Tandem Therapy with Eprosartan
Presynaptic and postsynaptic actions control systolic and diastolic BP better
Hypertension is a serious health concern.
People with hypertension are four times more likely to suffer cardiovascular disease, six times more likely to develop congestive heart failure, and seven times more likely to experience a stroke than normal individuals. The risk multiplies when the patient is a smoker or has concomitant diabetes mellitus or coronary heart disease.
The avalanche of antihypertensive drugs in the last 30 years notwithstanding, hypertension remains uncontrolled.
Even in countries with more sophisticated medical technologies and health-care systems where medicines are covered by insurance, only half of hypertensives are treated-and only 30 percent of those treated achieve blood pressure control.
This, according to Prof. Heinz Rupp of the department of internal medicine and cardiology of the University of Marburg, is a situation that will be compounded as the population in many countries grows bigger and older.
Speaking in a symposium organized by Solvay Pharma Inc. Philippines last February, Rupp said one problem with current hypertension management is that "very often, we just reduce the blood pressure; we don't care about the causes leading to that high blood pressure."
Those causes-and the underlying physiologic mechanism of hypertension-need to be addressed, said Rupp, not only to effectively control blood pressure, but more importantly to prevent hypertension-induced cardiovascular events.
The symposium served as launch pad for eprosartan (Teveten), the angiotensin-2 receptor blocker (ARB) that Rupp said addresses the underlying mechanism of hypertension through its unique dual mode of action.
Two-in-One Principle
Calling it "two treatment principles in one substance," Rupp said eprosartan's blood pressure-lowering action takes place at two levels-at the renin-angiotensin aldosterone system (RAAS) where it inhibits the blood pressure rising effects of angiotensin-2 and at the sympathetic nervous system (SNS) where it suppresses the amplification of nor epinephrine release induced by angiotensin-2.
"Normally, we think of hypertension as an increase in peripheral resistance coming from an adverse remodeling of the arterioles, which leads to cardiohypertrophy and heart failure," Rupp noted.
Pointing out that the RAAS and the SNS are the two most important determinants of total peripheral resistance, he said the activity of both systems is increased in hypertension, coupled with a decreased activity of the endogenous vasodilating system.
Rupp said eprosartan acts on both systems by directly blocking the effect of angiotensin-2 on the arterial wall and by suppressing its activity on the sympathetic nerve ending (Figure 1). First, it blocks angiotensin-2 from binding to AT1 receptors which results in greater vascular dilatation that leads to blood pressure reduction. Second, it blocks presynaptic AT1 receptors through which angiotensin-2 acts to augment the release of norepinephrine. Norepinephrine enhances blood vessel constriction and increases heart rate.
In other words, it has both postsynaptic and presynaptic action, which accounts for its ability to control diastolic BP consistently and systolic BP more pronouncedly than other ARBs, he said.
Sympathetic Overactivity
Rupp showed that where there is sympathetic overactivity, there is raised angiotensin-2, which by itself amplifies norepinephrine release. Norepinephrine release mediates vasoconstriction and increases heart rate. As expected, he said this "intriguing body reaction" appears whenever the body feels it needs to increase the constriction of its arteries.
The amplification of norepinephrine release occurs via presynaptic AT1B receptor which eprosartan is able to block with its unique chemical structure. Rupp said that unlike other drugs of the same class, eprosartan has a nonbiphenyl, nontetrazole chemical structure.
Other angiotensin receptor blockers, which have biphenyl structure, have greater affinity for postsynaptic AT1B receptors than presynaptic receptors, causing discrepancies between the needed presynaptic and postsynaptic doses. On the other hand, eprosartan has been shown to have roughly equal affinity for both receptors at the same dose, making it more effective in modifying norepinephrine release. Animal experiments by Ohlstein et al. have also shown that eprosartan reduced sympathetically stimulated blood pressure by 25 percent. It also significantly reduced the heart rate, and therefore sympathetic activity.
Adding Years and Pounds
Age and weight are the two most important external factors that give rise to high blood pressure, said Rupp, noting that hypertension prevalence is highest among those aged 65 and older and the overweight and obese sector of the population. In Germany, for instance, he said 50 percent of people ages 65 and older have hypertension. He said the trend is going to be seen worldwide as the elderly, now making up 30 percent of the population in industrialized countries and 10 to 15 percent in developing countries, further increases in number.
