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Hepatic impairment can alter the pharmacokinetic profiles of cardiovascular drugs, which can lead to unwanted toxicity. In the presence of cirrhosis, portosystemic shunting occurs and cytochrome P450 activity is reduced. Impaired oxygen uptake caused by changes in the liver's sinusoids, as proposed by the oxygen limitation theory, may also explain the alteration of drug metabolism seen in cirrhosis. With congestive heart failure, sinusoidal congestion and hypoperfusion of the liver are seen. Similar to cirrhosis, the common pathway for hepatic damage in congestive heart failure seems to be liver hypoxia, which may explain the disease's effect on drug metabolism. Since routine hepatic function tests do not always relate to the liver's ability to eliminate drugs, existing guidelines for dosing cardiovascular drugs in patients with hepatic impairment are limited. This article provides guidance for dosing cardiovascular drugs in cirrhotic and heart failure patients based on available research data. Altered drug metabolism, especially in congestive heart failure, tends to be overlooked or not realized in clinical practice. Therefore, further research is needed in congestive heart failure to better elucidate safe prescribing patterns. [ABSTRACT FROM PUBLISHER]

There is evidence from observational studies that estrogen replacement therapy in postmenopausal women can reduce the rates of morbidity and mortality of atherosclerotic heart disease. The mechanism of this cardiovascular protective effect is not yet established, but favorable actions of hormone therapy on plasma lipids and vascular endothelial function have been proposed. Estrogens can also increase the risk of breast and uterine carcinoma. The new selective estrogen receptor modulator (SERM) raloxifene appears to have benefits similar to estrogen on plasma lipids and osteoporosis, but it does not affect the rate of uterine carcinoma as does tamoxifen and estrogen. Animal studies suggest an antiatherosclerotic action of raloxifene, but this needs to be confirmed in long-term human studies. [ABSTRACT FROM PUBLISHER]

Abdominal aortic aneurysm (AAA) is a leading cause of death in the United States, and there is no effective treatment in the early course of disease. Therapy to retard or reverse aneurysmal growth requires an understanding of the underlying vascular pathology. Recent research has indicated that enzymatic degradation of structural matrix proteins plays a large role in the formation of AAAs. Specifically, many studies have implicated a family of matrix degrading enzymes, known as matrix metalloproteinases (MMPs), as vital factors in the disease. Although AAA was once thought to be purely secondary to atherosclerosis, investigators have demonstrated various differences between the diseases in both levels and distribution of MMPs, suggesting independent mechanisms. Experimental models have shown that inhibition of these proteinases may slow aortic wall matrix breakdown. The purpose of this article is to review the current literature regarding the role of individual MMPs in AAA, including their complex regulatory mechanisms and possible cellular sources, the importance of MMPs as a potential therapeutic target in the prevention and treatment of AAA, and their inhibition using novel pharmacologic interventions in animal models. [ABSTRACT FROM PUBLISHER]

The α-adrenergic blockers have played an important role in the treatment of vascular diseases. Nonselective α blockers have been used as treatments for patients with severe hypertension, including pheochromocytoma. Selective α1 blockers have been used in the treatment of hypertension and prostatic obstruction, and these drugs have also been considered in the treatment ofother vascular and nonvascular conditions. They have unique metabolic actions, specifically on plasma lipids and lipoproteins, which could be of clinical benefit. [ABSTRACT FROM PUBLISHER]

Over the past few years, it has been shown that the cardiac myocyte plasma membrane sodium ion/hydrogen ion exchanger (NHE) plays an important role in the maintenance of intracellular pH, sodium, and calcium ion homeostasis. From the results of various experimental studies, it is clear that this ion exchanger is an important mediator of ischemic-reperfusion injury of the heart. During myocardial ischemia, intracellular acidosis develops quickly, activating the exchanger to extrude H+ into the extracellular environment and bring Na+ into the cell. With further progression of ischemia, the cell is unable to handle the overload of Na+, causing it to use its Na+/Ca2+ exchanger to unload intracellular Na+ into the extracellular space. At the same time, however, calcium is being transported into the cell. This can lead to detrimental cardiac injury, such as contracture and necrosis. During myocardial reperfusion, these events are magnified because the return of blood flow lowers the extracellular H+ concentration, stimulating the NHE to extrude more intracellular H+ ion. This leads to intracellular Na+ excess and eventually, intracellular Ca2+ overload and cardiac injury. In an effort to alter these pathophysiologic events, a number of investigators have studied the ability of various NHE inhibitors, such as amiloride, analogues of amiloride, and other drugs (HOE 694, HOE 642), to prevent cardiac ischemic-reperfusion damage. Preliminary results from studies in animal models have revealed that most of these agents are able to attenuate the development of myocardial contracture, infarction, and arrhythmias during both ischemia and reperfusion. Their efficacy and cardioprotective effects in human beings have yet to be determined. These agents appear to be promising not only in the prevention and treatment of ischemic heart disease, but also in avoiding cardiac damage in situations where low-flow states are followed by immediate recovery of flow, as in coronary artery bypass graft surgery, percutaneous transluminal coronary angioplasty, thrombolytic therapy, and coronary arterial vasospasm. This article reviews the physiology of the NHE and analyzes the potential role of NHE inhibitors in the prevention of ischemic-reperfusion injury and other cardiac disease states. [ABSTRACT FROM AUTHOR]

Angiotensin-converting enzyme (ACE) inhibitors have earned an important place in medical therapy since their discovery about two decades ago. This family of drug has grown tremendously since the introduction of captopril in 1981. There are currently more than 14 ACE inhibitors in the world and 9 are available in the United States. Although these agents share many similarities, they differ in their pharmacokinetic properties, approved indications, and cost. This paper provides guidance for selection of ACE inhibitors by examining the pharmacokinetics, pharmacodynamics, drug interactions, adverse effects, and cost of these agents. Combination products of ACE inhibitors with either diuretics or calcium channel blockers also are reviewed. [ABSTRACT FROM AUTHOR]

