clonidine raises blood pressure in severe idiopathic orthostatic hypotension

8
Clonidine Raises Blood Pressure in Severe Idiopathic Orthostatic Hypotension DAVID ROBERTSON, M.D. MICHAEL R. GOLDBERG, M.D., Ph.D. ALAN S. HOLLISTER, M.D., Ph.D. DAWN WADE, R. N. ROSE MARIE ROBERTSON, M. D. Nashville, Tennessee From the Departments of Medicine and Pharma- cology, Vanderbilt University, Nashville, Ten- nessee. This study was supported in part by USPHS Grant GM 15431 and by the Hrafn Sve- inbjarnarson Foundation. D. Robertson is a Teaching and Research Scholar of the American College of Physicians. R. M. Robertson is an Es- tablished Investigator of the American Heart As- sociation. Dr. Goldberg is Clinical Associate Physician, Elliot V. Newman Clinical Research Center. Dr. Hollister is a Burroughs-Wellcome Fellow. This material was presented in abstract form at the American Heart Association meeting in Dallas, Texas, November 1981. Requests for reprints should be addressed to Dr. David Rob- ertson, Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232. Manu- script accepted April 26, 1982. The hemodynamic effects of clonidine were studied in four patients with severe idiopathic orthostatic hypotenskn and one patient with baroreceptor dysfunction. No depressor response to clonidine was observed in any patient with idiopathic orthostatic hypotension at any dosage. Rather, two patients responded to 0.4 mg of oral clo- nidine with a 40 mm Hg increment in systolic bkod pressure lasting several hours. Each has been receiving cknktine, 0.4 mg twke daily, for one year with greatly increased functional capacity. The other two patients with idiopathic orthostatic hypotension had an even greater pressor response to 0.8 mg of oral clonidine, but adverse effects prevented continued therapeutk use. In marked contrast, the patient with baroreceptor dysfunction had a profound depressor response to 0.2 mg of clonidine. In the treatment of idiopathic or- thostatk hypotenskn, the major advantage of clonidlne over other pressor agents is its longer duration of action. The major adverse effects of the drug in these patients are sedation, dry mouth, altered mentatkn, and excessive hypertension. The drug should not be given to patients with mild idkpathic orthostatk hypotenslon or selective baroreceptor dysfunction, since severe hypotension may result. Chronic autonomic insufficiency includes several clinical syndromes of unknown cause that are characterized by orthostatic hypotension, impotence, and reduced sweating [ 11. In some patients, these ab- normalities are accompanied by extrapyramidal symptoms, cerebellar dysfunction, or other neurologic abnormalities (Shy-Drager syndrome), whereas in others, the autonomic dysfunction appears to be an isolated phenomenon (idiopathic orthostatic hypotension). Still other patients appear to have selective baroreceptor dysfunction with otherwise intact sympathetic function. The major disability in most patients with these disorders is severe orthostatic hypotension. This hypotension can be so severe that the person is able to stand for only 15 to 30 seconds before passing out. Occasional patients are unable to rise from the supine position at all. Treatment of this debilitating syndrome has been inadequate. This is attested to by the great variety of therapeutic modalities that have been proposed over the years to ameliorate the symptomatic ortho- static hypotension. A partial list of such modalities includes maneuvers to increase blood volume [2,3], sympathomimetic amines [4,5], vasoconstrictors [ 61, beta blockers [ 71, prostaglandin synthesis in- hibitors [ 8,9], antihistamines [ lo], and antiserotonergics [ 111. Although these therapeutic maneuvers have helped occasional patients, severely affected persons are seldom significantly benefited. The essential problem in tailoring therapy for patients with chronic February 1983 The American Journal of Medicine Volume 74 193

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Page 1: Clonidine raises blood pressure in severe idiopathic orthostatic hypotension

Clonidine Raises Blood Pressure in

Severe Idiopathic Orthostatic Hypotension

DAVID ROBERTSON, M.D.

MICHAEL R. GOLDBERG, M.D., Ph.D.

ALAN S. HOLLISTER, M.D., Ph.D.

DAWN WADE, R. N.

ROSE MARIE ROBERTSON, M. D.

Nashville, Tennessee

From the Departments of Medicine and Pharma- cology, Vanderbilt University, Nashville, Ten- nessee. This study was supported in part by USPHS Grant GM 15431 and by the Hrafn Sve- inbjarnarson Foundation. D. Robertson is a Teaching and Research Scholar of the American College of Physicians. R. M. Robertson is an Es- tablished Investigator of the American Heart As- sociation. Dr. Goldberg is Clinical Associate Physician, Elliot V. Newman Clinical Research Center. Dr. Hollister is a Burroughs-Wellcome Fellow. This material was presented in abstract form at the American Heart Association meeting in Dallas, Texas, November 1981. Requests for reprints should be addressed to Dr. David Rob- ertson, Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232. Manu- script accepted April 26, 1982.

