Chemistry:Propranolol

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Short description: Beta blocker drug
Propranolol
Propranolol.svg
Propranolol-from-1977-crystal-structure-3D-balls-side.png
Clinical data
Pronunciation/proʊˈprænəˌlɑːl/
Trade namesInderal, others
AHFS/Drugs.comMonograph
License data
Pregnancy
category
  • AU: C
Routes of
administration		Oral, rectal, intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability26%
Protein binding90%
MetabolismLiver (extensive) 1A2, 2D6; minor: 2C19, 3A4
MetabolitesN-desisopropylpropranolol, 4'-hydroxypropanolol
Elimination half-life4–5 hours
ExcretionKidney (<1%)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC16H21NO2
Molar mass259.349 g·mol−1
3D model (JSmol)
ChiralityRacemic mixture
Melting point96 °C (205 °F)
  (verify)

Propranolol, sold under the brand name Inderal among others, is a medication of the beta blocker class.[1] It is used to treat high blood pressure, a number of types of irregular heart rate, thyrotoxicosis, capillary hemangiomas, performance anxiety, and essential tremors,[1][2][3] as well to prevent migraine headaches, and to prevent further heart problems in those with angina or previous heart attacks.[1] It can be taken orally (by mouth) or by intravenous injection (injection into a vein).[1] The formulation that is taken orally (by mouth) comes in short-acting and long-acting versions.[1] Propranolol appears in the blood after 30 minutes and has a maximum effect between 60 and 90 minutes when taken orally.[1][4]

Common side effects include nausea, abdominal pain, and constipation.[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] Caution is recommended in those with liver or kidney problems.[1] Propranolol may cause harmful effects for the baby if taken during pregnancy.[5] Its use during breastfeeding is probably safe, but the baby should be monitored for side effects.[6] It is a non-selective beta blocker which works by blocking β-adrenergic receptors.[1]

Propranolol was patented in 1962 and approved for medical use in 1964.[7] It is on the World Health Organization's List of Essential Medicines.[8] Propranolol is available as a generic medication.[1] In 2020, it was the 88th most commonly prescribed medication in the United States, with more than 8 million prescriptions.[9][10]

Medical uses

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

Propranolol is used for treating various conditions, including:

Cardiovascular

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.[11]

Propranolol is not recommended for the treatment of high blood pressure 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.[12]

Psychiatric

Propranolol is occasionally used to treat performance anxiety,[2] although evidence to support its use in any anxiety disorders is poor.[13] Its efficacy in managing panic disorder appears similar to benzodiazepines, while carrying lower risks for addiction or abuse.[13] Although beta-blockers such as propranolol have been suggested to be beneficial in managing physical symptoms of anxiety, its efficacy in treating generalized anxiety disorder and panic disorder remain unestablished.[14] Some experimentation has been conducted in other psychiatric areas:[15]

PTSD and phobias

Propranolol is being investigated as a potential treatment for PTSD.[19][20][21] Propranolol works to inhibit the actions of norepinephrine, a neurotransmitter that enhances memory consolidation.[22] 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.[23] 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.[13] It has also been found to be helpful for some individuals with Misophonia.[24]

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.[25] 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".[26]

Other uses

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.[32]

Contraindications

Propranolol may be contraindicated in people with:[33]

Adverse effects

Propranolol should be used with caution in people with:[33]

Pregnancy and lactation

Propranolol, like other beta blockers, is classified as pregnancy category C in the United States and ADEC category C in Australia. β-blocking agents in general reduce perfusion of the placenta, which may lead to adverse outcomes for the neonate, including lung or heart complications, or premature birth. The newborn may experience additional adverse effects such as low blood sugar and a slower than normal heart rate.[34]

Most β-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.[35] 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".[34][35][36][37]

Overdose

In overdose propranolol is associated with seizures.[38] Cardiac arrest may occur in propranolol overdose due to sudden ventricular arrhythmias, or cardiogenic shock which may ultimately culminate in bradycardic PEA.[39]

Interactions

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:[33]

Pharmacology

Pharmacodynamics

Site Ki (nM) Species Ref
5-HT1A 55–272 Human [41][42]
5-HT1B 56–85 Rat [43][44]
5-HT1D 4,070 Pig [45]
5-HT2A 4,280 Human [46]
5-HT2B 457–513 (+)
166–316 (–)		 Human [47]
5-HT2C 61,700 (+)
5,010 (–)
736–2,457		 Human
Human
Rodent		 [47]
[47]
[48][42]
5-HT3 >10,000 Human [49]
α1 ND ND ND
α2 1,297–2,789 Rat [50]
β1 0.02–2.69 Human [51][52]
β2 0.01–0.61 Human [51][52]
β3 450 Mouse [53]
D1 >10,000 Human [42]
D2 >10,000 Human [42]
H1 >10,000 Human [54]
DAT 29,000 (IC50) Rat [55]
Values are Ki (nM), unless otherwise noted. The smaller the value, the more strongly the drug binds to the site.

