efficacy of clonidine as transdermal therapeutic system: the international clinical trial experience

Volume 112 Number 4 Pathophysiology of essentirrl hypertension

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Berglund G, Anderson 0: Beta-blockade or diuretics in hypertension: A six-year follow-up of blood pressure and metabolic side effects. Lancet 1981;1:744. Schauer I, Schauer U, Ruhling K, Thielmann K: The effect of propranolol treatment on total cholesterol, HDL cholesterol, triglycerides, post hepatic lipolytic activity and leci- thin. Artery 1980;8:146. Leren P, Helgeland A: Effect of propranolol and prazosin on blood linids: The Oslo studv. Lancet 1980;2:4. Day JL, Metcalfe J, Simpson CN: Adrenergic mechanisms in control of plasma lipid concentration. Br Med J 1982; 284:1145. Ames RB, Hill P: Antihypertensive therapy and the risk of coronary heart disease. J Cardiovasc Pharmacol 1982; 4(suppl 2):206. Dujovne CH, DeCoursey S, Krehbiel P: Serum lipids in normo- and hyperlipidemics after methyldopa and propran- 0101. Clin Pharmacol Ther 1984;36:157. Riiddel H, Schmieder R, Langewitz W, Neus J, Wagner 0, von Eiff AW: Efficacy of nitrendipine as baseline antihypertensive therapy. J Cardiovasc Pharmacol 1984;6(suppl 7):39. Weinberger MH: Blood pressure and metabolic response to hydrochlorothiazide, captopril, and the combination in black and white mild to moderate hypertensive patients. J Cardiovasc Pharmacol 1.985;7(suppl 1):52. Weinberzer MH: Antihvnertensive theranv and lioids: Evi- dence, mechanisms ar;d implications. Arch Intern Med 1985;145:1102. Lowenstein J: Clonidine. Ann Intern Med 1980;92:74. Lawson AA, Keston M: Clonidine in hypertension: A 6 year review. Curr Med Res Opin 1979;6:168.

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Johnson P, Kitchin A: Treatment of hypertension with methyldopa. Br Med J 1966;1:133. Bayliss RIS, Harvey-Smith EA: Methyldopa in treatment of hypertension. Lancet 1962;1:763. Frohlich ED: Methyldopa-mechanisms and treatment twenty-five years later. Arch Intern Med 1980;140:954. Nies AS: Adverse reactions and interactions limiting the use of antihypertensive drug. Am J Med 1975;58:493. Safar ME, London GM: Effect of alpha-methyldopa on cardiac output in hypertension. Clin Pharmacol Ther 1979;25(B):266. Amery A, Verstraete M: Hypotensive action and side effects of clonodine-chlorthalidone and methyldopa-chlorthalidone in treatment of hypertension. Br Med J 1970,4:392. Toubes DB, McIntosh TJ, Kirkendall WM, Wilson WR: Hypertensive effects of clonidine and chlorthalidone. AM

HEART J 1971;82:312. Wortledge S, Carstairs KC, Dacie .JV: Autoimmune hemo- lytic anemia associated with alpha met hyldopa therapy. Lancet 1966;2:135. Taghill PJ, Smith PC, Benton P, Brown RC. Matthews HL: Methyldopa liver damage. Br Med J 1979;3:545. Glontz GE. Saslaw S: Methvldona fever Arch Intern Med

” _

1968;122:445. Thananopavarn C, Golub MS, Samblie Ml? Clonidine 1n the elderly hypertensive. Chest 1983;2(suppl):410. Weber HA. Draver JI. Brewer DD. I&son JL: Transdermal continuous antihypertensive therapy.&Lancet 1984;2:231. Popli S, Stroka G, Ing TS, Daugiradas JT, Norusis HJ, Hano JE, Gandhi VC: Transdermal clonidine for antihypcr- tensive patients. Clin Ther 1983:5:62-t.

