CVS Week 3 Course Pack 2023 PDF

CVS Week 3 Course Pack 2023 Mr Buthelezi`s Funny Turn Objectives 03.03.001. Interpret changes in blood pressure in the context of abnormalities of cardiovascular homeostasis. 03.03.002. Explain the mechanisms responsible for the long term control of blood pressure. 03.03.003. S...

CVS Week 3 Course Pack 2023 Mr Buthelezi`s Funny Turn Objectives 03.03.001. Interpret changes in blood pressure in the context of abnormalities of cardiovascular homeostasis. 03.03.002. Explain the mechanisms responsible for the long term control of blood pressure. 03.03.003. Show proficiency in the measurement of systemic blood pressure and identify common pitfalls in blood pressure measurement. 03.03.004. Explain the pathophysiological changes which could lead to an increased blood pressure. 03.03.005. Identify common forms of hypertension and explain the pathophysiological mechanisms. 03.03.006. Identify organs affected by a high blood pressure and provide potential physical and biological explanations for these organ changes. 03.03.007. Explain the clinical features of target organ damage in hypertension. 03.03.008. Explain the rationale for the approach to assessing a hypertensive patient on the first visit. 03.03.009. Explain the ECG and X-Ray changes that occur in hypertension. 03.03.010. Explain the rationale for the use of special investigations (blood tests and others) in the management of hypertension. 03.03.011. Indicate the prevalence of hypertension and cardiovascular disease in the diverse South African communities and suggest reasons for these differences. 03.03.012. Explain the mechanisms responsible for the beneficial effects of non-drug therapy in hypertension. 03.03.013. Explain the mechanisms responsible for the beneficial actions and side effects of drug therapy in hypertension. 03.03.014. Identify factors that determine medication compliance in hypertension. 03.03.015. Explain the rationale for the use of specific drug classes in certain circumstances in hypertension. 03.03.016. Identify risk factors for cardiovascular disease and describe the management of these risks. 03.03.017. Explain the ECG changes that occur in myocardial ischaemia and infarction. 03.03.018. Explain the major risk factors for cardiovascular disease and name one study to support your answer. 1 03.03.019. Distinguish between psychological and physiological causes of tiredness. 03.03.020. Using examples from research on Anaemia, compare the strengths and weaknesses of the following study designs: Descriptive, Cross sectional, Case control, Cohort, International. 03.03.021. Demonstrate a competent working knowledge of the applied anatomy and physiology of the cardiovascular system. 03.03.022. Demonstrate with a relevant and clear commentary the physical examination of the cardiovascular system. 03.03.023. Continue with developing skills necessary for the successful assessment of signs and symptoms using the eight-component history, a limited physical examination with non-standardised patients allocated in the teaching hospital wards. 03.03.024. To provide an introduction to cardiovascular disease prevention strategies. Learning Topics LT 03.03.001. Risk Factors for and the Pathogenesis of Systemic Hypertension LT 03.03.002. Clinical Investigation in Systemic Hypertension LT 03.03.003. Classes of Drugs Used in the Management of Systemic Hypertension LT 03.03.004. Cellular and Molecular Mechanisms of Cardiovascular Damage and the Adverse Effects Thereof LT 03.03.005. Cardiac Hypertrophy LT 03.03.001. Risk Factors for and the Pathogenesis of Systemic Hypertension Aim The aim of this learning topic is to explain the pathophysiological mechanisms of systemic hypertension. Delivery Objectives Explain the pathophysiological mechanisms responsible for different forms of systemic hypertension in order that students develop a better approach to managing primary and secondary forms of hypertension Content [] Indicates non-core material Around a quarter of all adults have systemic (as opposed to pulmonary) hypertension and in South Africa the rule of halves applies (half are unaware of it, a half who are aware are not treated and of those treated a half are uncontrolled). Thus, hypertension is one of the leading causes of death and hospitalizations in our country. The predominant form of systemic hypertension found in any community (over 95% of all hypertension) is “essential” hypertension (EHT) or primary hypertension, originally named "EHT" because it was thought (many years ago and incorrectly so) that a higher blood pressure was protective. A more appropriate name for EHT is probably “idiopathic” hypertension, because, as yet, no uniform hypothesis for the pathogenesis of EHT has been provided, and certainly no single cause has been discovered. More recently, a common form of systemic hypertension associated only with elevated systolic blood pressures in the elderly has been shown to be a “high risk” form of hypertension and this is called isolated systolic hypertension (ISH). As shall be discussed this simply represents a later stage of the evolution of EHT and although considered in a separate category 2 because of the blood pressure (BP) changes that accompany it, it is likely to reflect a similar pathophysiological process. Secondary hypertension, so named because the hypertension occurs secondary to an alternative primary disease, are rare forms of hypertension, but are important to identify because the primary disease should be treated whenever possible or practical. Lastly, although not classically considered a separate form of hypertension, severe hypertension is best considered under a separate heading as often the factors that maintain blood pressures in severe hypertension are relatively unique. This overview will discuss some general aspects of hypertension and then specific details will be provided regarding each of these forms of hypertension. Static versus dynamic components of blood pressure It is now well accepted that cardiovascular events (strokes, heart attacks, heart failure, renal failure, peripheral vascular disease and sudden cardiac death) are determined by increases in both the static (or steady) component of blood pressure (mean arterial blood pressure [MAP]), which, according to the equation MAP= diastolic BP + [(systolic- diastolic blood pressure)/3], is mainly a function of diastolic blood pressure, and the dynamic component of blood pressure (pulsatile or pulse pressure [systolic-diastolic blood pressure]), which is mainly a function of systolic blood pressure. Hence, when considering the pathophysiology of hypertension one has to consider the causes of increases in both the static and the dynamic components of arterial pressures. Is static blood pressure in hypertension increased because of changes in flow or resistance to flow? As indicated in numerous places throughout this block, assuming that right atrial pressure is 0 mm Hg, the static (steady) component of blood pressure (mean arterial blood pressure) is determined by cardiac output (CO) and total peripheral vascular resistance (TPR) better known as systemic vascular resistance (SVR). This is defined by the equation MAP=CO x TPR (P=FxR). It was previously thought that almost all patients with hypertension (irrespective of the cause) except those with ISH, have a normal CO and an elevated TPR. However, hypertension in its early form can start with increases in CO, because of an enhanced blood volume (through renal mechanisms-see below and lecture). Nevertheless, as a consequence of either autoregulatory changes (see L04.01.03), or because continuously high pressures produce compensatory vascular changes (which result in narrowing of the lumen-see below), even if the initiating event was an increased blood volume and CO, the ultimate result was always thought to be an increased TPR. More recent data have now provided clear and unequivocal evidence however, that increases in the steady component of BP in hypertension in Africa (those of African ancestry) are produced in-part by age-related increases in SV and hence CO, effects mediated largely by increases in filling volumes in the heart (Frank-Starling effect) and which presumably therefore reflect an enhanced blood volume (renal effects). This is an important issue as age-related increases in BP starting from early adulthood (late twenties) are the primary cause of hypertension. Moreover, as will be discussed in subsequent sections, unfortunately the focus on drug therapy in hypertension has been on vasodilation which has thus resulted in a glaring omission in the management of hypertension in Africa. Although SVR does indeed increase, which does to some degree allow for vasodilators to produce benefits, this is not an aging effect and hence targeting vasodilation often results in sustained hypertension or uncontrolled blood pressures at older ages. Determinants of the dynamic component of blood pressure Pulsatile pressure or pulse pressure (and hence systolic blood pressure) as determined at the brachial pulse is a function of the incident or outgoing (forward travelling) pressure wave produced by an interaction of two factors. This pressure wave is 3 generated by the force produced by ventricular ejection (aortic flow) of blood into a normally very compliant and large diameter (low resistance) artery (the aorta). It is important to recognise that as with steady component pressures, pulsatile pressures follow the same basic physical principle (P=FxR). Because flow in the aorta during ejection is very high, even a large diameter vessel such as the aorta can generate resistance to flow (R). This is nevertheless called impedance and not resistance and is termed characteristic impedance (abbreviated Zc). Thus, pulse pressure =Aortic flow during ejection x Zc. Two factors determine Zc and these are aortic diameter and the stiffness of the aorta. It is now recognised that increases in pulse pressure in hypertension are caused by arteriosclerotic-induced increases in stiffness and hence Zc and that compensatory dilatation of the aorta (increased diameter) tends to maintain Zc within normal levels until stiffness of the aorta is advanced. Arteriosclerosis will be discussed later in this week but is essentially “hardening” of the arteries caused by a loss of elastic tissue, increases in collagen and cross-linking of collagen molecules and calcification, effects produced by all cardiovascular risk factors, but in particular hypertension per se. These effects in the aorta decrease aortic elasticity, the ability of the aorta to buffer the load produced by ventricular ejection, and cause an increased Zc and pulsatile load. It is now accepted that even from an early adult age, with aging Zc increases and pulse pressure and systolic blood pressure increase. However, as with the steady component of pressure, more recent data have now provided clear and convincing evidence, that increases in the pulsatile component of BP in hypertension in Africa (those of African ancestry) are also produced by age-related increases in aortic flow produced by an enhanced SV and hence CO, effects produced largely by increases in filling volumes in the heart (Frank-Starling effect) and which presumably therefore reflect an enhanced blood volume (renal effects). Although Zc does indeed also increase in hypertension in Africa, the combined impact of increases in aortic flow and Zc produce a marked impact on the pulsatile component of BP often difficult to manage. Unfortunately, not measured at the brachial pulse, a second and equally as important determinant of central arterial pulsatile load is that generated by waves that are reflected back off points of vascular tapering (backward travelling waves) which may return to the central arteries during systole (the reflected waves). The effect of reflected waves is determined by two factors. The first is through Newton’s Laws of Motion (inertial forces and for every action there is an equal and opposite reaction), the magnitude of reflected waves is determined by the amplitude of the incident or forward travelling pressure wave discussed above. This is fortunate, as if we are able to reduce the forward wave and hence brachial pulse pressure with therapy, the reflected wave will automatically be reduced and hence it is not necessary to measure it. However, there is also a component of the magnitude of the reflected wave that is a function of vascular smooth muscle tone of medium and small sized arteries (vasoconstriction increases vascular tapering). Thus, a large component of the adverse effects of reflected wave cannot be determined from BP measures at the brachial pulse. At present there is uncertainty as to how to prevent damage caused by increases in reflected waves, effects which largely account for pulsatile load effects on the heart, but what is certain is that the lower the brachial pulse pressure, the lower the incident and hence reflected wave and the less chance that reflected waves will cause damage to the heart. Thus, most experts in the field would agree that in the treatment of hypertension, BP should be decreased to values that are as low as possible that patients can tolerate often far lower than accepted thresholds particularly if at a high overall risk. Vascular remodelling maintains high blood pressures irrespective of the cause of hypertension. Because hypertension increases vascular wall lateral tensile stress (increases in wall tension, where tension is approximately = Pxr/h in a vessel wall, and P is pressure, r is radius, and h is wall thickness), longitudinal shear stress, and pulsatile stress (if the 4 pulse pressure [systolic blood pressure-diastolic blood pressure] is high), “compensatory” vascular remodelling occurs to attempt to limit the wall stress changes. The term “compensatory” is a misnomer as vascular remodelling is ultimately what mediates vascular target organ damage (see L03.03.02 and L03.03.03) and is thought to be a major determinant of increases in both the static (through TPR) and the dynamic (through Zc) components of blood pressure in hypertension. Thus, irrespective of the cause of the hypertension to begin with, ultimately, high pressures in sustained hypertension are through structural remodelling of vessels. Three structural vascular changes can occur that ultimately maintain high pressures in any form of hypertension. These include:  eutrophic vascular remodelling in arterioles, where although the wall does not thicken, the lumen size decreases and the wall thickness-to-lumen radius ratio increases. The reduced lumen size creates a resistance to flow and increases TPR and hence static pressures.  hypertrophic vascular remodelling in large and medium sized arteries and to some degree in arterioles. Vascular smooth muscle cell hypertrophy and hyperplasia together with fibrosis of the vascular wall decrease lumen diameter. In arterioles this will increase TPR and hence static pressures. In small arteries, this will increase the magnitude of the reflected wave and hence the pulsatile component of blood pressure not detected in the brachial pulse. If this occurs in the aorta, this will increase Zc and hence the dynamic component of blood pressure.  damage to the endothelial surface of all vessels with a resultant inability to produce the vasodilator nitric oxide. This has particularly important effects on small arteries where this will increase the magnitude of the reflected wave and hence the pulsatile component of blood pressure. In arterioles, this will increase TPR and hence the static component of blood pressure. Primary (essential) hypertension Primary hypertension is well accepted to occur as a consequence of environmental, genetic (blood pressure is a polygenic trait in which multiple genes are likely to contribute to the disorder in one individual), and other related phenotypic factors (e.g. obesity, salt sensitivity, etc.). However, the exact mechanisms of EHT have not been established. Numerous studies have attempted to identify the primary physiological abnormality of renal or vascular function that will explain EHT. Unfortunately, although a multitude of physiological and cellular factors have been linked to EHT, there is no technique for distinguishing the primary cause from secondary changes that occur in response to EHT. A few facts regarding the pathogenesis of EHT are however of clinical relevance. Risk factors for hypertension  Obesity is associated with the development of hypertension, and it is possible that this effect is mediated through an increase in the activity of the renin- angiotensin-aldosterone system (adipose tissue synthesizes angiotensin- converting enzyme and angiotensinogen), and an enhanced sympathetic nervous system activity, particularly in the kidneys and mediated by excess leptin production (leptin is released from adipose tissue). For unidentified reasons, relations between obesity or weight gain and blood pressure in groups of African origins are nevertheless weak. Weight reduction is an important goal in preventing hypertension or decreasing elevated blood pressures, but is often insufficient to control blood pressure to target levels and weight loss is often difficult to sustain. The main effect of obesity appears to be on the static component of blood pressure. 5  Salt-intake determines blood pressure and a low salt diet is now well recognized as reducing blood pressure. An excessive salt intake can increase blood pressures through fluid retention as well as by increasing vascular resistance. It is also well recognized that some individuals are particularly sensitive to the blood pressure increasing effects of salt intake. These individuals are called “salt-sensitive” hypertensives. This may or may not be genetically determined, but recent evidence suggests that alternative dietary factors (unidentified factors which can be corrected through the use of the DASH diet-see lecture 5) are likely to play a major role in determining "salt sensitivity". Whether the impact of excessive salt intake on hypertension is through changes in the static and dynamic components of blood pressure is still controversial, but it is possible that it modifies both. In South Africa, there is a particularly strong relationship between salt intake and dynamic blood pressures, but this is accounted for by increases in Zc and not increases in SV or CO and aortic flow. Importantly, although reducing sodium intake is an important goal in the management of hypertension, the overall effect is modest and hence cannot form the basis of antihypertensive treatment. Moreover, once Zc is increased, this is an irreversible effect.  