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BLOOD PRESSURE

HYPOTENSION (LOW BLOOD PRESSURE)

PART 1: SUMMARY OF "ADRENALINE AND PSYCHIATRY" MATERIAL RELATIVE TO BLOOD PRESSURE DYSREGULATION 1/7/03

(Note: This material is original with Madisondoctrine. It is not verified by the experience of other physicians. Because the subject material is so extensive and new, there may be ideas presented which will later be shown to be inaccurate or incorrect. Ralph Ankenman M.D.)

The Madisondoctrine material on Adrenaline and Psychiatry emphasizes the necessity of understanding the two possible extremes of adrenaline activity in response to significant stimulations in life. It was demonstrated that excess Norepinephrine (NE) activity has the characteristic of aggressive tension and is more damaging to the physiological stability of the body than the excess Epinephrine (EPI) activity. It is the excess NE drive that causes the changes of body reactivity leading to many of the so-called functional or psychosomatic illnesses that are abundant and difficult to treat. Of those conditions, the easiest to understand are the changes in the set point of blood pressure - either too low (hypotension) or too high (hypertension). At the end of the Adrenaline and Psychiatry material, I described Mary Jane, a patient I cared for in the early 1980's, who was highly aggressive, extremely hyperactive, "impossible" for her caregivers to manage - and who had extremely low blood pressure, extremely rapid heart rate, and did not respond to any treatment available then. At that time, hypotension was not considered to be a disease by most physicians. Even now there are few who consider it a significant problem. Madisondoctrine considers it a common problem which can contribute greatly to physical and psychiatric symptoms-- one that is often easily treatable, and one which opens the way to understanding the nature of the negative effects of excess NE on body function. Madisondoctrine also considers that an imbalance of NE activity contributes in a great measure to the more well-known disease hypertension.

PART II "ESSENTIAL" HYPOTENSION.

This is the name used in Madisondoctrine material to describe the condition of symptomatic low blood pressure be caused by a disturbance in blood pressure regulation. It is an equivalent name to Essential Hypertension.

A1. POSTURAL HYPOTENSION AND PERSISTANT HYPOTENSION. The hypotensive condition that is gaining attention from standard medicine at this time is orthostatic hypotension-which is the drop of blood pressure when going from a lying or sitting position to standing. By some definitions, the BP drop must be 20mm before one can make the diagnosis. A good number of individuals with this big a drop tend to be older and have physical changes in their arteries and their sympathetic nervous system causing the problem. There are far more younger individuals who experience low blood pressure even when lying down. They may or may not have a drop on standing, but they will have other failures of BP stability which cause their symptoms of light-headedness on standing, weakness, lack of energy for sustained physical function, rapid heart rate, palpitations, symptoms of panic, cold hands and feet, mitral valve disease, and chest pain. These individuals do not have anything wrong with the physical makeup of their arteries and nervous system; their symptoms are due to a functional disorder.

A2. TYPES OF BLOOD PRESSURE CHANGES OF FUNCTIONAL HYPOTENSION There are many patterns of clinical findings seen in individuals with essential hypotension. I am listing a few examples here.

a) Normal blood pressure lying and after standing for a while, but a transient drop on standing - occasionally with light-headedness and even episodes of passing out.

b) Low blood pressure lying --e.g. 100/60 with a drop of 10+ mm on standing. Some light-headedness and a tendency for lowered physical endurance. Pulse may or may not be fast

c) Low blood pressure lying -- e.g. 110/50. When standing the BP will have a fall of pulse pressure- that is the systolic will drop to 90 and the diastolic go up to 70. The sound will be very hard to hear, and there is generally increased pulse rate. (Note that the standing blood pressure should be taken instantly on standing in essential hypotension in younger individuals. When testing for organic-based hypotension in older individuals, the fall in blood pressure may not occur for several minutes).

A3. THE PRESUMED CAUSE OF ESSENTIAL HYPOTENSION; ALTERED NE RECEPTOR FUNCTION RELATED TO EXCESS ACTIVITY - THE ADRENALINE FATIGUE SYNDROME. Patients with the cluster of symptoms of rapid heart rate, low blood pressure, cold extremities, and weakness are found in various doctor's offices seeking relief for their problems. Many come to psychiatrists, referred from their heart doctors, seeking psychological help because they are nearly disabled from the weakness and chest pain. Such individuals have had their symptoms come and go for years without any seeming relief from medications. These symptoms represent the natural results caused by the upset physiology occurring with chronic Norepinephrine reactivity. There is a "fatigue" of the alpha adrenaline receptors from the constant excess stimulation. In some individuals there also is a mechanism lowering blood volume which contributes the hypotension.

A4. EXAMPLE OF THE ADRENALINE HYPOTENSIVE SYNDROME. The following case history was an early successful medication treatment, which seemed to reverse the adrenaline dysfunction causing the hypotension state

CASE 1- HYPO The most serious case of cyanotic, hypotensive, dysfunctional physiology that I have seen in an otherwise normal individual was that of a 35 year old woman who was a very active professional and homemaker. She had arms that were "blue to the elbows" and mitral valve prolapse causing chest pain. She took the beta-blocker atenolol /Tenormin to slow down her racing heart - but was able to take only a small amount or else she was totally without physical energy. She did have much mental energy, with constant "racing" thoughts. At night, she recounted all the events of the day and planned all the events for the next day. She went to sleep only after several hours of lying in bed, and she woke after three to four hours. Obviously, she had alpha adrenaline over-activity; but her blood pressure was not high. It typically ran just below 90/60. If she tried to discontinue the atenolol, her heart rate became more rapid worse and she developed intolerable chest pain.

