New insights and new approaches for the treatment of essential hypertension: selection of therapy based on coronary heart disease risk factor analysis, hemodynamic profiles, quality of life, and subsets of hypertension

The pharmacologic therapy of mild primary hypertension (diastolic blood pressure less than 105 mm Hg) has effectively reduced hypertensive arteriolar end organ disease such as cerebrovascular accidents, congestive heart failure, and nephropathy, but there has been no convincing evidence that coronary heart disease (CHD) or its complications, acute myocardial infarction or angina, have been reduced. The risks of therapy with certain antihypertensive drugs may outweigh their treatment benefits as it relates to CHD. The optimal treatment strategy should be to reduce all CHD risk factors, reverse the hemodynamic abnormalities present by lowering the systemic vascular resistance (SVR), preserving cardiac output (CO) and perfusion, and to select the best antihypertensive drug for concomitant medical diseases or problems while maintaining a good quality of life. Antihypertensive drugs that have favorable or neutral effects on CHD risk factors include alpha blockers, calcium channel blockers, central alpha agonists, and angiotensin-converting enzyme inhibitors. On the other hand, diuretics and beta blockers without intrinsic sympathomimetic activity have unfavorable effects on many CHD risk factors. Baseline and serial evaluation of the effects of these drugs on serum lipids, lipid subfractions, glucose, uric acid, electrolytes, exercise tolerance, left ventricular hypertrophy, blood pressure, SVR, CO, perfusion, concomitant diseases, and side effects is necessary to evaluate overall cardiovascular risk.     

Antihypertensive drugs and glucose metabolism

Hypertension plays a major role in the development and progression of micro-and macrovascular disease.Moreover,increased blood pressure often coexists with additional cardiovascular risk factors such as insulin resistance.As a result the need for a comprehensive management of hypertensive patients is critical.However,the various antihypertensive drug categories have different effects on glucose metabolism.Indeed,angiotensin receptor blockers as well as angiotensin converting enzyme inhibitors have been associated with beneficial effects on glucose homeostasis.Calcium channel blockers(CCBs)have an overall neutral effect on glucose metabolism.However,some members of the CCBs class such as azelnidipine and manidipine have been shown to have advantageous effects on glucose homeostasis.On the other hand,diuretics andβ-blockers have an overall disadvantageous effect on glucose metabolism.Of note,carvedilol as well as nebivolol seem to differentiate themselves from the rest of theβ-blockers class,being more attractive options regarding their effect on glucose homeostasis.The adverse effects of some blood pressure lowering drugs on glucose metabolism may,to an extent,compromise their cardiovascular protective role.As a result the effects on glucose homeostasis of the various blood pressure lowering drugs should be taken into account when selecting an antihypertensive treatment,especially in patients which are at high risk for developing diabetes.     

The effects of beta-adrenergic blocking agents on blood lipid levels

This review examines the effects of beta-adrenergic blocking agents on blood lipids. These agents have been effective in the treatment of angina and hypertension and in the reduction of recurrence of ischemic cardiac disease, such as myocardial infarction. Many beta blockers, however, have an adverse effect on blood lipids, especially by reducing high-density lipoprotein (HDL) cholesterol and increasing triglycerides. One result is an unfavorable influence on the cholesterol ratio (expressed either as low-density lipoprotein [LDL]/HDL or total cholesterol/HDL). These cholesterol parameters have been shown to have a strong influence on coronary heart disease (CHD) risk. Studies have shown that antihypertensive therapy has reduced the incidence of cerebrovascular disease but, in many instances, has not reduced the incidence of CHD. A hypothesis for this lesser effect on coronary disease is that antihypertensive agents may be adversely affecting blood lipids. Thus, while one major risk factor for CHD is reduced, another may be somewhat enhanced. Pharmacologic properties of some beta blockers such as peripheral alpha blockade (e.g., with labetalol) or intrinsic sympathomimetic activity (ISA) (e.g., with pindolol) may counteract some of these negative lipid effects. An investigational beta blocker, bevantolol, which will be marketed shortly in the United States, has been effective in antihypertensive therapy. Bevantolol has been shown to lower LDL cholesterol and not adversely affect HDL cholesterol; in this way, bevantolol favorably influences the serum lipoprotein profile. Whether this effect will have clinical significance remains to be seen.     

