Summary

Drugs 11 (Suppl. 1): 164-171 (1976) © ADIS Press 1976

Session VII: Use of jj-Adrenoreceptor Blocking Drugs in Hypertension

Chairman: Dr G.S.M. Kellaway (Auckland)

Experience with jj-Adrenoreceptor Blockers in Hypertension

Hendrika J. Waal-Manning

Wellcome Medical Research Institute, Department of Medicine, University of Otago Medical School, Dunedin

At the Dunedin Hypertension Clinic (J·blockers are the drugs of choice for most hypertensive patients. usually in combination with diuretics (especially in older subjects) and often with other drugs in the more severe cases. All (J-blockers have an antihypertensive effect. regardless of other characteristics (e.g. cardio·selectivity. instrinsic sympathomimetic effect. or membrane activity). d·Propranolol has no significant effect on blood pressure. (J-Blockers do not prevent stress·induced (mental arithmetic) rises in blood pressure in hypertensive subjects though the level of blood pressure reached during stress tends to be lower because the base line is lower. Twice-daily dosage of (J·blockers is usually satisfactory.

At the Dunedin Hypertension Clinic we have now had a decade's experience with /3-blocking drugs in hypertension. Our present policy is that /3-blockers are the drugs of choice for most hyper-tensives who are free from heart failure and asthma. In the more severe cases of hypertension, they are given together with a diuretic and, if necessary, a vasodilator like hydrallazine or prazo-sin. Special indications for the use of /3-blockers in hypertensive patients include angina, arrhythmias, sinus tachycardia, dissecting aneurysm, side-effects or poor control of blood pressure on other drugs,

and a need to use tricyclic antidepressant drugs. However, there is no need to restrict the /3-blockers to such patients.

Contra-indications for /3-blocker therapy in-clude asthma and other chronic respiratory disease, impaired myocardial function (including symptomless cardiac enlargement), impaired A-V conduction, Raynaud's phenomenon, and severe hypertension when the need to reduce blood pres-sure is urgent. In depressed patients propranolol is best avoided. These contra-indications are in some cases relative only.

fj-Blockers in hypertension

Table I. Blood pressure in a patient with malignant hypertension, on various drugs

Months Day test mean Drug(s) Dose on treat- blood pressure (mg/day) ment (mm Hg)

Lying Standing

0 204/117 184/121 Nil 5 158/96 157/97 Cyclopen- 0.5

thiazide/K Methyldopa' 1500

10 190/122 187/120 Nil 16 206/124 192/122 Cyclopen- 0.5

thiazide/K Debrisoquine 165 'Hydergine' 0.5

22 179/115 1741115 Cyclopen- 0 .5 thiazide/K Bethanidine 155

22 191/120 1751120 Cyclopen- 0.5 thiazide/K

23 125/89 120/89 Cyclopen- 0.5 thiazide/K Oxprenolol 180

1 Haemolytic anaemia developed after 5 months and methyldopa was stopped

1. Efficacy of (3-Blockers in Comparison with Other Antihypertensive Drugs

Table I illustrates blood pressure control with various drugs in a malignant hypertensive. After five months, reasonable control was attained on cyc\openthiazide and methyldopa. However, haemolytic anaemia developed and methyldopa was stopped. Blood pressure control on both debrisoquine and bethanidine was unsatisfactory but on a daily dose of 180mg oxprenolol good blood pressure control was attained. Fig. 1 illu-strates another patient with malignant hyper-tension whose blood pressure responded well to propranolol alone.

165

In a formal study (Waal-Manning and Simpson, 1974), the efficacy of the j3-blocking drug pindolol was assessed in 6 groups of 8 patients whose blood pressure was not optimally controlled: one group was on a diuretic only, while the other 5 groups were, respectively, on rauwolfia, guanethidine, methyldopa, debrisoquine, or bethanidine (with, in two-thirds of the subjects, a diuretic, the dose of which was continued unchanged throughout the trial). After preliminary observations the treat-ment was switched stepwise to pindolol. 46 patients entered the trial, 41 completed it.

At the start of the trial (fig. 2) the patients showed moderately good blood pressure control on their previous therapy - blood pressures of 162/97 when lying, 147/94 when standing and 165/95 after exercise. The change to pin dolo I brought improvement in blood pressure control, especially in the lying position - the group mean lying blood pressure being 146/88, the standing one 133/87, and after exercise 159/90.