A5. PROLONGATION OF ALPHA ADRENALINE REACTIVITY, THE CAUSE OF ADRENALINE FATIGUE This patient's body was markedly different at night than the bodies of most people, since it really did not ever relax -- even during sleep. I liken her sleep patterns to those of a soldier in the front line trenches in a war - on alert even when asleep. When most people lie down to sleep at night, the activity of the sympathetic nerves relaxes. Through the day, this network of nerves have been stimulated by the brain's drive for functional accomplishment and by the reflex which prevents low blood pressure while the standing up. Normally, this "sympathetic tone" turns down at night, blood vessels relax, and the volume of the vascular bed is expanded. Because of this patient's cerebrally-stimulated excessive alpha adrenergic tone, she did not relax her blood vessels - thus maintaining a smaller fluid volume through the night. When she awakened the next day, her already overstressed alpha system would continue her overly active social function and also its reflex vasoconstriction in an attempt to prevent postural hypotension. But the blood pressure would stay low. The rapid heart rate occurred as a reflex phenomenon associated with the hypotension and low blood volume. The patient had tried unsuccessfully to take extra salt to increase her fluid volume, but her kidneys had immediately excreted the extra salt load according to its signals of salt to water ratio. The error was not in salt balance, but one of diminished volume capacity. Observing this phenomenon suggested a breakthrough concept concerning dysfunctional disorders and alpha over-reactivity caused by excess NE function.

A6. MEDICATION TREATMENT (BEDTIME CLONIDINE) FOR ESSENTIAL HYPOTENSION.

CASE 1-HYPO( continuation:) With the concept of prolonged NE activity in mind, it was easy to determine that turning down the NE brain drive with a small bedtime dose of alpha-2 blocker (0.05 to 0.1 mg of Clonidine) would start reversing this patient's dysfunctional process. After about three nights of better sleep and a relaxed vascular system, her arms ceased to be blue. She was able to function much more during the day because of her higher blood pressure and blood volume, and she had less significant symptoms of mitral valve prolapse. She was able to go to sleep more quickly because the clonidine turned off the revving "predator" mental tension. She herself tested the effect by discontinuing the clonidine after several weeks of therapy - and discovered that in about three days her arms again became blue and her cardiac pain recurred.

4) WIDER TREATMENT OF ADRENALINE FATIGUE/HYPOTENSION DISORDER With the discovery that Clonidine at night can reverse some of the hypotension seen in the essential hypotension syndrome, it was easy to move to other treatments which would further normalize the function of the NE/alpha adrenergic control of BP. There are two other potential means of improving blood pressure in such cases:

A-1) IMPROVING THE FUNCTION OF THE NE SYNAPSE. Since these individuals have "fatigue" of the NE system, it seems reasonable to give a medication which might stabilize the function of NE in the synapse. An anti-depressant which blocks re-uptake of NE would allow for increased use of the NE by that nerve and thus improve its function. There is one anti-depressant in the United States with NE action which has demonstrated its ability to help raise blood pressure and stabilize it in such individuals. This is venlafaxine /Effexor. (Most of the other NE acting anti-depressants have as a side effect the property of blocking the alpha-1 receptor mechanisms in the body thus causing low blood pressure.) Venlafaxine/Effexor is unique in its effect on NE. In fact, it has the side effects of causing high blood pressure in some individuals. (Buproprion/Wellbutrin, another anti-depressant with NE activity, does not seem to have the action which improve this particular NE function)

A-2) BENEFIT OFTEN SEEN WITH VERY LOW DOSES. Research investigation has determined that high doses of venlafaxine are needed before the NE component of its chemical activity was strongly in place. But in individuals who have adrenaline fatigue disorder, as small a dose as 37.5 mg or 75 mg a day is often enough to stabilize the adrenaline system and help individuals not have the weakness, dizziness, coldness, and other symptoms that have bothered them for years.

A-3) TREATMENT OF "REFRACTORY DEPRESSION" AND "REFRACTORY PANIC" IN INDIVIDUALS WITH ADRENALINE FATIGUE. One type of patient commonly seen as psychiatric consult is the patient who has classic symptoms of depression or panic/anxiety but who has obtained little benefits from the serotonin specific antidepressants commonly prescribed. They have symptoms of weakness and dizziness on standing. They have low blood pressure, which drops on standing. Such individuals are "miraculously improved" if placed on venlafaxine/Effexor -- either low dose of 37.5 to 75mg a day added to the serotonin specific antidepressant, or in standard dose of 75 to 300mg a day as the sole agent. Sometimes it takes months for complete recovery - as demonstrated by the following case:

CASE 2- HYPO: A 30+ year-old working mother was seen in consult for heart palpitations, heart pain. She had developed an intense phobic reaction that she had an undiscovered fatal disease. She had suffered from these symptoms for over three years. Her heart examination was outstanding in that she had a skipped heartbeat after every three normal beats as a regular pattern. Examination of lying blood pressure showed a low normal blood pressure (110/70) with a drop of 10+ mm on standing (90/60). She was treated with nighttime clonidine and venlafaxine/Effexor given in the day. After three weeks she felt improved enough to take a scheduled vacation (which of course relieved further her alpha adrenaline reactivity.) Seen four months after her original contact, she had minimal symptoms from day to day. Her standing blood pressure was still low (86/72). Her heart rate was regular when sitting; but when she stood up, she demonstrated some asymptomatic skipped heartbeats. After another four months of treatment with the same medications, she demonstrated no more skipped heartbeats or other symptoms. Her blood pressure sitting and standing was near 120/80. This demonstrates the cause of the disorder being a change in "adrenaline set point" from a prolonged period of adrenaline over-activity. It also points out that part of fatigue disorder can stabilize quickly, but other symptoms may persist for months.

