Hypertension 1988 Frishman II21

8/11/2019 Hypertension 1988 Frishman II21

1/10

W H FrishmanBeta-adrenergic receptor blockers. Adverse effects and drug interactions.

Print ISSN: 0194-911X. Online ISSN: 1524-4563Copyright 1988 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Hypertensiondoi: 10.1161/01.HYP.11.3_Pt_2.II21

1988;11:II21Hypertension.

http://hyper.ahajournals.org/content/11/3_Pt_2/II21

World Wide Web at:The online version of this article, along with updated information and services, is located on the

http://hyper.ahajournals.org//subscriptions/

is online at:HypertensionInformation about subscribing toSubscriptions:http://www.lww.com/reprints

Information about reprints can be found online at:Reprints:

document.Permissions and Rights Question and Answerprocess is available in theRequest Permissions in the middle column of the Web page under Services. Further information about thisOffice. Once the online version of the published article for which permission is being requested is located, click

can be obtained via RightsLink, a service of the Copyright Clearance Center, not the EditorialHypertensionRequests for permissions to reproduce figures, tables, or portions of articles originally published inPermissions:

by guest on May 21, 2014http://hyper.ahajournals.org/Downloaded from by guest on May 21, 2014http://hyper.ahajournals.org/Downloaded from
http://hyper.ahajournals.org/content/11/3_Pt_2/II21http://hyper.ahajournals.org//subscriptions/http://hyper.ahajournals.org//subscriptions/http://hyper.ahajournals.org//subscriptions/http://www.lww.com/reprintshttp://www.lww.com/reprintshttp://www.lww.com/reprintshttp://www.ahajournals.org/site/rights/http://www.ahajournals.org/site/rights/http://hyper.ahajournals.org/http://hyper.ahajournals.org/http://hyper.ahajournals.org/http://hyper.ahajournals.org/http://hyper.ahajournals.org/http://hyper.ahajournals.org//subscriptions/http://www.lww.com/reprintshttp://www.ahajournals.org/site/rights/http://hyper.ahajournals.org/content/11/3_Pt_2/II21


2/10

3 Adrenergic Receptor Blockers

Adverse Effects and Drug Interactions

WILL IAM H. FRISHMAN

SUMM ARY Adverse effects of /3-adrenergic receptor blocking drugs can be divided into two cate-

gories: 1) those that result from known pharmacological consequences of /3-adrenergic receptor

blockade; and 2) other reactions that do not appear to result from /3-adrenergic receptor blockade.

Adverse effects of the first type include bronchospasm, heart failure, prolonged hypoglycemia,

brady cardia, hear t block, intermittent claudication, and R aynaud's phenomenon. Neurological reac-

tions include depression, fatigue, and nightmares. It is not yet proven whether the /3,-selective

adrenergic blockers or those with partial agonist activity reduce the overall frequency of adverse

reactions seen with propranolol. Patient age does not appear, in itself,to be associated with m ore/3-

blocker side effects. Side effects of the second category are rare. They include an unusual oculomuco-

cutaneous reaction and the possibility of oncogenesis. There a re also many drugs th at interact with/3-

blockers, which may increase toxicity. Finally, there are specific patient characteristics where one

/3-blocker may be more effective and safer than another.

(Hypertension 11 [Suppl II]: II-21-II-29, 1988)

KEY

WORDS /3-adrenergic receptor blockers

drug interactions

adv erse effects /3-blocker toxicity

Adverse Effects of /3-Blockers

C

OMPARING and tabulating adverse effects

from different studies of /3-adrenergic

blockers is particularly difficult because of a

number of factors. These include the use of different

definitions of side effects, the kinds of patients stud-

ied, and study design features. Methods of ascertain-

ment and reporting advers e side effects also differ from

study to study.

1

Given these problems, the types and

frequencies of adverse effects attributed to various /9-

blocker compounds appear similar.

2

The side effect

profiles of /3-blockers are also remarkably close to

those seen with concurrent placebo treatments, attest-

ing to the remarkable safety margin of the /3-blockers

as a group.

1 3

The adverse effects of /3-adrenergic receptor

blockers can be divided into two categories: 1) those

from know n pharm acological co nsequences of /3-

adrenergic receptor blockade; and 2) other reactions

that do not appear to result from /3-adrenergic receptor

blockade.

Side effects of the first type are widespread because

of the ubiquitous nature of the sympathetic nervous

system in the control of physiological and metabolic

From the Department of Medicine, The Albert Einstein College

of Medicine, Bronx, New York.

Address for reprints: William Frishman, M.D., 1825 Eastchester

Road, Bronx, New York 10461.

function. They include asthma, heart failure, hypogly-

cemia, bradycardia, heart block, intermittent claudica-

tion, and Raynaud's phenomenon. The incidence of

these adverse effects varies with the /3-blocker used.

Side effects of the second category are rare. They

include an unusual oculomucocutaneous reaction and

the possibility of carcinogenesis.

Major Clinical Experiences

There have been extensive clinical studies designed

to identify the nature and frequency of side effects w ith

/3-blocking agents. The Boston Collaborative Drug

Surveillance Program

4

studied the effects of proprano-

lol (nonselective, no partial agonism) in 800 hospital-

ized patients and of practolol (/3,-selective with partial

agonism) in 199 patients. Forrest

3

reported on the ad-

verse reaction seen with oxprenolol (nonselective with

partial agonism) in 4400 patients receiving the drug for

angina pectoris. Zacharias et al.

6

reported on the side

effects seen with long-term atenolol 03,-selective,

long-acting) treatment in patients with hypertension.

The side effect profiles for pindolol (nonselective with

partial agonism)

7

9

and labetalol (nonselective, a-

blocker)

10

have also been assessed in extensive clinical

trials in hypertensive patients. The long-term /3-

blocker trials in thousands of myocardial infarct survi-

vors have reported on the adverse reactions w ith differ-

ent /3-blocking compounds used in this clinical

situation. '

3 >

-

|S

In the Boston Collaborative Surveillance Program,

4

11-21

by guest on May 21, 2014http://hyper.ahajournals.org/Downloaded from
http://hyper.ahajournals.org/http://hyper.ahajournals.org/http://hyper.ahajournals.org/


3/10

n-22 ANTIHYPERTENSIVE DRUG EFFECTS SUPPL II HYPERTENSION, VOL 11, No 3, MARCH 1988

TABLE 1.

