abrupt and gradual change from clonidine to beta blockers in hypertension

Acta Med Scand 21 1: 375-380, 1982

Abrupt and Gradual Change from Clonidine to Beta Blockers in Hypertension

Mauno Lilja, Antti J. Jounela, Heikki J . Juustila and Lennart Paalzow

From the Department of Medicine, University of Oulu, Oulu, Finland, and the Faculty of Pharmacy, University of Uppsala, Biomedical Center,

Uppsala, Sweden

ABSTRACT. Elective change of antihypertensive therapy from clonidine to /3-blockers was studied in 18 hypertensive inpatients on diuretic treatment. An abrupt cessation of clonidine (0.3 mg t.i.d.) and start of treatment 12 hours later with atenolol (50 mg b.i.d.) resulted, within 24-36 hours, in severe rise of blood pressure and intolerable symptoms of clonidine withdrawal in all 4 patients studied. Plasma noradrenaline levels were elevated 18-24 hours after the last dose of clonidine. Halving the previous daily clonidine dose (0.15 mg t.i.d.) and discontinuing it after three days on concomitant treatment with atenolol or timolol in increasing doses proved successful and caused only few side-effects in 14 hypertensive inpatients.

Key words: hypertension, withdrawal reaction, clonidine, atenolol, timolol, interaction. Acta Med Scand 211: 375-380, 1982. Received July 17, 1981.

Beta blockers and clonidine are widely used antihypertensive drugs. Abrupt cessation of clonidine may provoke a syndrome suggestive of catecholamine release. Severe rebound rise of blood pressure with tachycardia, sweating, restlessness and headache has been described (6, 8, 10).

Since an increasing number of hypertensive patients are liable to be treated with @-blockers, and because clonidine is also widely used both on a long-term basis and in hypertensive crisis, both concomitant and subsequent administration of these drugs is common in clinical practice. It has been shown that concomitant sotalol reverses the antihypertensive response to clonidine (15). We were not able to confirm this finding during administration of propranolol or atenolol simultaneously with clonidine (12). On the other hand, the deleterious effect of propranolol on the clonidine withdrawal reaction is well documented (2, 7).

The possible interaction of clonidine and P-blockers during elective change of antihypertensive therapy from clonidine to /3-blockers is investigated in this study.

PATIENTS AND METHODS

Abrupt Cessa t ion o j c l o n i d i n e and Subsequent Start with Atenolol

Four hypertensive inpatients on diuretic plus clonidine therapy were selected for this pilot study. They suffered from tiredness and dry mouth as side-effects of clonidine. Their previous drug treatment is shown in Table I. The patients were hospitalized on a Monday at noon and clonidine was withdrawn on Tuesday at 8p.m. (day 1, Fig. 1). Diuretic treatment was continued. On Wednesday morning (day 2, Fig. 1) administration of atenolol, 50 mg twice daily (at 8 a.m. and 8 p.m.), was started.

Blood pressure and heart rate. Blood pressure was measured with a sphygmomanometer in the right arm after 15 min rest in the supine position and after 3 min standing. Three readings were recorded in the supine and two in the standing position, each 1 min apart, and the results were calculated from the corresponding averages. The measurements were made at 4, 8 and 11 a.m. and at 2, 5, 8 and 12 p.m. by three trained nurses. Heart rate was measured after the blood pressure measurements in the supine and standing positions for 60 sec by palpation at the wrist.

Side-effects. At each blood pressure measurement the patients were questioned about side-effects possibly related to withdrawal of clonidine.

Exclusions. If the blood pressure exceeded 240 mmHg systolic or 125 mmHg diastolic, or if intolerable side-effects occurred, the patient was excluded from the study and clonidine treatment was reinstituted.

Laboratory examinations. On the first day, after examination of the medical history and when the patients had undergone a physical examination, a chest X-ray was taken and an ECG was recorded. Thereafter, blood and urine specimens were taken for laboratory determinations of blood count, ESR, serum concentrations of sodium,

Address for correspondence: M. Lilja, M.D., Department of Medicine, Oulu University Central Hospital, PL 191, SF-90100 Oulu 10, Finland.

