- Email: [email protected]
Guanfacine as monotherapy for systemic hypertension
Guanfacineas Monotherapyfor SystemicHypertension JOHN M. FILLINGIM, MD, JACK L. BLACKSHEAR, MD, ALVIN STRAUSS, and MARK STRAUSS, MD
MD,
differences between the treatment and the placebo groups. A statistically significant (p
Three clinical studies examined the effects of guanfacine as monotherapy. Study 1 was a double-blind, randomized, parallel trial with a placebo control with 26 patients with mild essential hypertension treated with 1-mg guanfacine or matching placebo daily at bedtime for 6 weeks. Pretreatment and posttreatment determinations of plasma volume, plasma aldosterone and blood pressure (BP) were made in all 26 patients. There were no significant differences between guanfacine and placebo with regard to changes in plasma volume or plasma aldosterone, but a significant decrease (p = 0.001) in both diastolic and mean BPS was seen with the active drug. No side effects were reported. From this study, it was concluded that guanfacine monotherapy is an effective and well-tolerated initial treatment for mild essential hypertension with no effect on either plasma volume or plasma aldosterone. Study 2 was a double-blind, randomized, parallel clinical study with placebo control with 42 patients with mild essential hypertension treated with either guanfacine (1 mg/day) or matching placebo at bedtime for 8 weeks. Pretreatment and posttreatment evaluations of serum cholesterol, triglycerides, low density lipoproteins, very low density lipoproteins and high density lipoproteins revealed no significant
T
and guanabenz, agonist.
he use of guanfacine, a centrally acting a-adrenoceptor agonist,1-5 as sole therapy in the treatment of hypertension has been suggested by the results achieved by a number of investigators who used the drug in this manner for periods ranging from 6 weeks6 to 6 months.7 Three studies that investigated important aspects of the use of guanfacine as monotherapy have recently been completed. The first study determined the effect of guanfacine on plasma aldosterone and plasma volume. The second investigated the effect of guanfacine on plasma lipids and lipoproteins. The third compared the efficacy and safety of guanfacine
another central
a-adrenoceptor
Methods Patient selection: Inclusion criteria for the 3 studies were similar: mild essential hypertension (90 to 100 mm Hg diastolic blood pressure [BP]) for studies 1 and 2, and mild-to-moderate essential hypertension (diastolic BP of 90 to 114 mg Hg] for study 3; general good health, except for hypertension; age between 21 and 70; and written informed consent. Exclusion criteria included requirement for certain concomitant medications, known sensitivity to guanfatine, weight more than 50% above ideal, diabetes, gout, malignancy or other serious disease, pregnancy
Address for reprints: John M. Fillingim, MD, 500 Eisenhower Drive, Savannah, Georgia 31406-2610. 50E
March 28, 1966
TABLE I
Demographic
Profile of Patients Participating Study 1
Guanfacine Patients (no.) Mean age (years) Race Black Non-black Mean weight W) Mean height (inches)
THE AMERICAN
JOURhlAL
in 3 Guanfacine
Monotherapy
Study 2 Placebo
17 55
Guanfacine
OF CARDIOLOGY
Study 3 Placebo
Guanfacine
Guanabenz
21 67
21 51
27 53
2% 56
1
2 19 195
2 25 194
5 23 194
70
69
67
185
5 16 179
64
70
68
a
or lactation and for studies 1 and 2, the use of reserpine or guanethidine within 2 months of entry into the study. The demographic profile of the 26 patients who participated in study 1 [effects of guanfacine on plasma aldosterone and plasma volume], the 42 patients in study 2 (effects of guanfacine on plasma lipids and lipoproteins) and the 55 patients in study 3 (guanfacine versus guanabenz) can be seen in Table I. Study design: All 3 investigations were doubleblind, randomized, parallel comparisons of guanfatine versus placebo control (studies 1 and 2) or guanabenz (study 3). At the first visit, a patient history and a physical examination, including vital signs, were performed. In studies 1 and 2, an electrocardiogram and chest x-ray were part of the initial evaluation, and weight and routine laboratory testing were part of the continuing assessment. In addition, plasma volume and plasma aldosterone were measured in study 1, lipid profiles were done in study 2 and adverse reactions, with particular reference to somnolence, were assessed in study 3. A l-month, drug-free screening period preceded the use of guanfacine in studies 1 and