The hemodynamic effects of clonidine were studied in four patients with severe idiopathic orthostatic hypotenskn and one patient with baroreceptor dysfunction. No depressor response to clonidine was observed in any patient with idiopathic orthostatic hypotension at any dosage. Rather, two patients responded to 0.4 mg of oral clo- nidine with a 40 mm Hg increment in systolic bkod pressure lasting several hours. Each has been receiving cknktine, 0.4 mg twke daily, for one year with greatly increased functional capacity. The other two patients with idiopathic orthostatic hypotension had an even greater pressor response to 0.8 mg of oral clonidine, but adverse effects prevented continued therapeutk use. In marked contrast, the patient with baroreceptor dysfunction had a profound depressor response to 0.2 mg of clonidine. In the treatment of idiopathic or- thostatk hypotenskn, the major advantage of clonidlne over other pressor agents is its longer duration of action. The major adverse effects of the drug in these patients are sedation, dry mouth, altered mentatkn, and excessive hypertension. The drug should not be given to patients with mild idkpathic orthostatk hypotenslon or selective baroreceptor dysfunction, since severe hypotension may result.

Chronic autonomic insufficiency includes several clinical syndromes of unknown cause that are characterized by orthostatic hypotension, impotence, and reduced sweating [ 11. In some patients, these ab- normalities are accompanied by extrapyramidal symptoms, cerebellar dysfunction, or other neurologic abnormalities (Shy-Drager syndrome), whereas in others, the autonomic dysfunction appears to be an isolated phenomenon (idiopathic orthostatic hypotension). Still other patients appear to have selective baroreceptor dysfunction with otherwise intact sympathetic function. The major disability in most patients with these disorders is severe orthostatic hypotension. This hypotension can be so severe that the person is able to stand for only 15 to 30 seconds before passing out. Occasional patients are unable to rise from the supine position at all.

Treatment of this debilitating syndrome has been inadequate. This is attested to by the great variety of therapeutic modalities that have been proposed over the years to ameliorate the symptomatic ortho- static hypotension. A partial list of such modalities includes maneuvers to increase blood volume [2,3], sympathomimetic amines [4,5], vasoconstrictors [ 61, beta blockers [ 71, prostaglandin synthesis in- hibitors [ 8,9], antihistamines [ lo], and antiserotonergics [ 111.

Although these therapeutic maneuvers have helped occasional patients, severely affected persons are seldom significantly benefited. The essential problem in tailoring therapy for patients with chronic

February 1983 The American Journal of Medicine Volume 74 193

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CLONIDINE FOR ORTHOSTATIC HYPOTENSION-ROBERTSON ET AL

autonomic dysfunction lies in the peculiar nature of their cardiovascular hemodynamics. Most severely affected patients have a raised peripheral vascular resistance in both supine and upright postures [ 121, although the mechanism of this remains unknown. This hinders maintenance of adequate cardiac output; however, the lack of tone in the venous capacitance bed is probably an even more consequential abnormality. Thus, in most patients with autonomic dysfunction, the fundamental problem is failure of venoconstriction in the capacitance bed when the patient is in an upright posture and the associated inadequate blood return to the right heart. An agent that would increase tone in the venous ca- pacitance bed without increasing resistance in the ar- teriolar circuit would offer significant advantages in the management of this disorder. In this regard, dihydro- ergotamine has been reported to have a relatively greater effect on capacitance vessels than on arteriolar resistance [ 6,13,14], but experience with this agent has not been uniformly favorable in patients with the most severe form of autonomic dysfunction. An alternate approach to therapy of autonomic dysfunction would be to stimulate preferentially the alpha adrenoreceptors in the venous capacitance bed.

On the basis of animal studies, it has been proposed that postjunctional alpha* receptors may predominate in veins as compared with arteries [ 151. If this were true in man, then an agonist highly selective for the alphap receptor might significantly reduce venous capacitance white increasing arteriolar resistance only modestly. In the past 10 years, several agents that have various degrees of selectivity for alpha* receptors have been introduced into clinical medicine. In many systems, clonidine is a relatively selective partial agonist for the alpha* receptor. It might therefore be of therapeutic value in patients with orthostatic hypotension due to autonomic dysfunction.

