A Simplified Guide to CARDIOVASCULAR PHARMACOLOGY JG SCHNELLMANN. Special Chapter Included: Heart Health by Joshua E. Kneff

Transcription

1 A Simplified Guide to CARDIOVASCULAR PHARMACOLOGY JG SCHNELLMANN Special Chapter Included: Heart Health by Joshua E. Kneff

2 CHAPTER 1 DRUGS TO TREAT HYPERTENSION What is hypertension? Hypertension simply means that the pressure in the blood vessels is higher than normal. To understand how blood pressure can be high (or low), one must understand how multiple factors contribute to the pressure exerted on blood and on the vessel walls which contain it. First, the blood volume that leaves the heart or the cardiac output contributes to (and is proportional to) the blood pressure. Thus, cardiac output is determined by the body s blood volume, which can be modified by manipulating the body s overall fluid volume. Fluid volume can be modified via hydration status (water balance) and renal function (how the kidneys balance electrolytes and water). Thus, fluid manipulation will alter blood volume and thus cardiac output. Blood pressure is lowest at night, and it rises upon wakening, fluctuating through the day. Next, the inherent resistance to blood flow in the vessels also contributes to overall blood pressure. Blood vessels are not absolutely smooth, so they offer intrinsic resistance to substances that flow through them. More vessel resistance means more pressure is exerted on the fluid that flows through it. Blood vessel diameter affects blood pressure as well: smaller vessels require more force to push fluid through them. Interestingly, blood vessel widening (vasodilation) and narrowing (vasoconstriction) occurs naturally and automatically throughout the day for minute to minute blood pressure control, and this is generally undetectable by most individuals. Also, vessel wall compliance (flexibility) contributes to resistance and blood pressure. The less flexible the vessels are to distension or widening to accept blood flow, the more pressure that is required to move blood through the vessels. 15 Page

3 Finally, blood viscosity or thickness due to the presence of circulating proteins and fats also increases blood pressure. 1, 2 Thinner blood is easier to move through the circulation, and thicker, more sluggish blood requires greater effort to circulate. Thicker blood is more likely to clot, as well. Specifically, a thrombus (blood clot) that forms in the vasculature (the vessels of the entire body) can stop blood flow completely. 3, 4 We can measure blood pressure and when we do, we obtain two types of data: a systolic value and a diastolic number which are expressed together as a single metric. The first or systolic value (the top number of a blood pressure reading) indicates the pressure in the vessels at the time of heart contraction (or systole) and the second or diastolic value (the bottom number of a blood pressure reading) expresses the pressure in the vessels when the heart is at rest, or between contractions (during diastole). Systolic pressure contributes 60% to the overall arterial pressure, and diastolic pressure contributes the remainder. Furthermore, blood pressure is expressed in the units of the method used to measure it: millimeters of mercury (mm Hg). The desirable range for an adult s blood pressure is less than 120/80 mm Hg. Hypertension, in contrast, is defined as a blood pressure reading of 140/90 mm Hg or more for an adult. 5, 6 Subcategories of high blood pressure exist as well. For example, pre hypertension is characterized by a blood pressure ranging from mm Hg for the systolic value and a diastolic number in the range of mm Hg. 7 On the other extreme, a hypertensive crisis exists when blood pressure exceeds 180 mm Hg for the systolic value or 110 mm Hg or more for the diastolic number or when there is a combined reading of 180/110 mm Hg or greater Blood pressure this high puts organs at great risk for permanent damage. Subcategories of hypertension may require unique treatments that range from inexpensive and non invasive lifestyle changes and other non drug therapies to multiple drug therapy or to immediate emergency intervention and management. Also, individual systolic or diastolic pressures can be abnormally elevated alone, and these isolated abnormalities are problematic and require assessment. Two types of hypertension are thought to exist: primary or essential (an older term) hypertension, which refers to hypertension with no known or discernable cause, and secondary hypertension, which refers to hypertension with a specific or known underlying cause. Causes of secondary hypertension may be temporary such as pregnancy or hypertension may be due to the presence of an advanced tumor or a genetic predisposition to high blood pressure. 13 Other causes of secondary hypertension may be non compliant kidney vessels due to high cholesterol induced hardening of the renal arteries. Renal vessels that restrict blood flow can cause renovascular hypertension as the body senses too little blood reaching the kidneys 16 Page