51E
Studies
9 57
4 13 194
Volume 57
2. A 2-week placebo phase preceded the use of the test drugs in study 3.
Results Study l-effects of guanfacine on plasma aldosterone and plasma volume: Of the 26 patients participating in study 1, 17 received 1-mg guanfacine orally at bedtime, and 9 received placebo. Determinations of plasma volume, plasma aldosterone and BP were made in all 26 patients at the start of treatment and at its conclusion. There were no significant changes in plasma volume (Fig. I), total blood volume or plasma aldosterone (Fig. 2) during the 8-week study in either the guanfacine or the placebo group, nor was there any difference between the effects of guanfacine and placebo. Mean arterial pressure for the guanfacine group decreased significantly from 149/W mm Hg at baseline to 140/84 mm Hg at the end of treatment, while mean pressure for the placebo group was virtually unchanged. Both systolic and diastolic BPS also decreased; the reduction in diastolic BP was both clinically relevant and statistically significant (p = O.OOlj.
4000 1 g E =r >o
2000
ii 3 0. 1000
2
3000 0 1
:
i
Baseline (Day 27) JcGuanfacine
FIGURE 1. Baseline measurements.
Endpoint
Baseline
Endpoint
(Day 55)
(Day 27)
0-w
+
and endpoint
p---Placebo means
55)
I
Endpoint
Baseline
Pay
(Day 27)
t+- Guanfacine
--+
of plasma
Baseline (Day 27)
volume
FIGURE 2. Baseline determinations.
55) -+
and endpoint
I+---
Endpoint
(Day 55)
Placebo _*1
means of plasma
aldosterone
52E
A SYMPOSIUM:
GUANFACINE-A
NEW CHOICE
IN CENTRALLY
Heart rate did not change in either the treatment or the control group. No side effects were reported by any patient during guanfacine therapy. Guanfacine (1 mg/day at bedtime) as monotherapy significantly decreased diastolic BP with no effect on plasma volume or plasma aldosterone for the duration of the study. In addition, the drug was well tolerated, as evidenced by the lack of adverse reactions reported. Study z-effects of guanfacine on lipid metabolism: In a study to elucidate the possible effects of guanfatine on plasma lipids and lipoproteins, 21 patients were given l-mg guanfacine daily at bedtime and an equal number were given placebo. Evaluations of serum cholesterol (Fig. 3), triglycerides, low density lipoproteins (Fig. 4) and high density lipoproteins (HDL) (Fig. 5) were made at the end of the drug-free screening period and at the conclusion of 8 weeks of therapy. There was no significant difference from the start of treatment to the finish between the guanfacine and the placebo groups, and there was no difference between the treatment and control groups in any parameter. There was a mean decrease in diastolic BP of 12.6 mm Hg with guanfacine compared with a 1.6 mm Hg decrease in the placebo group, a highly significant difference (p
300
P a b g
250
ACTING
ANTIHYPERTENSIVE
AGENTS
Study 3-guanfacine and guanabenz comparison: Among the 55 patients who participated-in study 3,27 received guanfacine (1 mg/day) at bedtime and 1 placebo tablet in the morning, while 28 patients received guanabenz (4 mg, 2 times a day for the first week of the study and 8 mg, 2 times a day for the remainder of the 8-week treatment period). Endpoint comparisons of decreases in sitting diastolic and systolic, as well as standing diastolic and systolic BPS,showed that both drugs when used alone were equally effective as antihypertensive agents. Normalization of BP was reported as a diastolic BP of <90 mm Hg. Using that criterion, the BP of 15 (56%) of the 27 guanfacine-treated patients had normalized by the end of 8 weeks of therapy, compared with 18 (64%) of the 28 patients treated with guanabenz. Among patients who had begun the study with mild hypertension (diastolic BP 90 to 100 mm Hg), 13 (72%) of 18 guanfacine-treated patients and 16 (70%) of 23 \ guanabenz-treated patients achieved this goal. Among those who started the study with moderate hypertension (diastolic BP 100 to 114 mm Hg; 9 in the guanfatine group and 5 in the guanabenz group), 2 in each group achieved normal readings. The degree of somnolence experienced by patients who were taking the 2 test drugs was assessedby asking them if they had been drowsy during 3 specific time periods during the day: from awakening to 12 noon, from 12:Ol P.M. to 6 P.M. and from 6:Ol P.M. to retiring. The degree of drowsiness was rated as none, mild, -moderate or severe, and it was rated as a change from baseline determinations obtained at the start of the study. An increase in morning drowsiness was reported by only 4 (15%) of the guanfacine-treated compared with 15 (54%) of the guanabenz-treated patients. Increased drowsiness occurred in the afternoon in 7 (26?‘0) of the guanfacine-treated compared with 16
