Oral Labetalol in Hypertensive Urgencies MICHELE ZELL-KANTER,
PHARMD,*
JERROLD
The response to incremental doses of oral labetalol in 16 patients with hypertensive urgencies is presented. After inadequate blood pressure control with 20 mg of intravenous furosemide, each patient received a 300 mg oral dose of labetalol. Subsequent oral doses of labetalol, 100 mg, were administered at P-hour intervals, if the diastolic blood pressure remained greater than 100 mm Hg. The maximum dose of labetalol per patient was 500 mg. Five patients required only the initial 300 mg dose of labetalol. Two patients required further therapy for satisfactory blood pressure control. Mean arterial pressure fell from 156 +. 12 mm Hg to 123 2 14 mm Hg. (Am J Emerg led 1991;9:136-138. Copyright 6 1991 by W.9. Saunders Company)
Emergency physicians are frequently faced with the dilemma of treating patients with hypertensive urgencies. Several questions arise in the care of such patients, the primary being which patients should be treated acutely for elevated blood pressure. The second most important question is how aggressive should the treatment be to achieve a therapeutic end-point. Lastly, does oral administration satisfactorily lower blood pressure in the time frame consistent with emergency practice. The term hypertensive urgency must be fully understood so that these questions may be most appropriately answered. A hypertensive urgency may be defined as any patient who has a severe elevation in blood pressure without any evidence of end-organ damage. Ideally, the blood pressure should be reduced and controlled within 24 hours using oral antihypertensive agents.’ The therapeutic end-point should be proportional to the blood pressure elevation on presentation. Characteristics of an ideal antihypertensive medication for the care of patients with hypertensive urgencies have been described.’ These characteristics include rapid onset after oral administration, titrating ability to desired effect. will not cause excessive hypotension. have few side effects, no need for minute-to-minute monitoring, may be combined with other medications, may be administered parenterally if oral route is to be avoided, should result in lowering of blood pressure proportional to the blood pressure elevation on pre-
From the *Division of Occupational Medicine, Section of Clinical Toxicology, Cook County Hospital, the TDepat-tment of Medicine, Section of Emergency Medicine, University of Illinois at Chicago, and the TDepartment of Medicine, Rush-Presbyterian St. Luke’s Medical Center, Chicago, IL. Manuscript received March 16, 1990; revision accepted October 26, 1990. Supported by the American College of Clinical Pharmacy/ Schering Research Institute Award. Presented, in part, at the 7th Annual Meeting of the American College of Clinical Pharmacy, Chicago, IL, July 29, 1986. Address reprint requests to Dr Zell-Kanter, Division of Occupational Medicine, Section of Clinical Toxicology, Cook County Hospital, 720 S Wolcott, Rm 13A, Chicago, IL 60612. Kev Words: Oral labetalol. hvoertensive urqencies. Copyright 0 1991 by W.B. Saunders Company 0735-6757/91/0902-0008$5.00/O 136
B. LEIKIN,
MDt
sentation, and lastly, patient may be maintained on the same agent for sustained oral therapy. As yet, no single antihypertensive agent studied in this patient population fulfills all of these criteria. Three of the currently popular oral medications in the management of patients with hypertensive urgencies include clonidine. captopril, and nifedipine. None of these are ideal nor devoid of adverse affect. Characteristics of labetalol. including its pharmacokinetic profile, make it an attractive alternative for the treatment of patients with hypertensive urgency. Several case reports have been published attesting to its efficacy.“’ The purpose of this study was to determine the efficacy and safety of oral labetalol in patients experiencing hypertensive urgency.