A-4) "NORMAL PEOPLE" WITH ADRENALINE FATIGUE POSTURAL HYPOTENSION. In the course of normal day-to-day conversation, I will hear stories about individuals who are functional but have problems with weakness or dizziness. Depending on their history these individuals have been offered a low dose clonidine at night or a low dose of venlafaxine/Effexor or both. One problem they sometimes have is convincing other doctors that low blood pressure can be improved with the medicine clonidine, which is on the market to treat high blood pressure!

A-5) CHRONIC FATIGUE SYNDROME AND "ADRENALINE FATIGUE." A certain percentage of individuals diagnosed as having Chronic Fatigue Syndrome actually have adrenaline fatigue and recover their strength when treated with bedtime clonidine and venlafaxine. However, most individuals with Chronic Fatigue Syndrome are only partially relieved of the intense lack of normal strength that is typical of this disorder.

B) INCREASED FLUID VOLUME BY CHANGING THE KIDNEY SET POINT It is sometimes necessary to use a medication which causes the body to develop a higher blood volume and thus raise blood pressure. This is called fludrocortisone /Florinef. It is an artificial hormone having the salt and water retention properties of cortisone. This medicine is approved for use to raise blood pressure. However, it is much better to use it in combination with the medications which stabilize NE activity and thus move the system back toward normal. Some individuals need fludrocortisone to elevate their blood pressure for a brief time (say three to eighteen months); a few individuals are not able to stop the fludrocortisone without their blood pressure being lowered again. However, when individuals who are on NE stabilizing medications generally have a more complete relief of their symptoms. (Individuals taking fludrocortisone on an extended basis require monitoring to show that they are maintaining their potassium levels).

C) DIRECT STIMULATION OF PERIPHERAL ALPHA-1 RECEPTORS There are medications which directly stimulate the alpha-1 receptors in the blood vessels. This can raise blood pressure. However, if the cause for low blood pressure is adrenaline receptor fatigue, this particular treatment may be like "beating a dead horse" since the receptors are already fatigued, and they are now being asked to produced more contraction. There also will be no improvement in the low blood volume of this disorder. A new medication, mididrine/Proamitine, is marketed to raise blood pressure; but it has a fairly significant problem of causing elevated blood pressure when lying down. Madisondoctrine has no experience with this medication.

1) ALTERED FUNCTION STATES RELATED TO CHRONIC ACTIVITY - THE ADRENALINE FATIGUE SYNDROME. Patients with the "Mary Jane" cluster of symptoms of rapid heart rate, low blood pressure, cold extremities, and weakness are found in various doctor's offices seeking relief for their problems. Many come to psychiatrists referred from their heart doctors seeking psychological help for patients who are nearly disabled from the weakness and pain of their mitral valve prolapse. Such individuals have their symptoms come and go for years without any seeming relief from medications. These symptoms represent a good place to look at the changes of upset physiology occurring with chronic adrenaline reactivity.

2) TREATMENT OF THE ADRENALINE HYPOTENSIVE SYNDROME. The following case history was an early successful medication treatment which seemed to reverse the adrenaline dysfunction causing the hypotension state CASE 3ADR The most serious case of cyanotic, hypotensive, dysfunctional physiology that I have seen in an otherwise normal individual was that of a 35 year old woman who was a very active professional and homemaker. She had arms that were "blue to the elbows" and mitral valve prolapse with pain. She took the beta-blocker atenolol /Tenormin to slow down her racing heart - but was able to take only a small amount or else she was totally without physical energy. She did have much mental energy, with constant "racing" thoughts. At night, she recounted all the events of the day and planned all the events for the next day. She went to sleep only after several hours of lying in bed, and she woke after three to four hours. Obviously, she had alpha adrenaline over-activity, but her blood pressure typically ran just below 90/60. If she tried to discontinued the atenolol, her heart rate became more rapid worse and she developed chest pain. This patient's body was markedly different at night than the bodies of most people, since it really did not ever relax even during sleep. I liken her sleep patterns to those of a soldier in the front line trenches in a war - on alert even when asleep. Observing this phenomenon suggested a breakthrough concept concerning dysfunctional disorders and alpha over-reactivity.

3) PROLONGATION OF ALPHA ADRENALINE REACTIVITY, THE CAUSE OF ADRENALINE FATIGUE When most people lie down to sleep at night, there is a relaxation of the alpha adrenergic tone of the sympathetic nerves. Through the day, This network of nerves have been stimulated by the brain's drive for functional accomplishment and by the reflex which prevents low blood pressure while the standing up. Normally, this "sympathetic tone turns down at night, blood vessels relax, and the volume of the vascular bed is expanded. Because of this patient's cerebrally-stimulated excessive alpha adrenergic tone, she did not relax her blood vessels - thus maintaining a smaller fluid volume through the night. When she awakened the next day, her already overstressed alpha system would cause further vasoconstriction in an attempt to prevent postural hypotension and continue her overly active social function. The rapid heart rate was a reflex phenomenon associated with the postural hypotension and low blood volume. The patient had tried unsuccessfully to take extra salt to increase her fluid volume, but her kidneys had immediately excreted the extra salt load according to its signals of salt to water ratio. The error was not in salt balance, but one of diminished volume capacity.