180
t
200
0
I5 I: 0, 3
150 100
F 50
-
0 m 0
Placebo (n = 21)
m
Placebo (n = 21)
Guanfacine
0
Guanfacine
(n = 21)
FIGURE 3. Baseline and endpoint means of total serum cholesterol
I
Endpoint
Endpoint (n = 21)
FIGURE 4. Baseline and endpoint means of low density lipoprotein (LDL) determinations.
March 28, 1986
(57%) of the guanabenz-treated patients, Evening drowsiness increased in 5 (18%] guanfacine-treated patients and in 11 (39%) guanabenz-treated patients. The significantly lower incidence of somnolence in patients taking guanfacine compared with those taking guanabenz is clearly evident in Figure 7. The incidence of other adverse reactions was also greater with guanabenz than with guanfacine. Only 2 (7%) of the 27 guanfacine patients reported side effects other than somnolence, compared with 7 (25%) of the 28 patients receiving guanabenz. These results indicate that monotherapy with guanfacine (1 mg/day) is as effective as monotherapy with guanabenz (8 mg, 2 times a day] in the treatment of mild to moderate hypertension. However, guanfacine offers the advantage of once-a-day dosage. Further, somnolence, which is a major reason for drug discontinuance with this class of drugs, was far less prevalent with guanfacine.
Discussion Treatment of patients with mild to moderate essential hypertension is most appropriately initiated with a single antihypertensive agent, as opposed to drug combinations. With monotherapy, the possibility of adverse reactions is reduced. In addition, the greater simplicity and convenience of the single-drug regimen encourage compliance, and thus promotes clinical success. Sympatholytic antihypertensive drugs, such as the central a-adrenoceptor agonists, are often effective initially; however, as single drugs they often lose therapeutic efficacy due to associated salt and water retention As a result, a diuretic agent must be added to the regimen.8 The lack of change in plasma volume and plasma aldosterone levels observed during guanfacine therapy indicates that this is not a major problem with guanfacine, extending the usefulness of this drug as monotherapy in hypertension. The lack of effect of guanfacine on lipid metabolism is also of great interest, because a number of class90
THE AMERICAN
JOURNAL
OF CARDiOLOGY
Volume 57
53E
es of drugs commonly used as monotherapy in the treatment of hypertension have been shown to alter the lipid profile. In periods as short as 4 to 8 weeks, diuretics have been shown to elevate total cholesterol, total triglycerides, low density lipoprotein cholesterol or very low density lipoprotein cholesterol,+13 as well as to reduce levels of HDL.1°-13 The most significant change in lipid metabolism seen with /3 blockers is a decrease in HDL,14J5 which has also been observed with the &3 blocker labetalol.13 Because elevations in low density lipoprotein cholesterol and reductions in HDL cholesterol have been associated with an increased risk of coronary artery disease and myocardial infarction,16 such changes in lipid metabolism, when induced by medication to lower blood pressure, may be substituting 1 coronary risk factor (altered lipid levels) for another (hypertension). The fact that guanfacine has been shown to have no effect on lipid metabolism according to the parameters measured in study 2 may make it a safer drug to use in
8 2 g e m y
0
Ii 5
100 90 80
P< .OOOl
70 1
0
Initiation of double-blind treatment with placebo (broken rule) or guanfacine (unbroken rule) I 0
I 5
I 25
I 15
I 35
I 45
I 55
Day oi Study FIGURE 6. Diastolic blood pressure (BP) means in guanfaclnetreated patients and placebo controls.