SUBJECTSAND METHODS All patients between IX and 65 years who presented to the emergency department at the University of Illinois Hospital over a 16month period with a diastolic blood pressure in three separate measurements over I hour of greater than 120 mm Hg received 20 mg intravenous (IV) furosemide. Patients were evaluated for study inclusion if their diastolic blood pressure remained greater than I20 mm Hg I hour after receiving the furosemide. Study exclusions included: suspected pheochromocytoma. insulin-dependent diabetes. sinus bradycardia or greater than first-degree heart block, asthma, chronic obstructive pulmonary disease, Raynaud’s disease, hypertensive encephalopathy. acute aortic dissection, congestive heart failure. recent cerebral vascular accident, myocardial infarction. or pulmonary embolism. Electrocardiograms, electrolytes, blood urea nitrogen. creatinine, glucose. and urine analyses was obtained on all patients to rule out acute end-organ damage. Sixteen patients were entered into the study after obtaining informed consent in accordance with the Investigational Review Board guidelines. Patients received 300 mg labetalol (Normodyne, Schering Corp. Kenilworth, NJ) orally after which blood pressure and pulse were measured every 10 minutes for 2 hours. If the diastolic blood pressure remained greater than 100 mm Hg, a second dose of labetalol (I00 mg) was then orally administered. Blood pressure and pulse were then measured every I5 minutes for 2 more hours. Patients whose diastolic blood pressure remained greater than 100 mm Hg then received a third dose (100 mg) of oral labetalol. Blood pressure and pulse were measured for an additional 2 hours. The maximum dose of labetalol that any patient could have received in this h-hour period was 500 mg. Repeated measures analysis of systolic, diastolic, mean arterial pressure, and pulse were performed to establish statistical significance.h RESULTS
There were 1I men and 5 women entered into the study. All the women were black. Of the 11 men. 7 were black. 3
ZELL-KANTER AND LEIKIN n ORAL LABETOL IN HYPERTENSIVE URGENCIES
white, and 1 hispanic. Their ages ranged from 19 to 64 years, with a mean age of 44 years. Eleven patients required a total dose of 500 mg. Five patients required only the initial 300 mg dose of labetalol to achieve a diastolic blood pressure of less than 100 mm Hg within the first 2 hours. Measurements for these five patients were completed only until 2 hours into the study, at which time the patients refused to remain for study completion. The mean measurements for systolic, diastolic, mean arterial pressure (MAP) and pulse are illustrated in Figure 1. Furosemide was administered at t = -60 minutes, and the first dose of labetalol at t = 0. It is not possible to completely discount furosemide’s affect after the initiation of labetalol. However, considering the pharmacokinetics and pharmacodynamics of furosemide on IV administration, its antihypertensive affect after 1 hour is minimal. Two sets of analyses were performed because data had been collected to 360 minutes postinitiation of labetalol in 11 patients, and to 120 minutes postlabetalol in 16 patients. Two Labetald 300 (N=16) 240
I
Dose, mg. -7 100 (N=llI
100 (N=ll)
I
I
r
137
hours after administration of 300 mg labetalol, the supine blood pressure decreased from 206 +- 23/132 f 9 mm Hg to 154 f 24023 -C 17. MAP decreased from 156 + 12 to 123 2 14 (22%). These changes are statistically significant at P -C .Ol. No significant changes in pulse rate were noted. Data for the 11 patients requiring the total dose of 500 mg labetalol was collected until t = 360. Blood pressures at this time were 165 2 14/117 ? 10 mm Hg. The MAP was 133 +9 mm Hg. These measurements are statistically significant at P < .Ol, P < .05, and P < .Ol for systolic, diastolic, and MAP, respectively. However, there is no significant difference between the intervals at which the subsequent 100 mg labetalol doses were administered, ie, between t = 120 and t = 240, t = 120 and t = 360, t = 240 and t = 360. No significant change in pulse was measured throughout. No adverse effects were noted throughout the study period. Two patients were hospitalized after completion of the study because the house-officer in charge wanted further control of blood pressure prior to discharge. No patient was discharged home with a diastolic blood pressure greater than 120 mm Hg. Two of the five patients who required only the initial 300 mg labetalol dose to achieve a diastolic blood pressure of 100 mm Hg were white men, two were black women, and one was a black man. All patients were instructed upon discharge to return for follow-up in 1 week. DISCUSSION
FIGURE 1. Hemodynamic response to labetalol. N indicates number of patients receiving dose of labetalol at specified times according to protocol. SBP = systolic blood pressure; DBP = diastolic blood pressure; MAP = mean arterial pressure (diastolic plus onethird of pulse pressure).