CASE ADR3 ( continuation:) With this concept in mind, it was easy to determine that turning down the NE brain drive with a small bedtime dose of alpha-2 blocker (0.05 to 0.1 mg of Clonidine) would start reversing this patient's dysfunctional process. After about three nights of better sleep and a relaxed vascular system, her arms ceased to be blue. She was able to function much more during the day because of her higher blood pressure and blood volume, and she had less significant symptoms of mitral valve prolapse. She was able to go to sleep more quickly because the clonidine turned off the revving "predator" mental tension. She herself tested the effect by discontinuing the clonidine after several weeks of therapy - and discovered that in about three days her arms again became blue and her cardiac pain recurred.

4) WIDER TREATMENT OF ADRENALINE FATIGUE/HYPOTENSION DISORDER With the discovery that Clonidine at night can reverse some of the hypotension seen in the "Mary Jane" syndrome, it was easy to move to other treatments which would also benefit by increasing fluid volume and normalizing the function of the NE/alpha adrenergic system. There are two other potential means of improving blood pressure in such cases:

A-1) IMPROVING THE FUNCTION OF THE NE SYNAPSE. Since these individuals have "fatigue" of the NE system, it seems reasonable to give a medication which might stabilize the function in the synapse of the NE nerves. An anti-depressant which blocks re-uptake of NE would allow for increased use of the NE by that nerve and thus stabilize its function. There is one anti-depressant with NE action in the United States which has demonstrated that ability to help stabilize and raise blood pressure in such individuals. This is venlafaxine /Effexor. (Most of the other NE acting anti-depressants have as a side effect a property of blocking the alpha-1 receptor mechanisms in the body thus causing decreased blood pressure.) Venlafaxine is unique in its ability to effect NE and not have a side effect of causing low blood pressure. In fact, one of its significant side effects is causing high blood pressure in some individuals. (Buproprion,/Wellbutrin, another anti-depressant with NE activity, does not seem to have the action to improve this particular NE function)

A-2) BENEFIT OFTEN SEEN WITH VERY LOW DOSED. Research investigations has determined that high doses of venlafaxine are needed before the NE component of its chemical activity was strongly in place. But in individuals who have adrenaline fatigue disorder, as small a dose as 37.5 mg or 75 mg a day is often enough to stabilize the adrenaline system and help individuals not have the weakness, dizziness, coldness, and other symptoms that have bothered them for years.

A-3) TREATMENT OF "REFRACTORY DEPRESSION" AND "REFRACTORY PANIC" IN INDIVIDUALS WITH ADRENALINE FATIGUE. One type of patient commonly seen as psychiatric consult is the patient who has classic symptoms of depression or panic but who has obtained minimal benefits from the serotonin specific antidepressants prescribed. They give symptoms of weakness and dizziness on standing. They have low blood pressure, which drops on standing. Such individuals are "miraculously improved" if placed on venlafaxine either low dose of 37.5 to 75mg a day added to the serotonin specific antidepressant, or in standard dose of 75 to 300mg a day as the sole agent. Sometimes it takes months for complete recovery - as demonstrated by the following case:

CASE 4ADR: A 30+ year old working mother was seen in consult for heart palpitations, heart pain. She had developed an intense phobic reaction that she had an undiscovered fatal disease. She had suffered from these symptoms for over three years. Her heart examination was outstanding in that she had a skipped heart beat after every three normal beats as a regular pattern. Examination of lying and standing blood pressure showed a drop of xxxx mm on standing. She was treated with nighttime clonidine and venlafaxine given in the day. After three weeks she felt improved enough to take a scheduled vacation (which of course relieved further her alpha adrenaline reactivity.) Seen four months later she had minimal symptoms from day to day. Her blood pressure was xxxx sitting and xxxx standing. Her heart rate was regular when sitting; but when she stood up, she demonstrated some skipped heartbeats. After another four months of treatment with the same medications, she demonstrated no more skipped heart beats or other symptoms. This demonstrates the cause of the disorder being a change in "adrenaline set point" from a prolonged period of adrenaline over-activity. It also points out that part of fatigue disorder can stabilize quickly but other symptoms may persist for months.

A-4) "NORMAL PEOPLE" WITH ADRENALINE FATIGUE POSTURAL HYPOTENSION. In the course of normal day-to-day conversation, I will hear stories about individuals who are functional but have problems with weakness or dizziness. Depending on their history these individuals have been offered a low dose clonidine at night or a low dose of venlafaxine/Effexor or both. One problem they sometimes have is convincing other doctors that they are helping their low blood pressure with the medicine clonidine, which is on the market to treat high blood pressure!

A-5) CHRONIC FATIGUE SYNDROME AND "ADRENALINE FATIGUE." A certain percentage of individuals diagnosed as having Chronic Fatigue Syndrome actually have adrenaline fatigue and recover their strength when treated with bedtime clonidine and venlafaxine. However, most individuals with Chronic Fatigue Syndrome are only partially relieved of their extreme lack of normal strength when their hypotension is treated.

B) INCREASED FLUID VOLUME BY CHANGING THE KIDNEY SET POINT The use of a medication called fludrocortisone /Florinef, which is an artificial hormone having the salt and water retention properties of cortisone, allows the body to develop a higher blood volume and thus raise blood pressure. This medicine is commonly used to raise blood pressure. However, it is much better to use it in combination with the medications which stabilize NE activity and thus move the system back toward normal. Some individuals need fludrocortisone to elevate their blood pressure for a brief time (say three to eighteen months); a few individuals are not able to stop the fludrocortisone without their blood pressure being lowered again. However, when individuals who are on NE stabilizing medications generally require fairly low doses of the fludrocortisone (0.1 mg - 0.2 mg per day) (Individuals taking fludrocortisone on an extended require monitoring to prevent developing low potassium levels).