r
.-5 5 P Baseline m
Placebo (n
0
Guanfaclne
0
Morning
Endpoint 21) (n
21)
FIGURE 5. Baseline and endpoint means of high density lipoprotein (HDL) determinations.
Afternoon
0
Guanfacine
(n = 27)
m
Guanabenz
(n = 28)
FtGURE 7. Incidence of somnolence treated patients.
in guanfacine-
Evening
and guanabenz-
54E
A SYMPOSIUM:
GUANFACINE-A
NEW CHOICE
IN CENTRALLY
patients who are already at greater risk of coronary disease. In summary, guanfacine is an effective monotherapy in the treatment of mild to moderate hypertension. No effect on plasma volume or plasma aldosterone was seen during a z-month study, and no alterations in serum lipid or lipoprotein levels were observed. Compared with guanabenz, another new central cu-adrenoceptor agonist, guanfacine was equally effective in reducing BP, but it produced a far lower incidence of somnolence and other side effects and has the added advantage of once-a-day dosage.
References 1. Jerie P, Lasance A. Guanfacine in the treatment of hypertension: two years experience with low dose monotherapy. Int J Clin Pharmocol Ther Toxicol 1981;19:279-287. 2. Saameli K, Scholtysik G. Waite R. Pharmacology of BS 100-141,a centrally acting antihypertensive drug. Clin Exp Pharmacol Physidl 1975;2:suppl 2:207-212. 3. Laura R, Reda G, Spallone L, Beretta Anguissola A. Hypotensive effect of
guanfacine in essential hypertension: a comparison with clonidine. Br 1 Clin Pharmacol 198O;lO:supp~:81S-82s. 4. Pacha W, Salzmann R, Scholtysik G. Inhibitory _ effects of clonidine and BS 100-141 on response to sympathetic nerve stimulation in cdts and rabbits. Br r Pharmacol 1975;53:513-5%. 5. Scholtysik G, jerie P. Pharmacological and clinical effects of BS 100-141,a
ACTING
ANTIHYPERTENSIVE
AGENTS
new antihypertensive agent. In: Scriabin A, Sweet C, eds. New Antihypertensive Drugs. New York: Spectrum, 1976:359-368. 6. Westelink K, Michotte Y. Low dose guanfacine once-a-day for the treatment of hypertension in general practice: a multicentre pilot study. Curr Med
Res Opin 1982;7:631-638. 7. Szam I, Ho1101. Long-term antihypertensive therapy with guanfacine. Int [ Clin Pharmacol Ther Toxicol 1982;20:388-392. 8. Blaschke TF, Melmon KL. Antihypertensive agents and the drug therapy of hypertension. In: Gilman AG, Goodman LS, Gilman A, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, sixth ed. New York: Macmillan. 1980:793-818. 9. Ames R@,Hill P. Elevation of serum lipid levels during diuretic therapy of hypertension. Am J Med 1976;61:748-757. 10. Gliick Z, Baumgartner G, Weidmann P, Peheim E, Bachmann C, Mordasini R, Flammer 1, Keusch G. Increased ratio between serum /3- and a-lipoproteins during diuretic therapy: an adverse effect? Clin Sci 1978;55:325S3288.
