Clonidine and the vasodilating beta blocker antihypertensive drug interaction Because propranolol is contraindicated in some patients and since clonidine can decrease heart rate and renin release, clonidine was substituted for propranolol in /4 severely hypertensive minoxidil-treated outpatients. Clonidine induced weight loss which, since plasma concentrations were not suppressed, was not due to inhibition of release of antidiuretic hormone or renin. These endocrine interrelations were confirmed by later administration of clonidine to 4 of the subjects under controlled circumstances in our General Clinical Research Center. When substituted for propranolol, clonidine controlled blood pressure and heart rate in 8 of the 9 outpatients whose blood pressure had been previously weil controlled. Clonidine and propranolol had additive antihypertensive effects in the other 5 patients . Thus, clonidine can substitute for propranolol or when added to the propranolol-vasodilator combination supply an additional blood pressure-lowering effect. This substitution or addition results in an increase in side effects. In addition, clonidine has a diuretic action under these circumstances byan unknown mechanism .
William A. Pettinger, M.D.,* Helen C. MitcheII, M.D., and Hans-Georg Güllner, M.D. Dallas , Texas The University of Texas Southwestern Medical School, Departments of Phannacology and Internal Medicine, Division of Clinical Pharmacology
The combination of vasodilating drugs with beta adrenergic receptor blocking drugs controls high blood pressure in most severely hypertensive subjects, with relatively few disabling side effects,": 7, 8, 15, 25, 26 but some patients cannot use propranolol because of bronchial asthma, cardiac enlargement and failure, Support was provided by grants from the Texas Heart Association and National Institutes of Health Grant No. 06-0-000076-0. Received for publication Sept. 27, 1976. Accepted for publication April I, 1977. Reprint requcsts to: William A. Pettinger. M.D., Division of Clinical Pharmacology, University of Texas Southwestem Medical School, 5323 Harry Hines Blvd., Dallas, Texas 75235. *Burroughs-Wellcome Scholar in Clinical Pharmacology.
164
bradycardia, drug eruption, nightmares, and other sleep disturbances. Clonidine and propranolol have similar hemodynamic and endocrine effects which are mediated by entirely different receptor mechanisms. We therefore substituted clonidine for propranolol in 14 minoxidil-treated subjects. An anticipated diuretic action of clonidine was evaluated by assessment of two major sodium and water control mechanisms in plasma, antidiuretic hormone and the renin-aldosterone axis, on an out-patient basis. Four subjects were later admitted to our Clinical Research Center for readministration of the clonidine under closer and
Clonidine and vasodilators
Volume 22 Number 2
165
Table I. Clinical characteristics and drug dosages of individual patients prior to and during this study Initial drug
regimens
Final drug regimen (mg/day)
MI-PR therapyt (mo)
Average BPt
Serum creatinine (mg%)
49/F/EH
22
130/86
2.8
20
160
45/M/EH 33/M/EH
38 6
137/84 215/143
2.1 2.5
20 40
4 5 6 7 8 9 10 11
40/F/EH(MP) 48/M/EH 45/M/NEPH 42/M/EH 48/F/EH(MP) 45/M/EH 30/M/NEPH 45/F/EH
6 37 11 17 20 12 9 9
135/92 146/94 150/100 163/108 165/87 158/103 141/110 130/88
5.0 4.3 8.5 2.5 2.1 3.9 4.4 3.6
20 40 40 40 40 40 40 20
12 13 14
54/M/EH 60/M/RVH 41/M/EH
35 28 30
126/78 149/87 146/93
1.6
40 40 40
160 20 0.6 0 160 40 0 160 Abdominal pain on clonidine 160 20 0.3 0 160 40 0.6 0 100 40 0 100 Obtunded on clonidine 160 40 0.8 160 160 40 I 0 160 40 0.8 320 160 40 0.4 160 160 20 0 160 Nausea and vomiting on clonidine 40 40 0.4 0 160 40 0.7 0 160 40 0.4 0
Case No.
2 3
Age/sex diagnosis*
1.1
1.1
(mg/day) MI
I PR
MI
ICL I PR
20 0.8 0
Side effects
Allergie skin reaetion to propranolol
MI: minoxidil; CL: clonidine; PR: propranoloI. *EH: essential hypertension; MP: malignant phase; NEPH: nephritis; RVH: renovascular hypertension. [Prior to clonidine.
better controlled hemodynamic and endoerine monitoring. Methods
Adult hypertensive patients were initially selected for minoxidil-propranolol therapy if diastolic blood press ure persisted above 100 mm Hg during administration in the hospital of optimal doses of standard antihypertensive drugs.'" Clinieal characteristies of the 14 patients, drug dosage and months on minoxidil-propranolol prior to initiating therapy with clonidine, and drug dosage in the final regimen are summarized in Table I. The patients used the minoxidil-propranolol eombination for 6 to 38 mo under close supervision at 1- to 4-wk intervals in the Parkland HospitalOutpatient Hypertension Clinic. Supine (5 min) and standing (2 min) systolic and diastolic indirect arterial pressure and pulse rate measurements were made by an independent observer on each clinic visit throughout this period and during the studies reported here.
