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Hypertension

posted Jan 5, 2012, 11:27 AM by George Finlay   [ updated Feb 1, 2012, 5:58 AM by Nathaniel Cauldwell ]
One afternoon recently, during one of those dreaded medical exams, Dr. Barry Zitomer, formerly an Air Force flight surgeon and now my AME, looked up from the scale on his mercury manometer, slipped his stethoscope earpieces out, unwrapped the cuff from my upper arm, frowned and said “156 over 95”.

I knew at once where he was going next. For years he had been warning me my blood pressure was a little high. My habit was to reply that I was not surprised it read high in his office, because he stood between me and the career I love. In the past, he had always given me a chance to relax a while, taken a new reading and satisfied himself that although it was a little high, it was safely below the level at which the FAA required him to withhold issuance of a new pilot’s medical certificate. That level is 155 systolic, 95 distolic.

So this scenario was similar to being pulled over by the highway patrol and told radar clocked you doing 20 mph more than the speed limit. That is the point at which the fines double, at least here in my home state of New Jersey. There is no point in arguing this with either with a patrolman or with an AME So I asked him what he wanted to do next. He said he wanted me to take quinapril for a week, then come back to see him again.

About a week later, after I had dutifully swallowed 40 mg of quinapril daily since our last visit, Dr. Zitomer again looked up from his manometer, smiling this time, and announced "120 over 80".

All well and good, but my compliance soon waned because I felt fatigued most of the time I was on quinapril and when I stood up quickly I often felt lightheaded as though I was working against a G load in the cockpit.

I fly with Dr. Wayne Isom, a heart surgeon at Weill Cornell Medical Center. When he offered the services of his staff and facilities to augment my periodic medical exams, I accepted, of course. They now have CT scans of my heart and surrounding blood vessels taken a year apart. Wayne’s colleague Dr. Len Girardi noticed a 2 mm increase year to year in the diameter of the ascending aorta, from 4.4 cm to 4.6. Aortic root diameter measured 3.6 cm, which is normal for my height, 77 in, (196 cm.). While aortas commonly dilate with age due to deterioration of elastin and collagen, the tough elastic proteins that give the artery its strength and flexibility, a rapidly dilating aorta may eventually dissect -- similar to delamination -- or rupture. A commonly used guideline recommends surgical repair if the rate of dilation exceeds a centimeter per year, or if the diameter increases beyond 5.5 cm for someone of average build, a little more for someone of my size.

Because lowering average blood pressure may help slow the dilation, Dr. Isom referred me to Cornell’s Dr. Mark Pecker, who went over the data his staff collected from a Spacelab ambulatory blood pressure monitor I wore for two days taking readings twice each hour. I had not taken any quinapril in over a month. Activities were typical for me during the data collection, including 2 flights about 3 hours long, as well as driving, walking, exercising, reading, and emailing. I kept notes on what I was doing at each reading, as requested by Dr. Pecker’s staff. 

When they sent me the results I first thought the monitor was not accurate at altitudes much above sea level, because the readings were unexpectedly high during the two routine flights. But the user manual for the monitor says the useful range is from 500 ft below sea level to 15,000 feet above. There were also several high readings when I was doing other things I would not consider alarming -- driving and meeting with a biologist about Savannah River water quality.

Dr. Pecker explained what the data revealed. Pressure normally drops during sleep; my sleeping average was 121/76 mmHg and my awake pressure averaged 148/99. Mean arterial pressure averaged 92 sleeping, 110 awake. And my average pulse pressure, the difference between systolic and diastolic, was 45 sleeping, 50 awake. These differences between awake and sleeping, referred to as dipping, are on the high end of normal.

Like aircraft stability and control systems and like government systems of checks and balances, mammals have an interconnected set of systems that allow variation in response to changes in short term conditions such as emergencies, changes in body position, activity level and dissolved oxygen, while damping variations and maintaining adequate stable pressure in response to changes in long term conditions such as blood volume.

