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Propranolol
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Propranolol Hydrochloride
Excipients:
Lactose, gelatine, stearic acid, magnesium stearate
Adverse Effects, Treatments and Precautions:
As for beta-adrenergic blocking agents in general.
Effects on the Gastro Intestinal Tract:
A report of retroperitoneal fibrosis associated with propranolol in one
patient. Pierce JR, et al. Propranolol and retroperitoneal fibrosis. Ann Intern
Med 1981- 95: 244.
Hypertension:
Of 44 mental patients receiving propranolol in doses of 0.6 to 5 g daily for
the treatment of psychoses, 8 developed a paradoxical rise in blood pressure- in
2 this was abrupt but in most the increase was progressive over 3 to 24 hours.
In all cases the hypertension responded immediately to a single dose of
phentolamine 15 to 30 mg intravenously, with phenoxybenzamine 10 to 20 mg daily
for 3 to 4 days reducing the blood pressure to the previous low levels without
discontinuing the propranolol. Blum I, et al. Paradoxical rise in blood pressure
during propranolol treatment. Br Med J 1975- 4: 623.
Overdosage:
A case of severe propranolol overdosage responded dramatically to treatment
with calcium chloride. Brimacombe JR, et al. Propranolol overdose-a dramatic
response to calcium chloride. Med J Aust 1991- 155: 267-8.
Uses and Administration:
Propranolol is a beta-blocker. It is non-cardioselective and does not
possess intrinsic-sympathomimetic activity. It is reported to have
membrane-stabilizing properties. It is lipophilic. Propranolol is used in the
treatment of hypertension and to improve the tolerance to exercise in-patients
with angina pectoris. It has been given for the prevention of re-infarction
in-patients who have suffered an acute myocardial infarction. Propranolol is
also used in the treatment of cardiac arrhythmias. It is often effective in
supraventricular tachyarrhythmias. It has been used with digitalis to reduce the
ventricle-rate in atrial fibrillation and flutter which are not effectively
controlled by digitalis alone. It has been used in the control of arrhythmias
associated with digoxin intoxication and general anesthesia. It is generally
less effective in ventricular than supraventricular arrhythmias but may be
useful in the treatment of symptomatic ventricular premature depolarization
in-patients with structurally normal hearts. In hyperthyroidism, propranolol is
given to reduce the heart rate and control other symptoms of sympathetic nervous
hyperactivity. In the surgical treatment of phaeochromocytoma, propranolol may
be given pre-operatively as an adjunct to an alpha blocking agent such as
phenoxybenzamine. Propranolol is also used for some symptoms of anxiety, for
migraine prophylaxis, for hypertrophic subaortic stenosis, for essential tremor,
and for prophylaxis of upper gastro-intestinal bleeding in-patients with portal
hypertension. Propranolol hydrochloride is usually given by mouth. Dosage is
largely determined by the response of the patient. In most conditions, treatment
should begin with a small dose, which should be gradually increased. Initial
doses used for hypertension are 40 to 80 mg of propranolol hydrochloride twice
daily increased as required to a usual range of 160 to 320 mg daily- some
patients may require up to 640 mg daily. Propranolol is not suitable for the
emergency treatment of hypertension- it should not be given intravenously in
hypertension. In angina, initials doses of propranolol hydrochloride 40 mg given
2 or 3 times daily are increased at weekly intervals as required to a usual
range of 120 to 240 mg daily. Some patients may require up to 320 mg daily.
