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Propranolol
Overview
What is Propranolol?
Propranolol hydrochloride is a synthetic beta-adrenergic receptor blocking agent
chemically described as (+)-1-(isopropylamino)-3-(1-naphthyloxy)-2-propanol
hydrochloride. Its structural formula is:
CHNO•HCl
Propranolol hydrochloride is a stable, white, crystalline solid which is
readily soluble in water and ethanol. Its molecular weight is 295.80.
Propranolol hydrochloride injection is available as a sterile injectable
solution for intravenous administration. Each mL contains 1 mg of propranolol
hydrochloride in Water for Injection. The pH is adjusted with citric acid.
What does Propranolol look like?
What are the available doses of Propranolol?
Sorry No records found.
What should I talk to my health care provider before I take Propranolol?
Sorry No records found
How should I use Propranolol?
Intravenous administration is usually reserved for
life-threatening arrhythmias or those occurring under anesthesia.
Parenteral drug products should be inspected visually for
particulate matter and discoloration prior to administration, whenever solution
and container permit.
The usual dose is 1 to 3 mg administered under careful monitoring, such as
electrocardiography and 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
propranolol hydrochloride should not be given when the desired alteration in
rate or rhythm is achieved.
Transfer to oral therapy as soon as possible.
What interacts with Propranolol?
Propranolol is contraindicated in 1) cardiogenic shock; 2) sinus bradycardia and greater than first-degree block; 3) bronchial asthma; and 4) in patients with known hypersensitivity to propranolol hydrochloride.
What are the warnings of Propranolol?
Research indicates that patients with impaired kidney function, including
premature neonates, who receive parenteral levels of aluminum at greater than 4
to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous
system and bone toxicity. Tissue loading may occur at even lower rates of
administration.
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, some have
been shown to be highly beneficial when used with close follow-up in patients
with a history of failure who are well compensated and are receiving additional
therapies, including diuretics as needed. Beta-adrenergic blocking agents do not
abolish the inotropic action of digitalis on heart muscle.
In general, patients with bronchospastic lung disease should not
receive beta blockers. Propranolol should be administered with caution in this
setting since it may block bronchodilation produced by endogenous and exogenous
catecholamine stimulation of beta-receptors.
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
in propranolol-treated patients might augment the risks of general anesthesia
and surgical procedures.
Propranolol 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.
Beta-adrenergic blockade may prevent the appearance of certain
premonitory signs and symptoms (pulse rate and pressure changes) of acute
hypoglycemia, especially in labile insulin-dependent diabetics. In these
patients, it may be more difficult to adjust the dosage of insulin.
Propranolol therapy, particularly in infants and children, diabetic or not,
has been associated with hypoglycemia especially during fasting, as in
preparation for surgery. Hypoglycemia has been reported after prolonged physical
exertion and in patients with renal insufficiency.
Beta-adrenergic 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 T and reverse T, and decreasing T.
Beta-adrenergic blockade in patients with Wolff-Parkinson-White
syndrome and tachycardia has been associated with severe bradycardia requiring
treatment with a pacemaker. In one case this resulted after an initial 5 mg dose
of intravenous propranolol.
What are the precautions of Propranolol?
Propranolol should be used with caution in patients with impaired
hepatic or renal function. Propranolol is not indicated for the treatment of
hypertensive emergencies.
Beta-adrenergic receptor blockade can cause reduction of intraocular
pressure. Patients should be told that propranolol might interfere with the
glaucoma screening test. Withdrawal may lead to a return of elevated intraocular
pressure.
Risk of anaphylactic reaction. While taking beta blockers, patients with a
history of severe anaphylactic reaction to a variety of allergens may be more
reactive to repeated challenge, either accidental, diagnostic, or therapeutic.
Such patients may be unresponsive to the usual doses of epinephrine used to
treat allergic reaction.
There have been reports of exacerbation of angina and, in some
cases, myocardial infarction, following abrupt discontinuance of propranolol
therapy. Therefore, when discontinuance of propranolol 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 a physician’s
advice. If propranolol therapy is interrupted and exacerbation of angina occurs,
it is usually advisable to reinstitute propranolol therapy and take other
measures appropriate for the management of 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.
In patients with hypertension, use of propranolol has been
associated with elevated levels of serum potassium, serum transaminases and
alkaline phosphatase. In severe heart failure, the use of propranolol has been
associated with increases in Blood Urea Nitrogen.
Caution should be exercised when propranolol is administered with
drugs that have an effect on CYP2D6, 1A2, or 2C19 metabolic pathways.
Co-administration of such drugs with propranolol may lead to clinically relevant
drug interactions and changes in its efficacy and/or toxicity (see ).
Propafenone has negative inotropic and beta-blocking properties
that can be additive to those of propranolol.
