Propranolol is a sympatholytic non-selective beta blocker. Sympatholytics are used to treat
hypertension, anxiety and panic. It was the first successful beta blocker developed. Propranolol
is available in generic form as Propranolol Hydrochloride; marketed in India under brand
names like Ciplar and Ciplar LA by Cipla, also other brands from AstraZeneca and Wyeth
under brand names Inderal, Inderal LA, Avlocardyl, Deralin, Dociton, Inderalici, InnoPran XL,
Sumial, Anaprilinum, Bedranol SR. It is on the World Health Organization's List
of Essential Medicines, a list of the most important medication needed in a basic health
system.
Medical uses Propranolol is indicated for the management
of various conditions including: Hypertension
Angina pectoris Tachyarrhythmias
Myocardial infarction Control of tachycardia/tremor associated with
anxiety, hyperthyroidism or lithium therapy. Essential tremor
Migraine prophylaxis Cluster headaches prophylaxis
Tension headache Hyperhidrosis
There has been some experimentation in psychiatric areas:Treating the excessive drinking of fluids
in psychogenic polydipsia, Antipsychotic-induced akathisia,
Aggressive behavior of patients with brain injuries
Post-traumatic stress disorder Calming down individuals with phobias via
sedative effects Performance anxiety
Glaucoma Thyrotoxicosis via deiodinase inhibition
Primary exertional headache While once first-line treatment for hypertension,
the role for beta-blockers was downgraded in June 2006 in the United Kingdom to fourth-line
as they do not perform as well as other drugs, particularly in the elderly, and evidence
is increasing that the most frequently used beta-blockers at usual doses carry an unacceptable
risk of provoking type 2 diabetes. Propranolol is also used to lower portal vein
pressure in portal hypertension and prevent esophageal variceal bleeding and ascites.
Other uses Propranolol is often used by musicians and
other performers to prevent stage fright. It has been taken by surgeons to reduce their
own innate hand tremors during surgery. Propranolol is currently being investigated
as a potential treatment for post-traumatic stress disorder. Propranolol works to inhibit
the actions of norepinephrine, a neurotransmitter that enhances memory consolidation. Studies
have shown that individuals given propranolol immediately after a traumatic experience show
less severe symptoms of PTSD compared to their respective control groups that did not receive
the drug. Propranolol reduces the effects of nightmare-related cardiac activity by keeping
sinus rhythm low during nightmares, as a higher pulse and increased adrenaline are associated
with severe nightmares. However, results remain inconclusive as to the success of propranolol
in treatment of PTSD, including nightmares experienced by those with PTSD.
Ethical and legal questions have been raised surrounding the use of Propranolol-based medications
for use as a "memory damper," including: altering evidence during an investigation, modifying
behavioral response to past experiences, the regulation of these drugs, and others. However,
Hall and Carter have argued that many such objections are "based on wildly exaggerated
and unrealistic scenarios that ignore the limited action of propranolol in affecting
memory, underplay the debilitating impact that PTSD has on those who suffer from it,
and fail to acknowledge the extent to which drugs like alcohol are already used for this
purpose." Propranolol in combination with etodolac is
currently being investigated in a Phase 3 trial of 400 colorectal cancer patients as
a potential treatment for prevention of colorectal cancer recurrence. The aim of this study is
to assess the use of perioperative medical intervention using a combination of a propranolol
and etodolac in order to attenuate the surgically induced immunosuppression and other physiological
perturbations, aiming to reduce the rate of tumor recurrence and distant metastatic disease.
Starting in 2008, reports of successful use of propranolol to treat severe infantile hemangiomas
began to emerge. This treatment shows promise as being superior to corticosteroids when
treating IHs. Extensive clinical case evidence and a small controlled trial support its efficacy.
Propranolol was investigated for possible effects on resting energy expenditure and
muscle catabolism in patients with severe burns. In children with burns, treatment with
propranolol during hospitalization attenuated hypermetabolism and reversed muscle wasting.
Propranolol along with a number of other membrane-acting drugs have been investigated for possible
effects on Plasmodium falciparum and so the treatment of malaria. In vitro positive effects
until recently had not been matched by useful in vivo anti-parasite activity against P.
vinckei, or P. yoelii nigeriensis. However, a single study from 2006 has suggested that
propranolol may reduce the dosages required for existing drugs to be effective against
P. falciparum by 5- to 10-fold, suggesting a role for combination therapies.
Oxford researcher Sylvia Terbeck gave volunteers the beta-blocker propranolol. The volunteers
scored lower on a range of psychological tests designed to reveal any racist attitudes than
a group who took a placebo. The region of the brain called the amygdala is involved
in processing emotion, including fear, and many psychologists think racist feelings are
driven by the fear center. Propranolol inhibits the amygdala.
In 2011, a small study conducted in two French allergy practices suggested that low doses
of propranolol were effective in the treatment of aquagenic pruritus.
Studies have found propranolol effectively decreases many of the side effects of marijuana.
Precautions and contraindications Propranolol should be used with caution in
people with: Diabetes mellitus or hyperthyroidism, since
signs and symptoms of hypoglycaemia may be masked.
Peripheral vascular disease and Raynaud's syndrome, which may be exacerbated
Phaeochromocytoma, as hypertension may be aggravated without prior alpha blocker therapy
Myasthenia gravis, may be worsened Other drugs with bradycardic effects
Propranolol is contraindicated in patients with:
Reversible airways diseases, particularly asthma or chronic obstructive pulmonary disease
Bradycardia Sick sinus syndrome
Atrioventricular block Shock
Severe hypotension Cocaine toxicity [per American Heart Association
guidelines, 2005] Adverse effects
Due to the high penetration across the blood brain barrier, lipophilic beta blockers such
as propranolol and metoprolol are more likely than other less lipophilic beta blockers to
cause sleep disturbances such as insomnia and vivid dreams and nightmares.