Exercise reduces blood pressure and the converse also applies, i.e. that a lack of exercise results in increased blood pressures. The mechanisms of these effects are not well understood, but are likely to be directly mediated through sustained increases in endothelial nitric oxide release (see LT 03.01.01), as well as through a number of indirect effects (e.g. decreased weight). Whether the impact of exercise on hypertension is through changes in the static and dynamic components of blood pressure is still uncertain, but it is likely to involve both. The mechanism of the impact on the dynamic component is through a haemodynamic change which involves the whole arterial bed (total arterial compliance) not specific to either large or small arteries.  Excessive alcohol intake is associated with hypertension. The mechanisms of these effects are entirely unclear and the strength of the relationship between alcohol intake and blood pressure is weak at best and whether it is through static or dynamic effects has not been determined.  Smoking in most studies has been shown to contribute little to blood pressure variation when blood pressure is measured in the office. However, recent South African data in a large study size indicates that smoking contributes strongly to the variation in out-of-office blood pressures in groups of African descent. This effect is largely on static blood pressures.  Starting from early adulthood (early twenties) an increased age is the factor that accounts for the most variability in blood pressures at a population level. This effect is noted for both the static (in groups of African ancestry through an increased SV and CO) and dynamic (through an increased aortic flow [in groups of African ancestry] and aortic stiffness-associated increases in Zc [in all population groups] and through an increased wave reflection possibly through an increased medium-sized arterial tone [in all population groups]) components of blood pressure.  Approximately 20-60% of the variation of blood pressure aggregates in families and hence there is a strong belief that genetic factors control blood pressures at a population level. However, in keeping with polygenic traits the genes involved have proved difficult to identify. Presently there is strong evidence to indicate that the angiotensinogen and angiotensin-converting enzyme genes are involved in blood pressure control and some suggestions of ethnic differences in the genetic impact of renal handling of sodium. However, this may be population specific as the penetrance may depend on existing risk factors, such as obesity and co-existing genetic variants. The overall impact on blood pressure of each gene is nevertheless minor at best.  A diet low in total fat or high in fish oils reduces blood pressure, and consequently fats are implicated in the development of hypertension. The exact mechanisms are uncertain, but it is speculated that a low fat diet may alter calcium 6  metabolism and a fish oil diet can influence prostaglandin production and hence both kidney and vascular function. Prostaglandins are well recognized as being important in mediating vasodilator and natriuretic effects. These prostaglandins include PGE2 and prostacyclin (PGI2). Although these relationships between fat intake and blood pressure have been reported, the magnitude of the effect may be small. Physiological, neuro-hormonal and cellular changes in hypertension From a perspective that lends insights into pharmacological management, EHT is associated with: o increases in circulating or renal angiotensinogen concentrations and excessive production of aldosterone relative to renin. o alterations in a number of renal tubular mechanisms that control fluid reabsorption. o changes in plasma and intracellular Ca2+ ion concentrations which may influence vascular tone. o excessive sympathetic nervous system activity and a decrease in vascular responses to ß2 adrenoreceptor-mediated vasodilation. o alterations in the activity of guanosine trisphosphate proteins (G protein) linked to ß adrenoreceptor-mediated effects. o alterations in endothelial function (decreased nitric oxide and increased endothelin production). Thus, a number of pharmacological agents have been developed to target these systems and these agents have all been shown to successfully decrease blood pressure. Note: An increased blood pressure tends to cluster with a number of adverse clinical phenotypes such as insulin resistance, obesity, hyperlipidaemia (usually increased triglyceride concentrations), "salt sensitivity", and hyperuricaemia. All of these phenotypes could contribute, through a variety of pathophysiological mechanisms to hypertension ("salt sensitivity" and obesity have been discussed above; insulin resistance may lead to hypertension through the development of obesity or through the well known effects of insulin on salt excretion; hyperlipidaemia and hyperuricaemia may lead to hypertension through oxidative stress). Consequently, it is possible that primary hypertension in those persons who demonstrate clear clustering of adverse clinical phenotypes may in fact be a secondary disorder. The clustering of the above clinical phenotypes has led to the development of the term “metabolic syndrome” or “syndrome X” and hypertension is now frequently referred to as a “metabolic change”. However, from a clinical perspective the above view-point can have a serious negative impact on clinical practice as more frequently practitioners are not treating hypertension unless metabolic features are present. Thus, the fallacy of hypertension occurring only in response to metabolic changes needs to be dispelled. Isolated systolic hypertension As indicated above, ISH is associated with aging. However, the development of ISH is also thought to be a natural progression from EHT in earlier life. ISH was originally thought to occur mainly because of the arteriosclerotic changes described above where the aorta and other large vessels lose their natural elasticity following the destruction of elastic fibres and their replacement with cross-linked collagen and subsequently with calcium. Stiffer large vessels are unable to expand during systole, and consequently these vessels create an increase in Zc and the incident pressure wave and hence in pulsatile (pulse) and systolic blood pressures. However, there is emerging evidence to suggest that ISH may also be a consequence of increases in reflective pressure waves, 7 and these increases in reflective waves are mediated by an increased medium sized artery tone and hence an increase in the magnitude of the reflective wave. Moreover, recent evidence in Africa and in other populations shows a clear contribution of increases in aortic flow (determined by SV and CO) as caused by what may be an increased blood volume (renal effects). Irrespective of the exact mechanism however, the major change is an increased pulse pressure and systolic blood pressure. The lack of recoil of inelastic arteries during diastole tends to reduce blood flow in diastole and hence diastolic BP is normal or even reduced. To understand this, please remember that the aorta stores energy during systole and through elastic recoil is a major determinant of flow during diastole. When stiffness increases elastic recoil is lost and hence flow and thus pressure during diastole decreases. Hence, over the age of 65 years diastolic blood pressure tends to decrease whereas systolic pressures tend to increase to very high levels. Indeed, elderly patients with blood pressures of around 210-230/60-70 mm Hg have been noted. For many years ISH was not adequately treated because the medical profession was concerned about giving antihypertensive agents to patients who already had low diastolic blood pressures (coronary blood flow only occurs in diastole). However, over the past 10 years it has become very clear that ISH is one of the most potent risk factors for cardiovascular events and that conventional antihypertensive medication (with the possible exception of ß-blocking agents) produces marked protective effects. Secondary hypertension The following disorders represent the most common causes of hypertension secondary to a problem that is easily identifiable. Others are discussed in L 03.03.03.  Renal failure. Renal failure causes fluid retention, a high blood volume and consequently through increases in SV and CO, combined with increases in TPR (produced by either autoregulatory changes or vascular remodelling) an increase in blood pressure. It is also thought that activation of the renin-angiotensin- aldosterone system (RAAS) may contribute to hypertension in renal failure.  Pregnancy. Despite the considerable risk that hypertension in pregnancy poses to both the mother and the foetus, the mechanisms of pregnancy-induced hypertension (PIH) remain obscure. However, it is known that an increased cardiac output occurs in PIH (produced by fluid retention and blood volume expansion), intense vasoconstriction characterizes pre-eclampsia (see later blocks for a full definition of pre-eclampsia), an increased sympathetic output occurs in pre-eclampsia, activation of the RAAS occurs in normal pregnancy, and that potential upregulation of angiotensin II receptors may occur in pre-eclampsia.  Cushing’s syndrome and disease (see endocrine block). Glucocorticoid excess is thought to contribute to hypertension by modulating vascular adrenergic receptor-sensitivity and altering the structure of the vascular wall. Cortisol at very high concentrations can also mediate mineralocorticoid (aldosterone-like) effects. The latter mechanism may be the predominant mechanism contributing to hypertension in Cushing’s syndrome. The major cause of hypertension produced by excess glucocorticoids is the administration of systemic corticosteroids in patients with inflammatory diseases, asthma and who require immunosupression.  