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Wikipedia

Propranolol

April 10, 2024

Not to be confused with Propanol or Propofol.

Propranolol, sold under the brand name Inderal among others, is a medication of the beta blocker class.[2] It is used to treat high blood pressure, a number of types of irregular heart rate, thyrotoxicosis, capillary hemangiomas, performance anxiety, and essential tremors,[2][3][4] as well to prevent migraine headaches, and to prevent further heart problems in those with angina or previous heart attacks.[2] It can be taken orally (by mouth) or by intravenous injection (injection into a vein).[2] The formulation that is taken orally (by mouth) comes in short-acting and long-acting versions.[2] Propranolol appears in the blood after 30 minutes and has a maximum effect between 60 and 90 minutes when taken orally.[2][5]

Propranolol
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) CYP1A2, CYP2D6; minor: CYP2C19, CYP3A4
MetabolitesN-desisopropylpropranolol, 4'-hydroxypropanolol
Elimination half-life4–5 hours
ExcretionKidney (<1%)
Identifiers
  • (RS)-1-(1-methylethylamino)-3-(1-naphthyloxy)propan-2-ol
CAS Number
  • 525-66-6 Y
PubChem CID
  • 4946
IUPHAR/BPS
  • 564
DrugBank
  • DB00571 Y
ChemSpider
  • 4777 Y
UNII
  • 9Y8NXQ24VQ
KEGG
  • D08443 Y
  • as HCl: D00483 Y
ChEBI
  • CHEBI:8499 Y
ChEMBL
  • ChEMBL27 Y
CompTox Dashboard (EPA)
  • DTXSID6023525
ECHA InfoCard100.007.618
Chemical and physical data
FormulaC16H21NO2
Molar mass259.349 g·mol−1
3D model (JSmol)
  • Interactive image
ChiralityRacemic mixture
Melting point96 °C (205 °F)
  • OC(COC1=C2C=CC=CC2=CC=C1)CNC(C)C
  • 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 Y
  • Key:AQHHHDLHHXJYJD-UHFFFAOYSA-N Y
  (verify)

Common side effects include nausea, abdominal pain, and constipation.[2] It may worsen the symptoms of asthma.[2] Propranolol may cause harmful effects for the baby if taken during pregnancy.[6] Its use during breastfeeding is probably safe.[7] It is a non-selective beta blocker which works by blocking β-adrenergic receptors.[2]

Propranolol was patented in 1962 and approved for medical use in 1964.[8] It is on the World Health Organization's List of Essential Medicines.[9] Propranolol is available as a generic medication.[2] In 2021, it was the 91st most commonly prescribed medication in the United States, with more than 7 million prescriptions.[10][11]

Medical uses edit

 
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 edit

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 edit

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]

PTSD and phobias edit

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]

Other uses edit

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]

Contraindications edit

See also: Beta blocker § Contraindications

Propranolol may be contraindicated in people with:[34]

Adverse effects edit

See also: Beta blocker § Adverse effects

Propranolol should be used with caution in people with:[34]

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. 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.[35]

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]

Overdose edit

In overdose propranolol is associated with seizures.[39] Cardiac arrest may occur in propranolol overdose due to sudden ventricular arrhythmias, or cardiogenic shock which may ultimately culminate in bradycardic PEA.[40]

Interactions edit

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]

Pharmacology edit

Pharmacodynamics edit

Propranolol[42]
Site Ki (nM) Species Ref
5-HT1A 55–272 Human [43][44]
5-HT1B 56–85 Rat [45][46]
5-HT1D 4,070 Pig [47]
5-HT2A 4,280 Human [48]
5-HT2B 457–513 (+)
166–316 (–)		 Human [49]
5-HT2C 61,700 (+)
5,010 (–)
736–2,457		 Human
Human
Rodent		 [49]
[49]
[50][44]
5-HT3 >10,000 Human [51]
α1 ND ND ND
α2 1,297–2,789 Rat [52]
β1 0.02–2.69 Human [53][54]
β2 0.01–0.61 Human [53][54]
β3 450 Mouse [55]
D1 >10,000 Human [44]
D2 >10,000 Human [44]
H1 >10,000 Human [56]
SERTTooltip Serotonin transporter 3,700 Rat [57]
NETTooltip Norepinephrine transporter 5,000 (IC50Tooltip Half-maximal inhibitory concentration) Rat [58]
DATTooltip Dopamine transporter 29,000 (IC50) Rat [58]
VDCCTooltip Voltage-dependent calcium channel >10,000 Rat [59]
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;[60] 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).[61] Propranolol is able to cross the blood–brain barrier and exert effects in the central nervous system in addition to its peripheral activity.[14]

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 edit

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 edit

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]

History edit

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

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.

