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Query: UMLS:C0010200 (cough)
 23,843 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The availability of orally active specific angiotensin receptor antagonists (AT1 antagonists) has opened new therapeutic choices and provided probes to test the specific role of the renin-angiotensin system in the pathogenesis of cardiovascular disease. 2. The data available so far suggest that the antihypertensive efficacy of angiotensin receptor antagonists is comparable to that of angiotensin-converting enzyme (ACE) inhibitors. This provides further evidence that this latter class of drugs exerts its effect mainly through blockade of the renin-angiotensin enzymatic cascade. As expected, the association of a diuretic exerts an equally strong additive effect to the antihypertensive efficacy of both classes of drugs. 3. The most common side effect of ACE inhibitors, dry cough, does not occur with AT1 antagonists, which confirms the long-held view that this untoward effect of the ACE inhibitors is due to renin-angiotensin-independent mechanisms. 4. Long-term studies with morbidity/mortality outcome results are needed, before a definite position can be assigned to this newcomer in the orchestra of modern antihypertensive drugs. Notwithstanding, this new class of agents already represents an exciting new addition to our therapeutic armamentarium.
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PMID:Experience with angiotensin II antagonists in hypertensive patients. 899 54

Raised blood pressure in the elderly is not a normal consequences of aging, but is a major risk factor for cardiovascular disease. Cardiac and cerebrovascular disease account for > 50% of deaths among people aged > 65 years. Because the percentage of elderly people in most populations is rising, blood pressure control in this group is becoming increasingly important. Several large intervention studies in the elderly have demonstrated that antihypertensive medication reduces cardiovascular morbidity and mortality. In addition, the absolute benefits of blood pressure reduction are higher in elderly compared with younger patients. ACE inhibitors are effective and well tolerated in the treatment of hypertension in the elderly. Their success led to interest in alternative ways of blocking the renin angiotensin system, and the subsequent development of angiotensin II (AII) receptor antagonists. Losartan was the first drug in this class to become commercially available. Since then, valsartan has been launched in some markets and others are likely to be launched in the near future. Losartan is effective in the treatment of essential hypertension and has a low incidence of adverse effects. First-dose hypotension is very uncommon and, at the present time, cough does not appear to be an adverse effect of these drugs, although long term tolerability studies are needed to confirm this. Angioedema, a rare but life-threatening adverse effect of ACE inhibitors, has also been associated with losartan. Current data suggest that All receptor antagonists are effective in elderly hypertensive patients, although further data are needed to confirm these findings. At present, All receptor antagonists are likely to be used in hypertensive patients who are intolerant of ACE inhibitors, although this may change with the availability of long term tolerability and clinical outcomes data.
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PMID:Angiotensin II receptor antagonists. Potential in elderly patients with cardiovascular disease. 920 48

As a net effect of ACE-inhibitors and AT1-receptor antagonists on the renin-angiotensin system (RAS) cardioprotection due to vasodilative (reduction of blood pressure, afterload reduction), antiproliferative (reduced cell growth, reduction of "vascular" and/or "ventricular remodeling", reduced formation of extracellular matrix), as well as antiadrenergic actions and due to the stimulating effect on natriuresis, reduction of blood pressure, preload reduction can be expected. These aims of therapy have mostly been confirmed for the action of ACE-inhibitors by experimental and clinical studies but except for the treatment of arterial hypertension and few preliminary reports concerning the treatment of cardiac dysfunction, no comparable data are available for AT1-receptor antagonists. To date, an antithrombotic and profibrinolytic action could only be demonstrated for ACE-inhibitors. This effect has been discussed to be responsible for the improvement of long-term prognosis in patients with coronary artery disease. Despite the similar spectrum of action there exist important differences between ACE-inhibitors and AT1-receptor antagonists that might underline the need of an individual use of these drugs: the dual action of ACE-inhibitors on the RAS and the kinin system bears many benefits but has been also shown to be accompanied by side-effects, mainly chronic dry cough, in a relatively high percentage of patients thus leading to discontinuation of therapy in 8-14%. This respective side-effect can be prevented by the use of AT1-receptor antagonists. It has been discussed whether the incomplete action of ACE-inhibitors on AT1-receptor-mediated effects is at least in part responsible for the efficacy of this drug which is relatively high (75-80%) as compared to other substances. Due to their direct action, AT1-receptor-blockers might also be of high effectiveness for the treatment of severe heart failure. A combination of the ACE-inhibitor-mediated activation of the kinin-system with the more specific blockade of AT1-receptors by AT1-receptor antagonists might be of benefit and is currently under investigation. Finally, it has been discussed that the increased AT II concentration in case of AT1-receptor-blockade activates AT2-receptor-mediated mechanisms thus leading to an additive vasoprotective effect.
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PMID:[Pathophysiological mechanisms of the renin-angiotensin system and its pharmacologic modification by ACE inhibitors or angiotensin II (type 1) receptor blockers in cardiovascular diseases]. 923 95