FINDING A KEY TO THE CAUSE OF ESSENTIAL HYPERTENSION 12/02/02

PART 1. BACKGROUND UNDERSTANDING OF HYPERTENSION

Hypertension is a very significant fact of life in modern civilization. A huge percent of the population over the age of forty have it mildly or severely. There are at least 60 different brand name medications listed as treatments for hypertension. These belong to the 10 or more different classes of antihypertensive agents. Yet hypertension, along with Diabetes Mellitus, has reached epidemic proportion. Most of the cases have no obvious cause; thus they belong the mysterious classification of “Essential Hypertension”; that is – the bodies of so many people have somehow “forgotten” the normal set point for BP. Our society takes this for granted, but why should we? We don’t see 30% of the population persistently run temperatures two to five degrees above 98.6*, do we? If we did, we certainly would demand to know what toxic industrial waste, newly escaped virus or international terrorist had caused such a plague. But we accept that high BP is a part of life that is without cause. We just have to live with it – or sometimes die with it.

A. TRY “LIFE STYLE” TREATMENT FIRST. The ordinary course of hypertension in an individual is a gradual elevation of the baseline BP – very, very slowly; say 1 to 2 mm a year, with occasionally spikes of higher pressure that come back down. Doctors are taught that this early “borderline” hypertension should be treated with various changes in life style rather than using medication. What they end up telling patients in this early state ends up sounding something like the following:

“The bad news is that, even though you don’t feel it, your BP is about 8 mm higher than it should be. If left alone, your BP will probably continue to rise; so that when you are twenty years older you will have heart trouble and strokes. The other bad news is that giving medication treatment at the present time is difficult. It often lowers the BP too much, making you feel like you were twenty years older and had heart trouble and strokes. So we don’t give medication until the BP gets high enough and has lasted long enough to have started doing some damage. The good news is that if you lose twenty pounds, quit smoking, drink only one drink a day, do aerobic exercises and eat only high roughage foods with no salt, your BP may come back down close to normal. You can also try meditation, biofeedback, and acupuncture, but these tend to help only a few individuals – mostly people who sponsor full color holistic medicine web sites.”

B. HYPERTENSION AND STRESS. Once hypertension was considered to be a prime example of a “psychosomatic disease”, but no longer. In the 50’s, 60’s, it was thought to be a direct result of stress. But research has determined that the temporary episodes of hypertension seen in times of acute stress are not highly related to the persistent elevation of BP seen in patients with . Furthermore, many hypertensive individuals are not what would be called the “nervous type” For several decades, modern medicine has sought to educate the public that hypertension is a medical disease caused by numerous factors such as heredity, life style -- and unknown forces The longer one has it, the more likely that it will lead to dangerous problems, but it is difficult impress many individuals with early hypertension that they have a disease because a most of them feel functionally healthy and are in their productive years of adulthood – especially since there is little hint what these unknown causes are.

C. “ESSENTIAL HYPOTENSION” MAY BE DUE TO IMBALANCED NOREPINEPHRINE ACTIVITY. In other sections of this web site, it has been stated that there is an excess use of the Norepinephrine (NE) predator aggression reflex in day-to-day civilized life. (back to Adrenaline). Furthermore, it was described how some individuals with excess NE activity develop a particular condition, which Madisondoctrine calls “Essential Hypotension” (Back to Hypotension). Hypotension seems to be caused by prolonged NE sympathetic reactivity – and it can be treated by several maneuvers with certain adrenaline-acting medications. One foundational treatment is use of clonidine at bedtime. This medicine turns down the NE reactivity in the brain and sympathetic nervous system -- allowing for mental and physical calming. This use of clonidine seems at first somewhat paradoxical because clonidine causes blood vessels to dilate, which normally lowers the BP. But if clonidine is given at bedtime, it causes changes in body mechanisms which raise daytime BP.

D. ESSENTIAL HYPERTENSION, ANOTHER PRODUCT OF EXCESS NE ACTIVITY.
It is reasonable to consider that “Essential Hypertension” is also related to the excess noradrenergic activity through the day -- since this overuse of body mechanic is standard for modern functional mankind. But how can NE excess reactivity lead to low BP in some and high BP in others? The next section introduces a reasonable, but unproven hypothesis that could represent a major breakthrough in the understanding the cause and treatment of Essential Hypertension.

PART 2. A NEW CONCEPT ABOUT THE CAUSE AND TREATMENT OF HYPERTENSION.

PROPOSING THAT ESSENTIAL HYPERTENSION IS CAUSED
BY PARTICULAR DYSFUNCTIONAL FLUCTUATIONS IN DAY-NIGHT
ALPHA ADRENERGIC ACTIVITY.

A. Let us assume that the idea concerning the cause of the “Essential Hypotension” is correct; that is, the hypotension is the result of low blood volume secondary to the failure of the alpha-adrenergic vasoconstrictive reflexes to relax at night, creating too small a container for adequate blood volume. Since hypertension is the effect of too much salt and fluid retention causing too much blood volume, could there be a mechanism whereby the blood vessels at night became too expanded and thus allowed too much fluid retention?

B. REBOUND – A NATURAL REACTION IN BODY REACTIVITY.
One of the commonly seen reactions of body physiology is that of rebound. When a receptor is stimulated intensely for a prolonged time by a chemical transmitter, the receptor becomes less sensitive to the chemical’s stimulation. When the excess chemical stimulation is withdrawn, there follows a period of dysfunction where the normal amount of chemical cannot produce the normal reaction. This is called “rebound” and is the problem seen in narcotic and alcohol withdrawal.