Blood for serum renin activity, aldosterone, and antidiuretic hormone was obtained after the patients walked 35 m and after 1 hr in the supine position. Serum renin activity was determined'"- 14 by radioimmunoassay of angiotensin I accumulated in vitro during a 2-hr incubation and is expressed as ng AI/ml/hr. Aldosterone was assayed according to the immunopurification technique of Gomez-Sanchez and associates" with modifications.' Antidiuretic hormone (ADH) was extracted from plasma and measured according to the technique of Skowsky and co-workers. 21 Plasma propranolol levels!' were monitored to determine compliance to the prescribed regimen. Clonidine, 0.4 mg to 0.6 mg, was substituted for propranolol (Table I) in the first 3 patients. In order to minimize sedation from these large initial doses, clonidine was added initially in smaller doses (0.2 mg daily) to the propranolol-rninoxidil combination in the other 11 patients. As blood pressure control was established with increasing doses of clonidine,
Pettinger. MitchelI , and Giillner
166
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William A. Pettinger, M.D.,* Helen C. MitcheII, M.D., and Hans-Georg Güllner, M.D. Dallas , Texas The University of Texas Southwestern Medical School, Departments of Phannacology and Internal Medicine, Division of Clinical Pharmacology
The combination of vasodilating drugs with beta adrenergic receptor blocking drugs controls high blood pressure in most severely hypertensive subjects, with relatively few disabling side effects,": 7, 8, 15, 25, 26 but some patients cannot use propranolol because of bronchial asthma, cardiac enlargement and failure, Support was provided by grants from the Texas Heart Association and National Institutes of Health Grant No. 06-0-000076-0. Received for publication Sept. 27, 1976. Accepted for publication April I, 1977. Reprint requcsts to: William A. Pettinger. M.D., Division of Clinical Pharmacology, University of Texas Southwestem Medical School, 5323 Harry Hines Blvd., Dallas, Texas 75235. *Burroughs-Wellcome Scholar in Clinical Pharmacology.
164
bradycardia, drug eruption, nightmares, and other sleep disturbances. Clonidine and propranolol have similar hemodynamic and endocrine effects which are mediated by entirely different receptor mechanisms. We therefore substituted clonidine for propranolol in 14 minoxidil-treated subjects. An anticipated diuretic action of clonidine was evaluated by assessment of two major sodium and water control mechanisms in plasma, antidiuretic hormone and the renin-aldosterone axis, on an out-patient basis. Four subjects were later admitted to our Clinical Research Center for readministration of the clonidine under closer and
Clonidine and vasodilators
Volume 22 Number 2
165
Table I. Clinical characteristics and drug dosages of individual patients prior to and during this study Initial drug
regimens
Final drug regimen (mg/day)
MI-PR therapyt (mo)
Average BPt
Serum creatinine (mg%)
49/F/EH
22
130/86
2.8
20
160
45/M/EH 33/M/EH
38 6
137/84 215/143
2.1 2.5
20 40
4 5 6 7 8 9 10 11
40/F/EH(MP) 48/M/EH 45/M/NEPH 42/M/EH 48/F/EH(MP) 45/M/EH 30/M/NEPH 45/F/EH
6 37 11 17 20 12 9 9
135/92 146/94 150/100 163/108 165/87 158/103 141/110 130/88
5.0 4.3 8.5 2.5 2.1 3.9 4.4 3.6
20 40 40 40 40 40 40 20
12 13 14
54/M/EH 60/M/RVH 41/M/EH
35 28 30
126/78 149/87 146/93
1.6
40 40 40
160 20 0.6 0 160 40 0 160 Abdominal pain on clonidine 160 20 0.3 0 160 40 0.6 0 100 40 0 100 Obtunded on clonidine 160 40 0.8 160 160 40 I 0 160 40 0.8 320 160 40 0.4 160 160 20 0 160 Nausea and vomiting on clonidine 40 40 0.4 0 160 40 0.7 0 160 40 0.4 0
Case No.
2 3
Age/sex diagnosis*
1.1
1.1
(mg/day) MI
I PR
MI
ICL I PR
20 0.8 0
Side effects
Allergie skin reaetion to propranolol
MI: minoxidil; CL: clonidine; PR: propranoloI. *EH: essential hypertension; MP: malignant phase; NEPH: nephritis; RVH: renovascular hypertension. [Prior to clonidine.
better controlled hemodynamic and endoerine monitoring. Methods
Adult hypertensive patients were initially selected for minoxidil-propranolol therapy if diastolic blood press ure persisted above 100 mm Hg during administration in the hospital of optimal doses of standard antihypertensive drugs.'" Clinieal characteristies of the 14 patients, drug dosage and months on minoxidil-propranolol prior to initiating therapy with clonidine, and drug dosage in the final regimen are summarized in Table I. The patients used the minoxidil-propranolol eombination for 6 to 38 mo under close supervision at 1- to 4-wk intervals in the Parkland HospitalOutpatient Hypertension Clinic. Supine (5 min) and standing (2 min) systolic and diastolic indirect arterial pressure and pulse rate measurements were made by an independent observer on each clinic visit throughout this period and during the studies reported here.
Blood for serum renin activity, aldosterone, and antidiuretic hormone was obtained after the patients walked 35 m and after 1 hr in the supine position. Serum renin activity was determined'"- 14 by radioimmunoassay of angiotensin I accumulated in vitro during a 2-hr incubation and is expressed as ng AI/ml/hr. Aldosterone was assayed according to the immunopurification technique of Gomez-Sanchez and associates" with modifications.' Antidiuretic hormone (ADH) was extracted from plasma and measured according to the technique of Skowsky and co-workers. 21 Plasma propranolol levels!' were monitored to determine compliance to the prescribed regimen. Clonidine, 0.4 mg to 0.6 mg, was substituted for propranolol (Table I) in the first 3 patients. In order to minimize sedation from these large initial doses, clonidine was added initially in smaller doses (0.2 mg daily) to the propranolol-rninoxidil combination in the other 11 patients. As blood pressure control was established with increasing doses of clonidine,
Pettinger. MitchelI , and Giillner
166
.'.
160 Sr slolic 14 0
."''. 1
Öo I
E
120
!
: ai
-,
Oioslolic 10 0
BO Bl ~a: 70
?....- BO "[
5
79
~
7B
W
~
« -
'!
~~ 3 ~ O
-
