Propranolol

Chemical:                                to order (prescription not required)
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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