Quinidine increases the concentration of propranolol and produces a greater
degree of clinical beta-blockade and may cause postural hypotension.
Disopyramide is a Type I antiarrhythmic drug with potent negative inotropic
and chronotropic effects and has been associated with severe bradycardia,
asystole and heart failure when administered with propranolol.
Amiodarone is an antiarrhythmic agent with negative chronotropic properties
that may be additive to those seen with propranolol.
The clearance of lidocaine is reduced when administered with propranolol.
Lidocaine toxicity has been reported following coadministration with
propranolol.
Caution should be exercised when administering propranolol with drugs that
slow A-V nodal conduction, e.g. digitalis, lidocaine and calcium channel
blockers.
Caution should be exercised when patients receiving a
beta-blocker are administered a calcium-channel-blocking drug with negative
inotropic and/or chronotropic effects. Both agents may depress myocardial
contractility or atrioventricular conduction.
There have been reports of significant bradycardia, heart failure, and
cardiovascular collapse with concurrent use of verapamil and beta-blockers.
Co-administration of propranolol and diltiazem in patients with cardiac
disease has been associated with bradycardia, hypotension, high degree heart
block, and heart failure.
When combined with beta-blockers, ACE inhibitors can cause
hypotension, particularly in the setting of acute myocardial infarction.
ACE inhibitors have been reported to increase bronchial hyperreactivity when
administered with propranolol.
The antihypertensive effects of clonidine may be antagonized by
beta-blockers. Propranolol should be administered cautiously to patients
withdrawing from clonidine.
Prazosin has been associated with prolongation of first dose
hypotension in the presence of beta-blockers.
Postural hypotension has been reported in patients taking both beta-blockers
and terazosin or doxazosin.
Patients receiving catecholamine-depleting drugs, such as
reserpine, with propranolol should be closely observed for excess reduction of
resting sympathetic nervous activity, which may result in hypotension, marked
bradycardia, vertigo, syncopal attacks, or orthostatic hypotension.
Administration of reserpine with propranolol may also potentiate
depression.
Patients on long-term therapy with propranolol may experience
uncontrolled hypertension if administered epinephrine as a consequence of
unopposed alpha-receptor stimulation. Epinephrine is therefore not indicated in
the treatment of propranolol overdose (see ).
Propranolol is a competitive inhibitor of beta-receptor agonists,
and its effects can be reversed by administration of such agents, e.g.,
dobutamine or isoproterenol. Also, propranolol may reduce sensitivity to
dobutamine stress echocardiography in patients undergoing evaluation for
myocardial ischemia.
Nonsteroidal anti-inflammatory drugs (NSAIDS) have been reported
to blunt the antihypertensive effect of beta-adrenoreceptor blocking agents.
Administration of indomethacin with propranolol may reduce the efficacy of
propranolol in reducing blood pressure and heart rate.
The hypotensive effects of MAO inhibitors or tricyclic
antidepressants may be exacerbated when administered with beta-blockers by
interfering with the beta blocking activity of propranolol.
Methoxyflurane and trichloroethylene may depress myocardial
contractility when administered with propranolol.
Administration of propranolol with warfarin increases the
concentration of warfarin. Therefore, the prothrombin time should be
monitored.
Hypotension and cardiac arrest have been reported with the
concomitant use of propranolol and haloperidol.
Thyroxine may result in a lower than expected T concentration when used concomitantly with propranolol.
In dietary administration studies in which mice and rats were
treated with propranolol hydrochloride for up to 18 months at doses of up to 150
mg/kg/day, there was no evidence of drug-related tumorigenesis. On a body
surface area basis, this dose in the mouse and rat is, respectively, about equal
to and about twice the maximum recommended human oral daily dose (MRHD) of 640
mg propranolol hydrochloride. In a study in which both male and female rats were
exposed to propranolol hydrochloride in their diets at concentrations of up to
0.05% (about 50 mg/kg body weight and less than the MRHD), from 60 days prior to
mating and throughout pregnancy and lactation for two generations, there were no
effects on fertility. Based on differing results from Ames Tests performed by
different laboratories, there is equivocal evidence for a genotoxic effect of
propranolol hydrochloride in bacteria ( strain TA 1538).
In a series of reproductive and developmental toxicology studies,
propranolol hydrochloride was given to rats by gavage or in the diet throughout
pregnancy and lactation. At doses of 150 mg/kg/day, but not at doses of 80
mg/kg/day (equivalent to the MRHD on a body surface area basis), treatment was
associated with embryotoxicity (reduced litter size and increased resorption
rates) as well as neonatal toxicity (deaths). Propranolol hydrochloride also was
administered (in the feed) to rabbits (throughout pregnancy and lactation) at
doses as high as 150 mg/kg/day (about 5 times the maximum recommended human oral
daily dose). No evidence of embryo or neonatal toxicity was noted.