Efficacy of clonidine as transdermal therapeutic system: The international clinical trial experience

Worldwide clinical trial data concerning the pharmacokinetic and pharmacodynamic characteristics of the clonidlne transdermal therapeutic system (TTS) are reviewed with reference to its antihypertensive efficacy. The amount of clonidlne delivered to the systemic circulation is a direct function of TTS size. After initial patch application, there is a delay of 2 to 3 days before the onset of action, but after removal of the patch, plasma clonldine levels decline slowly, at an elimination half-life of about 20 hours. Evaluation in approximately 2000 patients with mild to moderate hypertension has shown that the bioavailability of transdermal clonidine is comparable to that of oral clonidine and that equivalent blood pressure reductions are achieved. The rate at which dose increases were found necessary to maintain adequate blood pressure control over extended periods reflects a low incidence of tolerance to thfs new once-a-week dosage form of clonidine, and there has been ltttle evidence of rebound hypertension after discontinuation of TTS treatment. (AM HEART J 1988;112:893.)

D. T. Lowenthal, S. Saris, E. Paran, N. Cristal, K. Sharif, C. Bies, and T. Fagan. Philadelphia, Pa.

From Hahnemann University, Likoff Cardiovascular Institute.

Reprint requests: David T. Lowenthal, M.D., Hahnemann University, Clinical trial experience with the clonidine transder-

Likoff Cardiovascular Institute, 230 N. Broad St.. Philadelphia, PA mal therapeutic system (TTS) has been reported in 191w1. more than 40 papers and abstracts describing

893

894 Lowenthal et al. October, 1966

American Heart Journal

PLASMA CONCENTRATION no/ml

0 1 2 3 4 5

Fig. 1. Percent decrease in standing systolic blood pressure as a function of plasma clonidine concentration.10

research conducted in the United States, Holland, Switzerland, Germany, France, the United King- dom, and New Zealand.

PHARMACOKINETICS

The kinetics of oral clonidine are known to be linear over its normal dosing range, and the correlation between plasma clonidine levels and therapeutic effect has been well established. Pharmacokinet- ic and pharmacodynamic studies of clonidine in normotensive volunteers as well as in hypertensive subjects have in fact demonstrated a linear relation between decreases in blood pressure and the loga- rithm of plasma clonidine concentration within the range of 0.2 to 2.0 rig/ml (Fig. 1). Maximum reductions in mean arterial blood pressure (MAP) are observed between 2 and 3 hours after oral administration of clonidine and correspond closely to peak plasma concentrationsl-l3

Definitive bioavailability data on clonidine-TTS were generated in a crossover study in 17 normotensive subjects who received in random sequence oral clonidine, 0.1 mg twice daily for 4 days, and a 5 cm2 transdermal patch of clonidine to be worn for 7 days (Fig. 2).‘* After attainment of steady state on day 4 of treatment with this 5 cm2 TTS, the area under the plasma level curve equalled 76% of that obtained with 0.1 mg of oral clonidine given twice daily. From

2. Mean plasma concentrations of clonidine in 17 subjects during wearing and after removal of clonidine- TTS. Arrows indicate application (day 0) and removal (day 7) of system. (Adapted from Shaw JE: Pharmacoki- netics of nitroglycerin and clonidine delivered by the transdermal route. AM HEART J 1984;108:217-223.)

this it was inferred that a transdermal system with an area of approximately 7 cm2 would deliver amounts of the drug equivalent to 0.1 mg given twice a day orally. This extrapolation was based on a series of dose proportionality studies confirming that between patch surface areas of 3.5 and 10.5 cm2 the amount of clonidine available to the systemic circulation is a direct function of TTS size.15

According to these pharmacokinetic trials (per- formed in normotensive subjects), administration of a 3.5 cm2 patch (clonidine-TTS-1) provides a mean steady-state plasma clonidine level of 0.3 & 0.1 ng/ ml, falling within the established low end of the therapeutic range. Several clinical trials of the clonidine-TTS in which plasma levels were monitored have borne out this observation.“j* l7

Two other important kinetic characteristics related to the clinical efficacy of transdermal clonidine should be noted. The first is a delay of 2 to 3 days in the onset of action after initial patch application. This slow onset is attributed to formation of an epidermal clonidine reservoir beneath the patch as the drug binds to skin proteins. Use of the product is therefore not appropriate for the acute management of hypertensive urgencies; it also would not be efficacious when acutely administered during the perioperative period. This slow onset of effect must also be kept in mind when clonidine-TTS is to be substituted for other antihypertensive therapy. Gradual dose reduction of the previous medication is advisable. Particularly in patients with more severe forms of hypertension, the previous antihypertensive treatment may have to be continued in full or in part concomitantly with the TTS.