The Na+-Ca2+ exchanger is a non-ATP-dependent protein that, under steady-state conditions, extrudes Ca2+ from the interior of the cell into the extracellular space via facilitated transport. The activity of the exchanger seems to be reduced in myocardial ischemia, leading to increased intracellular Ca2+ in the ischemic heart, which can result in arrhythmia, myocardial stunning, and necrosis. In contrast, congestive heart failure and myocardial hypertrophy are associated with increased exchanger activity and a decreased inotropic state. Pharmacologic agents are being developed to modulate sodium ion levels in the cell, which could enhance or reduce sodium-calcium exchange as needed in various pathophysiologic states. At this time there are no available drugs that act specifically on the Na+-Ca2+ exchanger itself. The exchanger has been cloned, and inhibitory peptides of the exchanger may soon be available for possible use in treatment of congestive heart failure. [ABSTRACT FROM AUTHOR]

Myocarditis has been shown to be a common cause of cardiomyopathy and is believed to account for 25% of all cases in human beings. Unfortunately, the disease is difficult to detect before a myopathic process ensues. Treatment of myocarditis-induced heart failure includes the standard regimen of diuretics, digoxin, angiotensin-converting enzyme inhibitors, and currently, β-adrenergic blockers. Treatment of myocarditis itself is dependent on the etiology of the illness. Treatments under investigation include immunosuppressants, nonsteroidal antiinflammatory agents, immunoglobulins, immunomodulation, antiadrenergics, calcium-channel blockers, angiotensinconverting enzyme inhibitors, nitric oxide inhibition (e.g., aminoguanidine), and antiviral agents. Despite advances in treatment, more work needs to be done in the early detection of myocarditis. Additionally, better means need to be established for distinguishing between viral and autoimmune forms of the disease, so that appropriate treatment can be instituted. [ABSTRACT FROM AUTHOR]

This review was conducted to assess whether there is sufficient evidence for the clinical use of chelation therapy in cardiovascular disease based on original articles and abstracts published in the last 30 years, with emphasis placed on the most recent placebo-controlled studies. Articles postulating the mechanisms of chelation also were included. The majority of the literature focused on three chelators in particular, ethylenediaminetetraacetic acid (EDTA), deferoxamine, and dexrazoxane (ICRF-187). Historically, much has been written on the beneficial effects of EDTA. However, there are few controlled studies, and the mechanism of action of EDTA is poorly understood. Although studies of deferoxamine are more recent, most of the research is limited to animals and ex vivo models. Recently, dexrazoxane was approved, but only for parenteral use for reducing the incidence and severity of cardiomyopathy associated with doxorubicin administration in women with metastatic breast cancer. Given these limitations, it is concluded that more controlled studies are required to determine the efficacy of chelation therapy in cardiovascular disease before it can be used broadly in the clinical setting. [ABSTRACT FROM AUTHOR]

Matrix metalloproteinases (MMP) are a family of enzymes that selectively digest individual components of the extracellular matrix. Their function has been studied in both normal physiologic processes and pathologic states. In the blood vessel, MMPs play an important role in maintaining the vessel's integrity by breaking down extracellular matrix while new matrix is being synthesized. This is necessary to avoid weakening from continuous mechanical stresses. However, in certain environments, these MMPs may contribute to cardiovascular pathologic processes. The purpose of this review is to first discuss the role of MMPs in coronary vascular disease. Evidence suggests that MMPs contribute to the development of de novo atherosclerotic plaques and postangioplasty restenotic plaques by allowing smooth muscle cells to migrate from the vascular media to the intima. Evidence also suggests that MMPs contribute to the rupture of these plaques by degrading the fibrous cap that surrounds them. With this increased molecular information that concerns the pathogenesis of coronary vascular disease, new molecular therapies aimed at altering these processes are being investigated. The rationale, mode of delivery, and prospects for success of these therapies will also be discussed here. [ABSTRACT FROM AUTHOR]

Fenoldopam is a selective dopamine agonist that is being considered for the parenteral treatment of systemic hypertension. In both an oral and parenteral form, the drug causes peripheral vasodilation by stimulating dopamine-1 adrenergic receptors. Its pharmacodynamics are reviewed in this article, along with the clinical experiences in patients with hypertensive urgencies and emergencies. Intravenous fenoldopam may provide advantages over sodium nitroprusside because it can induce both a diuresis and natriuresis, is not light sensitive, and is not associated with cyanide toxicity. There is no evidence for rebound hypertension after discontinuation of fenoldopam influsion. J Clin Pharmacol 1998;38:2-13. [ABSTRACT FROM AUTHOR]

Obesity is a major risk factor for morbidity and mortality, and a series of pharmacologic approaches are available for helping to manage the problem. Obesity is caused by an imbalance between caloric intake and energy expenditure, which is influenced by both environmental and genetic factors. Pharmacologic treatments include anorexigenic agents, which fall into two broad categories: those that act via brain catecholamine pathways and those that act via serotonin pathways. The most recent oral agents approved are dexfenfluramine, which is currently being marketed, and sibutramine. Both agents inhibit the control reuptake of serotonin but in addition may have effects on thermogenesis. Under investigation are agents that increase energy expenditure: the β3-adrenergic receptor agonists and drugs that prevent the intestinal absorption of free fatty acids and cholesterol. In development are innovative approaches to influence leptin and its receptors, various obesity genes, and biologic substances thought to influence satiety (neuropeptide Y, enterostatin, cholecystokinin, bombesin, and amylin). Obesity has now become a major target for drug development not only for affecting obesity per se but also for managing and preventing comorbid conditions such as diabetes and cardiovascular disease. [ABSTRACT FROM AUTHOR]

