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 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 being investigated as a potential treatment for PTSD. Propranolol works to inhibit the actions of norepinephrine, a neurotransmitter that enhances memory consolidation. In one small study individuals given propranolol immediately after trauma experienced fewer stress-related symptoms and lower rates of PTSD than respective control groups who did not receive the drug. Due to the fact that memories and their emotional content are reconsolidated in the hours after they are recalled/re-experienced, propranolol can also diminish the emotional impact of already formed memories; for this reason, it is also being studied in the treatment of specific phobias, such as arachnophobia, dental fear, and social phobia.
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 may be used to treat severe infantile hemangiomas (IHs). This treatment shows promise as being superior to corticosteroids when treating IHs. Extensive clinical case evidence and a small controlled trial support its efficacy.
In overdose propranolol is associated with seizures. Cardiac arrest may occur in propranolol overdose due to sudden ventricular arrhythmias, or cardiogenic shock which may ultimately culminate in bradycardic PEA. Propranolol should be used with extreme caution in depressed or atypically depressed patients with possible suicidal ideation.
Since beta blockers are known to relax the cardiac muscle and to constrict the smooth muscle, 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:
Both enantiomers of propranolol have a local anesthetic (topical) effect, which is normally mediated by blockade of voltage-gated sodium channels. 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.
Mechanism of action
Propranolol is a competitive antagonist of beta-1-adrenergic receptors in the heart. It competes with sympathomimetic neurotransmitters for binding to receptors, which inhibits sympathetic stimulation of the heart. Blockage of neurotransmitter binding to beta 1 receptors on cardiac myocytes inhibits activation of adenylate cyclase, which in turn inhibits cAMP synthesis leading to reduced PKA production. This results in less calcium influx to cardiac myocytes through voltage gated L-type calcium channels meaning there is a decreased sympathetic effect on cardiac cells, resulting in antihypertensive effects including reduced heart rate and lower arterial blood pressure.
Propranolol is rapidly and completely absorbed, with peak plasma levels achieved about 1–3 hours after ingestion. More than 90% of the drug is found bound to plasma protein in the blood. 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. Most of the metabolites are excreted in the urine.
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.
British scientist James W. Black developed propranolol in the 1960s. In 1988, he was awarded the Nobel Prize in Medicine for this discovery. Propranolol was inspired by the early β-adrenergic antagonists dichloroisoprenaline and pronethalol. The key difference, which was carried through to essentially all subsequent beta blockers, was the inclusion of an oxymethylene group (-O-CH2-) between the aryl and ethanolamine moieties of pronethalol, greatly increasing the potency of the compound. This also apparently eliminated the carcinogenicity found with pronethalol in animal models.
In a 1987 study by the International Conference of Symphony and Opera Musicians, it was shown that 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. It has also been used as a performance-enhancing drug in sports where high accuracy is required, including archery, shooting, golf and snooker. In the 2008 Summer Olympics, 50-metre pistol silver medalist and 10-metre air pistol bronze medalist Kim Jong-su tested positive for propranolol and was stripped of his medals.
Original propranolol was marketed in 1965 under the brand name Inderal and manufactured by ICI Pharmaceuticals (now AstraZeneca). Propranolol is also marketed under brand names Avlocardyl, Deralin, Dociton, Inderalici, InnoPran XL, Sumial, Anaprilin, and Bedranol SR (Sandoz). In India it is marketed under brand names such as Ciplar and Ciplar LA by Cipla. Hemangeol, a 4.28 mg/mL solution of propranolol, is indicated for the treatment of proliferating infantile hemangioma.
Clinical research has been conducted to learn if propranolol could be useful in the treatment of some cancers.
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