Adverse Reactions to

Propranolol

Among 800

Hospitalized Medical Patients*

Nature of reaction

Life threatening

Shock

Bradycardia and angina

Pulmonary edema

Complete heart block

Subtotal

Non-life threatening

Bradycardia

Hypotension

Congestive heart failure or fluid retention

Gastrointestinal disturbances

CNS disturbances (headache, dizziness,

fatigue, tinnitus, blurring of vision,

paraesthesias, depression)

Bronchospasm

Sensitivity reactions (rash, fever)

2:1 heart block

Elevation in serum phenytoin level

Subtotal

Total with adverse reactions

Patients

()

5

1

3

1

10

17

16

9

9

9

4

3

1

1

69

79

Adverse

reactions

(%)

0.6

0.1

0.4

0.1

1.3

2.1

2.0

1.1

1.1

1.1

0.5

0.4

0.1

0.1

8.6

9.9

With bradycardia in 3 cases and congestive heart failure in 1;

with syncope in 5 cases.

Modified from Greenblatt and Koch-Weser

4

with permission.

propranolol was used for mixed clinical indications,

and adverse reactions were reported in 79 patients

(9 .9% ) .

The se are sum marized in Table 1. Ten adv erse

reactions were considered life threatening, and all ap-

peared to result from im paired cardiac function. Of the

69 other reactions, 43 also involved interference with

cardiac performance but were not deemed life threat-

ening. The frequency of side effects was independent

of the dose used. Adverse reactions were seen more

commonly among older patients.

4

In patients with hypertension, the frequency of ad-

verse reactions with atenolol were reported to be ap-

proximately 15% in a 4-year follow-up study.

6

In an

extensive literature survey in 15,753 patients receiving

pind olol, a similar in cidence of side effects was seen.

16

The frequency of side effects reported in labetalol-

treated patients was similar to those described with

atenolol and pindolol.

10

Forrest

3

reported a 13.7% incidence of side effects

with oxprenolol in patients with angina pectoris. In 12

placebo-controlled long-term studies of patients sur-

viving acute myocardial infarction, the incidence of

side effects ranged from 7 to

20% .

3

'

-

13

The overall

incidence of severe side effects was not much different

from that seen with placebo treatment (Table 2).

3

T he

reason for discontinuing treatment because of side ef-

fects in the largest of these trials (/3-Blocker Heart

Attack Trial [BHA T]: /3-Blocker Post-Infarction Trial)

are shown in Table 3.

In the long-term postinfarction studies using pro-

pranolol (BHAT) and timolol, analyses were per-

formed to assess the side effect profiles of /3-blockers

and placebo therapy in patients with regard to age.

1 7

In these trials, all patients that were entered were be-

lieved to be good candidates for /3-blocker therapy

without contraindications to their use. In the BHAT,

the percentages of patients with complaints were not

significantly different in patients under 60 years of age

from patients over 60 years of age.

17

When assessing

reasons for treatment discontinuation , the incidence of

congestive heart failure was greater in the older age

group; however, other adverse reactions were similar

in older and younger patients.

17

In the Norwegian ti-

molol study,

18

similar observations were made in pa-

tients under 65 years of age and in patients 65 or older.

Overall, it would appear that the nature and frequency

of side effects seen with /3-blocker use in the elderly

are similar to those seen with /3-blocker use in younger

patients.

Adverse Cardiac Effects Related to /3-Adrenergic

Receptor Blockade

MyocardialInfarction

There are several circumstances in which blockade

of/3-receptors may cause congestive heart failure: 1) in

an enlarged heart with impaired myocardial function,

where excessive sympathetic d rive is essential to main-

tain the myocardium on a compensated Starling curve;

and 2) when the left ventricular stroke volume is re-

stricted and tachycardia is needed to maintain cardiac

output.

Considering the factors noted above, any /3-block-

ing drug may be associated with the development of

heart failure. Furth ermore, it is possible that an impor-

tant component of heart failure may be accounted for

by increases in peripheral vascular resistance produced

by nonselective agents (e.g., propranolol, timolol, and

sotalol).

20

It has been claimed that /3-blockers with

intrinsic sympathomimetic activity are better in pre-

serving left ventricular function and less likely to pre-

TABLE 2. Percentage ofPatientsWho StoppedTakingStudyl-BlockersnVarious Long-Term Placebo-Controlled,

Postinfarction Trials

Side effects

Heart failure

Hypotension

Bradycardia

Depression

Fatigue

Pulmonary problems

Practolol

4.1/3.6*

0.6/0.1

0.5/0.1

0.2/0.3

0.3/0.1

NA

Timolol

12

2.9/2.1

2.8/1.2

3.9/0.2

NA

0.4/0.1

1.1/0.4

Metoprolol

13

0.6/1.0

4.2/1.9

2.6/0.7

0/0

0/0

0/0

Propranolol

3

4.0/3.5

1.2/0.3

0.7/0.3

0.4/0.4

1.5/1.0

0.9/0.7

Sotalol

14

2.6/3.8

2.1/0.7

4.4/0

0/0

0.9/0.7

0.5/0.2

Oxprenolol

15

1.8/1.2

0.3/0.2

NA

1.8/0.4

0.5/0.7

NA

Treatment group/placebo group. NA = not available.

Modified from Friedman

1

with permission.



4/10

SIDE EFFECTS OF P-BLOCKERS/Frishman

11-23

TABLE 3 .

Percentage of Patients Withdrawn for Medical

Reasons in fi-Blocker Heart Attack Trial

Adverse effect

Cardiopulmonary

Congestive heart failure

Hypotension

Pulmonary problems

Sinus bradycardia

New or extended

myocardial infarction

Serious ventricular

arrhythmia

Heart block

Syncope

Neuropsychiatric

Tiredness

Disorientation

Depression

Faintness

Nightmares

Insomnia

Reduced sexual activity

Other

Gastrointestinal problems

Dermatologic problems

Cancer

Propranolol

4.0

1.2

0.9

0.7

0.4

0.3

0.1

0.1

1.5

0.6

0.4

0.5

0.1

0.2

0.2

1.0

0.3

0.2

Placebo

3.5

0.3

0.7

0.3

0.4

1.0

0.1

0.1

1.0

0.6

0.4

0.2

0.2

0.0

0.0

0.3

0.1

0.1

Significant

difference

No

Yes

No

No

No

Yes

No

No

No

No

No

No

No

No

Yes

Yes

No

No

Modified from /3-Blocker Heart Attack Trial Research Group

3

with permission.

cipitate heart failure,

21

but there have been limited in

vivo studies in humans to support this contention. In

dog-transplanted, denervated heart preparations, /3-

blockers with intrinsic sympathomimetic activity have

a positive rather than negative inotropic effect.

22

The

clinical significance of this effect in the intact organ-

ism is uncertain.