Acrci Med Sccind 211

316 M . Libu et (11.

BP 200 mmHg 190

180 170 160 150 1LO 130 120 110 100 90

Table I. Previoirs drug treutment of foirr putients n7hose clonidine treatment n m abruptly chunged to atenolol

- - - L

- - - - - - - -

J-

Pat. Age WHO Drugs administered in the no. (y.) Sex class preceding 3 years

ng/rnl 0 6 O L 0 2

I 64 d 111 Clonidine 0.3 mg t.i.d., triamterene 50 mg + trichlormethiazide 1 mg q.d., digoxin 0.25 mg q.d.

chlorthalidone 50 mg q.d., digoxin 0.25 mg q.d.

hydrochlorothiazide 50 mg q.d.

hydrochlorothiazide 25 mg q.d.

2 51 0 I11 Clonidine 0.3 mg t.i.d.,

3 50 P I Clonidine 0.3 mg t.i.d.,

4 51 d I Clonidine 0.3 mg t.i.d.,

- - -

potassium, creatinine. calcium and phosphate, and G r a d i d Cessation of Clonidine und Concomitant Start with PBlockers in urinalysis. Further blood samples for determination of

plasma noradrenaline concentrations (1 1) were drawn at Increasing Doses 8 a.m. and at 2 and 8 p.m. after 15 min rest.

PIosma clonidinr drtrrtnination. Blood samples for de- Fourteen hypertensive inpatients with side-effects of termination of plasma clonidine concentrations (4) were clonidine participated in this trial. They were randomly taken at 8 a.m. and at 2 and 8 p.m. on day 2 (Fig. 1). allocated to groups treated with either atenolol or timolol. Plasma clonidine half-life was read from the linear part of Table I 1 shows their mean age, duration of hypertension the time-concentration curve on a semi log. graph. and WHO class. All patients had essential hypertension.

P-CL 20 nglrnl 15

0 5

/ / /A I

L’/6,3’mg/ ’t id / / A 1/ A’ 50 mg bid’/ // - D = I = U = R = E = - T = I = C

1 4 8 11 1L 17 20 I L 8 11 1L 17 20 I HRS

Day 1 Day 2

Fig. 1 . Mean (? SD) supine systolic and diastolic blood pressure (BP ), heart rate ( H R ) , plasma clonidine (P- C L ) and plasma noradrenaline ( P - N A ) at abrupt cessation of clonidine (CL) , 0.3 mg t.i.d. and subsequent initiation of atenolol ( A ) administration, 50 mg b.i.d., in four (day 1) and three (day 2) patients on diuretics. * p C0.05, * * p <O.O 1, ***p<O.OOl compared to values 24 hours earlier.

Arta Med Scand 211

Chnnges in antihypertensive therapy 377

Table 11. Clinical data on 14 patients whose clonidine treatment was gradually changed to atenolol or timolol

Sex Age (Y .) Duration of hypertension (y.) WHO class

d P Mean Range Mean Range I I1 111

Atenolol group 4 3 43 28-64 8 1-13 Timolol group 5 2 49 3 1-69 7 2-10

4 1 2 3 1 3

One patient in the timolol group had slightly elevated serum creatinine level (150 pmol/l). Due to the long duration of hypertension, it was impossible to get information about the pretreatment blood pressure and heart rate values of all patients at the time of diagnosis. All patients had taken clonidine, 0.15 mg t.i.d., for at least four months.

Drug treatnient. The previous dose of clonidine, 0.15 rng t.i.d., was diminished to 0.075 mg t.i.d. on admission (Monday at noon). On Tuesday the clonidine dose was 0.0375 mg t.i.d. and on Wednesday 0.0375 rng b.i.d. The last dose of clonidine was given on Wednesday at 8 p.m. On the day of admission, administration of atenolol, 12.5 mg twice daily (7 patients), or timolol, 2.5 mg twice daily

HEART RATE BEATSlmin 5 0

(7 patients), was initiated at random. On Tuesday the atenolol dose was increased to 25 mg b.i.d. and timolol dose to 5 mg b.i.d. The doses on Wednesday and thereafter were 50 mg atenolol b i d . and 10 mg timolol b.i.d. (Fig. 2). Diuretics were maintained throughout the study in 13 patients and diuretic plus hydralazine in one patient.

Procedures carried out in this part of the trial were the same as those described above. Plasma noradrenaline and clonidine concentrations were not determined.

Statistical analysis The paired t-test was used for comparison of mean values of blood pressure, heart rate, plasma noradrenaline and clonidine.