The oral armamentarium for treating patients with hypertensive urgency is continuously expanding. No drug is ideal for all patients. Clonidine’s utility gained wide acceptance in 1981, but side effects such as the antihypertensive withdrawal syndrome, have limited its chronic use.7*8 Captopril’s bioavailability makes it an attractive alternative in the care of patients with hypertensive urgency; however, its efficacy is unpredictable.9T10 Like clonidine, captopril’s side effects with chronic use limit its utility.“,” Nifedipine has been shown to promptly lower blood pressure; however, patient response in some studies, has not been uniform, and some major side effects have been documented.‘3,‘6 Labetalol’s pharmacologic profile includes nonselective B blockade and selective postsynaptic a-1 blockade. With oral administration, the cx to B blocking activity has been estimated to be 1:3.‘7-‘9 Labetalol is rapidly absorbed and maximum concentrations are achieved in about 1 hour. Antihypertensive activity begins within 2 hours, and peaks within 3 hours.‘,*’ The pharmacology of labetalol limits its use in patients with specific disease states, such as asthma, chronic obstructive pulmonary disease, and congestive heart failure. We chose to investigate the utility of labetalol in caring for patients with hypertensive urgencies. The specific purpose was to determine whether labetalol was safe and effective in lowering blood pressure in this patient population. Incremental doses of orally administered labetalol were found to be both safe and effective in lowering patient’s blood pressures. While a recent study reported no significant changes in blood pressure after one dose of labetalol, we believe that multiple dosing of the drug is necessary to achieve the desired effects.*l Reexamining the desirable characteristics of drugs used in treating patients with hypertensive urgency delineated by Ferguson et al,’ we find that
138
AMERICAN
JOURNAL
scores quite well. Labetalol lowered blood pressure consistently, but not precipitously. The extent of blood pressure reduction was proportional to initial blood pressure elevation. No excessive hypotension was noted in any patient, and no side effects were noted in this study group. Blood pressure reduction was achieved slowly and evenly. Labetalol may be administered intravenously should parenteral therapy be indicated, and transition to the oral route for sustained therapy is achievable. Labetalol is an attractive addition to the currently available armamentarium for the care of patients with hypertensive urgency. It should be considered among the first-line agents, barring contraindications for its use. A detailed history, including past medications, should be obtained in all patients prior to institution of therapy, so that the most appropriate antihypertensive agent may be initiated for the individual patient. labetalol
The authors thank project, and Sheila
Dr David Frobel for his assistance in this Rosner for preparing this manuscript.
REFERENCES 1. Ferguson RK, Vlasses PH: Hypertension emergencies and urgencies. JAMA 1986;255:1607-1613 2. Hana W, Grell GC: Labetalol in hypertensive emergencies. Br Med J 1978;2:772 3. Hana W, Grell GC: Oral labetalol in the management of sympathetic overactivity of severe tetanus. S Med J 1980;75:653654 4. Ghose RR, Mathur YB, Upadhyay M, et al: Treatment of hypertensive emergencies with oral labetalol. Br Med J 1978;2:96 5. Ghose RR: Acute management of severe hypertension with oral labetalol. Br J Clin Pharm 1979;8:189S-193s 6. SAS Institute, Inc, SAS User’s Guide: Statistics, Version 5, 1985 7. Pettinger WA: Clonidine, a new antihypertensive drug. N Engl J Med 1978;293:1179-1180
OF EMERGENCY
MEDICINE
n Volume 9, Number 2 n March 1991
8. Whitsett TL, Chrysant SG, Dillard BL, et al: Abrupt cessation of clonidine administration-A prospective study. Am J Cardiol 1978;41:1285-1290 9. Ferguson RK, Vlasses PH, Koplin JR, et al: Captopril in severe treatment-resistent hypertension. Am Heart J 1980; 99:579-583 10. Case DB, Atlas SA, Sullivan PA, et al: Acute and chronic treatment of severe hypertension and malignant hypertension with oral angio-tensin converting enzyme inhibitor captopril. Circulation 1981;64:765-771 11. Case DB, Atlas SA, Laragh JH, et al: Clinical experience with blockade of renin-angiotensin-aldosterone system by an oral converting enzyme inhibitor (SQ-14,225) in hypertensive patients. Prog