ALPRENOLOL
Adverse Effects, Treatment, Precautions, interactions as for beta blockers propranolol which is shown below :
PROPRANOLOL HCL
DESCRIPTION:
Inderal (propranolol hydrochloride) is a synthetic beta-adrenergic receptor
blocking agent chemically described as 1-(Isopropylamino)-3-(1-naphthyloxy)-2-
propanol hydrochloride.
Propranolol hydrochloride is a stable, white, crystalline solid which is readily
soluble in water and ethanol. Its molecular weight is 295.81.
Inderal is available as 10 mg, 20 mg, 40 mg, 60 mg, and 80 mg tablets for oral
administration and as a 1 mg/mL sterile injectable solution for intravenous
administration.
ACTIONS/CLINICAL PHARMACOLOGY:
Inderal is a nonselective beta-adrenergic receptor blocking agent possessing no
other autonomic nervous system activity. It specifically competes with beta-
adrenergic receptor stimulating agents for available receptor sites. When access
to beta-receptor sites is blocked by Inderal, the chronotropic, inotropic, and
vasodilator responses to beta- adrenergic stimulation are decreased
proportionately.
Propranolol is almost completely absorbed from the gastrointestinal tract, but a
portion is immediately bound by the liver. Peak effect occurs in one to one- and
one-half hours. The biologic half-life is approximately four hours.
There is no simple correlation between dose or plasma level and therapeutic
effect, and the dose-sensitivity range as observed in clinical practice is wide.
The principal reason for this is that sympathetic tone varies widely between
individuals. Since there is no reliable test to estimate sympathetic tone or to
determine whether total beta blockade has been achieved, proper dosage requires
titration.
The mechanism of the antihypertensive effect of Inderal has not been
established. Among the factors that may be involved in contributing to the
antihypertensive action are (1) decreased cardiac output, (2) inhibition of
renin release by the kidneys, and (3) diminution of tonic sympathetic nerve
outflow from vasomotor centers in the brain. Although total peripheral
resistance may increase initially, it readjusts to or below the pretreatment
level with chronic use. Effects on plasma volume appear to be minor and somewhat
variable. Inderal has been shown to cause a small increase in serum potassium
concentration when used in the treatment of hypertensive patients.
In angina pectoris, propranolol generally reduces the oxygen requirement of the
heart at any given level of effort by blocking the catecholamine- induced
increases in the heart rate, systolic blood pressure, and the velocity and
extent of myocardial contraction. Propranolol may increase oxygen requirements
by increasing left ventricular fiber length, end diastolic pressure, and
systolic ejection period. The net physiologic effect of beta-adrenergic blockade
is usually advantageous and is manifested during exercise by delayed onset of
pain and increased work capacity. Propranolol exerts its antiarrhythmic effects
in concentrations associated with beta- adrenergic blockade, and this appears to
be its principal antiarrhythmic mechanism of action. In dosages greater than
required for beta blockade, Inderal also exerts a quinidine-like or anesthetic-
like membrane action, which affects the cardiac action potential. The
significance of the membrane action in the treatment of arrhythmias is
uncertain.
The mechanism of the antimigraine effect of propranolol has not been
established. Beta- adrenergic receptors have been demonstrated in the pial
vessels of the brain.
The specific mechanism of Inderal's antitremor effects has not been established,
but beta-2 (noncardiac) receptors may be involved. A central effect is also
possible. Clinical studies have demonstrated that Inderal is of benefit in
exaggerated physiological and essential (familial) tremor.
Beta-receptor blockade can be useful in conditions in which, because of
pathologic or functional changes, sympathetic activity is detrimental to the
patient. But there are also situations in which sympathetic stimulation is
vital. For example, in patients with severely damaged hearts, adequate
ventricular function is maintained by virtue of sympathetic drive, which should
be preserved. In the presence of AV block greater than first degree, beta
blockade may prevent the necessary facilitating effect of sympathetic activity
on conduction. Beta blockade results in bronchial constriction by interfering
with adrenergic bronchodilator activity, which should be preserved in patients
subject to bronchospasm.