In each sub-group also (fig. 2), the change to pindolol led to an improvement in resting blood pressure. A small rise in post-exercise systolic blood pressure was seen in the ex-guanethidine group and in diastolic pressure in the ex-debriso-Quine group, presumably because of elimination of

. •• l'

"~tOto< . _~.'" {) .............. "'t I'"

0-,* . _ ... .. __ .l~'"

• (,

Fig. 1. Effect of propranolol therapy in a patient with malignant hypertension.

Symposium on hypertension 166

170 l I ~ I ' "!' I l 160 l 51 I I 150 I I 140 ' I l 1 .....

1 1 ... :::> 130 ~

~ CI 120 CI CI oJ CD

110

100

I~' 90 i05ll. ~

80 ALL 60n 80n Ion 6 on 5 on • on 41 cyclo Rouw guon mt-d dfbr b,1I1.

Fig. 2. Effect of change to pindolol (P; arrow heads) from previous drug (PO; ends of arrow shafts) i.e. cyclo-penthiazide, rauwolfia, guanethidine, methyldopa, debrisoquine or bethanidine. In each group of 3 arrows, the first represents lying blood pressure, the second standing, and the third post-exercise standing.

exercise hypotension in some subjects on these drugs.

Only 2 patients failed completely to respond to pindolol. One of these had to stop the trial. This gives a 90 to 95% response rate to pindolol in these patients. In our experience, the response rate of hypertension to J3-blockade with or without a diuretic has been rather higher than in other studies reported in the literature.

2. What Is There To Choose Between J3-Blockers?

Table II illustrates some of the different charac-teristics of some j3-adrenoreceptor blocking drugs.

On a mg for mg basis, they differ in potency with pindolol being the most potent. Oxprenolol, pindolol and practolol all exhibit partial agonist activity, pindolol probably possessing the most though this has to be assessed relative to the j3-blocking activity. Practolol and metoprolol are cardio-selective j3-blockers, and of the J3-blockers listed all except practolol and metoprolol possess lipid solubility and thus the ability readily to pene-trate the blood-brain barrier.

Membrane-stabilising activity is strong in pro-pranolol, not quite so strong in pindolol and oxprenolol, absent in practolol and only very slightly present in metoprolol.

How do these differences affect the clinical use of J3-blockers in hypertension?

{3-Blockers in hypertension

We gave propranolol, d-propranolol, oxprenolol, pindolol, practolol and placebo tablets in turn in fortnightly courses to mildly hypertensive patients known to respond to j3-blockers (Waal-Manning, 1970). The dosage levels selected for the 4 j3-blockers were in proportion to the reported j3-blocking potency of these drugs in animal experi-ments. d-Propranolol dosage was equivalent to racemic propranolol dosage or slightly higher.

The effect of these compounds on lying blood and standing blood pressure is seen in fig. 3. The falls in both systolic and diastolic blood pressure on racemic propranolol, oxprenolol, pin dolo I and practolol are approximately equal. d-Propranolol

No. 01 potients 35 35 31

180

~ '1 ,

~I 110

160 1-0 I + 150 I-

..... "" 140 I-::0 ~

~ 130 l:-e> 8 .....

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lowers blood pressure hardly at all; it has, of course, virtually no j3-blocking activity.

We concluded that the antihypertensive action of the various f3-blockers is approximately equal and is related to f3-blockade. As the cardio-selective compound practolol has antihypertensive activity, it is evident that f3-blockade is what is required.

The effect on heart rate is shown in fig. 4. Racemic propranolol slowed the pulse rate more than practolol, pindolol and oxprenolol, probably because it lacks partial agonist activity.

We have now also had experience with the cardio-selective drug metoprolol in some 60 hyper-tensive patients and have conducted a double-blind

3D 34

I I CD 110 -~ostl I ' ' l I l I 100

90 r-

80

mg/doy Dl propron. o propran. oxprfll. pind. pract. 15] 176 181 14· 5 SOD

Fig. 3. Effect of various j3.blockers (dl-propranolol, d-propranolol, oxprenolol, pindolol and practolol) given in turn to a group of patients. The blood pressure on each drug (0; arrow heads) can be compared with the blood pressure for the same patients during placebo treatment (P; ends of arrow shaftl. In each pair of arrows, the first represents lying blood pressure and the second standing.