Antihypertensive medications and their effects on lipid metabolism

Hypertension and hyperlipidemia are interrelated and share common pathophysiologic mechanisms, such as insulin resistance and endothelial dysfunction. Accumulating evidence shows that it is important to regulate hypertension and hyperlipidemia to reduce cardiovascular risk. However, medications such as β-blockers and thiazide diuretics, which are widely used for blood pressure regulation, are known to have several metabolic side effects. Despite deleterious effects on glucose metabolism and lipid metabolism, these medications have been proven to reduce cardiovascular risk. On the other hand, calcium channel blockers, angiotensin-converting enzyme inhibitors, and α-blockers have either no effect or favorable effects on the lipid profile. This review outlines the need to control hypertension, options for several antihypertensive medications, their differing effects on lipid metabolism, and the clinical implications of their effects on lipid parameters.     

Modification of lipoprotein metabolism by antihypertensive therapy

Of various antihypertensive drugs, particularly the unselective as well as the selective beta-receptor blockers but also diuretic drugs unfavourable effects on the lipid metabolism are reported, which above all consist of increases of triglycerides and decreases of HDL-cholesterol. The more modern antihypertensive drugs such as calcium antagonists, alpha 1-receptor blockers or angiotensin converting enzyme inhibitors according to the hitherto existing studies have no significant influence on the serum lipids. The final classification of the antihypertensive drugs regarding their influence on the atherogenic risk by negative changes in the lipoprotein metabolism is, however, at present not yet possible on account of insufficient long-term studies. For the reduction of adequate endangerings dietetic measures, reduction of overweight, physical training and when occasion arises change of the medication are recommended.     

Antihypertensive agents,insulin sensitivity,and new-onset diabetes

The effects of the antihypertensive drugs on carbohydrate metabolism and the development of diabetes have been a major research field for more than two decades. Many clinical studies have investigated the effects of the antihypertensive classes on insulin sensitivity and glycemic control, whereas several observational studies and large outcome trials have examined associations of antihypertensive agents with diabetes incidence. In general, thiazide diuretics and conventional beta blockers decrease insulin sensitivity and increase new-onset diabetes, whereas angiotensin-converting enzyme inhibitors, calcium channel blockers, and angiotensin II receptor blockers have neutral or beneficial effects on these parameters. However, several issues in this field, such as the specific properties of newer agents and the relationship of adverse metabolic outcomes and cardiovascular risk, remain to be fully elucidated. This article presents and evaluates the current knowledge in this important area.     

A "lipo-protective" effect of a fixed combination of captopril and hydrochlorothiazide in antihypertensive therapy.

Increases of triglycerides and total cholesterol have been reported during treatment with antihypertensive drugs, most notably with beta blockers and diuretics. ACE inhibitors, on the other hand, are not known for having a negative effect on lipid profile. To evaluate the effects of a fixed combination of captopril and hydrochlorothiazide on lipid metabolism, blood pressure, and quality of life, we performed an open prospective study. A total of 2,154 patients with or without hypercholesterolemia, but not receiving lipid lowering drugs, were enrolled. Of the 1891 evaluable patients at baseline, 34.1% had a moderate risk with total cholesterol between 5.2 and 6.5 mmol/l (mean 5.8 mmol/l) and 41.3% had a high coronary heart disease (CHD) risk with total cholesterol higher than 6.5 mmol/l (mean 7.3 mmol/l). After six months of treatment, the median cholesterol level in the moderate risk group decreased from 5.8 to 5.4 mmol/l (p less than 0.0003) and in the high risk group from 7.3 to 6.3 mmol/l (p less than 0.0001). Triglycerides also decreased, whereas high density lipoprotein (HDL) increased in both risk groups. Systolic and diastolic blood pressure fell as expected and quality of life improved. The fixed combination was well tolerated. We observed a significant improvement of lipid profile in patients with mild to moderate hypertension while undergoing treatment with the fixed combination of captopril and hydrochlorothiazide. We suggest that captopril may balance the negative effects of hydrochlorothiazide on lipid metabolism in patients with hypertension and concomitant hyperlipidemia.     