The second important product characteristic is

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Number 4 Eficac.y of transdrrmal vhnidine 895

10 m 1 uoniiilm-TTS

m 2 CbnklineTTS

6 m 3 ClonMim-l-rs

I

+3

f 2 4

0.2 mg oral 0.3 * OnI 0.4 mg ORI 0.6 mg OnI

Daily Ckmidina Dam

Fig. 3. Dosages of oral and transdermal clonidine (number of systems applied) needed for blood pressure control in patients in whom TTS was substituted for oral thera- PY.

the gradual tapering of plasma clonidine levels after removal of the patch, with an elimination half-life of about 20 hours. This natural tapering of plasma clonidine levels may lessen the risk of significant rebound hypertension after discontinuation of treatment. To date, there have been few reports of rebound hypertension following cessation of clonidine-TTS therapy. Additional clinical experience, particularly in patients with moderate to severe degrees of hypertension, is needed, however, to confirm the absence of rebound.

PHARMACODYNAMICS

In the first two (unpublished) clinical trials of the product, conducted in 1977 and 1978, two small circular patches, each measuring 1.6 cm2, were applied in the postauricular area of 20 patients. Adhesion of the patch at this site for the full 7 days proved unsatisfactory in several of these patients, and after 2 weeks of therapy the blood pressure was less effectively controlled than it had been prior to oral clonidine treatment.

This early experience led to employment of a larger patch (3.9 cm”) that was applied to the outer surface of the upper arm in two studies conducted in 1981 and 1982 (personal communication). Under a common protocol, the investigators evaluated the antihypertensive efficacy (and side effects) of this clonidine-TTS in 37 patients with mild to moderate hypertension who had previously been controlled with oral clonidine, 0.2 to 0.6 mg/day, and hydrochlorothiazide (50 mg/day). After discontinuation of oral clonidine administration, a TTS titration phase was initiated, the number of patches applied each

120-

1.00 -

s .Z 2 g .a0 -

0

[ eo-

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c 40-

20-

-L -

00 OHR 4l-m OHR 4HR OHR 4HR OHR 4HR

oral End 01 PwakaOf 4wuksol Chidb Titmtlon l-EisobkDor TTssmbbDoa

Fig. 4. Plasma clonidine concentration (nanograms per milliliter). Mean values during treatment wit,h oral clonidine and clonidine-TTS (n = 15).

week being increased, as needed, to a maximum of three per week. The goal was to lower the blood pressure to the reference level achieved during oral clonidine therapy. Oral hydrochlorothiazide treatment (50 mg daily) was continued throughout the period of transdermal clonidine therapy. The dosage of clonidine-TTS, that is, the number of systems needed for adequate blood pressure control in the two studies, is shown in Fig. 3. Most of the patients (31 of 37) were controlled with one or two patches. Eleven of thirteen patients who had previously been treated orally with 0.4 to 0.6 mg of clonidine required two or three patches for adequate blood pressure control. No unequivocal correlation between TTS dosage and the previous oral clonidine dose could be established, since the response to transdermal clonidine varied markedly from one subject to another.

Mean plasma clonidine concentrations recorded during treatment with oral clonidine and after clonidine-TTS, respectively, are presented in Fig. 4. Despite the substantial intersubject variability in response to oral and transdermal clonidine, the mean plasma levels obtained at the end of the titration phase and after 2 and 4 weeks of stable- dose clonidine-TTS therapy did not differ significantly from the steady-state trough levels obtained with oral clonidine. As anticipated, the clonidine levels reached after TTS administration were statis- tically significantly lower than the peak levels obtained during oral clonidine therapy.

696 Lowenthal et al. October, 1986


i

lhJdmdTIabnontma.

Fig. 5. Percentages of hypertensive patients (n = 85) whose blood pressures were normalized or who were classified as responders after 1, 2, and 3 months of treatment with clonidine hydrochloride administered transdermally.19

,001

Fig. 6. Diastolic blood pressures (mean -+ SEM) during initial placebo administration, active treatment with transdermally administered clonidine, and during post treatment placebo administration. (Adapted from Weber MA, Drayer JIM, et al: Transdermal continuous antihypertensive therapy. Lancet 1984;1:9-11.)

