECTIVE AND TASKS
2.1. OBJECTIVE
To evaluate the tendencies of utilization of angiotensin converting enzyme inhibitors and angiotensin II receptors antagonists in Lithuania during 2005-2007 years.
2.2. TASKS
The main tasks are as follows:
1. To introduce importance of Renin-angiotensin-aldosterone system for human blood pressure regulation – literature review.
2. To evaluate differences and similarities between angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists and the same within pharmaceutical group (to perform head-to-head comparison).
3. To evaluate utilization of angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists by ATC/DDD methodology in Lithuania during 2005-2007 years.
4. To compare utilization of angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists in Lithuania with other EU countries.
3. THE RENIN-ANGIOTENSIN ALDOSTERONE SYSTEM (RAAS): PATH PHYSIOLOGICAL ROLE AND PHARMACOLOGIC INHIBITION
The renin-angiotensin aldosterone system (RAAS) is a hormonal cascade that functions in the homeostatic control of arterial pressure, tissue perfusion, and extra cellular volume. Dysregulation of the RAAS plays an important role in the pathogenesis of cardiovascular and renal disorders. [9]
3.1 Components of the RAAS
As the name implies, there are three important components to this system: 1) renin, 2) angiotensin, and 3) aldosterone. [8]
The renin-angiotensin aldosterone hormonal cascade begins with the biosynthesis of renin by the juxtaglomerular cells (JG) that line the afferent (and occasionally efferent) arteriole of the renal glomerulus. Active renin secretion is regulated principally by 4 interdependent factors: (1) a renal baroreceptor mechanism in the afferent arteriole that senses changes in renal perfusion pressure, (2) changes in delivery of NaCl (sensed as changes in Cl- concentration) to the macula densa cells of the distal tubule (which lie close to the JG cells and, together, form the ―JG apparatus‖), (3) sympathetic nerve stimulation via beta-1 adrenergic receptors, and (4) negative feedback by a direct action of Ang II on the JG cells.
Renin secretion is stimulated by a fall in perfusion pressure or in NaCl delivery and by an increase in sympathetic activity. Control of renin secretion is a key determinant of the activity of the RAAS. Renin regulates the initial, rate-limiting step of the RAAS by cleaving the N-terminal portion of a large molecular weight globulin, angiotensinogen, to form the biologically inert decapeptide Ang I [9], which is changed through angiotensin-converting enzymes (ACE) to an octapeptide angiotensin II, a biologically active, potent vasoconstrictor. [9]
RAAS = renin-angiotensin-aldosterone system; ACE = angiotensin converting enzyme; LVH = left ventricular hypertrophy; LV = left ventricular.
Figure 2. Deleterious effects of the RAAS [6]
There are multiple pathways of angiotensin II production—2 of them are described here. On the left-hand side is the classical pathway where ACE is the enzyme responsible for the conversion of angiotensin-1 to angiotensin II. On the right-hand side there is depicted an alternate pathway, which is mainly tissue loss pathway and will involve different enzymes such as CAGE, cathepsin G, or chymase. [6]
NO = nitric oxide; AT = angiotensin II receptor; t-PA = tissue plasminogen factor; CAGE = chymostatin-sensitive angiotensin generating enzyme; ACEI = angiotensin converting enzyme inhibitors; ARB =
angiotensin receptor blocker.
ACE is a membrane-bound exopeptidase and is localized on the plasma membranes of various cell types, including vascular endothelial cells, microvillar brush border epithelial cells (e.g., renal proximal tubule cells), and neuroepithelial cells. It is this membrane-bound ACE that is thought to be physiologically important. ACE also exists in a soluble form in plasma, but this form may simply reflect turnover and clearance of membrane-bound ACE. ACE (also known as kininase II) metabolizes a number of other peptides, including the vasodilator peptides bradykinin and kallidin, to inactive metabolites. [7] Thus, functionally, the enzymatic actions of ACE potentially result in increased vasoconstriction and decreased vasodilatation. Although Ang II is the primary active product of the RAAS, there is evidence that other metabolites of Ang I and II may have significant biological activity, particularly in tissues. [9]
As already noted, Ang II is the primary effector of a variety of RAAS-induced physiological and path physiological actions. [9]
3.2. Description and classification of AT1 and AT2 receptors
Angiotensin-2 has multiple receptors, but 2 receptors are predominating or are better known. The AT1 receptor is responsible for hypertrophy/proliferation, vasoconstriction, aldosterone release, and also antidiuretic hormone. The second well-known receptor is the AT2 receptor. This AT2 receptor is responsible for antiproliferation or apoptosis, nitric oxide release, differentiation, and vasodilatation. [6]
Both receptors have high binding affinities for the AngII peptide. AT1 receptors are expressed in various parts of the body and are associated with their respective functions, such as blood vessels, adrenal cortex, liver, kidney and brain, while AT2 receptors are highest in fetal mesenchymal tissue, adrenal medulla, uterus and ovarian follicles. [7]
We know that the AT1 receptor is always expressed [6], The type 1 (AT1) receptor mediates most of the established physiological and pathophysiological effects of Ang II. These include actions on the cardiovascular system (vasoconstriction, [9] , and this is preferential to the coronary, the renal, and the cerebral paths, [6] increased blood pressure, increased cardiac contractility, vascular and cardiac hypertrophy, kidney (renal tubular sodium reabsorption, inhibition of renin release), sympathetic nervous system, and adrenal cortex (stimulation of aldosterone synthesis). [7] The AT1 receptor also mediates effects of Ang II on cell growth and proliferation, inflammatory responses, and oxidative stress. [9]
Figure 4. Angiotensin II receptor stimulation [6]
As already noted, Ang II, via the AT1 receptor, also stimulates the production of aldosterone by the zona glomerulosa, the outermost zone of the adrenal cortex. Aldosterone is a major regulator of sodium and potassium balance and thus plays a major role in regulating extracellular volume. It enhances the reabsorption of sodium and water in the distal tubules and collecting ducts (as well as in the colon and salivary and sweat glands) and thereby promotes potassium (and hydrogen ion) excretion.12 Ang II, together with extracellular potassium levels, are the major regulators of aldosterone, but Ang II synthesis may also be stimulated by adrenocorticotrophic hormone (ACTH; corticotrophin), norepinephrine, endothelin, and serotonin and inhibited by atrial natriuretic peptide and nitric oxide (NO). It is also important to note that Ang II is a major trophic factor for the zone glomerulosa, which can atrophy (reversibly) in its absence. [9]
3.3 Classical Endocrine Pathway of Angiotensin Biosynthesis
arteriole pressure is reduced, glomerular filtration decreases, and this reduces NaCl in the distal tubule. This serves as an important mechanism contributing to the release of renin when there is afferent arteriole hypotension.