4 and interprets this as a low systemic blood pressure that requires elevation. 14 Alcohol abuse can cause hypertension as well, and this is reported to be mediated by multiple pathways including changes in neurohormones and alterations to the sympathetic nervous system (stimulatory nerve impulses). 15 Also, an overactive thyroid gland that drives sympathetic nervous syst. m signaling can increase blood pressure. 16 In general, essential or primary hypertension is treated with drugs, and secondary hypertension treatments might initially include reversing the underlying cause of the high blood pressure if possible. Then, drugs may be required for secondary hypertension when lifestyle measures fail (or when patients refuse to enact these changes). Finally, drugs may be used as temporary adjuncts to lifestyle management plans until the hypertension is resolved and the drugs can be withdrawn. Again, the hows and whys of hypertension are more suitable for a text of pathophysiology, so these will not be thoroughly discussed here. However, they will be referred to in the context of explaining drug classes or individual agents to treat hypertension. Section Summary Blood vessel flexibility and diameter as well as fluid volume and viscosity contribute to blood pressure. Blood pressure readings consist of systolic (upper number) and diastolic (lower number) values, measured in mm Hg. Hypertension is elevated blood pressure, and this is considered to be a blood pressure reading of 140/90 mm Hg or greater. Primary hypertension has no identifiable cause and drugs are required to treat it. Secondary hypertension has an underlying cause which may be treatable at that level and/or drugs may still be required to lower blood pressure. Who has hypertension? Hypertension is thought to contribute to almost 350,000 premature deaths in the US annually; higher than normal blood pressure is estimated to affect 30% of American adults. 5 Interestingly the prevalence of hypertension roughly parallels the same proportion of US citizens who are obese. 17 Whether these statistics are from samples of the same people is uncertain, but the idea that one third of any population is overweight or hypertensive is certainly a cause for concern. The scientific consensus explanation for such pockets of poor health is often explained by a wealth of nations hypothesis: that industrialization and world development have provided sedentary occupations and lifestyles in addition to fast, cheap, unhealthy food. 18 There is truth to this, but modern man is actually not new to the effects of lifestyle on cardiovascular 17 Page

5 health. In fact, mummies from ancient Egypt have been documented to have atherosclerosis. 19 Although we may be able to identify causes of hypertension and we may have the means to treat it, most of us will not escape it in our lifetimes. Almost 80% of all US adults who are older than 80 years of age have hypertension due to changes in the heart and vasculature that render vessels less complaint and the heart less efficient. 5 Less compliant vascular tubing means less give and take as blood flows through these stiffer vessels. These changes can be due to dietary choices made over a lifetime or diseases that diminish health in small but cumulative ways. 20 Interestingly, adults who consume low sodium diets tend to avoid this type of age related hypertension later in life. 21, 22 This observation has led to the concept that sodium intake, namely salt, contributes to high blood pressure, a theory that is still under investigation by basic scientists. As indicated by the aforementioned example of salt or sodium restriction, the first steps in treating hypertension are often dietary and may also involve exercise. Salt intake causes fluid retention to balance the salt load, and this increases the body s total fluid volume, because water follows sodium or salt. Elevated fluid volumes due to high salt intake subsequently increase blood volume, necessitating more pressure to circulate through the body. Thus, salt restriction may offer some patients an inexpensive and easy method for reducing hypertension. Specifically, sodium restriction from the typical intake of 3,300 milligrams of sodium a day to 2,300 milligrams a day is purported to have the power to reduce hypertension for approximately 11 million people each year in the US. 5 Other researchers have suggested that salt, by itself, may not be as strong a contributor to hypertension as is salt sensitivity. 23 With this genetic predisposition, some individuals may have an exaggerated hypertensive response to dietary sodium. More research is needed to conclude whether excessive salt is harmful to specific populations only. 24 In contrast, hydration via fluid consumption also influences adjustments to blood pressure. This occurs via the transient receptor potential vanilloid 4 (TRPV4) protein which has a pressor (blood pressure raising) effect. 25 Thus, increased fluid intake triggers this protein to register a hypo osmolar (low salt concentration/high fluid concentration) environment in the body. This low salt environment sends a signal to the sympathetic nervous system to correct this by raising blood pressure to increase renal filtration, sodium reabsorption, and excess water excretion to re establish the proper salt and water balance. So, hydration status can be critical for blood pressure homeostasis. When sodium leaves the body, water will follow the sodium being excreted. When sodium stays in the body, water will be retained, as well. 18 Page