In 1982 a five-center study was initiated in the United States to evaluate clonidine-TTS monotherapy as initial treatment for mild hypertension. Each center was to contribute 20 patients with mild hypertension. On admission, the patients received placebo-TTS weekly for 2 weeks to confirm the diagnosis of mild hypertension. They then entered a titration phase of 1 to 3 weeks in which the dosage of clonidine-TTS (3.5 cm2) was increased from one to three patches if blood pressure was not adequately controlled, control being defined as a seated diastolic blood pressure of less than 90 mm Hg or a 10 mm Hg decrease in seated diastolic blood pressure if the baseline was between 100 and 104 mm Hg. Patients

mood Rrun

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10

I(0

120

100

00 i

Fig. 7. Systolic and diastolic blood pressure and heart rate during maintenance treatment with clonidine-TTS. Significant changes from baseline values are indicated by an asterisk (*p < 0.001). (Adapted from Groth H, et al: Transdermales Clonidin: ein neues Therapieprinzip bei essentieller Hypertonie? Schweiz Rundsch Med Prax 1985;74:10-14.)

adequately controlled during the titration phase then continued to be treated at the effective dose level for 3 months.

Eighty-five patients completed at least 3 weeks of therapy and were included in the published efficacy analysis.‘8 Adequate blood pressure control was achieved in 54 patients (64%); 17 patients required only one patch, 27 patients responded to two patches, and 10 to three (Fig. 5). No development of tolerance was observed inasmuch as the degree of response to clonidine-TTS monotherapy did not decline during the 3-month stable-dose period. Responsiveness to clonidine-TTS therapy was not related to sex, race, age, or body weight. At one center, placebo patches were substituted for clonidine-TTS after 3 months of treatment in 12 patients (Fig. 6). During a l-week post-treatment placebo period, blood pressures rose slowly to before-treatment levels in these patients; in none was there any evidence of acute rebound hypertension.20

Concurrently with the multiclinic trial in the United States, several clinical studies of clonidine- TTS were being conducted in Europe and New Zealand. While Dr. Vetter’s group in ZiirichzO was the first to report contact sensitization associated with chronic clonidine-TTS therapy, this 36-patient study with a mean observation period of 10.2 months (range of 1 to 25 months) confirmed that excellent short-term and long-term control of blood pressure can be achieved by this transdermal treatment. Clonidine-TTS significantly reduced average systolic and diastolic blood pressure from 168/107

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Number 4 Efficacy of transdermal c1onidin.e 897

100 02.2~2.2 82.Sf2.5

60

r

Oral clcntdina AttwTTs Aftw4tiTTS AttW1~lT.S tnmtbll shbbdaa

Fig. 8. Sitting blood pressure (millimeters of mercury); mean values (n = 17) + SEM.

mm Hg to 148/91 mm Hg after 4 weeks of treatment. Twenty-three patients achieved adequate blood pressure control with clonidine-TTS alone (Fig. 7). Thirteen patients (37 % ) received, in addition, daily doses of 50 mg hydrochlorothiazide; the combined medication normalized the blood pressure in eight of them. When the diuretic was later withdrawn in two cases, no increase in blood pressure resulted. No development of tolerance to clonidine-TTS was apparent during long-term treatment.

Boekhorst et aL21 evaluated clonidine-TTS (in combination with a diuretic) in patients with mild to moderate hypertension who had been controlled with oral clonidine at a maximal daily dose of 0.45 mg. Seventeen of 20 patients enrolled in this study completed 1 year of treatment with one to three 3.5 cm2 patches per week. In 10 of the 17 patients, the dosage of clonidine-TTS remained unchanged throughout the year. In two patients the clonidine- TTS dose was increased; in two other patients it was increased and additional antihypertensive medication was given, and three patients required the addition of another antihypertensive drug. The blood pressure values obtained with the TTS did not significantly differ from those in the preceding oral clonidine treatment phase (Fig. 8).

Schaller et a1.22 were the first to report results of ambulatory blood pressure monitoring during and after clonidine-TTS therapy, which was carried out in seven patients for 4 weeks. While blood pressure decreases recorded in the clinician’s office fell short of statistical significance, significant reductions from a baseline of 159/97 mm Hg to 136/76 mm Hg were noted on ambulatory monitoring during the patients’ customary daily activities (Fig. 9). Kella- way et al.23 reported results of an open-label trial of

