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.[12]
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.[13]
Psychiatric
Propranolol is occasionally used to treat
performance anxiety,[3] although evidence to support its use in any
anxiety disorders is poor.[14] Its efficacy in managing
panic disorder appears similar to
benzodiazepines, while carrying lower risks for addiction or abuse.[14] 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.[15] Some experimentation has been conducted in other psychiatric areas:[16]
Propranolol is being investigated as a potential treatment for PTSD.[20][21][22] Propranolol works to inhibit the actions of
norepinephrine (
noradrenaline), a
neurotransmitter that enhances
memory consolidation.[23] 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.[24] 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.[14] It has also been found to be helpful for some individuals with
misophonia.[25]
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.[26] 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".[27]
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.[33]
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.[36] 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".[35][36][37][38]
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:[34]
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).[62][58] 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.[62][58] Therefore, it can be looked upon as a weak indirect α1-adrenoceptor
agonist in addition to potent β-adrenoceptor antagonist.[62][58] 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.[63][64][49] The latter may be involved in the effectiveness of propranolol in the treatment of
migraine at high doses.[49]
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.[65][66][67]
Mechanism of action
Propranolol is a non-selective beta receptor antagonist.[60] 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.[68] 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.[68] Coadministration with food appears to enhance
bioavailability.[69] 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.[68]
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).[70] 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]
Scottish scientist
James W. Black developed propranolol in the 1960s.[71] It was the first beta-blocker effectively used in the treatment of
coronary artery disease and
hypertension.[72] 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.
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.[73] For about 10–16% of performers, their degree of stage fright is considered pathological.[73][74] Propranolol is used by musicians, actors, and public speakers for its ability to treat anxiety symptoms activated by the sympathetic nervous system.[75] It has also been used as a
performance-enhancing drug in sports where high accuracy is required, including
archery,
shooting,
golf,[76] and
snooker.[76] 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.[77]
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.[78]
Propranolol is also marketed under brand names Avlocardyl, Deralin, Dociton, Inderalici, InnoPran XL, Indoblok,[79] 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.[80]
^
abDavidson JR (2006). "Pharmacotherapy of social anxiety disorder: what does the evidence tell us?". The Journal of Clinical Psychiatry. 67 (Suppl 12): 20–26.
doi:
10.1016/j.genhosppsych.2005.07.002.
PMID17092192.
^World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization.
hdl:
10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
^Thibaut F, Colonna L (1993). "[Anti-aggressive effect of beta-blockers]". L'Encephale (in French). 19 (3): 263–267.
PMID7903928.
^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.
PMID7737786.
S2CID22703210.
^Kolber AJ (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 W, Carter A (September 2007). "Debunking alarmist objections to the pharmacological prevention of PTSD". The American Journal of Bioethics. 7 (9): 23–25.
doi:
10.1080/15265160701551244.
PMID17849333.
S2CID27063524.
^Chen T, Gudipudi R, Nguyen SA, Carroll W, Clemmens C (April 2022). "Should Propranolol Remain the Gold Standard for Treatment of Infantile Hemangioma? A Systematic Review and Meta-Analysis of Propranolol Versus Atenolol". The Annals of Otology, Rhinology, and Laryngology. 132 (3): 332–340.
doi:
10.1177/00034894221089758.
PMID35466712.
S2CID248375711.
^
ab[No authors listed] (2007). "Propranolol". In: Drugs and Lactation Database. U.S.
National Library of Medicine Toxicology Data Network. Retrieved 25 February 2013.
^Spencer JP, Gonzalez LS, Barnhart DJ (July 2001). "Medications in the breast-feeding mother". American Family Physician. 64 (1): 119–126.
PMID11456429.
^Reith DM, Dawson AH, Epid D, Whyte IM, Buckley NA, Sayer GP (1996). "Relative toxicity of beta blockers in overdose". Journal of Toxicology. Clinical Toxicology. 34 (3): 273–278.
doi:
10.3109/15563659609013789.
PMID8667464.
^Holstege CP, Eldridge DL, Rowden AK (February 2006). "ECG manifestations: the poisoned patient". Emergency Medicine Clinics of North America. 24 (1): 159–77, vii.
doi:
10.1016/j.emc.2005.08.012.
PMID16308118.
^Roth BL, Driscol J.
"PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 14 August 2017.
^Hamon M, Lanfumey L, el Mestikawy S, Boni C, Miquel MC, Bolaños F, et al. (1990). "The main features of central 5-HT1 receptors". Neuropsychopharmacology. 3 (5–6): 349–360.
PMID2078271.
^
abcdToll L, Berzetei-Gurske IP, Polgar WE, Brandt SR, Adapa ID, Rodriguez L, et al. (March 1998). "Standard binding and functional assays related to medications development division testing for potential cocaine and opiate narcotic treatment medications". NIDA Research Monograph. 178: 440–466.
PMID9686407.