Use of beta-blockers in obesity hypertension: potential role of weight gain

Beta‐blockers are the most frequently used drugs for the treatment of hypertension. Apart from concerns regarding potential adverse metabolic effects on lipids or insulin sensitivity, beta‐blockers can also cause weight gain in some patients. This fact appears little known to clinical practitioners and trialists. Thus, only a minority of clinical trials with beta‐blockers report weight changes during treatment. In trials that do report weight changes, beta‐blockers are associated with a weight gain of 1.2 (range ?0.4–3.5) kg. This may be attributable to the fact that beta blockade can decrease metabolic rate by 10%. Beta‐blockers may also have other negative effects on energy metabolism. Obesity management in overweight hypertensive patients may therefore be more difficult in the presence of beta‐blocker treatment. We therefore question the use of beta‐blockers as first‐line therapy for overweight or obese patients with uncomplicated hypertension.     

Effects of adrenoceptor-blocking drugs on plasma lipoprotein concentrations

Evidence from numerous clinical trials has indicated that beta-adrenoceptor blocking agents without intrinsic sympathomimetic activity increase plasma triglycerides and decrease high density lipoprotein cholesterol in patients with hypertension or coronary artery disease. There appears to be little or no difference between the nonselective and cardioselective drugs in this regard. In contrast, beta blockers with intrinsic sympathomimetic activity and alpha 1 blockers appear not to have these effects. The changes induced by adrenoceptor-blocking agents in lipid and lipoprotein metabolism and their possible significance in relation to the pathogenesis of coronary artery disease are discussed.     

Clinical differences between beta-adrenergic blocking agents: implications for therapeutic substitution

The beta blockers exhibit clinically significant differences in beta-receptor selectivity, intrinsic sympathomimetic activity, and alpha-adrenergic blocking activity. These agents also show important differences in their pharmacokinetic profiles, including gastrointestinal absorption, first-pass hepatic metabolism, lipid solubility, protein binding, hepatic biotransformation, pharmacologic activity of metabolites, and renal clearance of unchanged drug and metabolites. These many differences determine the appropriateness of administering a given beta blocker in a given clinical situation. The selection of beta blockers must also take into account concurrent therapy with other agents. Concurrent administration of beta blockers with drugs that alter gastric, hepatic, or renal function may affect blood levels, duration of action, or efficacy of beta-blocker action. The beta blockers vary in the extent to which their action is altered when they are given with other agents, and therapeutic substitution may produce unwanted side effects and toxicity. Elderly patients should be carefully monitored following interchange among beta blockers, since the probability of drug interaction, impact of adverse effects, unpredictability of response, and physiologic variability of renal and liver function is greater than for younger individuals. Therapeutic substitution among beta blockers in patients already stabilized on a given agent will require careful monitoring. Retitration with the new beta blocker will be required in many cases to assure therapeutic equivalence. Beta blockers are currently used for over 20 medical conditions. There is wide variation in the strength of the clinical evidence supporting the use and efficacy of specific beta blockers for specific conditions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Beta-blockers in hypertension