Accordingly, in a carefully selected group of patients with severe autonomic dysfunction of the peripheral variety [ 161 and in a patient with selective baroreceptor dysfunction, we assessed the efficacy of clonidine as a pressor agent. Employment of a widely used antihy- pertensive agent in an effort to increase blood pressure might seem paradoxic, but was considered reasonable since the drug’s antihypertensive effect is thought to be mediated through central inhibition of sympathetic outflow. In the highly selected subgroup of patients with chronic autonomic insufficiency in this study, no sig-

nificant level of sympathetic outflow was demonstrated

in the basal state, and, therefore, it was not anticipated

that clonidine could lower their blood pressure. Fur-

thermore, the postjunctional supersensitivity to pressor amines demonstrated in these patients in response to alpha, agonists such as phenylephrine [ 171 might also occur with administration of alpha2 agonists.

PATIENTS AND METHODS

Patients. We studied four patients (two men, two women) with idiopathic orthostatic hypotension. According to the criteria of Ziegler et al [ 161, these patients had defects of the peripheral variety. Each had circulating plasma norepi- nephrine levels below 50 pg/ml in both the supine and upright postures. They ranged in age from 62 to 74 years. None had extrapyramidal symptoms or cerebellar dysfunction. They had had symptoms of syncope for periods ranging from one to 11 years. The patients otherwise had been in excellent health, although one had had a stroke in the distribution of the right middle cerebral artery five years before admission with nearly complete subsequent resolution. The severity of the autonomic dysfunction in these patients is attested to by their inability to maintain upright posture longer than 60 seconds in the untreated state. In each case, standard therapy (flu- drocortisone, indomethacin, propranolol, etc) either had been ineffective or had been associated with unacceptable adverse effects. At the time of study, all patients had been free of medication for at least two weeks.

The patient with baroreceptor dysfunction was a 78- year-old woman who had received irradiation (4,500 rads) to the neck after excision of a lymphorna localized to the thyroid gland (three years before admission). She had orthostatic symptoms for one year before our study. When she was standing, her blood pressure fell from 190/100 to 80150 mm Hg without change in heart rate. She was able to stand longer than the patients with idiopathic orthostatic hypotension and, although she had had an episode of syncope one year before admission, had relatively milder symptoms. Her plasma and urinary norepinephrine levels were low (134 pg/ml plasma, 14 pg per 24 hours urine), but were not as low as in the pa- tients with idiopathic orthostatic hypotension. She had modest (8 to 15 torr) increases in blood pressure in response to cold pressor, handgrip, and psychic stress tests. During Valsalva’s maneuver, she had a fixed heart rate and no pressure over- shoot. She had increased sensitivity to pressor effects of phenylephrine and depressor effects of isoproterenol, without reflex-induced changes in heart rate in response to either agent.

Methods. The following studies were carried out: (1) as- sessment of plasma and urinary catecholamines levels; (2) assessment of responsiveness to intravenous injection of phenylephrine, tyramine, isoproterenol, atropine, and pro- pranolol; (3) physiologic tests (isometric exercise, cold pressor test, mental arithmetic, and food ingestion); and (4) oral dose-ranging therapeutic trials of clonidine at 0.1 mg, 0.2 mg, 0.4 mg, and 0.8 mg, each dose administered at 9 AM

on the day of the study with the patient in the seated posture. During the trial, the patient remained seated and automated sphygmomanometric blood pressure determinations (Dina- map) were made every five minutes. When a sustained pressor response was obtained, the patient was asked to stand motionless for as long as could be tolerated to assess improvement in functional capacity. The drug was given after an overnight fast during which the patient had remained in the supine posture. Only one dose was given on any single day. Two patients did not receive the 0.8 mg dose of clonidine because of an adequate pressor response to the 0.4 mg dose.

194 February 1993 The American Journal of Medicine Volume 74

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CLONIOINE FOR ORTHOSTATIC HYPOTENSION-ROBERTSON ET AL

TABLE I

Subjects

Plasma and Urinary Noreplnephrlne Levels

Plasma NoreplwPhrine Urinary Norqinepbrins

(pg/W (~~24 ft0t

TABLE II Pharmacologic Testing

W=ts P&s MY Is025 (d TYR25 hi)*

Normal (n = 8) 225 f 20 2.8 f 0.6 2.8 f 0.4

Normal (n = 8) 368 f 24 41 f 16 IOH 1 27 5 IOH 2 42 5 IOH 3 34 9 IOH 4 34 7 BD 134 14

l Reported in patients in the supine position. t Determinations made in hospitalized subjects. BD= baroreceptor dysfunction: IOH = idiopathic orthostatic hy- potension. Difference between patients and normal subjects is significant (p <O.Ol).

All patients received a diet containing approximately 150 rneq of sodium during the inpatient study.