Cardiovasc Dis 1978;21:195-206 12. Maskill MP, Orme ML, Maciver M, et al: Efficiency and adverse effects of captopril in severe refractory hypertension. J Cardiovasc Pharmacol 1981;3:1287-1295 13. Beer N, Gallegos I, Cohen A, et al: Efficiency of sublingual nifedipine in the acute treatment of systemic hypertension. Chest 1981;79:571-574 14. Bertel 0, Conner D, Radu EW, et al: Nifedipine in hypertensive emergencies. Br Med J 1983;286:19-21 15. Cohen D, Bertel 0, Dudoe UC: An oral calcium antagonist for treatment of hypertensive emergencies. J Cardiovasc Pharmacol 1981;3:1287-1295 16. O’Mailia JJ, Sander E. GilesTD: Nifedipine-associated myocardial ischemia or infarction in the treatment of hypertensive urgencies. Ann Intern Med 1987;107:185-186 17. Physician’s Desk Reference. Oradell, NJ, Medical Economics Company, 1988, pp 1932-1935 18. Brittain RT, Levy GP: A review of the animal pharmacology of labetalol, combined alpha and beta adrenoreceptor blocking drug. Br J Clin Pharmacol 1976;3:681-694 (suppl 3) 19. Richards DA, Maconochie JG, Bland RE, et al: Relationship between plasma concentrations and pharmacologic effects of labetalol. Eur J Clin Pharmacol 1977;11:85-90 20. Serlin MJ, Orme ML, Maciver M, et al: Rate of onset of hypotensive effect of oral labetalol. Br J Clin Pharmacol 1979;7:165-168 21. Wright SW, Hedges JR, Wright MB, et al: Ineffectiveness of oral labetalol for hypertensive urgency. Am J Emerg Med 1990;8:472-473
PHARMD,*
JERROLD
The response to incremental doses of oral labetalol in 16 patients with hypertensive urgencies is presented. After inadequate blood pressure control with 20 mg of intravenous furosemide, each patient received a 300 mg oral dose of labetalol. Subsequent oral doses of labetalol, 100 mg, were administered at P-hour intervals, if the diastolic blood pressure remained greater than 100 mm Hg. The maximum dose of labetalol per patient was 500 mg. Five patients required only the initial 300 mg dose of labetalol. Two patients required further therapy for satisfactory blood pressure control. Mean arterial pressure fell from 156 +. 12 mm Hg to 123 2 14 mm Hg. (Am J Emerg led 1991;9:136-138. Copyright 6 1991 by W.9. Saunders Company)
Emergency physicians are frequently faced with the dilemma of treating patients with hypertensive urgencies. Several questions arise in the care of such patients, the primary being which patients should be treated acutely for elevated blood pressure. The second most important question is how aggressive should the treatment be to achieve a therapeutic end-point. Lastly, does oral administration satisfactorily lower blood pressure in the time frame consistent with emergency practice. The term hypertensive urgency must be fully understood so that these questions may be most appropriately answered. A hypertensive urgency may be defined as any patient who has a severe elevation in blood pressure without any evidence of end-organ damage. Ideally, the blood pressure should be reduced and controlled within 24 hours using oral antihypertensive agents.’ The therapeutic end-point should be proportional to the blood pressure elevation on presentation. Characteristics of an ideal antihypertensive medication for the care of patients with hypertensive urgencies have been described.’ These characteristics include rapid onset after oral administration, titrating ability to desired effect. will not cause excessive hypotension. have few side effects, no need for minute-to-minute monitoring, may be combined with other medications, may be administered parenterally if oral route is to be avoided, should result in lowering of blood pressure proportional to the blood pressure elevation on pre-
From the *Division of Occupational Medicine, Section of Clinical Toxicology, Cook County Hospital, the TDepat-tment of Medicine, Section of Emergency Medicine, University of Illinois at Chicago, and the TDepartment of Medicine, Rush-Presbyterian St. Luke’s Medical Center, Chicago, IL. Manuscript received March 16, 1990; revision accepted October 26, 1990. Supported by the American College of Clinical Pharmacy/ Schering Research Institute Award. Presented, in part, at the 7th Annual Meeting of the American College of Clinical Pharmacy, Chicago, IL, July 29, 1986. Address reprint requests to Dr Zell-Kanter, Division of Occupational Medicine, Section of Clinical Toxicology, Cook County Hospital, 720 S Wolcott, Rm 13A, Chicago, IL 60612. Kev Words: Oral labetalol. hvoertensive urqencies. Copyright 0 1991 by W.B. Saunders Company 0735-6757/91/0902-0008$5.00/O 136