Nicorandil is the first oral potassium channel activating drug to be used for the treatment of symptomatic coronary artery disease. It appears to relax vascular smooth muscle through membrane hyperpolarization via increased transmembrane potassium conductance and, like nitrates, through an increase in intracellular cyclic GMP. In addition, nicorandil, in a nitrate-like manner, dilates normal and stenotic coronary arteries and reduces both ventricular preload and afterload. In contrast to nitrates, however, nicorandil does not appear to cause tolerance with long-term administration. In placebo and comparison clinical trials, nicorandil has demonstrated some efficacy and safety in patients with both stable and vasospastic angina pectoris, and it was found to be a myocardial protective agent in animal studies. The antianginal activity of nicorandil, however, is relatively short lived after dosing, which will necessitate the development of extended-release formulations of the drug. [ABSTRACT FROM AUTHOR]

The imidazoline receptors have recently been discovered to be involved in central nervous system control of blood pressure (I-1 receptor) and in neuroprotection for cerebral ischemia (I-2 receptor). A new class of central-acting antihypertensive agents has been developed, the imidazoline receptor agonists (rilmenidine and moxonidine), which control blood pressure effectively without the adverse effects of sedation and mental depression that are usually associated with central-acting antihypertensives. This new generation of central-acting antihypertensive agents are highly selective for the imidazoline receptor, while having a low affinity for α2-adrenergic receptors. [ABSTRACT FROM AUTHOR]

A single-blind, run-in, randomized, double-blind, parallel-group, placebo-controlled comparison trial was conducted to assess the safety and efficacy of low-dose amlodipine 2.5 mg daily, low-dose benazepril 10 mg daily, and the combination of the two drugs at the same doses used once daily in patients (n = 401) with mild to moderate (stages I and II) systemic hypertension. Both monotherapy regimens were shown to significantly reduce both systolic and diastolic blood pressure compared with baseline placebo values, and the combination regimen was shown to be superior in lowering systolic and diastolic blood pressure when compared with either of the monotherapy regimens. The combination therapy also resulted in a greater percentage of patients having successful clinical response in mean sitting diastolic blood pressure. The amlodipine and benazepril regimen was also shown to be associated with a similar incidence of adverse experiences as the active monotherapy or placebo regimens, although the group given combination therapy appeared to have a lower incidence of edema than the group given amlodipine alone. Low-dose amlodipine (2.5 mg) plus benazepril (10 mg) provides greater blood-pressure-lowering efficacy than either monotherapy, and has an excellent safety profile. [ABSTRACT FROM AUTHOR]

Systemic hypertension, a vascular disease with multiple origins, now is being linked to subtle abnormalities in glucose metabolism, which include insulin resistance and hyperinsulinemia. These conditions often occur together in patients with obesity, noninsulin-dependent diabetes, or both. Hyperinsulinemia and insulin resistance may cause systemic hypertension through multiple mechanisms. Insulin has a salt-retaining effect on the kidney. Also, insulin can augment catecholamine release, increase vascular sensitivity to vasoconstrictor substances, and decrease vascular sensitivity to vasodilator substances. In addition, insulin can increase production of tissue growth factors and help retain sodium and calcium in cells. Insulin resistance in patients can be treated with regular aerobic exercise, weight reduction, and a high-fiber diet. Pharmacologic approaches include hypoglycemic drugs, weight-reducing agents, and certain antihypertensive drugs that may have a favorable impact on both blood pressure and insulin resistance. [ABSTRACT FROM AUTHOR]

Hypertensive emergency is a condition in which there is elevation of both systolic and diastolic blood pressure with the presence of acute target organ disease. Hypertensive urgency is a condition where the blood pressure is elevated (diastolic > 120 mmHg) with the absence of acute target organ disease. Hypertensive emergencies are best managed with parenteral drugs and careful intraarterial blood pressure monitoring. Hydralazine has been widely used in treatment of hypertension in eclampsia and preeclampsia, and its safety has been demonstrated in these patients. Sodium nitroprusside (SNP) has the most reliable antihypertensive activity, which begins immediately after its administration and ends when the infusion is stopped. As with diazoxide, it should be used with caution in patients with impaired cerebral flow. SNP is the preferred drug in obtaining controlled hypotension in patients undergoing neurovascular surgery. Intravenous nitroglycerin is useful in patients prone to myocardial ischemia, but should be avoided in patients with increased intracranial pressure. Esmolol is effective in controlling both supraventricular tachyarrhythmias and severe hypertension. Its short onset of duration of action make it useful in the emergent setting, but because of its negative inotropic effect its use should be avoided in patients with low cardiac output. Verapamil should not be used in patients with preexisting conduction abnormalities. Nicardipine is a potent arteriolar vasodilator without a significant direct depressant effect on myocardium. As with other afterload reducing agents, it should not be used in patients with severe aortic stenosis. Because angiotensin-converting enzyme (ACE) inhibitors generally cause cerebral vasodilatation, enalaprilat may be particularly beneficial for patients who are at high risk of developing cerebral hypotensive episodes secondary to impaired cerebral circulation. Fenoldopam, a selective post-synaptic dopaminergic receptor (DA1) has been shown to be effective in treating severe hypertension with a lower incidence of side effects than SNP. Hypertensive urgencies can usually be managed with oral agents. Oral nifedipine, captopril, clonidine, labetalol, prazosin, and nimodipine have all been shown to be effective in these situations. [ABSTRACT FROM AUTHOR]

Serotonin, or 5-hydroxytryptamine, is a naturally-occurring vasoactive substance found primarily in the brain, enterochromaffin tissue, and blood platelets. It has diffuse cardiophysiologic effects. The multiple effects of serotonin on blood vessels can be explained by the existence of 2 serotonergic receptor subtypes (the S1 receptor mediates vasodilation, and the S2 receptor vasoconstriction). Serotonin via the S2 receptor also augments the actions of several other vasoconstricting substances. Serotonin may be responsible for causing, or at least perpetuating, some forms of systemic hypertension through peripheral and central nervous system (CNS) actions. Ketanserin is a highly selective S2-serotonergic antagonist with additional α-adrenergic blocking activity, which has been proposed as a therapy for various cardiovascular diseases including hypertension. It has been shown to be more effective than placebo in treating hypertension and comparable in effectiveness to other antihypertensive drugs. Its major side effects relate to the CNS, and prolongation of the electrocardiogram QT interval has been described. Caution must be used when using ketanserin in patients receiving potassium- and magnesium-losing agents, because of the risk of torsades de pointes. Ketanserin has potential utility in the treatment of eclampsia, peripheral vascular disease, carcinoid syndrome, and 'shock lung.' The drug is not yet approved for clinical use in the United States. [ABSTRACT FROM AUTHOR]