RESULTS

Catecholamines. Supine plasma norepinephrine levels were extremely low in the four patients with id- iopathic orthostatic hypotension (Table I). For com- parison, the values for plasma catecholamines in a group of normal subjects of the same age in the supine posture are given. The norepinephrine levels in the four patients with autonomic insufficiency were only about 10 percent of the levels in the age-matched normal subjects. The plasma levels of epinephrine and dopa- mine were also reduced in the patients with idiopathic orthostatic hypotension. However, since the plasma levels of epinephrine and dopamine are near the limits of sensitivity of the radioenzymatic assay in plasma, this differential could not be quantitated as well as that of norepinephrine.

The 24-hour urinary catecholamine measurements show a similar general pattern. Urinary norepinephrine was approximately 20 percent of normal levels in the subjects with autonomic dysfunction, urinary epi- nephrine was approximately 20 percent of normal, and urinary dopamine was approximately 50 percent of normal. Thus, normal subjects have urinary epinephrine and dopamine levels of 13.4 f 2.3 pg per 24 hours and 26 1 pg per 24 hours, respectively; the corresponding values for the patients with idiopathic orthostatic hy- potension were 3.7 f 1 .O pg per 24 hours and 105 pg per 24 hours. The patient with baroreceptor dysfunction had intermediate levels of plasma and urinary cate- cholamines (Table I). Pharmacologic Testing. As can be seen in Table II and Flgure 1, all subjects had a greatly enhanced pressor responsiveness to small boluses (10 to 100 pg) of in- travenous phenylephrine. They were six times as sen- sitive, on the average, as normal subjects. There was a four-fold increase in sensitivity to the chronotropic effect of isoproterenol(O.1 to 5 pg) and an even greater

IOH(n = 4) 34 f a 0.8 f 0.1 4.9 f 1.0 BD(n = 1) 40 - 3.5

l PHE25 = the intravenous bolus dose of phenylephrine (in micro- grams) required to raise diastolic pressure by 25 mm Hg. t IBO25 = the intravenous bolus dose of isoproterenol (in micro-

9 rams) required to increase heart rate by 25 beats per minute. TYRz5 = the intravenous bolus dose of tyramine (in milligrams)

required to raise diastolic pressure by 25 mm Hg. BD = patients with baroreceptor dysfunction; IOH = patients with idiopathic orthostatic hypotension. Patients with idiopathic ortho- static hypotension and normal subjects are significantly different in terms of all three parameters (p CO.05).

response to the depressor effect of the drug. The patient with baroreceptor dysfunction had marked depressor response to low doses of isoproterenol (for example, 0.4 pg reduced her blood pressure from 213188 to 153/55 mm Hg and her heart rate increased from 75 to 80 beats per minute). We did not proceed to determine the intravenous dose of isoproterenol required to in- crease the heart rate by 25 beats per minute. We chose not to complete the isoproterenol test because the patient had occasional atrial premature contractions during early portions of the study and because she had had a myocardial infarction after an episode of pulmo- nary edema two months before the study. The episode of pulmonary edema occurred during therapy of her orthostatic hypotension with fludrocortisone.

The response to tyramine in the subjects was sub- normal (Table II). The dose of tyramine required to raise blood pressure 25 mm Hg was almost twice as high in the patients as in normal subjects. This subnormal re- sponse is even more impressive in patients in whom phenylephrine and isoproterenol tests demonstrated great hypersensitivity to directly acting sympathomi- metic amines. Tyramine responsiveness was nearer normal in the patient with baroreceptor dysfunction.

Propranolol was administered intravenously at a rate of 1.1 mg per minute for nine minutes, followed by a constant infusion of 0.055 mg per minute over the succeeding 21 minutes. The patients generally had little response to propranolol; one patient’s heart rate was lowered by 5 beats per minute. In other subjects, the effect was less marked. The pressor effect of pro- pranolol seen by other investigators in chronic auto- nomic insufficiency [7] was minimal or absent in these four patients while they were in the supine position. Propranolol was not given to the patient with barore- ceptor dysfunction.

In response to the administration of atropine, 0.04 mg/kg intravenously, the increase in heart rate was quite limited: only 8 beats per minute. The comparable response in normal subjects is usually an increase of

February 1993 The American Journal of Medicine Volume 74 195

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CLONIDINE FOR ORTHOSTATIC HYPCTENSION-ROBERTSON ET AL

PheZS 200

100

AMAP

+60 1

-20 CLONIOINE (mg)

CLONlgl;E (mg)