When renin is released into the blood, it acts upon a circulating substrate, angiotensinogen, that undergoes proteolytic cleavage to form the decapeptide angiotensin I. Vascular endothelium, particularly in the lungs, has an enzyme, angiotensin converting enzyme (ACE), that cleaves off two amino acids to form the octapeptide, angiotensin II (AII), although many other tissues in the body (heart, brain, vascular) also can form AII. [8]
The concept of a circulating endocrine cascade has been frequently misinterpreted to imply that Ang II is a circulating ―hormone,‖ but this is in fact unlikely. Instead, both Ang I and Ang II, which have very short half-lives, are probably synthesized very close to their site of action, with renin serving as the circulating hormonal signal that initiates the pathway at local sites. The diverse actions of Ang II mediated by the AT1 receptor play a key role in restoring or maintaining circulatory homeostasis. In addition to stimulating the production (and release) of aldosterone from the adrenal cortex, Ang II promotes the constriction of renal and systemic arterioles and the reabsorption of sodium in proximal segments of the nephron. The increase in blood pressure and volume, resulting from the effects of Ang II and aldosterone on their target organs, serves to restore renal perfusion and thereby inhibits further release of renin. Although the RAAS thus plays an important role in normal circulatory homeostasis, continued or inappropriate activation of the system is thought to contribute to the pathophysiology of diseases such as hypertension and heart failure. [9]
3.4 Tissue RAAS and Alternative Pathways of Angiotensin Biosynthesis
The evidence that angiotensin synthesis can occur in several tissues as well as the circulation, together with the characterization of several subtypes of angiotensin receptors and signal transduction pathways, the identification of truncated angiotensin peptides with possible unique actions, and most recently, the identification of putative cell surface receptors for renin and prorenin, has resulted in expansion of the traditional circulating RAAS paradigm to include the so-called ―tissue RAAS.‖ The prevailing concept is that the RAAS functions both as a circulating system and as a tissue paracrine/autocrine system. [9]
Studies have suggested that non-ACE pathways are, by inference, responsible for about 40% of Ang II generation in the intact human kidney and that chymase is the dominant Ang II-generating pathway in the human heart, coronary arteries, and atherosclerotic aorta in vitro. It has thus been proposed that abnormal activation of the tissue RAAS may contribute to the pathogenesis of cardiovascular disease even in the absence of derangements in the circulating system.
It must be considered, however, that the bulk of the evidence favoring alternate enzymatic pathways in the synthesis of angiotensin peptides comes from in vitro or indirect observations, so that such concepts remain speculative at present. [9]
Under physiological conditions, the apparent function of the cardiac RAAS is to maintain cellular balance of inhibiting and inducing cell growth, and proliferation and mediation of adaptive responses to myocardial stretch. The majority of Ang II in cardiac tissue appears to be produced by local synthesis of Ang I and subsequent local conversion to Ang II, rather than from uptake of peptides from the systemic circulation. Although it has been suggested that locally synthesized renin and/or additional proteolytic enzymes may be involved in this synthetic process, current evidence favors the concept that circulating renin and angiotensinogen, which are able to pass through the endothelial barrier, are taken up by cardiac tissue where they act locally. Ang II exerts an inotropic effect (at least in atrial preparations), mediates myocyte hypertrophy via the AT1 receptor, and is involved in cardiac remodeling. Pathologic activation of cardiac RAAS, perhaps through local upregulation of ACE levels, has been proposed to contribute to the development and maintenance of left ventricular hypertrophy. [9]
Vascular smooth muscle, endothelial, and endocardial cells generate Ang I and Ang II, again apparently via the uptake of circulating renin. It has been suggested that the vascular RAAS contributes to the maintenance of cardiovascular homeostasis through its effects on both AT1 and AT2 receptors and mediates long-term effects on vascular remodeling by stimulating proliferation of vascular smooth muscle cells and fibroblasts. Endothelial dysfunction is associated with upregulation of local tissue ACE, which might contribute to disrupting the balance of vasodilation and vasoconstriction. Activation of vascular ACE may also alter other functions, including vascular smooth muscle cell growth and the inflammatory and oxidative state of the vessel wall. In addition, the production of reactive oxidative species (superoxide and hydrogen peroxide), which is enhanced by Ang II, has been associated with inflammation, atherosclerosis, hypertrophy, remodeling, and angiogenesis. [9]
afferent and efferent arterioles and stimulates mesangial cell contraction, which results in reduced renal blood flow, glomerular filtration rate (GFR), and filtered sodium load. On the one hand, overactivation of the intrarenal RAAS may thus contribute to the pathophysiology of sodium-retaining states, such as hypertension and congestive heart failure (CHF). On the other hand, in conditions characterized by severe impairment of renal perfusion, such as renal artery stenosis, the afferent circulation, which is dilated as a result of autoregulation, is relatively refractory to the constrictive actions of Ang II, and the predominant constriction of efferent arterioles by Ang II plays a major role in maintaining glomerular perfusion pressure and, thus, GFR. Although systemic Ang II may affect CNS function at selected sites, the brain is largely isolated from the circulating RAAS by the blood-brain barrier. Therefore, local Ang II synthesis by a brain RAAS has been proposed to play a role in central blood pressure regulation. Increases in brain renin activity, renin and angiotensinogen mRNA, and detectable numbers of AT1- and AT2-receptor subtypes have been reported in hypertensive rats. Selective inhibition of brain AT1- and AT2-receptors has been shown to lower blood pressure in hypertensive rats. Furthermore, direct administration of Ang II into the brain has been shown to increase blood pressure as a result of the combined effects of vasopressin release, sympathetic nervous system activation, and inhibition of baroreflexes. Studies in transgenic rats with permanent inhibition of brain angiotensinogen synthesis have demonstrated significantly lower systolic blood pressure compared with controls. [9]
All components of the RAAS are present in adrenal cortex and comprise the adrenal RAAS. Renin and angiotensinogen mRNA have been identified in the adrenal gland, and Ang II formation has been demonstrated in zona glomerulosa cells. Most (90%) adrenal renin activity has been localized to the zona glomerulosa, and more than 90% of adrenal Ang II originates at local tissue sites. In transgenic animal models it has been shown that sodium restriction can increase adrenal renin and aldosterone independently of plasma or kidney renin concentrations. Additionally, bilateral nephrectomy, which decreases cardiac and vascular renin, does not decrease adrenal renin in experimental animals. These findings support the concept of kidney-independent renin (and thus, Ang II) production in the adrenal glands. It is not known if the adrenal RAAS functions as a paracrine or autocrine system or if it has a pathophysiologic role, and the relative importance of systemic versus locally synthesized Ang II in the control of adrenal function is uncertain. [9]