The use of estrogens in postmenopausal women has been the subject of much controversy regarding hormone formulation, dosage, use in combination with progestins, duration of treatment, and contraindications. Estrogens have been prescribed to relieve menopausal symptoms for more than three decades. The hormones reduce the gynecologic and psychologic changes associated with menopause while inhibiting bone resorption and possibly reducing the risk of cardiovascular disease. Their use however has been complicated by an increased risk of endometrial cancer and possibly breast cancer. The use of estrogens as cardioprotective agents is discussed and the clinical experiences and the possible mechanisms of action are reviewed. The clinical pharmacology of estrogens and the various formulations that are available as monotherapy or in combination with progestins will also be reviewed. [ABSTRACT FROM AUTHOR]

This 30-center, randomized, double-blind, placebo-controlled, parallel-group study was designed to (1) establish that 6.25 mg of hydrochlorothiazide (HCTZ) given once daily with 5 mg of bisoprolol fumarate can contribute to antihypertensive effectiveness in patients with stage I and stage II (mild to moderate) systemic hypertension; and (2) assess whether this formulation was more effective or possessed a safety advantage over standard monotherapy with bisoprolol or 25 mg of HCTZ. Results showed that HCTZ 6.25 mg contributed significantly to the antihypertensive effectiveness of bisoprolol 5 mg. Bisoprolol 5 mg/HCTZ 6.25 mg (B5/H6.25) produced significantly greater mean reductions from baseline in sitting systolic and diastolic blood pressure (−15.8 mm Hg/−12.6 mm Hg) than bisoprolol 5 mg alone (−10.0 mm Hg/−10.5 mm Hg) and HCTZ 25 mg alone (−10.2 mm Hg/−8.5 mm Hg). A 73% response rate was achieved with the low-dose formulation compared with 61% for the bisoprolol 5 mg (B5) group and 47% for the HCTZ 25 mg (H25) group. B5/H6.25 was found to be significantly more effective than B5 or H25 in all subgroups of patients, regardless of gender, race, age, or smoking history. Antihypertensive effects were maintained during the 24-hour dosing interval. The incremental effectiveness of B5/H6.25 was not accompanied by an increase in the frequency or severity of adverse experiences; the incidence of adverse experiences in the B5/H6.25 group was comparable to that in the placebo group. B5/H6.25 was shown to provide safety advantages over H25, as shown by less hypokalemia (<1% with B5/H6.25 versus 6.5% with H25). Treatment effects on triglycerides were similar to placebo, although small decreases in high-density lipoprotein (HDL) cholesterol were observed in the bisoprolol-treated groups. The benefits of low-dose bisoprolol 5 mg/HCTZ 6.25 mg provide a rational basis for the use of this medication in the first-line treatment of patients with stage I and stage II systemic hypertension. [ABSTRACT FROM AUTHOR]

Atrial natriuretic peptide (ANP) is a 28 amino-acid polypeptide secreted into the blood by atrial myocytes after atrial pressure and distension. Although its role in humans is not clear, it can produce a variety of physiologic effects including vasodilatation, natriuresis, and suppression of the renin-angiotensin-aldosterone axis. These actions are potentially useful in a variety of pathologic states such as hypertension and congestive heart failure, and diverse methods to augment the effects of ANP in these states have been devised. The results are exciting and, despite some problems, may lead to the pharmacologic use of enhancement of ANP actions in several clinical disorders. [ABSTRACT FROM AUTHOR]

In the treatment of hypertension in renally impaired patients, normalization of blood pressure alone may not be sufficient to prevent significant morbidity to the kidneys. Treatment must reduce pressure in the renal vasculature, otherwise glomerular filtration rate and renal plasma flow will continue to deteriorate. Isradipine, a dihydropyridine calcium-channel blocker, has been investigated as a suitable treatment in this setting. Isradipine maintains glomerular filtration rate, preserves or enhances renal plasma flow, decreases renal vascular resistance, maintains or reduces filtration fraction, and exerts a sustained natriuretic effect, all of which may enable isradipine to slow the rate of progression of renal deterioration. In addition, isradipine may decrease proteinuria and may decrease glomerular capillary pressure by dilating both the efferent and afferent arterioles. Unlike older calcium-channel blockers, isradipine exhibits minimal cardiodepressant activity and is not associated with any negative inotropic effects. It is metabolized in the liver and dosage adjustments may not be necessary when administered to patients with renal insufficiency. Isradipine has a favorable renal effect profile and also has several properties that meet the requirements of other patient populations where an extra measure of antihypertensive safety is required, such as diabetics, dialysis patients, and transplant recipients. Side effects with isradipine are usually mild and transient, occurring in a dose-dependent manner. [ABSTRACT FROM AUTHOR]

Undesirable cutaneous reactions to drugs may occur early or late in the course of treatment. The ingestion of drugs may also aggravate existing dermatologic conditions. The adverse dermatologic reactions from antiarrhythmic drug therapy are reviewed. The exact incidence of dermatologic side effects from cardiovascular drugs has been difficult to estimate because of sporadic reporting. In this review, the cutaneous side effects are discussed according to drug class and the type of dermatologic reaction. [ABSTRACT FROM AUTHOR]