There are no adequate and well-controlled studies in pregnant women.
Intrauterine growth retardation has been reported for neonates whose mothers
received propranolol hydrochloride during pregnancy. Neonates whose mothers
received propranolol hydrochloride at parturition have exhibited bradycardia,
hypoglycemia, and respiratory depression. Adequate facilities for monitoring
such infants at birth should be available. Propranolol should be used during
pregnancy only if the potential benefit justifies the potential risk to the
fetus.
Propranolol is excreted in human milk. Caution should be
exercised when propranolol is administered to a nursing woman.
Safety and effectiveness of propranolol in pediatric patients
have not been established.
Clinical studies of intravenous propranolol did not include
sufficient numbers of subjects aged 65 and over to determine whether they
respond differently from younger subjects. Elderly subjects have decreased
clearance and a longer mean elimination half-life. These findings suggest that
dose adjustment of propranolol injection may be required for elderly patients
(see ). In general, dose selection for an elderly
patient should be cautious, usually starting at the low end of the dosing range,
reflecting the greater frequency of the decreased hepatic, renal or cardiac
function, and of concomitant disease or other drug therapy.
Propranolol is extensively metabolized by the liver. Compared to
normal subjects, patients with chronic liver disease have decreased clearance of
propranolol, increased volume of distribution, decreased protein-binding and
considerable variation in half life. Consideration should be given to lowering
the dose of intravenously administered propranolol in patients with hepatic
insufficiency.
What are the side effects of Propranolol?
In a series of 225 patients, there were 6 deaths (see ).
Cardiovascular events (hypotension, congestive heart failure, bradycardia, and
heart block) were the most common. The only other event reported by more than
one patient was nausea.
Other adverse events for intravenous propranolol, reported during
post-marketing surveillance include cardiac arrest, dyspnea, and cutaneous
ulcers.
The following adverse events have been reported with use of formulations of
sustained- or immediate-release oral propranolol and may be expected with
intravenous propranolol.
Bradycardia; congestive heart failure; intensification of AV
block; hypotension; paresthesia of hands; thrombocytopenic purpura; arterial
insufficiency, usually of the Raynaud type.
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. For immediate-release formulations,
fatigue, lethargy, and vivid dreams appear dose related.
Nausea, vomiting, epigastric distress, abdominal cramping,
diarrhea, constipation, mesenteric arterial thrombosis, ischemic colitis.
Pharyngitis and agranulocytosis; erythematous rash, fever
combined with aching and sore throat; laryngospasm, and respiratory
distress.
Bronchospasm.
Agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic
purpura.
In extremely rare instances, systemic lupus erythematosus has
been reported.
Alopecia, LE-like reactions, psoriaform 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.
What should I look out for while using Propranolol?
Propranolol is contraindicated in 1) cardiogenic shock; 2) sinus bradycardia and
greater than first-degree block; 3) bronchial asthma; and 4) in patients with
known hypersensitivity to propranolol hydrochloride.
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, some have
been shown to be highly beneficial when used with close follow-up in patients
with a history of failure who are well compensated and are receiving additional
therapies, including diuretics as needed. Beta-adrenergic blocking agents do not
abolish the inotropic action of digitalis on heart muscle.
In general, patients with bronchospastic lung disease should not
receive beta blockers. Propranolol should be administered with caution in this
setting since it may block bronchodilation produced by endogenous and exogenous
catecholamine stimulation of beta-receptors.
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
in propranolol-treated patients might augment the risks of general anesthesia
and surgical procedures.
Propranolol 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.
Beta-adrenergic blockade may prevent the appearance of certain
premonitory signs and symptoms (pulse rate and pressure changes) of acute
hypoglycemia, especially in labile insulin-dependent diabetics. In these
patients, it may be more difficult to adjust the dosage of insulin.
Propranolol therapy, particularly in infants and children, diabetic or not,
has been associated with hypoglycemia especially during fasting, as in
preparation for surgery. Hypoglycemia has been reported after prolonged physical
exertion and in patients with renal insufficiency.
Beta-adrenergic 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 T and reverse T, and decreasing T.
Beta-adrenergic blockade in patients with Wolff-Parkinson-White
syndrome and tachycardia has been associated with severe bradycardia requiring
treatment with a pacemaker. In one case this resulted after an initial 5 mg dose
of intravenous propranolol.
What might happen if I take too much Propranolol?
Propranolol is not significantly dialyzable. In the event of
overdose or exaggerated response, the following measures should be employed:
Hypotension and bradycardia have been reported following propranolol overdose
and should be treated appropriately. Glucagon can exert potent inotropic and
chronotropic effects and may be particularly useful for the treatment of
hypotension or depressed myocardial function after a propranolol overdose.
