Propranolol

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Propranolol
Propranolol-skeletal.svg
Propranolol-from-xtal-3D-balls.png
Systematic (IUPAC) name
(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 YesY
ATC code C07AA05
PubChem CID 4946
IUPHAR ligand 564
DrugBank DB00571
ChemSpider 4777 YesY
UNII 9Y8NXQ24VQ YesY
KEGG D08443 YesY
ChEBI CHEBI:8499 YesY
ChEMBL CHEMBL27 YesY
Chemical data
Formula C16H21NO2 
Mol. mass 259.34 g/mol
 YesY (what is this?)  (verify)
An 80 mg capsule of propranolol

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.[1] 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 (Sandoz).

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.[2]

Medical uses[edit]

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 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.[11]

Propranolol is also used to lower portal vein pressure in portal hypertension and prevent esophageal variceal bleeding and ascites.

Other uses[edit]

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.[12]

Propranolol is currently being investigated as a potential treatment for post-traumatic stress disorder.[13][14][15] Propranolol works to inhibit the actions of norepinephrine (noradrenaline), 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.[16] 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.[17] 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." [18]

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.[19] 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 (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.[20]

Propranolol was investigated for possible effects on resting energy expenditure and muscle catabolism in patients with severe burns.[21] 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,[22] or P. yoelii nigeriensis.[23] 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.[24]

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.[25] 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.[26]

In 2011, a small study conducted in two French allergy practices suggested that low doses of propranolol (10–40 mg daily) were effective in the treatment of aquagenic pruritus.[27]

Studies have found propranolol effectively decreases many of the side effects of marijuana.[28][29]

Precautions and contraindications[edit]

Propranolol should be used with caution in people with:[30]

Propranolol is contraindicated in patients with:[30]

Adverse effects[edit]

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.[31]

Adverse drug reactions (ADRs) associated with propranolol therapy are similar to other lipophilic beta blockers (see beta blocker).

Pregnancy and lactation[edit]

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.[32]

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.[33] 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."[32][33][34][35]

Pharmacokinetics[edit]

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 mg/mL.

Toxic levels are associated with plasma concentrations above 2000 mg/ml.

Mechanism of action[edit]

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).[36] 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.[37][38][39]

Interactions[edit]

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:[30]

Chemistry[edit]

Propranolol is a racemate, a mixture of two enantiomers. The (R)-enantiomer is known as dexpropranolol or dextropropranolol. The (S)-enantiomer is known as levopropranolol.

Propranolol can be synthesized in two ways from the same initial substance.[41][42][43][44][45][46] 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.

Propranolol synthesis.png

History[edit]

British scientist James W. Black successfully developed propranolol in the 1960s.[1] 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.

Social Implications[edit]

In a 1987 study by the International Conference of Symphony and Opera Musicians (ICSOM), it was revealed that 27% of interviewed members admitted to using beta blockers such as propranolol for musical performances.[47] For approximately 10-16% of performers, the degree of stage fright is considered as pathological.[47][48] Propranolol is used by musicians, actors and public speakers for its ability to treat anxiety symptoms activated by the sympathetic nervous system.[49] 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.[50]

References[edit]

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External links[edit]