In patients with impaired myocardial function who

require /3-blocking agents, digitalis and diuretics can

be used, preferably with drugs having intrinsic sym-

pathomimetic activity or a-adrenergic blocking prop-

erties.

Sinus

Node Dysfunction and

Atrioventricular

Conduction Delay

Slowing of the resting heart rate is a normal re-

sponse to treatment with ^-blocking drugs with and

without intrinsic sympathomimetic activity. Healthy

individuals can sustain a heart rate of 40 to 50 without

disability, unless there is clinical evidence of heart

failure.

23

Drugs with intrinsic sympathomimetic activ-

ity do not lower the resting heart rate to the same

degree as propranolol

24

; how ever, all /3-blocking drugs

are contraindicated (unless an artificial pacemaker is

present) in patients with the sick sinus syndrome.

25

If there is a partial or comp lete atrioventricular con -

duction defect, use of a /3-blocking drug may lead to a

serious bradyarrhythmia.

23

The risk of atrioventricular

impairment is not the same with all )3-blockers. Giudi-

celli and Lhoste

26

showed that in dogs, /3-blockade and

not membrane stabilizing activity is responsible for

atrioventricular conduction impairment. Compounds

like pindolol or oxprenolol, which have intrinsic sym-

pathomimetic activity in dosages producing /3-block-

ade, do not impair atrioventricular conduction to the

same extent as propranolol. The clinical significance

of this electrophysiolog ical difference amon g /3-

blockers in patients with atrioventricular conduction

disease has not been determined.

fi-Adrenergic

Receptor Blocker

Withdrawal

Following abrupt cessation of chronic /3-blocker

therapy, exacerbation of angina pectoris and, in some

cases, acute myocardial infarction and death have been

reported.

27

29

Multiple double-blind randomized trials have con-

firmed the reality of a propranolol withdrawal reac-

tion.

27

30

The exact mechanism for the propranolol

withdrawal reaction is unclear. There is some ev idence

that the withdrawal phenomenon may be due to the

generation of additional /3-adrenergic receptors during

the period of /3-adrenergic receptor blockade.

31

'

32

When the /3-adrenergic receptor blocker is then with-

drawn, the increased /3-receptor population readily re-

sults in excessive /3-receptor stimulation that will be

clinically important when the delivery and use of oxy-

gen is finely balanced, as occurs in ischemic heart

disease. Other suggested mechanisms for the with-

drawal reaction include heightened platelet aggregabil-

ity,

29

an elevation in thyroid hormo ne activity,

33

and an

increase in circulating catecholamines.

34

As it seems possible that postadrenergic receptor

blockade sensitivity may be due to the generation of

additional /3-adrenergic receptors, a /3-adrenergic re-

ceptor blocking drug w ith some partial agonist activity

might provide enough receptor stimulation to prevent

the generat ion of addition al /3-adrenergic receptors.

33

Studies with atenolol, metoprolol, pindolol, and pro-

pranolol in normal subjects and patients indicate that

administration of pindolol is not associated with in-

creased sensitivity to isoproterenol after pindolol is

stopp ed, in contrast to the other /3-adrenergic receptor

blocking drugs that do not possess partial agonist activ-

ity.

Mi37

Despite this difference with pindolol, it is still

prudent to discontinue all /3-blockers with caution in

patients with ischemic heart disease.

38

Adverse Noncardiac Side Effects Related to

-Adrenergic Receptor Blockade

Effect onVentilatoryFunction

The bronchod ilator effects of catecholamines on the

bronchial /3

2

-adrenergic receptors (JiJ are inhibited by

nonselective /3-blockers (e.g., propranolol and nado-

lol).

39

Comparative studies have shown, though, that

/3-blocking compounds with partial agonist activity,

40

0,-selectivity,

41

-

42

and a-adrenergic blocking actions

43

are less likely to increase airways resistance in asthma-

tics than propranolol. /3,-Selectivity, however, is not

absolute and may be lost with high therapeutic d oses as

shown with atenolol and metoprolol. It is possible in

asthma to use a /3

2

-selective agonist (such as albuterol)

in certain patients with concomitant low-dose /3,-selec-

tive blocker treatment.

44

In general, all /3-blockers



5/10

11-24 ANTIHY PERTENSIVE DRUG EFFECTS SUPPL n HYPERTENSION, VOL 11, No 3, MARCH 1988

should be avoided in patients with bronchospastic

disease.

Peripheral

Vascular

Effects (Raymud's

Phenomenon

Cold extrem ities and absent pulses have been report-

ed to occur m ore frequently in patients receiving /3-

blockers for hypertension compared with treatment

with methyldopa.

45

Among the /3-blockers, the inci-

dence was highest with propranolol and lower with

drugs having /3,-selectivity or intrinsic sympathomi-

metic activity. In some instances, vascular compro-

mise has been severe enough to cause cyanosis and

impending gangrene.

4

* This is probably due to the re-

duction in cardiac output and blockade of /3

2

-adrener-

gic receptor-mediated skeletal muscle vasodilation,

resulting in unopposed a-adrenergic receptor vasocon-

striction.

47

/3-blocking drugs with /3

r

selectivity or par-

tial agonist activity will not affect peripheral vessels to

the same degree as will propranolol.

Ray nau d's phenom enon is one of the more comm on

side effects of propranolol treatment.

4 8 4 9

It is more

troublesome with propranolol than practolol probably

because of the /3

2

-blocking properties of propranolol.

Patients with peripheral vascular disease who suffer

from intermittent claudication often report worsening

of the claudication when treated with /3-blocking

drugs .

5 0

'

31

Whether drugs with /3,-selectivity or partial

agonist activity can protect against this adverse reac-

tion has yet to be determined.

Hypogfycemia andHypergtycemia

Several authors have described severe hypoglyce-

mic reactions during therapy with /3-adrenergic block-

i n g d r u g s .

3 2

Som e of the patients affected were

insulin-dependent diabetics, while others were nondia-

betic. Studies of resting normal volunteers have dem-

onstrated that propranolol produces no alteration in

blood glucose values,

54

although the hyperglycemic

response to exercise is blunted.

In humans, mobilization of muscle glycogen is a /3-

receptor-mediated function (/3

2

-mediated), while

mobilization of liver glycogen depends on a-receptor

stimulation.

55

'

**

As a result, /3-receptor blocking drugs

(especially no nselective /3-blockers) may retard recov-

ery from insulin-induced hypoglycemia. In humans,

Abramson et al.