6 Additional lifestyle or dietary steps to reduce blood pressure may include decreased consumption of saturated fats. 26, 27 Fats are reported to thicken the blood, and more pressure is required to move this viscous fluid around the body, compared to less fatty, thinner blood. 28, 29 These non drug steps to reduce blood pressure are usually simple for patients to implement and they cost very little. However, as evidenced by patient compliance data, many patients cannot or will not change their lifestyle to manage their 30, 31 hypertension and pharmacological agents become necessary. Why treat hypertension? Although there is disagreement among researchers about whether a blood pressure reading of 140/90 mm Hg actually requires aggressive treatment, scientists and clinicians suggest that the risk of a cardiovascular event (a heart attack, for example) doubles with every 20 mm Hg incremental increase in systolic pressure and every 10 mm Hg incremental increase in diastolic blood pressure Thus, hypertension is worth our attention because it is considered by health care professionals to be the primary cause of cardiovascular related death, and hypertension can damage several organs in the meantime. 37 For example, over time, high blood pressure can damage artery walls, stretching and weakening them. 38 This can occur in the peripheral vasculature vessels in the head, legs, and arms as well as within vessels that perfuse (send blood to) the heart, kidneys, and lungs. Other, less obvious organs can sustain injury as well. For example, damage to vessels of the eye can injure the retina. 39, 40 Such damage may be first identified during a routine visit to the ophthalmologist or optometrist who may see abnormal arterioles and venules in the eye or small hemorrhages that suggest an initial diagnosis of hypertension Eye vessel injury or insult can lead to vision disturbances and headaches in susceptible individuals. Damage to other organs due to hypertension may take years to manifest, but once injured, these tissues may be unable to recover. For instance, prolonged hypertension compromises kidney filtering capacity and this can perturb body fluid homeostasis, or the water and salt balance. 44 In some individuals, these renal effects can precipitate a perpetual cycle of increased fluid volume and increased blood pressure that exacerbates or worsens the initial hypertension. In fact, hypertension is a primary cause of renal failure in the US. 45 Finally, vascular dementia may be an issue for hypertensive individuals due to changes in perfusion within the brain When vessels under high pressure are weakened to the point of rupturing, additional problems may arise. Specifically, tears in the vessel wall attract circulating Until 45 years-of-age, men are at the greatest risk of hypertension and 55 years-of-age, women have the greater risk. 19 Page