3.5 Dysregulation of the RAAS in Cardiovascular Disorders
Dysregulation of the RAAS is involved in the pathogenesis of several hypertensive disorders. It should be noted that RAAS dysregulation in clinical hypertensive disorders has been conceptualized at the level of the classical circulating RAAS, and the potential contributions of tissue RAAS dysregulation remain poorly defined. In addition to RAAS involvement in secondary forms of hypertension, there is evidence that perturbations of the RAAS are involved in essential hypertension as well as in the responses of cardiovascular and renal tissue to hypertensive and nonhypertensive injury. It is established that plasma renin levels vary widely in patients with ―essential‖ hypertension. Approximately 15% of patients with essential hypertension have mild to moderate increases in plasma renin activity (PRA), with several postulated mechanisms, including increased sympathetic activity and mild volume depletion. Such high-renin essential hypertension is particularly prevalent among younger males. The majority (50% to 60%) of essential hypertensive patients have PRA within the ―normal‖ range, although it has been argued that a normal renin level in the face of hypertension (which ought to suppress renin secretion) may be inappropriate. Therapeutic responses to RAAS blocking agents indicate that maintenance of normal renin levels may indeed contribute to blood pressure elevation, suggesting that renin-dependent mechanisms may be involved in more than 70% of patients with essential hypertension. On the other hand, about 25% to 30% have evidence of low or suppressed renin levels, a finding that may be an expected response or that may, in some cases, reflect, by analogy to primary aldosteronism, sodium or volume excess (so-called ―volume-dependent‖ hypertension). Low-renin hypertension is more common among older people with hypertension, women, African Americans, and patients with type 2 diabetes, as well as among patients with chronic renal parenchyma disease. Although such patients often have lesser blood pressure lowering benefit from RAAS blocking agents, there is evidence that the circulating levels of PRA might not necessarily reflect tissue activities of the system. This is particularly evident with regard to the kidney, with several lines of evidence pointing to substantial involvement of intrarenal Ang II in progression of renal damage (and substantial benefit of RAAS blockade), despite low circulating levels of renin and Ang II. [9]
The RAAS also plays a pivotal role in several nonhypertensive conditions, and in particular in CHF and the other oedematous disorders (cirrhosis with ascites and the nephrotic syndrome). In these conditions, all characterized by under perfusion of the kidneys due to reduced ―effective arterial volume,‖ secondary hypersecretion of renin leads to secondary aldosteronism, which makes an important contribution to progressive edema. In addition, with regard to heart failure, the contribution of Ang II to increased peripheral vascular resistance (cardiac after load) also plays a major role in progressive ventricular dysfunction. [9]
remodeling, as well as on mechanisms that contribute to vascular damage and atherosclerosis, effects that appear to have major impact on morbidity and mortality. Unlike the case for secondary hypertensive syndromes where the nature of RAAS dysregulation is well defined, the reasons for these pathologic effects of Ang II are uncertain since they often occur in the absence of any perturbation of the circulating RAAS. It has been inferred that there may be dysregulation of some component(s), such as of ACE levels, the balance of AT-receptor subtypes, or even local synthesis of renin or angiotensinogen, to account for such phenomena, but clear cut evidence of such derangements are mostly lacking. It also remains possible that the RAAS plays a ―passive‖ role in such events—that is, that tissue injury can be accelerated even in the presence of ―normal‖ Ang II levels. [9]
3.6. RAAS Inhibition. Early Preclinical Findings
Because renin is the initial and rate-limiting step in the RAAS cascade, it has long been considered the logical therapeutic target for blocking the system. Preclinical studies with antirenin antibodies and then with early synthetic renin inhibitors established the potential utility of RAAS inhibition. In these studies, renin inhibition induced decreases in plasma renin levels (generally measured in these early studies as plasma renin activity or PRA), Ang I, Ang II, and aldosterone, along with decreases in blood pressure.25 These studies also provided evidence that blood pressure-lowering activity was due to inhibition of PRA.25 However, pharmacologic activity of the early renin inhibitors could only be achieved with intravenous infusion, and the development of an orally active direct renin inhibitor was fraught with numerous difficulties arising from issues of potency, low bioavailability, duration of action, and costs of synthesis. As a result, further development of these agents was halted in the mid-1990s. Concurrently, other strategies for inhibiting the RAAS progressed to clinical use. [9]
3.7. Pharmacologic Intervention in the Renin-Angiotensin System Cascade
Inhibition of the RAS as part of an effective BP lowering regimen is also a successful strategy for preventing or delaying end-organ damage. Two drug classes directly target angiotensin II through complementary mechanisms. ACE inhibitors block the conversion of angiotensin I to the active peptide angiotensin II and increase the availability of bradykinin. ARBs selectively antagonize angiotensin II at AT 1 receptors. The beneficial effects of ARBs may also include increased activation of the AT 2 receptor and modulation of the effects of angiotensin II breakdown products.[18] See Figure 2.
Angiotensin-converting enzyme (ACE) inhibitors can cause bradykinin-induced angioedema. See Figures 3 and 5.
Figure 5. Detrimental and beneficial effects of activation of BKR-2 in humans. [25]
ACEIs also decrease aldosterone and vasopressin secretion and sympathetic nerve activity, but there is controversy regarding their efficacy in blocking other ―tissue‖ actions of the RAAS. [9]
Short-term ACEI therapy is associated with a decrease in Ang II and aldosterone and an increase in renin release and Ang I. There is some evidence, however, that over the long term ACE inhibition may be associated with a return of Ang II and aldosterone toward baseline levels (―ACE escape‖)—perhaps, it is proposed, through activation of the so-called alternate pathways. See Figure 3. [9] Such pathways rely on chymase and other proteases to independently produce angiotensin-II in myocardial and vascular tissue. [16] Undoubtedly this phenomenon has been greatly exaggerated, particularly from early studies using faulty methodology that did not specifically measure Ang II, and the relevance of alternate pathways of Ang II synthesis in the intact human is unclear at present. [9]
