|Systematic (IUPAC) name|
|Licence data||US FDA:|
|Oral, rectal, IV|
|Metabolism||hepatic (extensive) 1A2, 2D6; minor: 2C19, 3A4|
|(what is this?)|
Propranolol (INN) is a sympatholytic nonselective beta blocker. It is used to treat high blood pressure, a number of heart dysrhythmias, those with thyrotoxicosis, and essential tremors. It is used to prevent migraine headaches, and further heart problems in those with angina or previous myocardial infarction. It comes in both oral and intravenous forms.
It should not be used in those with an already slow heart rate and most of those with heart failure. Quickly stopping the medication in those with coronary artery disease may worsen symptoms. It may worsen the symptoms of asthma. Common side effects include: nausea, abdominal pain, and constipation. Greater care is recommended in those with liver or kidney problems. It may possibly cause harmful effects to the infant if taken during pregnancy.
It was the first successful beta blocker developed. It is on the World Health Organization's List of Essential Medicines, a list of the most important medications needed in a basic health system. Propranolol is available in generic form; it is marketed in India under brand names such as 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, and Bedranol SR (Sandoz). Hemangeol, a 4.28 mg/mL solution of propranolol, is indicated for the treatment of proliferating infantile hemangioma.
Propranolol is indicated for the management of various conditions, including:
- Angina pectoris (with the exception of variant angina)
- Myocardial infarction
- Control of tachycardia/tremor associated with anxiety, hyperthyroidism, or lithium therapy.
- Essential tremor
- Migraine prevention
- Cluster headache prevention
- Proliferating infantile hemangioma
- Some experimentation has been conducted in psychiatric areas:
- Thyrotoxicosis by deiodinase inhibition
- Primary exertional headache
While once a 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 currently not recommended for the treatment of hypertension by the Eighth Joint National Committee(JNC 8) because a higher rate of the primary composite outcome of cardiovascular death, myocardial infarction, or stroke compared to an angiotensin receptor blocker was noted in one study.
Propranolol is currently being investigated as a potential treatment for post-traumatic stress disorder. Propranolol works to inhibit the actions of norepinephrine (noradrenaline), a neurotransmitter that enhances memory consolidation. Individuals given propranolol immediately after a traumatic experienced fewer stress-related symptoms and lower rates of PTSD than respective control groups who 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 memory-recalled evidence during an investigation, modifying behavioral response to past (albeit traumatic) 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-III 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 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 (IHs) 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, has 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 antiparasite activity against P. vinckei, or P. yoelii nigeriensis. However, propranolol may reduce the dosages required for existing drugs to be effective against P. falciparum by five- to 10-fold, suggesting a role for combination therapies.
Volunteers given the beta blocker propranolol scored lower on a range of psychological tests designed to reveal any racist attitudes than a group who took a placebo. 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.
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 (<60 beats/minute)
- Sick sinus syndrome
- Atrioventricular block (second- or third-degree)
- Severe hypotension
- Cocaine toxicity [per American Heart Association guidelines, 2005]
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.
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".
Propranolol is rapidly and completely absorbed, with peak plasma levels achieved about 1–3 hours after ingestion. Coadministration with food appears to enhance bioavailability. Despite complete absorption, propranolol has a variable bioavailability due to extensive first-pass metabolism. Hepatic impairment therefore increases its bioavailability. The main metabolite 4-hydroxypropranolol, with a longer half-life (5.2–7.5 hours) than the parent compound (3–4 hours), 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 (e.g., 80 mg). Effective plasma concentrations are between 10 and 100 mg/l. Toxic levels are associated with plasma concentrations above 2000 mg/l.
Mechanism of action
Propranolol is a nonselective 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 (only at high blood concentrations, e.g. overdosage). Propranolol has inhibitory effects on the norepinephrine transporter and/or stimulates norepinephrine release (the concentration of norepinephrine is increased in the synapse). 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, it can 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 propranolol may function as a partial agonist at one or more serotonin receptors (possibly 5-HT1B).
Both enantiomers of the drug have a local anesthetic (topical) 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 antiarrhythmic and other central nervous system effects.
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:
- β2-adrenergic receptor agonists
- ergot alkaloids
- nonsteroidal anti-inflammatory drugs
- Fluvoxamine slows down the metabolism of propranolol significantly, leading to increased blood levels of propranolol.
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.
Society and culture
In a 1987 study by the International Conference of Symphony and Opera Musicians, 27% of interviewed members admitted to using beta blockers such as propranolol for musical performances. For about 10-16% of performers, their degree of stage fright is considered 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 competitions, akin to the use of performance-enhancing drugs in athletes.
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