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Propranolol (n.)
1.(MeSH)A widely used non-cardioselective beta-adrenergic antagonist. Propranolol has been used for MYOCARDIAL INFARCTION; ARRHYTHMIA; ANGINA PECTORIS; HYPERTENSION; HYPERTHYROIDISM; MIGRAINE; PHEOCHROMOCYTOMA; and ANXIETY but adverse effects instigate replacement by newer drugs.
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Propranolol (n.) (MeSH)
D02.033.100.624.836, D02.033.755.624.836, D02.092.063.624.698.711, D02.455.426.559.847.638.945, D04.615.638.945, Anaprilin (MeSH), Anapriline (MeSH), Avlocardyl (MeSH), AY-20694 (MeSH), Betadren (MeSH), Dexpropranolol (MeSH), Dociton (MeSH), Inderal (MeSH), Obsidan (MeSH), Obzidan (MeSH), Propanolol (MeSH), Propranolol Hydrochloride (MeSH), Rexigen (MeSH)
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Propranolol (n.) [MeSH]
Wikipedia
Systematic (IUPAC) name | |
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(RS)-1-(1-methylethylamino)-3-(1-naphthyloxy)propan-2-ol | |
Clinical data | |
AHFS/Drugs.com | monograph |
Licence data | US FDA:link |
Pregnancy cat. | C (AU) C (US) |
Legal status | Prescription Only (S4) (AU) POM (UK) ℞-only (US) |
Routes | oral, anal, IV |
Pharmacokinetic data | |
Bioavailability | 26% |
Metabolism | hepatic (extensive) |
Half-life | 4-5 hours |
Excretion | renal <1% |
Identifiers | |
CAS number | 525-66-6 |
ATC code | C07AA05 |
PubChem | CID 4946 |
IUPHAR ligand | 564 |
DrugBank | DB00571 |
ChemSpider | 4777 |
UNII | 9Y8NXQ24VQ |
KEGG | D08443 |
ChEBI | CHEBI:8499 |
ChEMBL | CHEMBL27 |
Chemical data | |
Formula | C16H21NO2 |
Mol. mass | 259.34 g/mol |
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Propranolol (INN) 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, as well as an AstraZeneca and Wyeth product under the brand names Inderal, Inderal LA, Avlocardyl, Deralin, Dociton, Inderalici, InnoPran XL, Sumial, Anaprilinum, Bedranol SR (Sandoz).
Like other beta blockers, propranolol is a banned substance in several Olympic sports.[1]
Contents |
Scottish 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 (such as nebivolol, carvedilol, or metoprolol) are now used in the treatment of hypertension.
Propranolol is indicated for the management of various conditions including:
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 perform less well than 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.[10]
Propranolol is also used to lower portal vein pressure in portal hypertension and prevent esophageal variceal bleeding.
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.[11]
Propranolol 80 mg daily can be used post discharge in STEMI patients.[citation needed]
Propranolol is currently being investigated as a potential treatment for post-traumatic stress disorder.[12][13][14] Propranolol works to inhibit the actions of norepinephrine (CBS reported adrenaline), 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 (Vaiva et al., 2003)[full citation needed]. 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. There are also many ethical and legal questions surrounding the use of Propranolol-based medications for use as a "memory dampener," including: altering (memory-recalled) evidence during an investigation, modifying behavioral response to past (albeit traumatic) experiences, the regulation of these drugs, and others.[15]
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.[16] 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.
Evidence from June 2008 suggests that propranolol can be used to treat severe infantile hemangiomas (IHs).[17] This treatment shows promise as being superior to corticosteroids when treating IHs, but there are no controlled trials to date that prove this.
Propranolol was investigated for possible effects on resting energy expenditure and muscle catabolism in patients with severe burns.[18] 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,[19] or P. yoelii nigeriensis.[20] 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.[21]
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.[22] 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.[23]
In 2011, a small study conducted in two French allergy practices suggested that low doses of propanolol (10–40 mg daily) were effective in the treatment of aquagenic pruritus.[24]
Propranolol should be used with caution in patients with:[25]
Propranolol is contraindicated in patients with:[25]
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.[26]
Adverse drug reactions (ADRs) associated with propranolol therapy are similar to other lipophilic beta blockers (see beta blocker).
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.[citation needed]
Most beta-blocking agents appear in the milk of lactating women. This is especially the case for a lipophilic drug like propranolol. Propranolol therapy is not recommended for patients who are breastfeeding.[citation needed]
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 (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 10–100 ng/mL.
Toxic levels are associated with plasma concentrations above 2000 ng/ml.
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 (ISA) but has strong membrane stabilizing activity (only at high blood concentrations, e.g. overdosage). Research has also shown that propranolol has inhibitory effects on the norepinephrine transporter and/or stimulates norepinephrine release (present experiments have shown that the concentration of norepinephrine is increased in the synapse but do not have the ability to discern which effect is taking place).[27] 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 (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 anti-arrhythmic and other central nervous system effects.[28][29][30]
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:[25]
The usual maintenance dose ranges for oral propranolol therapy vary by indication:
Intravenous (IV) propranolol may be used in acute arrhythmia or thyrotoxic crisis.[33]
Propranolol is synthesized in two ways from the same initial substance.[34][35][36][37][38][39] 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.
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