^Engel G, Göthert M, Hoyer D, Schlicker E, Hillenbrand K (January 1986). "Identity of inhibitory presynaptic 5-hydroxytryptamine (5-HT) autoreceptors in the rat brain cortex with 5-HT1B binding sites". Naunyn-Schmiedeberg's Archives of Pharmacology. 332 (1): 1–7.
doi:
10.1007/bf00633189.
PMID2936965.
S2CID5999838.
^Schlicker E, Fink K, Göthert M, Hoyer D, Molderings G, Roschke I, Schoeffter P (July 1989). "The pharmacological properties of the presynaptic serotonin autoreceptor in the pig brain cortex conform to the 5-HT1D receptor subtype". Naunyn-Schmiedeberg's Archives of Pharmacology. 340 (1): 45–51.
doi:
10.1007/bf00169206.
PMID2797214.
S2CID2287040.
^Elliott JM, Kent A (July 1989). "Comparison of [125I]iodolysergic acid diethylamide binding in human frontal cortex and platelet tissue". Journal of Neurochemistry. 53 (1): 191–196.
doi:
10.1111/j.1471-4159.1989.tb07313.x.
PMID2723656.
S2CID25820829.
^
abcdeSchmuck K, Ullmer C, Kalkman HO, Probst A, Lubbert H (May 1996). "Activation of meningeal 5-HT2B receptors: an early step in the generation of migraine headache?". The European Journal of Neuroscience. 8 (5): 959–967.
doi:
10.1111/j.1460-9568.1996.tb01583.x.
PMID8743744.
S2CID19578349.
^Barnes JM, Barnes NM, Costall B, Ironside JW, Naylor RJ (December 1989). "Identification and characterisation of 5-hydroxytryptamine 3 recognition sites in human brain tissue". Journal of Neurochemistry. 53 (6): 1787–1793.
doi:
10.1111/j.1471-4159.1989.tb09244.x.
PMID2809591.
S2CID46356673.
^Boyajian CL, Leslie FM (June 1987). "Pharmacological evidence for alpha-2 adrenoceptor heterogeneity: differential binding properties of [3H]rauwolscine and [3H]idazoxan in rat brain". The Journal of Pharmacology and Experimental Therapeutics. 241 (3): 1092–1098.
PMID2885406.
^
abSchotte A, Janssen PF, Gommeren W, Luyten WH, Van Gompel P, Lesage AS, et al. (March 1996). "Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding". Psychopharmacology. 124 (1–2): 57–73.
doi:
10.1007/bf02245606.
PMID8935801.
S2CID12028979.
^
abFraundorfer PF, Fertel RH, Miller DD, Feller DR (August 1994). "Biochemical and pharmacological characterization of high-affinity trimetoquinol analogs on guinea pig and human beta adrenergic receptor subtypes: evidence for partial agonism". The Journal of Pharmacology and Experimental Therapeutics. 270 (2): 665–674.
PMID7915318.
^Kovachich GB, Aronson CE, Brunswick DJ, Frazer A (June 1988). "Quantitative autoradiography of serotonin uptake sites in rat brain using [3H]cyanoimipramine". Brain Research. 454 (1–2): 78–88.
doi:
10.1016/0006-8993(88)90805-0.
PMID2970277.
S2CID9586842.
^
abcdeTuross N, Patrick RL (June 1986). "Effects of propranolol on catecholamine synthesis and uptake in the central nervous system of the rat". The Journal of Pharmacology and Experimental Therapeutics. 237 (3): 739–745.
PMID2872325.
^Zobrist RH, Mecca TE (May 1990). "[3H]TA-3090, a selective benzothiazepine-type calcium channel receptor antagonist: in vitro characterization". The Journal of Pharmacology and Experimental Therapeutics. 253 (2): 461–465.
PMID2338642.
^Davids E, Lesch KP (November 1996). "[The 5-HT1A receptor: a new effective principle in psychopharmacologic therapy?]". Fortschritte der Neurologie-Psychiatrie (in German). 64 (11): 460–472.
doi:
10.1055/s-2007-996592.
PMID9064274.
S2CID147793142.
^Hoyer D, Clarke DE, Fozard JR, Hartig PR, Martin GR, Mylecharane EJ, et al. (June 1994). "International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin)". Pharmacological Reviews. 46 (2): 157–203.
PMID7938165.
^Rang HP (2011). Rang & Dale's pharmacology (7th ed.). Edinburgh: Churchill Livingstone. p. 106.
ISBN9780702034718.
^"Propranolol". pubchem.ncbi.nlm.nih.gov. Retrieved 31 January 2019.
^Black JW, Crowther AF, Shanks RG, Smith LH, Dornhorst AC (May 1964). "A New Adrenergic Beta-Receptor Antagonist". Lancet. 1 (7342): 1080–1081.
doi:
10.1016/S0140-6736(64)91275-9.
PMID14132613.
^
abFishbein 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.