"1

150 +++ + r” *I* * * ++ + + + +I+ + E

II bm + t ij

*+ l + * ++a**** l **+

MM 1MM 12PM 2PM @#A opu WM

Fig. 9. Profiles of blood pressure recorded by ambulatory system before and after 4 weeks of transdermal treatment with clonidine hydrochloride (n = 7, means i. SEM). Asterisks indicate p < 0.05, and crosses indicate p < 0.01. (Adapted from Schaller MD, Nussberger J, Waeber B, Porchet M, Brunner HR: Transdermal clonidine therapy in hypertensive patients. JAMA 1985;253:233- 235.)

loo 88

3 I, * * * * 96 \

60 ’ I I I I 1

Wine Endct 1 Month 2MonttM 3 Months TitnHon

MMtonanw Thmpy

Fig. 10. Mean sitting and standing diastolic blood pressure (millimeters of mercury) over time for patients controlled by clonidine-TTS. *p < 0.0005. dashed line = standing BP; solid line = sitting BP. (Adapted from Kellaway GSM, Lubbe WF: Catapres-TTS monotherapy for the treatment of mild hypertension in general practice: A preliminary report. In Weber MA, et al, editors: Low dose oral and transdermal therapy of hypertension. Darm- stadt, 1985, Steinkopff, pp. 122-125.)

clonidine-TTS in mild hypertension designed simi- larly to the multiclinic study in the United States (Fig. 10). Blood pressure control was achieved in 32 of 36 patients (89%), and there were no significant differences between blood pressure levels after 1, 2, and 3 months of stable-dose treatment as compared with the values at the end of the titration period

898 Lowenthal et al. October. 1986


Table I. Blood pressure and pulse in responders to transdermal clonidine

Control

Titration Maintenance

(2-6 weeks) (3 + months)

No. 9 9 6 Sitting BP (mm Hg) 159 ~fr 6/98 2 1 135 +- 5*/19 + 2* 129 I 8*/73 t 3* Sitting pulse (bpm) 76 t 3 76 t 3 75 + 3 Standing BP (mm Hg) 155 iz 5/93 2 2 135 * 9*/77 i 3* 123 + lo*/67 i 3*

Standing pulse (bpm) 74 * 2 79 i 2 79 i 2

*p < 0.001 vs control (Student’s paired t test).

BP = blood pressure.

(Fig. 10). Sixteen, eight, and eight patients, respectively, required one, two, and three patches, each containing 2.5 mg of clonidine.

Meanwhile, several additional U.S. studies have been published that sought to evaluate the useful- ness of the clonidine transdermal system in special subgroups of hypertensive patients.

Two of these studies were concerned with the geriatric population. Klein et a1.24 studied 20 men between the ages of 60 and 75 who had mild hypertension. Seventeen patients (85 % ) were found to be clonidine-TTS responders, response being defined as a lowering of diastolic blood pressure to less than 90 mm Hg with at least a 5 mm Hg decrement from baseline. Therapy was associated with a sustained decline in plasma norepinephrine levels; however, changes in plasma catecholamines did not significantly correlate with changes in blood pressure. Patient acceptance was generally excellent, with most responders choosing to continue clonidine-TTS therapy after completion of the study.

Golub et a1.25 reported preliminary results of an ongoing study of clonidine-TTS in elderly mildly hypertensive patients. Nine of 10 patients achieved the desired blood pressure reduction. One patient required two TTS-2 patches (corresponding to 0.4 mg of clonidine per day), and one patient required two TTS-3 patches (corresponding to 0.6 mg daily).* From a mean baseline level of 159/98 mm Hg, the average seated blood pressure was reduced to 135/79 mm Hg after a titration period of 2 to 6 weeks. After 3 months of maintenance therapy, the mean seated blood pressure was 129/73 mm Hg (Table I). While plasma norepinephrine levels decreased significantly in responsive patients, no relation between the changes in plasma norepinephrine and the blood pressure response was demonstrable.

*One TTS-1 patch provides a daily dose ofO.1 mg, one TTS-2 patch a daily dose of 0.2 mg, and one TTS-3 patch a daily dose of 0.3 mg over a 7.day period.

Wallin et alz6 evaluated clonidine-TTS therapy in 16 diabetic patients with mild hypertension. Supine blood pressure was reduced from a mean baseline of 144194 mm Hg to 132/81 mm Hg at the end of the titration period. Twelve of the patients maintained adequate blood pressure control on the lowest dose, clonidine-TTS-1, over the entire 3-month treatment period (Fig. 11).

