| Revision as of 14:19, 15 November 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Script assisted update of identifiers for the Chem/Drugbox validation project (updated: 'DrugBank').← Previous edit |
Latest revision as of 15:25, 21 October 2024 edit undo90.203.187.154 (talk) Changed labels on 2D and 3D structural diagrams from resperine to reserpine. |
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{{Short description|Drug used to treat high blood pressure}} |
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{{Citation style|date=August 2008|article|There are two forms of citations in this article. This hinders readability and flow.}} |
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{{cs1 config|name-list-style=vanc|display-authors=6}} |
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{{Distinguish|Reserpidine|Risperidone}} |
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{{Drugbox |
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{{Infobox drug |
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| Verifiedfields = changed |
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| Watchedfields = changed |
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| Watchedfields = changed |
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| verifiedrevid = 408741475 |
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| verifiedrevid = 460779417 |
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| IUPAC_name = ''methyl-11,17α-dimethoxy-18β-[(3,4,5-trimethoxybenzoyl)<br> |
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| IUPAC_name = methyl (3β,16β,17α,18β,20α)-11,17-dimethoxy-18-yohimban-16-carboxylate and |
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| image = Reserpine.png |
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| image = ] |
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| width = 250px |
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| width = 320 |
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| image2 = ] |
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| width2 = 320 |
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<!--Clinical data--> |
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<!--Clinical data--> |
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| tradename = |
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| tradename = Serpasil, others |
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| Drugs.com = {{drugs.com|CDI|reserpine}} |
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| Drugs.com = {{drugs.com|CDI|reserpine}} |
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| MedlinePlus = a601107 |
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| MedlinePlus = a601107 |
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| licence_US = Reserpine |
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| licence_US = Reserpine |
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| pregnancy_category = D (fetotoxic) |
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| pregnancy_category = C |
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| legal_status = Rx-only (some countries banned/discontinued) |
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| legal_status = Rx-only (banned/discontinued in some countries) |
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| routes_of_administration = oral |
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| routes_of_administration = Oral |
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<!--Pharmacokinetic data--> |
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<!--Pharmacokinetic data--> |
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| bioavailability = 50% |
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| bioavailability = 50% |
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| metabolism = gut/liver |
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| metabolism = gut/liver |
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| elimination_half-life = phase 1 = 4.5h,</br> phase 2 = 271h, </br> average = 33h |
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| elimination_half-life = phase 1 = 4.5h,<br /> phase 2 = 271h, <br /> average = 33h |
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| excretion = 62% feces / 8% urine |
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| excretion = 62% feces / 8% urine |