Propranolol hydrochloride is administered within 5 to 21 days of myocardial
infarction to prevent re-infarction in doses of 40 mg given four times daily for
2 or 3 days followed by 80 mg twice daily. Another regimen is to give 180 to 240
mg daily in divided doses. Propranolol may be given orally in doses of 30 to 160
mg daily in divided doses in the long-term management of cardiac arrhythmias-
some suggest doses of up to 320 mg daily. For the emergency treatment of cardiac
arrhythmias, propranolol hydrochloride may be given by slow intravenous
injection in a dose of 1 mg injected over a period of 1 minute. Repeated if
necessary every 2 minutes until a maximum total of 10 mg has been given in
conscious patients and 5-mg in-patients under anesthesia. Patients receiving
propranolol intravenously should be carefully monitored. Doses for the temporary
suppression of thyrotoxicosis and in thyrotoxic crisis are usually 10 to 40 mg
three or four time’s daily. Intravenous administration may be necessary- the
dose is 1 mg injected over 1 minute, repeated at 2-minute intervals until a
response is observed or to a maximum dose of 10 mg in conscious patients or 5 mg
in-patients under anesthesia. In phaeochromocytoma, 60 mg daily should be given
on 3 pre-operative days always in association with alpha blockade. If the tumor
is inoperable prolonged treatment may be given with a daily dose of 30 mg. A
suggested dose for anxiety is 40-mg daily- this may be increased to 40 mg two or
three times daily. An initial doses of 40 mg two or three times daily is used in
migraine prophylaxis- the dose can be increased at weekly intervals up to 160 mg
daily. Some patients have been given 240 mg daily. In hypertrophic subaortic
stenosis, the usual dose of propranolol hydrochloride is 10 to 40 mg given three
to four times daily. Essential tremor may be treated with 40 mg given two to
three times daily- the dose can be increased at weekly intervals to 160 mg daily
although doses up to 320 mg may be necessary. In portal hypertension,
propranolol hydrochloride should be given in initial doses of 40 mg twice daily-
the dose may be increased as required up to 160 mg twice daily. Children.
Propranolol has been used in the treatment of hypertension in children in
initial doses of 1 mg per kg body-weight daily in divided doses by mouth,
increased as required to a usual range of 2 to 4 mg per kg daily in divided
doses. For arrhythmias, phaeochromocytoma, and thyrotoxicosis, the suggested
dose is 250 to 500 mcg per kg three or four times daily by mouth. Children
requiring intravenous administration may be given 25 to 50 mcg per kg injected
slowly with appropriate monitoring- this dose may be repeated three or four
times daily. Children under 12 years of age may be given 20 mg two or three
times daily for the prophylactic management of migraine.
Administration in Hepatic Failure:
A study of the effects of cirrhosis on the disposition of propranolol during
steady-state oral administration in 9 normal subjects and 7 with cirrhosis
demonstrated a mean 3-fold increase in unbound propranolol concentrations in the
blood in patients with cirrhosis when compared with the controls. Mean
half-lives for the 2 groups were 11.2 and 4 hours respectively. (1) Another
study of the pharmacokinetics of propranolol gave as a single dose of a 20-mg
tablet and as a 160-mg controlled-release preparation daily for 7 days in 10
patients with cirrhosis and portal hypertension. It demonstrated higher plasma
concentration in-patients with severe liver disease compared with those reported
in normal controls. (2) Others have reported similar pharmacokinetic findings.
(3) In patients with severe liver disease, it has been suggested that
propranolol therapy be started at a low dose such as 20 mg three times daily, or
80 mg of a controlled-release preparation given once daily, (2) or 160 mg of a
controlled-release preparation given every other day. (3) Monitoring of beta
blockade is essential- checking the heart-rate (2) or exercise testing (3) has
been suggested as suitable methods to assess the extent of beta blockade
in-patients with cirrhosis.
1. Wood AJJ, et al. The influence of cirrhosis on steady-state blood
concentrations of unbound propranolol after oral administration. Clin
Pharmacokinet 1978- 3: 478-87.
2. Arthur MJP, et al. Pharmacology of propranolol in-patients with cirrhosis and
portal hypertension. Gut 1985- 26: 14-19.
3. Cales P, et al. Pharmacodynamic and pharmacokinetic study of propranolol
in-patients with cirrhosis and portal hypertension. Br J Clin Pharmacol 1989-
27: 763-70.
Administration in Renal Failure:
A study of the pharmacokinetics of propranolol in 11 patients with chronic
renal insufficiency showed no impairment in the elimination kinetics of
propranolol compared with 8 subjects with normal renal function. (1) Peak
concentrations of propranolol reported in-patients with chronic renal failure
have been 2 to 3 times higher than those reported in-patients receiving dialysis
or normal subjects. (1,2) Additional studies indicate that there is no
pharmacokinetic reason to amend the dosage of propranolol in patients with renal
failure. (3) Findings from a study in 8 patients on haemodialysis include a
slight elevation of propranolol-plasma concentrations, no elevation of plasma
concentration of 4-hydroxypropranolol, but extremely high plasma concentrations
of other propranolol metabolites. (4)
1. Lowenthal DT, et al. Pharmacokinetics of oral propranolol in chronic renal
disease. Clin Pharmacol Ther 1974- 16: 761-9.