Adverse drug reactions associated with propranolol therapy are similar to other lipophilic beta
blockers. Pregnancy and lactation
Propranolol, like other beta blockers, is classified as pregnancy category C in the
United States and ADEC Category C in Australia. Beta-blocking agents in general reduce perfusion
of the placenta which may lead to adverse outcomes for the neonate, including pulmonary
or cardiac complications, or premature birth. The newborn may experience additional adverse
effects such as hypoglycemia and bradycardia. Most beta-blocking agents appear in the milk
of lactating women. However, propranolol is highly bound to proteins in the bloodstream
and is distributed into breast milk at very low levels. These low levels are not expected
to pose any risk to the breastfeeding infant, and the American Academy of Pediatrics considers
propranolol therapy "generally compatible with breastfeeding."
Pharmacokinetics Propranolol is rapidly and completely absorbed,
with peak plasma levels achieved approximately 1–3 hours after ingestion. Co-administration
with food appears to enhance bioavailability. Despite complete absorption, propranolol has
a variable bioavailability due to extensive first-pass metabolism. Hepatic impairment
will therefore increase its bioavailability. The main metabolite 4-hydroxypropranolol,
with a longer half-life than the parent compound, is also pharmacologically active.
Propranolol is a highly lipophilic drug achieving high concentrations in the brain. The duration
of action of a single oral dose is longer than the half-life and may be up to 12 hours,
if the single dose is high enough. Effective plasma concentrations are between 10–100 mg/mL.
Toxic levels are associated with plasma concentrations above 2000 mg/ml.
Mechanism of action Propranolol is a non-selective beta blocker,
that is, it blocks the action of epinephrine and norepinephrine on both β1- and β2-adrenergic
receptors. It has little intrinsic sympathomimetic activity but has strong membrane stabilizing
activity. Research has also shown that propranolol has inhibitory effects on the norepinephrine
transporter and/or stimulates norepinephrine release. Since propranolol blocks β-adrenoceptors,
the increase in synaptic norepinephrine only results in α-adrenergic activation, with
the α1-adrenoceptor being particularly important for effects observed in animal models. Therefore,
some have suggested that it be looked upon as an indirect α1 agonist as well as a β
antagonist. Probably owing to the effect at the α1-adrenoceptor, the racemic and the
individual enantiomers of propranolol have been shown to substitute for cocaine in rats,
with the most potent enantiomer being S-(–)-propranolol. In addition, some evidence suggests that propranolol
may function as a partial agonist at one or more serotonin receptors.
Both enantiomers of the drug have a local anesthetic effect, which is normally mediated
by blockade of voltage-gated sodium channels. Few studies have demonstrated propranolol's
ability to block cardiac, neuronal, and skeletal voltage-gated sodium channels, accounting
for its known "membrane stabilizing effect" and anti-arrhythmic and other central nervous
system effects. Interactions
Since beta blockers are known to relax the cardiac muscle and to constrict the smooth
muscle, these beta adrenergic antagonists, including propranolol, have an additive effect
with other drugs which decrease blood pressure, or which decrease cardiac contractility or
conductivity. Clinically significant interactions particularly occur with:
verapamil epinephrine
β2-adrenergic receptor agonists Salbutamol, Levosalbutamol, Formoterol, Salmeterol,
etc.
clonidine ergot alkaloids
isoprenaline non-steroidal anti-inflammatory drugs
quinidine cimetidine
lidocaine phenobarbital
rifampicin Fluvoxamine slows down the metabolism of propranolol
significantly leading to increased blood levels of propranolol.
Chemistry Propranolol is a racemate, a mixture of two
enantiomers. The-enantiomer is known as dexpropranolol or dextropropranolol. The-enantiomer is known
as levopropranolol. Propranolol can be synthesized in two ways
from the same initial substance. The first way consists of reacting 1-naphthol with epichlorohydrin.
Opening of the epoxide ring gives 1-chloro-3-(1-naphthyloxy)-2-propanol, which is reacted further with isopropylamine,
giving propranolol. The second method uses the same reagents in the presence of a base
and consists of initially making 3-(1-naphthyloxy)propylenoxide, the subsequent reaction with isopropylamine
which results in epoxide ring opening leading to the formation of propranolol.
History British scientist James W. Black successfully
developed propranolol in the 1960s. In 1988, he was awarded the Nobel Prize in Medicine
for this discovery. Propranolol was derived from the early β-adrenergic antagonists dichloroisoprenaline
and pronethalol. The key structural modification, which was carried through to essentially all
subsequent beta blockers, was the insertion of an oxymethylene group into the arylethanolamine
structure of pronethalol thus greatly increasing the potency of the compound. This also apparently
eliminated the carcinogenicity found with pronethalol in animal models.
Newer, more selective beta-blockers are now used in the treatment of hypertension.
Social Implications In a 1987 study by the International Conference
of Symphony and Opera Musicians, it was revealed that 27% of interviewed members admitted to
using beta blockers such as propranolol for musical performances. For approximately 10-16%
of performers, the degree of stage fright is considered as pathological. Propranolol
is used by musicians, actors and public speakers for its ability to treat anxiety symptoms
activated by the sympathetic nervous system. This can be seen as giving participating individuals
an unfair advantage, especially in competition scenarios, akin to the use of performance
enhancing drugs in athletes. References
External links Stapleton MP. "Sir James Black and propranolol.
The role of the basic sciences in the history of cardiovascular pharmacology". Texas Heart
Institute Journal 24: 336–42. PMC 325477. PMID 9456487.
Scientific American Interview with James McGaugh U.S. National Library of Medicine: Drug Information
Portal - Propranolol