Newer, more cardio-selective beta blockers (such as bisoprolol, nebivolol, carvedilol, or metoprolol) are now used preferentially in the treatment of hypertension.[72]

Society and culture edit

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 edit

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]

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Further reading edit

  • 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): 336–342. PMC 325477. PMID 9456487.

April 10, 2024
propranolol, confused, with, propanol, propofol, sold, under, brand, name, inderal, among, others, medication, beta, blocker, class, used, treat, high, blood, pressure, number, types, irregular, heart, rate, thyrotoxicosis, capillary, hemangiomas, performance,. Not to be confused with Propanol or Propofol Propranolol sold under the brand name Inderal among others is a medication of the beta blocker class 2 It is used to treat high blood pressure a number of types of irregular heart rate thyrotoxicosis capillary hemangiomas performance anxiety and essential tremors 2 3 4 as well to prevent migraine headaches and to prevent further heart problems in those with angina or previous heart attacks 2 It can be taken orally by mouth or by intravenous injection injection into a vein 2 The formulation that is taken orally by mouth comes in short acting and long acting versions 2 Propranolol appears in the blood after 30 minutes and has a maximum effect between 60 and 90 minutes when taken orally 2 5 PropranololClinical dataPronunciation p r oʊ ˈ p r ae n e ˌ l ɑː l Trade namesInderal othersAHFS Drugs comMonographLicense dataUS DailyMed PropranololPregnancycategoryAU CRoutes ofadministrationOral rectal intravenousATC codeC07AA05 WHO Legal statusLegal statusAU S4 Prescription only CA only UK POM Prescription only US WARNING 1 Rx only EU Rx onlyPharmacokinetic dataBioavailability26 Protein binding90 MetabolismLiver extensive CYP1A2 CYP2D6 minor CYP2C19 CYP3A4MetabolitesN desisopropylpropranolol 4 hydroxypropanololElimination half life4 5 hoursExcretionKidney lt 1 IdentifiersIUPAC name RS 1 1 methylethylamino 3 1 naphthyloxy propan 2 olCAS Number525 66 6 YPubChem CID4946IUPHAR BPS564DrugBankDB00571 YChemSpider4777 YUNII9Y8NXQ24VQKEGGD08443 Yas HCl D00483 YChEBICHEBI 8499 YChEMBLChEMBL27 YCompTox Dashboard EPA DTXSID6023525ECHA InfoCard100 007 618Chemical and physical dataFormulaC 16H 21N O 2Molar mass259 349 g mol 13D model JSmol Interactive imageChiralityRacemic mixtureMelting point96 C 205 F SMILES OC COC1 C2C CC CC2 CC C1 CNC C CInChI 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 YKey AQHHHDLHHXJYJD UHFFFAOYSA N Y verify Common side effects include nausea abdominal pain and constipation 2 It may worsen the symptoms of asthma 2 Propranolol may cause harmful effects for the baby if taken during pregnancy 6 Its use during breastfeeding is probably safe 7 It is a non selective beta blocker which works by blocking b adrenergic receptors 2 Propranolol was patented in 1962 and approved for medical use in 1964 8 It is on the World Health Organization s List of Essential Medicines 9 Propranolol is available as a generic medication 2 In 2021 it was the 91st most commonly prescribed medication in the United States with more than 7 million prescriptions 10 11 Contents 1 Medical uses 1 1 Cardiovascular 1 2 Psychiatric 1 2 1 PTSD and phobias 1 3 Other uses 2 Contraindications 3 Adverse effects 3 1 Pregnancy and lactation 4 Overdose 5 Interactions 6 Pharmacology 6 1 Pharmacodynamics 6 2 Mechanism of action 6 3 Pharmacokinetics 7 History 8 Society and culture 8 1 Brand names 9 References 10 Further readingMedical uses edit nbsp An 80 mg capsule of extended release propranolol nbsp A mixture of 20 mg and 10 mg propranolol tablets nbsp Propranolol blister packPropranolol is used for treating various conditions including Cardiovascular edit Hypertension Angina pectoris with the exception of variant angina Myocardial infarction Tachycardia and other sympathetic nervous system symptoms such as muscle tremor associated with various conditions including anxiety panic hyperthyroidism and lithium therapy Portal hypertension to lower portal vein pressure Prevention of esophageal variceal bleeding and ascites Anxiety Hypertrophic cardiomyopathyWhile 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 edit 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 Post traumatic stress disorder PTSD and specific phobias Aggressive behavior of patients with brain injuries 17 Treating the excessive drinking of fluids in psychogenic polydipsia 18 19 PTSD and phobias edit 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 Other uses edit Essential tremor Evidence for use for akathisia however is insufficient 28 Migraine and cluster headache prevention 29 30 and in primary exertional headache 2 31 Hyperhidrosis excessive sweating