C. DAY-NIGHT DIFFERENTIAL: There is a significant difference in alpha adrenergic tone through the waking hours when the head is upright and the mind is alert and during the sleeping hours when the head is on the same horizontal plane as the heart and the mind is asleep. Let us consider the possibility that there is a significant rebound when excessive alpha-adrenergic states of hypertensive individuals are turned off at night. Such a rebound could lead to dilatation of the blood vessels creating a relative low BP and an increased fluid volume within the flexible “bag” of the cardiovascular network. Upon standing again in the morning, the hypertensive individual would again demonstrate increased alpha adrenergic tone of the postural reflex combined with the excessive “predator” alpha adrenergic drive that is the norm for functional productive people. This increased tone exerts more pressure on a system that is too full, and the BP is elevate slightly. One would expect the homeostatic mechanisms of the body to seek to reduce BP and fluid volume by putting out more urine through the daytime, but this may be hindered by several factors.

1. Because of the excessive alpha adrenergic tone, the renal vessels in the day may be excessively constricted making kidney function less efficient.
2. These same renal arterioles might be subject to a relatively lowered BP during the nighttime rebound vasodilatation. This relatively low BP may have turned on the renin/angiotensin/aldosterone system to a “hypotensive” salt-saving mode. Over time, such constant daily shifts could change the system’s set point-- thus allowing for the slow rise in what the body’s regulatory systems seeks as a normal BP.

D. LET’S TRY TO EXPLAIN THIS AGAIN. This concept is so important that it will be repeated with different words. Madisondoctrine presumes that the excessive alpha adrenergic drive (that is increased activity of the brain NE system and sympathetic nerves) in individuals with “Essential” Hypertension occurs only in the daytime. This increase is a combination of excessive mental drive and the normal daytime increase alpha adrenergic activity to maintain BP while upright .This excess activity causes an adaptive reaction in which the alpha adrenergic receptors become subsensitive through the daytime. At night when the activity of the sympathetic nervous system is markedly lowered, this subsensitivity would allow for excessive vasodilatation -- causing a relative low BP. There would be increased blood volume collected in this dilated system, and the renin/angiotensin/aldosterone system would move to a mode of operating to save fluid and salt. On arising in the morning, there would be a slight increase of BP for several reasons:
1.) Because of increased sympathetic tone during the day’s activity.
2.) Because there was increased fluid retention from vasodilatation the night before.
3.) Because the relative hypotension of the renal blood vessels which occurred on going to bed may have switched the renin/angiotensin /aldosterone system to a mode seeking to raise BP during the night.

E. WHOA! DON’T TREAT THE DAY AND NIGHT THE SAME! If the above concept is valid, a major point can immediately be made: Treatment for hypertension should involve a different treatment regime for daytime and nighttime since there is a force for causing high BP in the daytime and one causing a relative low BP at night. With the exception of certain behavioral and biofeedback techniques, which can be performed only when the patient is awake, I know of no standard treatment program which seeks to treat hypertension differently during different times of the day. It may well be that standard therapy using a medication preparation that lasts 24-hours perpetuates homeostatic upset because the benefit of the medication obtained during the daytime standing position is lost during the nighttime recumbent position– or vice versa. This concept may give some credibility to the statements of holistic therapists who claim that their relaxation or biofeedback methods can “cure” hypertension, whereas drug therapy only “controls” it.

F. TRY A “PARADOXICAL” TREATMENT. With this particular model in mind, how then would one design an effective drug therapy regime to treat Essential Hypertension at the theoretic cause? The first step would be to give a medicine at bedtime which causes constriction of the blood vessels. This would eliminate the body’s reaction to the relative hypotension caused by rebound and prevent excess fluid building up at night. But what medicine would work? The vasoconstricting medication should not act on the alpha-1 Receptors since they are in the state of recovery from the excessive use through the day. It should have a rapid onset and its effect should last about four to six hours till somewhat after 4AM, at which time the predawn adrenaline arousal begins.

G. USING A “PARADOXICAL” BP MEDICATION. Actually there is a class of antihypertensive medications that causes vasoconstriction – even though such an action is theoretically a detriment to the goal of lowering daytime BP. These medicines are the beta adrenaline blockers, which cause vasoconstriction by blocking the vasodilating effect of epinephrine on the beta receptors on small arteries.. There is one particular beta-blocker, called timolol, which has the properties necessary to provide four to six hours of vasoconstriction. Since 1990, Madisondoctrine has treated a number of individuals with early hypertension using a regime of 5 or 10 mgs of timolol at night. It has been fairly consistent in keeping their BP at a near normal level, and seems to prevent progression on to the disorder of Essential Hypertension. A major advantage of this regime is that little antihypertensive medication is in the system during the day to cause the side effects of weakness and tiredness. Such a treatment is totally different from the standard treatment concept that 24-hour coverage is necessary for control of hypertension. It may represent a major breakthrough in treating hypertension, since it can eliminate the consequences of the daily imbalance of adrenergic activity that may be a major cause of the disease. Furthermore, it represents a medication regime that causes little problem for those patients with early hypertension.

PART 3. EVIDENCE OF SUCCESS WITH “PARADOXICAL’ TREATMENT. There are about two dozen individuals who have been on the nighttime timolol regime between 3 and 10 years, and who have not demonstrated a progression to significant hypertension. (Among these patients are middle-aged individuals of Afro-American heritage. This is significant since it is considered that both middle-aged individuals and Afro-Americans do not respond well to the use of beta-blocker medication.). Since Madisondoctine is a psychiatric service, there have been only a few individuals who happened to have had no one else to provide treatment. But even though the numbers are few, it is impressive that all of those who have remained on the timolol have maintained acceptable BPs. It is hoped that specialists in hypertension will do controlled trials to prove or disprove the real efficacy of this med regime.