The effectiveness of the transdermal system in the treatment of adolescent hypertension was inves- tigated by Falkner et a1.27 Twenty-two patients, with an age range of 14 to 19 years and diastolic blood pressures in excess of the ninety-fifth percentile for age, were treated with clonidine-TTS with the objective of reducing the blood pressure to the ninetieth percentile. Baseline blood pressures were 145/100 mm Hg in 14 male patients and 139/97 mm Hg in eight female patients. When dosage had been stabilized, mean blood pressure was reduced to 130/85 mm Hg in the men, and to 125/82 mm Hg in the women. Adequate blood pressure control was obtained with clonidine-TTS-1 in 12 patients, with TTS-2 in six, and with TTS-3 in three. Only one patient required concomitant diuretic treatment for adequate control.

The pharmacodynamic effects of oral and transdermal clonidine were studied by Lowenthal et a1.17 in eight hypertensive patients with chronic renal insufficiency. Following gradual withdrawal of previously administered antihypertensive drugs, the patients received oral clonidine together with a diuretic, and when the end point for the diastolic pressure was reached, clonidine-TTS was substituted in a dosage approximating the maximal dose level reached with oral clonidine. The maximal blood pressure reduction achieved at the maximal oral level was maintained after 4 weeks of transder- ma1 therapy (Fig. 12).

According to preliminary long-term efhcacy data from 242 patients with mild hypertension partici- pating in a continuing multicenter trial of chronic clonidine-TTS therapy, seated blood pressure was

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Number 4 Efficacy of transdumni c,i:midintl 899

Fig. 11. Baseline blood pressure, blood pressure at end of clonidine-TTS titration, and after 3 months of clonidine-TTS maintenance therapy. (Adapted from Wallin JD, Krane NK, Bergman S, Morgan M: The use of transcutaneous clonidine hydrochloride in the patient with diabetes mellitus and mild hypertension. J Clin Hypertension 1985;4:315-21.)

reduced after a titration period of 2 to 6 weeks to 130/83 mm Hg from a mean baseline level of 142/95 mm Hg. Adequate blood pressure control has been maintained in 85% to 90% of the patients during a treatment period of 1 year. An analysis of the frequency with which dosage had to be readjusted during this period has shown that, to date, 171 of the 242 patients (71%) have required no change in dosage. Fifty-four patients (22%) required one dose adjustment, while 14 patients (6%) had their dose revised twice during the year and two patients had three dose adjustments (personal communication).

The only double-blind, placebo-controlled trial of clonidine-TTS was conducted by Dr. Ing’s group at the Hines (Illinois) Veterans Administration Hospi- tal.** In this parallel-group study, 30 mildly hypertensive patients were treated for 5 weeks. Control of blood pressure, with diastolic values reduced to less than 90 mm Hg, was obtained in 11 of 15 clonidine- treated patients but in only 4 of 15 placebo patients (p < 0.05). Blood pressure reductions averaged 12/8 mm Hg in the clonidine-TTS group as compared with 4/4 mm Hg in the placebo group. In the clonidine group, blood pressures and plasma clonidine levels (mean value: 0.58 + 0.06 rig/ml) remained stable during a representative 7-day period. On completion of the treatment course, all the patients received a placebo-TTS in order to test for any evidence of rebound hypertension after 24 hours, 48 hours, and 1 week. None of the patients developed clonidine withdrawal symptoms and no rebound hypertension occurred.

Fig. 12. Standing systolic and diastolic blood pressure before treatment, after oral clonidine titration, and during clonidine-TTS therapy.”

In sum, approximately 2000 patients have taken part in international clinical trials of the clonidine- TTS. All the studies were designed to evaluate this novel delivery system in patients with mild to moderate hypertension; as yet, it has not been studied in severe hypertension. We thus have abun- dant evidence that the bioavailability of transder- ma1 clonidine is comparable to that of oral clonidine and that equivalent blood pressure reductions are achieved. While some patients require dosage adjustment during long-term treatment, the rate at which dose increases were found necessary to maintain adequate blood pressure control over extended periods reflects a low incidence of tolerance to clonidine-TTS. This new once-a-week dosage form of clonidine may therefore be considered as effective as conventional oral clonidine treatment. Its poten- tial advantages in terms of tolerability and compli- ance are the subject of a separate review. REFERENCES

1. Arndts D, Doevandans J, Kirsten R, Heintz B: New aspects of the pharmacokinetics and pharmacodynamics of clonidine in man. Eur J Clin Pharmacol 1983;24:21-30

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Lowenthal et al. October, 1966


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16. Kolloch R, Finster H, Overlack A, Miiller HM, Stumpe KO: Low-dose oral and transdermal application of clonidine in mild hypertension: Hemodynamic and biochemical corre- lates. In Weber MA, et al, editors: Low dose oral and transdermal therapy of hypertension. Darmstadt, 1985, Steinkopff, pp. 71-80.