Propranolol is not significantly dialyzable.
The Beta-Blocker Heart Attack Trial (BHAT) was a National Heart, Lung and Blood
Institute- sponsored multicenter, randomized, double-blind, placebo-controlled
trial conducted in 31 U.S. centers (plus one in Canada) in 3,837 persons without
history of severe congestive heart failure or presence of recent heart failure;
certain conduction defects; angina since infarction, who had survived the acute
phase of myocardial infarction. Propranolol was administered at either 60 or 80
mg t.i.d. based on blood levels achieved during an initial trial of 40 mg t.i.d.
Therapy with Inderal, begun 5 to 21 days following infarction, was shown to
reduce overall mortality up to 39 months, the longest period of follow-up. This
was primarily attributable to a reduction in cardiovascular mortality. The
protective effect of Inderal was consistent regardless of age, sex, or site of
infarction. Compared with placebo, total mortality was reduced 39% at 12 months
and 26% over an average follow-up period of 25 months. The Norwegian Multicenter
Trial in which propranolol was administered at 40 mg q.i.d. gave overall results
which support the findings in the BHAT.
Although the clinical trials used either t.i.d. or q.i.d. dosing, clinical,
pharmacologic, and pharmacokinetic data provide a reasonable basis for
concluding that b.i.d. dosing with propranolol should be adequate in the
treatment of postinfarction patients.
CLINICAL
In the BHAT, patients on Inderal were prescribed either 180 mg/day (82% of
patients) or 240 mg/day (18% of patients). Patients were instructed to take the
medication 3 times a day at mealtimes. This dosing schedule would result in an
overnight dosing interval of 12 to 14 hours which is similar to the dosing
interval for a b.i.d regimen. In addition, blood samples were drawn at various
times and analyzed for propranolol. When the patients were grouped into tertiles
based on the blood levels observed and the mortality in the upper and lower
tertiles was compared, there was no evidence that blood levels affected
mortality.
PHARMACOLOGIC
Studies in normal volunteers have shown that a 90mg b.i.d. regimen maintains
beta blockade at, or above, the minimum for 60 mg t.i.d. dosing for 24 hours
even though differences occurred at two time intervals. At 10 to 12 hours after
the first dose of the day, t.i.d. dosing gave more beta blockade than b.i.d.
dosing; at 20 to 24 hours the trend of the relationship was reversed. These
relationships were similar in direction to those observed for plasma propranolol
levels. (See "PHARMACOKINETIC.")
PHARMACOKINETIC
A bioavailability study in normal volunteers showed that the blood levels
produced by 180 mg/day given b.i.d. are below those provided by the same daily
dosage given t.i.d. at 10 to 12 hours after the first dose of the day, but above
those of a t.i.d. regimen at 20 to 24 hours. However, the blood levels produced
by b.i.d. dosing were always equivalent to or above the minimum for t.i.d.
dosing throughout the 24 hours. In addition, the mean AUC on the fourth day for
the b.i.d. regimen was about 17% greater than for the t.i.d. regimen (1,194 Vs.
1,024 ng/mL-hr).
INDICATIONS AND USAGE:
HYPERTENSION
Inderal is indicated in the management of hypertension. It may be used alone or
used in combination with other antihypertensive agents, particularly a thiazide
diuretic. Inderal is not indicated in the management of hypertensive
emergencies.
ANGINA PECTORIS DUE TO CORONARY ATHEROSCLEROSIS
Inderal is indicated for the long-term management of patients with angina
pectoris.