A. EXAMPLES OF GOOD RESULTS FROM TIMOLOL ALONE.

CASE HYPERTENSION 1. A 45 year old woman with depression, who had received no benefit from a standard dose of the antidepressant Paxil ran a BP of 190/120 for two weeks prior to being seen for the first time. After three weeks of treatment with timolol 5 mg at night and the antidepressant Celexa 20 mg in the morning, her depression was 80% improved, and her BP ran only occasionally as high as 130/85.

CASE HYPERTENSION 2. A 50 year old professional women with a heavy work schedule developed headaches and episodes of fast heart rate. Her BP read 160/110. She had no previous history of hypertension. She was placed on timolol 10 mg qHS – but this caused her too much daytime tiredness. On timolol 5 mg qHS, she has maintained a BP below 130/80, except on occasions of extreme stress.

CASE HYPERTENSION 3. A 35 year old professional woman being treated for Post Traumatic Stress Disorder and Depression would run blood intermittent BPs as high as XX/XX which caused symptoms of XXXXXXX. She was given an ACE inhibitor antihypertensive by her family doctor, but even on ¼ the dose, she developed a BP that was too low to allow for daytime function. On timolol 10mg at night, she has maintained normal BP for the last 4 years.

Dean cool, Jim Woltz

B. TREATING THE LONG-STANDING HYPERTENSIVE. Needless to say, hypertensive patients are not a “one size fits all” group. Many have physical complications and risk factors – such as family tendency, diabetes, smoking history, overweight, etc. Many individuals with “early” hypertension have actually had undetected BP elevations for years causing physical changes in the structure of the cardiovascular system which further increases the BP in several ways: (1) Their heart muscle enlarges, making the fluid holding capacity less and the internal pressure more. (2) The muscles of the small arteries enlarge, increasing the resistance to blood flow. Most of these individuals will still need standard antihypertensive medications. But they too seem to benefit from the bedtime timolol because it helps stabilize the set point of the system.

C. A LITTLE BIT HERE AND A LITTLE BIT THERE. There are several ways to seek to treat chronic Essential Hypertension: 1. Lower the increased alpha-adrenergic activity in the dayyime, 2. Eliminate the activation of the Renin/angiotensis/aldosterone system, 3. Seek to lower the force that the muscles of the heart and the blood vessels encounter and thus seek to bring the size down to normal. Madisondoctrine considers that it is easier to maintain acceptable BP in these hypertensive individuals by using nighttime timolol plus small doses of appropriate medicines which deal with the other contributing factors rather than using a large doses of one medicine, which may correct only one problem area.

CASE HYPERTENSION- 4. A 53 year old female, who sought treatment for chronic depression, also demonstrated persistent hypertension of 140/90. She had symptoms of tiredness and poor function. When started on timolol 10 mg at night, her BP lowered somewhat, but was still high. She did state that she had the sense of considerable stress at work, and was therefore was placed on 0.025 mg (¼ tablet) Clonidine twice a day on weekdays. She was also given hydrochlorthiazide 25 mg in the morning three times a week. Her BP readings were then normal except for an occasional high reading. The regime also eliminated palpitations, which had long awakened her at the night.

CASE HYPERTENSION- 5. A 49 year old, overweight female was admitted to a psychiatric unit for psychotic depression. Her BP on admission was 160/120. She was being treated with a calcium channel blocker, the generally accepted treatment for a middle-aged, Black female. When she was discharged two weeks later, her BP was as low as 120/70. Her medication regime was timolol 10 mg at night, hydrochlorothiazide 12.5 mg in the morning, and Vasotec 1.25 mg two times a day. There has not been a BP above 120/80 in four years follow-up.

D. A USER-FRIENDLY REGIME. Although these patients were on three different medications, the dosages of the drugs are small and promise not to cause major side effects. Over time, the patients develop security that their medication regime will keep their blood pressures stable. Furthermore, the some individuals gain a sense of control over their hypertension that formerly only was available for stalwart individuals who could master their body’s reflexes through yoga, transcendental meditation, biofeedback, etc. Instead of being treated for a fixed disease state with a rigid medicine regime, some patients can develop an awareness of whether their system is in or out of balance, and the medicines can be adjusted accordingly. For example, patient 4 omitted the daytime clonidine during the less stressful days of the weekends.

D. HOW CAN WE BE SURE THAT ALL THIS IS TRUE? Of course, there is much presumption in the material presented on both hypertension and hypotension. Furthermore, it is the idea of only one physician. Certainly there have been many similar ideas, which sounded good in theory but were shown invalid by scientific trials. But the prolonged improvement produces by the use of nighttime “paradoxical” medications given for both hypotension and hypertension certainly provides some credibility to the regimes proposed. Since there are no standard treatments for either “Essential Hypotension” or early Essential Hypertension, it seems reasonable for ordinary physicians to try these regimes for appropriate patients. If enough physicians find this treatment works, it will inspire scientific investigators to do definitive research in this area.

E. BLOOD PRESSURE REGULATION IS VERY COMPLEX: The effect of hypertension on mankind and the complexities involved in the regulation of BP are so extensive that it is impossible to predict the many issues that will arise in the future if the concept presented here is valid. However, it seems we should try to deal with some of the questions that will naturally be raised.

1) Is there any proof that the nighttime dose of timolol actually works by means of its vasoconstriction action and not by a typical beta-blocking effect on the heart? There are no controlled tests demonstrating any proofs. However, in many patients, round-the-clock beta-blockers do not demonstrate the ability to prevent progress to more serious hypertension; whereas the nighttime low dose of timolol apparently does.