The renin-angiotensin system (RAS) functions as a primary regulator in the short-term and long-term control of blood pressure. Pharmacologic inhibition of the RAS with angiotensin-converting enzyme (ACE) inhibition is effective for treating systemic hypertension and congestive heart failure. As a more specific therapy, the development of renin inhibitors has evolved through various approaches: specific renin antibodies, peptides developed from prosegments of renin precursor, oligopeptides related to pepstatin a universal inhibitor of aspartyl proteinase enzyme, and analogs of angiotensinogen (the renin substrate). Angiotensinogen analogs are promising as therapeutic agents because of high potency, metabolic stability, and good oral bioavailability. Ongoing research is directed towards the application of renin inhibition, the treatment of various cardiovascular disorders, and as a biological probe for understanding the role of the RAS in control of blood pressure and blood volume. [ABSTRACT FROM AUTHOR]

Since the late 1970s, topical β-adrenergic blockers have been the drugs of choice in treating ocular hypertension and associated glaucoma. The currently available drugs are timolol, betaxolol, levobunolol, metipranolol, and carteolol. All reduce intraocular pressure by decreasing the production of aqueous humor. Although these drugs are applied locally in the eye, they may enter the general circulation and reach concentrations high enough to cause systemic effects, including alterations in heart rate and rhythm, bronchoconstriction, dyslipidemia, and central nervous system abnormalities. Interactions with other drugs may also occur. Ocular β- blockers differ in β1-selectivity (betaxolol is β1-selective, whereas the other drugs are nonselective) and in intrinsic sympathomimetic activity (ISA) or partial agonist properties (only carteolol possesses ISA). These differences give betaxolol and carteolol potential advantages in minimizing certain side effects. The advantage of betaxolol vis-à-vis systemic side effects is more clearly established than that of carteolol. Further systematic study is needed to determine what advantages, if any, are conferred by the presence of ISA. [ABSTRACT FROM AUTHOR]

Through the multiple actions of angiotensin II (AII), the renin-angiotensin system (RAS) participates in cardiovascular homeostasis. Angiotensin II acts by binding to specific membrane-bound receptors, which are coupled to one of several signal transduction pathways. These AII receptors exhibit heterogeneity, represented by AT1 and AT2 receptor subtypes. The AT1 receptor mediates the major cardiovascular action of the RAS. This receptor has been cloned from multiple species, disclosing features consistent with a transmembrane, G-protein-linked receptor. Further AII receptor heterogeneity is evident by the cloning of isotypes of the AT1 receptor. Blocking the interaction of AII with its receptor is the most direct site to inhibit the actions of the RAS. Many AII receptor antagonists, including peptide analogs of AII and antibodies directed against AII, possess unfavorable properties that have limited their clinical utility. The discovery and further development of imidazole compounds with AII antagonist properties and favorable characteristics, however, has promise for clinical utility. The leader in this field is a selective AT1 receptor antagonist losartan (previously known as DuP 753 or MK-954). Losartan was demonstrated to be an effective antagonist of many AII-induced actions and an effective antihypertensive agent in many animal models of hypertension (HTN). Losartan also demonstrated secondary benefits in preventing stroke, treating congestive heart failure (CHF), and delaying the progression of renal disease in animal models. Clinical studies confirm the AII antagonist action of losartan and suggest that losartan will be effective in the treatment of essential HTN. AII antagonism is likely to provide useful treatment in essential HTN and CHF, conditions in which the RAS is known to play a major role. The utility of AII antagonism may extend beyond that of HTN and CHF, as suggested by the potential usefulness of angiotensin-converting enzyme (ACE) inhibition in the treatment or prevention of many other diseases. The key advantage AII antagonists provide over ACE inhibitors is that they may avoid unwanted side effects, related to bradykinin potentiation with the latter drugs. The AII antagonists will help determine the role of the RAS in physiologic regulation and in the pathophysiology of various disease states. [ABSTRACT FROM AUTHOR]

Calcium-channel blockers have been shown to be both safe and effective for treatment of patients with systemic hypertension. These drugs reduce peripheral vascular resistance predominantly by the inhibition of transmembrane calcium ion fluxes in vascular smooth muscle, and by this mechanism can reduce elevated blood pressure. To maximize blood pressure lowering efficacy in patients, calcium-channel blockers have also been used in combination with other antihypertensive treatments that have included diuretics, β-adrenergic blockers, and angiotensin-converting enzyme inhibitors. [ABSTRACT FROM AUTHOR]

Calcium-channel blockers are a safe and effective treatment modality and have been used extensively in the treatment of angina and hypertension. Dilacor™ XR capsules, a new extended-release formulation of diltiazem, has been developed for the treatment of hypertension. Dilacor XR (Rhône-Poulenc Rorer Pharmaceuticals Inc., Collegeville, PA) uses a novel drug delivery system, the Geomatrix™ (JAGO Research AG, Zollikon, Switzerland) controlled-release system, to deliver diltiazem at a constant rate for 24 hours. The rate of absorption is also slower. As doses of Dilacor XR were increased from 120 mg to 540 mg/day, there were disproportionate increases observed in area under the curve, maximum peak plasma concentration, minimum peak plasma concentration, and average peak plasma concentration. The efficacy data from two clinical trials have confirmed the established efficacy of diltiazem and the 24-hour efficacy of Dilacor XR in the control of mild-to-moderate hypertension. The incidence of adverse effects with Dilacor XR in doses as high as 540 mg/day was generally comparable to that of placebo. This new extended-release formulation of diltiazem should significantly facilitate blood pressure control because of better patient compliance with a once daily regimen. [ABSTRACT FROM AUTHOR]

Nisoldipine is a new calcium-channel blocker of the dihydropyridine subclass, with a chemical structure similar to nifedipine. It has been used in clinical trials to assess its efficacy and safety in patients with hypertension, angina pectoris, and congestive heart failure. Similar to other dihydropyridines, nisoldipine is a potent peripheral and coronary dilator. The most optimal dosage regimen has not been established in clinical trials. The drug appears to have a favorable side-effect profile. [ABSTRACT FROM AUTHOR]

