|Systematic (IUPAC) name|
|Licence data||US FDA:|
|Routes||Oral, rectal, IV|
|Metabolism||hepatic (extensive) 1A2, 2D6; minor: 2C19, 3A4|
|Molecular mass||259.34 g/mol|
|(what is this?)|
Propranolol (INN) is a sympatholytic nonselective beta blocker. It is used to treat high blood pressure, a number of heart dysrhythmias, those with thyrotoxicosis, and essential tremors. It is used to prevent migraine headaches, and further heart problems in those with angina or previous myocardial infarction. It comes in both oral and intravenous forms.
It should not be used in those with an already slow heart rate and most of those with heart failure. Quickly stopping the medication in those with coronary artery disease may worsen symptoms. It may worsen the symptoms of asthma. Common side effects include: nausea, abdominal pain, and constipation. Greater care is recommended in those with liver or kidney problems. It may possibly cause harmful effects to the infant if taken during pregnancy.
It was the first successful beta blocker developed. 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. Propranolol is available in generic form; it 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).
Propranolol is indicated for the management of various conditions, including:
- Angina pectoris (with the exception of variant angina)
- Myocardial infarction
- Control of tachycardia/tremor associated with anxiety, hyperthyroidism, or lithium therapy.
- Essential tremor
- Migraine prevention
- Cluster headache prevention
- Some experimentation has been conducted in psychiatric areas:
- Thyrotoxicosis by deiodinase inhibition
- Primary exertional headache
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 currently being investigated as a potential treatment for post-traumatic stress disorder. Propranolol works to inhibit the actions of norepinephrine (noradrenaline), a neurotransmitter that enhances memory consolidation. Individuals given propranolol immediately after a traumatic experience show less severe symptoms of PTSD compared to their respective control groups who did not receive the drug. 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. 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 in combination with etodolac is currently being investigated in a phase-III trial of 400 colorectal cancer patients as a potential treatment for prevention of colorectal cancer recurrence. The aim of this study is to assess the use of perioperative medical intervention using a combination of a propranolol and etodolac 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.
Propranolol was investigated for possible effects on resting energy expenditure and muscle catabolism in patients with severe burns. 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, has 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 antiparasite activity against P. vinckei, or P. yoelii nigeriensis. However, propranolol may reduce the dosages required for existing drugs to be effective against P. falciparum by five- to 10-fold, suggesting a role for combination therapies.
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. 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.
Precautions and contraindications
Propranolol should be used with caution in people with:
- Diabetes mellitus or hyperthyroidism, since signs and symptoms of hypoglycaemia may be masked
- Peripheral vascular disease and Raynaud's syndrome, which may be exacerbated
- Phaeochromocytoma, as hypertension may be aggravated without prior alpha blocker therapy
- Myasthenia gravis may be worsened
- Other drugs with bradycardic effects
Propranolol is contraindicated in patients with:
- Reversible airways diseases, particularly asthma or chronic obstructive pulmonary disease
- Bradycardia (<60 beats/minute)
- Sick sinus syndrome
- Atrioventricular block (second- or third-degree)
- Severe hypotension
- Cocaine toxicity [per American Heart Association guidelines, 2005]
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.
Pregnancy and lactation
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.
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. 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".
Propranolol is rapidly and completely absorbed, with peak plasma levels achieved about 1–3 hours after ingestion. 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.
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
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). 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.
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:
- β2-adrenergic receptor agonists
- ergot alkaloids
- nonsteroidal anti-inflammatory drugs
- Fluvoxamine slows down the metabolism of propranolol significantly, leading to increased blood levels of propranolol.
British 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.
Society and culture
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. 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. This can be seen as giving participating individuals an unfair advantage, especially in competitions, akin to the use of performance-enhancing drugs in athletes.
- "Propranolol hydrochloride". Monograph. The American Society of Health-System Pharmacists. Retrieved Jan 1, 2015.
- "Prescribing medicines in pregnancy database". Australian Government. 3 March 2014. Retrieved 22 April 2014.