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<!--Identifiers--> |
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<!--Identifiers--> |
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| IUPHAR_ligand = 4823 |
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| CASNo_Ref = {{cascite|correct|CAS}} |
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| CAS_number_Ref = {{cascite|correct|??}} |
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| CAS_number_Ref = {{cascite|correct|??}} |
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| CAS_number = 50-55-5 |
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| CAS_number = 50-55-5 |
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| ATC_prefix = C02 |
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| ATC_prefix = C02 |
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| ATC_suffix = AA02 |
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| ATC_suffix = AA02 |
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| PubChem = 5770 |
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| PubChem = 5770 |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| DrugBank = DB00206 |
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| DrugBank = DB00206 |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID = 5566 |
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| ChemSpiderID = 5566 |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| UNII = 8B1QWR724A |
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| UNII = 8B1QWR724A |
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| KEGG_Ref = {{keggcite|correct|kegg}} |
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| KEGG_Ref = {{keggcite|correct|kegg}} |
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| KEGG = D00197 |
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| KEGG = D00197 |
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| ChEBI_Ref = {{ebicite|changed|EBI}} |
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| ChEBI_Ref = {{ebicite|correct|EBI}} |
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| ChEBI = 28487 |
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| ChEBI = 28487 |
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| ChEMBL_Ref = {{ebicite|correct|EBI}} |
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| ChEMBL_Ref = {{ebicite|correct|EBI}} |
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| ChEMBL = 772 |
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| ChEMBL = 772 |
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<!--Chemical data--> |
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<!--Chemical data--> |
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| C=33 | H=40 | N=2 | O=9 |
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| C = 33 | H=40 | N=2 | O=9 |
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| smiles = 26C(OC(=O)c1cc(OC)c(OC)c(OC)c1)(OC)(C(=O)OC)2()C5()c4c3cc(OC)ccc3c4CCN5C6 |
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| molecular_weight = 608.68 g/mol |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| smiles = O=C(OC)64C3c2nc1cc(OC)ccc1c2CCN3C4C(OC(=O)c5cc(OC)c(OC)c(OC)c5)6OC |
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| InChI = 1/C33H40N2O9/c1-38-19-7-8-20-21-9-10-35-16-18-13-27(44-32(36)17-11-25(39-2)30(41-4)26(12-17)40-3)31(42-5)28(33(37)43-6)22(18)15-24(35)29(21)34-23(20)14-19/h7-8,11-12,14,18,22,24,27-28,31,34H,9-10,13,15-16H2,1-6H3/t18-,22+,24-,27-,28+,31+/m1/s1 |
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| StdInChI = 1S/C33H40N2O9/c1-38-19-7-8-20-21-9-10-35-16-18-13-27(44-32(36)17-11-25(39-2)30(41-4)26(12-17)40-3)31(42-5)28(33(37)43-6)22(18)15-24(35)29(21)34-23(20)14-19/h7-8,11-12,14,18,22,24,27-28,31,34H,9-10,13,15-16H2,1-6H3/t18-,22+,24-,27-,28+,31+/m1/s1 |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| InChIKey = QEVHRUUCFGRFIF-MDEJGZGSBW |
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| StdInChIKey = QEVHRUUCFGRFIF-MDEJGZGSSA-N |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI = 1S/C33H40N2O9/c1-38-19-7-8-20-21-9-10-35-16-18-13-27(44-32(36)17-11-25(39-2)30(41-4)26(12-17)40-3)31(42-5)28(33(37)43-6)22(18)15-24(35)29(21)34-23(20)14-19/h7-8,11-12,14,18,22,24,27-28,31,34H,9-10,13,15-16H2,1-6H3/t18-,22+,24-,27-,28+,31+/m1/s1 |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey = QEVHRUUCFGRFIF-MDEJGZGSSA-N |
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}} |
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}} |
