Resistant hypertension

Fig. 14.5 Forms, localization and systematics of portal hypertension (resistance-related and volume-related hypertension can occur either as primary or secondary forms)...

Figure 1. Effect of alpha-methyldopa and chlorthalidone (Hygroton) compared to guanethidine plus chlorthalidone in patient with hypertension resistant to treatment...

While class 1 calcium channel blockers are used to treat atrial arrhythmia, class II and class 111 calcium channel blockers are now considered first-line therapy for many patients with hypertension. Resistant hypertension can be treated with add-on drugs ai-antagonists, centrally acting antihypertensives and adrenergic neurone blockers. 

Insulin and Amylin. Insulin is a member of a family of related peptides, the insulin-like growth factors (IGFs), including IGF-I and IGF-II (60) and amylin (75), a 37-amino acid peptide that mimics the secretory pattern of insulin. Amylin is deficient ia type 1 diabetes meUitus but is elevated ia hyperinsulinemic states such as insulin resistance, mild glucose iatolerance, and hypertension (33). Insulin is synthesized ia pancreatic P cells from proinsulin, giving rise to the two peptide chains, 4. and B, of the insulin molecule. IGF-I and IGF-II have stmctures that are homologous to that of proinsulin (see INSULIN AND OTHER ANTIDIABETIC DRUGS). 

It is well accepted that hypertension is a multifactorial disease. Only about 10% of the hypertensive patients have secondary hypertension for which causes, ie, partial coarctation of the renal artery, pheochromacytoma, aldosteronism, hormonal imbalances, etc, are known. The hallmark of hypertension is an abnormally elevated total peripheral resistance. In most patients hypertension produces no serious symptoms particularly in the early phase of the disease. This is why hypertension is called a silent killer. However, prolonged suffering of high arterial blood pressure leads to end organ damage, causing stroke, myocardial infarction, and heart failure, etc. Adequate treatment of hypertension has been proven to decrease the incidence of cardiovascular morbidity and mortaUty and therefore prolong life (176—183). 

Calcium channel blockers reduce arterial blood pressure by decreasing calcium influx, resulting in a decrease in intracellular calcium (236,237). The arterial smooth muscle tone decreases, thereby decreasing total peripheral resistance. The increase in vascular resistance in hypertension is found to depend much on calcium influx. Calcium channel blockers reduce blood pressure at rest and during exercise. They decrease the transmembranous calcium influx or entry that lead to a net decrease of intracellular calcium and therefore the vascular tone falls, as does blood pressure. 

Nifedipine (Table 3) is a potent vasodilator that selectively dilates resistance vessels and has fewer effects on venous vessels. It does not cause reflex tachycardia during chronic therapy. Nifedipine is one of the first-line choices for black or elderly patients and patients having concomitant angina pectoris, diabetes, or peripheral vascular diseases. Nifedipine, sublingually, is also suitable for the treatment of hypertensive emergencies. Nifedipine does not impair sexual function or worsen blood Hpid profile. The side effects are flushing, headache, and dizziness. 

DHPs are potent arterial vasodilators. They act on resistance vessels and therefore reduce peripheral vascular resistance, lower arterial blood pressure, and antagonize vasospasms in coronary or peripheral arteries. By reducing afterload, DHPs also reduce cardiac oxygen demand. Together with their vascular spasmolytic effect, this explains most of the beneficial actions of DHPs in angina pectoris. Most DHPs are only licensed for the therapy of hypertension, some of them also for the treatment of angina pectoris and vasospastic (Prinzmetal) angina. 

Insulin resistance occurs when the normal response to a given amount of insulin is reduced. Resistance of liver to the effects of insulin results in inadequate suppression of hepatic glucose production insulin resistance of skeletal muscle reduces the amount of glucose taken out of the circulation into skeletal muscle for storage and insulin resistance of adipose tissue results in impaired suppression of lipolysis and increased levels of free fatty acids. Therefore, insulin resistance is associated with a cluster of metabolic abnormalities including elevated blood glucose levels, abnormal blood lipid profile (dyslipidemia), hypertension, and increased expression of inflammatory markers (inflammation). Insulin resistance and this cluster of metabolic abnormalities is strongly associated with obesity, predominantly abdominal (visceral) obesity, and physical inactivity and increased risk for type 2 diabetes, cardiovascular and renal disease, as well as some forms of cancer. In addition to obesity, other situations in which insulin resistance occurs includes... 

Patients failing to achieve goal blood pressure despite maximum doses of three antihypertensives including a diuretic should be carefully screened for resistant hypertension. 

The pathophysiology of primary hypertension is heterogeneous, but ultimately exerts its effects through the two primary determinants of blood pressure cardiac output and peripheral resistance. 

In addition to primary and secondary hypertension, the clinician may encounter what is referred to as resistant hypertension. Patients failing to achieve goal blood pressure despite maximum doses of three antihypertensives including a diuretic should be carefully screened for resistant hypertension. Several causes of resistant hypertension are listed in Table 2-2 and should be carefully considered in such patients. 

Overactivation of the sympathetic nervous system (SNS) may also play a role in the development and maintenance of primary hypertension for some individuals. Among other effects, direct activation of the SNS may lead to enhanced sodium retention, insulin resistance, and baroreceptor dysfunction.9 Regardless of which mechanism(s) underlie the role the SNS may play in the development of primary hypertension, the SNS remains a target of many antihypertensive agents. 

Elevated peripheral arterial resistance is a hallmark of primary hypertension. The increase in peripheral resistance typically observed may be due to a reduction in the arterial lumen size as a result of vascular remodeling. This remodeling, or change in vascular tone, may be modulated by various endothelium-derived vasoactive substances, growth factors, and cytokines. This increase in arterial stiffness or reduced compliance results in the observed increase in systolic blood pressure.9... 

Other Agents Reserpine No recommendations at this time Mental depression May be used in resistant hypertension when combined with a thiazide... 

P-blocker therapy was ineffective in preventing coronary heart disease, cardiovascular mortality, and all-cause mortality when compared to diuretics for elderly patients (60 years of age or greater) treated for primary hypertension. Clearly, the effects of P-blockers on blood pressure are complex and difficult to ascribe to one or two mechanisms. Rather, the varied effects of negative chronotropic and inotropic properties along with reduced renin levels (Fig. 2-3) appear to result in an overall reduction in cardiac output and/or reduction in peripheral resistance. 

Two types of diuretics are used for volume management in HF thiazides and loop diuretics. Thiazide diuretics such as hydrochlorothiazide, chlorthalidone, and metolazone block sodium and chloride reabsorption in the distal convoluted tubule. Thiazides are weaker than loop diuretics in terms of effecting an increase in urine output and therefore are not utilized frequently as monotherapy in HF. They are optimally suited for patients with hypertension who have mild congestion. Additionally, the action of thiazides is limited in patients with renal insufficiency (creatinine clearance less than 30 mL/minute) due to reduced secretion into their site of action. An exception is metolazone, which retains its potent action in patients with renal dysfunction. Metolazone is often used in combination with loop diuretics when patients exhibit diuretic resistance, defined as edema unresponsive to loop diuretics alone. 

Patients with metabolic syndrome are twice as likely to develop type 2 diabetes and four times more likely to develop CHD.3,11 These individuals are usually insulin resistant, obese, have hypertension, are in a prothrombotic state, and have atherogenic dyslipidemia characterized by low HDL cholesterol and elevated triglycerides, and an increased proportion of their LDL particles are small and dense.3... 

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