Glucagon should be administered as 50-150 mcg/kg intravenously followed by
continuous drip of 1-5 mg/hour for positive chronotropic effect. Isoproterenol,
dopamine, or phosphodiesterase inhibitors may also be useful. Epinephrine,
however, may provoke uncontrolled hypertension. Bradycardia can be treated with
atropine or isoproterenol. Serious bradycardia may require temporary cardiac
pacing.
The electrocardiogram, pulse, blood pressure, neurobehavioral status and
intake and output balance must be monitored. Isoproterenol and aminophylline may
be useful for bronchospasm.
How should I store and handle Propranolol?
Store at 20° to 25ºC (68° to 77°F).[See USP Controlled Room Temperature]Dispense in a tight container as defined in the USP.Store at 20° to 25ºC (68° to 77°F).[See USP Controlled Room Temperature]Dispense in a tight container as defined in the USP.Store at 20° to 25ºC (68° to 77°F).[See USP Controlled Room Temperature]Dispense in a tight container as defined in the USP.Each mL contains 1 mg of propranolol hydrochloride in Water for Injection. The pH is adjusted with citric acid. Supplied as: 1 mL vials in boxes of 10 ().Store at controlled room temperature 20° to 25°C (68° to 77°F). Protect from freezing or excessive heat.Manufactured by: Estrada do Rio da Mo n8, 8A e 8B - Fervenca2705-906 Terrugem - SNTPORTUGALDistributed by: 465 Industrial Way WestEATONTOWN NJ 07724USAIss. Aug. 2007Relabeling of "Additional Barcode" by:Physicians Total Care, Inc.Tulsa, OK 74146 Each mL contains 1 mg of propranolol hydrochloride in Water for Injection. The pH is adjusted with citric acid. Supplied as: 1 mL vials in boxes of 10 ().Store at controlled room temperature 20° to 25°C (68° to 77°F). Protect from freezing or excessive heat.Manufactured by: Estrada do Rio da Mo n8, 8A e 8B - Fervenca2705-906 Terrugem - SNTPORTUGALDistributed by: 465 Industrial Way WestEATONTOWN NJ 07724USAIss. Aug. 2007Relabeling of "Additional Barcode" by:Physicians Total Care, Inc.Tulsa, OK 74146 Each mL contains 1 mg of propranolol hydrochloride in Water for Injection. The pH is adjusted with citric acid. Supplied as: 1 mL vials in boxes of 10 ().Store at controlled room temperature 20° to 25°C (68° to 77°F). Protect from freezing or excessive heat.Manufactured by: Estrada do Rio da Mo n8, 8A e 8B - Fervenca2705-906 Terrugem - SNTPORTUGALDistributed by: 465 Industrial Way WestEATONTOWN NJ 07724USAIss. Aug. 2007Relabeling of "Additional Barcode" by:Physicians Total Care, Inc.Tulsa, OK 74146 Each mL contains 1 mg of propranolol hydrochloride in Water for Injection. The pH is adjusted with citric acid. Supplied as: 1 mL vials in boxes of 10 ().Store at controlled room temperature 20° to 25°C (68° to 77°F). Protect from freezing or excessive heat.Manufactured by: Estrada do Rio da Mo n8, 8A e 8B - Fervenca2705-906 Terrugem - SNTPORTUGALDistributed by: 465 Industrial Way WestEATONTOWN NJ 07724USAIss. Aug. 2007Relabeling of "Additional Barcode" by:Physicians Total Care, Inc.Tulsa, OK 74146 Each mL contains 1 mg of propranolol hydrochloride in Water for Injection. The pH is adjusted with citric acid. Supplied as: 1 mL vials in boxes of 10 ().Store at controlled room temperature 20° to 25°C (68° to 77°F). Protect from freezing or excessive heat.Manufactured by: Estrada do Rio da Mo n8, 8A e 8B - Fervenca2705-906 Terrugem - SNTPORTUGALDistributed by: 465 Industrial Way WestEATONTOWN NJ 07724USAIss. Aug. 2007Relabeling of "Additional Barcode" by:Physicians Total Care, Inc.Tulsa, OK 74146 Each mL contains 1 mg of propranolol hydrochloride in Water for Injection. The pH is adjusted with citric acid. Supplied as: 1 mL vials in boxes of 10 ().Store at controlled room temperature 20° to 25°C (68° to 77°F). Protect from freezing or excessive heat.Manufactured by: Estrada do Rio da Mo n8, 8A e 8B - Fervenca2705-906 Terrugem - SNTPORTUGALDistributed by: 465 Industrial Way WestEATONTOWN NJ 07724USAIss. Aug. 2007Relabeling of "Additional Barcode" by:Physicians Total Care, Inc.Tulsa, OK 74146
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
Propranolol 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 propranolol,
chronotropic, inotropic, and vasodilator responses to beta-adrenergic
stimulation are decreased proportionately. At doses greater than required for
beta blockade, propranolol 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 effects of propranolol are due to selective blockade of
beta-adrenergic receptors, leaving alpha-adrenergic responses intact. There are
two well-characterized subtypes of beta receptors (beta
and beta); propranolol interacts with both subtypes
equally. Beta-adrenergic receptors are found primarily
in the heart. Blockade of cardiac beta-adrenergic
receptors leads to a decrease in the activity of both normal and ectopic
pacemaker cells and a decrease in A-V nodal conduction velocity. All of these
actions can contribute to antiarrhythmic activity and control of ventricular
rate during arrhythmias. Blockade of cardiac beta-adrenergic receptors also decreases the myocardial force of
contraction and may provoke cardiac decompensation in patients with minimal
cardiac reserve.
