Propranolol

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Not to be confused with Profadol, Propanol, or Propofol.
Propranolol (INN)
Propranolol-skeletal.svg
Propranolol-from-xtal-3D-balls.png
Systematic (IUPAC) name
(RS)-1-(1-methylethylamino)-3-(1-naphthyloxy)propan-2-ol
Clinical data
Trade names Inderal
AHFS/Drugs.com monograph
Licence data US FDA:link
Pregnancy
category
  • AU: C
  • US: C (Risk not ruled out)
Legal status
Routes of
administration		 Oral, rectal, IV
Pharmacokinetic data
Bioavailability 26%
Metabolism hepatic (extensive) 1A2, 2D6; minor: 2C19, 3A4
Biological half-life 4–5 hours
Excretion renal <1%
Identifiers
CAS Number 525-66-6 YesY
ATC code C07AA05
PubChem CID: 4946
IUPHAR/BPS 564
DrugBank DB00571 YesY
ChemSpider 4777 YesY
UNII 9Y8NXQ24VQ YesY
KEGG D08443 YesY
ChEBI CHEBI:8499 YesY
ChEMBL CHEMBL27 YesY
Chemical data
Formula C16H21NO2
Molecular mass 259.34 g/mol
 YesY (what is this?)  (verify)

Propranolol is a sympatholytic nonselective beta blocker. It is used to treat high blood pressure, a number of heart dysrhythmias, thyrotoxicosis, and essential tremors.[1] It is used to prevent migraine headaches, and to prevent further heart problems in those with angina or previous heart attacks.[1] It comes in both oral and intravenous forms.[1]

It should not be used in those with an already slow heart rate and most of those with heart failure.[1] Quickly stopping the medication in those with coronary artery disease may worsen symptoms.[1] It may worsen the symptoms of asthma.[1] Common side effects include nausea, abdominal pain, and constipation.[1] Greater care is recommended in those with liver or kidney problems.[1] It may possibly cause harmful effects to the infant if taken during pregnancy.[2]

It was the first successful beta blocker developed.[3] 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.[4] Propranolol is available in generic form.

Medical uses[edit]

An 80 mg capsule of extended-release propranolol
A mixture of 20 mg and 10 mg propranolol tablets

Propranolol is indicated for the management of various conditions, including:

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.[13]

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.[14]

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.[15]

Propranolol is being investigated as a potential treatment for post-traumatic stress disorder(PTSD).[16][17][18] Propranolol works to inhibit the actions of norepinephrine, a neurotransmitter that enhances memory consolidation. 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.[19] 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.[20] 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."[21]

Propranolol maybe used 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.[22]

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.[23] The amygdala is involved in processing emotion, including fear, and has been shown to be inhibited by propranolol.[24]

Adverse effects[edit]

See also: Beta_blocker § 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.[25]

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

Precautions and contraindications[edit]

Propranolol should be used with caution in people with:[26]

Propranolol is contraindicated in patients with:[26]

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.[27]

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.[28] 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".[27][28][29][30]

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:[26]

Pharmacokinetics[edit]

Propranolol is rapidly and completely absorbed, with peak plasma levels achieved about 1–3 hours after ingestion. Coadministration with food appears to enhance bioavailability.[32] 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[edit]

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).[33] 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.[34][35][36]

History[edit]

Main article: Discovery and development of beta-adrenergic receptor antagonists (beta-blockers)

British scientist James W. Black developed propranolol in the 1960s.[3] 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 aryl ethanolamine 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 cardio-selective beta blockers (such as nebivolol, carvedilol, or metoprolol) are now used in the treatment of hypertension.

Society and culture[edit]

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.[37] For about 10-16% of performers, their degree of stage fright is considered pathological.[37][38] Propranolol is used by musicians, actors, and public speakers for its ability to treat anxiety symptoms activated by the sympathetic nervous system.[39] This can be seen as giving participating individuals an unfair advantage, especially in competitions, akin to the use of performance-enhancing drugs in athletes.[40]

Brandnames[edit]

Propranolol 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.[41]

Research[edit]

In 2015, a trial in women with epithelial ovarian cancer showed that the intake of a nonselective β-blocker was associated with a longer survival compared to a β1-selective β-blocker or no β-blocker.[42] Currently, an interventional study is being conducted at the M.D. Anderson Cancer Center to access the feasibility of a nonselective β-blocker plus standard chemotherapy (paclitaxel and carboplatin or possibly docetaxel) to treat ovarian cancer.[43]

See also[edit]

References[edit]

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  12. ^ Clinical summary
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  18. ^ A pill to forget
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  24. ^ Pill for Racism
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  34. ^ Wang D. W., Mistry A. M., Kahlig K. M., Kearney J. A., Xiang J., George A. L. Jr (2010). "Propranolol blocks cardiac and neuronal voltage-gated sodium channels". Front. Pharmacol 1: 144. doi:10.3389/fphar.2010.00144. 
  35. ^ Bankston J. R., Kass R. S. (2010). "Molecular determinants of local anesthetic action of beta-blocking drugs: implications for therapeutic management of long QT syndrome variant 3". J. Mol. Cell. Cardiol 48: 246–253. doi:10.1016/j.yjmcc.2009.05.012. 
  36. ^ Desaphy J. F., Pierno S., De Luca A., Didonna P., Camerino D. C. (2003). "Different ability of clenbuterol and salbutamol to block sodium channels predicts their therapeutic use in muscle excitability disorders". Mol. Pharmacol 63 (3): 659–670. doi:10.1124/mol.63.3.659. PMID 12606775. 
  37. ^ a b Fishbein M, Middlestadt SE, Ottati V, Straus S, Ellis A (1988). "Medical problems among ICSOM musicians: overview of a national survey". Med Probl Perform Artist 3: 1–8. 
  38. ^ Steptoe A, Malik F, Pay C, Pearson P, Price C, Win Z (1995). "The impact of stage fright on student actors". Br J Psychol 86: 27–39. doi:10.1111/j.2044-8295.1995.tb02544.x. 
  39. ^ Alan H. Lockwood (1989). "Medical Problems of Musicians". NEJM 320 (4): 221–227. doi:10.1056/nejm198901263200405. 
  40. ^ Thomas H. Murray (1983). "The Coercive Power of Drugs in Sports". Hastings Center Report 13 (4): 24–30. doi:10.2307/3561718. 
  41. ^ "Hemangeol - Food and Drug Administration" (PDF). 1 March 2014. Retrieved 23 March 2015. 
  42. ^ A.K. Sood, J.L.Watkins, P.H. Thaker (2015). "Clinical impact of selective and nonselective beta-blockers on survival in patients with ovarian cancer". Cancer: Online-first. doi:10.1002/cncr.29392. 
  43. ^ https://clinicaltrials.gov/show/NCT01504126. Retrieved 17 October 2015.  Missing or empty |title= (help)

External links[edit]
β, non-selective
β1-selective
β2-selective
α1- + β-selective
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