Liver disease. (see later block) An often unrecognized cause of hypertension is liver disease where blood pressure is increased because of the inability of the liver to metabolize aldosterone. The increased circulating aldosterone concentrations cause fluid retention and consequently an increased CO, with a subsequent increase in TPR following autoregulatory changes and vascular structural alterations.  Polycystic kidney disease even prior to the development of overt renal failure. The mechanisms of the hypertension are not entirely clear, but do involve activation of the RAAS and fluid retention. 8   Conn’s syndrome, which can occur following the development of an adrenal cortical tumour (Conn’s disease) or adrenal cortical hyperplasia. In both circumstances the adrenal gland synthesizes more aldosterone and consequently produces fluid retention (effects on the kidney).  Glomerulonephritis even prior to the development of overt renal failure. The mechanisms of the hypertension are through fluid retention and activation of the RAAS.  Renal artery stenosis. Stenosis of a single renal artery can occur as a consequence of atheromatous changes in large arteries and results in a decreased perfusion of a single kidney, a decrease in pressures in the juxta-glomerular apparatus of that kidney and consequently activation of the RAAS through renal baroreceptor mechanisms. Alternatively, a decrease in perfusion of both kidneys because of a vascular lesion in the aorta proximal to both renal arteries results in hypertension because of a decreased glomerular filtration, renal failure and fluid retention.  Coarctation of the aorta. A congenital coarctation of the ascending aorta or a coarctation of the aorta because of an aortic aneurysm, will produce hypertension through a fixed resistance to flow.  Phaeochromocytoma, which is a catecholamine-producing tumour of the adrenal medulla. An increase in circulating catecholamines can cause hypertension through activation of both ß and a receptors, by directly enhancing TPR (a1 receptor-mediated effect), retaining more fluid (a1-receptor mediated effect on proximal tubules and glomerular permeability), activating the RAAS (ß1 receptor mediated effect on the juxta-glomerular apparatus), and increasing SV and HR (ß1 receptor mediated effect) and hence CO.  Acromegaly (see endocrine block), which is mediated through an excess growth hormone production, can produce hypertension through growth hormone- mediated effects on vascular structure (remodelling with a decrease in lumen diameter and hence an increase in TPR).  Hyperthyroidism (see endocrine block) which can increase systolic blood pressure through an enhanced cardiac output (thyroid hormone increases adrenergic- mediated effects on the heart). However, TPR remains low because a high rate of metabolism associated with hyperthyroidism leads to vasodilation.  Hypothyroidism (see endocrine block) with an increase in systolic blood pressure following a bradycardia (→ increased time for cardiac filling → increased SV → increased BP).  Oral contraceptives. Oral contraceptives seem to be able to produce hypertension only in a few cases. Indeed, this potential side effect of oral contraceptives should never be seen to over-ride the need to use them. A potential explanation for the relatively low impact of oral contraceptive use on blood pressures is that they are more frequently used by that age group who are not at risk of developing hypertension. Consequently, this side effect is seldom of importance, but may contribute to resistant hypertension (see below). [The immunosuppressive agent cyclosporine, used in transplant patients, also frequently leads to hypertension. Cyclosporin is a calcineurin inhibitor. Calcineurin is a regulator of sarcoplasmic/endoplasmic reticulum Ca2+ release. Cyclosporine promotes excessive Ca 2+ release and hence can enhance the activity of sympathetic nerve terminals, promote vasoconstriction, and increase fluid retention, all of which will lead to an increased blood pressure.] Severe and refractory (resistant) hypertension Any cause of hypertension (excluding the use of oral contraceptives and some endocrine causes-including hyperthyroidism and acromegaly) can ultimately result in severe or refractory hypertension. The definitions of severe and refractory (resistant) hypertension 9 will be provided in L 03.03.04. It is important to consider the pathogenesis of these problems separately from the above topics. What has become clear is that severe hypertension is associated with intense activation of the RAAS and an increase in endothelin production and activity. Often severe and hence refractory hypertension occurs in patients of African ancestry who will then respond well to the addition of pharmacological agents that inhibit the actions of the RAAS. This is important to recognize as often patients of African ancestry with mild-to- moderate hypertension are unresponsive to the use of pharmacological agents that inhibit the actions of the RAAS when they are used as monotherapy (because these patients are salt-sensitive and hence tend to have a suppressed RAAS). As so often occurs this is interpreted to indicate that these agents will be less and less effective the more severe the hypertension. Clearly this is not the case. Refractory (resistant) hypertension is defined as persistently high blood pressures following the use of three or more antihypertensive agents. Attending physicians should always be aware of the fact that there are additional causes of refractory hypertension and these will be discussed in L 03.03.04 Importantly, associated with poor blood pressure control is  more severe forms of hypertension.  an older age  obesity  poor medication adherance (compliance),  the exogenous use of non-steroidal anti-inflammatory agents, oral contraceptives, and sympathomimetic agents (e.g. decongestants and cough medications).  excessive alcohol intake.  sleep apnea (a disorder involving upper airways obstruction when asleep with associated periods of hypoxia).  secondary causes of hypertension. LT 03.03.002. Clinical Investigation in Systemic Hypertension Aim The aim of this learning topic is to describe the clinical assessments that should be performed when evaluating a patient with systemic hypertension or suspected systemic hypertension. Delivery Objectives Describe clinical investigations performed in systemic hypertension in order for students to develop an appropriate clinical approach to patients with hypertension. Content The approach to the management of a patient with systemic hypertension (which will be discussed in L 03.03.04) is ultimately based on your ability to:  correctly diagnose the presence of hypertension.  exclude secondary causes of hypertension.  identify the presence of target organ damage  assess overall cardiovascular risk  ensure that adequate blood pressure targets are acquired. In order to adequately fulfill the above, the following principles should be employed: 10 To correctly diagnose hypertension  Ensure that auscultatory blood pressure measurement techniques are employed whenever practically possible as these are the most accurate techniques if utilized correctly. However, with the phasing out of mercury, and the unreliability of alternative devices such as anaeroid manometers often favoured by students, experts now advocate the use of validated oscillometric devices wherever possible.  Oscillometric techniques are used in circumstances when “white coat” effects (where blood pressures are falsely increased only when visiting a doctor) are suspected, where acceptable oscillometric devices are used and regularly calibrated and where patients can measure their own blood pressures out of the clinic environment. With the phasing out of mercury and the general unreliability of anaeroid manometers (they require 3 monthly servicing to ensure that the gauge does not slip), oscillometric devices are preferred even in clinics or hospital environments.  Auscultators are utilised who are members of the nursing profession whenever possible to avoid “white coat” effects produced particularly by doctors. If oscillometric devices are used, the “white-coat” response may be limited.  A diastolic blood pressure > 90 mm Hg and/or a systolic blood pressure >140 mm Hg on three separate visits, in the absence of antihypertensive medication, is required. These blood pressure values apply for all age groups in otherwise healthy individuals. However, lower blood pressures may warrant treatment in special circumstances including diabetes mellitus, and in renal disease (see L 03.03.04).  