4. ANGIOTENSIN - CONVERTING ENZYME INHIBITORS. HISTORY. CHEMICAL STRUCTURE. PHARMACOKINETIC.
4.1 History
Early studies performed in the 1960s showed that peptides from the venom of the Brazilian arrowhead viper (Bothrops jararaca) inhibited kinase II, an enzyme that facilitates degradation of bradykinin, and which was later shown to be identical to ACE. [9] Mixtures of peptides from the venom of South American pit vipers are effective at lowering blood pressure when injected, but inactive orally. Even though the snake venom peptides were not active orally the realization that peptides could inhibit ACE initiated the search for smaller peptide based inhibitors which could be administered orally. A screen of N-acylated tripeptides led to the discovery that N-acylated tripeptides could be inhibitors. [19]
Synthetic analogues of the peptide fraction of snake venom, such as the nonapeptide teprotide, were shown to lower blood pressure in patients with hypertension and produce beneficial hemodynamic effects in patients with heart failure. [9]
Figure 6. The structure of teprotide and N-acylated tripeptides [19]
4.2 Chemical structure
ACE inhibitors can be divided into three groups based on their molecular structure. For example, the active chemical side group or ligand on captopril, which binds to ACE, is a sulfhydryl group; for fosinopril, it is a phosphinyl group, with the remaining ACEIs containing a carboxyl group. [16]
Classification according to chemical structure: I. Sulfhydryl-containing agents
Captopril, the first ACE inhibitor Zofenopril
II. Dicarboxylate-containing agents
Enalapril, Ramipril, Quinapril, Perindopril (Non-thiol), Lisinopril, Benazepril, Cilazapril, Moexipril, Trandolapril, Spirapril
Cilazapril Fosinopri sodium Temocapril Spirapril Delapril Imidapril Pentopril Zofenopril
4.3 Pharmacokinetics of the ACE inhibitors Drug Dosage mg Active metabolite Bioavailability % Effect
of food Tmax (h) Half life (h) Protein binding % Vd (L) Excretion (Renal/fecal) [%]
Benazepril 10 Benazeprilat >37 None 0,5 10-11 >95 8,7 20/11-12
(benezeprilat)
Captopril 100 NA 70 R 0,93-1 <2 25-30 0,76
L/kg
>95R,as disulfides
Cilazapril 2,5 Cilazaprilat 57-77,5 R 0,83 9 25,4 91/and F
Delapril 30(60) Delapril diacid Delapril 5-hydroxy diacid
>55 SR 1.0–1.1 0,5
(delapril)
56/and F
Enalapril 10 Enalaprilat 60 None 1 11-13 50-60 94/ and F
Fosinopril 10 Fosinoprilat 32 SR 3 12 >95 10 50/50
Imidapril 10 Imidaprilat R 2 7-9 85 40/50
Lisinopril 10 NA ≈25 widely variable
between individuals
None 7 11-12 10 2,4±1,4
L/kg
100/0
Moexipril 15 Moexiprilat 13-22 MR 1d 2-9 50 180 13/53
Pentopril 250 Pentopril diacid >58 1(1,28) <1 56a
Perindopril 8 Perindoprilat 65-95 SR 1 1,5-3 60 0,22 L/kg 75/25
Quinapril 40 Quinaprilat
Quinapril diacid
>60 R 0,63 2 97 0,4L/kg 61/37
Ramipril 10 Ramiprilat >60 None 1 13-17 73 60/40
Spirapril 6 Spiraprilat 28-69 1 25-35 89 28c 40/85
Temocapril 20 Temocaprilat 1b 1.6 17- 24/36 - 44
Trandolapril 2 Trandolaprilat 10 R 0,5-1 6-10 80 trandolapril
65-94 trandolaprilat
18 33/66
Zofenopril 30 Zofenoprilat 93%. 0.4e -1,5f 5.5 88 1,3L/kg 69/26
a. Estimated value obtained by calculation or by averaging a representative set of results; b. Reported as median; c. intravenous dose; d. Estimated value obtained from graph in study; e-solution; f-tablet
tmax = time to Cmax; Vd = apparent volume of distribution; R = reduced, SR = slightly reduced, MR =markedly reduced; NA-not available Table.3. Comparative pharmacokinetics of the ACE inhibitors
Classifying agents by duration of action— ACEIs were classified as short, intermediate, or long-acting based on five characteristics: onset of action, time-to-peak effect, half-life, duration of action, and dosing interval. Several characteristics of chosen medicines are in Table 4. []
Short-Acting Onset of action(h) T peak(h) Duration of action(h)
Captopril 0,2-03 1 Dose related
Intermediate-Acting Benazepril 1 2-4 16-24 Enalapril 1 4-6 18-24 Moexipril 1 2 12-24 Quinapril 1-2 4 18-24 Ramipril 1-2 3-6 18-24 Long-Acting Fosinopril 1 2-6 24 Lisinopril 1 4-6 24 Perindopril 1 3-4 24 Trandolapril 2-4 6-8 24
Table.4. Duration of action of angiotensin converting enzyme inhibitors Adapted from: Anne Stoysich & Fred Massoomi., 2002.
KEY FACTORS EXAMINED IN ACEI CLASS COMPARISON Enalaprilat is the only ACEI available for intravenous dosing;
Captopril was classified as the only short-acting agent;
Captopril and lisinopril are the only ACEIs that are not prodrugs and therefore do not require hepatic activation;
In patients with severe renal dysfunction, dosage adjustment may be necessary for all ACE inhibitors except fosinopril (because of its dual and equal routes of elimination);
Lisinopril is the optimal agent for patients with hepatic dysfunction because its parent compound is exclusively renally eliminated;
Fosinopril does not significantly accumulate in patients with hepatic impairment because it has compensatory dual routes of elimination;
Only captopril and moexipril have shown potential drug-food interactions, with a decrease in the rate but not in extent of absorption. [20]
5. ANGIOTENSIN II ANTAGONISTS. HISTORY. CHEMICAL STRUCTURE. PHARMACOKINETICS.
5.1 History
In 1982, Furakawa, Kishimoto, and Nishikawa first described a nonapeptide angiotensin II receptor antagonist, S-8307, that became the structural model for what was to become an entirely new class of antihypertensive agents. Further development led to a panoply of promising orally active substances with improved effectiveness, optimised receptor kinetics, and longer durations of action. In the mid-1990s, losartan was the first of these pharmacological agents to be licensed and marketed, followed soon thereafter by valsartan, eprosartan, irbesartan, candesartan, and telmisartan (Table 2). Based on the convincing evidence of their safety and efficacy, angiotensin II type 1 (AT1) receptor antagonists have recently been included in the World Health Organisation's recommendations for the treatment of high blood pressure. [15]
5.2 Chemical structure
The ARBs are non-peptide compounds with varied structures. There are some structural similarities among the ARBs:
(a) candesartan, irbesartan, losartan, valsartan [21] and olmesartan [22] have a common tetrazolobiphenyl structure;
(b) candesartan and telmisartan have a common benzimidazole group;
Candesartan cilexetil Losartan Eprosartan mesylate Telmisartan Valsartan Olmesartan Irbesartan
5.3 Pharmacokinetics of angiotensin II antagonists Dr u g Dosage mg Ac tive m et ab oli te Re ce p to r an tagoni sm B ioavai lab il ity % E ff ec t o f f ood T max ( h ) Hal f life ( h ) Pr ot ein b in d in g% V d (L) Exc re tion (R en al/ fe cal) [%]
Losartan 25-100 E-3174 Both b 33 AUC/Cmax ↓ 10% 1–2
(3–4) 1–3 (6–9) Both ≥99 34 (12) 40/60 Valsartan 80-320 No Non-competitive 10-35 AUC/Cmax ↓40–50% 2–4 6–9 94–97 17 13/83 Irbesartan 150-300 No Non-competitive 60-80 No 1.5–2 11–15 90–96 53–93 20/80 Candesartan cilexetil 8-32 Candesartan Non-competitive 15 No 3–5 5–9 >99 0.13 L/kg 33/67 Telmisartan 20-80 No Non-competitive 40–60 AUC ↓ 6–19% 0.5–1 20–38 >99.5 500–2000 <2/98
Eprosartan 400-800 No Competitive 13 AUC/Cmax ↓ 25% 1–3 5–9 98 13 7/90
Olmesartan medoxomil
20-40 Olmesartan Competitive 26–29 No 1–3 10–15 99 17 35–50/50–65
b Losartan = competitive; E-3174 = non-competitive. ↓ indicates decrease; indicates increase. Table.6. Comparative pharmacokinetics of the angiotensin II antagonists
KEY FACTORS EXAMINED IN AIIA CLASS COMPARISON
Candesartan cilexetil and olmesartan medoxomil are the ester prodrugs
Eprosartan, olmesartan and losartan are competitive or surmountable antagonists of the receptor. All these agents are still effective with once daily administration, although losartan and eprosartan
may provide better 24-hour effect if given twice daily, especially when lower doses are used. AT1 receptor antagonists are predominantly eliminated by biliary excretion, although compared
6. HEAD-TO-HEAD EFFICACY COMPARISONS
Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) play a role in the treatment of hypertension (HTN) and heart failure (HF). The literature shows that in patients with HTN with co morbidities, such as HF, myocardial infarction (MI), diabetes mellitus, chronic kidney disease, and stroke, ACE inhibitors and ARBs appear to provide added benefit beyond solely lowering blood pressure. In addition, clinical trials have also demonstrated that ACE inhibitors and ARBs may be beneficial in the prevention of diabetes, atrial fibrillation (AF), and recurrent stroke. [23]
Table.7. Licensed indications of ACE inhibitors and angiotensin II receptor antagonists and WHO Defined Daily Doses for Hypertension
Adapted from: APC/DTC Briefing Document., 2008
1. The differences between ACEIs and ARBs in blood pressure control, cardiovascular risk reduction, cardiovascular events, quality of life, and other outcomes for adult patients with essential hypertension. 2. The differences between ACEIs and ARBs in safety, adverse events, tolerability, persistence, and adherence for adult patients with essential hypertension.