32

showed that propranolol delayed the

return of blood glucose values to normal after insulin-

induced hypoglycemia. If liver glycogen is reduced by

fasting or illness, the concomitant use of nonselective

/3-blocking drugs may further prolong recovery from

hypoglycemia, since alternative stores cannot be mo-

1

bilized.

37

'

58

With propranolol, the normal hemody-

namic response to hypoglycemia may be altered with

an elevation of diastolic blood pressure due to an

a-

constrictive response to reflex increases in plasma

catecholamines.

38

This enhancement of insulin-induced hyp oglycemia

and its hemodynamic consequences may be less with

cardioselective agents (where there is no blocking

effect on /3

2

-receptors) and agents with intrinsic

symp athom imetic activ ity (wh ich may stimu late /32-

receptors).

59

There is also marked diminution in the clinical

manifestations of sympathetic discharge associated

with hypoglycemia (tachycardia and tremor).

60

These

findings suggest that /3-blockers interfere with com-

pensatory responses to hypoglycemia and can mask

certain warning signs of this conditions. Other hypo-

glycemic reactions, such as diaphoresis, are not affect-

ed by /3-adrenergic blockade.

Central

Nervous System Effects

Dreams, hallucinations, insomnia, and depression

can occur during therapy with /3-blockers.

48

'

61

These

symptoms are evidence of drug entry into the central

nervous system (CNS) and are especially common

with the highly lipid-soluble /3-blockers (propranolol

and metoprolol) that presumably penetrate the CNS

better. It has been claimed that /3-blockers with less

lipid-solubility (atenolol and nadolol) will cause fewer

CNS side effects.

42

'

a

~

6

*This claim is intriguing, but its

validity must be corroborated with more extensive

clinical experiences.

A recent retrospective study suggested that patients

receiving /3-adrenergic blockers had a higher incidence

of depression requiring antidepressant m edication than

did patients not receiving the drug .

63

There were many

methodological problems in this study, and no firm

conclusions about depression incidenc e can be made.

63

Our group was unable to demonstrate the abov e obser-

vation in a large prospective study in patients over 80

years of age in which the prevalence and incidence of

depression on propranolol was identical to that of pa-

tients not receiving /3-blocker therapy.

66

In this same

study, patients on minor tranquilizers were much m ore

prone to depression than patients on /3-blockers.

66

Clinical pharmacological studies have generally

supported the view that /3-blockers do not have any

marked sedative effects. No such action could be

detected for propranolol, sotalol, oxprenolol, or

atenolol.

6

'

Skeletal Muscle Effects

In vitro studies demonstrate that propranolol can

produce neuromuscular blockade.

67

The direct actions

of epinephrine on skeletal muscle are mediated prob-

ably through /3

2

-receptors, and trem or is the most com-

mon side effect of /3

2

-stimulating drugs. Propranolol

has been shown to attenuate the ankle jerk, and a

prolonged curare-like effect has been described in one

patient.

68

Wh ether the cardioselective /3-blockers have

similar effects remains to be determined.

Muscle cramps can also occur with pindolol

48

and

have been described with practolol and propranolol.

69

The etiology of this side effect is unknown.

MiscellaneousS ide Effects

Diarrhea, nausea, gastric pain, constipation, and

flatulence have been seen occas ionally with all /3-

blockers ( 2 - 1 1 % of patients).

70

Patients on /3-blockers who develop anaphylac-



6/10

SIDE EFFECTS OF P-BLOCKERS/Frishman

11-25

tic shock may not respond to the usual doses of /3-

agonists.

Hematologic reactions are rare. Rare cases of purpu-

ra

71

and agranulocytosis

72

have been described with

propranolol.

A devastating blood pressure rebound effect has

been described in patients who discontinued clonidine

while being treated with nonselective /3-blocking

agents. The mechanism for this may be related to an

increase in circulating catecholamines and an increase

in peripheral vascular resistance.

7374

Whether /3,-

selective or partial agonist /3-blockers have similar ef-

fects after clonidine withdrawal remains to be deter-

mined. It has not been a problem with labetalol.

75

Increases in patient weight may occur. Bengtsson

76

noted an average 1-kg weight increment in patients

taking alprenolol. A similar weight gain in patients has

also been noted with propranolol,

77

pindolol,

38

-

78

and

oxprenolol. The mechanism of this weight gain has not

been elucidated. However, treatment with diuretic

agents will commonly relieve it.

Adverse Effects Unrelated to /3 Adrenergic

Receptor Blockade

/8-Blockers have been associated with the develop-

ment of antinuclear antibodies.

79

In prospective clini-

cal trials, patients receiving acebutolol had a dose-

dependent increase in the development of positive

TABLE 4.

Drug Interactions That May Occur withi-AdrenoceptorBlockingDrugs

Drug

Possible effects Precautions

Aluminum hydroxide

gel

Aminophylline

Antidiabetic agents

Calcium channel inhibitors

(e.g., verapamil, diltiazem)

Cimetidine

Clonidine

Digitalis glycosides

Epinephnne

Ergot alkaloids

Glucagon

Halofenate

Indomethacin

Isoproterenol

Levodopa

Lidocaine

Methyldopa

Decreases /3-blocker absorption

and

therapeutic

effect

Mutual inhibition

Enhanced hypoglycemia; hypertension

Potentiation

of

bradycardia, myocardial

depression,

and

hypotension

Prolongs half-life of propranolol

Hypertension during clonidine withdrawal

Potentiationofbradycardia

Hypertension; bradycardia

Excessive vasoconstriction

Inhibitionof hyperglycemic effect

Reduced /3-blocking activity; production

of

propranolol withdrawal rebound syndrome

Inhibition

of

antihypertensive response

to

/3-blockade

Mutual inhibition

Antagonism of levodopa's hypotensiveand

positive inotropic effects

Propranolol pretreatment increases lidocaine blood

levelsandpotential toxicity

Hypertension during stress

Manoamine oxidase inhibitors Uncertain, theoretical

Phenothiazines

Phenylpropranolamine

Phenytoin

Quinidinc

Reserpine

Tricyclic antidepressants

Tubocurarine

Additive hypotensive effects

Severe hypertensive reaction

Additive cardiac depressant effects

Additive cardiac depressant effects

Excessive sympathetic blockade

Inhibits negative inotropic and chronotropic effects

of /3-blockers

Enhanced neuromuscular blockade

Avoid /3-blocker

and

aluminum hydroxide

combination

Observe patient's response

Monitor

for

altered diabetic respo nse

Avoid use, although

few

patients show

ill

effects

Combination should be used with caution

Monitorforhypertensive response; withdraw

/3-blocker before withdrawing clonidine

Observe patient's response; interactionsmay

benefit angina patients with abnormal ventricular

function

Administer epinephnne cautiously;

cardio-selective /3-blocker may

be

safer

Observe patient's response;few patients showill

effects

Monitorforreduced response

Observeforimpaired resonseto/3-blockade


Avoid concurrent use of cardio-selective /3-blocker

Monitorforaltered response; interaction may have

favorable res ults

Combination shouldbeused with caution;use

lower dosesoflidocaine

Monitor

for

hypertensive episodes

Manufacturer

of

propranolol considers concurrent

use contraindicated

Monitorfor altered response, especially with high

dosesof phenothiazine

Avoid use, especially in hypertension controlled by

both methyldopa and /3-blockers

Administer

i.v.

phenytoin with great caution

Observe patient's response;

few

patients show

ill

effects



Observe response

in

surgical patients, especially

after high dosesofpropranolol

Modified from Hansten

93

with permission.