Whether any class of antihypertensive drugs has specific renoprotective effects above and beyond lowering of blood pressure is still debatable. The renin-angiotensin system (RAS) is both localized and has many actions within the kidney, on intrarenal hemodynamics, on the mesangial cell, as well as stimulating growth factors and cytokines. Angiotensin converting enzyme (ACE) inhibitors have been shown to ameliorate the progression of renal failure. How much of this beneficial effect is due to their hemodynamic effects, how much to non-hemodynamic effects and how much to their effects on bradykinin and other putative ACE substrates is still unclear. Experimentally it can be shown that inhibiting ACE but preventing the fall in systemic blood pressure by salt loading abolishes renoprotection. Bradykinin has been implicated in both the beneficial and the adverse effects of ACE inhibitors. Because of this and because ACE inhibitors may not provide complete blockade of the RAS, angiotensin receptor (AT1R) antagonists have been developed. Experimentally AT1R antagonists have been shown to reproduce most of the beneficial effects of ACE inhibitors. The experience in humans is more limited but they have been demonstrated to be efficacious in hypertension, to reduce proteinuria, and produce a favorable hemodynamic effect in congestive cardiac failure with a low incidence of adverse effects and without cough. Calcium channel blockers (CCB) also have additional properties that may provide renoprotection beyond lowering blood pressure. However, as the different types of CCB block different calcium channels their effects may differ substantially. The inconsistency of the data in the renoprotective effect of CCB may reflect these differences. Quantitatively probably the most important factor in preventing the progress of renal failure by antihypertensive drugs is strict control of blood pressure. Lowering blood pressure by drugs is most likely effective by both reducing physical and sheer stress damage, as well as turning off the signal for the activation and production of vasoactive peptides and cytokines.
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PMID:Comparison of renin-angiotensin to calcium channel blockade in renal disease. 940 14

Angiotensin II type 1 (AT1) receptor antagonists inhibit the renin-angiotensin system more completely than ACE inhibitors, and do not increase bradykinin levels as ACE inhibitors do. ACE inhibitors have been proven to increase survival and improve quality of life in patients with congestive heart failure (CHF). At the 48-week follow-up of the Evaluation of Losartan in the Elderly (ELITE) Study, the AT1 receptor antagonist losartan (at a dosage of 50 mg/day) was found to be superior to captopril 50 mg 3 times daily in terms of its effects on total mortality, total mortality and/or hospitalisation for CHF, and hospitalisation for any reason. Hospitalisation for CHF was the same for both drugs. Adverse effects occurred in 12 and 21% of those receiving losartan and captopril, respectively. Cough, rash, angioedema or taste disturbances/reduced appetite prompted the cessation of drug treatment in 0 and 7% of those receiving losartan and captopril, respectively. Until additional data are available, this author recommends that elderly patients with CHF and an abnormal or normal left ventricular ejection fraction, and who are unable to tolerate ACE inhibitors, should receive losartan 50 mg/day.
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PMID:The ELITE Study. What are its implications for the drug treatment of heart failure? Evaluation of Losartan in the Elderly Study. 963 91