Propranolol is classified as a competitive non-cardioselective sympatholytic beta blocker that crosses the blood–brain barrier. It is lipid soluble and also has sodium channel blocking effects. Propranolol is a non-selective β-adrenergic receptor antagonist, or beta blocker;[56] that is, it blocks the action of epinephrine (adrenaline) and norepinephrine (noradrenaline) at 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. overdose).[57] Propranolol is able to cross the blood–brain barrier and exert effects in the central nervous system in addition to its peripheral activity.[13]

In addition to blockade of adrenergic receptors, propranolol has very weak inhibitory effects on the norepinephrine transporter and/or weakly stimulates norepinephrine release (i.e., the concentration of norepinephrine is increased in the synapse).[58][55] Since propranolol blocks β-adrenoceptors, the increase in synaptic norepinephrine only results in α-adrenoceptor activation, with the α1-adrenoceptor being particularly important for effects observed in animal models.[58][55] Therefore, it can be looked upon as a weak indirect α1-adrenoceptor agonist in addition to potent β-adrenoceptor antagonist.[58][55] In addition to its effects on the adrenergic system, there is evidence that indicates that propranolol may act as a weak antagonist of certain serotonin receptors, namely the 5-HT1A, 5-HT1B, and 5-HT2B receptors.[59][60][47] The latter may be involved in the effectiveness of propranolol in the treatment of migraine at high doses.[47]

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.[61][62][63]

Mechanism of action

Propranolol is a non-selective beta receptor antagonist.[56] This means that it does not have preference to β1 or β2 receptors. It competes with sympathomimetic neurotransmitters for binding to receptors, which inhibits sympathetic stimulation of the heart. Blockage of neurotransmitter binding to β1 receptors on cardiac myocytes inhibits activation of adenylate cyclase, which in turn inhibits cAMP synthesis leading to reduced PKA (Protein Kinase A) activation. 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.[64] Blockage of neurotransmitter binding to β2 receptors on smooth muscle cells will increase contraction, which will increase hypertension.

Pharmacokinetics

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.[64] Coadministration with food appears to enhance bioavailability.[65] 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.[64]

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).[66] Effective plasma concentrations are between 10 and 100 mg/L.[citation needed] Toxic levels are associated with plasma concentrations above 2000 mg/L.[citation needed]

History

Scottish scientist James W. Black developed propranolol in the 1960s.[67] It was the first beta-blocker effectively used in the treatment of coronary artery disease and hypertension.[68] In 1988, Black 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.

Newer, more cardio-selective beta blockers (such as bisoprolol, nebivolol, carvedilol, or metoprolol) are now used preferentially in the treatment of hypertension.[68]

Society and culture

In a 1987 study by the International Conference of Symphony and Opera Musicians, it was reported that 27% of interviewed members said they used beta blockers such as propranolol for musical performances.[69] For about 10–16% of performers, their degree of stage fright is considered pathological.[69][70] Propranolol is used by musicians, actors, and public speakers for its ability to treat anxiety symptoms activated by the sympathetic nervous system.[71] It has also been used as a performance-enhancing drug in sports where high accuracy is required, including archery, shooting, golf,[72] and snooker.[72] 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.[73]

Brand names

Propranolol was first marketed under the brand name Inderal, manufactured by ICI Pharmaceuticals (now AstraZeneca), in 1965. "Inderal" is a quasi-anagram of "Alderlin", the trade name of pronethalol (which propranolol replaced); both names are an homage to Alderley Park, the ICI headquarters where the drugs were first developed.[74]

Propranolol is also marketed under brand names Avlocardyl, Deralin, Dociton, Inderalici, InnoPran XL, Indoblok,[75] 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.[76]