7/10

11-26 AN+IHYPERTENSlVE DRUG EFFECTS SUPPLn HYPERTENSION, VOL 11, No 3, MARCH 1988

antinuclear antibody titers, and the overall incidence

was higher than that observed with propranolol.

79

Symptoms (generally persistent arthralgias and myal-

gias) related to this abnormality were infrequent (less

thari

1

with both drugs). Symptoms and antinuclear

antibody.titers were reversible upon discontinuation of

treatment.

79

Oculomucocutaneous Syndrome

A characteristic, immune reaction, the oculomuco-

cutaneous syndrome, affecting singly or in combina-

tion eyes, mucous and Serous membranes, and the

skin, often in association with a positive antinuclear

factor, has-been reported in patients treated with prac-

tolol ahd has led to the curtailment of its clinical

use.

80

'

Close attention,has been focused on this syn-

drome because of fears that other /3-adrenergic recep-

tor blocking drugs may be associated with it. In 19

patients with such a reaction withpractolol,the lesions

healed after switching to atenolol treatment.

The main features in this syndrome in 439 patients

reviewed by Nichols (see ConOlly

23

) were as follows:

1)

Eye:

A gritty feeling in the eye may occur that can

progress to a panconjunctivitis; keratitis, and panniis

formation. In Nichols series, 18 patients manifested

severe eye changes> 112 had corneal damage without

loss ofsight,and 146 had eye changes without corneal

involvement. The average time to develop this syn-

drome was 23 months after initiating treatment.

2)Skin:The skin changes usually begin With a pruri-

tic rash involving the palms and.the soles of the feet.

Thickened .plaques that resemble psoriasis may ap-

pear. Immunofluorescent studies haverevealedgranu-

lar deposits at the dermalectodermal junction in some

cases.

82

. , .

3) Ear: Deafness with serious otitis media has been

reported in some patients receiving practolol.

Sclerosing Peritonitis

Thirty-three patients with this syndrome were in-

cluded in Nichols report. Patients may present with

colicky abdominal pain or with an abdominal mass.

This condition may progress in spite of withdrawal of

the drug and may first develop up to a year after the

discontinuation ofpractolol.The peritoneum becomes

covered with a

film

of whitefibrous

issue

with thicker

plaques.

83

The natural history of this condition is Uh

T

known, and the diagnosis has usually been made at

laparotomy or autopsy. Most patients appear.to im-

prove with time after cessation oftreatment.The mean

time to diagnosis of sclerosing peritonitis after starting

practolol was 37 months.

As with sclerosing peritonitis; many Of the other

practolol reactions arereversibleby withdrawal of the

drug,together with treatment with topical corticoster-

oids,

artificial tearsolutions,antibiotic eye drops, and

oral corticosteroids.

84

An important consideration is whether the practolol

TABLE 5. .Clinical Situations ThatWould Influence the Choice ofa

i-Blocking

Drug

Condition Choice of /3-blbcker

Asthma, chronic bronchitis with

bronchospasm

Congestive heart failure

Angina

Atrioventricular conduction defects

Bradycardia

Rayriaud s phenomenon,

intermittent claudicatiori, cold

extremities

Depression

Diabetes mellitus

Thyrotoxicosis

Pneochrombcytoma

Renal failure

Insulin ahd sulphonylurea use

Clonidine

Oculomucocutaneous syndrome

Hyperlipidemia

Avoid all /3-blockers if possible; however, small,doses of /3i-selective blockers (e.g., acebutolol,

atenolol, metoprolol) can be used. ,-Selectivity islost with higher

doses.

Drugs with partial agonist

activity (e.g., pindolol, oxprdnolol) and labetalol with a-adrenergic blocking properties can also be

used

Drugs with partial agonist activity and labetalol might have an advantage, although /3-blockers are

usually contraindicated

In patients with angina at low heart rates, drugs with partial agonist activity probably contraindicated.

Patients with angina at high heart rates,but who have resting bradycardia, might benefit from a drug

with partial agonist activity. In vasospastic angina, labetalol may be useful; other jS-blockers should

be used with caution

/3-Blockers generally contraindicated, but drugs with partial agonist activity and labetalol can be tried

with caution

/3-Blockers with partial agonist activity and labetalol have less pulse slowing effect and are preferable

/3i-Selective blocking agents, labetalol, and those with partial agonist activity might have an advantage

Avoid propranolol. Substitute a /S-blocker With partial agonist activity or low lipid solubility

j9

r

Selective agents and partial agonist drugs are preferable

All agents will control symptoms, but agents without partial agonist activity are preferred

Avoid all /3-blockers unless an a-blocker is given. Labetalol may be used as a treatment of choice

Use reduced doses of compounds largely eliminated by renal mechanisms (nadolol, sotalbl, atenolol)

andthosedrugs whose bioavailability is increased in uremia (propranolol, alprtnolol). Also consider

possible accumulation of active metabolites (alprenolol, propranolol)

Danger of hypoglycemia but is possibly reduced using drugs with /3,-selectivity

Avoid sotalol (and other nonselective /3-blockers). Severe rebound effect with clonidine withdrawal

Stop drug. Substitute any other /3-blocker

Avoid nonselective /3-blockers; Use agents with partial agonism, /3,-selectivity or labetalol

Modified from Frishman

94

with permission.



8/10

SIDE EFFECTS OF /3-BLOCKERS/FWj/iman

H-27

reaction is specific for practolol or is the direct and

specific result of pharmacologically induced changes

by /3-blockade.

83

There have been few convincing pub-

lished reports of the oculomucocutaneous reaction

with oxprenolol

86

' and propranolol.

88

'

w

In view of

the extensive clinical use of both oxprenolol and pro-

pranolol, these reactions, even if drug induced, are

exceedingly rare. There is need, however, for vigi-

lance during therapy with the newer /3-blockers.

