Choosing the First Agent
Hypertension is an asymptomatic disease that we frequently render symptomatic with our recommended lifestyle modifications and anti-hypertensive therapy. This alteration of an asymptomatic disease into a symptomatic one likely explains the inadequate current hypertension treatment and control rates. Nonadherence to prescribed therapy is one of the most serious problems we face in clinical practice. The source of this problem relates to inadequate education, a poor physician/patient relationship, and a lack of understanding of the pathophysiology contributing to hypertension. The statistics of nonadherence and inadequate control rates are alarming. The most recent data from the National Health and Nutrition Examination Survey 3 (Phase II) show that only one in four Americans has blood pressure control to a level of 140/90 mmHg or less. Even more surprising is that only 50% of patients who are treated actually achieve this level of blood pressure control. In fact, there has been a steady erosion in hypertension control rates over the past 10 yr. Thus, current strategies are not working.
Historically, physicians have been taught to keep the treatment of hypertension simple. Once behavioral modification efforts have proven unsuccessful, the physician should start with a single agent and titrate it sufficiently in order to control blood pressure. Unfortunately, in the majority of cases, higher doses of individual agents result in an increased risk of adverse events. Thus, rather than a symptomatic improvement in the condition, symptoms develop that encourage the patient to be noncom-pliant. More recent effort has focused on studying the use of lower doses of two or more medications in order to facilitate better blood pressure reduction yet avoid adverse events associated with higher doses of the individual drugs.
More intensive reduction in blood pressure is also an area of growing interest, as numerous outcome clinical trials demonstrate the benefits of lower systolic blood pressure and diastolic blood pressure in reducing the risk for stroke, congestive heart failure, myocardial infarction, and the rate of progression of renal disease. In their sixth report, the Joint National Committee stressed the importance of controlling blood pressure to 130/85 mmHg, or less, particularly in patients with diabetes, target organ disease, or renal insufficiency. Consequently, it is unlikely that there will be a single therapeutic agent that provides sufficient efficacy and tolerability that it can be used in many patients as successful monotherapy. Our future approaches to the treatment of hypertension will rest largely with the optimal combination of two or more drugs to more intensively lower blood pressure yet avoid the hazards of higher dose monotherapy. Ultimately, this may prove to be the key strategy. Note, however, that no two patients are alike. Adverse events are not uncommon and may vary substantially between patients, not only for different drugs but also for different doses of medications. Pathophysiologic explanations for hypertension remain unidentified although abnormalities of the renin-angiotensin system, the sympathetic nervous system (sympathetic nervous system), and salt and water handling by the kidney are leading candidates. Consequently, pharmacologic strategies must consider targeting one or all of these possible contributing factors.
The purpose of this post is to highlight some of the key factors the physician must consider when choosing the first agent, while also realizing that in the vast majority of patients a second and possibly even a third agent will be required.
Table Consideration for Initial Therapy in Older Patients
| Pathophysiology | Desirable pharmacologic approach” |
| Decreased vascular compliance and f PVR | Use a vasodilator (e.g., hydrochlorothiazide, ACEI, ARB, calcium channel blocker, a-blockers). |
| Isolated systolic hypertension and wider pulse pressure | Use hydrochlorothiazide. |
| Reduction of cardiovascular baroreflex function with blood lability | Avoid sympatholytics and volume depletion. |
| Orthostatic hypotension | Consider using short-acting meds (<8 h duration) at bedtime during recumbency. |
| Reduced metabolic capability | Adjust all medications for renal/hepatic function — start at half dose. |
| Prostatic hypertrophy (BPH) | Use prostatic urethral dilation (a-blockers). |
The first agent may then be viewed as the starting point on which subsequent therapies will be added depending on the patient’s underlying demographic variables and comorbid medical conditions. This chapter also highlights my own personal opinions with regard to optimal starting points in different types of patients.
Considerations for initial therapy in older patients
With aging there is a substantial decrease in vascular compliance and an increase in peripheral vascular resistance. This results in a wider pulse pressure with an increase in systolic blood pressure and a decrease in diastolic blood pressure. Frequently, there is an associated reduction in cardiovascular baroreceptor reflex function and greater blood pressure lability, orthostatic hypotension, reduced left ventricular compliance and function, and impaired renal blood flow.
An ideal starling point in older patients would be a vasodilator. I believe that the ideal “conditioning” agent is a low dose of hydrochlorothiazide approx 12.5 mg. This dose improves the blood vessels’ response to other commonly used drugs. Low doses of diuretics are extremely well tolerated and have a very low risk for causing abnormalities in glycemic control, potassium homeostasis, and cholesterol metabolism. They have been shown to be particularly effective in controlling systolic blood pressure. Diuretics primarily control blood pressure through a reduction in peripheral vascular resistance. At the beginning of treatment, they induce very mild volume contraction. The biologic half-life of diuretics extends for many months, far beyond their pharmacologic half-life.