B. LEIKIN,
MDt
sentation, and lastly, patient may be maintained on the same agent for sustained oral therapy. As yet, no single antihypertensive agent studied in this patient population fulfills all of these criteria. Three of the currently popular oral medications in the management of patients with hypertensive urgencies include clonidine. captopril, and nifedipine. None of these are ideal nor devoid of adverse affect. Characteristics of labetalol. including its pharmacokinetic profile, make it an attractive alternative for the treatment of patients with hypertensive urgency. Several case reports have been published attesting to its efficacy.“’ The purpose of this study was to determine the efficacy and safety of oral labetalol in patients experiencing hypertensive urgency.
SUBJECTSAND METHODS All patients between IX and 65 years who presented to the emergency department at the University of Illinois Hospital over a 16month period with a diastolic blood pressure in three separate measurements over I hour of greater than 120 mm Hg received 20 mg intravenous (IV) furosemide. Patients were evaluated for study inclusion if their diastolic blood pressure remained greater than I20 mm Hg I hour after receiving the furosemide. Study exclusions included: suspected pheochromocytoma. insulin-dependent diabetes. sinus bradycardia or greater than first-degree heart block, asthma, chronic obstructive pulmonary disease, Raynaud’s disease, hypertensive encephalopathy. acute aortic dissection, congestive heart failure. recent cerebral vascular accident, myocardial infarction. or pulmonary embolism. Electrocardiograms, electrolytes, blood urea nitrogen. creatinine, glucose. and urine analyses was obtained on all patients to rule out acute end-organ damage. Sixteen patients were entered into the study after obtaining informed consent in accordance with the Investigational Review Board guidelines. Patients received 300 mg labetalol (Normodyne, Schering Corp. Kenilworth, NJ) orally after which blood pressure and pulse were measured every 10 minutes for 2 hours. If the diastolic blood pressure remained greater than 100 mm Hg, a second dose of labetalol (I00 mg) was then orally administered. Blood pressure and pulse were then measured every I5 minutes for 2 more hours. Patients whose diastolic blood pressure remained greater than 100 mm Hg then received a third dose (100 mg) of oral labetalol. Blood pressure and pulse were measured for an additional 2 hours. The maximum dose of labetalol that any patient could have received in this h-hour period was 500 mg. Repeated measures analysis of systolic, diastolic, mean arterial pressure, and pulse were performed to establish statistical significance.h RESULTS
There were 1I men and 5 women entered into the study. All the women were black. Of the 11 men. 7 were black. 3
ZELL-KANTER AND LEIKIN n ORAL LABETOL IN HYPERTENSIVE URGENCIES
white, and 1 hispanic. Their ages ranged from 19 to 64 years, with a mean age of 44 years. Eleven patients required a total dose of 500 mg. Five patients required only the initial 300 mg dose of labetalol to achieve a diastolic blood pressure of less than 100 mm Hg within the first 2 hours. Measurements for these five patients were completed only until 2 hours into the study, at which time the patients refused to remain for study completion. The mean measurements for systolic, diastolic, mean arterial pressure (MAP) and pulse are illustrated in Figure 1. Furosemide was administered at t = -60 minutes, and the first dose of labetalol at t = 0. It is not possible to completely discount furosemide’s affect after the initiation of labetalol. However, considering the pharmacokinetics and pharmacodynamics of furosemide on IV administration, its antihypertensive affect after 1 hour is minimal. Two sets of analyses were performed because data had been collected to 360 minutes postinitiation of labetalol in 11 patients, and to 120 minutes postlabetalol in 16 patients. Two Labetald 300 (N=16) 240
I
Dose, mg. -7 100 (N=llI
100 (N=ll)
I
I
r
137