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'''Reserpine''' is a drug that is used for the treatment of ], usually in combination with a ] diuretic or vasodilator.<ref>{{cite journal | vauthors = Tsioufis C, Thomopoulos C | title = Combination drug treatment in hypertension | journal = Pharmacological Research | volume = 125 | issue = Pt B | pages = 266–271 | date = November 2017 | pmid = 28939201 | doi = 10.1016/j.phrs.2017.09.011 | s2cid = 32904492 }}</ref> Large clinical trials have shown that combined treatment with reserpine plus a thiazide diuretic reduces mortality of people with hypertension. Although the use of reserpine as a solo drug has declined since it was first approved by the FDA in 1955,<ref>{{Cite web|url=http://drugcentral.org/drugcard/2370|title=Reserpine}}</ref> the combined use of reserpine and a thiazide diuretic or vasodilator is still recommended in patients who do not achieve adequate lowering of blood pressure with first-line drug treatment alone.<ref>{{cite journal | vauthors = James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, Lackland DT, LeFevre ML, MacKenzie TD, Ogedegbe O, Smith SC, Svetkey LP, Taler SJ, Townsend RR, Wright JT, Narva AS, Ortiz E | title = 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8) | journal = JAMA | volume = 311 | issue = 5 | pages = 507–20 | date = February 2014 | pmid = 24352797 | doi = 10.1001/jama.2013.284427 | doi-access = }}</ref><ref>{{cite journal | vauthors = Weir MR | title = Reserpine: A New Consideration of and Old Drug for Refractory Hypertension | journal = American Journal of Hypertension | volume = 33 | issue = 8 | pages = 708–710 | date = August 2020 | pmid = 32303749 | pmc = 7402223 | doi = 10.1093/ajh/hpaa069 }}</ref><ref>{{cite journal | vauthors = Barzilay J, Grimm R, Cushman W, Bertoni AG, Basile J | title = Getting to goal blood pressure: why reserpine deserves a second look | journal = Journal of Clinical Hypertension | volume = 9 | issue = 8 | pages = 591–4 | date = August 2007 | pmid = 17673879 | doi = 10.1111/j.1524-6175.2007.07229.x | pmc = 8110058 | doi-access = free }}</ref> The reserpine-] combo pill was the 17th most commonly prescribed of the 43 combination antihypertensive pills available in 2012.<ref>{{cite journal | vauthors = Wang B, Choudhry NK, Gagne JJ, Landon J, Kesselheim AS | title = Availability and utilization of cardiovascular fixed-dose combination drugs in the United States | journal = American Heart Journal | volume = 169 | issue = 3 | pages = 379–386.e1 | date = March 2015 | pmid = 25728728 | doi = 10.1016/j.ahj.2014.12.014 }}</ref> |
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'''Reserpine''' is an ] ]{{ref|indole-alkaloid}} ] and ] drug that has been used for the control of ] and for the relief of ] symptoms, although because of the development of better drugs for these purposes and because of its numerous side-effects, it is rarely used today.<ref name="Columbia"> The Columbia Encyclopedia, Sixth Edition. Copyright © 2001-05 Columbia University Press.</ref> The antihypertensive actions of reserpine are a result of its ability to deplete ]s (among other ]) from peripheral sympathetic nerve endings. These substances are normally involved in controlling heart rate, force of cardiac contraction and peripheral resistance.{{ref|veterinary1}} |
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The antihypertensive actions of reserpine are largely due to its antinoradrenergic effects, which are a result of its ability to deplete ]s (among other ]) from ] ] nerve endings. These substances are normally involved in controlling heart rate, force of cardiac contraction and peripheral vascular resistance.<ref name="veterinary1">Forney, Barbara. Wedgewood Pharmacy. 2001-2002.</ref> |
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Reserpine mediated depletion of monoamine ]s in the ]s is often cited as evidence to the theory that depletion of the neurotransmitters causes subsequent ] in humans (c.f. ]). However, this claim is not without controversy; Some have called reserpine-induced depression a myth, while others claim that teas made out of the plant roots containing reserpine have a calming, sedative action that can actually be considered '''anti'''depressant.<ref>{{Cite pmid|12953623}}</ref> Though this remains to be demonstrated in the clinic, it is worth noting that reserpine was the first compound shown to be an effective antidepressant in a randomized placebo-controlled trial.<ref>D. L. Davies and M. Shepherd, “Reserpine in the Treatment of Anxious and Depressed Patients,” The Lancet 269 (1955): 117–20</ref> |