Symposium on hypertension

Table II. Some differences of {3-adrenorecptor blocking drugs

{3-recep- Partial Car Lipid Mem-tor agonist dio- sol. brane blockade activity sel- Stabil.

ect. activity

Propranolol ++ + ++ (+)-propranolol ± + ++ Oxprenolol ++ + + + Pindolol ++++ ++ + + Practolol + + + Metoprolol ++ + ± ±

crossover trial in 19 of the milder ones who were on a steady dose. Table III illustrates the results of the double-blind crossover trial of metoprolol and shows that during metoprolol therapy lying and standing blood pressure fell by an average of 20mm Hg systolic and 10mm Hg diastolic. The blood pressure during mental arithmetic was also reduced, although the rise in BP during mental arithmetic was, if anything, slightly enhanced. In addition to its blood pressure lowering effect, metoprolol had also a striking effect in slowing heart rate, by 15 beats per minute in the lying posture, 20 in the standing and 18 during mental arithmetic. Metoprolol has no intrinsic sympa-thomimetic effect.

Metoprolol is probably not lipid soluble and in our experience no eNS side-effects have occurred in contrast to propranolol with which we have had serious depressions (Waal, 1967). Propranolol is lipid soluble and therefore penetrates into the brain; so do pindolol and oxprenolol but they have partial agonist activity which may protect against depression.

The rather stronger partial agonist activity of pindolol may be responsible for a phenomenon which we have observed among pindolol-treated patients over the last 2 years and which we have termed 'high-dose pindolol hypertension'.

We were alerted to the possibility of this phenomenon in a patient with malignant hyper-

168

tension who responded quite well to pindolol 15mg/day initially and then, as the dose was increased to 25mg/day, the BP rose. It fell again when the dose was reduced.

Subsequently we looked for this hypertensive effect (perhaps more precisely called reversal of antihypertensive effect) of pindolol in patients with poorly controlled blood pressures on rela-tively high pindolol dosages (Waal-Manning and Simpson, 1975). Nine patients who had poor BP control while taking a high dose of pindolol came for a morning test during which 5 lying and standing blood pressure and pulse readings were taken by trained technicians. The dose of pindolol was then reduced and a further morning test was. done after an interval of 1 to 4 weeks. In all 9 patients the blood pressure fell as illustrated in table IV. The pulse rate did not alter Significantly. We have not observed this phenomenon with other /3-blockers.

3. Frequency of Dosage

Another point of difference between the i3-blockers is the duration of action. Pindolol, for instance, has a relatively prolonged /3-blocking action. In man a single oral dose of 10mg pro-

No of patients ( --'-Iymg; -standing) 3!5 35 31 30 34

w V> -'

90

so

ir 70

!

j j . I : •

d I·propron. d-propran oxpren mg/day 153 176 181

. j ~

! !

I ...

proct 500

Fig. 4. Effect of various {3-blockers on heart rate in the same group of patients as in fig. 3. P = placebo, 0 = drug.

J3-Blockers in hypertension

Table III. Metoprolol double-blind crossover trial in 19 patients; eight patients were on a diuretic throughout the trial

Lying Systolic (mm Hg) Diastolic (mm Hg) Pulse (beats/min)

Standing Systolic (mm Hg) Diastolic (mm Hg) Pulse (beats/min)

Placebo Meto-for pro-3 wks 101 for

3 wks1

162 143 97 86 73 58

152 135 100 88 83 63

During mental stress (sitting) Systolic (mm Hg) 182 171 Diastolic (mm Hg) 115 108 Pulse (beats/min) 83 65

1 Mean dose 206mg/day 2 p < 0.05 3 p < 0.001 (paired 't' test)

Change

-193 -11 3 -153

-183 -123 -203

-112 -72 -183

duced {3-blockade, assessed by the effect of iso-prenaline infusion on the heart rate, for up to 24 hours (Olsson and Varnauskas, 1973). We (Waal-Manning and Wood, 1975) did a formal trial of b.d. versus t.d.s. dosage of pindolol by measuring afternoon lying and standing blood pressure, pulse rate and plasma pindolol levels, on two occasions, a month apart, in 16 patients whose hypertension was well-controlled either on pindolol alone or on pindolol with a diuretic. During the first month preceding the afternoon test the daily dose of pindolol was given in either 2 or 3 divided doses, eight patients being in each dosage schedule. During the second month patients had the alter-native schedule.