Carcinogenicity

Pronethanol, the first /3-adrenergic receptor block-

ing drug to achieve widespread use, was withdrawn

by its manufacturer because it caused thymic tumors

and lymphosarcomata in mice, although it did not

do so in rats or dogs.

90

The doses used to produce these

tumors were 10 times the maximum therapeutic

concentration.

Tolamolol and pamatolol, two cardioselective

(3-

adrenergic receptor blocking drugs, were withdrawn

from clinical trials because they caused mammary tu-

mors in mice and rats at high doses.

91

Other /3-

blockers, alprenolol, practolol, and timolol, have giv-

en some indication of tumorigenicity in rodents.

42

The relevance of these findings to causation of tu-

mors in humans is difficult to evaluate.

42

The doses

were high, and the relationship between malignant tu-

mors in animals and humans is not defined.

42

A dis-

turbing aspect has been the suggestion that this might

be a pharmacological property of /3-adrenergic recep-

tor antagonism rather than carcinogenicity by another

mechanism. Against the /3-blocker theory of carcino-

genesis is the fact that many /3-blocking drugs have

successfully undergone stringent carcinogenicity test-

ing in animals and have been used safely in humans.

Drug Interactions

The wide diversity of diseases for which /3-blockers

are employed raised the likelihood of their concurrent

administration with other drugs.

92

It is imperative,

therefore, that familiarity be obtained regarding the

interactions of /3-blockers with other pharmacological

agents. The list of commonly used drugs with which

/3-

blockers interact is extensive (Table 4).

93

The majority

of the reported interactions have been reported for pro-

pranolol, the best studied of the /3-blockers, and may

not apply to other drugs in this case.

How to Choose a /3 Blocker

The various /3-blocking compounds given in ade-

quate dosage appear to have comparable, antihyper-

tensive, antiarrhythmic, and antianginal effects.

Therefore, the /3-blocking drug of choice in an individ-

ual patient is determined by the pharmacodynamic and

pharmacokinetic differences between the drugs in con-

junction with the other medical conditions the patient

might have (Table 5).

References

1. Friedman LM. How

do the

various beta-blockers compare

in

type, frequency, and severity of their adverse effects? Circula-

tion 1983;67(suppl R:I-89-I-90

2.

Frishman W, Silverman

R,

Strom

J,

Elkayam U, Sonnenblick

E. Clinical pharmacology

of

thenew beta-adrenoceptor block-

ing drugs. Part 4. Adverse effects. Choosing a /3-adrenoceptor

blocker. Am HeartJ 1979;98:256-262

3. /3-Blockcr Heart Attack Trial Research Grou p.Arandomized

trial

of

propranolol

in

patients with acute myocardial infarc-

tion.

1.

Mortality Results. JAMA 1982;247:1707-1714

4.

Greenblatt DJ, Koch-Weser J. Clinical toxicity

of

propranolol

and practolol:a report from the Boston Collaborative Drug

Surveillance Program. In: A very G, ed . Cardiovascular drug s,

vol2. Baltimore: University Park Press, 1978:179-195

5. Forrest WA: A monitored release study: a clinical trialof

oxprenolol in general practice. Practitioner 1972;208:412416

6. Zacharias FJ, Cowan KJ, Cuthbertson PJR,

et

a). A tenolol

in

hypertension: astudyof long-term therapy. PostgradMed J

1977;53(suppl3):102-110

7. CollinsIS ,King IW . Pindolol (ViskenLB46),anew treatment

for hypertension: reportofa multicentre open study. Cur Ther

Res 1972;14:185-194

8. Morgan TO, Louis WJ, Dawborn JK, Doyle AE.

The

use

of

pindolol (Visken) in the treatment of hypertension. Med J A ust

2: 1972;2:3O9-315

9. Gonasun L, Langrall H. Adverse reactions to pindolol adminis-

tration.AmHeartJ

1982;

104:482-486

10.

Michelson

EL,

Frishman WH, Lewis

JE, et al.

Multicenter

clinical evaluation ofthelong-term safety and efficacy

of

labe-

talol in the treatment of hypertension. Am J Med 1983;

75(suppl 4A):68-80

11. Multicentre International Study. Improvementinprognosisof

myocardial infarction by long-term beta-adrenoreceptor block-

ade using practolol.

Br

Med

J

1975;3:735-74O

12. The

Norwegian M ulticenter Study G roup. Timolol-induced

reduction in mortality andreinfarction in patients surviving

acute myocardial infarction. N EnglJ Med 1981;304:8Ol-807

13.

Hjalmarson A, HerlitzJ,MalekI, etal. Effect on mortalityof

metoprolol

in

acute myocardial infarction:

a

double-blind ran-

domized trial. Lancet 1981;2:823-827

14.

Julian

DG,

Prescott

RJ,

Jackson

FS,

Szekely

P.

Controlled

trial

of

sotalol for one year after myocardial infarction. Lancet

1982;1:1142-1147

15. Taylor SH, SilkeB,EbbuttA,Sutton GC, ProutBJ,Burley

DM. A long-term prevention study with oxprenololincoronary

heart disease.

N

Engl

J Med

1982;3O7:1293-1300

16.

Krupp

P,

Fanchamps

A.

Pindolol: experience gained

in 10

yearsof safety monitoring. Am HeartJ 1982:104:486-490

17. Hawkins CM, Richardson

DW,

Vokonas

PS.

Effect

of

pro-

pranolol in reducing mortality in old myocardial infarction

patients: The Beta-Blocker Heart Attack Trial Experience. C ir-

culation 1983;67(suppl R:I-94-I-97

18.Gunderson T, Abrahamsen M, Kjekshus

J,

Ronnevik PK.

Ti-

molol-related reduction in mortality and

reinfarction

npatients

aged 65- 75 years surviving acute myocardial infarction. Circu-

lation 1982;66:1179-1184

19. Frishman WH, BaumanJ,SobermanJ,Nadelmann J, W urzel-

mann J, Aronson M. T reatment of ischemic heart disease in the

elderly: beta-adrenergic blockade and coronary artery disease.

In: Wonger NK,Furberg CD,Pitt E, eds. Coronary heart

diseasein theelderly. NewYork: Elsevier, 1986:153 -197

20. Vaughan-Williams EM, Baywell EE, Singh BN. Cardiospeci-

ficity of beta-receptor blockade. A comparisonof the relative

potencies

on

cardiac

and

peripheral vascular beta-adrenocep-

tors

of

propranolol,

of

practolol

and its

ortho-substituted

isc-

mer and of oxprenolol and its para-substituted isomer. Cardio-

vascRes 1973;7:226-240

21 .

