Angiotensin antihypertensives

A patent (95JAP07196655) deseribed the preparation of a 2//-indazole derivative of speeifie formula 109 useful as a therapeutie agent for a eireulatory disease sueh as hypertension, having angiotensin II antagonism and antihypertensive aetion. In formula 109 r = lower alkyl or alkenyl R, R = H, halogen, lower... 

Thiazide diuretics have a venerable history as antihypertensive agents until the advent of the angiotensin-converting enzyme (ACE) inhibitors this class of drugs completely dominated first line therapy for hypertension. The size of thi.s market led until surprisingly recently to the syntheses of new sulfonamides related to the thiazides. Preparation of one of the last of these compounds starts by exhaustive reduction of the Diels-Alder adduct from cyclopentadiene and malei-mide (207). Nitrosation of the product (208), followed by reduction of the nitroso group of 209,... 

The ready acceptance of angiotensin convCTting enzyme inhibitors as antihypertensive agents has, as noted previously in this volume, engendered intensive investigation into the limits of the... 

Antihypertensive drugp are contraindicated in patients with known hypersensitivity to the individual dm. When an antihypertensive is administered by a trans-derrnal system (eg, clonidine), the system is contraindicated if the patient is allergic to any component of the adhesive layer of the transdermal system. Use of the angiotensin II receptor antagonists during the second and third trimester of pregnancy is contraindicated... 

The hypotensive effects of most antihypertensive dru are increased when administered with diuretics and other antihypertensives. Many dnigp can interact with the antihypertensive drugs and decrease their effectiveness (eg, antidepressants, monoamine oxidase inhibitors, antihistamines, and sympathomimetic bronchodilators). When the ACE inhibitors are administered with the NSAIDs, their antihypertensive effect may be decreased. Absorption of the ACE inhibitors may be decreased when administered with the antacids. Administration of potassium-sparing diuretics or potassium supplements concurrently with the ACE inhibitors may cause hyperkalemia. When the angiotensin II receptor agonists are administered with... 

A closely related reaction that is currently receiving much attention is the palladium-catalysed Suzuki coupling of arylboronic acids with aryl halides (Fu and Littke, 1998). For example, this technology has recently been applied by Clariant workers for the production of o-tolyl-benzonitrile (Eqn. (13)), an intermediate to a series of so-called angiotensin-II antagonists, a new class of antihypertensive drugs (Bernhagen, 1998). 

Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs. diuretic The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002 288(23) =2981-2997. 

ACE inhibitors and angiotensin-receptor blockers (ARB) have definite benefits in patients with nephropathy and are believed to have renoprotective effects in most patients. Due to their ability to cause an initial bump in serum creatinine, these agents should be used cautiously when employed in combination with the calcineurin inhibitors. The dihydropyridine calcium channel blockers have demonstrated an ability to reverse the nephrotoxicity associated with cyclosporine and tacrolimus (Table 52-8). In general, antihypertensive therapy should focus on agents with proven benefit in reducing the progression of cardiovascular disease and should be chosen on a patient-specific basis.55 See Chapter 2 for further recommendations for treating HTN. 

Captopril 678 and enalapril 679 are potent angiotensin converting enzyme (ACE) inhibitors used as antihypertensives. Molecular manipulation based on the enzyme model led to the discovery of some perspective bicyclic structures, for example, cilazapril 680 and compound 681, highly active antihypertensives in vivo. Compound 681 belongs to the most potent conformationally restricted ACE inhibitors and is often used as a model for molecular modeling studies <1996JA8231>. 

Compound 686 (PNU-97018) is an orally active nonpeptide angiotensin II receptor antagonist without any agonistic activity that has an insurmountably high antihypertensive effect <2002CPB1022, 1995JEP1042, 1995MI880>. 

Dudley C, Keavney B, Casadei B, Conway J, Bird R, Ratcliffe P. Prediction of patient responses to antihypertensive drugs using genetic polymorphisms investigation of renin-angiotensin system genes. J Hypertens 1996 14 259-262. 

The most potentially serious drug interactions include the concomitant use of NSAIDs with lithium, warfarin, oral hypoglycemics, high-dose methotrexate, antihypertensives, angiotensin-converting enzyme inhibitors, fi-blockers, and diuretics. 

Aliskiren blocks the renin-angiotensin-aldosterone system at its point of a activation, which results in reduced plasma renin activity and BP. It provides BP reductions comparable to an ACE inhibitor, ARB, or CCB. It also has additive antihypertensive effects when used in combination with thiazides, ACE inhibitors, ARBs, or CCBs. It is approved for monotherapy or in combination with other agents. 

For women with 140 to 179 mm Hg systolic or 90 to 109 mm Hg diastolic, the decision to continue or stop antihypertensive therapy during pregnancy is controversial. Antihypertensive drugs may be continued during pregnancy except for ACEIs and angiotensin II receptor blockers. 

Antihypertensive therapy should be initiated in diabetic or nondiabetic CKD patients with an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin II receptor blocker. Nondihydropyridine calcium channel blockers are generally used as second-line antiproteinuric drugs when ACEIs or angiotensin II receptor blockers are not tolerated. 

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