Table.8. Number of included studies (number of publications) that evaluated various treatment comparisons [24]
1. The differences between ACEIs and ARBs in blood pressure control, cardiovascular risk reduction, cardiovascular events, quality of life, and other outcomes for adult patients with essential hypertension. [24]
Key Points
Effect on Blood Pressure
• There was no clear difference in the blood pressure lowering efficacy between ACEIs and ARBs.
Mortality and Major Cardiovascular Events
• Few deaths or major cardiovascular events occurred in the identified studies comparing ACEIs to ARBs; this precluded any assessment of a differential effect of ACEIs and ARBs on these events.
Effect on Quality of Life
• No significant difference was observed between ACEIs and ARBs in terms of their impact on quality of life.
Effect on Rate of Use of a Single Antihypertensive Agent
Effect on Lipid Levels
• Available evidence suggests that ACEIs and ARBs have a similar lack of impact on lipid levels for individuals with essential hypertension.
Diabetes Control
• Available evidence suggests that ACEIs and ARBs have a similar lack of impact on glucose levels or HgbA1c for individuals with essential hypertension.
LV mass/function outcomes
• Evidence does not demonstrate a difference between ACEIs and ARBs with regard to their effect on LV mass or function for individuals with essential hypertension.
Renal disease
• There are no consistently demonstrated differential effects related to renal function as measured by creatinine or GFR with use of ACEIs versus ARBs.
• There is a consistent finding of no differential effect related to reduction of urinary protein or albumin excretion among patients with essential hypertension with use of ACEIs versus ARBs. [24]
2. The differences between ACEIs and ARBs in safety, adverse events, tolerability, persistence, and adherence for adult patients with essential hypertension. [24]
Key Points
• Cough was modestly more frequently observed as an adverse event in groups treated with ACEIs than in groups treated with ARBs.
• Withdrawals due to adverse events were modestly more frequent for groups receiving an ACEI rather than an ARB; this is consistent with differential rates of cough.
• No significant between-class differences were observed in the rates of any other commonly reported adverse events.
Table.9. Studies reporting angioedema [24]
Figure 8. Studies reporting withdrawals due to adverse events for ACEIs vs. ARBs [24]
3. The differences of effectiveness and tolerability of ACEIs or ARBs for subgroups of patients based on demographic characteristics (age, racial and ethnic groups, sex). [24]
Key Points
• Evidence does not support conclusions regarding the comparative effectiveness, adverse events, or tolerability of ACEIs and ARBs for any particular patient subgroup.[24]
Key question Strength of
evidence
Conclusions
1. The differences between ACEIs and ARBs in the following health outcomes:
retrospective cohort study, and 1 case-control study) in which 13,532 patients receiving an ACEI or an ARB were followed for periods from 12 weeks to 5 years (median 16.5 weeks).
Blood pressure outcomes were confounded by additional treatments and varying dose escalation protocols.
b. Mortality and major cardiovascular events
Moderate Due to insufficient numbers of deaths or major cardiovascular events in the included studies, it was not possible to discern any differential effect of ACEIs vs. ARBs for these critical outcomes. In 9 studies that reported mortality, MI, or clinical stroke as outcomes among 3,356 subjects, 16 deaths and 13 strokes were reported. This may reflect low event rates among otherwise healthy patients and relatively few studies with extended followup.
c. Quality of life Low No differences were found in measures of general quality of life; this is based on 4 studies, 2 of which did not provide quantitative data. d. Rate of use of a single
antihypertensive
High There was no statistically evident difference in the rate of treatment success based on use of a single antihypertensive for ARBs compared to ACEIs. The trend toward less frequent addition of a second agent to an ARB was heavily influenced by retrospective cohort studies, where medication discontinuation rates were higher in ACEI-treated patients, and by RCTs with very loosely defined protocols for medication titration and switching e. Risk factor reduction and
other intermediate outcomes
Moderate (lipid levels, markers of carbohydrate metabolism/ diabetes control,
There were no consistent differential effects of ACEIs vs. ARBs on several potentially important clinical outcomes, including lipid levels,
progression of renal disease) to Low (progression to type 2 diabetes and LV mass/function
progression of renal disease (either based on creatinine, GFR, or proteinuria). Relatively few studies assessed these outcomes over the long term.
2. The differences between ACEIs and ARBs in safety, adverse events, tolerability, persistence, and adherence
High (cough, withdrawals due to adverse events) to Moderate (persistence/ adherence) to Low (angioedema)
ACEIs have been consistently shown to be associated with greater risk of cough than ARBs: pooled odds ratio (Peto) = 0.32. For RCTs, this translates to a difference in rates of cough of 6.7 percent (NNT = 15); however, for cohort studies with lower rates of cough, this translates to a difference of 1.1 percent (NNT = 87). This is generally consistent with evidence reviewed regarding withdrawals due to adverse events, in which the NNT is on the order of 27—that is, 1 more withdrawal per 27 patients treated with an ACEI vs. An ARB. There was no evidence of differences in rates of other commonly reported specific adverse events.
Angioedema was reported only in patients treated with ACEIs; however, because angioedema was rarely explicitly reported in the included studies, it was not possible to estimate its frequency in this population.