Understanding the mechanism of action and the pharmacokinetic properties of vasodilatory drugs facilitates optimal use in clinical practice. It should be kept in mind that a drug belongs to a class but is a distinct entity, sometimes derived from a prototype to achieve a specific effect. The most common pharmacokinetic drug improvement is the development of a drug with a half-life sufficiently long to allow an adequate once-daily dosage. Developing a controlled release preparation can increase the apparent half-life of a drug. Altering the molecular structure may also increase the half-life of a prototype drug. Another desirable improvement is increasing the specificity of a drug, which may result in fewer adverse effects, or more efficacy at the target site. This is especially important for vasodilatory drugs which may be administered over decades for the treatment of hypertension, which usually does not interfere with subjective well-being. Compliance is greatly increased with once-daily dosing. Vasodilatory agents cause relaxation by either a decrease in cytoplasmic calcium, an increase in nitric oxide (NO) or by inhibiting myosin light chain kinase. They are divided into 9 classes: calcium antagonists, potassium channel openers, ACE inhibitors, angiotensin-II receptor antagonists, alpha-adrenergic and imidazole receptor antagonists, beta 1-adrenergic agonist, phosphodiesterase inhibitors, eicosanoids and NO donors. Despite chemical differences, the pharmacokinetic properties of calcium antagonists are similar. Absorption from the gastrointestinal tract is high, with all substances undergoing considerable first-pass metabolism by the liver, resulting in low bioavailability and pronounced individual variation in pharmacokinetics. Renal impairment has little effect on pharmacokinetics since renal elimination of these agents is minimal. Except for the newer drugs of the dihydropyridine type, amlodipine, felodipine, isradipine, nilvadipine, nisoldipine and nitrendipine, the half-life of calcium antagonists is short. Maintaining an effective drug concentration for the remainder of these agents requires multiple daily dosing, in some cases even with controlled release formulations. However, a coat-core preparation of nifedipine has been developed to allow once-daily administration. Adverse effects are directly correlated to the potency of the individual calcium antagonists. Treatment with the potassium channel opener minoxidil is reserved for patients with moderately severe to severe hypertension which is refractory to other treatment. Diazoxide and hydralazine are chiefly used to treat severe hypertensive emergencies, primary pulmonary and malignant hypertension and in severe preeclampsia. ACE inhibitors prevent conversion of angiotensin-I to angiotensin-II and are most effective when renin production is increased. Since ACE is identical to kininase-II, which inactivates the potent endogenous vasodilator bradykinin, ACE inhibition causes a reduction in bradykinin degradation. ACE inhibitors exert cardioprotective and cardioreparative effects by preventing and reversing cardiac fibrosis and ventricular hypertrophy in animal models. The predominant elimination pathway of most ACE inhibitors is via renal excretion. Therefore, renal impairment is associated with reduced elimination and a dosage reduction of 25 to 50% is recommended in patients with moderate to severe renal impairment. Separating angiotensin-II inhibition from bradykinin potentiation has been the goal in developing angiotensin-II receptor antagonists. The incidence of adverse effects of such an agent, losartan, is comparable to that encountered with placebo treatment, and the troublesome cough associated with ACE inhibitors is absent.
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PMID:Clinical pharmacokinetics of vasodilators. Part I. 964 8

The renin-angiotensin-aldosterone system (RAAS) plays an important role in both the short-term and long-term regulation of arterial blood pressure, and fluid and electrolyte balance. The RAAS is a dual hormone system, serving as both a circulating and a local tissue hormone system (i.e., local mediator) as well as neurotransmitter or neuromediator functions in CNS. Control of blood pressure by the RAAS is exerted through multiple actions of angiotensin II, a small peptide which is a potent vasoconstrictor hormone implicated in the genesis and maintenance of hypertension. Hypertension is a primary risk factor associated with cardiovascular, cerebral and renal vascular disease. One of the approaches to the treatment of hypertension, which may be considered as a major scientific advancement, involves the use of drugs affecting the RAAS. Pharmacological interruption of the RAAS was initially employed in the late 1970s with the advent of the angiotensin converting enzyme (ACE) inhibitor, captopril. ACE inhibitors have since gained widespread use in the treatment of mild to moderate hypertension, congestive heart failure, myocardial infarction, and diabetic nephropathy. As the roles of the RAAS in the pathophysiology of several diseases was explored, so did the realization of the importance of inhibiting the actions of angiotensin II. Although ACE inhibitors are well tolerated, they are also involved in the activation of bradykinin, enkephalins, and other biologically active peptides. These actions result in adverse effects such as cough, increased bronchial reactivity, and angioedema. Thus, the goal of achieving a more specific blockade of the effects of angiotensin II than is possible with ACE inhibition. The introduction of the nonpeptide angiotensin II receptor antagonist losartan in 1995 marked the achievement of this objective and has opened new vistas in understanding and controlling the additional biological effects of angiotensin II. Complementary investigations into the cloning and sequencing of angiotensin II receptors have demonstrated the existence of a family of angiotensin II receptor subtypes. Two major types of angiotensin II receptors have been identified in humans. The type 1 receptor (AT1) mediates most known effects of angiotensin II. The type 2 receptor (AT2), for which no precise function was known in the past, has gained importance recently and new mechanisms of intracellular signalling have been proposed. This review presents recent advances in angiotensin II receptor pharmacology, molecular biology, and signal transduction, with particular reference to the AT1 receptor. Excellent reviews have appeared recently on this subject.
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PMID:Angiotensin II receptors-antagonists, molecular biology, and signal transduction. 1009 99