Verapamil, the first calcium-channel blocker to be introduced for clinical use, is a major drug used for the treatment of systemic hypertension. During the past 10 years, the use of verapamil for hypertension has produced a considerable clinical database to support the efficacy and safety of the agent in many patients. Because of its short half-life, verapamil was originally administered 3 to 4 times daily. During the past decade, a sustained-release formulation of verapamil has been marketed in the US. This product allows for once-daily dosing up to 240 mg/d; however, when higher doses are needed, this sustained-release formulation should be administered twice daily. In addition, the medicine should be taken with food to avoid the high peak blood levels of verapamil, which appears to be related to the delivery system. A new pellet-filled capsule formulation of verapamil (Verelan, Lederle, Wayne, NJ and Wyeth-Ayerst, Philadelphia, PA) is available and provides controlled absorption, 24-hour blood pressure control, improved peak-to-trough plasma levels, and once-daily dosing regardless of dosage size. Prolonged-release verapamil can be taken without food. [ABSTRACT FROM AUTHOR]

The efficacy and safety of once-daily 2.5- or 5.0-mg methyclothiazide (MCTZ) added to once-daily 5.0-mg terazosin (TRZ) versus 5.0-mg TRZ alone was evaluated in this double-blind, multicenter study. All patients received TRZ during a 6-week titration period. Hypertensive patients (222) (mean blood pressure of 159/104 mm Hg) were randomized to one of three treatment groups: TRZ alone (N = 76); TRZ + MCTZ-2.5 mg (N = 74); and TRZ + MCTZ-5.0 mg (N = 72) for the 8-week double-blind period. Changes in the supine and standing SBP/DBP from preTRZ period were: TRZ alone (−4.8/−8.1 and −2.0/−6.1 mm Hg); TRZ + MCTZ-2.5 mg (−17.3/−12.4 and −16.0/−11.2 mm Hg); and TRZ + MCTZ-5.0 mg (−20.6/−14.4 and −23.3/−14.6 mm Hg). Blood pressure changes in the combination groups were significantly greater than those in the TRZ alone group. However, there were no statistically significant differences between the TRZ + MCTZ-2.5-mg and TRZ + MCTZ-5.0-mg groups. The combination of TRZ and MCTZ tends to mitigate the adverse effects on serum glucose, uric, potassium and lipids usually associated with thiazide diuretics. Thus, combination treatment that begins with TRZ and adds MCTZ is effective in lowering blood pressure without any significant adverse metabolic effects. [ABSTRACT FROM AUTHOR]

A limited number of ectoenzymes appear to be involved in the inactivation of circulating-regulatory peptides. Neutral endopeptidase 24.11, a metallopeptidase, is known to inactivate atrial natriuretic peptide (ANP), a substance with diuretic, natriuretic, and vasodilatory effects. Synthetic inhibitors of endopeptidase 24.11, which can prolong the activity of ANP, are currently available. These agents are being evaluated as possible innovative therapies for patients with hypertension and congestive heart failure. [ABSTRACT FROM AUTHOR]

Nicotinic acid is a water-soluble B-complex vitamin that has been shown, in high doses, to lower total plasma cholesterol (C), LDL-C, and VLDL-triglycerides (Tg), while raising HDL-C in patients with type II, III, IV, and V hyperlipoproteinemia. Its exact mechanism of action is not known, but it appears to lower the production of VLDL in the liver while activating lipoprotein lipase. The drug may also influence the metabolism of HDL-C. The drug is a second or third choice for isolated hypercholesterolemia because of a high incidence of side effects. However, it has a therapeutic advantage as a monotherapy when reduction of both LDL-C and triglycerides are needed in patients with severe combined hyperlipidemia. The drug can be used in combination with other cholesterol-lowering agents to maximize lipid-lowering activity. Nicotinic acid has been associated with a reduced risk of cardiovascular morbidity in clinical trials. [ABSTRACT FROM AUTHOR]

Fibric acid derivatives (FADs) are a class of drugs that have been shown to reduce the production of very low-density lipoprotein (VLDL) while enhancing VLDL clearance due to the stimulation of lipoprotein lipase activity. The drugs can reduce plasma triglyceride levels while raising high-density lipoprotein (HDL) cholesterol levels. Their effects on low-density lipoprotein (LDL) cholesterol levels are less marked and more variable. There is evidence that oral gemfibrozil (Lopid®, Parke-Davis, Morris Plains, NJ) can reduce the risk of serious coronary events, specifically in those patients who had elevations of both LDL cholesterol levels and total plasma triglyceride levels with lower HDL cholesterol levels. Newer FADs (bezafibrate, ciprofibrate, fenofibrate) have been shown to have greater efficacy in reducing LDL cholesterol than gemfibrozil but, in general, these drugs are not as effective as the other primary drugs used to lower LDL levels. The FADs are also used to treat adult patients with very high levels of triglycerides who have pancreatitis and whose disease cannot be managed with dietary therapy. The FADs are well tolerated, with dyspepsia and abdominal pain the most common adverse effects. A small risk of cholelithiasis exists with these drugs, and caution should be used when combining these drugs with HMG-CoA reductase inhibitors because the combination increases the incidence of hyperlipidemic myositis and rhabdomyolysis. [ABSTRACT FROM AUTHOR]

Betaxolol (Searle, Skokie, Illinois) is a new beta1-selective adrenergic blocker with no partial agonist action and minimal membrane stabilizing activity. Its pharmacokinetic profile is characterized by a long serum half-life and excellent oral bioavailability, with little first-pass metabolism. The mean 16-hour half-life of betaxolol has been shown to provide full 24-hour control of blood pressure and heart rate. Betaxolol has been proven to be a safe and effective antihypertensive agent, and was recently approved for clinical use in the United States for this indication. [ABSTRACT FROM AUTHOR]