Ensure that the auscultator is adequately trained in the technique of blood pressure measurement. It is important to ensure that: o Karotkoff phase I (when turbulence is first heard) and V (when turbulence dissapears completely) sounds are used to assess blood pressure except in certain circumstances (e.g. children or aortic incompetence when Karotkoff IV (when turbulence is muffled) sounds can be used to assess diastolic blood pressure). o auscultatory gaps are not missed as they often result in the underestimation of systolic blood pressure. o blood pressures are measured to the nearest 2 mm Hg. Often auscultators have a “digit preference” to 5 or 10 mm Hg and record pressures such as 140/90 mm Hg or 145/95 mm Hg. This is incorrect. o the auscultator understands the importance of appropriate speeds used to decrease the pressure in the cuff, o the auscultator always measures pressures with the patient seated and the cuff at the level of the heart, o the auscultator always uses the correct cuff size which is determined by arm circumference, o the auscultator never elevates the pressures in the cuff beyond systolic blood pressure by more than 20 mm Hg when pressures are being measured. This should be avoided by estimating systolic pressures initially using the radial pulse prior to determining blood pressures. o the auscultator only uses equipment which has neither fast nor slow leaks. This only occurs when fraying of the rubber components of the sphygmomanometer, including the bladder, occurs. o the auscultator only uses a mercury sphygmomanometer where the mercury makes adequate contact with glass. Clearly, when bubbles in the mercury occur or when the meniscus is not perfectly lined, the equipment should be replaced. 11  o the auscultator only measures pressures with her/his eyes at the level of the meniscus, as errors of parallax frequently occur and pressures are either over- or underestimated. o the auscultator utilizes 24 hour ambulatory blood pressure monitoring only when blood pressures are not consistently >140/90 mm Hg or < 140/90 mm Hg on three separate occasions or when “white coat effects” are suspected. To exclude secondary causes of hypertension.  A careful history should be taken, an equally careful clinical examination should be performed, and some routine blood tests should be conducted on the first visit. Once a reasonable degree of suspicion is present there are special investigations which can be utilized, but only in certain circumstances. The following symptoms, signs and routine blood test results should create a reasonable degree of suspicion: o a cluster of symptoms or signs which indicate the presence of either acromegaly, hyperthyroidism or Cushing’s syndrome (see endocrine block). o a careful history to detect the presence of pregnancy or the use of oral contraceptives. o a cluster of symptoms and signs and results on routine blood tests which may indicate liver disease (see liver block). o the presence of fluctuating blood pressures, facial flushing, palpitations, and episodes of unexplained sweating and tachycardia indicate the presence of excess catecholamines and hence possible phaeochromocytoma. o radio-femoral delay clinches the diagnosis of coarctation of the aorta. o a ballotable kidney indicates the presence of polycystic kidney disease. o an abdominal bruit indicates renal artery stenosis. o the presence of proteinuria and/or haematuria suggests renal disease (renal failure, polycystic kidney disease and glomerulonephritis). Usually acute glomerulonephritis is accompanied by an acutely ill and febrile patient. o a raised plasma urea and creatinine concentration indicates renal failure from any cause including polycystic kidney disease and glomerulonephritis. o unexplained hypokalaemia in a patient should arouse a suspicion of Conn’s syndrome.  Special investigations should be performed when appropriate only, as follows: o plasma cortisol, growth hormone, or thyroid stimulating hormone concentrations when clinical symptoms and signs suggest the presence of Cushing’s syndrome, acromegaly (due to excessive growth hormone) or thyroid disease. It is inappropriate to perform these tests without a reasonable degree of suspicion. o plasma catecholamine or metanephrine determinations, or the 24 hour excretion of urinary catecholamine metabolites should be measured when phaeochromocytoma is suspected. It is inappropriate to perform these tests without a reasonable degree of suspicion. o a renal ultrasound to detect cysts in polycystic kidney disease or an atrophic kidney in renal artery stenosis. o an adrenal ultrasound to detect the presence of adrenal tumours (this is a very insensitive investigation). 12 Importantly, it has recently been suggested that Conn’s syndrome and disease exist with a much higher prevalence than previously predicted. Because of this it has also been suggested that all patients should have a plasma renin activity and aldosterone concentration measured and that suggestive data (elevated aldosterone relative to renin ratio) in any patient should then be followed up with special investigations. These investigations will ultimately lead to the invasive adrenal vein blood sampling required to identify those who would benefit from surgery. This approach has been suggested because patients who have a unilateral adrenal tumour can then have an adrenalectomy and will not be subjected to life-long antihypertensive medication. Moreover, surgery in these patients as opposed to medical therapy has been demonstrated to improve outcomes. However, this approach requires access to those trained in adrenal venous sampling, and in most areas of South Africa, this training has not been provided. Thus, medical therapy with aldosterone receptor antagonists is the only option in those with suspected Conn’s disease or syndrome (unexplained hypokalaemia and refractory to therapy). To identify the presence of target organ damage A thorough clinical history and examination followed by routine investigations should be performed. The following are important to detect:  symptoms and signs, and ECG evidence (see L 03.03.05 and week 4) of heart failure, ischaemic heart disease, arrhythmic events, and cardiac hypertrophy.  retinal evidence of vascular damage in hypertension.  urine (proteinuria detected with a urine dipstick) and blood (increases in plasma urea and creatinine concentrations) evidence of renal damage. Urinary micro- albumin concentrations should only be assessed in patients with diabetes mellitus who are particularly susceptible to renal disease.  clinical evidence of large vessel disease including poor peripheral pulses, carotid bruit and evidence of abdominal aortic aneurysm formation (a pulsatile abdominal mass). NB: There is increasing concern that the above investigations are insufficient assessments of target organ damage (neither ECG, retinal nor renal changes may be found in those who have strokes or who develop critical limb ischaemia, particularly at a young age). In contrast non-invasive measurements of carotid vessels (which detect atheroma) and simple and easy to perform measures of aortic stiffness (aortic pulse wave velocity) may reveal advanced end organ changes which herald events. These changes may occur even in the absence of the above alterations. If these measurements are available they should be considered particularly in high risk patients with a number of risk factors or in young persons with risk factors. They do nevertheless increase the costs of screening hypertensives. To assess overall cardiovascular risk A thorough clinical history and examination followed by routine investigations should be performed. The following are important to assess:  smoking  the severity of the hypertension.  age.  gender and menopausal status (premenopausal women carry a lower cardiovascular risk than men of the same age, but after menopause the risk is equivalent).  the presence of diabetes mellitus.  total, low density and high density cholesterol concentrations. 13   a family history of cardiovascular events.  previous cardiovascular events in the patient.  evidence of target organ damage. In L 03.03.04 or L03.03.05 you will be shown how to assess overall cardiovascular risk by including all of the above in the final equation. To ensure that adequate targets are acquired in patients with hypertension The following are important to consider:  that blood pressures are measured appropriately at each subsequent visit. The same principles apply as discussed above.  that blood pressures are measured at least 6 monthly and even more frequently in patients who have not reached blood pressure targets, and in high risk patients.  that routine blood investigations to assess overall risk analysis and target organ damage are performed at least annually in all patients and more frequently (6 monthly) in high risk patients. LT 03.03.003. Classes of Drugs Used in the Management of Systemic Hypertension Aim The aim of this learning topic is to explain the pharmacological approaches that may be employed in the management of hypertension. Delivery Objectives Explain the mechanisms of action of classes of pharmacological agents utilized in the management of hypertension. An understanding of this learning topic will provide students with insight into the therapeutic benefits and side effect profiles mediated by antihypertensive agents. Content This learning topic will only be understood if you have fully grasped the content of week 1, especially LT 03.01.01 and LT 03.01.02, as well as the preceding learning topics for the present week. Do antihypertensive agents target the cause of hypertension? Although the mechanisms of secondary hypertension have been known for a few decades, as indicated in LT 03.03.02, the mechanisms of the commonest form of hypertension, primary or essential hypertension, are presently unclear. Consequently, the development of pharmacological agents for the treatment of hypertension, have largely been based on our understanding of the physiological mechanisms that control blood pressure. These mechanisms have been outlined in L 03.01.06 and L 03.03.01. Fortuitously, many of the mechanisms that are thought to contribute to primary hypertension are indeed targeted by the pharmacological agents that have been developed to date. It is therefore still possible that in the management of hypertension we are indeed targeting the pathophysiological mechanisms. Antihypertensive agents classified according to physiological effects. 