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 "Propranolol hydrochloride". Monograph. The American Society of Health-System Pharmacists. https://www.drugs.com/monograph/propranolol-hydrochloride.html. 
  2. ↑ 2.0 2.1 "Pharmacotherapy of social anxiety disorder: what does the evidence tell us?". The Journal of Clinical Psychiatry 67 (Suppl 12): 20–26. 2006. doi:10.1016/j.genhosppsych.2005.07.002. PMID 17092192. 
  3. ↑ "Pharmacologic Interventions for Infantile Hemangioma: A Meta-analysis". Pediatrics 137 (2): e20153896. February 2016. doi:10.1542/peds.2015-3896. PMID 26772662. http://pediatrics.aappublications.org/content/pediatrics/137/2/e20153896.full.pdf. 
  4. ↑ Comprehensive review in toxicology for emergency clinicians (3 ed.). Washington, DC: Taylor & Francis. 1997. p. 167. ISBN 9781560326120. https://books.google.com/books?id=f7009NkJv70C&pg=PA167. 
  5. ↑ "Prescribing medicines in pregnancy database". Australian Government. 3 March 2014. http://www.tga.gov.au/hp/medicines-pregnancy.htm. 
  6. ↑ Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk (9th ed.). Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. 2011. p. 1226. ISBN 9781608317080. https://books.google.com/books?id=OIgTE4aynrMC&pg=PA1226. 
  7. ↑ (in en) Analogue-based Drug Discovery. John Wiley & Sons. 2006. p. 460. ISBN 9783527607495. https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA460. 
  8. ↑ World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. 2019. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO. 
  9. ↑ "The Top 300 of 2020". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  10. ↑ "Propranolol - Drug Usage Statistics". https://clincalc.com/DrugStats/Drugs/Propranolol. 
  11. ↑ "NICE and BHS launch updated hypertension guideline". National Institute for Health and Clinical Excellence. 28 June 2006. http://www.nice.org.uk/download.aspx?o=335988. 
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  48. ↑ "125I-lysergic acid diethylamide binds to a novel serotonergic site on rat choroid plexus epithelial cells". The Journal of Neuroscience 5 (12): 3178–3183. December 1985. doi:10.1523/JNEUROSCI.05-12-03178.1985. PMID 4078623. 
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  53. ↑ "Molecular characterization of the mouse beta 3-adrenergic receptor: relationship with the atypical receptor of adipocytes". The EMBO Journal 10 (12): 3721–3727. December 1991. doi:10.1002/j.1460-2075.1991.tb04940.x. PMID 1718744. 
  54. ↑ "Histamine H1 receptors in human brain labelled with [3H]doxepin". Brain Research 304 (1): 1–7. June 1984. doi:10.1016/0006-8993(84)90856-4. PMID 6146381. 
  55. ↑ 55.0 55.1 55.2 55.3 Cite error: Invalid <ref> tag; no text was provided for refs named pmid2872325
  56. ↑ 56.0 56.1 "Propranolol". Profiles of Drug Substances, Excipients, and Related Methodology 42: 287–338. 2017. doi:10.1016/bs.podrm.2017.02.006. ISBN 9780128122266. PMID 28431779. 
  57. ↑ Medical sciences (Second ed.). Elsevier Health Sciences. 2014. p. 150. ISBN 978-0702052491. 
  58. ↑ 58.0 58.1 58.2 "S(-)Propranolol as a discriminative stimulus and its comparison to the stimulus effects of cocaine in rats". Psychopharmacology 203 (2): 369–382. April 2009. doi:10.1007/s00213-008-1317-2. PMID 18795268. 
  59. ↑ "[The 5-HT1A receptor: a new effective principle in psychopharmacologic therapy?]" (in de). Fortschritte der Neurologie-Psychiatrie 64 (11): 460–472. November 1996. doi:10.1055/s-2007-996592. PMID 9064274. 
  60. ↑ "International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin)". Pharmacological Reviews 46 (2): 157–203. June 1994. PMID 7938165. 
  61. ↑ "Propranolol blocks cardiac and neuronal voltage-gated sodium channels". Frontiers in Pharmacology 1: 144. 2010. doi:10.3389/fphar.2010.00144. PMID 21833183. 
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  63. ↑ "Different ability of clenbuterol and salbutamol to block sodium channels predicts their therapeutic use in muscle excitability disorders". Molecular Pharmacology 63 (3): 659–670. March 2003. doi:10.1124/mol.63.3.659. PMID 12606775. http://pdfs.semanticscholar.org/20af/2edd8d1cb9f3874aee83a478c5af152298c0.pdf. 
  64. ↑ 64.0 64.1 64.2 "Propranolol". https://www.drugbank.ca/drugs/DB00571. 
  65. ↑ Rang & Dale's pharmacology (7th ed.). Edinburgh: Churchill Livingstone. 2011. p. 106. ISBN 9780702034718. 
  66. ↑ "Propranolol" (in en). https://pubchem.ncbi.nlm.nih.gov/compound/propranolol#section=Top. 
  67. ↑ "A New Adrenergic Beta-Receptor Antagonist". Lancet 1 (7342): 1080–1081. May 1964. doi:10.1016/S0140-6736(64)91275-9. PMID 14132613. 
  68. ↑ 68.0 68.1 "Antihypertensive Agents". Basic & Clinical Pharmacology (14th ed.). McGraw-Hill. 2017. ISBN 9781259641152. 
  69. ↑ 69.0 69.1 "Medical problems among ICSOM musicians: overview of a national survey". Med Probl Perform Artist 3: 1–8. 1988. 
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  76. ↑ "Hemangeol - Food and Drug Administration". 1 March 2014. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205410s000lbl.pdf. 

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