hours after administration of 300 mg labetalol, the supine blood pressure decreased from 206 +- 23/132 f 9 mm Hg to 154 f 24023 -C 17. MAP decreased from 156 + 12 to 123 2 14 (22%). These changes are statistically significant at P -C .Ol. No significant changes in pulse rate were noted. Data for the 11 patients requiring the total dose of 500 mg labetalol was collected until t = 360. Blood pressures at this time were 165 2 14/117 ? 10 mm Hg. The MAP was 133 +9 mm Hg. These measurements are statistically significant at P < .Ol, P < .05, and P < .Ol for systolic, diastolic, and MAP, respectively. However, there is no significant difference between the intervals at which the subsequent 100 mg labetalol doses were administered, ie, between t = 120 and t = 240, t = 120 and t = 360, t = 240 and t = 360. No significant change in pulse was measured throughout. No adverse effects were noted throughout the study period. Two patients were hospitalized after completion of the study because the house-officer in charge wanted further control of blood pressure prior to discharge. No patient was discharged home with a diastolic blood pressure greater than 120 mm Hg. Two of the five patients who required only the initial 300 mg labetalol dose to achieve a diastolic blood pressure of 100 mm Hg were white men, two were black women, and one was a black man. All patients were instructed upon discharge to return for follow-up in 1 week. DISCUSSION
FIGURE 1. Hemodynamic response to labetalol. N indicates number of patients receiving dose of labetalol at specified times according to protocol. SBP = systolic blood pressure; DBP = diastolic blood pressure; MAP = mean arterial pressure (diastolic plus onethird of pulse pressure).
The oral armamentarium for treating patients with hypertensive urgency is continuously expanding. No drug is ideal for all patients. Clonidine’s utility gained wide acceptance in 1981, but side effects such as the antihypertensive withdrawal syndrome, have limited its chronic use.7*8 Captopril’s bioavailability makes it an attractive alternative in the care of patients with hypertensive urgency; however, its efficacy is unpredictable.9T10 Like clonidine, captopril’s side effects with chronic use limit its utility.“,” Nifedipine has been shown to promptly lower blood pressure; however, patient response in some studies, has not been uniform, and some major side effects have been documented.‘3,‘6 Labetalol’s pharmacologic profile includes nonselective B blockade and selective postsynaptic a-1 blockade. With oral administration, the cx to B blocking activity has been estimated to be 1:3.‘7-‘9 Labetalol is rapidly absorbed and maximum concentrations are achieved in about 1 hour. Antihypertensive activity begins within 2 hours, and peaks within 3 hours.‘,*’ The pharmacology of labetalol limits its use in patients with specific disease states, such as asthma, chronic obstructive pulmonary disease, and congestive heart failure. We chose to investigate the utility of labetalol in caring for patients with hypertensive urgencies. The specific purpose was to determine whether labetalol was safe and effective in lowering blood pressure in this patient population. Incremental doses of orally administered labetalol were found to be both safe and effective in lowering patient’s blood pressures. While a recent study reported no significant changes in blood pressure after one dose of labetalol, we believe that multiple dosing of the drug is necessary to achieve the desired effects.*l Reexamining the desirable characteristics of drugs used in treating patients with hypertensive urgency delineated by Ferguson et al,’ we find that
138
AMERICAN
JOURNAL
scores quite well. Labetalol lowered blood pressure consistently, but not precipitously. The extent of blood pressure reduction was proportional to initial blood pressure elevation. No excessive hypotension was noted in any patient, and no side effects were noted in this study group. Blood pressure reduction was achieved slowly and evenly. Labetalol may be administered intravenously should parenteral therapy be indicated, and transition to the oral route for sustained therapy is achievable. Labetalol is an attractive addition to the currently available armamentarium for the care of patients with hypertensive urgency. It should be considered among the first-line agents, barring contraindications for its use. A detailed history, including past medications, should be obtained in all patients prior to institution of therapy, so that the most appropriate antihypertensive agent may be initiated for the individual patient. labetalol
The authors thank project, and Sheila
Dr David Frobel for his assistance in this Rosner for preparing this manuscript.