Beta-adrenergic receptors are found predominantly in
smooth muscle—vascular, bronchial, gastrointestinal and genitourinary. Blockade
of these receptors results in constriction. Clinically, propranolol may
exacerbate respiratory symptoms in patients with obstructive pulmonary diseases
such as asthma and emphysema (see and ).
Propranolol’s beta blocking effects are attributable to its S(-)
enantiomer.
Propranolol has a distribution half-life (T alpha) of 5-10 minutes and a volume of distribution of about
4 to 5 L/kg. Approximately 90% of circulating propranolol is bound to plasma
proteins. The binding is enantiomer-selective. The S-isomer is preferentially
bound to alpha glycoprotein and the R-isomer is
preferentially bound to albumin.
The elimination half-life (T beta) is
between 2 and 5.5 hours. Propranolol is extensively metabolized with most
metabolites appearing in the urine. The major metabolites include propranolol
glucuronide, naphthyloxylactic acid, and glucuronic acid and sulfate conjugates
of 4-hydroxy propranolol. Following single-dose intravenous administration,
side-chain oxidative products account for approximately 40% of the metabolites,
direct conjugation products account for approximately 45-50% of metabolites, and
ring oxidative products account for approximately 10-15% of metabolites. Of
these, only the primary ring oxidative product (4-hydroxypropranolol) possesses
beta-adrenergic receptor blocking activity.
In vitro
As propranolol concentration increases, so does its beta-blocking
effect, as evidenced by a reduction in exercise-induced tachycardia (n=6 normal
volunteers).
The pharmacokinetics of propranolol have not been investigated in
patients under 18 years of age. Propranolol injection is not recommended for
treatment of cardiac arrhythmias in pediatric patients.
Elevated propranolol plasma concentrations, a longer mean
elimination half-life (254 vs. 152 minutes), and decreased systemic clearance (8
vs. 13 mL/kg/min) have been observed in elderly subjects when compared to young
subjects. However, the apparent volume of distribution seems to be similar in
elderly and young subjects. These findings suggest that dose adjustment of
propranolol injection may be required for elderly patients (see ).
Intravenously administered propranolol was evaluated in 5 women
and 6 men. When adjusted for weight, there were no gender-related differences in
elimination half-life, volume of distribution, protein binding, or systemic
clearance.
In a study of intravenously administered propranolol, obese
subjects had a higher AUC (161 versus 109 hr•µg/L) and lower total clearance
than did non-obese subjects. Propranolol plasma protein binding was similar in
both groups.
The pharmacokinetics of propranolol and its metabolites were
evaluated in 15 subjects with varying degrees of renal function after
propranolol administration via the intravenous and oral routes. When compared
with normal subjects, an increase in fecal excretion of propranolol conjugates
was observed in patients with increased renal impairment. Propranolol was also
evaluated in 5 patients with chronic renal failure, 6 patients on regular
dialysis, and 5 healthy subjects, following a single oral dose of 40 mg of
propranolol. The peak plasma concentrations (C) of
propranolol in the chronic renal failure group were 2- to 3-fold higher (161
ng/mL) than those observed in the dialysis patients (47 ng/mL) and in the
healthy subjects (26 ng/mL). Propranolol plasma clearance was also reduced in
the patients with chronic renal failure.
Chronic renal failure has been associated with a decrease in drug metabolism
via downregulation of hepatic cytochrome P450 activity.
Propranolol is extensively metabolized by the liver. In a study
conducted in 6 normal subjects and 20 patients with chronic liver disease,
including hepatic cirrhosis, 40 mg of R-propranolol was administered
intravenously. Compared to normal subjects, patients with chronic liver disease
had decreased clearance of propranolol, increased volume of distribution,
decreased protein-binding, and considerable variation in half-life. Caution
should be exercised when propranolol is used in this population. Consideration
should be given to lowering the dose of intravenous propranolol in patients with
hepatic insufficiency (see ).