CARDIAC ARRHYTHMIAS
1.) Supraventricular arrhythmias
a) Paroxysmal atrial tachycardias, particularly those arrhythmias induced by
catecholamines or digitalis or associated with the Wolff-Parkinson- White
syndrome. (See W-P-W under "Warnings.")
b) Persistent sinus tachycardia which is noncompensatory and impairs the well-
being of the patient.
c) Tachycardias and arrhythmias due to thyrotoxicosis when causing distress or
increased hazard and when immediate effect is necessary as adjunctive, short-
term (2 to 4 weeks) therapy. May be used with, but not in place of, specific
therapy. (See "THYROTOXICOSIS" under "Warnings.")
d) Persistent atrial extrasystoles which impair the well-being of the patient
and do not respond to conventional measures.
e) Atrial flutter and fibrillation when ventricular rate cannot be controlled by
digitalis alone, or when digitalis is contraindicated.
2.) Ventricular tachycardias.
Ventricular arrhythmias do not respond to propranolol as predictably as do the
supraventricular arrhythmias.
a) Ventricular tachycardias
With the exception of those induced by catecholamines or digitalis, Inderal is
not the drug of first choice. In critical situations when cardioversion
techniques or other drugs are not indicated or are not effective, Inderal may be
considered. If, after consideration of the risks involved, Inderal is used, it
should be given intravenously in low dosage and very slowly. (See "Dosage and
Administration.") Care In The Administration Of Inderal With Constant
Electrocardiographic Monitoring Is Essential As The Failing Heart Requires Some
Sympathetic Drive For Maintenance Of Myocardial Tone.
b) Persistent premature ventricular extrasystoles which do not respond to
conventional measures and impair the well-being of the patient.
3.) Tachyarrhythmias of digitalis intoxication
If digitalis-induced tachyarrhythmias persist following discontinuance of
digitalis and correction of electrolyte abnormalities, they are usually
reversible with Oral Inderal. Severe bradycardia may occur. (See "OVERDOSAGE.")
Intravenous propranolol hydrochloride is reserved for life-threatening
arrhythmias. Temporary maintenance with oral therapy may be indicated. (See
"Dosage and Administration.")
4.) Resistant tachyarrhythmias due to excessive catecholamine action during
anesthesia
Tachyarrhythmias due to excessive catecholamine action during anesthesia may
sometimes arise because of release of endogenous catecholamines or
administration of catecholamines. When usual measures fail in such arrhythmias,
Inderal may be given intravenously to abolish them. All general inhalation
anesthetics produce some degree of myocardial depression. Therefore, when
Inderal is used to treat arrhythmias during anesthesia, it should be used with
extreme caution and constant ECG and central venous pressure monitoring. (See
"Warnings.")
MYOCARDIAL INFARCTION
Inderal is indicated to reduce cardiovascular mortality in patients who have
survived the acute phase of myocardial infarction and are clinically stable.
MIGRAINE
Inderal is indicated for the prophylaxis of common migraine headache. The
efficacy of propranolol in the treatment of a migraine attack that has started
has not been established, and propranolol is not indicated for such use.
ESSENTIAL TREMOR
Inderal is indicated in the management of familial or hereditary essential
tremor. Familial or essential tremor consists of involuntary, rhythmic,
oscillatory movements, usually limited to the upper limbs. It is absent at rest
but occurs when the limb is held in a fixed posture or position against gravity
and during active movement. Inderal causes a reduction in the tremor amplitude
but not in the tremor frequency. Inderal is not indicated for the treatment of
tremor associated with Parkinsonism.
HYPERTROPHIC SUBAORTIC STENOSIS
Inderal is useful in the management of hypertrophic subaortic stenosis,
especially for treatment of exertional or other stress-induced angina,
palpitations, and syncope. Inderal also improves exercise performance. The
effectiveness of propranolol hydrochloride in this disease appears to be due to
a reduction of the elevated outflow pressure gradient, which is exacerbated by
beta-receptor stimulation. Clinical improvement may be temporary.
PHEOCHROMOCYTOMA
After primary treatment with an alpha-adrenergic blocking agent has been
instituted, Inderal may be useful as Adjunctive therapy if the control of
tachycardia becomes necessary before or during surgery. It is hazardous to use
Inderal unless alpha-adrenergic blocking drugs are already in use, since this
would predispose to serious blood pressure elevation. Blocking only the
peripheral dilator (beta) action of epinephrine leaves its constrictor (alpha)
action unopposed. In the event of hemorrhage or shock, there is a disadvantage
in having both beta and alpha blockade since the combination prevents the
increase in heart rate and peripheral vasoconstriction needed to maintain blood
pressure.