Beta blockers have been used in the treatment of cardiovascular conditions for decades. Despite a long history and status as a guideline-recommended treatment option for hypertension, recent meta-analyses have brought into question whether β blockers are still an appropriate therapy given outcomes data from other antihypertensive drug classes. However, β blockers are a heterogenous class of agents with diverse pharmacologic and physiologic properties. Much of the unfavorable data revealed in the recent meta-analyses were gleaned from studies involving nonvasodilating, traditional β blockers, such as atenolol. However, findings with traditional β blockers may not be extrapolated to other members of the class, particularly those agents with vasodilatory activity. Vasodilatory β blockers (i.e., carvedilol and nebivolol) reduce blood pressure in large part through reducing systemic vascular resistance rather than by decreasing cardiac output, as is observed with traditional β blockers. Vasodilating ability may also ameliorate some of the concerns associated with traditional β blockade, such as the adverse effects on metabolic and lipid parameters, including an increased risk for new-onset diabetes. Furthermore, vasodilating ability is physiologically relevant and important in treating a condition with common co-morbidities involving metabolic and lipid abnormalities such as hypertension. In patients with hypertension and diabetes or coronary artery disease, vasodilating β blockers provide effective blood pressure control with neutral or beneficial effects on important parameters for the co-morbid disease. In conclusion, it is time for a reexamination of the clinical evidence for the use of β blockers in hypertension, recognizing that there are patients for whom β blockers, particularly those with vasodilatory actions, are an appropriate treatment option.     

Antihypertensive therapy and atherosclerosis

Hypertension and atherosclerosis make independent contributions to the pathogenesis of cardiovascular disease. Diuretics and beta adrenergic blockers, effective antihypertensive medications, exhibit some untoward effects on lipid metabolism, while most other antihypertensive medications tend not to exhibit such effects. In animal models, beta adrenergic blockers, angiotensin converting enzyme (ACE) inhibitors, and calcium antagonists have anti-atherogenic effects. A vascular biological approach to therapy for the patient with both hypertension and atherosclerosis is recommended. This includes effective reduction of blood pressure--preferably with agents that do not adversely affect lipid metabolism--and treatment of lipid metabolism disorders.     

氨氯地平对阿托伐他汀调脂作用的影响

目的观察氨氯地平对高血压合并冠心病患者阿托伐他汀调脂作用的影响。方法选择高血压合并冠心病患者174例,根据用药情况将患者分为2组,A组86例,以氨氯地平为基础的降压方案+阿托伐他汀;B组88例,无氨氯地平的降压方案+阿托伐他汀。分别观察2组在治疗前,治疗后2、4、8周时血脂、肝功、肌酸激酶等变化及不良反应发生情况。结果 A组与B组患者治疗前血清TC、TG、LDL-C、HDL-C水平差异无统计学意义(P0.05)。与治疗前比较,A组和B组患者治疗后2、4、8周血清TC、LDL-C水平明显降低,差异有统计学意义(P0.05);A组患者治疗后4、8周血清HDL-C水平明显升高,8周血清TG水平明显降低,差异有统计学意义(P0.05);B组患者治疗后2、4、8周血清HDL-C水平虽有升高趋势,TG水平虽有下降趋势,但差异无统计学意义(P0.05)。与B组比较,A组患者治疗后4、8周血清TC、LDL-C水平明显下降;治疗后8周血清HDL-C水平明显升高,差异有统计学意义(P0.05)。结论氨氯地平可能加强高血压合并冠心病患者阿托伐他汀的调脂作用,合用无明显不良反应。     

Review of state-of-the-art beta-blocker therapy.

Beta-adrenoceptor blocking drugs have been used in the treatment of hypertension for more than 2 decades. During this time they have reached the position of first-line therapy for hypertension and are recommended as such by the Joint National Committee (U.S.A.) in 1988 and by the World Health Organization/International Society of Hypertension in 1983 and 1989. This is because of the favorable relationship between the antihypertensive efficacy of these drugs and the rate and severity of their adverse effects. Of particular interest is the possibility that beta blockers may protect against coronary artery disease (CAD). With regard to secondary prevention against CAD, statistically highly significant and clinically relevant reductions of mortality and the risk of reinfarction have been shown in prospective, double-blind, placebo-controlled trials. A primary preventive effect against CAD, on the other hand, has only been shown in open trials without placebo control. However, in spite of the lack of clear proof, this effect still appears to be a logical possibility. Some new findings with beta blockers appear to be of particular interest: beta blockade may reduce myocardial necrosis in patients with marked elevations of plasma catecholamines due to traumatic head injury; a similar protective effect in other situations of severe stress, e.g., acute myocardial infarction, would be of great clinical value. Experimental studies also suggest that beta blockers may have antiatherosclerotic effect in animals fed an atherogenic diet and subjected to stress. Again, clinical confirmation of such results would be of great significance.     