No pharmacokinetic changes were observed in hyperthyroid or
hypothyroid patients when compared to their corresponding euthyroid state.
Dosage adjustment does not seem necessary in either patient population based on
pharmacokinetic findings.
Because propranolol’s metabolism involves multiple pathways in
the cytochrome P-450 system (CYP2D6, 1A2, 2C19), administration of propranolol
with drugs that are metabolized by, or affect the activity (induction or
inhibition) of one or more of these pathways may lead to clinically relevant
drug interactions (see ).
Blood levels of propranolol may be increased by administration of
propranolol with substrates or inhibitors of CYP2D6, such as amiodarone,
cimetidine, delavirdine, fluoxetine, paroxetine, quinidine, and ritonavir. No
interactions were observed with either ranitidine or lansoprazole.
Blood levels of propranolol may be increased by administration of
propranolol with substrates or inhibitors of CYP1A2, such as imipramine,
cimetidine, ciprofloxacin, fluvoxamine, isoniazid, ritonavir, theophylline,
zileuton, zolmitriptan, and rizatriptan.
Blood levels of propranolol may be increased by administration of
propranolol with substrates or inhibitors of CYP2C19, such as fluconazole,
cimetidine, fluoxetine, fluvoxamine, teniposide, and tolbutamide. No interaction
was observed with omeprazole.
Blood levels of propranolol may be decreased by administration of
propranolol with inducers such as rifampin and ethanol. Cigarette smoking also
induces hepatic metabolism and has been shown to increase up to 100% the
clearance of propranolol, resulting in decreased plasma concentrations.
The AUC of propafenone is increased by more than 200% with
co-administration of propranolol.
The metabolism of propranolol is reduced by co-administration of quinidine,
leading to a 2- to 3-fold increased blood concentrations and greater
beta-blockade.
The metabolism of lidocaine is inhibited by co-administration of propranolol,
resulting in a 25% increase in lidocaine concentrations.
The mean C and AUC of propranolol are
increased respectively, by 50% and 30% by co-administration of nisoldipine and
by 80% and 47%, by co-administration of nicardipine.
The mean values of C and AUC of nifedipine are
increased by 64% and 79%, respectively, by co-administration of propranolol.
Propranolol does not affect the pharmacokinetics of verapamil and
norverapamil. Verapamil does not affect the pharmacokinetics of
propranolol.
Administration of zolmitriptan or rizatriptan with propranolol
resulted in increased concentrations of zolmitriptan (AUC increased by 56% and
C by 37%) or rizatriptan (the AUC and C were increased by 67% and 75%, respectively).
Co-administration of theophylline with propranolol decreases
theophylline clearance by 33% to 52%.
Propranolol can inhibit the metabolism of diazepam, resulting in
increased concentrations of diazepam and its metabolites. Diazepam does not
alter the pharmacokinetics of propranolol.
The pharmacokinetics of oxazepam, triazolam, lorazepam, and alprazolam are
not affected by co-administration of propranolol.
Co-administration of propranolol at doses greater than or equal
to 160 mg/day resulted in increased thioridazine plasma concentrations ranging
from 50% to 370% and increased thioridazine metabolites concentrations ranging
from 33% to 210%.
Co-administration of chlorpromazine with propranolol resulted in increased
plasma levels of both drugs (70% increase in propranolol concentrations).
Co-administration of propranolol with cimetidine, a non-specific
CYP450 inhibitor, increased propranolol concentrations by about 40%.
Co-administration with aluminum hydroxide gel (1200 mg) resulted in a 50%
decrease in propranolol concentrations.
Co-administration of metoclopramide with propranolol did not have a
significant effect on propranolol’s pharmacokinetics.
Co-administration of cholesteramine or colestipol with
propranolol resulted in up to 50% decrease in propranolol concentrations.
Co-administration of propranolol with lovastatin or pravastatin decreased 20%
to 25% the AUC of both, but did not alter their pharmacodynamics. Propranolol
did not have an effect on the pharmacokinetics of fluvastatin.
Concomitant administration of propranolol and warfarin has been
shown to increase warfarin bioavailability and increase prothrombin time.
Non-Clinical Toxicology
Propranolol is contraindicated in 1) cardiogenic shock; 2) sinus bradycardia and greater than first-degree block; 3) bronchial asthma; and 4) in patients with known hypersensitivity to propranolol hydrochloride.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, some have been shown to be highly beneficial when used with close follow-up in patients with a history of failure who are well compensated and are receiving additional therapies, including diuretics as needed. Beta-adrenergic blocking agents do not abolish the inotropic action of digitalis on heart muscle.