11. Gliick Z, Weidmann P, Mordasini R, Bachmann C, Riesen W, Peheim E. Keusch G, Meier A. Increased serum low-density lipoprotein cholesterol in men treated short-term with the diuretic chlorthalidone. Metabolism 1980;29:240-245. 12. Grimm RH Jr, Leon AS, Hunninghake DB, Lenz K, Hannan P, Blackburn H. Effects of thiazide diuretics on plasma lipids and lipoproteins in mildly hypertensive patients. Ann Intern Med 1981;94:7-11. 13. Johnson BF. The emerging problem of plasma lipid changes during antihypertensive therapy. 1 Cardiovasc Pharmacol 1982;4:suppl2:S213-5221. 14. England ]DF, Simsons LA, Gibson JC, Carlton M. Beta-blockers and highdensity lipoprotein levels. Aust NZ J Med 1979;9:747. 15. Waal-Manning HJ. The effect of beta-blockers on plasma lipids. Symposium on Beta-Blocker Therapy, Atlanta, January 13-14, 1981. 16. Rbssner S. Serum lipouroteins and ischemic vascular disease: On the interpretation of serum Jipih versus serum lipoprotein concentrations. 1 Cardiovasc Pharmacoi 1982;4:suppl 2:S201-5205.
MD,
differences between the treatment and the placebo groups. A statistically significant (p
Three clinical studies examined the effects of guanfacine as monotherapy. Study 1 was a double-blind, randomized, parallel trial with a placebo control with 26 patients with mild essential hypertension treated with 1-mg guanfacine or matching placebo daily at bedtime for 6 weeks. Pretreatment and posttreatment determinations of plasma volume, plasma aldosterone and blood pressure (BP) were made in all 26 patients. There were no significant differences between guanfacine and placebo with regard to changes in plasma volume or plasma aldosterone, but a significant decrease (p = 0.001) in both diastolic and mean BPS was seen with the active drug. No side effects were reported. From this study, it was concluded that guanfacine monotherapy is an effective and well-tolerated initial treatment for mild essential hypertension with no effect on either plasma volume or plasma aldosterone. Study 2 was a double-blind, randomized, parallel clinical study with placebo control with 42 patients with mild essential hypertension treated with either guanfacine (1 mg/day) or matching placebo at bedtime for 8 weeks. Pretreatment and posttreatment evaluations of serum cholesterol, triglycerides, low density lipoproteins, very low density lipoproteins and high density lipoproteins revealed no significant
T
and guanabenz, agonist.
he use of guanfacine, a centrally acting a-adrenoceptor agonist,1-5 as sole therapy in the treatment of hypertension has been suggested by the results achieved by a number of investigators who used the drug in this manner for periods ranging from 6 weeks6 to 6 months.7 Three studies that investigated important aspects of the use of guanfacine as monotherapy have recently been completed. The first study determined the effect of guanfacine on plasma aldosterone and plasma volume. The second investigated the effect of guanfacine on plasma lipids and lipoproteins. The third compared the efficacy and safety of guanfacine
another central
a-adrenoceptor