With inoperable or metastatic pheochromocytoma, Inderal may be useful as an
adjunct to the management of symptoms due to excessive beta- receptor
stimulation.
CONTRAINDICATIONS:
Inderal is contraindicated in 1) cardiogenic shock, 2) sinus bradycardia and
greater than first degree block, 3) bronchial asthma, 4) congestive heart
failure (see "Warnings") unless the failure is secondary to a tachyarrhythmia
treatable with Inderal.
WARNINGS:
CARDIAC FAILURE
Sympathetic stimulation may be a vital component supporting circulatory function
in patients with congestive heart failure, and its inhibition by beta blockade
may precipitate more severe failure. Although beta blockers should be avoided in
overt congestive heart failure, if necessary, they can be used with close
follow-up in patients with a history of failure who are well compensated and are
receiving digitalis and diuretics. Beta-adrenergic blocking agents do not
abolish the inotropic action of digitalis on heart muscle. IN PATIENTS WITHOUT A
HISTORY OF HEART FAILURE, continued use of beta blockers can, in some cases,
lead to cardiac failure. Therefore, at the first sign or symptom of heart
failure, the patient should be digitalized and/or treated with diuretics, and
the response observed closely, or Inderal should be discontinued (gradually, if
possible).
*************************************************
* *
* IN PATIENTS WITH ANGINA PECTORIS, there *
* have been reports of exacerbation of angina *
* and, in some cases, myocardial infarction, *
* following Abrupt discontinuance of Inderal *
* therapy. Therefore, when discontinuance of *
* Inderal is planned, the dosage should be *
* gradually reduced over at least a few weeks *
* and the patient should be cautioned against *
* interruption or cessation of therapy *
* without the physician's advice. If Inderal *
* therapy is interrupted and exacerbation of *
* angina occurs, it usually is advisable to *
* reinstitute Inderal therapy and take other *
* measures appropriate for the management of *
* unstable angina pectoris. Since coronary *
* artery disease may be unrecognized, it may *
* be prudent to follow the above advice in *
* patients considered at risk of having *
* occult atherosclerotic heart disease who *
* are given propranolol for other *
* indications. *
* *
*************************************************
NONALLERGIC BRONCHOSPASM (E.G., CHRONIC BRONCHITIS, EMPHYSEMA)
PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD IN GENERAL NOT RECEIVE BETA
BLOCKERS. Inderal should be administered with caution since it may block
bronchodilation produced by endogenous and exogenous catecholamine stimulation
of beta receptors.
MAJOR SURGERY
The necessity or desirability of withdrawal of beta-blocking therapy prior to
major surgery is controversial. It should be noted, however, that the impaired
ability of the heart to respond to reflex adrenergic stimuli may augment the
risks of general anesthesia and surgical procedures.
Inderal, like other beta blockers, is a competitive inhibitor of beta-receptor
agonists and its effects can be reversed by administration of such agents, e.g.,
dobutamine or isoproterenol. However, such patients may be subject to protracted
severe hypotension. Difficulty in starting and maintaining the heartbeat has
also been reported with beta blockers.
DIABETES AND HYPOGLYCEMIA
Beta blockers should be used with caution in diabetic patients if a beta-
blocking agent is required. Beta blockers may mask tachycardia occurring with
hypoglycemia, but other manifestations such as dizziness and sweating may not be
significantly affected. Following insulin- induced hypoglycemia, propranolol may
cause a delay in the recovery of blood glucose to normal levels.
THYROTOXICOSIS
Beta blockade may mask certain clinical signs of hyperthyroidism. Therefore,
abrupt withdrawal of propranolol may be followed by an exacerbation of symptoms
of hyperthyroidism, including thyroid storm. Propranolol may change thyroid-
function tests, increasing T4 and reverse T3 and decreasing T3.