2. Bianchetti G, et al. Pharmacokinetics and effects of propranolol in terminal
uraemic patients and with patients undergoing regular dialysis treatment. Clin
Pharmacokinet 1976- 1: 373-84.
3. Wood AJJ, et al. Propranolol disposition in renal failure. Br J Clin
Pharmacol 1980- 10: 561-6.
4. Stone WJ, Walle T. Massive propranolol metabolite retention during
maintenance haemodialysis. Clin Pharmacol Ther 1980- 28: 449-55.
Contraception:
Propranolol inhibits human sperm motility in vitro (1) and has been
evaluated as a contraceptive agent in 198 women. (2) Propranolol hydrochloride
80 mg (as an oral tablet) was inserted into the vagina every evening, except
during menstruation, for 11 months. Over 127 woman-years, the pregnancy-rate at
one year was calculated as 3.4 per 100 women, compared with an expected rate of
88.2 per 100 in the absence of contraception. Over the period of the study 33
women discontinued treatment because of local itching or discomfort. Systemic
bioavailability was greater with vaginal administration than oral
administration, (3) presumably due to the avoidance of first-pass hepatic
biotransformation. Another approach to contraception with propranolol is for men
to take it by mouth to reduce their sperm counts. Unfortunately the
concentrations of propranolol in seminal fluid from 6 healthy males following a
dose of 80 mg by mouth were much less than those required inhibiting sperm
motility. (4) It was concluded that in the dose administered in this study,
propranolol was unlikely to affect fertility by its presence in semen.
1. Hong CY, et al. Comparison of local anaesthetic effects of (+)-propranolol,
(+/-)-propranolol and procaine on human sperm. Br J Clin Pharmacol 1982- 13:
285P.
2. Zipper J, et al. Propranolol as a novel, effective spermicide: preliminary
findings. Br Med J 1983- 287: 1245-6.
3. Patel LG, et al. Propranolol concentrations in plasma after insertion into
the vagina. Br Med J 1983- 287: 1247-8.
4. Mahajan P, et al. Propranolol concentrations in blood serum, seminal plasma
and saliva in man after a single oral dose. Br J Clin Pharmacol 1984- 18:
849-52.
Explosive Rage:
Of 8 patients with intermittent explosive disorder (episodic outbursts of
inappropriate rage), 2 had complete remission and 3 had substantial behavioral
improvement when treated with propranolol in doses of 80 to 300 mg daily.
Jenkins SC, Maruta T. Therapeutic use of propranolol for intermittent explosive
disorder. Mayo Clin Proc 1987- 62: 204-14.
Hepatic Disorders:
Long-term treatment with propranolol, in a dosage which reduced the heart
rate by about 25% (dose range, 20 to 180 mg twice daily), prevented recurrent
gastro-intestinal bleeding in a controlled study of 74 patients with cirrhosis.
A year after inclusions in the study 96% of treated patients were free of
re-bleeding compared with 50% of the placebo group. (1) In another controlled
study in 48 patients’ (2) with cirrhosis and demonstrated variceal bleeding,
26 were given propranolol in doses of 80 to 800 mg daily and 22 patients
received placebo. Despite a fall in hepatic venous pressure gradient with
propranolol in all patients measured, 12 of the 26 patients in the propranolol
group rebelled from oesophageal varices- this was not significantly different
from the figure of 11 among the 22-receiving placebo. Four patients in the
propranolol group and 2 in the placebo group died from variceal rebleeding.
These results contrast markedly with those of Lebrec et al. (1) which may
possibly be due to differences in patient selection- whereas the former study
included mostly patients with alcoholic cirrhosis who had good liver function,
the study by Burroughs et al. (2) included patients with cirrhosis from a
variety of causes and with varying severity of liver disease. A similar study in
50 patients’ (3) with non-cirrhotic portal fibrosis showed that after one
year, 5 of 25 patients who had received propranolol had recurrent
gastro-intestinal bleeding compared with 20 of 25 patients who received placebo.