Cardiovascular drug therapy in the elderly

Pharmacokinetic considerations in the elderly include absorption, bioavailablility, drug distribution, half-life, drug metabolism, and drug excretion. There are numerous physiologic changes with aging that affect pharmacodynamics with alterations in end-organ responsiveness. This article discusses use of cardiovascular drugs in the elderly including digoxin, diuretics, beta-adrenergic blockers, angiotensin-converting enzyme inhibitors, angiotensin-II receptor blockers, nitrates, calcium channel blockers, alpha-adrenergic blockers, antiarrhythmic drugs, lipid-lowering drugs, and anticoagulants. This article also discusses the adverse effects of cardiovascular drugs in the elderly, medications best to avoid in the elderly, and the prudent use of medications in the elderly.     

Individualization of calcium entry-blocker dosage for systemic hypertension

The calcium entry blockers are used in a wide variety of clinical situations. Coexisting disease states, such as renal or hepatic dysfunction, may require individualized dosing of these agents. The physiologic changes associated with aging may also affect the pharmacokinetic properties of the drugs. If calcium entry blockers are used concurrently with other medications, dosage adjustment or selection of an alternative drug may be needed. Drug interactions between calcium entry blockers and cimetidine, digoxin and quinidine appear to be clinically significant. Individualized dosing in patients who have coexisting disease or who are using other medications is essential to achieve an adequate therapeutic response and avoid adverse effects. Considerations to attain an optimal response in such situations are presented.     

The role of pharmacogenetics in nonmalignant gastrointestinal diseases

Genetic variation influences the absorption and efflux of drugs in the intestine, the metabolism of drugs in the liver and the effects of these drugs on their target proteins. Indeed, variations in genes whose products have a role in the pathophysiology of nonmalignant gastrointestinal diseases, such as IBD, have been shown to affect the response of patients to therapy. This Review provides an overview of pharmacogenetics in the management of nonmalignant gastrointestinal diseases on the basis of data from clinical trials. Genetic variants that have the greatest effect on the management of patients with IBD involve the metabolism of thiopurines. Variation in drug metabolism by cytochrome P450 enzymes also requires attention so as to avoid drug interactions in patients receiving tricyclic antidepressants and PPIs. Few genotyping tests are currently used in the clinical management of patients with nonmalignant gastrointestinal diseases, owing to a lack of data from clinical trials showing their effectiveness in predicting nonresponse or adverse outcomes. However, pharmacogenetics could have a beneficial role in enabling pharmacotherapy for nonmalignant gastrointestinal diseases to be targeted to the individual patient.     