While these controls are not fully understood, some of the functioning has been studied in detail:

The first control system, the renin/angiotensin system, centers on juxtaglomerular apparatus (JGA) located in the kidneys where it can detect the pressure of the blood entering the kidneys as well as changes in the volume of blood exiting the filtering mechanisms in that organ. The JGA receives signals from the macula densa, a group of cells that detects sodium chloride in the fluid extracted from the blood by the kidneys. In response to a sodium decrease, a blood pressure decrease, and/or a decrease in exiting blood volume, the juxtaglomerular cells secrete renin which splits
angiotensinogen found in blood plasma, forming angiotensin I. 

While this peptide has no known biological effect, it can be changed by angiotensin converting enzyme (ACE) to three forms that impact blood pressure through various means, angiotensin II (A II)  and to a lesser extent, III and IV. A II immediately raises blood pressure by constricting blood vessels. It also triggers aldosterone secretion by the adrenal gland and that hormone causes the kidneys to retain more sodium relative to potassium which by osmosis with body cells increases water content of the blood, raising pressure. A II triggers the pituitary to secrete arginine vasopressin (AVP) which directly decreases the amount of water secreted into urine by the kidneys, increasing water content in the blood, raising pressure.

Dr. Pecker  rechecked my plasma renal activity which Dr. John Laraugh had found at 2.24 ng/mL/hr in 2008. This normal value indicates that an ACE inhibitor like quinapril would be expected to lower overall pressure, which might make it uncomfortably low in some scenarios.


A second pressure control system involves pressure sensors in the circulatory system referred to as baroreceptors . Those located in the aortic arch and carotid arteries are specialized to sense increases in pressure and send signals to the medulla which then controls the rate and strength of heart contractions. Those located in the vena cava and pulmonary veins are sensitive to decreases in volume, which links into the first system by stimulating alderstone secretion by the adrenal gland.

A third control system is based around norepinephrine/epinephrine (aka adrenaline) and is what people are thinking of when they say a situation raises their blood pressure. To rapidly increase the organism’s ability to respond to an approaching challenge, whether that be the approach of a saber-toothed tiger in the old days or perhaps a critical presentation these days, adrenaline secreted by the adrenal gland quickly opens airways to maximize respiration and increase heart rate and contraction strength, and constricts blood vessels to increase perfusion of body cells, while it releases increased glucose and fatty acids into the blood to provide fuel.

With my normal sleeping pressure and significant spikes during my work day, Dr. Pecker suggested drug therapy aimed at the norepinephrine/epinephrine control system might be a worthwhile experiment, targeting the higher pressures seen when I am reacting -- perhaps overreacting -- to stimuli.

Many cells contain receptors triggered specifically by epinephrine. A drug that selectively blocks receptors in cells that control quick constriction of blood vessels and/or output of heart, with a minimum of other impacts would be ideal.

Dr. Pecker is focusing on drugs that block one or more of the three beta receptors, not the other main class, alpha receptors. In that group there are currently drugs that focus on beta 1 receptors, which tend to target heart and vascular functioning more specifically. He recommended starting with nebivolol hydrochloride (CAS No.152520-56-4) marketed in the US by Forest Labs and Mylan Labs as Bystolic. I went home with enough samples of 5 mg Bystolic tablets to keep me supplied until a scheduled follow up with Dr. Pecker, instructed to take one per day. 

A study of drug-drug interaction with warfarin (CAS No. 81-81-2) in 12 healthy adult volunteers showed no impact on the effect of either nebivolol or warfarin. I take 10 mg daily of warfarin after suffering deep vein thrombosis and pulmonary embolism in the last decade. (see article “Pulmonary Embolism” on this site.)
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According to DailyMed, a website with information about marketed drugs maintained by the U.S. National Library of Medicine (NLM), the active isomer is d-nebivolol. It reaches peak plasma concentration in most people about 1.5 hours after being taken orally and has a half-life of about 12 hours.  

​Multiple large scale double blind trials have shown nebivolol to be effective at reducing blood pressure in adults with mild or moderate hypertension. Effect was uniform across age and gender subgroups, uniform over the 24 hour dosing period, and observed within two weeks of the start of treatment.
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