IN PATIENTS WITH WOLFF-PARKINSON-WHITE SYNDROME, several cases have been
reported in which, after propranolol, the tachycardia was replaced by a severe
bradycardia requiring a demand pacemaker. In one case this resulted after an
initial dose of 5 mg propranolol.
PRECAUTIONS:
GENERAL
Propranolol should be used with caution in patients with impaired hepatic or
renal function. Inderal is not indicated for the treatment of hypertensive
emergencies.
Beta-adrenoreceptor blockade can cause reduction of intraocular pressure.
Patients should be told that Inderal may interfere with the glaucoma screening
test. Withdrawal may lead to a return of increased intraocular pressure.
CLINICAL LABORATORY TESTS
Elevated blood urea levels in patients with severe heart disease, elevated serum
transaminase, alkaline phosphatase, lactate dehydrogenase.
DRUG INTERACTIONS
Patients receiving catecholamine-depleting drugs such as reserpine should be
closely observed if Inderal is administered. The added catecholamine- blocking
action may produce an excessive reduction of resting sympathetic nervous
activity, which may result in hypotension, marked bradycardia, vertigo, syncopal
attacks, or orthostatic hypotension.
Caution should be exercised when patients receiving a beta blocker are
administered a calcium-channel blocking drug, especially intravenous verapamil,
for both agents may depress myocardial contractility or atrioventricular
conduction. On rare occasions, the concomitant intravenous use of a beta blocker
and verapamil has resulted in serious adverse reactions, especially in patients
with severe cardiomyopathy, congestive heart failure or recent myocardial
infarction.
Blunting of the antihypertensive effect of beta- adrenoceptor blocking agents by
nonsteroidal anti-inflammatory drugs has been reported.
Hypotension and cardiac arrest have been reported with the concomitant use of
propranolol and haloperidol.
Aluminum Hydroxide Gel greatly reduces intestinal absorption of propranolol.
Ethanol slows the rate of absorption of propranolol.
Phenytoin, Phenobarbitone, and Rifampin accelerate propranolol clearance.
Chlorpromazine, when used concomitantly with propranolol, results in increased
plasma levels of both drugs.
Antipyrine and Lidocaine have reduced clearance when used concomitantly with
propranolol.
Thyroxine may result in a lower than expected T3 concentration when used
concomitantly with propranolol.
Cimetidine decreases the hepatic metabolism of propranolol, delaying elimination
and increasing blood levels.
Theophylline clearance is reduced when used concomitantly with propranolol.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
Long-term studies in animals have been conducted to evaluate toxic effects and
carcinogenic potential. In 18-month studies, in both rats and mice, employing
doses up to 150 mg/kg/day, there was no evidence of significant drug-induced
toxicity. There were no drug-related tumorigenic effects at any of the dosage
levels. Reproductive studies in animals did not show any impairment of fertility
that was attributable to the drug.
PREGNANCY: PREGNANCY CATEGORY C
In a series of reproduction and developmental toxicology studies, propranolol
was given to rats at dosages up to 150 mg/kg/day by gavage or in the diet
throughout pregnancy and through lactation. In rats given 150 mg/kg/day (about
10 times the maximum recommended human dose) propranolol was embryotoxic
(reduced litter sizes and increased resorption sites). In addition, an
unexplained increase in neonatal toxicity (death) was noted at all dosage groups
in some of the studies. Maternal toxicity (decreased body weight) was evident at
150 mg/kg/day. Propranolol also was given to rabbits at dosages up to 250
mg/kg/day (approximately 20 times the maximum recommended human dose) throughout
pregnancy. No evidence of embryotoxicity was noted.
Teratogenicity was not noted in either species.
There are no adequate and well-controlled studies in pregnant women.