ACEIs and ARBs have similar rates of adherence based on pill counts; this result may not be applicable outside the clinical trial setting. Rates of continuation with therapy appear to be
somewhat better with ARBs than with ACEIs; however, due to variability in definitions,
and relatively small sample sizes for ARBs, the precise magnitude of this effect is difficult to quantify.
3. The differences of effectiveness and tolerability of ACEIs or ARBs for subgroups of patients based on demographic characteristics (age, racial and ethnic groups, sex).
Very low Evidence does not support conclusions regarding the comparative effectiveness, adverse events, or tolerability of ACEIs and ARBs for any particular patient subgroup.
Abbreviations: ACEI(s) = angiotensin-converting enzyme inhibitor(s); ARB(s) = angiotensin II receptor blocker(s)/antagonist(s);
GFR = glomerular filtration rate; LV = left ventricular;
MI = myocardial infarction; NNT = number-needed-to-treat;
RCT(s) = randomized controlled trial(s)
7. RESULTS
7.1 Comparison of consumption over the three years period
Figure 9. Comparison of consumption of agents acting the Renin-angiotensin-aldosterone system between states in 2005-2007
111,10 131,57 153,44 96,30 109,20 121,70 137,87 150,77 166,01 106,22 112,34 117,91 0,00 20,00 40,00 60,00 80,00 100,00 120,00 140,00 160,00 180,00 DDD/100 0 i n h abit ant s/day
Lithuania Denmark Finland Norway
2005 2006 2007
Figure 10. Comparison of consumption of agents acting the Renin-angiotensin-aldosterone system between states in 2005 97,57 12,52 1,005 0,001 55,10 6,70 22,10 12,50 75,34 14,74 30,97 16,82 42,89 7,35 30,62 25,36 0,00 10,00 20,00 30,00 40,00 50,00 60,00 70,00 80,00 90,00 100,00 DDD/100 0 i n h abit ant s/day
Lithuania Denmark Finland Norway
Figure 11. Comparison of consumption of agents acting the Renin-angiotensin-aldosterone system between states in 2006 107,94 16,45 7,08 0,10 62,00 8,50 24,60 14,10 78,88 14,40 37,54 19,95 43,40 7,11 33,58 28,25 0,00 20,00 40,00 60,00 80,00 100,00 120,00 DDD/100 0 i n h abit ant s/day
Lithuania Denmark Finland Norway
Figure 12. Comparison of consumption of agents acting the Renin-angiotensin-aldosterone system between states in 2007 118,33 21,44 12,03 1,64 67,40 10,60 27,60 16,00 86,20 14,97 42,61 22,23 43,92 6,99 36,39 30,61 0,00 20,00 40,00 60,00 80,00 100,00 120,00 DDD/100 0 i n h abit a n ts/day
Lithuania Denmark Finland Norway
7.2 Comparison of consumption over the three years period in Lithuania
Figure 13. Utilization of Agents acting on the Renin-angiotensin-aldosterone system in 2005-2007 in Lithuania
7.3 Pharmacoeconomic calculations suggesting the reference price
1.Utilization of Angiotensin converting enzyme inhibitor‘s and Angiotensin II antagonist‘s per 2007. Utilization of Angiotensin converting enzyme inhibitor‘s combined with diuretics or calcium channel blockers and Angiotensin II antagonist‘s combined with diuretics per 2007.
Table.11. The calculated data of Utlization of Angiotensin converting enzyme inhibitor‘s (plain and combinations with diuretics and calcium channel blockers) per 2007
Table.12. The calculated data of Utlization of Angiotensin II antagonist‘s (plain and combinations with diuretics) per 2007
1. DDD/1000inhabitants/day
Figure 16. Utilization of Angiotensin converting enzyme inhibitor‘s per 2007 (DDD/1000inhabitants/day)
7,1 26,2 4,1 16,4 41,8 8,6 6,3 1,5 1,1 5,2 0,0 5,0 10,0 15,0 20,0 25,0 30,0 35,0 40,0 45,0 DDD/1000/day
Captopril Enalapril Lisinopril Perindopril Ramipril Quinapril Fosinopril Trandolapril Spirapril Zofenopril
Figure 17. Utilization of Angiotensin II antagonist‘s per 2007 (DDD/1000inhabitants/day) 9,7 0,1 0,7 0,4 0,2 0,4 0,6 0,0 1,0 2,0 3,0 4,0 5,0 6,0 7,0 8,0 9,0 10,0 DDD/1000/day
Losartan Eprosartan Valsartan Irbesartan Candesartan Telmisartan Olmesartan
medoxomil
Utilization of Angiotensin II antagonist's per 2007 (DDD/1000/day)
Figure 18. Utilization of Angiotensin converting enzyme inhibitor‘s and Angiotensin II antagonist‘s combinations with diuretics or calcium channel blockers per 2007 (DDD/1000inhabitants/day)
2,9 8,7 0,4 6,8 2,1 0,5 1,6 0,04 0,001 0,003 0,0 1,0 2,0 3,0 4,0 5,0 6,0 7,0 8,0 9,0 Enalapril and diuretics Perindopril and diuretics Ramipril and diuretics Quinapril and diuretics Fosinopril and diuretics Trandolapril and calcium channel blockers Losartan and diuretics Valsartan and diuretics Telmisartan and diuretics Olmesartan medoxomil and diuretics DDD/1000/day
Figure 19. Utilization of Angiotensin converting enzyme inhibitor‘s and Angiotensin II antagonist‘s and combinations with diuretics and calcium channel blockers per 2007 (DDD/1000inhabitants/day)
DDD/1000 inhabitants/day 118,33; 77% 1,64; 1% 21,44; 14% 12,03; 8% ACEI, plain ACEI, combinations AIIA, plain AIIA, combinations
Figure 20. Utilization of Angiotensin converting enzyme inhibitor‘s and Angiotensin II antagonist‘s (plain and combinations with diuretics and calcium channel blockers) per 2007 (DDD/1000inhabitants/day)
139,7; 91% 13,6;
9%
ACEI (plain and combinations with diuretics or calcium channel blockers)
AIIA (plain and combinations with diuretics)
2. The actual amounts of money spent on Angiotensin converting enzyme inhibitor’s and Angiotensin II antagonist’s in 2007 Figure 21. The amount of money spent on Angiotensin converting enzyme inhibitor‘s in 2007
3 819 908,26 Lt 9 164 817,80 Lt 2 643 673,30 Lt 15 560 019,05 Lt 16 835 944,06 Lt 7 860 526,81 Lt 6 879 577,40 Lt 1 634 913,60 Lt 1 098 601,85 Lt 9 247 214,54 Lt 0,00 Lt 2 000 000,00 Lt 4 000 000,00 Lt 6 000 000,00 Lt 8 000 000,00 Lt 10 000 000,00 Lt 12 000 000,00 Lt 14 000 000,00 Lt 16 000 000,00 Lt 18 000 000,00 Lt
Figure 22. The amount of money spent on Angiotensin II antagonist‘s in 2007 8 313 815,63 Lt 269 482,16 Lt 1 407 699,68 Lt 957 756,62 Lt 406 634,73 Lt 729 186,06 Lt 1 794 760,56 Lt 0,00 Lt 1 000 000,00 Lt 2 000 000,00 Lt 3 000 000,00 Lt 4 000 000,00 Lt 5 000 000,00 Lt 6 000 000,00 Lt 7 000 000,00 Lt 8 000 000,00 Lt 9 000 000,00 Lt
Losartan Eprosartan Valsartan Irbesartan Candesartan Telmisartan Olmesartan
Figure 23. The amount of money spent on Angiotensin converting enzyme inhibitor‘s and Angiotensin II antagonist‘s combinations with diuretics or calcium channel blockers in 2007
Figure 24. The amount of money spent on Angiotensin converting enzyme inhibitor‘s and Angiotensin II antagonist‘s and combinations with diuretics and calcium channel blockers in 2007
Figure 25. The amount of money spent on of Angiotensin converting enzyme inhibitor‘s and Angiotensin II antagonist‘s (plain and combinations with diuretics and calcium channel blockers) in 2007
88 624 532,08 Lt; 76% 27 996 465,92 Lt;
24%
ACEI and AIIA plain
3. Pharmacoeconomic analysis of angiotensin converting enzyme inhibitor‘s and angiotensin II receptor antagonist‘s by cost minimisation and reference price analysis.