Soluble dietary fiber, including psyllium, has been shown to have mild to modest cholesterol lowering properties. Psyllium hydrophilic mucilloid (Metamucil®, Procter and Gamble, Cincinnati, OH), a bulk laxative, when used as a dietary supplement in combination with a low fat diet, can lower total serum cholesterol and low-density lipoprotein (LDL) cholesterol, and raise high-density lipoprotein (HDL) cholesterol in hypercholesterolemic patients. The cholesterol lowering effects of psyllium are much less evident than those observed with cholestyramine and the HMG-CoA reductase inhibitors. The mechanism for the cholesterol lowering effect of psyllium is not known. The substance is well tolerated with long-term use. [ABSTRACT FROM AUTHOR]

Co-enzyme Q10 (ubiquinone) is a naturally occurring substance which has properties potentially beneficial for preventing cellular damage during myocardial ischemia and reperfusion. It plays a role in oxidative phosphorylation and has membrane stabilizing activity. The substance has been used in oral form to treat various cardiovascular disorders including angina pectoris, hypertension, and congestive heart failure. Its clinical importance is now being established in clinical trials worldwide. [ABSTRACT FROM AUTHOR]

Penbutolol and carteolol are two new long acting, nonselective beta-adrenergic blockers which have been approved for the treatment of systemic hypertension. Both drugs have intrinsic sympathomimetic activity (partial agonist activity), however, less than that seen with pindolol. They appear to cause less resting bradycardia than propranolol, have no effect on lipids and lipoproteins, and have favorable side effect profiles. [ABSTRACT FROM AUTHOR]

Parenteral antihypertensive agents are useful in those clinical situations where rapid reduction of blood pressure is necessary or where treatment with oral antihypertensive medications is not feasible. Given the diverse selection of parenteral antihypertensive drugs now available, therapy can be individualized. The presence of concurrent diseases will often influence the decision-making process regarding choice of an agent. Complications of parenteral antihypertensive therapy can arise from the intrinsic properties of the various drugs or the development of severe hypotension. Gradual lowering of blood pressure, in conjunction with careful clinical evaluation, will minimize the risks of acute parenteral antihypertensive therapy. Given that parenteral antihypertensive therapy often needs to be replaced by oral therapy, those drugs that can be used both parenterally and orally may have an advantage. [ABSTRACT FROM AUTHOR]

The bile acid sequestrants, cholestyramine and colestipol, are the drugs of choice for the treatment of patients with hypercholesterolemia caused by increases in LDL-cholesterol levels without concurrent hypertriglyceridemia (type IIA and type IIB hyperlipoproteinemia). Longitudinal clinical studies with these drugs have shown their ability to slow the progression of atherosclerosis and to limit the consequences of the disease. Bile acid sequestrants can be used with other lipid-lowering drugs such as nicotinic acid or HMG CoA reductase inhibitors, to maximize the cholesterol-lowering effects. The side effect profile of the bile acid sequestrants is tolerable, with most complaints related to effects on the gastrointestinal tract and the bulkiness of the resins. [ABSTRACT FROM AUTHOR]

Increased levels of cholesterol, LDL-cholesterol, and VLDL-cholesterol are known risk factors for the development of atherosclerotic vascular disease. Probucol is an orally active agent that can reduce total cholesterol and LDL-cholesterol. The drug also reduces HDL-cholesterol. However, it may modify the lipoprotein in such a way that removal of cholesterol from peripheral tissues is still enhanced. Probucol also has antioxidant activity, which may inhibit the oxidative modification of LDL that contributes to lipid deposition in blood vessel walls. Probucol is a well tolerated agent. However, its ability to prolong life in human subjects still needs to be determined. [ABSTRACT FROM AUTHOR]

The safety and efficacy of using continuous high-dose transcutaneous nitroglycerin in doses up to 100 mg/24 hours in chronic stable angina was assessed in 20 patients using serial treadmill testing. Patients had first to show a response to sublingual nitroglycerin with a 20% improvement in exercise time. All patients were then titrated with 20 mg (40 cm2), 60 mg (120 cm2), 80 mg (160 cm2) or 100 mg (200 cm2) patches, until intolerable headache in association with a 10 mmHg reduction in blood pressure and a ten-beat increment in heart rate. Drug was then discontinued for 2 days and patients underwent three repeat stress tests to reestablish a consistent drug-free baseline. Patients were then randomized in double-blind fashion to receive either active patch (N = 11) in previous titration dose or placebo patch (N = 9), with treadmill tests performed at 0 (1 hour after previous patch removal), 4, and 24 hours after patch application at baseline and at weeks 1 and 2. Venous blood was obtained for measurement of plasma nitroglycerin levels. After the first 24 hours of active patch therapy, there was a significant reduction in systolic blood pressure (P = .05), a significant increase in heart rate (P = .01), and a minor increase in exercise tolerance (P = .06) compared to placebo. At weeks 1 and 2, there was an attenuation of drug effect in all of these parameters. Plasma nitroglycerin levels demonstrated consistently high plasma levels over each 24-hour dosing interval, on day 1, week 1, and week 2. Headache was the most common side effect, and with the 1-hour treatment withdrawal there was no evidence of angina rebound. High-dose continuous nitroglycerin patch therapy is well tolerated in patients, and there is some evidence of antianginal efficacy during the first 24 hours of therapy. However, despite the high plasma nitroglycerin drug levels seen with continued use of high-dose therapy, there is an attenuation of hemodynamic and antianginal effects, suggesting the development of pharmacological tolerance. [ABSTRACT FROM AUTHOR]

Dilevalol is the R-R' optical isomer of labetalol and differs pharmacologically from the racemic mixture in the following ways: it is seven-fold more potent as a selective beta-2 agonist; it is four times more potent as a nonselective beta antagonist; it has no clinically significant alpha antagonist property. Dilevalol is a vasodilator and reduces blood pressure by reducing systemic vascular resistance. It has a half-life of 15-18 hours, and is demonstrated to he effective as an antihypertensive agent for 24-30 hours. Hemodynamic studies in humans show that following administration of dilevalol either orally or intravenously, blood pressure falls as a consequence of a decrease in systemic vascular resistance. Cardiac index is unchanged and heart rate decreases slightly. Dilevalol is shown to cause regression of left ventricular hypertrophy in younger individuals, to improve left ventricular performance and to have no effect on parameters of renal function. Prospective double-blinded clinical trials in comparison with placebo, propranolol, metoprolol and atenolol were conducted and demonstrate dilevalol to be an effective antihypertensive agent with a favorable side effect profile with a particularly low incidence of central nervous system side effects. [ABSTRACT FROM AUTHOR]