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At doses of 0.05 to 0.2 mg per day, reserpine is well tolerated;<ref>{{cite journal | vauthors = Morley JE | title = Treatment of hypertension in older persons: what is the evidence? | journal = Drugs & Aging | volume = 31 | issue = 5 | pages = 331–7 | date = May 2014 | pmid = 24668034 | doi = 10.1007/s40266-014-0171-7 | s2cid = 207489850 }}</ref> the most common adverse effect being nasal stuffiness. |
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Moreover, reserpine has a peripheral action in many parts of the body, resulting in a preponderance of the cholinergic part of the nervous system (GI tract, smooth muscles vessels). |
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Reserpine has also been used for relief of ] symptoms.<ref>{{cite journal | vauthors = Hoenders HJ, Bartels-Velthuis AA, Vollbehr NK, Bruggeman R, Knegtering H, de Jong JT | title = Natural Medicines for Psychotic Disorders: A Systematic Review | journal = The Journal of Nervous and Mental Disease | volume = 206 | issue = 2 | pages = 81–101 | date = February 2018 | pmid = 29373456 | pmc = 5794244 | doi = 10.1097/NMD.0000000000000782 }}</ref> A review found that in persons with schizophrenia, reserpine and chlorpromazine had similar rates of adverse effects, but that reserpine was less effective than ] for improving a person's global state.<ref>{{cite journal | vauthors = Nur S, Adams CE | title = Chlorpromazine versus reserpine for schizophrenia | journal = The Cochrane Database of Systematic Reviews | volume = 2016 | pages = CD012122 | date = April 2016 | issue = 4 | pmid = 27124109 | doi = 10.1002/14651858.CD012122.pub2 | pmc = 10350329 }}</ref> |
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==Mechanism of Action== |
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Reserpine is an irreversible antagonist of VMAT. It acts by blocking the vesicular monoamine transporter ].<ref>{{Cite pmid|2667522}}</ref> This normally transports free ], ], and ] from the cytoplasm of the presynaptic nerve terminal into storage vesicles for subsequent release into the ] ("]"); unprotected neurotransmitters are metabolized by ] (as well as by ]) in the cytoplasm and therefore never reach the synapse. |
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==Medical uses== |
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It could take days to weeks by the body to replenish the depleted VMAT and hence reserpine's effects are long-lasting. |
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Reserpine is recommended as an alternative drug for treating hypertension by the JNC 8.<ref>{{cite journal | vauthors = James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, Lackland DT, LeFevre ML, MacKenzie TD, Ogedegbe O, Smith SC, Svetkey LP, Taler SJ, Townsend RR, Wright JT, Narva AS, Ortiz E | title = 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8) | journal = JAMA | volume = 311 | issue = 5 | pages = 507–20 | date = February 2014 | pmid = 24352797 | doi = 10.1001/jama.2013.284427 | doi-access = }}</ref> A 2016 Cochrane review found reserpine to be as effective as other first-line antihypertensive drugs for lowering of blood pressure.<ref>{{cite journal | vauthors = Shamon SD, Perez MI | title = Blood pressure-lowering efficacy of reserpine for primary hypertension | journal = The Cochrane Database of Systematic Reviews | volume = 2016 | issue = 12 | pages = CD007655 | date = December 2016 | pmid = 27997978 | pmc = 6464022 | doi = 10.1002/14651858.CD007655.pub3 }}</ref> The reserpine–thiazide diuretic combination is one of the few drug treatments shown to reduce mortality in ]: The Hypertension Detection and Follow-up Program,<ref name="pmid490882">{{cite journal | vauthors = <!-- No authors listed --> | title = Five-year findings of the hypertension detection and follow-up program. I. Reduction in mortality of persons with high blood pressure, including mild hypertension. Hypertension Detection and Follow-up Program Cooperative Group | journal = JAMA | volume = 242 | issue = 23 | pages = 2562–71 | date = December 1979 | pmid = 490882 | doi = 10.1001/jama.242.23.2562 }} </ref> the Veterans Administration Cooperative Study Group in Anti-hypertensive Agents,<ref name="pmid4862069">{{cite journal | vauthors = <!