a) Reference prices of Angiotensin converting enzyme inhibitor‘s
Name of agent
DDD per 2007
1DDD
price Spent Reference price Spent
Reference price Spent Captopril 8806922,50 0,43 Lt 3 819 908,26 Lt 0,33 Lt 2 880 022,40 Lt 0,43 Lt 3 819 908,26 Lt Enalapril 32260016,87 0,28 Lt 9 164 817,80 Lt 0,28 Lt 9 164 817,80 Lt 0,28 Lt 9 164 817,80 Lt Lisinopril 5034705,00 0,53 Lt 2 643 673,30 Lt 0,33 Lt 1 646 439,29 Lt 0,53 Lt 2 643 673,30 Lt Perindopril 20254897,50 0,77 Lt 15 560 019,05 Lt 0,33 Lt 6 623 716,57 Lt 0,53 Lt 10 635 644,34 Lt Ramipril 51483229,60 0,33 Lt 16 835 944,06 Lt 0,33 Lt 16 835 944,06 Lt 0,33 Lt 16 835 944,06 Lt Quinapril 10619759,87 0,74 Lt 7 860 526,81 Lt 0,33 Lt 3 472 852,90 Lt 0,53 Lt 5 576 329,82 Lt Fosinopril 7783336,21 0,88 Lt 6 879 577,40 Lt 0,33 Lt 2 545 291,24 Lt 0,53 Lt 4 086 952,09 Lt Trandolapril 1823808,00 0,90 Lt 1 634 913,60 Lt 0,33 Lt 596 418,09 Lt 0,53 Lt 957 663,36 Lt Spirapril 1338670,00 0,82 Lt 1 098 601,85 Lt 0,33 Lt 437 769,22 Lt 0,53 Lt 702 922,24 Lt Zofenopril 6386828,00 1,45 Lt 9 247 214,54 Lt 0,33 Lt 2 088 607,88 Lt 0,53 Lt 3 353 659,58 Lt Total 74 745 196,65 Lt Total 46 291 879,44 Lt Total 57 777 514,84 Lt
Save: Save: 28 453 317,22 Lt Save:
b) Reference prices of Angiotensin II antagonist‘s Name of agent
DDD per 2007
1DDD
price Spent Referent price Spent Referent price Spent
c) Reference prices of Angiotensin converting enzyme inhibitor‘s combinations with diuretics or calcium channel blockers Name of agent
DDD per 2007
1DDD
price Spent Reference price Spent
Reference
price Spent
Enalapril and diuretics 3570989,964 0,35 Lt 1 252 277,88 Lt 0,35 Lt 1 252 277,88 Lt 0,35 Lt 1 252 277,88 Lt Perindopril and diuretics 10727418,75 1,43 Lt
15 312 229,20
Lt 0,35 Lt 3 761 900,57 Lt 0,79 Lt 8 458 437,74 Lt
Ramipril and diuretics 551614 0,43 Lt 236 504,74 Lt 0,35 Lt 193 440,48 Lt 0,43 Lt 236 504,74 Lt Quinapril and diuretics 8403239,707 0,79 Lt 6 625 851,15 Lt 0,35 Lt 2 946 855,43 Lt 0,79 Lt 6 625 851,15 Lt Fosinopril and diuretics 2592741,333 0,89 Lt 2 304 817,17 Lt 0,35 Lt 909 224,79 Lt 0,79 Lt 2 044 344,65 Lt Trandolapril and calcium
d) Reference prices of Angiotensin II antagonist‘s combinations with diuretics
Name of agent
DDD per 2007
1DDD
price Spent Reference price Spent
e) One reference price of Angiotensin converting enzyme inhibitor‘s and Angiotensin II antagonist‘s Name of agent DDD per 2007 1DDD price Spent Reference price Spent Reference price Spent Reference price Spent Captopril 8806922,50 0,43 Lt 3 819 908,26 Lt 0,33 Lt 2 880 022,40 Lt 0,43 Lt 3 819 908,26 Lt 0,43 Lt 3 819 908,26 Lt Enalapril 32260016,87 0,28 Lt 9 164 817,80 Lt 0,28 Lt 9 164 817,80 Lt 0,28 Lt 9 164 817,80 Lt 0,28 Lt 9 164 817,80 Lt Lisinopril 5034705,00 0,53 Lt 2 643 673,30 Lt 0,33 Lt 1 646 439,29 Lt 0,53 Lt 2 643 673,30 Lt 0,53 Lt 2 643 673,30 Lt Perindopril 20254897,50 0,77 Lt 15 560 019,05 Lt 0,33 Lt 6 623 716,57 Lt 0,53 Lt 10 635 644,34 Lt 0,70 Lt 14 133 559,65 Lt Ramipril 51483229,60 0,33 Lt 16 835 944,06 Lt 0,33 Lt 16 835 944,06 Lt 0,33 Lt 16 835 944,06 Lt 0,33 Lt 16 835 944,06 Lt Quinapril 10619759,87 0,74 Lt 7 860 526,81 Lt 0,33 Lt 3 472 852,90 Lt 0,53 Lt 5 576 329,82 Lt 0,70 Lt 7 410 307,04 Lt Fosinopril 7783336,21 0,88 Lt 6 879 577,40 Lt 0,33 Lt 2 545 291,24 Lt 0,53 Lt 4 086 952,09 Lt 0,70 Lt 5 431 093,72 Lt Trandolapril 1823808,00 0,90 Lt 1 634 913,60 Lt 0,33 Lt 596 418,09 Lt 0,53 Lt 957 663,36 Lt 0,70 Lt 1 272 625,50 Lt Spirapril 1338670,00 0,82 Lt 1 098 601,85 Lt 0,33 Lt 437 769,22 Lt 0,53 Lt 702 922,24 Lt 0,70 Lt 934 103,58 Lt Zofenopril 6386828,00 1,45 Lt 9 247 214,54 Lt 0,33 Lt 2 088 607,88 Lt 0,53 Lt 3 353 659,58 Lt 0,70 Lt 4 456 631,51 Lt Losartan 11914583,98 0,70 Lt 8 313 815,63 Lt 0,33 Lt 3 896 283,72 Lt 0,53 Lt 6 256 229,02 Lt 0,70 Lt 8 313 815,63 Lt Eprosartan 103264,00 