Aldosterone Antagonists

Aldosterone antagonists such as spironolactone, and eplerenone (Fig. 5-3) modulate vascular tone through a variety of mechanisms besides diuresis. Their potassium-sparing effects mediated through aldosterone antagonism, complement the potassium-wasting effects of more potent diuretics such as thiazide or loop diuretics. Patients with resistant hypertension (with or without primary aldosteronism) experience significant BP reductions with the addition of low-dose spironolactone (12.5-50 mg/day) to diuretics, ACE inhibitors, and ARBs.68 Although functional in this circumstance, it is important to recognize their potential to enhance the risk for hyperkalemia when used in conjunction with ACE inhibitors, ARBs, and now potentially DRIs. This is particularly relevant for individuals with comorbidities associated with reduced renal function or those receiving either potassium supplements or NSAIDs. The most commonly used potassium-sparing diuretic is spironolactone; however, eplerenone has been used with increasing frequency in patients with heart failure following acute myocardial infarction (AMI). 8 Although spironolactone is commonly associated with gynecomastia, eplerenone rarely causes this complication.69 The risk of hyperkalemia

is also more commonly reported with patients on spironolactone. P-Blockers

Controversy surrounds the JNC 7 recommended role of Pblockers as first-line anti-

hypertensive agents. For example, a meta-analysis by Lindholm et al. demonstrated a higher risk of stroke in patients treated for primary hypertension with P-blockers

compared to other antihypertensives. Moreover, Messerli et al. showed that P-block-ers were ineffective in preventing coronary heart disease, cardiovascular mortality, and all-cause mortality compared to diuretics for elderly patients (60 years of age or older) treated for primary hypertension. Consequently, current evidence suggests patients with uncomplicated hypertension may not benefit as much, if at all, from P-blocker therapy relative to other antihypertensives. This may be in part due to their tendency to reduce central aortic pressure and cardiac afterload to a lesser degree re-

lative to other agents. It must be noted that all of these analyses were conducted with a limited number of P-blockers such as atenolol and metoprolol tartrate. Whether newer formulations such as metoprolol succinate, or agents with unique properties such as carvedilol would be more efficacious in reducing morbidity and mortality is unknown. The drug with the most prominent difference in the increased risk of stroke between the three P-blocker use subgroups was atenolol. The concern regarding P-blocker use in hypertensive patients without compelling indications is reflected in American Heart Association's recommendations and the European Society of Cardiology's abandonment of P-blockers as first-line antihypertensive agents. On the other hand, the role of P-blockers in patients with specific select comorbidities is well established (Table 5-5). Specific outcome-based studies conducted in patients with comorbidities such as heart failure and recent MI have clearly demonstrated a benefit 74

from P-blocker use. Their hemodynamic effects and antiarrhythmic properties make them desirable agents for hypertensive patients who suffer from ischemic conditions including AMI.6 When used judiciously in hypertensive patients with heart failure, P-blocker inhibition of neurohormonal mediated cardiac remodeling reduces morbidity and mortality relative to standard heart failure therapies. The mechanisms through which P-blockers affect BP are complex, but most certainly include their modulation of renin (Fig. 5-3) which appears to result in a reduction in CO and/or reduction in PR along with their negative inotropic/chronotropic actions.

The specific pharmacologic properties of P-blockers are varied and diverse. An understanding of these properties may assist in the selection of one agent over others given a patient's specific condition(s). One of these properties is cardioselectiv-ity—the property of some P-blockers that preferentially block Pi-versus P2-receptors. Another property exhibited by some P-blockers is membrane stabilization activity, which relates to the propensity of the P-blocker to possess some capacity for antiar-rhythmic properties, in addition to P-receptor blocking properties. Some P-blockers (Fig. 5-4) possess properties referred to as intrinsic sympathomimetic activity (ISA). P-Blockers possessing this property effectively block the P-receptor at higher circulating catecholamine levels, such as during exercise, while having modest P-blocking

activity at times of lower catecholamine levels, such as at rest.