Intrauterine growth retardation has been reported in neonates whose mothers
received propranolol during pregnancy. Neonates whose mothers are receiving
propranolol at parturition have exhibited bradycardia, hypoglycemia and
respiratory depression. Adequate facilities for monitoring these infants at
birth should be available. Inderal should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.
NURSING MOTHERS
Inderal is excreted in human milk. Caution should be exercised when Inderal is
administered to a nursing woman.
PEDIATRIC USE
High serum propranolol levels have been noted in patients with Down's syndrome
(trisomy 21), suggesting that the bioavailability of propranolol may be
increased in patients with this condition.
Evaluation of the effects of propranolol in children, relative to the drug's
efficacy and safety, has not been as systematically performed as in adults.
Information is available in the medical literature to allow fair estimates, and
specific dosing information has been reasonably studied.
Cardiovascular diseases that are common to adults and children are generally as
responsive to propranolol intervention in children as they are in adults.
Adverse reactions are also similar: for example, bronchospasm and congestive
heart failure related to propranolol therapy have been reported in children and
occur through the same mechanisms as previously described in adults.
The normal echocardiogram evolves through a series of changes as the heart
matures during growth and development in children. Should echocardiography be
used to monitor propranolol therapy in children, the age-related changes in the
echocardiogram need to be borne in mind.
DRUG INTERACTIONS:
Patients receiving catecholamine-depleting drugs such as reserpine should be
closely observed if Inderal is administered. The added catecholamine- blocking
action may produce an excessive reduction of resting sympathetic nervous
activity, which may result in hypotension, marked bradycardia, vertigo, syncopal
attacks, or orthostatic hypotension.
Caution should be exercised when patients receiving a beta blocker are
administered a calcium-channel blocking drug, especially intravenous verapamil,
for both agents may depress myocardial contractility or atrioventricular
conduction. On rare occasions, the concomitant intravenous use of a beta blocker
and verapamil has resulted in serious adverse reactions, especially in patients
with severe cardiomyopathy, congestive heart failure or recent myocardial
infarction.
Blunting of the antihypertensive effect of beta- adrenoceptor blocking agents by
nonsteroidal anti-inflammatory drugs has been reported.
Hypotension and cardiac arrest have been reported with the concomitant use of
propranolol and haloperidol.
Aluminum Hydroxide Gel greatly reduces intestinal absorption of propranolol.
Ethanol slows the rate of absorption of propranolol.
Phenytoin, Phenobarbitone, and Rifampin accelerate propranolol clearance.
Chlorpromazine, when used concomitantly with propranolol, results in increased
plasma levels of both drugs.
Antipyrine and Lidocaine have reduced clearance when used concomitantly with
propranolol.
Thyroxine may result in a lower than expected T3 concentration when used
concomitantly with propranolol.
Cimetidine decreases the hepatic metabolism of propranolol, delaying elimination
and increasing blood levels.
Theophylline clearance is reduced when used concomitantly with propranolol.
(See Also PRECAUTIONS)
ADVERSE REACTIONS:
Most adverse effects have been mild and transient and have rarely required the
withdrawal of therapy.
CARDIOVASCULAR: Bradycardia; congestive heart failure; intensification of AV
block; hypotension; paresthesia of hands; thrombocytopenic purpura; arterial
insufficiency, usually of the Raynaud type.
CENTRAL NERVOUS SYSTEM: Light-headedness; mental depression manifested by
insomnia, lassitude, weakness, fatigue; reversible mental depression progressing
to catatonia; visual disturbances; hallucinations, vivid dreams, an acute
reversible syndrome characterized by disorientation for time and place, short-
term memory loss, emotional lability, slightly clouded sensorium, and decreased
performance on neuropsychometrics. Total daily doses above 160 mg (when
administered as divided doses of greater than 80 mg each) may be associated with
an increased incidence of fatigue, lethargy, and vivid dreams.
GASTROINTESTINAL: Nausea, vomiting, epigastric distress, abdominal cramping,
diarrhea, constipation, mesenteric arterial thrombosis, ischemic colitis.