T T ! r

T

1 A or T ' A o r T

1 I,T b

CL CL I

Day 1 Day 2 Day 3 Day 4 Day 5 Fig. 2 . Mean (+ SD) supine systolic and diastolic blood pressure (BP) and heart rate ( H R ) during gradual cessation of clonidine (CL) and concomitant initiation of

atenolol (A) (-, 7 patients) and timolol (T) administration in increasing doses (---, 7 patients).

Acta Med Srand 211

378 M . Liija et al.

Table 111. Supine and standing blood pressure (BP, mmHg) and heart rate (HR, beatslmin), and plasma noradrenaline (P-NA, nglml) in four patients ut various times afler cessation of clonidine, 0.3 mg t . i .d. Atenolol (50 mg b.i.d.) was started at 12 hours

Hours after cessation of clonidine Pat. Side- no. - 12 0 12 18 24 28 36 effectsc

1 Supine BP HR

Standing BP HR

P-NA 2 Supine

BP HR

Standing BP HR

P-NA 3 Supine

BP HR

Standing BP HR

P-NA 4 Supine

BP HR

Standing BP HR

P-NA Mean f SD

Supine BP

HR Standing

BP

130/100 50

120/100 66 0.44

130180 48

150195

0.21

130190

60

50

120195

0.52

160/100

78

48

1401110 68 0. I6

135t151 9 5 t I3 49t 1

l33f 151 100t7

120/80 50

120190

0. I6

170/105

64

50

160/105

0.36

1601100

54

56

I45195 80 0.30

150190 46

135/100

0.33 72

150k221 94+ 11 51k4

l40f 171 91k15

6617 73I20 P-NA 0.33k0.17 0.29f0.09

135/95 50

1451 105

0.44

170/100

76

52

1401110

0.21

1501100 68

1401110

0.34

130170

48

68

46

120175 64

0.55

146k181 91t14 58f8

l36f 11/ 100k17 64f 12

135/100 52

l50/l05

0.92

1901110

60

48

l85/ I05

0.65

l8OlllO

52

60

170/120

0.85

160190

80

58

l5OlllO 64

0.40

166t 24"l l03f 10 55t6

164+ 17"/ 110t7 64f 12

0.38f0.14 0.71 k0.23b

1 501 105 48

160/110

1.23

2251115

60

40

210/110

0.61

210/120

42

56

1901130

0.80

210/120

80

64

170/120 68 -

199f 39b/ 115f7b 52f7

1 94f 2461 118k10 63f I6 0.88f0.24"

160/100 1801120 50 48

165/105 140/120 +++ 60 70

2401 120 42

2351120 42

+++

2201 130 52

++

+++

~ < 0 . 0 5 , ~ ~ ~ 0 . 0 1 compared to values 24 hours earlier. ++=Moderate. +++=severe.

RESULTS

Abrupt Cessation of Clonidine and Subsequent Start with Atenolol

The antihypertensive treatment of four patients was abruptly changed from clonidine, 0.3 mg t.i.d., to atenolol, 50 mg b.i.d., while on continuous diuretic therapy. All four patients had experienced disturbing subjective symptoms of restlessness, sweating, headache and insomnia within 24-36 hours after the last dose of clonidine (Table 111). Fig. 1 shows the significant rises in the mean values of supine sys-

Actu Mrd Scund 21 I

tolic and diastolic blood pressures. The heart rate, however, remained unchanged. Plasma noradrenaline measured 18-24 hours after the last dose o f clonidine was also elevated compared to the values 24 hours earlier (Fig. 1, Table 111). Readministra- tion of clonidine was necessary in all four patients because of side-effects. These disappeared and the blood pressure was normalized 2-4 hours thereafter.

Plasma clonidine determinations. The approximate half-life of clonidine in these patients was

Changes in crntihypertensive therapy 379

Table IV. Plasma clonidine (CL) Concentration, approximate half-life ( T 112) of clonidine, plasma noradrenaline (P-NA) and blood pressure (BP) after abrupt cessation of clonidine, 0.3 mg t.i.d. Atenolol, 50 mg b.i.d., was started 12 hours after cessation of clonidine

Hours Plasma BP (mmHg)

no. cessation (nglrnl) (h) (nglrnl) Supine Standing Pat. after CL CL T1/2 Of CL P-NA

1 12 18 24

2 12 18 24

3 12 24

4 12 18

2.0 1.4 1 .o 1.4 1 . 1 0.8 1.4 0.6

I .9 0.5

0.44 0.92

12.0 1.23 0.21 0.65

14.9 0.61 0.34

9.8 0.80 0.55

3 .1 0.40

135/95 1351 100 l50/l05 170/100 190/110 225/ 1 I5 l50/ 100 210/120 130/70 160/90

145/ 105 l50/l05 160/110

140/110 1 85/ I05 210/110 140/110 190/130 120/75 l50/l10

9.8-14.6 hours, except for one patient with very low concentration at 18 hours and, consequently, a short half-life (Table IV). To prevent the rebound rise in the blood pressure, it appeared that a plasma level of about 1 nglrnl or more was needed (Table IV, Fig. 1).