-- No authors listed --> | title = Effects of treatment on morbidity in hypertension. Results in patients with diastolic blood pressures averaging 115 through 129 mm Hg | journal = JAMA | volume = 202 | issue = 11 | pages = 1028–34 | date = December 1967 | pmid = 4862069 | doi = 10.1001/jama.202.11.1028 }}</ref> and the Systolic Hypertension in the Elderly Program.<ref name="pmid2046107">{{cite journal | vauthors = | title = Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). SHEP Cooperative Research Group | journal = JAMA | volume = 265 | issue = 24 | pages = 3255–64 | date = June 1991 | pmid = 2046107 | doi = 10.1001/jama.265.24.3255 }}</ref> Moreover, reserpine was included as a secondary antihypertensive option for patients who did not achieve blood pressure lowering targets in the ALLHAT study.<ref name="allhat">{{cite journal | author = ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial | title = Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) | journal = JAMA | volume = 288 | issue = 23 | pages = 2981–97 | date = December 2002 | pmid = 12479763 | doi = 10.1001/jama.288.23.2981 | url = http://jama.ama-assn.org/cgi/content/full/288/23/2981 | url-status = live | doi-access = free | archive-url = https://web.archive.org/web/20091126004644/http://jama.ama-assn.org/cgi/content/full/288/23/2981 | archive-date = November 26, 2009 }}</ref> |
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It was previously used to treat symptoms of ] in patients with ],<ref name="pharmnemonics">{{Cite book|author=Shen, Howard|title=Illustrated Pharmacology Memory Cards: PharMnemonics|publisher=Minireview|year=2008|isbn=978-1-59541-101-3|page=11}}</ref> but alternative medications are preferred today.<ref>{{cite journal | vauthors = Thanvi B, Lo N, Robinson T | title = Levodopa-induced dyskinesia in Parkinson's disease: clinical features, pathogenesis, prevention and treatment | journal = Postgraduate Medical Journal | volume = 83 | issue = 980 | pages = 384–8 | date = June 2007 | pmid = 17551069 | pmc = 2600052 | doi = 10.1136/pgmj.2006.054759 }}</ref> |
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==Biosynthetic pathway== |
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Tryptophan is the starting material in the biosynthetic pathway of reserpine, and is converted to tryptamine by tryptophan decarboxylase enzyme. Tryptamine is combined with secologanin in the presence of strictosidine synthetase enzyme and yields strictosidine. Various enzymatic conversion reactions lead to the synthesis of reserpine from strictosidine.<ref>Ramawat et al, 1999.{{citation needed|date=November 2011}}</ref> |
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The daily dose of reserpine in antihypertensive treatment is as low as 0.05 to 0.25 mg. The use of reserpine as an antipsychotic drug had been nearly completely abandoned, but more recently it made a comeback as adjunctive treatment, in combination with other antipsychotics, so that more refractory patients get dopamine blockade from the other antipsychotic, and dopamine depletion from reserpine. Doses for this kind of adjunctive goal can be kept low, resulting in better tolerability. Originally, doses of 0.5 mg to 40 mg daily were used to treat psychotic diseases. |
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==History== |
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Reserpine was isolated in 1952 from the dried root of '']'' (Indian snakeroot),{{ref|mercksource}} (which had been known as ''Sarpaganda'' and had been used for centuries in India for the treatment of insanity, as well as fever and snakebites<ref name="Columbia"/> — even ] used it as a ].<ref>, '']'', November 8, 1954</ref> It was first used in the United States by ] in 1950. Its molecular structure was elucidated in 1953 and natural ] published in 1955.<ref name="Nicolaou">{{cite book |title= Classics in Total Synthesis|last= Nicolaou|first= K. C.|authorlink=K. C. Nicolaou |coauthors= E. J. Sorensen|year= 1996|publisher= VCH|location= Weinheim, Germany|isbn= 3-527-29284-5|page= 55|pages= |url= |accessdate= }}</ref> It was introduced in 1954, two years after ].{{ref|history1}} The first ] was accomplished by ] in 1958.<ref name="Nicolaou"/> |
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Doses in excess of 3 mg daily often required use of an anticholinergic drug to combat excessive cholinergic activity in many parts of the body as well as parkinsonism. For adjunctive treatment, doses are typically kept at or below 0.25 mg twice a day. |