Hypertension occurs frequently in patients with renal disease and contributes to the development of end-stage renal disease. Because the renin angiotensin system (RAS) influences hypertension and renal disease, angiotensin-converting enzyme (ACE) inhibitors have been used successfully to treat and reduce renal consequences of hypertension. This review assesses how angiotensin II (A-II) influences renal disease and explores the effectiveness of losartan, a selective A-II receptor blocker, in patients with renal disease. Clinical trials have demonstrated that losartan is a safe and effective treatment for hypertension in renally impaired patients and produces renal hemodynamic effects akin to those seen with ACE inhibitors. However, losartan demonstrates a greater uricosuric effect than ACE inhibitors and does not produce cough, a significant side effect frequently associated with ACE inhibitors. Further studies will determine whether combination therapy with an ACE inhibitor and A-II receptor blocker will provide additional RAS blockade and synergistic benefits in patients with renal disease.
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PMID:The benefits of angiotensin II receptor blockers in patients with renal insufficiency or failure. 1009 45

One possible intervention to interrupt the deleterious effects of the renin-angiotensin system is suppression of angiotensin II (Ang II) formation by inhibition of angiotensin-converting enzyme (ACE). However, ACE inhibition incompletely suppresses Ang II formation and also leads to accumulation of bradykinin. Angiotensin II type 1 (AT1) receptors are believed to promote the known deleterious effects of Ang II. Therefore, AT1 receptor antagonists have been recently introduced into therapy for hypertension and congestive heart failure (CHF). Although there are significant differences between the effects of AT1 receptor antagonists and ACE inhibitors including the unopposed stimulation of angiotensin II type 2 (AT2) receptors by AT1 receptor antagonists, the discussion of whether ACE inhibitors, AT1 receptor antagonists or the combination of both are superior in the pharmacotherapy of CHF is still largely theoretical. Accordingly, AT1 receptor antagonists are still investigational. Angiotensin-converting enzyme inhibitors remain first line therapy in patients with CHF due to systolic dysfunction. However, in patients not able to tolerate ACE inhibitor induced side effects, in particular cough, AT1 receptor antagonism is a good alternative. In clinical practice, emphasis should be placed on increasing the utilization of ACE inhibitors, as more than 50% of patients with CHF do not receive ACE inhibitors. In addition, the majority of those on ACE inhibitors receive doses lower than the dosage used in the large clinical trials. Although not yet completely proved, it is likely that high doses of ACE inhibition are superior to low doses with respect to prognosis and symptoms.
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PMID:Recent insight into therapy of congestive heart failure: focus on ACE inhibition and angiotensin-II antagonism. 1019 12

A double-blind comparator study was performed in 528 hypertensive patients [baseline sitting diastolic blood pressure (SitDBP) 95-114 mmHg]. The primary objective was to compare the incidence of drug-related cough in patients treated with enalapril and eprosartan. The secondary objective was to compare antihypertensive efficacy between treatments. This paper reports the effects seen on the safety profile, plasma renin activity, aldosterone and angiotensin II (A-II) in each treatment group. Eprosartan was titrated from 200 mg b.i.d. to 300 mg b.i.d. and enalapril from 5 mg o.d. to 20 mg o.d. over 12 weeks. Hydrochlorothiazide (HCTZ) 12.5-25 mg o.d. could be added where required to the treatment for the final six weeks of the titration phase if SitDBP > or = 90 mmHg. Patients received the maximum titrated dosage during the maintenance phase. In the study overall, similar mean changes in blood pressure from baseline were evident with each treatment. Measurement of mean plasma neurohormone levels showed significant increases in renin activity in both groups and statistically significant A-II elevations in the eprosartan group (p < 0.05). Neither eprosartan nor enalapril significantly altered serum lipid profiles or electrolyte levels. Most adverse experiences reported throughout the study were mild or moderate in both treatment groups. Fewer patients receiving eprosartan (4.9%) than enalapril (9.1%) discontinued treatment because of adverse experiences. In conclusion, the results of this study show that eprosartan is well tolerated. Both eprosartan and enalapril significantly increased plasma renin activity while plasma A-II was elevated in the eprosartan group.
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PMID:Effects of eprosartan versus enalapril in hypertensive patients on the renin-angiotensin-aldosterone system and safety parameters: results from a 26-week, double-blind, multicentre study. Eprosartan Multinational Study Group. 1021 7


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