Antihypertensives combination therapy

Patients with asymptomatic left ventricular systolic dysfunction and hypertension should be treated with P-blockers and ACE inhibitors. Those with heart failure secondary to left ventricular dysfunction and hypertension should be treated with drugs proven to also reduce the morbidity and mortality of heart failure, including P-blockers, ACE inhibitors, ARBs, aldosterone antagonists, and diuretics for symptom control as well as antihypertensive effect. In African-Americans with heart failure and left ventricular systolic dysfunction, combination therapy with nitrates and hydralazine not only affords a morbidity and mortality benefit, but may also be useful as antihypertensive therapy if needed.66 The dihydropyridine calcium channel blockers amlodipine or felodipine may also be used in patients with heart failure and left ventricular systolic dysfunction for uncontrolled blood pressure, although they have no effect on heart failure morbidity and mortality in these patients.49 For patients with heart failure and preserved ejection fraction, antihypertensive therapies that should be considered include P-blockers, ACE inhibitors, ARBs, calcium channel blockers (including nondihydropyridine agents), diuretics, and others as needed to control blood pressure.2,49... 

Diuretics, ACE inhibitors, ARBs, and CCBs are primary agents acceptable as first-line options based on outcome data demonstrating CV risk reduction benefits (Table 10-2). /TBIockers may be used either to treat a specific compelling indication or as combination therapy with a primary antihypertensive agent for patients without a compelling indication. 

Second and subsequent weeks Increase dosage to 50 mg 4 times daily. Maintenance Adjust dosage to lowest effective level. Twice daily dosage may be adequate. In a few resistant patients, up to 300 mg/day may be required for a significant antihypertensive effect. In such cases, consider a lower dosage of hydralazine combined with a thiazide or reserpine or a beta-blocker. However, when combining therapy, individual titration is essential to ensure the lowest possible therapeutic dose of each drug. 

Their antihypertensive efficacy is comparable to that of (3-adrenergic blockers and angiotensin-converting enzyme (ACE) inhibitors. The choice of a calcium channel blocker, especially for combination therapy, is largely influenced by the effect of the drug on cardiac pacemakers and contractility and coexisting diseases, such as angina, asthma, and peripheral vascular disease. 

Hydralazine, a hydrazine derivative, dilates arterioles but not veins. It has been available for many years, although it was initially thought not to be particularly effective because tachyphylaxis to its antihypertensive effects developed rapidly. The benefits of combination therapy are now recognized, and hydralazine may be used more effectively, particularly in severe hypertension. The combination of hydralazine with nitrates is effective in heart failure and should be considered in patients with both hypertension and heart failure, especially in African-American patients. 

Therapeutic uses Thiazide diuretics decrease blood pressure in both the supine and standing positions postural hypotension is rarely observed, except in elderly, volume-depleted patients. These agents counteract the sodium and water retention observed with other agents used in the treatment of hypertension (for example, hydralazine). Thiazides are therefore useful in combination therapy with a variety of other antihypertensive agents including (3-blockers and ACE inhibitors. Thiazide diuretics are particularly useful in the treatment of black or elderly patients, and in those with chronic renal disease. Thiazide diuretics are not effective in patients with inadequate kidney function (creatinine clearance less than 50 mls/min). Loop diuretics may be required in these patients. 

Apart from surgical and interventional therapy of occlusive carotid artery disease, the major approach to preventing vascular disease and subsequent stroke is to pay close attention to the control of modifiable risk factors such as hypertension, smoking, diabetes, and hypercholesterolemia. Coumadin, an anticoagulant, is effective for the primary and secondary prevention of stroke in patients with atrial fibrillation. Aspirin, clopidogrel, and the combination of aspirin and cUpyridamole have been proven to be effective for secondary stroke prevention along with the antihypertensive combination of indap-amide and perindopril. 