1. Diuretic agents. 14 As indicated in previous lectures and learning topics (LT 03.03.01, and L 03.03.01), the kidney is crucial to the long-term control of blood pressure. Indeed, renal mechanisms are thought to play a central role in the maintenance of high blood pressures in primary hypertension. As a consequence, the use of agents that enhance renal fluid and salt excretion-diuretic agents-are central to the treatment of hypertension (primary, secondary and isolated systolic hypertension). At present however, there is no evidence that the increases in SV, CO and aortic flow that account for a major part of hypertension in groups of African ancestry (see previous lectures and learning topics), and which are thought to be mediated by increases in blood volume (Frank-Starling effects) through renal effects, is adequately targeted by diuretics. Further research is underway to answer this question. The mechanisms of action, potential therapeutic effects, side effects, and drug interactions of the various diuretic agents presently available will be discussed in the renal block. However, briefly there are 4 main types of diuretic agents that can be used in the management of hypertension and these are the thiazide diuretics, the loop diuretics, amiloride, and aldosterone receptor antagonists. All are used at low doses in the management of hypertension in order that increases in cholesterol, urate, and glucose, and decreases in plasma K+ concentrations do not occur. The commonest diuretics presently in use in the management of hypertension are hydrochlorothiazide (HCTZ) and indapamide, a thiazide-like diuretic. Sometimes HCTZ is combined with amiloride (Moduretic), a K+ sparing diuretic to retain K+ in patients with hypokalaemia. Loop diuretics (e.g. furosemide) are often used in patients with marked fluid retention such as occurs in renal and cardiac failure. However, because the aforementioned metabolic effects are most potent with furosemide, and because furosemide can lead to dehydration and hence prerenal damage, it is not advocated for use in the treatment of uncomplicated primary hypertension. Spironolactone is used in patients with suspected Conn’s syndrome (unexplained hypokalaemia) and in liver failure, and more recently in heart failure and in hypertension refractory to therapy (see below). All of the diuretic agents used in the management of hypertension reduce the ability of renal tubules to reabsorb sodium and hence water. The exact cellular effects will be discussed in the "Renal Block". A diuresis is the natural consequence. However, it is also acknowledged that a continued diuresis would eventually lead to death through hypovolaemic shock and hence that the body compensates for the fluid loss after a few days if survival is to occur. The main mechanism of action may therefore be a vascular effect. Indeed, diuretic agents are widely accepted as producing direct vasodilator actions and indirect vascular effects through autoregulatory changes. 2. Agents that influence the activity of the renin-angiotensin II system As described in weeks 1, 2 and 3, the renin-angiotensin-aldosterone system (RAAS) is a key regulatory system in blood pressure control. Angiotensin II has vasoconstrictor effects that are mediated to some extent utilizing the same mechanism as those described for alpha1 adrenoreceptor-mediated effects (see LT 03.01.01). Angiotensin II also contributes to fluid retention by enhancing proximal renal tubule fluid reabsorption, decreasing renal blood flow (which reduces fluid filtration), decreasing the permeability of the glomerular membrane (which reduces fluid filtration), and activating the production of aldosterone to induce distal tubular fluid reabsorption in the kidney. Angiotensin II also promotes sympathetic effects to mediate all of those changes discussed in LT 03.01.02. Hence, it is sensible to inhibit the actions of the RAAS to lower blood pressures. Indeed, three classes of agents reduce the effects of the RAAS and subsequently produce antihypertensive effects. Angiotensin-converting enzyme inhibitors (ACEIs) prevent the conversion of angiotensin I to angiotensin II and are therefore effective 15 antihypertensive agents. In addition, angiotensin II receptor blockers (ARBs) mediate similar actions as those produced by ACEIs. Importantly, never use ACEIs and ARBs together as the toxicity and adverse effects are striking and mortality increases. ACEIs may have the advantage over ARBs in that they also activate bradykinin systems which are known to produce further vasodilatory actions. However, ARBs may have an advantage over ACEIs in that angiotensin II is not only produced by the action of the ACE enzyme, but also through effects of additional chymases. For cost- related reasons ACEIs are preferred except when ACEIs, through effects on bradykinin, induce a chronic and irritating cough. In this circumstance an ARB is always preferred over an ACEI. Both ACEIs and ARBs produce modest side effects. Other than the cough mediated by ACEIs, the only other potential side effect of ACEIs is that of angioedema, where through bradykinin, an allergic response results in swelling of the face and upper airways. Sometimes (seldom reported) this can require intubation. Aldosterone receptor blockers or antagonists, including aldactone (spironolactone) and eplerenone have been popularized by their success as fourth-line agents in refractory hypertension. These agents must only be used if K+ concentrations are known as they cause hyperkalaemia and hyponatraemia. In addition, aldactone blocks androgen receptors and hence may produce gynaecomastia and/or breast pain in men (although this tends to be infrequent). Eplerenone however, does not have this side effect, but is an expensive agent. Whilst there is significant evidence that ACEIs and ARBs should not be combined because together they may increase mortality in some populations, aldosterone receptor antagonists may be used together with ACEIs or ARBs, although one must be wary of hyperkalaemia. The main reason for the efficacy even in the presence of an ACEI or ARB is that with the use of the latter agents, aldosterone “escape” occurs through unexplained mechanisms and hence after 6 months neither ACEI nor ARB use will reduce aldosterone concentrations. 3. Adrenergic receptor blockers As described in LT 03.01.01, activation of the sympathetic nervous system produces alpha1 adrenoreceptor-mediated vasoconstriction, and ß1 adrenoreceptor-mediated increases in stroke volume and cardiac output (which will promote autoregulatory changes to increase vascular resistance). As discussed in L 03.03.01, activation of the sympathetic nervous system also produces alpha1 adrenoreceptor-mediated renal proximal tubule fluid reabsorption, alpha1 adrenoreceptor-mediated decreases in glomerular membrane permeability (with a decreased filtration), and ß1 adrenoreceptor- mediated activation of renin release from the kidney, with subsequent increases in blood volume and cardiac output and consequently autoregulatory changes to increase vascular resistance. It is therefore entirely logical to employ receptor blockers of either alpha1 adrenoreceptors, ß1 adrenoreceptors, or both alpha1 and ß1 adrenoreceptors for the management of hypertension. Due to the side-effects of postural hypotension and dizziness sometimes produced by alpha blockers, and the lesser benefits on mortality as compared to other antihypertensive agents, presently alpha blockers are often only used as fifth or sixth-line agents. However, alpha blockers do have beneficial effects in prostatic hypertrophy (See renal block) and they are effective therapies in refractory hypertension. Presently the ß blockers are not used as a principle therapeutic approach to the management of hypertension because of data which show that the ß1 adrenoreceptor blocker, atenolol, may not reduce mortality as well as other agents; data which show a greater prevalence of new onset diabetes mellitus with atenolol as compared to other agents; and data that show a lack of ability of atenolol to decrease aortic blood pressures as well as other antihypertensives, despite similar reductions in brachial blood pressure. There are nevertheless compelling indications for the use of beta blockers, particularly carvedilol, bisoprolol and metoprolol in hypertensives with heart failure, ischaemic heart disease or tachyarrhythmias. Although the older non- selective adrenergic blocker, propanolol is still sometimes used in the management of hypertension, it is generally avoided because it has the capacity to block vasodilator ß2 adrenoreceptors. However, newer alpha-beta adrenoreceptor blockers have been viewed 16 by some more favorably than atenolol as they do not appear to have the same adverse effects on type II diabetes mellitus and aortic blood pressure as atenolol. This has nevertheless never been clearly demonstrated. There are important side effects produced and pharmacological profiles of ß adrenergic receptor blockers. This information should be obtained from the textbook reference sources. Importantly, ß-adrenergic receptor blockers can induce bronchoconstriction in patients with obstructive lung disease (see respiratory block)(through blockade of ß 2 receptors) and can mask the hypoglycaemic symptoms in patients with diabetes mellitus, which are largely mediated through activation of the sympathetic nervous system. As indicated ß adrenoreceptor blockers may also increase the chances of patients developing diabetes mellitus. 