Methods Patient selection: Inclusion criteria for the 3 studies were similar: mild essential hypertension (90 to 100 mm Hg diastolic blood pressure [BP]) for studies 1 and 2, and mild-to-moderate essential hypertension (diastolic BP of 90 to 114 mg Hg] for study 3; general good health, except for hypertension; age between 21 and 70; and written informed consent. Exclusion criteria included requirement for certain concomitant medications, known sensitivity to guanfatine, weight more than 50% above ideal, diabetes, gout, malignancy or other serious disease, pregnancy
Address for reprints: John M. Fillingim, MD, 500 Eisenhower Drive, Savannah, Georgia 31406-2610. 50E
March 28, 1966
TABLE I
Demographic
Profile of Patients Participating Study 1
Guanfacine Patients (no.) Mean age (years) Race Black Non-black Mean weight W) Mean height (inches)
THE AMERICAN
JOURhlAL
in 3 Guanfacine
Monotherapy
Study 2 Placebo
17 55
Guanfacine
OF CARDIOLOGY
Study 3 Placebo
Guanfacine
Guanabenz
21 67
21 51
27 53
2% 56
1
2 19 195
2 25 194
5 23 194
70
69
67
185
5 16 179
64
70
68
a
or lactation and for studies 1 and 2, the use of reserpine or guanethidine within 2 months of entry into the study. The demographic profile of the 26 patients who participated in study 1 [effects of guanfacine on plasma aldosterone and plasma volume], the 42 patients in study 2 (effects of guanfacine on plasma lipids and lipoproteins) and the 55 patients in study 3 (guanfacine versus guanabenz) can be seen in Table I. Study design: All 3 investigations were doubleblind, randomized, parallel comparisons of guanfatine versus placebo control (studies 1 and 2) or guanabenz (study 3). At the first visit, a patient history and a physical examination, including vital signs, were performed. In studies 1 and 2, an electrocardiogram and chest x-ray were part of the initial evaluation, and weight and routine laboratory testing were part of the continuing assessment. In addition, plasma volume and plasma aldosterone were measured in study 1, lipid profiles were done in study 2 and adverse reactions, with particular reference to somnolence, were assessed in study 3. A l-month, drug-free screening period preceded the use of guanfacine in studies 1 and
51E
Studies
9 57
4 13 194
Volume 57
2. A 2-week placebo phase preceded the use of the test drugs in study 3.
Results Study l-effects of guanfacine on plasma aldosterone and plasma volume: Of the 26 patients participating in study 1, 17 received 1-mg guanfacine orally at bedtime, and 9 received placebo. Determinations of plasma volume, plasma aldosterone and BP were made in all 26 patients at the start of treatment and at its conclusion. There were no significant changes in plasma volume (Fig. I), total blood volume or plasma aldosterone (Fig. 2) during the 8-week study in either the guanfacine or the placebo group, nor was there any difference between the effects of guanfacine and placebo. Mean arterial pressure for the guanfacine group decreased significantly from 149/W mm Hg at baseline to 140/84 mm Hg at the end of treatment, while mean pressure for the placebo group was virtually unchanged. Both systolic and diastolic BPS also decreased; the reduction in diastolic BP was both clinically relevant and statistically significant (p = O.OOlj.
4000 1 g E =r >o
2000
ii 3 0. 1000
2
3000 0 1
:
i
Baseline (Day 27) JcGuanfacine
FIGURE 1. Baseline measurements.
Endpoint
Baseline
Endpoint
(Day 55)
(Day 27)
0-w
+
and endpoint
p---Placebo means
55)
I
Endpoint
Baseline
Pay
(Day 27)
t+- Guanfacine
--+
of plasma
Baseline (Day 27)
volume
FIGURE 2. Baseline determinations.