Table V illustrates the blood pressure levels and pulse rate levels in all the 16 patients on the b.d. and t.d.s. regimens. It appears that for the control of hypertension, pindolol can be given as a b.d. regimen in most patients, although mean standing

169

pulse levels were Significantly higher on the b.d. regimen. Plasma pindolollevels were measured in 7 patients: the mean 4pm level on the t.d.s. regi-men was 38ng/ml (range 22 to 60ng/ml), with a mean fall of 14ng/ml (range 2.5 to 35ng/ml) on the b.d. regimen (p < 0.02; paired '1' test).

4. Conclusion

In conclusion, {3-blockers, both non-selective and cardio-selective, all lower blood pressure in responsive hypertensive patients by virtue of j3-blockade, although the mechanism is not certain. Their other properties modify the degree of pulse slowing and possibly their antiarrhythmic effect, and determine the incidence of side-effects, e.g. cardio-selectivity lessens the risk of bronchospasm and peripheral vasoconstriction, while partial agonist activity may prevent depression with the lipid soluble j3-blockers but may also be respon-sible for 'high-dose hypertension'. {3-Blockers with a relatively prolonged action can be given on a b.d. basis.

Table/V. Effect of lowering dosage of pindolol in 9 patients

Pindo- Pindo- Change 101 101 re-high- duced-dose1 dose2

Lying Systolic (mm Hg) 196 179 -175

Diastolic (mm Hg) 120 108 -123 Pulse (beats/m'in) 76 75 -1

Standing Systolic (mm Hg) 176 160 -165 Diastolic (mm Hg) 115 106 -94 Pulse (beats/min) 79 76 -3

Mean dose 48mg/day (range -27.5 to 67.5mg/day) 2 Mean dose 19m9/day (range 7.5 to 30mg day) 3 p <0.05 4 p <0.01 5 p <0.002

Symposium on hypertension

Table V. Comparison between twice daily and thrice daily dosage of pindolol 1

Lying BP (mm Hg) Pulse (beats/min)

Standing BP (mm Hg) Pulse (beats/min)

t.d.s Effect of dosage

141/83 71

129/86 79

change to b.d. dosage

+7/+2 +3

+1/+2 +52

n = 16; mean daily dose of pindolol21mg 2 p<0.02 (paired 't' test!

Acknowledgement

These studies were supported by the Medical Research Council of New Zealand.

References

Olsson, S.B. and Varnauskas, F.: Duration of beta-receptor blockade after oral administration of LB46. European Journal of Clinical Pharmacology 5: 214 (1973).

Waal-Manning, H.J.: Propranolol-induced depression. British Medical Journal 2: 50 (1967).

Waal-Manning, H.J.: Comparative studies on the hypo-tensive effects of beta-adrenergic receptor blockers; in Simpson (Ed.) Beta-adrenergic Receptor Blocking Drugs, p.64-72, Ciba Symposium, Auckland 1970 (Australasian Drug Information Services, Auckland 1970).

Waal-Manning, H.J. and Simpson, F .0.: Pindolol: A comparison with other antihypertensive drugs and a double-blind placebo trial. New Zealand Medical Jour-na180: 151-157 (1974).

Waal-Manning, H.J. and Simpson, F.O.: Paradoxical effect of pindolol. British Medical Journal 2: 155-156 (1975).

Waal-Manning, H.J. and Wood, A.J.: Pindolol in hyper-tension: Twice-daily versus thrice-daily dosage. Medical Journal of Australia 2: 274-275 (1975).

170

Author's address: Dr H.I. Waal·Manning, Wellcome Medical Research Institute, Department of Medicine, Uni-versity of Otago Medical School, P.O. Box 913, Dunedin (New Zealand).

Discussion

Dr I.G. Lyall (Geelong): Does metoprolol cause de-pression? Secondly, if one has a patient who develops Raynaud's phenomenon on one drug such as propranolol, and yet because of angina and other reasons is best suited to control by P-blockers, is there an alternative P-blocker on which they are unlikely to have this complication?