Effects of antihypertensives on plasma lipids and lipoprotein metabolism

There is good epidemiologic evidence that hypertension is associated with a high risk of cardiovascular disease. However, primary intervention trials have failed to demonstrate that a reduction in blood pressure in hypertensive patients reduces morbidity and mortality from cardiac events. Since various antihypertensive drugs adversely affect lipoprotein metabolism, these drugs may increase associated coronary risk and offset the beneficial effects of lowering blood pressure. This article reviews the effects of various antihypertensive drugs on plasma lipids, lipoproteins, and apolipoproteins. They can be summarized as follows: thiazide-type diuretics cause a marked elevation of plasma triglycerides and very low-density lipoprotein (VLDL) and minor increases in total cholesterol and low-density lipoprotein (LDL), but have little effects on high-density lipoprotein (HDL). The nonselective β-blockers do not significantly affect total cholesterol and LDL, but increase total triglycerides and VLDL and decrease HDL. The changes in plasma lipids and lipoproteins caused by cardioselective β-blockers and β-blockers with intrinsic sympathomimetic activity are qualitatively similar but less pronounced. Calcium antagonists and angiotensin-converting enzyme inhibitors appear to have no significant effects on plasma lipids. α₁-inhibitors reduce total triglycerides, total cholesterol, VLDL, and LDL and increase HDL. The possible mechanisms by which antihypertensive drugs affect cellular lipid metabolism (e.g., LDL receptor, lipid synthesis, lipoprotein lipase, lecithin cholesteryl acyltransferase, acylcholesteryl acyltransferase, and cholesteryl ester hydrolase) are described. The clinical significance of changes in blood lipids and cellular lipid metabolism caused by antihypertensive drugs is not yet totally clear. Nevertheless, before antihypertensive drug treatment is initiated, blood lipid levels should be measured to identify preexisting hyperlipidemia. Blood lipoprotein levels should be monitored during long-term antihypertensive therapy to reconsider the therapeutic regimen if adverse lipid changes are observed.     

Effect of drugs on homocysteine concentrations

Many studies conducted over the last two decades have shown that drug treatment for common medical conditions may have an adverse effect on plasma total homocysteine (tHcy) concentrations. The mechanism for the effects of individual drugs on tHcy concentrations is frequently unknown, as the mechanism of action of the drug may not be established, or the drug is typically administered in combination with other drugs. Some drugs are believed to alter tHcy concentrations by interfering in the metabolism of folate or vitamins B (12) or B (6) or by altering renal function, but the underlying mechanisms for the effects on tHcy concentrations of many drugs remains to be discovered. Several widely used drugs, such as lipid-lowering drugs (like fibrates and niacin) or oral hypoglycemic drugs (like metformin), insulin, drugs used in rheumatoid arthritis, and anticonvulsants cause elevated tHcy concentrations. Sex hormones have variable effects on tHcy levels, and N-acetylcysteine lowers tHcy. The mechanisms of action of drugs on tHcy concentrations and strategies to avoid tHcy elevation have been studied. Assuming that the association of tHcy with cardiovascular disease is causal, this article focuses on the adverse effect on tHcy levels of fibrates, statins and niacin, antihypertensive drugs, metformin, methotrexate and sulfasalazine, anticonvulsant drugs, and levodopa and reviews strategies to avoid such effects. The clinical significance, if any, of these adverse effects on plasma tHcy concentrations remains to be determined.     

Relation between lipids and atherosclerosis: Epidemiologie evidence and clinical implications

Coronary artery disease (CAD) is the leading cause of death in most developed countries. Therefore, elucidation of risk factors and associated mechanisms for CAD has been a high priority. Data from the Framingham Heart Study and other large-scale epidemiologic studies have identified major risk factors associated with CAD, demonstrating the adverse effects of increased total and low-density lipoprotein cholesterol levels and the protective effect of high-density lipoprotein cholesterol. Other more recent investigations, including the Lipid Research Clinics Trial and the Helsinki Heart Study, have shown that lowering total cholesterol and raising high-density lipoprotein cholesterol significantly reduce the risk for CAD. Because hypertension is also a significant risk factor for CAD, the assumption has been that blood pressure reduction should offer significant benefits in terms of CAD risk. However, despite their antihypertensive efficacy, diuretics and β blockers have failed to significantly reduce CAD morbidity or mortality. The adverse effects of these antihypertensive agents on lipid profiles, glucose metabolism and other metabolic parameters may account for their disappointing performance in reducing CAD morbidity and mortality. As a result, newer agents such as angiotensin-converting enzyme inhibitors and calcium antagonists that appear to be free of such adverse effects have garnered considerable attention for their potential to reduce CAD risk.