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Reserpine almost irreversibly blocks the uptake (and storage) of ] (i.e. ]) and ] into synaptic vesicles by inhibiting the Vesicular Monoamine Transporters (]).{{ref|VMAT}} |
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==Adverse effects== |
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Reserpine has been discontinued in the UK for some years due to its numerous interactions and side effects. |
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At doses of less than 0.2 mg/day, reserpine has few adverse effects, the most common of which is nasal congestion.<ref name="pmid3350594">{{cite journal | vauthors = Curb JD, Schneider K, Taylor JO, Maxwell M, Shulman N | title = Antihypertensive drug side effects in the Hypertension Detection and Follow-up Program | journal = Hypertension | volume = 11 | issue = 3 Pt 2 | pages = II51-5 | date = March 1988 | pmid = 3350594 | doi = 10.1161/01.hyp.11.3_pt_2.ii51 | doi-access = free }}</ref> |
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Reserpine can cause: nasal congestion, nausea, vomiting, weight gain, gastric intolerance, gastric ulceration (due to increased cholinergic activity in gastric tissue and impaired mucosal quality), stomach cramps and diarrhea. The drug causes hypotension and bradycardia and may worsen asthma. Congested nose and erectile dysfunction are other consequences of alpha-blockade.<ref name="Giannini">AJ Giannini, HR Black. Psychiatric, Psychogenic, and Somatopsychic Disorders Handbook. Garden City, NY. Medical Examination Publishing, 1978. Pg. 233. {{ISBN|0-87488-596-5}}.</ref> |
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Reserpine was also highly influential in promoting the thought of a ] hypothesis of depression - see Everett & Tolman, 1959. |
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Central nervous system effects at higher doses (0.5 mg or higher) include drowsiness, dizziness, nightmares, Parkinsonism, general weakness and fatigue. |
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==Uses today== |
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<ref name="Barcelos 2010">{{cite journal | vauthors = Barcelos RC, Benvegnú DM, Boufleur N, Pase C, Teixeira AM, Reckziegel P, Emanuelli T, da Rocha JB, Bürger ME | title = Short term dietary fish oil supplementation improves motor deficiencies related to reserpine-induced parkinsonism in rats | journal = Lipids | volume = 46 | issue = 2 | pages = 143–9 | date = February 2011 | pmid = 21161603 | doi = 10.1007/s11745-010-3514-0 | s2cid = 4036935 }}</ref> |
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High dose studies in rodents found reserpine to cause fibroadenoma of the breast and malignant tumors of the seminal vesicles among others. Early suggestions that reserpine causes breast cancer in women (risk approximately doubled) were not confirmed. It may also cause ].<ref name="Giannini" /> |
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] |
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Reserpine is one of the few antihypertensive medications that have been shown in ] to reduce mortality: The Hypertension Detection and Follow-up Program,<ref name="pmid490882">{{cite journal |author= ,|title=Five-year findings of the hypertension detection and follow-up program. I. Reduction in mortality of persons with high blood pressure, including mild hypertension. Hypertension Detection and Follow-up Program Cooperative Group |journal=JAMA |volume=242 |issue=23 |pages=2562–71 |year=1979 |pmid=490882 |doi=10.1001/jama.242.23.2562}} </ref> the Veterans Administration Cooperative Study Group in Anti-hypertensive Agents,<ref name="pmid4862069">{{cite journal |author= ,|title=Effects of treatment on morbidity in hypertension. Results in patients with diastolic blood pressures averaging 115 through 129 mm Hg |journal=JAMA |volume=202 |issue=11 |pages=1028–34 |year=1967 |pmid=4862069 |doi=10.1001/jama.202.11.1028}}</ref> and the Systolic Hypertension in the Elderly Program.<ref name="pmid2046107">{{cite journal |author= ,|title=Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). SHEP Cooperative Research Group |journal=JAMA |volume=265 |issue=24 |pages=3255–64 |year=1991 |pmid=2046107 |doi=10.1001/jama.265.24.3255}}</ref> |