All of the patients were in good general health suggesting that propranolol is
effective in preventing rebleeding in patients with good liver function
regardless of cause of portal fibrosis. In a study of patients with varying
severity of cirrhosis, (4) propranolol was no more effective than placebo during
the first 60 days following hemorrhage but after 60 days patients who received
propranolol had fewer bleeding episodes. Non-variceal bleeding in portal
hypertension is now termed portal hypertensive gastropathy. (7) In a recent
controlled study propranolol reduced the incidence of recurrent bleeding from
portal hypertensive gastropathy in-patients with cirrhosis. (8) The goal of
prophylactic treatment is to prevent the first episode of oesophageal variceal
bleeding and thus improve survival. In their review, Terblanche and co-workers
(5) noted that one-third of patients with cirrhosis and varices were considered
likely to bleed. Propranolol decreased the incidence of first bleed and death in
a prospective, randomized, multicentre; single-blind study (6) and this and
other studies reviewed by Poynard et al. (9) endorsed the prophylactic value of
beta-blockers. After meta-analysis of randomized studies, Pagliaro et al. (10)
considered that there was now sufficient evidence to recommend beta-blockers for
the prevention of first bleeding in-patients with cirrhosis and varices.
1. Lebrec D, et al. Propranolol for prevention of recurrent gastrointestinal
bleeding in-patients with cirrhosis. N Engl J Med 1981- 305: 1371-4.
2. Burroughs AK, et al. Controlled trial of propranolol for the prevention of
recurrent variceal hemorrhage in-patients with cirrhosis. N Engl J Med 1983-
309: 1539-42.
3. Kiire CF. Controlled trial of propranolol to prevent recurrent variceal
bleeding in-patients with non-cirrhotic portal fibrosis. Br Med J 1989- 298:
1363-5.
4. Garden OJ, et al. Propranolol in the prevention of recurrent variceal
hemorrhage in cirrhotic patients: a controlled trial. Gastroenterology 1990- 98:
185-90.
5. Terblanche J, et al. Controversies in the management of bleeding esophageal
varices. N Engl J Med 1989- 320: 1469-75.
6. Pascal J-P, et al. Propranolol in the prevention of first upper
gastrointestinal tract hemorrhage in patients with cirrhosis of the liver and
esophageal varices. N Engl J Med 1987- 317: 856-61.
7. Anonymous. Portal hypertensive gastropathy. Lancet 1991- 338: 1045-6.
8. Perez-Ayuso RM, et al. Propranolol in prevention of recurrent bleeding from
severe portal hypertensive gastropathy in cirrhosis. Lancet 1991- 337:
1431-4.
9. Poynard T, et al. Beta-adrenergic-antagonist drugs in the prevention of
gastrointestinal bleeding in patients with cirrhosis and esophageal varices: an
analysis of data and prognostic factors in 589 patients from four randomized
clinical trials. N Engl J Med 1991- 324: 1532-8.
10. Pagliaro L, et al. Prevention of first bleeding in cirrhosis: a
meta-analysis of randomized trials of nonsurgical treatment. Ann Intern Med
1992- 117: 59-70.
Schizophrenia:
Peet and Yates have reviewed the use of propranolol in schizophrenia. (1)
Although there have been reports of benefit from uncontrolled studies, often
with very high doses of around 3 g daily, controlled studies have failed to show
any advantage over placebo. Other work has shown that propranolol is less
effective than chlorpromazine in the treatment of acute schizophrenia.
Propranolol has sometimes been given as an adjunct to neuroleptic therapy, but
any resultant clinical improvement is likely to be due to a pharmacokinetic
interaction leading to increased plasma concentrations of the neuroleptic.
Although the evidence does not support the use of propranolol in schizophrenia
there is some evidence from case studies of a beneficial effect in-patients with
mania. However, in a subsequent paper (2) a favorable effect of
propranolol on both positive and negative symptoms of chronic schizophrenia was
noted in 22 patients- in contrast, thioridazine given to a further 23 improved
positive but not negative symptoms.
1. Peet M, Yates RA. Beta-blockers in the treatment of neurological and
psychiatric disorders. J Clin Hosp Pharm 1981- 6: 155-71.
2. Eccleston D, et al. The effect of propranolol and thioridazine on positive
and negative symptoms of schizophrenia. Br J Psychiatry 1985- 147: 623-30
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