- Black JW, Crowther AF, Shanks RG, Smith LH, Dornhorst AC (1964). "A new adrenergic betareceptor antagonist". The Lancet 283 (7342): 1080–1081. doi:10.1016/S0140-6736(64)91275-9. PMID 14132613.
- "WHO Model List of EssentialMedicines". World Health Organization. October 2013. Retrieved 22 April 2014.
- Shields, Kevin G.; Peter J. Goadsby (January 2005). "Propranolol modulates trigeminovascular responses in thalamic ventroposteromedial nucleus: a role in migraine?". Brain 128 (1): 86–97. doi:10.1093/brain/awh298. Retrieved 17 August 2012.
- Eadie, M.; J. H. Tyrer (1985). The Biochemistry of Migraine. New York: Springer. p. 148. ISBN 9780852007310. OCLC 11726870.[dead link]
- Kornischka J, Cordes J, Agelink MW (April 2007). "[40 years beta-adrenoceptor blockers in psychiatry]". Fortschritte Der Neurologie-Psychiatrie (in German) 75 (4): 199–210. doi:10.1055/s-2006-944295. PMID 17200914.
- Vieweg V, Pandurangi A, Levenson J, Silverman J (1994). "The consulting psychiatrist and the polydipsia-hyponatremia syndrome in schizophrenia". International Journal of Psychiatry in Medicine 24 (4): 275–303. doi:10.2190/5WG5-VV1V-BXAD-805K. PMID 7737786.
- Kishi Y, Kurosawa H, Endo S (1998). "Is propranolol effective in primary polydipsia?". International Journal of Psychiatry in Medicine 28 (3): 315–25. doi:10.2190/QPWL-14H7-HPGG-A29D. PMID 9844835.
- Kramer MS, Gorkin R, DiJohnson C (1989). "Treatment of neuroleptic-induced akathisia with propranolol: a controlled replication study". The Hillside Journal of Clinical Psychiatry 11 (2): 107–19. PMID 2577308.
- Thibaut F, Colonna L (1993). "[Anti-aggressive effect of beta-blockers]". L'Encéphale (in French) 19 (3): 263–7. PMID 7903928.
- Clinical summary
- Sheetal Ladva (2006-06-28). "NICE and BHS launch updated hypertension guideline". National Institute for Health and Clinical Excellence. Retrieved 2009-10-11.
- Elman MJ, Sugar J, Fiscella R, et al. (1998). "The effect of propranolol versus placebo on resident surgical performance". Transactions of the American Ophthalmological Society 96: 283–91; discussion 291–4. PMC 1298399. PMID 10360293.
- "Doctors test a drug to ease traumatic memories - Mental Health - MSNBC.com". Retrieved 2007-06-30.
- Brunet A, Orr SP, Tremblay J, Robertson K, Nader K, Pitman RK (May 2008). "Effect of post-retrieval propranolol on psychophysiologic responding during subsequent script-driven traumatic imagery in post-traumatic stress disorder". Journal of Psychiatric Research 42 (6): 503–6. doi:10.1016/j.jpsychires.2007.05.006. PMID 17588604.
- A pill to forget
- Vaiva, G.; Ducrocq, F.; Jezekiel, K.; Averland, B.; Lestavel, P.; Brunet, A.; Marmar, C.R. (2003). "Immediate treatment with propranolol decreases post-traumatic stress disorder two months after trauma". Biological Psychiatry 54: 947–949. doi:10.1016/s0006-3223(03)00412-8.
- Kolber, Adam J. (2006). "Therapeutic Forgetting: The Legal and Ethical Implications of Memory Dampening". Vanderbilt Law Review, San Diego Legal Studies Paper No. 07-37. 59: 1561.
- Hall, Wayne; Carter, Adrian (2007). "Debunking Alarmist Objections to the Pharmacological Prevention of PTSD". American Journal of Bioethics 7 (9): 23–25. doi:10.1080/15265160701551244.
- "β-adrenergic Blocker and a COX2 Inhibitor for Prevention of Colorectal Cancer Recurrence". Retrieved 2010-07-19.