4. Calcium channel blockers Intracellular Ca2+ released from the sarcoplasmic reticulum (SR) or endoplasmic reticulum (ER) is probably the most important regulator of cellular function. SR and ER Ca2+ release is often determined by the activity of a cell membrane Ca 2+ channel. Three classes of cell membrane Ca2+ channel blockers (CCBs) have been developed, two of which act on both vascular as well as cardiac cell membrane Ca 2+ channels (see week 5), and one class which acts predominantly on vascular cell membrane Ca 2+ channels, (so called dihydropyridine CCBs-DHP CCBs). All three classes of CCBs can be used in the management of hypertension, but most frequently the DHP CCB class of agents is used. The most popular and the single most efficacious agent with minimal side effects employed to-date in all population groups for the treatment of hypertension are CCBs (amlodipine and long acting nifedipine are presently the most commonly used). However, the marked ability of these agents to vasodilate often results in increases in flow through peripheral capillaries and consequently produces and enhanced capillary hydrostatic pressure and leg swelling (oedema). This may be a limiting factor in its use. Furthermore, only long acting CCBs should be used as short acting CCBs (short acting nifedipine) may increase the risk of myocardial ischaemic events in patients with underlying coronary artery disease because of the dramatic decreases in blood pressure and hence coronary perfusion pressure they produce. 5. Pharmacological agents that deplete catecholamine stores or act centrally to reduce sympathetic nervous system activity. Utilizing the same principles as for adrenergic receptor blockers, agents have been developed that either deplete presynaptic catecholamine stores (reserpine) or act centrally to reduce sympathetic output (reserpine and centrally acting alpha2 receptor agonists [stimulants] such as a-methyldopa) to treat hypertension. Centrally acting a2 receptor agonists are thought to reduce sympathetic nervous system output by decreasing presynaptic terminal catecholamine release in the central nervous system (remember that alpha2 adrenoreceptors act as sympathetic terminal autoreceptors-see LT 03.01.01). Although these agents have not been that popular because alpha- methyldopa has to be taken 3-to-4 times daily to be effective, the mood effects (depression) of these agents are uncertain even at the lowest therapeutic doses, and impotence may be more of a problem than patients will freely admit, these agents are very cheap and can be used safely if costs for healthcare become self-limiting. Alpha- methyldopa is also well recognised as being free of teratogenic effects which makes it a safe agent to use in the first trimester of pregnancy. Reserpine is generally difficult to obtain and there is concern over adverse mood effects produced even at the low doses employed to treat hypertension. 6. Non-specific vasodilators 17 Potent vasodilator agents, with uncertain modes of action, have been available for many years, but the intolerable side effects produced by these agents such as headaches, dizziness, and postural hypotension, have limited their use to patients with severe and refractory hypertension. Two such agents are hydrallazine and minoxidol. Hydrallazine is the most frequently used of the two agents and in combination with other agents is usually sufficient to provide adequate blood pressure control even in very severe hypertension. However, this does not mean that it should be used in place of other agents in severe hypertension. Rather, it is used as the last line in a series of failed attempts at controlling blood pressures. There is however, some concern with the use of these agents in hypertension as hydrallazine does not reverse adverse cardiovascular remodelling (see lectures 2 and 3) and minoxidol actually promotes adverse remodelling. Hydrallazine mediates effects by promoting NO-mediated vascular actions (see L 03.01.06). Approach to the use of antihypertensive agents To manage hypertension it has become quite clear that combinations of drugs are often required to control blood pressure to appropriate targets. Indeed, many guidelines recommend starting with two classes at once at low doses even in mild hypertension, an approach that nevertheless does not appeal to many clinicians due to the potential for more adverse effects. Thus, initiating treatment with a single agent and then within a week or two, at consecutive patient visits, doses of agents are first increased to maximum levels and then additional agents are added on to the initial drug. For years there has been debate about what should be considered the most appropriate sequence of pharmacological agents to use in the management of hypertension. It has really only been over the past decade that some clarity has been derived with respect to this question. This clarity has been the consequence of a number of large clinical studies performed to assess both the control of blood pressure and the ability of individual agents to prevent adverse cardiovascular events from occurring. At this point the following guidelines are appropriate:  in mild-to-moderate uncomplicated hypertension or isolated systolic hypertension when you are satisfied that pharmacological therapy is warranted o One of 3 main classes (thiazide or thiazide-like [indapamide] diuretics, CCBs or ACEIs) should be initiated. Thiazide or thiazide-like diuretic agents should be initiated at doses which do not increase plasma cholesterol, glucose or urate concentrations, or decrease plasma K+ concentrations (12.5 mg of HCTZ daily), and do not promote arrhythmias (ventricular extrasystoles and impotence). If an ACEI is necessary but side effects occur an ARB may be employed. Importantly, neither ACEIs nor ARBs are effective when used alone in groups of African ancestry and hence if required as first line therapy should be used in combination with an alternative agent. o Doses of agents should be increased to maximum doses to achieve blood pressure control with the highest dose of HCTZ being 25 mg daily. o A combination diuretic consisting of HCTZ and amiloride (Moduretic) can be used to prevent hypokalaemia, or in patients with a low K+ concentration, but unfortunately the preparation uses very high doses of HCTZ (50 mg) and hence there should be a high degree of suspicion that metabolic side effects may occur. o If blood pressure is not at target, another of the 3 main classes not being used can then be added (medication should never be stopped unless there are side effects) so that the following combinations are achieved  Diuretic + ACEIs or ARB.  Diuretic + CCB.  CCB + ACEI or ARB. 18  The diuretic + ACEI or ARB combination may not be as effective as other combinations in groups of African ancestry, but if an ACEI or ARB are required, then a CCB may also be required together with a diuretic (SV is a cause of increases in BP and hence a diuretic is necessary). Also remember that an ACEI and ARB should never be used together. o If blood pressure is not controlled, add the third of the 3 main classes. Add therapy and increase doses until patients are receiving a diuretic, ACEI and CCB or a diuretic, ARB and CCB. If blood pressure is still uncontrolled then consider a diagnosis of refractory or resistant hypertension (see below)  in some regions of South Africa the above agents may not be available and medication such as alpha-methyldopa (aldomet) can be used. The major limiting factor in the use of this agent is that it should be taken 3-4 times per day to be effective. Consequently, medication adherence may not be appropriate.  continue to add agents (rather than replace agents) until blood pressures are controlled. The “add-on” approach is important as combinations may produce synergistic effects on blood pressure.  in severe hypertension o the same approach is employed as that used in mild-to-moderate hypertension, but with more frequent visits scheduled and always start with a combination approach. A diuretic and an ACEI; a diuretic and an ARB; an ACEI and a CCB; an ARB and a CCB; or a diuretic and a CCB are very effective when used as first line therapy in severe hypertension.  in resistant hypertension after all potential confounding factors have been eliminated consider the addition of: o aldosterone receptor blocker if K+ is known. o beta-adrenoreceptor blocker if blood pressures are not that high o hydrallazine if blood pressures are particularly high. o alpha adrenoreceptor blocker if blood pressures are particularly high.  in complicated hypertension compelling indications for the use of specific agents exist: o ß-blockers are important to use in patients with angina, after a myocardial infarct, with tachyarrhythmias, and with heart failure in selected patients. o ACE inhibitors should be used in patients with heart failure, after a myocardial infarction, or a stroke, and with diabetic nephropathy. The reasons for the benefits of these pharmacological agents in these disorders should be apparent from preceding lectures and learning topics. o angiotensin II receptor blockers could be used in patients who respond well to ACEIs but develop an ACEI-induced cough. o spironolactone (an aldosterone receptor antagonist) should be used in suspected Conn’s syndrome, hypertension associated with liver disease, refractory hypertension (see above, but only if the K+ is known) and in heart failure.  