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lgure 7. A, dose of phenylephrine (pg) that raises b/o

u cd

pressure 25 torr (ms) in normal control subjects (C), in four patients with idiopathic orthostatic hypotension (/OH), and in one patient with baroreceptor dysfunction (BD). 6, changes in sitting mean arterial blood pressure (MAP) of patients with idiopathic otthostatic hyootension (IOH) and with baroreceptor dystMction (So) in response to oral clonidine at the indicated doses (in milligrams). All four patients with idiopathic ortho- static hypotension received doses of 0. I, 0.2, and 0.4 mg; only two patients received 0.8 mg.

at least 30 beats per minute. This would suggest that the patients with autonomic dysfunction in this study had significant impairment of parasympathetic as well as sympathetic nervous system function. Atropine was not given to the patient with baroreceptor dysfunction. Physiologic Testing. None of the patients with idio- pathic orthostatic hypotension responded to standard physiologic tests [ 181, including mental arithmetic, the cold pressor test, or isometric handgrip exercise, either in terms of increased heart rate or increased blood pressure. This suggests impairment not only of the sympathetic adrenergic system and the parasympa- thetic cholinergic system, but also of the sympathetic cholinergic vasodilator fibers that are activated in certain patients with autonomic insufficiency [ 191. In contrast, the patient with baroreceptor dysfunction did have an increase in blood pressure with mental arith- metic, isometric handgrip, and the cold pressor test (Table III). None of the patients, including the patient with baroreceptor dysfunction, had a lowered heart rate in response to phenylephrine administration. The re-

TABLE Ill Cold Presser Test

Mean Blood Pressure Change Subjects (mm W’

Normal (n = 9) +24f7 Idiopathic orthostatic hypotension -2f4

(n = 4) Baroreceptor dysfunction (n = 1) t11

l Change in mean blood pressure in response to the placement of the right hand in a bath of half ice and half water for one minute.

sponse to food ingestion in all these patients was quite marked. A mean decline of 32 mm Hg (range 22 to 48) in the supine blood pressure occurred within minutes after consumption of a standard meal [20]. This was not, however, attended by an increase in heart rate. In normal subjects, the supine blood pressure decreases less than 10 mm Hg after food ingestion.

Clonidlne Testing. The seated posture was selected for the clonidine trials because the subjects were hy- pertensive in the supine posture (mean blood pressure 21 l/l04 mm Hg), and the additional pressor stimulus of the sympathomimetic agent could have raised pressure to dangerous levels.

The results of the short-term clonidine therapeutic trial are shown in Figures 1 and 2. The oral adminis- tration of the 0.1 mg dose of clonidine did not increase blood pressure as much as 10 mm Hg in any subject with idiopathic orthostatic hypotension. However, the administration of 0.2 mg of clonidine did cause a modest pressor effect in the four patients with idiopathic or- thostatic hypotension. The onset of this pressor effect was 60 minutes after oral ingestion in patients with an empty stomach, and its duration was 180 minutes.

The administration of 0.4 mg of clonidine raised blood pressure 18 to 24 mm Hg (Figure 2). The pressor re- sponse after this dose began at about 60 minutes and was maintained for a period of at least six hours. In the two subjects who had the smaller responses to the 0.4 mg dose, a subsequent 0.8 mg dose was administered using the same protocol (Figure 2). Both patients had marked elevations in blood pressure. In one patient, the peak elevation in systolic pressure in the seated posture was 50 mm Hg; in the other patient, it was 80 mm Hg. At the highest dose of drug, all patients were able to stand for significantly longer periods of time than before therapy (Table IV).

The two patients who responded to the 0.4 mg dose with increases in blood pressure of 40 mm Hg also had dry mouth and mild sedation, adverse effects similar to those in hypertensive patients. The two patients who received the 0.8 mg dose of the drug also had dry mouth and sedation. The sedation was quite marked in one subject who dozed off several times in the course of the

196 February 1963 The American Journal of Medicine Volume 74

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CLONIDINE FOR ORTHOSTATIC HYPOTENSION-ROBERTSON ET AL

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Qure 2. Cardiovascular effects of oral clonidine. Lefl, the upper panel depicts the blood pressure and heart rate response to clonidine, 0.4 mg orally, in Patient 1. The lower panel depicts these variables in Patient 2. Right, the upper panel depicts the blood pressure and heart rate response to clonidine 0.8 mg orally in Patient 3. The lower panel depicts these variables in Patient 4. Closed circles = systolic and diastolic blood pressure: open circles = heart rate.

TABLE IV Clonidine in Severe ldlopathlc Orthostatic Hypoteneion

Patient Ase, Sex Clonidlns Dose StandIng Time’ (Control) Standlq Time’ (Clonldtne)

1 62, F 0.4 mg 60 seconds > 15 minutes 2 66, M 0.4 mg 60 seconds > 15 minutes 3 74. M 0.8 mg 20 seconds 120 seconds 4 69. F 0.8 mg 30 seconds 600seconds

l Period the patient can remain motionless in the upright posture before the onset of herald symptom (see text). A standing time greater than 15 minutes usually implies normal otthostatic functional capacity. Each patient showed marked benefit at all times tested. Patients 1 and 2 were not given the 0.8 mg oral dose.