Other initial pharmacologic approaches would include other vasodilator classes such as an angiotensin-converting enzyme inhibitor, an angiotensin type 1 receptor blocker, a calcium channel blocker, or an a-blocker. These drugs are also safe and effective and well tolerated particularly when used in lower doses. In particular, the angiotensin-converting enzyme inhibitor and the angiotensin type 1 receptor blocker can be titrated effectively without a substantial increase in adverse events. Calcium channel blockers and a-blockers are much better tolerated in the lower half of their dosing range. Calcium channel blockers are quite effective even in the face of a high-salt diet, perhaps owing to their renal vasodilatory effects and an intrinsic ability to facilitate natriuresis. α-Blockers may have a particular advantage in elderly males in facilitating prostatic urethral relaxation and improving urinary stream.
Whatever drugs are chosen, slow, careful titration is recommended, preferably not more frequently than every 3 mo, in order to gain more intensive control of both systolic blood pressure and diastolic blood pressure. In many patients, it has taken them 3CM-0 yr to develop hypertensive vascular disease. Physicians should not try to correct that in a matter of weeks. The use of lower doses of more drugs appears to be ideal in these types of patients, particularly when one of those drugs is a low-dose thiazide diuretic.
If orthostasis is present, shorter-acting medications dosed at night may provide an ideal approach. One also needs to remember to adjust medications for renal and hepatic dysfunction, which is also more common in older hypertensive patients.
Considerations for initial therapy based on gender
Considerations for initial therapy in african-american patients
African-American hypertensive patients present at an earlier age and more commonly have greater degrees of blood pressure elevation compared with their Caucasian counterparts. They also develop target organ damage sooner and have a greater proclivity for hypertensive renal insufficiency. Because these patients are younger and have greater blood pressure elevation, they frequently pose therapeutic dilemmas. How to avoid side effects yet provide needed blood pressure reduction requires careful effort. Lower doses of two or more drugs are frequently necessary.
In African Americans diuretics and calcium channel blockers have been demonstrated to possess more robust antihypertensive properties in lower doses than other drugs. These agents are preferable starting points to which could be added drugs that block the renin-angiotensin system in order not only to potentiate reduction in blood pressure but also reduce the likelihood of target organ damage, particularly to the heart and kidneys.
Table Considerations for Initial Therapy in Obese Hypertensive Patients
| Pathophysiology | Desirable pharmacologic approach |
| Hyperdynamic circulation | Reduce HR and sympathoadrenal outflow (β-blocker). |
| Increased PVR | Use vasodilation (e.g., hydrochlorothiazide, angiotensin-converting enzyme inhibitor, ARB, calcium channel blocker). |
| Salt sensitivity | Use natriuresis (hydrochlorothiazide, angiotensin-converting enzyme inhibitor, ARB, calcium channel blocker). |
| Expanded plasma volume | Use diuresis. |
Because African
Americans frequently have elevated peripheral vascular resistance, blood pressure salt sensitivity associated with a subtle increase in vascular volume, and more target organ disease, multiple drug therapy is of increased importance. Because many African-American patients are also younger, it is even more necessary to explain fully the rationale behind treatment and to focus on therapeutic strategies that do not impair quality of life. This is another reason that lower doses of more drugs may be an ideal therapeutic strategy given younger age, greater risk for hypertensive vascular disease, and inherent salt sensitivity.
Considerations for initial therapy in obese hypertensive patients
Obese hypertensive patients tend to have a hyperdynamic circulation, increased peripheral vascular resistance, expanded plasma volume, and greater sensitivity to the influence of dietary salt to raise blood pressure. Therapeutic strategies targeted to these specific abnormalities are desirable. A β-blocker may be helpful in diminishing sympathoadrenal outflow. Vasodilators such as hydrochlorothiazide, angiotensin-converting enzyme inhibitors, angiotensin type 1 receptor blockers, and calcium channel blockers are suitable for reducing peripheral vascular resistance. A thiazide diuretic, angiotensin-converting enzyme inhibitor, angiotensin type 1 receptor blocker, or calcium channel blocker may be helpful for facilitating natriuresis. If expanded plasma volume is clinically present, a diuretic would be the ideal drug with which to start. Otherwise, the choice of a first agent could be any of the previously listed agents. More often than not, multiple drug therapy will be required in order to facilitate blood pressure reduction to levels <130/85 mmHg.