Table 5-5 Compelling Indications for Individual Drug Classes

Rrrn mmcnrifrf Dfut) C la1»

Table 5-5 Compelling Indications for Individual Drug Classes

Rrrn mmcnrifrf Dfut) C la1»

Compelling Iridicaliûn

Diuretic

Aid AM

HB

CCBA

ME-)

ARB

Dir Vjso

Heart (allure

X

X

X

X

X

X

Roilmywardkil infarction

K

X

X

Highccmonarydüsase risk

X

X

X

Si

Diabetes

X

X

X

X

X

C hccniL kklife-)' diw.ttL1

X

X

Rkui iwit Krake perertlon

X

X

Atfc I an^oiirtiin I Onvifliflt)enzyme inhif>nur: AW Ant, aMOSHnoiv antagonist ARU ingiOiefiiirtrttcpWr Ut* Ins; IB. P felOdtflçGtfl^ iifiumilwnnel hkuting agera: fJir Vasti, lîihtt viiculilara.

Atfc I an^oiirtiin I Onvifliflt)enzyme inhif>nur: AW Ant, aMOSHnoiv antagonist ARU ingiOiefiiirtrttcpWr Ut* Ins; IB. P felOdtflçGtfl^ iifiumilwnnel hkuting agera: fJir Vasti, lîihtt viiculilara.

FIGURE 5-4. Flowchart listing P-blocking agenvarious P-receptor activity and intrinsic sympathomimetic activty.*P-1 Cardioselective. (ISA, intrinsic sympathomimetic activity; NO, nitrous oxide.)

When selecting a P-blockers, some of these properties may be of practical value while others, such as membrane stabilization activity and ISA, are of theoretical interest only. Because neither membrane stablization activity nor ISA has been directly proven value in the clinical setting, they will not be discussed further other than to point out that P-blockers with ISA are not recommended for use in the post-MI patient.76 With regards to cardioselectivity, consider a patient with mild asthma, chronic obstructive pulmonary disease, or peripheral vascular disease (intermittent claudication). A P-blocker with relative cardioselectivity to block Pi-receptors may be more desirable in such a patient, while a nonselective P-blocker (Fig. 5-4) may be potentially disadvantageous. In such a patient, low doses of cardioselective P-blockers may achieve adequate blockade of ßi-receptor in the heart and kidneys while minimizing the undesirable effects of ß2-blockade on the smooth muscle lining the bronchioles. In doing so, hypertension may be managed while avoiding complications of the coexisting reactive airway disease, which is mediated by ß-receptor stimulation. Similarly, either because of a reduction in the ß-mediated vascular blood flow or by enhanced unopposed a-agonist-mediated vasoconstriction, a patient with peripheral vascular disease (intermittent claudication) may experience a worsening of symptoms with use of a nonselective ß-blocker (Fig. 5-4). It is important to remember that cardioselectiv-ity is dependent upon dose, with diminished selectivity exhibited with higher doses.

A limited number of ß-blockers also possess vasodilatory properties that are either mediated through a1-receptor blockade (carvedilol, labetalol) or via L-arginine/nitric oxide-induced release from endothelial cells with subsequent increased nitric oxide bioavailability in the endothelium (nebivolol; Fig. 5-4). Reductions in PR through a1-receptor mediated blockade or via L-arginine/nitric oxide-induced release, in addition to ß-blockade, may benefit patients with hypertension. Such combinations should theoretically contribute to enhanced reductions in vascular tone. Nonetheless, there has been no proven evidence of superior outcomes from the use of ß-blockers with vasodilatory properties through either means compared to those with only ß-blocking activity.

The adverse effects of ß-blockers logically follow their pharmacology. Initiating ß-blockers to treat patients with hypertension may have the potential to precipitate bradycardia, various degrees of heart block, or signs and symptoms of heart failure. The latter is usually limited to those with a subclinical diagnosis and should be considered in the elderly or those with documented reductions in left ventricular function. Conversely, abrupt discontinuation of ß-blockers has been cited as a precipitating factor in the development of ischemic syndromes—especially for those patients in whom ß-blockers were used for extended periods of time, at higher doses, or who had underlying ischemic heart disease. In such cases, the dose of these agents should be reduced (tapered) over a period of several days to perhaps 1 or even 2 weeks depending on patient-related factors.

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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