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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

Propranolol is indicated for the management of various conditions including:

Hypertension
Angina pectoris
Tachyarrhythmias
Myocardial infarction
Control of tachycardia/tremor associated with anxiety, hyperthyroidism or lithium therapy.
Essential tremor
Migraine prophylaxis^[3]^[4]
Cluster headaches prophylaxis
Tension headache (Off label use)
Shaky hands
Hyperhidrosis

There has been some experimentation in psychiatric areas:^[5]
- Treating the excessive drinking of fluids in psychogenic polydipsia,^[6]^[7]
- Antipsychotic-induced akathisia,^[8]
- Aggressive behavior of patients with brain injuries^[9]
- Post-traumatic stress disorder
- Calming down individuals with phobias via sedative effects
- Performance anxiety
Glaucoma
Thyrotoxicosis via deiodinase inhibition
Primary exertional headache^[10]

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

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

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

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:^[30]

Reversible airways disease, particularly asthma or chronic obstructive pulmonary disease (COPD)
Bradycardia (<60 beats/minute)
Sick sinus syndrome
Atrioventricular block (second or third degree)
Shock
Severe hypotension
Cocaine toxicity [per American Heart Association guidelines, 2005]

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.^[31]

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

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.^[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

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

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-HT_1B).

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

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]

verapamil
epinephrine
β₂-adrenergic receptor agonists
- Salbutamol, Levosalbutamol, Formoterol, Salmeterol, etc.
clonidine
ergot alkaloids
isoprenaline
non-steroidal anti-inflammatory drugs
quinidine
cimetidine
lidocaine
phenobarbital
rifampicin
Fluvoxamine slows down the metabolism of propranolol significantly leading to increased blood levels of propranolol.^[40]

Chemistry

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.

History

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

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

^ ^a ^b 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. Cite uses deprecated parameters (help)
^ Eadie, M.; J. H. Tyrer (1985). The Biochemistry of Migraine. New York: Springer. p. 148. ISBN 9780852007310. OCLC 11726870. Cite uses deprecated parameters (help)^{[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., F. Ducrocq, K. Jezekiel, B. Averland, P. Lestavel, A. Brunet, and C.R. Marmar. 2003. Immediate treatment with propranolol de- creases post-traumatic stress disorder two months after trauma. Biological Psychiatry 54: 947–949.
^ 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. Cite uses deprecated parameters (help); |accessdate= requires |url= (help)
^ "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. edit
^ 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.
^ ^a ^b ^c 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.
^ ^a ^b 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.
^ ^a ^b [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: 659–670. doi:10.1124/mol.63.3.659.
^ 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.
^ A.F. Crowther, L.H. Smith, U.S. Patent 3,337,628 (1967)
^ A.F. Crowther, L.H. Smith, U.S. Patent 3,520,919 (1970)
^ A.F. Crowther, L.H. Smith, GB 994918 (1963)
^ A.F. Crowther, L.H. Smith, DE 1493897 (1963)
^ A.F. Crowther, L.H. Smith, BE 640312 (1964)
^ A.F. Crowther, L.H. Smith, BE 640313 (1964)
^ ^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.
^ 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). 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.

External links

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

UpToDate Contents

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★リンクテーブル★

リンク元	「プロプラノロール」
関連記事	「inderal」

「プロプラノロール」

Propranolol
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
ATC code	C07AA05
PubChem	CID 4946
IUPHAR ligand	564
DrugBank	DB00571
ChemSpider	4777
UNII	9Y8NXQ24VQ
KEGG	D08443
ChEBI	CHEBI:8499
ChEMBL	CHEMBL27
Chemical data
Formula	C16H21NO2
Mol. mass	259.34 g/mol
	SMILES CC(C)NCC(COc1cccc2c1cccc2)O;
	InChI InChI=1S/C16H21NO2/c1-12(2)17-10-14(18)11-19-16-9-5-7-13-6-3-4-8-15(13)16/h3-9,12,14,17-18H,10-11H2,1-2H3 ; Key:AQHHHDLHHXJYJD-UHFFFAOYSA-N ;
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　　[★]

英: propranolol
ラ: propranololum
化: 塩酸プロプラノロール propranolol hydrochloride
商: アイデイトロール、インデラル Inderal、サワタール、ソラシロール、ノルモテンス、ヘルツベース、メントリース
関: 血圧降下剤

非選択的β受容体遮断薬 (β₁受容体＝β₂受容体)
競合的
内因性交感神経刺激作用：無
膜安定化作用：有
脳血管関門：通過
レニン分泌抑制作用：有
降圧作用を示す
作用

抗狭心作用

抗不整脈作用

「inderal」

　　[★]

同: Inderal
関: Propranolol

[Black_JW.2C_Crowther_AF.2C_Shanks_RG.2C_Smith_LH.2C_Dornhorst_AC_1964_1080.E2.80.931081-1] 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.

[2] "WHO Model List of EssentialMedicines". World Health Organization. October 2013. Retrieved 22 April 2014.

[3] 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. Cite uses deprecated parameters (help)

[4] Eadie, M.; J. H. Tyrer (1985). The Biochemistry of Migraine. New York: Springer. p. 148. ISBN 9780852007310. OCLC 11726870. Cite uses deprecated parameters (help)^{[dead link]}

[pmid17200914-5] 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.

[pmid7737786-6] 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.

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