citation needed Infantile hemangioma Propranolol showed a higher rate of complete response than atenolol 32 Glaucoma citation needed Thyrotoxicosis by deiodinase inhibition citation needed 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 Contraindications editSee also Beta blocker Contraindications Propranolol may be contraindicated in people with 34 Reversible airway diseases particularly asthma or chronic obstructive pulmonary disease COPD Slow heart rate bradycardia lt 60 beats minute Sick sinus syndrome Atrioventricular block second or third degree Shock Severe low blood pressureAdverse effects editSee also Beta blocker Adverse effects Propranolol should be used with caution in people with 34 Diabetes mellitus or hyperthyroidism since signs and symptoms of hypoglycaemia may be masked Peripheral artery disease and Raynaud s syndrome which may be exacerbated Phaeochromocytoma as hypertension may be aggravated without prior alpha blocker therapy Myasthenia gravis which may be worsened Other drugs with bradycardic effectsPregnancy and lactation edit Propranolol like other beta blockers is classified as pregnancy category C in the United States and ADEC category C in Australia b 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 35 Most b 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 Overdose editIn overdose propranolol is associated with seizures 39 Cardiac arrest may occur in propranolol overdose due to sudden ventricular arrhythmias or cardiogenic shock which may ultimately culminate in bradycardic PEA 40 Interactions editSince 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 Verapamil Epinephrine adrenaline b2 adrenergic receptor agonists Salbutamol levosalbutamol formoterol salmeterol clenbuterol etc Clonidine Ergot alkaloids Isoprenaline isoproterenol Nonsteroidal anti inflammatory drugs NSAIDs Quinidine Cimetidine Lidocaine Phenobarbital Rifampicin Fluvoxamine slows down the metabolism of propranolol significantly leading to increased blood levels of propranolol 41 Pharmacology editPharmacodynamics edit Propranolol 42 Site Ki nM Species Ref5 HT1A 55 272 Human 43 44 5 HT1B 56 85 Rat 45 46 5 HT1D 4 070 Pig 47 5 HT2A 4 280 Human 48 5 HT2B 457 513 166 316 Human 49 5 HT2C 61 700 5 010 736 2 457 HumanHumanRodent 49 49 50 44 5 HT3 gt 10 000 Human 51 a1 ND ND NDa2 1 297 2 789 Rat 52 b1 0 02 2 69 Human 53 54 b2 0 01 0 61 Human 53 54 b3 450 Mouse 55 D1 gt 10 000 Human 44 D2 gt 10 000 Human 44 H1 gt 10 000 Human 56 SERTTooltip Serotonin transporter 3 700 Rat 57 NETTooltip Norepinephrine transporter 5 000 IC50Tooltip Half maximal inhibitory concentration Rat 58 DATTooltip Dopamine transporter 29 000 IC50 Rat 58 VDCCTooltip Voltage dependent calcium channel gt 10 000 Rat 59 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 b adrenergic receptor antagonist or beta blocker 60 that is it blocks the action of epinephrine adrenaline and norepinephrine noradrenaline at both b1 and b2 adrenergic receptors It has little intrinsic sympathomimetic activity but has strong membrane stabilizing activity only at high blood concentrations e g overdose 61 Propranolol is able to cross the blood brain barrier and exert effects in the central nervous system in addition to its peripheral activity 14 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 b adrenoceptors the increase in synaptic norepinephrine only results in a adrenoceptor activation with the a1 adrenoceptor being particularly important for effects observed in animal models 62 58 Therefore it can be looked upon as a weak indirect a1 adrenoceptor agonist in addition to potent b 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 edit Propranolol is a non selective beta receptor antagonist 60 This means that it does not have preference to b1 or b2 receptors It competes with sympathomimetic neurotransmitters for binding to receptors which inhibits sympathetic stimulation of the heart Blockage of neurotransmitter binding to b1 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 b2 receptors on smooth muscle cells will increase contraction which will increase hypertension Pharmacokinetics edit 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 History editMain article Discovery and development of b adrenergic receptor antagonists beta blockers 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 b 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 72 Society and culture editIn 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 edit 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 References edit FDA sourced list of all drugs 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325477 PMID 9456487 Portal nbsp Medicine Retrieved from https en wikipedia org w index php title Propranolol amp oldid 1215519481, wikipedia, wiki, book, books, library,

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