A new generation of dihydropyridine calcium antagonists which are related structurally to nifedipine is undergoing clinical investigation. Among these newer agents, nicardipine and nimodipine have become available for clinical use. In controlled trials, nicardipine is superior to placebo and equal to other antihypertensive agents for the treatment of systemic hypertension. Nicardipine is associated with a low incidence of adverse effects that are related primarily to its peripheral vasodilatory actions. In addition, nicardipine appears to have little if any negative effects on myocardial contractility or conduction. [ABSTRACT FROM AUTHOR]

The clinical utility of nifedipine and diltiazem blood levels in patients with angina pectoris receiving monotherapy (N = 14) and combination treatment (N = 9) were assessed in a placebo run-in, double blind, randomized, crossover study. Compared to placebo, diltiazem (mean daily dose 360 mg), nifedipine (mean daily dose 90 mg) and combination diltiazem-nifedipine therapy (mean daily dose 55 mg of nifedipine, 360 mg of diltiazem) were associated with reductions in weekly angina attacks and nitroglycerin consumption. Although both drugs used as monotherapy and in combination were also associated with significant increments in exercise tolerance and other improved angina parameters, these changes were not related to the plasma levels of either drug. Nifedipine plasma levels were measured by gas chromatography and diltiazem plasma levels measured by reverse high-pressure liquid chromatography from specimens obtained 2-5 hours after the last previous dose, after 1, 2 and 3 weeks of treatment, and during baseline placebo and placebo washout periods. With combination therapy, there was no effect on the diltiazem plasma level compared to monotherapy. The significant decrease in the nifedipine dose in patients on combination therapy did not significantly change nifedipine plasma levels. Determinations of plasma levels of diltiazem and nifedipine in the management of patients is of no value in the management of patients with angina pectoris except for monitoring treatment compliance and overdosage. [ABSTRACT FROM AUTHOR]

Labetalol is a non-selective β-adrenoceptor antagonist agent with added α1-adrenergic blocking properties, β2-stimulating action, and direct vasodilatory activity. A multicenter, double-blind, parallel group study compared the safety and efficacy of labetalol to propranolol in the treatment of patients with both exertional angina and mild to moderate systemic hypertension. An initial 4 to 5 week placebo washout phase was followed by a five week titration phase and a four month maintenance phase. Labetalol and propranolol had similar effects in reducing supine and standing blood pressures, except for a greater reduction in standing systolic blood pressure seen in the labetalol group. There were comparable effects by both treatments on angina attacks, nitroglycerin use, and exercise tolerance. Adverse effects were frequent with both drugs, but were generally minor. Thus, labetalol appears to be an effective alternative to propranolol in the treatment of patients with coexisting angina pectoris and hypertension, with the choice of agent dependent on the clinical situation. [ABSTRACT FROM AUTHOR]

The safety and efficacy of ketanserin, a competitive serotonin blocking agent, and Propranolol were compared in 33 patients with mild to moderate hypertension (sitting diastolic blood pressure {DBP} 95-115 mm Hg) using a placebo run-in, randomized, double-blind, parallel study design. All patients received placebo for 4 weeks, then were randomized to receive increasing doses of either ketanerin (20, 40 mg twice daily) or propranolol (40, 80 mg twice daily) to achieve a goal sitting DBP <90 mm Hg. Patients not achieving the goal blood pressure with either drug as monotherapy, received the other drug in combination. At the end of the active monotherapy phase (week 10 of the study), propranolol demonstrated a greater decrease in DBP from baseline, as compared to ketanserin (−7.9 ± 10.9 mm Hg with propranolol, P < 0.05; -1.0 ± 7.2 mm Hg with ketanserin, P = NS). Four out of 16 patients achieved goal response on propranolol, compared to 3/17 for ketanserin. With combination treatment, 9/18 patients reached the goal response; the addition of propranolol to ketanserin in non-responders resulted in further reduction of sitting DBP of −10.3 ± 6.3 compared to monotherapy (P < 0.001), while the addition of ketanserin to non-responders produced no significant response in sitting DBP. Propranolol showed a consistent effect in slowing heart rate. Ketanserin displayed less frequent side effects than propranolol. Propranolol used twice daily appears to be more effective than twice daily ketanserin use in patients with mild to moderate hypertension. [ABSTRACT FROM AUTHOR]

The hemodynamic effects of flestolol were evaluated in 30 patients undergoing routine cardiac catheterization. Hemodynamic measurements were obtained during baseline (prior to flestolol), at steady state during IV flestolol infusion (1, 5, and 10 μg/kg/min) and at 20 to 30 minutes after discontinuation (postinfusion). Flestolol-induced hemodynamic changes were similar to those induced by other beta blockers without intrinsic sympathomimetic activity. Significant dose-dependent reduction in heart rate, rate pressure product, and increase in peripheral vascular resistance were seen. Flestolol produced clinically insignificant decrease in myocardial contractility as shown by slight decrease in LVdp/dt, CI, and LVEF. Hemodynamic data from patients with paced heart rate, further confirms a direct mild cardiac depressant effect of flestolol, a finding common to other beta blockers. Consistent with the short elimination half-life of flestolol (t1/2 = 6.5 minutes), most of the hemodynamic changes rapidly returned to preinfusion level within 20 to 30 minutes following its discontinuation. Thus flestolol, with its unique pharmacokinetic profile and titrability, may be beneficial in the treatment of critically ill patients. [ABSTRACT FROM AUTHOR]