Gradual Cessation of Clonidine and Concomitant Start with p-Blockers in Increasing

Doses In a group of seven patients the treatment was gradually changed within three days from clonidine, 0.15 mg t.i.d., to atenolol, 50 mg b.i.d., and in another group of seven patients to timolol, 10 mg b.i.d. The mean values of supine systolic and diastolic blood pressures did not show the same tenden- cy towards hypertensive reaction as in patients whose clonidine treatment was abruptly replaced by atenolol (Fig. 2, Table V). An alarming rise of supine blood pressure was, however, observed in one patient changed to atenolol (30/25 mmHg) and in another changed to timolol (75/40 mmHg). No patient on either timolol or atenolol had disturbing side-effects demanding retreatment with clonidine.

DISCUSSION

Beta blocker therapy may exacerbate clonidine withdrawal hypertension (2, 7), possibly due to the blockade of &receptor mediated vasodilatation. In such situations p,-selective blockers should be ben- eficial. The present results do not confirm this hypothesis. Change to p,-selective atenolol resulted in intolerable subjective symptoms of clonidine withdrawal as well as in a severe rise of blood

pressure, necessitating reinstitution of clonidine treatment in all four patients. This might depend on the strong a-receptor mediated vasoconstriction during catecholamine release uninfluenced by the relatively weak &mediated vasodilatation.

The absence of tachycardia, common in the clonidine withdrawal reaction, proves an efficient p- blockade in our patients. It should be noted that treatment with parenteral phentolamine plus p- blocker has successfully counteracted the clonidine withdrawal reaction (6). Other drugs reported to be useful in this situation are parenteral hydralazine, diazoxide or labetalol (1, 14).

Patients showing a pronounced rebound increase in the blood pressure also exhibited a significant increase in plasma noradrenaline. This is in agree- ment with previous findings (6, 10).

Plasma clonidine levels indicated that about 1 ng/ml is necessary to prevent the increase in blood pressure. No detailed pharmacokinetic evaluation has been performed in our patients but approximate half-lives of clonidine in three of them corre- sponded to those reported for clonidine administered per 0s (3, 5).

The incidence and severity of the clonidine withdrawal reaction seem to be related to the dose (9), although this assumption has not been confirmed by animal experiments (13). A gradual cessation of clonidine therapy replaced by p-blockers in increasing doses proved to be successful in all 14 of our patients whose drugs were changed in this way. However, the doses of clonidine at the beginning of the change procedure were only half of those given in the pilot study, and the blood pressures varied

Acta Med Scond 21 I

380 M . Lilja et al.

Table V. Supine and standing blood pressure (BP, mmHg) trnd heart rate ( H R , beatslmin) (mean 5 SD) during gradual cessation of clonidine and concomitanf replacement by utenolol (A) in 7 patients and timolol (T) in 7 patients

Supine BP Supine HR Standing BP Standing HR

A T A T A T A T Monday

2 p.m. 151f10/96+10 159f23/106f9 67f15 6 5 f 6 151+9/306+9 141+13/97f9 6626 72f10 8p.m. 150+21/101f10 150+10/101f6 6225 6 1 f 6 145+26/104+13 141+16/99+10 73f15 6 6 f 9

8a.m. 159214/106+8 165+29/108f14 65f10 6145 155+14/109+6 146+21/101+11 79f18 6725 2 p.m. 157fI6/102f8 166f33/106f11 6 4 f 5 6 0 f 6 158f17/112f8 149+18/106f12 68+9 6.524 8p.m. 154+21/101f11 165f27/106f9 6 1 f 3 6 1 f 4 158+21/109+9 149+8/107+10 7 1 f 7 67+9

8a.m. 156fI8/104f 10 169f29/109k11 6 3 f 6 6 0 f 6 148+17/108+7 149+17/109+9 73f8 69+5 2 p.m. 152f20/101f13 163222/106f8 6 1 f 4 6 1 f 5 151f11/108f10 146+15/10127 69210 6 5 i 6 8p.m. 164+29/104+13 170f27/104f11 61f4 56+8 157f30/114216 157f18/108t13 71f8 61 f8