February 1983 The Amerkan Journal of Medkine Volume 74 197

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CLONIDINE FOR ORTHOSTATIC HYPOTENSION_ROSERTSON ET AL

study, but who could be aroused by conversation. In addition, both patients noted some degree of transiently altered perception during the time of peak pressor ef- fect. These sensations were described as “mildly un- comfortable” in one case and “not unpleasant” in the other.

The two patients in whom adverse effects were mildest after clonidine administration were given the drug on a long-term protocol. Because of its six-hour duration of action, the drug was administered in a 0.4 mg dose with breakfast and a 0.4 mg dose with lunch. Because these patients had hypertension when in the supine position, no dose was given at supper. These patients have been followed up for a period of one year and have had great improvement in their functional capacity. During long-term clonidine therapy in these persons, supine blood pressures were 1621104 and 185198 mm Hg and respective standing pressures were 98168 and 115/79 mm Hg; before therapy, the re- spective supine pressures had been 152190 and 170198 mm Hg with standing pressures of less than 60/O and less than 60/O mm Hg, respectively. The adverse ef- fects of sedation and dry mouth diminished over time and are no longer present. No tachyphylaxis has ap- peared.

The patient with baroreceptor dysfunction had a marked depressor response to 0.2 mg of clonidine. Within 30 minutes of drug administration, her blood pressure in the seated position had fallen from 175180 to 65/32 mm Hg with a fall in heart rate from 78 to 72 beats per minute. She had considerable sedation as well. Blood pressure rose to 105/50 after placement in the head-down position and returned to 180/90 over the next four to five hours, and the sedation disap- peared. Clonidine was not further studied in this pa- tient.

COMMENTS

Our results demonstrate that clonidine is an effective pressor agent in selected patients with severe idiopathic orthostatic hypotension. Since our subjects had ex- tremely low supine plasma catecholamine levels and markedly diminished sensitivity to tyramine, they may be classified as having orthostatic hypotension of the peripheral variety [ 161. These patients had no auto- nomic pressor reflexes and were exquisitely sensitive to directly acting sympathomimetic agents. On the basis of these latter observations, we assumed that our subjects would not have a depressor response to clo- nidine since they had no functioning sympathetic out- flow to be inhibited by the drug. Furthermore, since clonidine is an alpha agonist [21], its direct pressor activity might be exaggerated in intensity in super- sensitive persons. Since clonidine has a relatively long plasma half-life [22], it could provide a more sustained

response than shorter-acting agents such as phenyl- ephrine. These assumptions were apparently correct; clonidine was of great value in two of our four patients for at least one year. In the other two patients, central side effects precluded long-term therapy.

Clonidine is a selective partial agonist at alpha* re- ceptors in a variety of sites [23]. Pharmacologic and radioligand binding studies suggest that clonidine is lOO- to l,OOO-fold more potent at alpha2 than at alpha, re- ceptors [24,25]. In regard to this latter finding, animal studies have demonstrated that postjunctional alpha* receptors mediate vasoconstriction in a variety of species and that these receptors play a role in the pressor response to exogenously administered cate- cholamines, for example, norepinephrine [26,27]. There has also been a suggestion that alpha* receptors are predominantly located in the venous capacitance bed and are preferentially stimulated by circulating catecholamines [ 151. Postjunctional alpha* receptors have not yet been rigorously demonstrated in normal humans. However, since clonidine is relatively selective for these receptors in many systems [26], the present study could be a dramatic demonstration in man of postjunctional alpha;, receptor stimulation after orally administered drug. This is consistent with the view that alpha:! receptors on vascular smooth muscle contribute to the maintenance of blood pressure and cardiac out- put. Confirmation of this proposal will require demon- stration of selective antagonism of pressor responses to catecholamines and clonidine by alpha*-blocking drugs (for example, yohimbine). The results of the present study do not rule out stimulation of postjunc- tional alpha, receptors as the mechanism of the pressor effect of clonidine observed.

Clonidine has certain advantages over the other commonly used drug that acts on the alpha:, receptor. Alpha-methyldopa’s effects depend on its transport into, metabolism by, and release from adrenergic terminals as alpha-methylnorepinephrine or alpha-methylepine- phrine [28]. These metabolites may be pressor under special conditions [29]. Since our patients do not ap- pear to have functioning peripheral adrenergic termi- nals, it is unlikely that they would have the capacity to synthesize or release active sympathomimetic me- tabolites from methyldopa.