Taylor

SH,

Silke

B, Lee PS.

Intravenous beta-blockade

in

coronary heart disease: iscardioselectivity or intrinsicsym-

pathomimetic activity hemodynamically useful? N EnglJMed

1982;3O6:631-634

22. Nayler WG.Theeffect of beta-adrenergic receptor blocking

drugs on myocardial function: an explanation of the subcellular

level.

In:

Simpson

F , ed.

Ciba Symposium Beta-Adrenergic

Receptor Blocking Drugs. Sydney, Australasian Drug Infor-

mation Services, 1970:1-12

23.

Conolly M E, Kersting F, D ollery CT. The clinical pharmacol-



9/10

n-28 ANTIHYPERTENSIVE DRUG EFFECTS SUPPL U HYPERTENSION, VOL 11, No 3, M A RCH 1988

ogy of bcta-adrenoceptor blocking drugs. Prog Cardiovasc Dis

1976;19:203-234

24.

Frishman W, Kostis J, Strom J, et

al .

Clinical pharmacology of

the new beta-adrenergic blocking drugs. Part 6. A comparison

of pindolol and propranolol in treatment of patients w ith angina

pectoris. The role of intrinsic sympathomimetic activity. Am

Heart J 1979;98:526-535

25 . Singh BN, Jewitt D E. /3-Adrenoceptor blocking drugs in cardi-

ac arrhythmias. In: Avery G, ed. Cardiovascular

drugs,

vol 11.

Baltimore: University Park Press, 1978:119-159

26.

Giudicelli JF, L hoste F. /3-Adrenoceptor blockade and atrio-

ventricular conduction in dogs. Role of intrinsic sympathomi-

metic activity. BrJClin Pharmacol 1982; 13(suppl2):167-174

27. Alderman EL, Coltart DJ, Wettach GE, Harrison IX . Coro-

nary artery syndromes after sudden propranolol withdrawal.

Ann Intern Med 1974;81:925-927

28.

Miller RR, Olson HG , Amsterdam EA, Mason DT. Proprano-

lol withdrawal rebou nd phenom enon: exacerbation of coronary

events after abrupt cessation of anti-anginal therapy. N Engl J

Med 1975;293:416-418

29. Frishman W H, Christodoulou J, WekslerB ,Smithen C, Killip

T, Scheidt S: Abrupt propranolol withdrawal in angina pec-

toris:

effects of platelet aggregation and exercise tolerance. Am

Heart J 1978 ;95:169-17 9

30. Frishman WH. Beta-adrenergic blocker withdrawal.Am JCar-

diol 1987;59:26F-32F

31 .

Lefkowitz R. D irect binding studies of adrenergic receptors:

biochem ical, physiologic and clinical implications. Ann Intern

Med 1979;91:450-458

32. Glaub iger G, Lefkowitz R. Elevated /3-rcceptor number after

chronic propranolol treatment. Biochem Biophys Res Com-

mun 1977;78:720-725

33 .

Kristensen BO , Steiness E, W eeke J. Propranolol withdrawal

and thyroid hormones in patients with essential hypertension.

Clin Pharmacol Ther 1978;23:624-629

34.

Rangno R, Nattel S. Prevention of propranolol withdrawal

phenomena by gradual dose reduction [Abstract]. Clin Res

1980;28:214A

35.

Molinoff PB, Aarons RD, Nies AS, Gerber JG, Wolfe BB,

Goens B. Effects of pindolol and propranolol on /3-adrenergic

receptors on human lymphocytes. Br J Clin Pharmacol

1982;13(suppl 2):365S-367S

36.

Prichard BNC , Walden RJ. The syndrome associated with the

withdrawal of /3-adrenoceptor blocking drugs. Br J Clin Phar-

macol 1982;13(suppl 2):337S-343S

37. Rangno RE, Lang lois S. Comparison of withdrawal phenom-

ena after propranolol, metoprolol and pindolol. Am Heart J

1982; 104:473^178

38. Frishman W H. P indolol: a new /3-adrenoceptor antagonist with

partial agonist activity. N Engl J Med 1983;308:940-944

39. Dunlop D, Shanks RG. Selective blockade of adrenoceptive

beta receptors in the heart. Br J Pharmacol Chemother

1968;32:201-218

40 . Ruffin R E, Mclntyre EL M, Latimer KM, Ward HE, Crochett

AJ, Alpers JH. Assessment of/3-adrenoceptor antagonists in

asthmatic patients. Br J Clin Pharmacol 1982;13(suppl 2):

325S-335S

41 . Koch-W eser J. Metoprolol. N Engl J Med 1979;30 1:698-703

42 . Frishman W H. A tenolol and timolol, two new systemic /3-

adrenoceptor antagonists. N Engl J Med 1982;306:1456-1462

43 .

George RB, Manocha K, Burford J, Conrad S, Kinasew itzGT.

Effects of labetalol in hypertensive patients with chronic ob-

structive pulmonary disease. Chest 1983;83:457-460

44 .

Benson MK, Berrill WT, Cruickshank JM, Sterling GS. A

comparison of four adrenoceptor antagonists in patients with

asthma. Br J Clin Pharmacol 1978;5:415-419

45 .

Waal-Mann ing HJ. Hypertension: which beta-blocker. Drugs

46 .

Frolich ED, Tarazi RC , Dustan HP . Peripheral arterial

insuf-

ficiency: a complication of beta-adrenergic blocking therapy.

JAMA 1969;208:2471-2472

47 .

Lundvall J, Jarhult J. B eta-adrenergic dilator component of the

sympathetic vascu lar respons e in skeletal muscle. A cta Physiol

Scand 1976;96:180-192

48 .

Simpson FO. /3-Adrenergic receptor blocking drugs in hyper-

tension. Drugs 1974;7:85-105

49 .

Zacharias FJ, Cowen KJ, Prestt J, Vickers J, Wall BG. Pro-

pranolol in hypertension: a study of long-term therapy, 1964

1970. Am Heart J 1972;83:755-761

50.

George CF. Beta-receptor blocking agents. Prescriber's J

1974; 14:93-9 8

51 . Rodger J, Sheldon CD, Lerski RA, Livingston WR. Intermit-

tent claudication complicating beta-blockade. Br Med J

1976;1:1125-1134

52. Abramson EA, Arky RA , Woeber KA . Effects of propranolol

on the hormonal and metabolic responses to insulin induced

hypoglycemia. Lancet 1966;2:1386-1388

53.