2) Why does Essential Hypertension occur when it does to whom it does? Essential Hypertension is a problem mostly for the older years of life. This may relate a little to the increased “hardness” of the arteries, but it would seem most related to the lifestyle of this population. They generally are in the “mental focus” years, and they are not doing the exuberant beta-adrenaline driven physical exercise that they did in their younger years. They are not necessarily “over-stressed”; but they do have a relative overactivity of vasoconstrictive alpha adrenaline activity in the day, which is not balanced out by the vasodilating effects of beta adrenaline activity. Their excess alpha adrenaline activity is relative, but is enough to drive the change of BP set point. (Younger individuals with Essential Hypertension are more likely to have significant stress reactivity in their lives.)

3) Why might nighttime short-acting vasoconstrictor like timolol be superior to other regimes for early hypertensive individuals? The basic principle of modifying the rebound phenomenon seems to be significant to changing the course of the disease state. Furthermore, a long term plan which involves taking a medication at bedtime seems more likely to succeed than relying on individuals to remain faithful to the rigors of exercise, weight loss, salt restriction, stress reduction and relaxation techniques – or trying to tolerate the excess low blood pressure caused by standard regimes.

4) How do the “natural treatments” work? These treatments seem to confirm the concept of the relative imbalance of alpha and beta adrenaline reactivity. The non-medical techniques of treating Essential Hypertension are aimed at either lowering the daytime alpha adrenergic activity (meditation. Bio-feedback to increase the temperature of the hand.) or increasing the daytime beta adrenergic tone (exercise). Doing these things on a regular schedule can reverse the slow change of the system to a higher set point.

5) Have any non-beta blocker vasoconstrictors been shown to lower BP and prevent the occurrence of Essential Hypertension? Not yet, but if it is proven that timolol does work through its vasoconstrictive action, substitutes will surely be looked for. Other drugs are needed because many people have an absolute or relative contraindication to taking beta-blocker medications:
a. Diabetics, especially those taking insulin,
b. Individuals with asthma or chronic lung disease,
c. Some individuals with significant bowel spasm
Furthermore, a few people who take timolol at night develop vivid dreams, which can disturb their sleep. Therefore, it is possible that some other type of medication will be developed to produce nighttime blood vessel constriction. Medications causing vasoconstriction via serotonin action and those mimicking the vasoconstriction properties of certain peptide hormones are possible candidates.

6) In individuals with more advanced hypertension, is there any special regime that might be ideal for use with nighttime timolol? There is the possibility that using two other medicines at bedtime might also help lower the negative effect of the early nighttime rebound phenomenon. Since the relative low blood pressure which occurs after bedtime may be the stimulus to activate the Renin-angiotensin-aldosterone system to constrict blood vessels and store water and salt. It seems that this would be the best time to give medicines which would further counteracting the forces causing hypertension. There are two medication actions that might be especially effective at this time.

a. Spirinolactone a diuretic which counteracts the fluid storing effect of the hormone aldosterone, which is released from the adrenal cortex. We have seen individuals maintain a more stable BP when receiving nighttime spironolactone than when on standard diuretics alone.
b. An ACE inhibitor to counteract the vasoconstriction effects of the renin-angiotenin activation. It is possible that a short acting ACE inhibitor like captopril might be better, but this is not proven..

7) What alternatives medication regimes might prove or disprove the theory that nighttime vasoconstriction is the a key to the stabilization of BP?

a. If giving a.beta-1 selective beta-blocker were as effective as the non-selective medication timolol, then the benefit would presumably be related to Beta 1 receptors in the heart or brain rather than the Beta-2 receptors of the peripheral vessels.
b. If showing that a long-acting beta-blocker provided equal hypotensive effect as the short-acting medication timolol, it would then be questionable whether timolol’s benefit was related to preventing rebound vasodilatation during the early hours of sleep.
c. If short-acting ACE inhibitors given with nighttime timolol were not as effective as those with 24-hour coverage, it might prove wrong the theory that early night relative hypotension is a key to Essential Hypertension?

8) Has timolol plus additional medicines demonstrated superior ability to treat every case of hypertension? No, but the addition of timolol has seemed to diminish the spikes of increased BP and the symptoms that accompany them.

9) What about patients who need 24 hour protection of their heart by a beta-blocker? Such individuals might be prescribed a beta-1 selective medicine in the day because it would have minimal effect on the blood vessels at normal doses. This should preserve the effectiveness of the beta 2 blockade of the nighttime timolol. Using a beta-1 selective medicine through the day also protects the vascular network from undesirable vasoconstrictive effects of non-selective beta-blockers.

10) Is it useful to treat the daytime vasoconstriction from alpha adrenaline overactivity? Some individuals with excess alpha adrenergic mental tension do well on low dose daytime clonidine along with nighttime timolol. However, many do not tolerate the lowered the mental intensity caused by daytime clonidine. It is possible that a low dose alpha-1 blocking medicine could be used. (Note that some individuals have elevations of BP only in the afternoon, and might take low dose clonidine or the short-acting alpha-1 blocker prazosin/Minipress to treat this situation.

11) Can hypertension still be considered a “psychosomatic disease” as it formerly was? Not in the way early psychoanalysis interpreted it --with some definite cause that could be traced to personal life conflict. Neither is it “all in the head” as the general population often interprets the term “psychosomatic”. However, there does seem a definite link to the particular over-use of focused NE activity which is part of our culture’s normal function. This over-use is part of the success of civilized mankind. However, such use overextends the capacity of the alpha adrenaline system to maintain its normal limits of function. The cause of the dysfunction may be called psychological, sociological, or cultural, but the imbalance is persistent over years. Therefore, it seems well to seek out a medication therapy which will counteract the negative effect. The use of medications which work at bedtime may be such a counteracting force.

Appendix