Tracing the pathophysiology of hypertension to arterial remodeling, Rupp noted that age and lifestyle contribute a lot to the process. "Remodeling appears [as part of] normal ageing," he pointed out citing a 1937 study (Hallock P., Benson ICL, J Clin Invest 1937; 16 :595), which showed that stiffness of the arteries increased with age independent of lifestyle. "The older you get, the more your arteries stiffen," he said, adding that "modern lifestyle amplifies the increase in [arterial] stiffness."
This is where diet and inactivity leading to excess weight and obesity come in because of their implication on sympathetic activity. Rupp said studies have found that the body's sympathetic activity body increases concomitantly with body mass index. A hike in sympathetic activity will also result in an increase in norepinephrine release from the sympathetic fibers. This is in proportion to an increase in caloric intake. Hence, obesity has been implicated in the pathophysiology of hypertension.
What is more dangerous with diet is not just high fat, but when fat is in combination with sugar (typical hamburger-French fries-soft drink diet), Rupp said. He cited an experiment with rats in which it was shown that adding sucrose to a high-fat diet pushed up both systolic and diastolic blood pressure, as well as heart rate. "It is this combination, typical in many Westernized societies, that is responsible for insulin resistance, hyperinsulinemia, and overstimulation of the sympathetic system," he stressed.
The sympathetic system is the master control for the release of angiotensin-2. Sympathetic overactivity releases renin, which leads to the release of angiotensin-2, which stimulates collagen production, which leads to arterial remodeling, which leads to hypertension.
He explained that collagen production is a response mediated by AT1 receptors. When angiotensin-2 binds to these receptors, there is an increase in collagen production. Hence, when angiotensin-2 is inhibited, there will also be a decrease in collagen and arterial remodeling. But the problem, he said, is that angiotensin-2 is produced not only by the angiotensin converting enzyme (ACE) but also by chymase-an enzyme that is not inhibited by ACE inhibitors.
Rupp said eprosartan exhibits competitive binding to AT1 receptors, which other ARBs do not do.
When eprosartan was studied, he said, it was found that the drug prevented the expression of markers (collagen and fibronectin) of cardiovascular remodeling. Even TGF beta, the perpetrator of collagen synthesis and extracellular matrix of remodeling, was affected.
Rupp said remodeling is critical, particularly in the elderly, and eprosartan is able to counter adverse remodeling by taking away influences from angiotensin-2.
Reverse Remodeling
Rupp said clinical trials from Europe and the US showed that a single daily dose of eprosartan effectively reduces both systolic and diastolic blood pressure. Blood pressure reduction using a 600 mg daily dose of eprosartan in mild to moderate hypertension is comparable with the reduction seen with ACE inhibitor enalapril and is significantly greater compared with placebo. The response rate to the drug is also better in any age group and patient type. Even for severe hypertension, eprosartan performed better than enalapril (Figure 2).
Also, eprosartan has little potential for drug interaction as it has no significant effect on cytochrome P-450 enzymes.
Eprosartan has been found to have a very satisfactory side effect profile no different from that of placebo, said Rupp. No significant complaint or adverse effect was noted among the patients taking the drug. Coupled with once-daily dosing, this makes long-term compliance more feasible.
But what is more significant, noted Rupp, is eprosartan's effects on vascular integrity and its ability to induce a reverse remodeling of the vasculature. "Reducing hypertension is essential, but we should do more than just reduce hypertension, he said, citing studies that compared the effects of eprosartan with hydrochlorothiazide on vascular oxidation and inflammation. He said the study showed that eprosartan reduced not only blood pressure but also the levels of soluble monocyte chemotactic protein-1 and soluble vascular cell adhesion molecule. It has also been found to have antioxidant effect in that it was shown to reduce the superoxide generation of neutrophils.
Rupp said experiments combining eprosartan with hydrochlorothiazide in the treatment of spontaneous hypertensive rats also showed delayed return to high blood pressure when treatment was stopped, indicating he said "a reverse remodeling of the vasculature".
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