in pregnancy: o Alpha-methyldopa is the drug of choice. o other relatively safe agents that may be used include thiazide diuretics (although they should be withdrawn if pre-eclampsia occurs), ß-blockers, CCBs; and hydrallazine. Importantly, after the use of a-methyldopa, hydrallazine is a commonly used drug in pregnancy-induced hypertension when there is difficulty with blood pressure control. o ACEIs and ARBs should never be used because of the potential of a number of major side effects to the foetus. The following conditions may preclude the use of certain pharmacological agents in hypertension:  diuretic agents in gout. 19   amiloride (Moduretic) or spironolactone/eplerenone diuretic agents in hyperkalaemia or renal disease.  ß-blockers in asthma and chronic obstructive airways disease (may bronchoconstrict by blocking ß2 adrenoreceptors), diabetes mellitus and syndrome X (where ß blockers may worsen the chances of producing diabetes mellitus and syndrome X) and heart block (by blocking ß1 adrenoreceptors they will promote further heart block).  ACE inhibitors and ARBs in pregnancy (teratogenic effects are likely), hyperkalaemia (further retain K+) and bilateral renal artery stenosis (by afferent arteriolar dilating they will further reduce glomerular filtration and renal perfusion).  Non-dihydropyridine CCBs (verapamil and diltiazem) (i.e. CCBs which have a cardiac and vascular effect) in either heart block or congestive cardiac failure (as both pacemaker and contractile tissue are modulated by Ca2+ channels). LT 03.03.004. Cellular and Molecular Mechanisms of Cardiovascular Damage and the Adverse Effects Thereof Aim This learning topic is aimed at providing you with an understanding of the cellular and molecular mechanisms responsible for cardiovascular damage and the impact that this damage has to produce cardiovascular events. The emphasis will be on the impact of the risk factor hypertension, but other risk factors will also be discussed. This knowledge should provide you with some insight into why cardiovascular disease occurs and which therapeutic agents would therefore best prevent cardiovascular events. Delivery Objectives Explain the cellular and molecular mechanisms of vascular disease and the adverse effects thereof with an emphasis on hypertension. Content [] Indicates non-core material There are two main end (target)-organ diseases of the arterial vasculature associated with hypertension, namely arteriosclerosis (hardening of the arteries) and atherosclerosis (the build-up of fatty deposits in the innermost lining of arteries), the pathology of which will be comprehensively dealt with in week 4. These arterial changes are the fundamental alterations caused by any major risk factor (smoking, diabetes mellitus, hypertension, dyslipidaemia) responsible for the cardiovascular events involving arteries including stroke, myocardial infarction, critical limb ischaemia, and aneurysm rupture or dissection. Arteriosclerosis has been alluded to in previous learning topics and is a pathological change that was thought to occur over a number of years. However, this view has now dramatically changed as even in patients with arterial events in their early twenties, marked arteriosclerosis may contribute to the event. Briefly, the media of large arteries, particularly the aorta, becomes thickened, there is loss of elasticity (fragmentation of the elastic lamina occurs, cross-linked collagen increases and calcium is deposited in the walls). The adverse impact of arteriosclerosis is largely produced by the haemodynamic consequences of increases in aortic stiffness (see below). In contrast, atherosclerosis, which occurs mainly in large and medium-sized arteries often leads to coronary artery disease, strokes and critical limb ischaemia because of the occurrence of atheromatous plaques and thrombi which protrude into the lumen and hence reduce blood flow or dislodge and cause emboli. The terms arteriosclerosis and atherosclerosis are often used as synonyms for each other as there are many commonalities in their pathogenesis. 20 However, the pathological features and effects are quite distinct and should not be considered as the same process unless atherosclerosis has caused arteriosclerosis (a subtype of arteriosclerosis). In this instance, the causative factors (particularly hypertension, diabetes mellitus, smoking and obesity) are common to both forms of vascular disease. The vasculature is not the only site of cardiovascular damage, the heart is also a prime target. Cardiac hypertrophy and remodelling, interstitial changes and myocyte necrosis (necrotic cell death – cell death caused by the progressive degradative action of enzymes which usually affects whole groups of cells) and apoptosis (programmed cell death – cell death signalled by the nuclei in normally functioning cells when age or state of cell health and condition dictates) are all known to occur. The cellular and molecular mechanisms that lead to interstitial changes and myocyte necrosis and apoptosis in the heart have been discussed in LT 03.02.05 and will be further discussed in LT 03.03.06 and L 03.03.02. Hence, in the present learning topic, the focus will be on the cellular and molecular mechanisms of arteriosclerosis and atherosclerosis and the adverse effects thereof. Pathophysiology of arteriosclerosis a) Causative factors:  Hypertension (main cause)  Aging (also a main cause)  Diabetes mellitus  Smoking  Obesity b) Cellular and molecular mechanisms and consequences of arteriosclerosis: The mechanisms of arteriosclerosis have been elucidated over the past several decades. In hypertension, as a consequence of increases in vessel wall tension, longitudinal shear stress and pulsatile stress, fragmentation of the elastic lamina occurs and “compensatory” vascular remodelling is an attempt to reduce the wall stress (see LT 03.03.02). Vascular remodelling is critical to the arteriosclerotic process. In arteriosclerosis, medial thickening through vascular smooth muscle cell hypertrophy and hyperplasia together with fibrosis (increase in collagen) and a loss of elastic tissue (and fracture and fragmentation of the elastin lamina which is not replaced) occurs. Moreover, deposition of calcium occurs in the media. This process which is associated with aging is accentuated in the presence of hypertension, diabetes mellitus, smoking and obesity. The mechanisms by which these risk factors mediate their effects are obscure. However, vascular mineralization follows a similar process to that in bone and is regulated by factors including leptin (an adipokine released from adipose tissue) and oxidized lipids (associated with smoking and poor diet) as well as inflammatory changes (also increased by risk factors). In diabetes mellitus, the formation of advanced glycosylation products enhances cross-linking of the collagen molecule and increases its tensile strength. Arteriosclerosis is also associated with structural degeneration and damage of the endothelium. The endothelial abnormalities are due to a reduced nitric oxide production or activity. Hypertension, diabetes mellitus and smoking have all been shown to inhibit nitric oxide release from the endothelium. The clinical impact of arteriosclerosis is through several mechanisms some of which have previously been discussed, but additional mechanisms will be further expanded on. First, arteriosclerosis enhances aortic stiffness and hence Zc, the consequence being an increased forward travelling pressure wave and hence pulsatile load and systolic blood pressure. These effects have been described in previous learning topics and are indexed 21 by pulse pressure. Second, by increasing aortic impedance (Zc) arteriosclerosis decreases the difference between impedance in the aorta and more distal vessels (an impedance mismatch). This mismatch occurs because more distal vessels have a smaller diameter and are stiffer vessels than the aorta (they generate a higher impedance to flow). Consequently, the reduced impedance mismatch allows for the transmission of a greater amount of energy into distal vessels (through an enhanced pulsatile flow) even when pulse pressure is unaltered. This increases pulsatile damage in distal vessels. Third, through an impact of changes in collagen and elastin molecules and through alterations in elasticity in regional walls, arteriosclerosis contributes toward the atherosclerotic process by decreasing endothelial function. Thus, atherosclerosis is worse in arteriosclerotic aorta the consequence being a greater chance of aortic aneurysm formation. Again, these effects are independent of pulse pressure and hence systolic blood pressure. Because of the impact of arteriosclerosis on aortic stiffness and hence vascular damage beyond pulse pressure, easy to acquire indices of aortic stiffness (aortic pulse wave velocity) are now recommended by guidelines to enhance risk prediction beyond pulse pressure or systolic blood pressure. Importantly, this measure may predict risk best in younger as opposed to older adults. Pathophysiology of atherosclerosis a) Causative risk factors:  Hypercholesterolaemia  Hypertriglyceridaemia  Hypertension  Obesity  Diabetes mellitus  Cigarette smoking  Aging  Male gender  Genetic (Family history of premature atherosclerosis - in females