17. Lowenthal DT, Saris SD, Falkner B, Porter RS, Haratz A, Packer J, Bies C, Conry K: Pharmacodynamics and pharmacokinetics of oral and transdermal clonidine in chronic renal insufficiency. In Weber MA, et al, editors: Low dose oral and

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transdermal therapy of hypertension, Darmstadt, 1985, Steinkopff, pp. 86-92. Weber MA, Drayer JI, McMahon FG, Hamburger R, Shah AR, Kirk LN: Transdermal administration of clonidine for treatment of high BP. Arch Intern Med 1984;144:1211- 1213. Weber MA, Drayer JIM, Brewer DD, Lipson JI: Transdermal continuous antihypertensive therapy. Lancet 1984;1:9-11. Groth H, Greminger P, Vetter H, Kniisel J, Baumgart P, Siegenthaler W, Vetter W: Transdermales Clonidin: ein neues Therapieprinzip bei essentieller Hypertonie? Schweiz Rundsch Med Prax 1985;74:10-14. Boekhorst JC, von To1 RGL: Catapres transdermal therapeutic system (TI’S) for long-term treatment of hypertension. In Weber MA, et al, editors: Low dose oral and transdermal therapy of hypertension. Darmstadt, 1985, Steinkopff, pp. 106-110. Schaller MD, Nussberger J, Waeber B, Porchet M, Brunner HR: Transdermal clonidine therapy in hypertensive patients. JAMA 1985;253:233-235. Kellawav GSM. Lubbe WF: Catanres-TTS monotheranv for the trea*tment of mild hyperteniion in general practice: A preliminary report. In Weber MA, et al, editors: Low dose oral and transdermal therapy of hypertension. Darmstadt, 1985, Steinkopff, pp. 122-125. Klein C, Morton N, Kellery S, Metz S: Transdermal clonidine in elderly mild hypertensives. In: The sympathetic nervous system in the pathogenesis, complications, and treatment of hypertension. (abstr). Symposium, Milan, Italy, 1985. Golub MS, Thananopavarn C, Sambhi MP: Transdermal clonidine in elderly patients with mild hypertension: Effects on blood pressure and plasma catecholamines. In Weber MA, et al, editors: Low dose oral and transdermal therapy of hypertension. Darmstadt, 1985, Steinkopff, pp. 16-21. Wallin JD, Krane NK, Bergman S, Morgan M: The use of transcutaneous clonidine hydrochloride in the patient with diabetes mellitus and mild hypertension. J Clin Hypertension 1985;4:315-21. Falkner B, Lowenthal DT, Thanki B: Transcutaneous clonidine in the treatment of adolescent hypertension. Clin Phar- macol Ther 1985;37:195. Popli S, Daugirdas JT, Ing TS, Neubauer JA, Hockenberry B, Hano JE: A double-blind, placebo-controlled trial of transdermal clonidine in mild hypertension. Circulation 1985;72(suppl III):lll-112.

Clinical acceptability of transdermal clonidine: A large-scale evaluation by practitioners

John Hollifield, M.D. Nashville, Tenn.

The centrally acting antihypertensive agent, clonidine hydrochloride, has been used effectively for many years, eithsr alone or in combination with other drugs, for oral treatment of mild, moderate,

From University of Tennessee School of Medicine, and Nashville Hyper- tension Center.

Reprint requests: John Hollifield, M.D., Dept. of Medicine, Hypertension Center, Vanderbilt University Medical School, Nashville, TN 37232

and severe hypertension. 1-3 Its mechanism of action involves the stimulation of a-adrenoceptors in the brain stem, which results in reduced sympathetic outflow from the central nervous system and decreases in peripheral vascular resistance, heart rate, and blood pressure, with essentially no change in renal blood flow or glomerular filtration rate. The drug does not alter normal hemodynamic responses to exercise.4

efficacy of clonidine as transdermal therapeutic system: the international clinical trial experience

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