The effects of antihypertensive agents have been evaluated in patients taking ciclosporin. Collectively, dihydropyridine calcium channel blockers that do not affect ciclosporin blood concentrations substantially or at all (felodipine, isradipine, and nifedipine) are usually considered to be the drugs of choice. However, the risk of gingival hyperplasia with nifedipine, which ciclosporin also causes, should be borne in mind. Combination therapy with angiotensin-converting enzyme inhibitors or beta-blockers, or the use of other calcium channel blockers (verapamil or diltiazem) should also be considered, but careful monitoring of ciclosporin blood concentrations is recommended with the latter because they inhibit ciclosporin metabolism. 

Treatment of hypertension alone or in combination with other antihypertensives. Adjunctive therapy for CHF (in combination with cardiac glycosides, diuretics). Treatment of diabetic nephropathy, hypertension, or renal crisis in scleroderma. Half-life 11 hours Onset PO 1 hour IV 15 minutes Peaks PO Duration PO 4-6 hours 24 hours IV 1 1 IV 6 hours hours... 

Starting therapy with a combination of two drugs is now recommended in patients far from their BP goal, for patients in whom goal achievement may be difficult (i.e., those with diabetes or chronic kidney disease and African-Americans), or in patients with multiple compelling indications for different antihypertensive agents. However, combination therapy is often needed to control BP in patients already on therapy, and most patients reqnire two or more agents. ° °... 

Monotherapy with these mixed-acting antihypertensive drugs reduces blood pressure as effectively as other major antihypertensives and their combinations (15,16,17). In the stepped-care approach to antihypertensive drug therapy, mixed a/p-blockers are recommended for initial management of mild to moderate hypertension (step 1). Both drugs effectively lower blood pressure in essential and renal hypertension. Carvediioi also is effective in ischemic heart disease. 

Combination therapy for the treatment of essential hypertension is an attractive option for achieving rapid and effective control of blood pressure, especially for patients with moderate to severe hypertension. While trials of combination therapy often demonstrate this intended effect, and certain combinations are efficacious for good physiological and clinical reasons, there are also some potential drawbacks of combining different classes of antihypertensive agents. Here we describe the beneficial and adverse effects of combination antihypertensive therapies. 

It certainly seems prudent that given the fact that many antihypertensive agents have dose-related adverse effects, forced dose titration is less likely to be favored by patients than low-dose combination therapy. However, it is clear that the range of potential adverse effects and reactions will be... 

The double whammy—additive detrimental effects and novel adverse reactions Combination therapy takes advantage of synergistic mechanisms of antihypertensive action, but this can also be detrimental, particularly if patients are over-treated, leading to dizziness and orthostatic hypotension. Additive effects of certain combinations can also exacerbate adverse reactions that are common with individual agents. For example, calcium channel blockers and alpha-adrenoceptor antagonists both cause peripheral edema, which can be severe if these agents are used together. 

While each of these was a therapeutic use randomized clinical trial, the designs of the trials differed such that the most appropriate control treatment was employed in each case to best answer the research question of interest (Turner and Hoofwijk 2013). SHEP was a multicenter, randomized, double-blind, placebo-controlled trial of chlorthalidone for isolated systolic hypertension. ALLHAT employed a multicenter, randomized, double-blind, active-controlled design to compare chlorthalidone with each of three alternative antihypertensive treatments with regard to the incidence of nonfatal myocardial infarction and fatal coronary heart disease in hypertensive patients with at least one other risk factor for coronary heart disease. ACCOMPLISH was also a multicenter, randomized, double-blind, active-controlled clinical trial, but one that differed from ALLHAT in that a combination therapy comprising benazepril plus amlodipine was compared with benazepril plus hydrochlorothiazide with regard to reduction of cardiovascular events in high-risk hypertensive patients (Turner and Hoofwijk 2013). 

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. 

Because data suggest that doxazosin (and probably other oq-receptor blockers) are not as protective against CV events as other therapies, they should be reserved as alternative agents for unique situations, such as men with benign prostatic hyperplasia. If used to lower BP in this situation, they should only be used in combination with primary antihypertensive agents. 

A universally accepted principle of antihypertension therapy is the simultaneous use of several drugs that act on the primary regions controlling arterial blood pressure, and it is generally recommended to use a combination of diuretics, adrenoblockers, angiotensinconverting enzyme inhibitors, or calcium channel blockers. 

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