REFERENCES 1. Ferguson RK, Vlasses PH: Hypertension emergencies and urgencies. JAMA 1986;255:1607-1613 2. Hana W, Grell GC: Labetalol in hypertensive emergencies. Br Med J 1978;2:772 3. Hana W, Grell GC: Oral labetalol in the management of sympathetic overactivity of severe tetanus. S Med J 1980;75:653654 4. Ghose RR, Mathur YB, Upadhyay M, et al: Treatment of hypertensive emergencies with oral labetalol. Br Med J 1978;2:96 5. Ghose RR: Acute management of severe hypertension with oral labetalol. Br J Clin Pharm 1979;8:189S-193s 6. SAS Institute, Inc, SAS User’s Guide: Statistics, Version 5, 1985 7. Pettinger WA: Clonidine, a new antihypertensive drug. N Engl J Med 1978;293:1179-1180
OF EMERGENCY
MEDICINE
n Volume 9, Number 2 n March 1991
8. Whitsett TL, Chrysant SG, Dillard BL, et al: Abrupt cessation of clonidine administration-A prospective study. Am J Cardiol 1978;41:1285-1290 9. Ferguson RK, Vlasses PH, Koplin JR, et al: Captopril in severe treatment-resistent hypertension. Am Heart J 1980; 99:579-583 10. Case DB, Atlas SA, Sullivan PA, et al: Acute and chronic treatment of severe hypertension and malignant hypertension with oral angio-tensin converting enzyme inhibitor captopril. Circulation 1981;64:765-771 11. Case DB, Atlas SA, Laragh JH, et al: Clinical experience with blockade of renin-angiotensin-aldosterone system by an oral converting enzyme inhibitor (SQ-14,225) in hypertensive patients. Prog Cardiovasc Dis 1978;21:195-206 12. Maskill MP, Orme ML, Maciver M, et al: Efficiency and adverse effects of captopril in severe refractory hypertension. J Cardiovasc Pharmacol 1981;3:1287-1295 13. Beer N, Gallegos I, Cohen A, et al: Efficiency of sublingual nifedipine in the acute treatment of systemic hypertension. Chest 1981;79:571-574 14. Bertel 0, Conner D, Radu EW, et al: Nifedipine in hypertensive emergencies. Br Med J 1983;286:19-21 15. Cohen D, Bertel 0, Dudoe UC: An oral calcium antagonist for treatment of hypertensive emergencies. J Cardiovasc Pharmacol 1981;3:1287-1295 16. O’Mailia JJ, Sander E. GilesTD: Nifedipine-associated myocardial ischemia or infarction in the treatment of hypertensive urgencies. Ann Intern Med 1987;107:185-186 17. Physician’s Desk Reference. Oradell, NJ, Medical Economics Company, 1988, pp 1932-1935 18. Brittain RT, Levy GP: A review of the animal pharmacology of labetalol, combined alpha and beta adrenoreceptor blocking drug. Br J Clin Pharmacol 1976;3:681-694 (suppl 3) 19. Richards DA, Maconochie JG, Bland RE, et al: Relationship between plasma concentrations and pharmacologic effects of labetalol. Eur J Clin Pharmacol 1977;11:85-90 20. Serlin MJ, Orme ML, Maciver M, et al: Rate of onset of hypotensive effect of oral labetalol. Br J Clin Pharmacol 1979;7:165-168 21. Wright SW, Hedges JR, Wright MB, et al: Ineffectiveness of oral labetalol for hypertensive urgency. Am J Emerg Med 1990;8:472-473