ALLERGIC: Pharyngitis and agranulocytosis, erythematous rash, fever combined
with aching and sore throat, laryngospasm, and respiratory distress.
RESPIRATORY: Bronchospasm.
HEMATOLOGIC: Agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic
purpura.
AUTOIMMUNE: In extremely rare instances, systemic lupus erythematosus has been
reported.
MISCELLANEOUS: Alopecia, LE-like reactions, psoriasiform rashes, dry eyes, male
impotence, and Peyronie's disease have been reported rarely. Oculomucocutaneous
reactions involving the skin, serous membranes and conjunctivae reported for a
beta blocker (practolol) have not been associated with propranolol.
DOSAGE AND ADMINISTRATION:
THE DOSAGE RANGE FOR INDERAL IS DIFFERENT FOR EACH INDICATION.
ORAL
HYPERTENSION--Dosage Must Be Individualized.
The usual initial dosage is 40 mg Inderal twice daily, whether used alone or
added to a diuretic. Dosage may be increased gradually until adequate blood
pressure control is achieved. The usual maintenance dosage is 120 mg to 240 mg
per day. In some instances a dosage of 640 mg a day may be required. The time
needed for full antihypertensive response to a given dosage is variable and may
range from a few days to several weeks.
While twice-daily dosing is effective and can maintain a reduction in blood
pressure throughout the day, some patients, especially when lower doses are
used, may experience a modest rise in blood pressure toward the end of the 12-
hour dosing interval. This can be evaluated by measuring blood pressure near the
end of the dosing interval to determine whether satisfactory control is being
maintained throughout the day. If control is not adequate, a larger dose, or 3-
times-daily therapy may achieve better control.
ANGINA PECTORIS--Dosage Must Be Individualized.
Total daily doses of 80 mg to 320 mg, when administered orally, twice a day,
three times a day, or four times a day, have been shown to increase exercise
tolerance and to reduce ischemic changes in the ECG. If treatment is to be
discontinued, reduce dosage gradually over a period of several weeks. (See
"Warnings.")
ARRHYTHMIAS--10 mg to 30 mg three or four times daily, before meals and at
bedtime.
MYOCARDIAL INFARCTION--The recommended daily dosage is 180 mg to 240 mg per day
in divided doses. Although a t.i.d. regimen was used in the Beta-Blocker Heart
Attack Trial and a q.i.d. regimen in the Norwegian Multicenter Trial, there is a
reasonable basis for the use of either a t.i.d. or b.i.d. regimen (see
"Actions/Clinical Pharmacology.") The effectiveness and safety of daily dosages
greater than 240 mg for prevention of cardiac mortality have not been
established. However, higher dosages may be needed to effectively treat
coexisting diseases such as angina or hypertension (see above).
MIGRAINE--Dosage Must Be Individualized.
The initial oral dose is 80 mg Inderal daily in divided doses. The usual
effective dose range is 160 mg to 240 mg per day. The dosage may be increased
gradually to achieve optimum migraine prophylaxis. If a satisfactory response is
not obtained within four to six weeks after reaching the maximum dose, Inderal
therapy should be discontinued. It may be advisable to withdraw the drug
gradually over a period of several weeks.
ESSENTIAL TREMOR--Dosage Must Be Individualized.
The initial dosage is 40 mg Inderal twice daily. Optimum reduction of essential
tremor is usually achieved with a dose of 120 mg per day. Occasionally, it may
be necessary to administer 240 mg to 320 mg per day.
HYPERTROPHIC SUBAORTIC STENOSIS--20 mg to 40 mg three or four times daily,
before meals and at bedtime.
PHEOCHROMOCYTOMA--Preoperatively--60 mg daily in divided doses for three days
prior to surgery, concomitantly with an alpha-adrenergic blocking agent.
--Management Of Inoperable Tumor--30 mg daily in divided doses.
USE IN CHILDREN: Intravenous administration of Inderal is not recommended in
children. Oral dosage for treating hypertension requires individual titration,
beginning with a 1.0 mg perkg (body weight) per day dosage regimen (i.e., 0.5 mg
per kg b.i.d.).