2,61 Lt 269 482,16 Lt 0,33 Lt 33 769,19 Lt 0,53 Lt 54 222,89 Lt 0,70 Lt 72 056,05 Lt Valsartan 899724,00 1,56 Lt 1 407 699,68 Lt 0,33 Lt 294 225,97 Lt 0,53 Lt 472 436,08 Lt 0,70 Lt 627 813,73 Lt Irbesartan 481544,00 1,99 Lt 957 756,62 Lt 0,33 Lt 157 473,57 Lt 0,53 Lt 252 853,94 Lt 0,70 Lt 336 014,08 Lt Candesartan 293020,00 1,39 Lt 406 634,73 Lt 0,33 Lt 95 822,82 Lt 0,53 Lt 153 861,87 Lt 0,70 Lt 204 464,90 Lt Telmisartan 442008,00 1,65 Lt 729 186,06 Lt 0,33 Lt 144 544,58 Lt 0,53 Lt 232 093,99 Lt 0,70 Lt 308 426,46 Lt Olmesartan medoxomil 686476,00 2,61 Lt 1 794 760,56 Lt 0,33 Lt 224 490,03 Lt 0,53 Lt 360 461,69 Lt 0,70 Lt 479 012,52 Lt
Total 88 624 532,08 Lt Total 51 138 489,31 Lt Total 65 559 674,34 Lt Total 76 444 267,80 Lt
f) one reference price of Angiotensin converting enzyme inhibitor‘s and Angiotensin II antagonist‘s combinations with diuretics and calcium channel blockers Name of agent DDD per 2007 1DDD
price Spent Referent price Spent Referent price Spent
Enalapril and diuretics 3570989,964 0,35 Lt 1 252 277,88 Lt 0,35 Lt 1 252 277,88 Lt 0,35 Lt 1 252 277,88 Lt Perindopril and diuretics 10727418,75 1,43 Lt
15 312 229,20
Lt 0,35 Lt 3 761 900,57 Lt 0,71 Lt 7 662 982,63 Lt
Ramipril and diuretics 551614 0,43 Lt 236 504,74 Lt 0,35 Lt 193 440,48 Lt 0,43 Lt 236 504,74 Lt Quinapril and diuretics 8403239,707 0,79 Lt 6 625 851,15 Lt 0,35 Lt 2 946 855,43 Lt 0,71 Lt 6 002 737,60 Lt Fosinopril and diuretics 2592741,333 0,89 Lt 2 304 817,17 Lt 0,35 Lt 909 224,79 Lt 0,71 Lt 1 852 088,77 Lt Trandolapril and calcium
channel blockers 572180 1,27 Lt 726 259,90 Lt 0,35 Lt 200 652,58 Lt 0,71 Lt 408 728,84 Lt
4. Predictable savings
Figure 26. Actual spend comparing with amount of money could be spent if reference prices were adapted for ACEI and AIIA separately
0,00 Lt 10 000 000,00 Lt 20 000 000,00 Lt 30 000 000,00 Lt 40 000 000,00 Lt 50 000 000,00 Lt 60 000 000,00 Lt 70 000 000,00 Lt 80 000 000,00 Lt 1 DDD price 74 745 196,65 Lt 13 879 335,43 Lt 26 457 940,03 Lt 1 534 329,69 Lt 1 Reference price 57 777 514,84 Lt 12 346 629,65 Lt 19 068 573,04 Lt 1 444 969,09 Lt 2 Reference price 46 291 879,44 Lt 10 341 603,38 Lt 9 264 351,73 Lt
ACEI plain AIIA plain ACEI combinations AIIA combinations
Table.13. The reference prices of Angiotensin converting enzyme inhibitor‘s Name of agent 1DDD price 1 Reference price 2 Reference price
Captopril 0,43 Lt 0,43 Lt 0,33 Lt Enalapril 0,28 Lt 0,28 Lt 0,28 Lt Lisinopril 0,53 Lt 0,53 Lt 0,33 Lt Perindopril 0,77 Lt 0,53 Lt 0,33 Lt Ramipril 0,33 Lt 0,33 Lt 0,33 Lt Quinapril 0,74 Lt 0,53 Lt 0,33 Lt Fosinopril 0,88 Lt 0,53 Lt 0,33 Lt Trandolapril 0,90 Lt 0,53 Lt 0,33 Lt Spirapril 0,82 Lt 0,53 Lt 0,33 Lt Zofenopril 1,45 Lt 0,53 Lt 0,33 Lt
Table.14. The reference prices of Angiotensin II antagonist‘s
Name of agent 1DDD price 1 Reference price 2 Reference price
Losartan 0,70 Lt 0,70 Lt 0,70 Lt Eprosartan 2,61 Lt 1,39 Lt 0,70 Lt Valsartan 1,56 Lt 1,39 Lt 0,70 Lt Irbesartan 1,99 Lt 1,39 Lt 0,70 Lt Candesartan 1,39 Lt 1,39 Lt 0,70 Lt Telmisartan 1,65 Lt 1,39 Lt 0,70 Lt Olmesartan medoxomil 2,61 Lt 1,39 Lt 0,70 Lt
Table.15. The reference prices of ACEI combinations with diuretics and calcium channel blockers Name of agent 1DDD price 1 Reference price 2 Reference price
Enalapril and diuretics 0,35 Lt 0,35 Lt 0,35 Lt
Perindopril and diuretics 1,43 Lt 0,79 Lt 0,35 Lt
Ramipril and diuretics 0,43 Lt 0,43 Lt 0,35 Lt
Quinapril and diuretics 0,79 Lt 0,79 Lt 0,35 Lt
Fosinopril and diuretics 0,89 Lt 0,79 Lt 0,35 Lt
Trandolapril and calcium
channel blockers 1,27 Lt 0,79 Lt 0,35 Lt
Table.16. The reference prices of AIIA combinations with diuretics
Name of agent 1DDD price 1 Reference price
Losartan and diuretics 0,71 Lt 0,71 Lt
Valsartan and diuretics 2,49 Lt 0,71 Lt
Telmisartan and diuretics 2,06 Lt 0,71 Lt