55) -+
and endpoint
I+---
Endpoint
(Day 55)
Placebo _*1
means of plasma
aldosterone
52E
A SYMPOSIUM:
GUANFACINE-A
NEW CHOICE
IN CENTRALLY
Heart rate did not change in either the treatment or the control group. No side effects were reported by any patient during guanfacine therapy. Guanfacine (1 mg/day at bedtime) as monotherapy significantly decreased diastolic BP with no effect on plasma volume or plasma aldosterone for the duration of the study. In addition, the drug was well tolerated, as evidenced by the lack of adverse reactions reported. Study z-effects of guanfacine on lipid metabolism: In a study to elucidate the possible effects of guanfatine on plasma lipids and lipoproteins, 21 patients were given l-mg guanfacine daily at bedtime and an equal number were given placebo. Evaluations of serum cholesterol (Fig. 3), triglycerides, low density lipoproteins (Fig. 4) and high density lipoproteins (HDL) (Fig. 5) were made at the end of the drug-free screening period and at the conclusion of 8 weeks of therapy. There was no significant difference from the start of treatment to the finish between the guanfacine and the placebo groups, and there was no difference between the treatment and control groups in any parameter. There was a mean decrease in diastolic BP of 12.6 mm Hg with guanfacine compared with a 1.6 mm Hg decrease in the placebo group, a highly significant difference (p
300
P a b g
250
ACTING
ANTIHYPERTENSIVE
AGENTS
Study 3-guanfacine and guanabenz comparison: Among the 55 patients who participated-in study 3,27 received guanfacine (1 mg/day) at bedtime and 1 placebo tablet in the morning, while 28 patients received guanabenz (4 mg, 2 times a day for the first week of the study and 8 mg, 2 times a day for the remainder of the 8-week treatment period). Endpoint comparisons of decreases in sitting diastolic and systolic, as well as standing diastolic and systolic BPS,showed that both drugs when used alone were equally effective as antihypertensive agents. Normalization of BP was reported as a diastolic BP of <90 mm Hg. Using that criterion, the BP of 15 (56%) of the 27 guanfacine-treated patients had normalized by the end of 8 weeks of therapy, compared with 18 (64%) of the 28 patients treated with guanabenz. Among patients who had begun the study with mild hypertension (diastolic BP 90 to 100 mm Hg), 13 (72%) of 18 guanfacine-treated patients and 16 (70%) of 23 \ guanabenz-treated patients achieved this goal. Among those who started the study with moderate hypertension (diastolic BP 100 to 114 mm Hg; 9 in the guanfatine group and 5 in the guanabenz group), 2 in each group achieved normal readings. The degree of somnolence experienced by patients who were taking the 2 test drugs was assessedby asking them if they had been drowsy during 3 specific time periods during the day: from awakening to 12 noon, from 12:Ol P.M. to 6 P.M. and from 6:Ol P.M. to retiring. The degree of drowsiness was rated as none, mild, -moderate or severe, and it was rated as a change from baseline determinations obtained at the start of the study. An increase in morning drowsiness was reported by only 4 (15%) of the guanfacine-treated compared with 15 (54%) of the guanabenz-treated patients. Increased drowsiness occurred in the afternoon in 7 (26?‘0) of the guanfacine-treated compared with 16
180
t
200
0
I5 I: 0, 3
150 100
F 50
-
0 m 0
Placebo (n = 21)
m
Placebo (n = 21)
Guanfacine
0
Guanfacine
(n = 21)
FIGURE 3. Baseline and endpoint means of total serum cholesterol
I
Endpoint
Endpoint (n = 21)
FIGURE 4. Baseline and endpoint means of low density lipoprotein (LDL) determinations.
March 28, 1986
(57%) of the guanabenz-treated patients, Evening drowsiness increased in 5 (18%] guanfacine-treated patients and in 11 (39%) guanabenz-treated patients. The significantly lower incidence of somnolence in patients taking guanfacine compared with those taking guanabenz is clearly evident in Figure 7. The incidence of other adverse reactions was also greater with guanabenz than with guanfacine. Only 2 (7%) of the 27 guanfacine patients reported side effects other than somnolence, compared with 7 (25%) of the 28 patients receiving guanabenz. These results indicate that monotherapy with guanfacine (1 mg/day) is as effective as monotherapy with guanabenz (8 mg, 2 times a day] in the treatment of mild to moderate hypertension. However, guanfacine offers the advantage of once-a-day dosage. Further, somnolence, which is a major reason for drug discontinuance with this class of drugs, was far less prevalent with guanfacine.