The usual pediatric dosage range is 2 mg to 4 mg per kg per day in two equally
divided doses (i.e., 1.0 mg per kg b.i.d. to 2.0 mg per kg b.i.d.). Pediatric
dosage calculated by weight (recommended) generally produces propranolol plasma
levels in a therapeutic range similar to that in adults. On the other hand,
pediatric doses calculated on the basis of body surface area (Not recommended)
usually result in plasma levels above the mean adult therapeutic range. Doses
above 16 mg per kg per day should not be used in children. If treatment with
Inderal is to be discontinued, a gradually decreasing dose titration over a 7-to
14-day period is necessary.
INTRAVENOUS
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container permit.
Intravenous administration is reserved for life- threatening arrhythmias or
those occurring under anesthesia. The usual dose is from 1 mg to 3 mg
administered under careful monitoring, e.g., electrocardiographic, central
venous pressure. The rate of administration should not exceed 1 mg (1 mL) per
minute to diminish the possibility of lowering blood pressure and causing
cardiac standstill. Sufficient time should be allowed for the drug to reach the
site of action even when a slow circulation is present. If necessary, a second
dose may be given after two minutes. Thereafter, additional drug should not be
given in less than four hours. Additional Inderal should not be given when the
desired alteration in rate and/or rhythm is achieved.
Transference to oral therapy should be made as soon as possible.
The intravenous administration of Inderal has not been evaluated adequately in
the management of hypertensive emergencies.
OVERDOSAGE:
Inderal is not significantly dialyzable. In the event of overdosage or
exaggerated response, the following measures should be employed:
General--If ingestion is or may have been recent, evacuate gastric contents,
taking care to prevent pulmonary aspiration.
BRADYCARDIA--ADMINISTER ATROPINE (0.25 mg to 1.0 mg); IF THERE IS NO RESPONSE TO
VAGAL BLOCKADE, ADMINISTER ISOPROTERENOL CAUTIOUSLY.
CARDIAC FAILURE--DIGITALIZATION AND DIURETICS.
HYPOTENSION--VASOPRESSORS, E.G., LEVARTERENOL OR EPINEPHRINE (THERE IS EVIDENCE
THAT EPINEPHRINE IS THE DRUG OF CHOICE).
BRONCHOSPASM--ADMINISTER ISOPROTERENOL AND AMINOPHYLLINE.
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ALPRENOLOL :
Hypersensitivity. A report of contact eczema in workers exposed to alprenolol.
Pharmacokinetics
Alprenolol is almost completely absorbed from the
gastro-intestinal tract but is subject to considerable
first-pass metabolism in the liver. Peak plasma con-
centrations are achieved about I hour after a dose. It
has high lipid solubility. Alprenolol is about 85%
bound to plasma proteins. It is distributed into breast
milk. It is metabolised in the liver, primarily to 4-
hydroxyalprenolol, which is active. The plasma
half-life of alprenolol is about 3 hours and the plas-
ma half-life of 4-hydroxy alprenolol is about 20 min-
utes. It is excreted in the urine mainly in the form of
its metabolites.
Uses and Administration
Alprenolol is a non-cardioselective beta blocker.
It is reported to have intrinsic sympathomi-
metic activity and some membrane-stabilising prop-
erties.
Alprenolol is used in the management of hyperten-
sion, angina pectoris and cardiac ar-
rhythmias.
It is given by mouth, as the benzoate or hydrochlo-
ride; doses have been expressed in terms of the base
or of the hydrochloride.
In hypertension the usual initial dose is 200 mg dai-
ly, in divided doses by mouth, increased weekly ac-
cording to the response of the patient up to a total of
800 mg daily in divided doses. The usual dose for
angina pectoris. cardiac arrhythmias, and other
cardiac disorders is 50 to 100 mg four times daily. It
may be necessary to reduce the dose in patients with
renal or hepatic impairment.