In general, patients with bronchospastic lung disease should not receive beta blockers. Propranolol should be administered with caution in this setting since it may block bronchodilation produced by endogenous and exogenous catecholamine stimulation of beta-receptors.
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 in propranolol-treated patients might augment the risks of general anesthesia and surgical procedures.
Propranolol 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.
Beta-adrenergic blockade may prevent the appearance of certain premonitory signs and symptoms (pulse rate and pressure changes) of acute hypoglycemia, especially in labile insulin-dependent diabetics. In these patients, it may be more difficult to adjust the dosage of insulin.
Propranolol therapy, particularly in infants and children, diabetic or not, has been associated with hypoglycemia especially during fasting, as in preparation for surgery. Hypoglycemia has been reported after prolonged physical exertion and in patients with renal insufficiency.
Beta-adrenergic 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 T and reverse T, and decreasing T.
Beta-adrenergic blockade in patients with Wolff-Parkinson-White syndrome and tachycardia has been associated with severe bradycardia requiring treatment with a pacemaker. In one case this resulted after an initial 5 mg dose of intravenous propranolol.
Echothiophate iodide for ophthalmic solution potentiates other cholinesterase inhibitors such as succinylcholine or organophosphate and carbamate insecticides. Patients undergoing systemic anticholinesterase treatment should be warned of the possible additive effects of echothiophate iodide for ophthalmic solution.
Propranolol should be used with caution in patients with impaired hepatic or renal function. Propranolol is not indicated for the treatment of hypertensive emergencies.
Beta-adrenergic receptor blockade can cause reduction of intraocular pressure. Patients should be told that propranolol might interfere with the glaucoma screening test. Withdrawal may lead to a return of elevated intraocular pressure.
Risk of anaphylactic reaction. While taking beta blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.
There have been reports of exacerbation of angina and, in some cases, myocardial infarction, following abrupt discontinuance of propranolol therapy. Therefore, when discontinuance of propranolol 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 a physician’s advice. If propranolol therapy is interrupted and exacerbation of angina occurs, it is usually advisable to reinstitute propranolol therapy and take other measures appropriate for the management of 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.
In patients with hypertension, use of propranolol has been associated with elevated levels of serum potassium, serum transaminases and alkaline phosphatase. In severe heart failure, the use of propranolol has been associated with increases in Blood Urea Nitrogen.
Caution should be exercised when propranolol is administered with drugs that have an effect on CYP2D6, 1A2, or 2C19 metabolic pathways. Co-administration of such drugs with propranolol may lead to clinically relevant drug interactions and changes in its efficacy and/or toxicity (see ).
Propafenone has negative inotropic and beta-blocking properties that can be additive to those of propranolol.
Quinidine increases the concentration of propranolol and produces a greater degree of clinical beta-blockade and may cause postural hypotension.
Disopyramide is a Type I antiarrhythmic drug with potent negative inotropic and chronotropic effects and has been associated with severe bradycardia, asystole and heart failure when administered with propranolol.
Amiodarone is an antiarrhythmic agent with negative chronotropic properties that may be additive to those seen with propranolol.
The clearance of lidocaine is reduced when administered with propranolol. Lidocaine toxicity has been reported following coadministration with propranolol.
Caution should be exercised when administering propranolol with drugs that slow A-V nodal conduction, e.g. digitalis, lidocaine and calcium channel blockers.
Caution should be exercised when patients receiving a beta-blocker are administered a calcium-channel-blocking drug with negative inotropic and/or chronotropic effects. Both agents may depress myocardial contractility or atrioventricular conduction.
There have been reports of significant bradycardia, heart failure, and cardiovascular collapse with concurrent use of verapamil and beta-blockers.
Co-administration of propranolol and diltiazem in patients with cardiac disease has been associated with bradycardia, hypotension, high degree heart block, and heart failure.
When combined with beta-blockers, ACE inhibitors can cause hypotension, particularly in the setting of acute myocardial infarction.
ACE inhibitors have been reported to increase bronchial hyperreactivity when administered with propranolol.
The antihypertensive effects of clonidine may be antagonized by beta-blockers. Propranolol should be administered cautiously to patients withdrawing from clonidine.
Prazosin has been associated with prolongation of first dose hypotension in the presence of beta-blockers.
Postural hypotension has been reported in patients taking both beta-blockers and terazosin or doxazosin.
Patients receiving catecholamine-depleting drugs, such as reserpine, with propranolol should be closely observed for excess reduction of resting sympathetic nervous activity, which may result in hypotension, marked bradycardia, vertigo, syncopal attacks, or orthostatic hypotension. Administration of reserpine with propranolol may also potentiate depression.
Patients on long-term therapy with propranolol may experience uncontrolled hypertension if administered epinephrine as a consequence of unopposed alpha-receptor stimulation. Epinephrine is therefore not indicated in the treatment of propranolol overdose (see ).
