Resistant hypertension is multifactorial in etiology, requires combinations of drugs

A coalescence of factors usually conspires to cause resistant hypertension, which is defined as the failure to reach goal blood pressure in patients adhering to full doses of an appropriate three-drug antihypertensive treatment regimen, says Domenic Sica, MD.

As such, multiple drugs that attack various effector systems are needed, as well as identification and treatment of anxiety and sleep problems.

In suggesting a treatment regimen for the patient with resistant hypertension, he advises controlling for volume, pulse rate, and activation of the renin-angiotensin aldosterone system (RAAS) and the sympathetic nervous system.

A strategy to block each of the effector systems in hypertension is necessary “to come up with a treatment regimen that actually works,” says Dr. Sica, professor of medicine and pharmacology at Virginia Commonwealth University, Richmond. Diuretics will correct abnormal renal salt/water handling, calcium channel blockers will treat vasoconstriction due to multiple mediators, and blockers of the RAAS will suppress inappropriately high aldosterone and/or plasma renin activity.

Even in the face of resistant hypertension, Dr. Sica cautions against using maximal doses of medications, instead opting for “optimal” doses. “The majority of response that you get from an antihypertensive agent is at submaximal doses,” he says. Maximal doses of a drug can cause unwanted side effects and even negate the effect of the drug on blood pressure reduction, such as with the salt and water retention that may occur with maximal doses of doxazosin.

When choosing drugs within a class of agents, take into account the considerable class heterogeneity among diuretics and calcium channel blockers, he says. There is no heterogeneity among ACE inhibitors or angiotensin receptor blockers.

Centrally acting agents are useful to control hypertension exacerbated by sympathetic nervous system activation, with clonidine being the prototypical drug in this class. Some caveats with clonidine’s use:

• Avoid excessive dose titration, and use it carefully in patients with renal disease, since it is partially cleared renally.

• Limit volume expansion by using a diuretic concomitantly.

• Use carefully in those susceptible to rebound hypertension, particularly in those receiving a beta blocker.

Beta blockers are appropriate to control heart rate. When selecting a beta blocker, consider its ancillary features and its route of elimination, says Dr. Sica.

Choices of diuretics are loop diuretics, thiazide diuretics, and potassium-sparing diuretics. With respect to blood-pressure lowering, “If you want the most bang for your buck with diuretics, chlorthalidone does it,” Dr. Sica says, “but it will give you a greater distal sodium delivery and, with that, more side effects over time.” A phenomenon with diuretic therapy that is especially beneficial in the treatment of resistant hypertension is activation of the RAAS in a dose-dependent fashion, which may augment the response to RAAS-blocking drugs.

With more advanced chronic kidney disease (stage 3), “You need to convert from a thiazide diuretic to a loop diuretic,” Dr. Sica says, for more effective volume and blood pressure control. A combination of loop diuretics and thiazides is advised in stages 4 and 5 of chronic kidney disease.

High levels of aldosterone and plasma renin activity are prevalent in resistant hypertension. Beta blockers and combine alpha/beta blockers are the only class of drugs that reduce plasma aldosterone levels. In resistant hypertension, the response to aldosterone blockers (ie, spirinolactone, eplerenone) is consistent regardless of the plasma aldosterone level, with reductions in systolic blood pressure of about 25 mmHg.

Finally, ancillary treatment measures must be done in parallel with antihypertensive therapy, Dr. Sica recommends. “If I can treat anxiety or panic disorder, often I can drop off one, two, or three drugs, because the driving force is sympathetic activation from anxiety,” he says.