Discussion Treatment of patients with mild to moderate essential hypertension is most appropriately initiated with a single antihypertensive agent, as opposed to drug combinations. With monotherapy, the possibility of adverse reactions is reduced. In addition, the greater simplicity and convenience of the single-drug regimen encourage compliance, and thus promotes clinical success. Sympatholytic antihypertensive drugs, such as the central a-adrenoceptor agonists, are often effective initially; however, as single drugs they often lose therapeutic efficacy due to associated salt and water retention As a result, a diuretic agent must be added to the regimen.8 The lack of change in plasma volume and plasma aldosterone levels observed during guanfacine therapy indicates that this is not a major problem with guanfacine, extending the usefulness of this drug as monotherapy in hypertension. The lack of effect of guanfacine on lipid metabolism is also of great interest, because a number of class90
THE AMERICAN
JOURNAL
OF CARDiOLOGY
Volume 57
53E
es of drugs commonly used as monotherapy in the treatment of hypertension have been shown to alter the lipid profile. In periods as short as 4 to 8 weeks, diuretics have been shown to elevate total cholesterol, total triglycerides, low density lipoprotein cholesterol or very low density lipoprotein cholesterol,+13 as well as to reduce levels of HDL.1°-13 The most significant change in lipid metabolism seen with /3 blockers is a decrease in HDL,14J5 which has also been observed with the &3 blocker labetalol.13 Because elevations in low density lipoprotein cholesterol and reductions in HDL cholesterol have been associated with an increased risk of coronary artery disease and myocardial infarction,16 such changes in lipid metabolism, when induced by medication to lower blood pressure, may be substituting 1 coronary risk factor (altered lipid levels) for another (hypertension). The fact that guanfacine has been shown to have no effect on lipid metabolism according to the parameters measured in study 2 may make it a safer drug to use in
8 2 g e m y
0
Ii 5
100 90 80
P< .OOOl
70 1
0
Initiation of double-blind treatment with placebo (broken rule) or guanfacine (unbroken rule) I 0
I 5
I 25
I 15
I 35
I 45
I 55
Day oi Study FIGURE 6. Diastolic blood pressure (BP) means in guanfaclnetreated patients and placebo controls.
r
.-5 5 P Baseline m
Placebo (n
0
Guanfaclne
0
Morning
Endpoint 21) (n
21)
FIGURE 5. Baseline and endpoint means of high density lipoprotein (HDL) determinations.
Afternoon
0
Guanfacine
(n = 27)
m
Guanabenz
(n = 28)
FtGURE 7. Incidence of somnolence treated patients.
in guanfacine-
Evening
and guanabenz-
54E
A SYMPOSIUM:
GUANFACINE-A
NEW CHOICE
IN CENTRALLY
patients who are already at greater risk of coronary disease. In summary, guanfacine is an effective monotherapy in the treatment of mild to moderate hypertension. No effect on plasma volume or plasma aldosterone was seen during a z-month study, and no alterations in serum lipid or lipoprotein levels were observed. Compared with guanabenz, another new central cu-adrenoceptor agonist, guanfacine was equally effective in reducing BP, but it produced a far lower incidence of somnolence and other side effects and has the added advantage of once-a-day dosage.
References 1. Jerie P, Lasance A. Guanfacine in the treatment of hypertension: two years experience with low dose monotherapy. Int J Clin Pharmocol Ther Toxicol 1981;19:279-287. 2. Saameli K, Scholtysik G. Waite R. Pharmacology of BS 100-141,a centrally acting antihypertensive drug. Clin Exp Pharmacol Physidl 1975;2:suppl 2:207-212. 3. Laura R, Reda G, Spallone L, Beretta Anguissola A. Hypotensive effect of
guanfacine in essential hypertension: a comparison with clonidine. Br 1 Clin Pharmacol 198O;lO:supp~:81S-82s. 4. Pacha W, Salzmann R, Scholtysik G. Inhibitory _ effects of clonidine and BS 100-141 on response to sympathetic nerve stimulation in cdts and rabbits. Br r Pharmacol 1975;53:513-5%. 5. Scholtysik G, jerie P. Pharmacological and clinical effects of BS 100-141,a
ACTING
ANTIHYPERTENSIVE
AGENTS
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