8a.m. 161f29/99f8 165+23/104+8 60f5 56+8 144f19/105+12 144+14/104+8 75+7 67f8 2 p.m. 156+17/96+10 164f23/108+7 60+5 58f6 144f13/106+8 146+15/106+9 6 8 f 7 64+5 8p.m. 158f16/101+6 173f38/107+13 6 1 f 9 5 4 f 5 147t19/106+11 152+26/106+10 66f11 6 0 f 6

8a.m. 164+20/100+5 154+24/109f11 6 3 f 8 5 7 f 5 146+8/111+13 147+21/111+11 70f7 68+7

Tuesday

Wednesday

Thursday

Friday

greatly between individuals in both groups. On the other hand, subjective symptoms were few and, as a rule, mild.

It can be conluded that an abrupt change from clonidine to a p-blocker was unsuccessful. A gradual change from clonidine to p-blockers was more successful, but even this procedure necessitates a careful patient observation, preferably in hospital. Beta,-selective atenolol was not advantageous in this context.

1.

2.

3.

4.

5 .

6.

REFERENCES Agabiti Rosei, E. , Brown, J . J., Lever, A. F., Robertson, J . I. S. & Trust, P. M.: Treatment of pheochromocytoma and clonidine withdrawal hypertension with labetalol. Br J Clin Pharmacol 3: 809, 1976. Bailey, R. R. Br Neale, T . J.: Rapid clonidine withdrawal with blood pressure overshoot exaggerated by Beta-blockade. Br Med J 1: 942, 1976. Dollery, C. T., Davies, D. S., Draffan, G. H. et al.: Clinical pharmacology and pharmacokinetics of clonidine. Clin Pharmacol Ther 19: 11, 1976. Edlund, P. 0.: Determination of clonidine in human plasma by glass capillary gas chromatography with electron-capture detection. J Chromatography 187: 161, 1979. Frisk-Holmberg, M., Edlund, P. 0. & Paalzow, L.: Pharmacokinetics of clonidine and its relation to the hypotensive effect in patients. Br J Clin Pharmacol 6227, 1978. Hansson, L., Hunyor, S. N., Julius, S. & Hoobler, S.

W.: Blood pressure crisis following withdrawal of clonidine (Catapres, Catapresan) with special refer- ence to arterial and urinary catecholamine levels, and suggestion for acute management. Am Heart J 85: 605, 1973.

7. Harris, A. I.: Clonidine withdrawal and blockade. Lancet 1: 596, 1976.

8. Hokfelt, B., Hedeland, H. & Dymling, J . D.: Studies on catecholamines, renin and aldosterone following Catapresan (2-2,6dichlorphenylamine-2 imidazoline hydrochloride) in hypertensive patients. Eur J Phar- macol 10: 389, 1970.

9. Hoobler, S. W. & Kashima, T.: Central nervous sys- tem actions of clonidine in hypertension. Mayo Clin R o c 52: 395, 1977.

10. Hunyor, S. N., Hansson, L., Harrison, T . S. & Hoo- bler, S. W.: Effects of clonidine withdrawal: Possible mechanisms and suggestion for management. Br Med J 2: 209, 1973.

1 1 . Lake, C. R., Ziegler, M. G. & Kopin, I. J.: Use of plasma norepinephrine for evaluation of sympathetic neuronal function in man. Life Sci 18: 1315, 1976.

12. Lilja, M., Jounela, A. J., Juustila, H. & Mattila, M. J.: Interaction of clonidine and p-blockers. Acta Med Scand 207: 173, 1980.

13. Oates, H. F . , Stokes, L. M., Monaghan, J . C. & Stokes, G. S.: Withdrawal of clonidine: Effects of varying dosage or duration of treatment on subsequent blood pressure and heart rate responses. J Pharmacol Exp Ther 206 268, 1978.

14. Reid, J . L., Dargie, H. J. , Davies, D. S., Wing, L. M. H., Hamilton, C. A. & Dollery, C. T.: Clonidine withdrawal in hypertension. Changes in blood pressure and urinary noradrenaline. Lancet 1: 1171, 1977.

15. Saarimaa, H.: Combination of clonidine and sotalol in hypertension. Br Med J 1: 810, 1976.

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abrupt and gradual change from clonidine to beta blockers in hypertension

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