- Hogeling, M. (2012). "Propranolol for Infantile Hemangiomas: A Review". Current Dermatology Reports: Online-first. doi:10.1007/s13671-012-0026-6.
- Herndon DN et al. (October 2001). "Reversal of Catabolism by Beta-Blockade after Severe Burns". New England Journal of Medicine 345 (17): 1223–1229. doi:10.1056/NEJMoa010342. PMID 11680441.
- Ohnishi S, Sadanaga K, Katsuoka M, Weidanz W (1990). "Effects of membrane acting-drugs on plasmodium species and sickle cell erythrocytes". Mol Cell Biochem 91 (1–2): 159–65. doi:10.1007/BF00228091. PMID 2695829.
- Singh N, Puri S (2000). "Interaction between chloroquine and diverse pharmacological agents in chloroquine-resistant Plasmodium yoelii nigeriensis". Acta Trop 77 (2): 185–93. doi:10.1016/S0001-706X(00)00133-9. PMID 11080509.
- Murphy S, Harrison T, Hamm H, Lomasney J, Mohandas N, Haldar K (December 2006). "Erythrocyte G Protein as a Novel Target for Malarial Chemotherapy". PLoS Med 3 (12): e528. doi:10.1371/journal.pmed.0030528. PMC 1716186. PMID 17194200.
- Sheetal Ladva (2012-03-15). "Drug 'reduces implicit racial bias,' study suggests". Oxford Medical School. Retrieved 2012-03-16.
- Pill for Racism
- Journal of Allergy and Clinical Immunology, May 2011
- Sulkowski, A.; Vachon, L.; Rich Jr, E. S. (1977). "Propranolol effects on acute marihuana intoxication in man". Psychopharmacology 52 (1): 47–53. doi:10.1007/BF00426599. PMID 403557.
- Hollister, Leo E. "Interactions of cannabis with other drugs in man." Strategies for research on the interactions of drugs of abuse. National Institute on Drug Abuse Research monograph 68 (1986): 110-116.
- Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006.
- Cruickshank JM (2010). "Beta-blockers and heart failure". Indian Heart J 62 (2): 101–10. PMID 21180298.
- Sweetman, Sean C., ed. (2009). "Cardiovascular Drugs". Martindale: The complete drug reference (36th ed.). London: Pharmaceutical Press. pp. 1226–1381. ISBN 978-0-85369-840-1.
- [No authors listed] (2007). "Propranolol". In: Drugs and Lactation Database. U.S. National Library of Medicine Toxicology Data Network. Retrieved 2013-02-25.
- [No authors listed] (September 2001). "Transfer of drugs and other chemicals into human milk". Pediatrics 108 (3): 776–89. PMID 11533352.
- Spencer JP, Gonzalez LS, Barnhart DJ (July 2001). "Medications in the breast-feeding mother". Am Fam Physician 64 (1): 119–26. PMID 11456429.
- Young R, Glennon RA (April 2009). "S(-)Propranolol as a discriminative stimulus and its comparison to the stimulus effects of cocaine in rats". Psychopharmacology (Berl.) 203 (2): 369–82. doi:10.1007/s00213-008-1317-2. PMID 18795268.
- 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.
- 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.
- 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.
- van Harten J (1995). "Overview of the pharmacokinetics of fluvoxamine". Clinical Pharmacokinetics 29 (Suppl 1): 1–9. doi:10.2165/00003088-199500291-00003. PMID 8846617.
- 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.
- 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.
- Alan H. Lockwood (1989). "Medical Problems of Musicians". NEJM 320 (4): 221–227.
- Thomas H. Murray (1983). "The Coercive Power of Drugs in Sports". Hastings Center Report 13 (4): 24–30. doi:10.2307/3561718.
- Stapleton MP (1997). "Sir James Black and propranolol. The role of the basic sciences in the history of cardiovascular pharmacology". Texas Heart Institute Journal 24 (4): 336–42. PMC 325477. PMID 9456487.
- Scientific American Interview with James McGaugh[dead link]
- U.S. National Library of Medicine: Drug Information Portal - Propranolol