Reveno WS, Rosenbaum H. Propranolol hypoglycemia. Lan-

cet 1968;1:920-927

54. Allison SP, Chamberlain MI, M iller

JE .

Effects of propranolol

on blood sugar, insulin, and free fatty acids. Diabetologia

1969;5:339-342

55 . Porte D. Sympathetic regulatio n of insulin secretion. Its re la-

tion to diabetes mellitus. Arch Intern M ed 1969;183:252-260

56. Antonis A, Clark ML, Hodge RL, et al. Receptor mechanisms

in the hyperglycaemic response to adrenaline in man. Lancet

1967;1:1135-1137

57. Dollery CT, Paterson JW, Conolly ME. Clinical pharmacol-

ogy of beta-blocking drugs. Clin Pharmacol Ther 1969;

10:765-799

58. Smith U. Effect of beta-adrenoceptor blocking agents on the

reaction to hypoglycemia and the physical working capacity.

Cardiol Rev Rep 1981;2:563-567

59.

Deacon S P, Baroett D. Comparison of atenolol and proprano-

lol during insulin-induced hypoglycaemia. Br Med J 1976;2:

7-9

60. Lloyd-Mostyn RH, Oram S. Modification by propranolol of

cardiovascular effects of induced hypoglycaemia. Lancet

1975;2:1213-1221

61 .

Frishman WH, Razin A, Swencionis C, Sonnenblick EH.

Beta-adrenoceptor blockade in anxiety states: a new approach

to therapy? Cardiol Rev Rep 1981;2:447

62.

Frishman W H. N adolol: a new /3-adrenoceptor antagonist. N

Engl J Med 1981;305:678-682

63 .

Kostis JB, Rosen RC. Beta-blocker effects on central nervous

system. A controlled comparative study [A bstract]. J Am Coll

Cardiol 1986;7:25A

64.

Engler RL, Conant J, Maisel A, Janowsky D, LeWinter M.

Lipid solubility determines the relative CNS effects of beta-

blocking drugs [Abstract]. J Am Coll Cardiol 1986;7:25A

65. Avom J, Everitt DE, Weiss S. Increased antidepressant use by

inpatients prescribed /3-blockers. JAMA 1986; 255:357-360

66.

Wurzelmann J, Bauman J, Frishman WH. Beta-adrenoceptor

blocker therapy in elderly patients. Quality of Life 1986;

2:208-221

67. Herishanu Y, Rosenberg P . Beta-blockers and myathenia gra-

vis. Ann Intern Med 1975;83:834-838

68. Rozen MS, Whan FM . Prolonged curarization associated with

propranolol. Med J Aust 1972;l:467-4 68

69. Green blattDJ, Koch -Wes erJ. Adverse reactions to/3-adrener-

gic receptor blocking drugs: a repo rt from the Boston Collabo-

rative Drug Surveillance Program. Drugs 1974;7:118-129

70. Jacob H, Brandt LJ, Farhas P, Frishman W. Beta-adrenergic

blockade and die gastrointestinal system. Am J Med

1983 ;74:1042-10 51

71 . Stephen SA. Unwanted effects of propranolol. Am J Cardiol

1966;18:463^72

72. Nawabi IU, Ritz ND. Agranulocytosis due to propranolol.

JAMA 1973 ;223:1376-137 7

73. Bailey R, Neale TJ. Rapid clonidine withdrawal with blood

pressure overshoot exaggerated by beta-blockade. Br Med J

1976;1:942-943

74. Cairns SA, Marshall AJ. Clonidine withdrawal. Lancet

1976; 1:368

75 .

Agabiti-Rosei E, Brown JJ, Lever AF, et al. Treatment of

phaeochrornocytoma and clonidine withdrawal hypertension

with labetalol. Br J Clin Pharmacol 1976;3(suppl 3):8O9-811

76. Bengtsson C. Comparison between alprenolol and chlorthali-



10/10

SIDE EFFECTS OF /S-BLOCKERS/Frw/imo/j

n-29

done as anti-hypertensive agents. Acta Med Scand 1972;

191:433^*38

77.

Seedat YK, Stewart-Wynne E. Clinical experiences with pin-

dolol (Visken) in the therapy of hypertension. South Afr Med J

1972;46:1524-1528

78. Waal-Manning H I, Simpson FO. P indolol: a comparison with

other anti-hypertensive drugs and a double-blind placebo trial.

Aust NZ Med J 1974;80:151-153

79. Frishman W . Acebutolol: a new oral /9-blocker for hyperten-

sion and ventricular arrythmias. Cardiovasc Rev Rep 1979;

6:979-985

80. Wright P. Untoward effect associated with practolol adminis-

tration. Oculomucocutaneous syndrome. Br Med J 1975;

1:595-598

81.

Waal-Manning H. Problems with practolol. Drugs 1975;

10:336-342

82. Felix RH, Ive FA, Dahl MCG . Cutaneous and ocular reactions

to practolol. Br Med J 1974;4:321-3 24

83.

Windsor WP, Durrein F, Dyer NH. Rbrinous peritonitis: a

complication of practolol therapy. Br Med J 1975;2:68

84.

Gaylarde PM, Sukany I. Side effects of practolol. Br Med J

1975;2:435

85. Zacharias FJ. Cross-sensitivity between practolol and otherfi-

blockers. Br MedJ 1976;1:1213 1215

86. Holt PJA, Waddington E. Oculocutaneous reaction to oxpren-

olol. Br Med J 1975;2:539-540

87. Knapp MS, Gallaway HR, Clayden JR. Ocular reactions to

beta-blockers. Br Med J 1975;2:557-565

88. Cubey RB, Taylor SH. Ocular reaction to propianolol and

resolution on continued treatment with a different beta-block-

ing drug. Br Med J 1975;4:327-328

89. Harty RP . Sclerosing peritonitis and propranolol. Arch Intern

Med 1978:138:1424-1426

90. Paget GE. Carcinogenic actions of pronethalol. Br Med J

1963;2:1266-1267

91 .

Status Report on Beta-Blockers. US Food and Drug Adminis-

tration, Drug Bulletinno .8. Washington,

DC :

US Government

Printing Office, 1978:13

92. MissriJC.How do beta-blockers interact with other commonly

used drugs? Cardiovasc Med 1983;8:668-669

93 . Hansten P . Drug interactions, 4th ed. Philadelphia: Lea and

Febiger, 1979:13-24

94. Frishman WH. The beta-adrenoceptor blocking drugs. Int J

Cardiol 1982;2:165-178


Hypertension 1988 Frishman II21

Documents

Transcript of Hypertension 1988 Frishman II21