The improvement in standing time following clonidine (Table IV) deserves special comment. This determi- nation is made with the patient motionless and in the upright posture. For each patient, the herald symptom of impending loss of consciousness (usually dimming of vision) is identified and he stands until the onset of that symptom. We have found this to be a more reliable and reproducible index of disease severity and func- tional capacity than upright blood pressure, and more useful in monitoring the course of autonomic dysfunc-

198 February 1983 The American Journal of Medlclne Volume 74

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CLONIDINE FOR ORTHOSTATIC HYPOTENSION-ROBERTSON ET AL

tion. Furthermore, because of the efficiency of the muscular pump in aiding blood return to the right heart, standing time greatly underestimates “walking time.” Thus, the apparently modest increase in standing time from 20 seconds to two minutes in the third patient would actually translate into marked improvement in functional capacity. A standing time of 15 minutes usually implies near normal orthostatic functional ca- pacity.

In conclusion, clonidine appears to be an effective, long-acting pressor agent for the treatment of selected patients with autonomic insufficiency of the peripheral variety and with severe orthostatic hypotension. We have not investigated the use of clonidine in patients with Shy-Drager syndrome or the autonomic dysfunction of Parkinsonism, but would assume that their response would be less favorable because of their reduced pressor hypersensitivity [30]. We would also expect less favorable results in patients whose idiopathic or- thostatic hypotension is characterized by a degree of residual sympathetic function. The markedly hypoten- sive response to clonidine in the patient with barore- ceptor dysfunction is a major drawback to the thera- peutic use of clonidine, because clinically idiopathic orthostatic hypotension and baroreceptor dysfunction are only subtly distinguished and the latter may in fact be a forme fruste of the former.

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4.

5.

6.

7.

8.

9.

10.

Ziegler MG: Postural hypotension. Annu Rev Med 1980; 31: 239-245.

Chobanfan AV. Volicer L, Tifft CP, Gavras H, Liang C-S, Faxon D: Mineralocorticoidinduced hypertension in patients with orthostatic hypotension. N Engl J Med 1979; 301: 68- 73.

Bannister R, Ardill L. Fentem P: An assessment of various methods of treatment of idiopathic orthostatic hypotension. Q J Med 1969; 38: 377-395.

Barnett AJ: Idiopathic orthostatic hypotension: a pharmaco- logical study of the action of sympathomimetic drugs. Med J Aust 1968; 1: 212-216.

Diamond MA, Murray RH, Schmid PG: Idiopathic postural hy- potension: physiologic observations and report of a new mode of therapy. J Clin Invest 1970; 49: 1341-1348.

Nordenfelt I, Mellander S: Central hemodynamic effects of dihydroergotamine in patients with orthostatic hypotension. Acta Med Stand 1972; 191: 115-120.

Chobanian AV. Volicer L, Liang CS, Kershaw G. Tifft C: Use of propranolol in the treatment of idiopathic orthostatic hypotension. Trans Assoc Am Physicians 1977; 90: 324-334.

Kochar MS, ltskovitz HD: Treatment of idiopathic orthostatic hypotension (Shy-Drager syndrome) with indomethacin. Lancet 1978; I: 101 l-1014.

Crook JE, Robertson D, Whorton AR: Prostaglandin sup- pression: Inability to correct severe idiopathic orthostatic hypotension. South Med J 1981; 73: 318-320.

Stacpoole P, Robertson D: Combination Hr and H2 receptor antagonist therapy in diabetic autonomic neuropathy. South Med J, 1982; 75: 634-635.

When used for idiopathic orthostatic hypotension, clonidine appears to have some of the same adverse effects as when it is used to treat hypertension. Para- doxically, an additional limiting adverse effect of clo- nidine in these persons is marked hypertension or aggravation of preexisting supine hypertension. This limitation applies to other therapeutic modalities as well; in the case of fludrocortisone, the risk is probably even greater since its long biologic half-life carries the full pressor effect of that drug into the sleeping period, whereas clonidine’s effect can be tailored to wear off before bedtime.

Initial trials of clonidine in these patients should therefore be made under controlled conditions (that is, in the hospital) and dosage timing should be adjusted so that maximal hypertensive effects occur at times of greatest need and not at times when these subjects are exposed to the risks of supine hypertension (for in- stance, at bedtime).

Successful use of pressor agents in cases of idio- pathic orthostatic hypotension requires considerable intelligence and cooperation on the part of the patient. At the time of peak pressor effect, the patient’s as- sumption of supine posture or head-down tilt leads to profound hypertension with all the attendant risk of stroke. The risk-benefit ratio of such therapy must be judged on an individual basis and rigorously applied.