7 calcium and fat to form sticky masses referred to as plaques. As plaques grow, they obstruct blood from flowing around them. Blood that cannot flow past a plaque can thicken and adhere to the plaque to create a thrombus and this thrombus/plaque complex can expand and further reduce or block blood flow in the vessel. 49 Also, tears in stressed and damaged vessel walls activate clotting mechanisms in the body and call for the influx of vasoconstrictive and inflammatory signals to mend the tear. This, too, can cause clot formation due to normal repair processes. When blood cannot flow to an area of the body, oxygen cannot be provided to essential tissues. Thus, tissues attempt to respond to low oxygen immediately. For example, vessels can occasionally address blocked blood flow and ischemia or lack of oxygen by dilating the vessel surrounding the area of the blockade. This is accomplished by the release of vasodilatory substances such as carbon dioxide, adenosine, histamine, potassium, and hydrogen ions. These substances dilate veins more than arteries. Also, veins and capillaries create and release from a layer of cells lining the vessels (or the endothelium) endothelialderived relaxing factor which stimulates the release of vasodilatory nitric oxide. Furthermore, vessels can generate additional channels for blood flow. These new channels or blood vessel networks are created through a process of angiogenesis (literally, the creation of vessels) and this can occur within days in healthy, young individuals. In fact, angiogenesis is such a common process within the body that almost all individuals older than 60 years of age have some form of collateral vessel formation due to some type of arterial blockage that has arisen over time. In athletes, new vessels that form are used to deliver blood and oxygen during exertion or exercise, and during rest, these vessels constrict until needed again. When vessels cannot work around blocked blood flow, cells deprived of oxygen begin to die. Often, these cells cannot be regenerated. 50 This leaves a dead or necrotic area in the organ affected by the ischemia. When this occurs in the heart, it must compensate for loss of function in necrotic areas. This can give rise to cardiac overwork or a progressive enlargement of the heart referred to as hypertrophy. Any muscle, including the heart, will become more muscular if subjected to stress or a heavy workload, but for the heart, this is undesirable. Abnormal heart enlargement compromises the heart s pumping efficiency, which initiates a destructive cycle of further increased blood pressure as the heart beats more forcefully to push blood around areas of poor flow. Clots or plaques can also detach from the vessel wall and travel to other areas of the body (such as the heart) to block blood flow and cause a myocardial infarction (heart attack). Clots may travel to the lungs to cause a pulmonary embolism (thrombi are characterized by vessel attachment; an embolus is a free floating thrombus). In the brain, vessel blockage can cause a stroke, and this can be debilitating or 46, 51, 52 fatal. 20 Page

8 Hypertension, for most people, is a painless condition, so many patients are often unaware of their problem until organ disease or failure manifests. Even when aware of hypertension, patients may forget to treat their condition, or they may choose to have no treatment at all. This is especially true if multiple and expensive medications are required to lower blood pressure or if instructions for therapy are confusing. For instance, treatment of hypertension with one drug is associated with reasonable patient compliance and lower treatment costs, but when a second drug is added to a therapeutic regimen, cost may increase and compliance is documented to decrease. 53 This is unfortunate news for healthcare professionals who desire such patient compliance because studies of antihypertensive combination therapy indicate that approximately 40% of hypertensive patients will not respond to one or even two drugs alone to treat hypertension. 54, 55 These particular patients are referred to as having resistant hypertension. 56 Something also often misunderstood by patients is that once hypertension is initially treated with medication, and it is under managed control, drugs and monitoring may still be necessary for the next 30 to 40 years, which may impose significant inconvenience, costs, and potential side effects. 57 Section Summary Hypertension contributes to cardiovascular disease and death, so treatment is necessary. Dietary or lifestyle choices can help reverse hypertension. Hypertension damages blood vessels and the organs which receive blood and oxygen from those vessels, often irreversibly. Hypertension can lead to retinal damage, renal failure, and heart attack or stroke. Often, simple lifestyle choices to reduce hypertension are the least expensive but probably the most unappealing strategies for patients to control high blood pressure. Hypertension is painless, so patients may be reluctant to start or stay with a course of therapy. For most people with hypertension, one drug may not be sufficient to control blood pressure, and drug therapy for hypertension may last a lifetime. Because blood pressure and the organ perfusion that depends on this pressure is so critical, the body has redundant and overlapping mechanisms to ensure that blood flow is sufficient for servicing the organs that need it most: the heart, brain, lungs, and kidneys. These areas of redundancy of control offer unique sites for drugs to act on hypertension as well. 21 Page