Propranolol is a competitive inhibitor of beta-receptor agonists, and its effects can be reversed by administration of such agents, e.g., dobutamine or isoproterenol. Also, propranolol may reduce sensitivity to dobutamine stress echocardiography in patients undergoing evaluation for myocardial ischemia.
Nonsteroidal anti-inflammatory drugs (NSAIDS) have been reported to blunt the antihypertensive effect of beta-adrenoreceptor blocking agents.
Administration of indomethacin with propranolol may reduce the efficacy of propranolol in reducing blood pressure and heart rate.
The hypotensive effects of MAO inhibitors or tricyclic antidepressants may be exacerbated when administered with beta-blockers by interfering with the beta blocking activity of propranolol.
Methoxyflurane and trichloroethylene may depress myocardial contractility when administered with propranolol.
Administration of propranolol with warfarin increases the concentration of warfarin. Therefore, the prothrombin time should be monitored.
Hypotension and cardiac arrest have been reported with the concomitant use of propranolol and haloperidol.
Thyroxine may result in a lower than expected T concentration when used concomitantly with propranolol.
In dietary administration studies in which mice and rats were treated with propranolol hydrochloride for up to 18 months at doses of up to 150 mg/kg/day, there was no evidence of drug-related tumorigenesis. On a body surface area basis, this dose in the mouse and rat is, respectively, about equal to and about twice the maximum recommended human oral daily dose (MRHD) of 640 mg propranolol hydrochloride. In a study in which both male and female rats were exposed to propranolol hydrochloride in their diets at concentrations of up to 0.05% (about 50 mg/kg body weight and less than the MRHD), from 60 days prior to mating and throughout pregnancy and lactation for two generations, there were no effects on fertility. Based on differing results from Ames Tests performed by different laboratories, there is equivocal evidence for a genotoxic effect of propranolol hydrochloride in bacteria ( strain TA 1538).
In a series of reproductive and developmental toxicology studies, propranolol hydrochloride was given to rats by gavage or in the diet throughout pregnancy and lactation. At doses of 150 mg/kg/day, but not at doses of 80 mg/kg/day (equivalent to the MRHD on a body surface area basis), treatment was associated with embryotoxicity (reduced litter size and increased resorption rates) as well as neonatal toxicity (deaths). Propranolol hydrochloride also was administered (in the feed) to rabbits (throughout pregnancy and lactation) at doses as high as 150 mg/kg/day (about 5 times the maximum recommended human oral daily dose). No evidence of embryo or neonatal toxicity was noted.
There are no adequate and well-controlled studies in pregnant women. Intrauterine growth retardation has been reported for neonates whose mothers received propranolol hydrochloride during pregnancy. Neonates whose mothers received propranolol hydrochloride at parturition have exhibited bradycardia, hypoglycemia, and respiratory depression. Adequate facilities for monitoring such infants at birth should be available. Propranolol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Propranolol is excreted in human milk. Caution should be exercised when propranolol is administered to a nursing woman.
Safety and effectiveness of propranolol in pediatric patients have not been established.
Clinical studies of intravenous propranolol did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Elderly subjects have decreased clearance and a longer mean elimination half-life. These findings suggest that dose adjustment of propranolol injection may be required for elderly patients (see ). In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of the decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.
Propranolol is extensively metabolized by the liver. Compared to normal subjects, patients with chronic liver disease have decreased clearance of propranolol, increased volume of distribution, decreased protein-binding and considerable variation in half life. Consideration should be given to lowering the dose of intravenously administered propranolol in patients with hepatic insufficiency.
In a series of 225 patients, there were 6 deaths (see ). Cardiovascular events (hypotension, congestive heart failure, bradycardia, and heart block) were the most common. The only other event reported by more than one patient was nausea.
Other adverse events for intravenous propranolol, reported during post-marketing surveillance include cardiac arrest, dyspnea, and cutaneous ulcers.
The following adverse events have been reported with use of formulations of sustained- or immediate-release oral propranolol and may be expected with intravenous propranolol.
Bradycardia; congestive heart failure; intensification of AV block; hypotension; paresthesia of hands; thrombocytopenic purpura; arterial insufficiency, usually of the Raynaud type.
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. For immediate-release formulations, fatigue, lethargy, and vivid dreams appear dose related.
Nausea, vomiting, epigastric distress, abdominal cramping, diarrhea, constipation, mesenteric arterial thrombosis, ischemic colitis.
Pharyngitis and agranulocytosis; erythematous rash, fever combined with aching and sore throat; laryngospasm, and respiratory distress.
Bronchospasm.
Agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic purpura.
In extremely rare instances, systemic lupus erythematosus has been reported.
Alopecia, LE-like reactions, psoriaform 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.
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
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Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72Tips
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