REFERENCES

11. Mahoudeau D, Singer B, Gilbert JC, Goulon M, Gajados P: A propos d’un cas de maladie de Shy et Drager: etudes hemodynamiques et pharmacodynamiques: interet de la cyproheptadine. Rev Neurol (Paris) 1971; 126: 402-414.

12. Magrini F. lbrahim MM, Tarazi RC: Abnormalities of supine hemodynamics in idiopathic orthostatic hypotension. Cardiology 1976; 61 (suppl 1): 125-135.

13. Bevegard S, Castenfors J, Lindblad L-E: Effekten av dihydro- ergotamin (Orstanorme) pa central och perifer cirkulation vid postural hypotension. Forskning Och Praktik 1974; 6: 99-101.

14. Bevegard S, Castenfors J, Lindblad L-E: Circulatory effects of dihydroergotamine in patients with disturbed sympathetic vasomotor control with special reference to postural hy- potension. Cardiology 1976; 61 (suppl 1): 322-332.

15. DeMey JG, Vanhoutte PM: Differences in pharmacological properties of postjunctional a-adrenergic receptors among arteries and veins. Arch Int Pharmacodyn Ther 1980; 244: 328-329.

16. Ziegler MG, Lake CR, Kopin IJ: The sympathetic-nervous- system defect in primary orthostatic hypotension. N Engl J Med 1977; 296: 293-297.

17. Robertson D: Idiopathic orthostatic hypotension: contraindi- cation to the use of ocular phenylephrine. Am J Ophthalmol 1979; 87: 819-822.

18. Robertson D: Clinical assessment of autonomic nervous system function. In: Baughman KL, Greene BM, eds. Clinical Diagnostic Manual for the House Officer, Chapt 5. Balti- more: Williams & Wilkins, 1981; 86-101.

19. Abboud FM, Eckstein JW: Active reflex vasodilatation in man. Fed Proc 1966; 25: 1611-1619.

February 1983 The American Journal of Medicine Volume 74 199

Page 8: Clonidine raises blood pressure in severe idiopathic orthostatic hypotension

CLONIDINE FOR ORTHOSTATIC HYPOTENSION-ROBERTSON ET AL

20. Robertson D, Wade D, Robertson RM: Postprandial alterations in cardiovascular hemodynamics in autonomic dysfunc- tional states. Am J Cardiol 1981; 48: 1048-1052.

21. Kobinger W: Central a-adrenergic systems as targets for hypotensive drugs. Rev Physiol Biochem Pharmacol 1978; 81: 39-100.

22. Wing LMH, Reid JL, Davies DS, Neil1 EHM, Tippett P, Dollery CT: Pharmacokinetic and concentration-effect relationships of clonidine in essential hypertension. Eur J Clin Pharmacol 1977; 12: 483-469.

23. Medgett IL, McCulloch MW, Rand MJ: Partial agonist action of clonidine on prejunctional and postjunctional cu-adre- noreceptors. Naunyn Schmiedebergs Arch Pharmacol 1978; 304: 2150-2221.

24. Starke K, Monte1 H, Gayk W, Merker R: Comparison of the effects of clonidine on pm- and postsynaptic adrenore- ceptors in the rabbit pulmonary artery. Naunyn Schmiedebergs Arch Pharmacol 1974; 285: 133- 150.

25. UPrichard DC, Greenberg DA, Snyder SH: Binding charac- teristics of a radiolabeled agonist and antagonist at central

nervous system alpha noradrenergic receptors. Mel Pharmacol 1977; 13: 454-473.

26. Constantine JW, Gunnell D, Weeks RA: (Y, and cus-Vascular adrenoceptors in the dog. Eur J Pharmacol 1980; 66: 281-286.

27. Doherty JR, McGrath JC: A comparison of pre- and post- junctional potencies of several alpha-adrenoceptor agonists in the cardiovascular system and anococcygeus muscle of the rat. Naunyn Schmiedebergs Arch Pharmacol 1980; 312: 107-116.

28. Goldberg MR. Gerkens JF, Oates JA, Robertson D: o!- Methylepinephrine, a methyldopa metabolite that binds to a-receptors in rat brain. Eur J Pharmacol 1981; 89: 95- 99.

29. Nies AS, Shand DG. Hypertensive response to propranolol in a patient treated with methyldopa-a proposed mech- anism. Clin Pharmacol Ther 1972; 14: 823-826.

30. Polinsky RJ, Kopin IJ, Ebert MH, Weise V: Pharmacologic distinction of different orthostatic hypotension syndromes. Neurology 1981; 31: l-7.

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