Table Considerations for Initial Therapy in Patients with Heart Disease
| Pathophysiology | Desirable pharmacologic approach |
| Angina | Reduce heart rate and use antianginal therapy (reduce HR 10-20% or to 60-65 bpm). |
| Left ventricular hypertrophy | Reduce systolic blood pressure (hydrochlorothiazide, β-blocker, angiotensin-converting enzyme inhibitor, calcium channel blocker, ARB). Avoid nonspecific vasodilator or therapies that result in reflex f HR. |
| Systolic dysfunction | Reduce afterload and use natriuresis (angiotensin-converting enzyme inhibitor, hydrochlorothiazide, ARB). Sympathetic inhibitor -» β-blocker (carvedilol, others?). |
| Diastolic dysfunction | Improve myocardial compliance, reduce HR, avoid volume depletion (β-blocker, calcium channel blocker, avoid loop diuretics). |
| myocardial infarction | Reduce heart rate (β-blocker, angiotensin-converting enzyme inhibitor if left ventricular dysfunction). |
This is frequently desirable in obese hypertensive patients simply because of their frequent comorbid risks and cardiovascular risk clustering. Drug therapies that are inherently metabolically neutral are ideal in this regard, such as the angiotensin-converting enzyme inhibitor, angiotensin type 1 receptor blocker, calcium channel blocker, or α-blocker.
Considerations for initial therapy in patients with heart disease
Control of heart rate is an important factor in patients with ischemic heart disease. The vast majority of coronary artery perfusion occurs during diastole. Hence, pharmacotherapy that increases heart rate could lower the threshold for an ischemic event, whereas pharmacotherapy that reduces heart rate can diminish that likelihood. For this reason, if concomitant antihypertensive and anti-ischemic therapy is required, a heart rate-lowering β-blocker or nondihydropyridine calcium channel blocker would be ideal. If a hypertensive patient has had a recent myocardial infarction, then a heart rate-lowering β-blocker should be employed.
In patients with left ventricular hypertrophy, it is important to note that intensive blood pressure reduction is the most important factor for reducing Left ventricular hypertrophy regardless of the pharmacotherapy employed. Systolic blood pressure reduction reduces left ventricular strain. Ideally, hydrochlorothiazide, angiotensin-converting enzyme inhibitors, angiotensin type 1 receptor blockers, and calcium channel blockers should be used. There may be some benefits for specific antagonism of the renin-angiotensin system in reducing Left ventricular hypertrophy, as has been suggested in some clinical studies. If heart rate reduction were also necessary, either a β-blocker or a nondihydropyridine calcium channel blocker blocker would be ideal. This is frequently necessary if there is associated diastolic dysfunction. To improve myocardial compliance, it is necessary to facilitate ventricular relaxation and reduce heart rate ; β-blockers and calcium channel blockers are well suited for this. It is important to avoid nonspecific vasodilator therapies that may result in a reflex increase in heart rate. This reflex response may incite myocardial hypertrophic changes and explain why drugs such as hydra-lazine and minoxidil have not been proven to be useful in reducing Left ventricular hypertrophy despite their antihypertensive properties. Additionally, it is also necessary to avoid volume depletion, which can compromise preload to the heart and result in a reflex increase in heart rate. This is important to avoid in patients with Left ventricular hypertrophy and diastolic dysfunction because it may impair cardiac output.
In patients with systolic dysfunction and an ejection fraction <30%, pharmacotherapy that offers afterload and preload reduction and natriuresis are ideal. Volume control may be necessary, but it is hazardous to cause volume depletion because this may precipitate hypotension and functional renal insufficiency and cause an abrupt drop in cardiac output. Thiazide diuretics are preferred, and only loop diuretics should be employed in the presence of recalcitrant edema or renal insufficiency (serum creatinine >2.0 mg/dL). angiotensin-converting enzyme inhibitors are the ideal preload and afterload reducing agents. Angiotensin-converting enzyme inhibitors provide definite survival advantages in patients with systolic heart failure. More recent data suggest that metoprolol and cavedilol may also provide morbidity and mortality benefits in conjunction with angiotensin-converting enzyme inhibitor therapy. This may be related to inhibition of the activity of the sympathetic nervous system. The angiotensin type 1 receptor blocker losartan also demonstrated a survival benefit in a short-term clinical study.
Considerations for initial therapy in patients with renal disease
Conclusion
The initial choice of the medication in the treatment of hypertension should always be in conjunction with efforts at behavioral modification including reduced dietary salt intake, cessation of smoking, reduced alcohol intake, reduced saturated fat intake, regular exercise, and obtain-ment of ideal body weight. There is no ideal first-choice agent. Demographic factors and comorbid issues must be assessed with the well-recognized need of more intensive blood pressure reduction. It is also important to realize that the majority of patients will require two or more drugs in order to achieve the lower recommended level of blood pressure now recognized as being beneficial in reducing morbidity and mortality. Lower doses of two or more drugs also provide an improved opportunity to reduce blood pressure, utilize possible synergy between the agents, and reduce the likelihood of dose-dependent adverse events associated with higher doses of the individual monotherapies. Traditional strategies for controlling blood pressure using single agents titrated to their full extent has not been shown to be practical or effective in controlling blood pressure over prolonged periods. Consequently, new approaches need to be adopted. Using lower doses of more medications with the initial choice being directed toward identified pathophysiology contributing to hypertension and specific demographic variables and associated comorbid events may be the ideal long-term strategy.
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