Dr Waal-Manning: The first question, metoprolol and CNS depression: we have not encountered depression among the 60 patients we have treated so far. The Ray-naud's phenomenon on non-selective p-blockade often improves on selective P-blockade. In other words, if the patient treated with propranolol for angina is switched to metoprolol for instance (seeing we no longer have practo-101 available to us), the effect on angina is usually equally good and we usually see less Raynaud's phenomenon. However, Raynaud's phenomenon can occur with meto-prolol.

Dr Berglund: You stated that increased A-V con-duction time was a contra-indication. Do you mean even of the first degree? You don't give P-blockers when there is a longer PQ time than normal?

Dr Waal-Manning: Unless there are other over-riding considerations, no.

Dr Berglund: We haven't used that contra-indication in Goteborg in our material and we haven't seen many prob-lems in giving p-blockers to patients with increased A-V conduction time of grade 1. Could I ask also whether you had any form of placebo period between the study periods?

Dr Waal-Manning: Yes, we had one placebo period, not necessarily in the beginning, sometimes in the middle.

Dr Berglund: The carryover effect of P-blockers can be very long and could seriously distort the results.

Dr IG. McPherson (Hastings): Bearing in mind your paper in session V and your statement that you fre-q uently use thiazide diuretics and P-blockers together, do you now have any disquiet about using two drugs each of which impairs carbohydrate tolerance?

Dr Waal-Manning: My message was that perhaps with selective P-blockade you might improve the carbohydrate intolerance.

Dr McPherson: In other words you have to pick your drugs?

Dr Waal-Manning: Yes.

/3-Slockers and lung function

Dr Hallwright: Would Dr Waal-Manning agree that the Raynaud's phenomenon is only relatively a contra-indication because many of the strong agents precipitate or aggravate Raynaud's phenomenon - this goes back to the days of pentolinium. We find that although we certainly aggravate Raynaud's phenomenon with treat-ment, most patients tolerate it, and we have not found it a great drawback.

Dr Waal-Manning: I would agree that it is only a rela-tive contra-indication.

Dr Corbett: Can you tell us how certain the evidence is that propranolol is causing depression in your patients? It is a common condition, and can you tell us how many patients and how clear is the evidence that this is a direct

171

result of the drug? Dr Waal-Manning: I am speaking from my own experi-

ences with the drug about a decade ago when we lost two patients who committed suicide while taking it. We then analysed our patients and reported the results in the liter-ature at the time (Brit. med. J. 2: 50, 1967).

Dr Gordon: Dr Waal-Manning has raised the question of twice daily versus three times daily administration. I would like to briefly make the comment that using home blood pressures we have compared once daily, twice daily and thrice daily administration with both pindolol and propranolol and found that once daily administration (a single dose at breakfast time) is as effective as the other two regimens.

Drugs 11 (Suppl. 1): 171-177 (1976) © ADIS Press 1976

Summary

Use of ~-Adrenoreceptor Blockers in Combination with ~-Stimulators in Patients with Obstructive Lung Disease

G. Johnsson

Medical Department, AS Hassle, Molndal

Lung function can be reduced not only by a non-selective /3-blocker but also by a selective /3. -receptor blocker. If both types 0/0 drug are without intrinsic sympathomimetic activity, the effect of the non-selective drug is more pronounced than that of a /31 -receptor selective drug under balllli conditions.

The effect of a /32-receptor stimulating drug on the bronchi is inhibited by a non-selec· tive drug, but much less by a selective /3, -receptor blocker. A selective i3, -receptor blocker can be used in asthmatics when it is combined with optimal anti-asthmatic therapy, while a non-selective drug is contra-indicated in patients with broncho-obstructive diseases.

It is necessary to induce bronchodilatation (e.g. with a /32 -stimulator) in order to test whether or not a /3-blocker can be used in broncho-obstructive disease.

Patients with asthma and other broncho-obstructive diseases often suffer from other diseases such as angina pectoris, arrhythmias, etc. for which a l3-adrenoreceptor blocking drug may

be indicated. Non-selective I3-blockers are contra-indicated in patients with chronic asthma, while from a theoretical point of view selective i31-receptor blockers can be used in these patients.