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Reserpine passes into ] and is harmful to breast-fed infants, and should therefore be avoided during breastfeeding if possible.<ref name="kidsgrowth"> {{webarchive|url=https://archive.today/20070623011707/http://www.kidsgrowth.org/resources/articledetail.cfm?id=471|date=2007-06-23}} Retrieved on June 19, 2009</ref> |
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Reserpine is rarely used in the management of hypertension today. Reserpine is listed as an option by the ].<ref name="pmid12748199">{{cite journal |author=Chobanian AV, Bakris GL, Black HR, ''et al.'' |title=The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report |journal=JAMA |volume=289 |issue=19 |pages=2560–72 |year=2003 |pmid=12748199 |doi=10.1001/jama.289.19.2560}} </ref> Reserpine is a second-line adjunct agent for patients who are uncontrolled on a diuretic when cost is an issue.<ref name="pmid3592424">{{cite journal |author=Moser M |title="Cost containment" in the management of hypertension |journal=Ann. Intern. Med. |volume=107 |issue=1 |pages=107–9 |year=1987 |pmid=3592424 |doi=}}</ref> |
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It may produce an excessive decline in blood pressure at doses needed for treatment of anxiety, depression, or psychosis.<ref>{{cite book| vauthors = Pinel JP |title=Biopsychology|date=2011|publisher=Allyn & Bacon|isbn=978-0-205-83256-9|edition=8th|location=Boston|pages=469}}</ref> |
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It is also used to treat symptoms of ] in patients suffering from ].<ref name=pharmnemonics>{{Cite book | author=Shen, Howard | title=Illustrated Pharmacology Memory Cards: PharMnemonics | year=2008 | publisher=Minireview | isbn=1-59541-101-1 | page=11}}</ref> |
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==Mechanism of action== |
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In some countries reserpine is still available as part of combination drugs for the treatment of hypertension, in most cases they contain also a diuretic and/or a vasodilator like ]. These combinations are currently regarded as second choice drugs. The daily dose of reserpine in antihypertensive treatment is as low as 0.1 to 0.25 mg. The use of reserpine as an antipsychotic drug had been nearly completely abandoned, but more recently it made a comeback as adjunctive treatment, in combination with other antipsychotics, so that more refractory patients get dopamine blockade from the other antipsychotic, and dopamine depletion from reserpine. Doses for this kind of adjunctive goal can be kept low, resulting in better tolerability. Originally, doses of 0.5 mg to 40 mg daily were used to treat psychotic diseases. Doses in excess of 3 mg daily often required use of an anticholinergic drug to combat excessive cholinergic activity in many parts of the body as well as parkinsonism. For adjunctive treatment, doses are typically kept at or below 0.25 mg twice a day. Reserpine may be used as a sedative for horses. |
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{{See also|Monoamine-depleting agent}} |
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Reserpine irreversibly blocks the H<sup>+</sup>-coupled ]s, ] and ]. ] is mostly expressed in neuroendocrine cells. VMAT2 is mostly expressed in neurons. Thus, it is the blockade of neuronal VMAT2 by reserpine that inhibits uptake and reduces stores of the ]s ], ], ] and ] in the synaptic vesicles of neurons.<ref>{{cite journal | vauthors = Yaffe D, Forrest LR, Schuldiner S | title = The ins and outs of vesicular monoamine transporters | journal = The Journal of General Physiology | volume = 150 | issue = 5 | pages = 671–682 | date = May 2018 | pmid = 29666153 | pmc = 5940252 | doi = 10.1085/jgp.201711980 }}</ref> VMAT2 normally transports free intracellular norepinephrine, serotonin, and dopamine in the presynaptic nerve terminal into presynaptic vesicles for subsequent release into the ] ("]"). Unprotected neurotransmitters are metabolized by ] (as well as by ]), attached to the outer membrane of the mitochondria in the cytosol of the axon terminals, and consequently never excite the post-synaptic cell. Thus, reserpine increases removal of monoamine neurotransmitters from neurons, decreasing the size of the neurotransmitter pools, and thereby decreasing the amplitude of neurotransmitter release.<ref>{{cite journal | vauthors = Eiden LE, Weihe E | title = VMAT2: a dynamic regulator of brain monoaminergic neuronal function interacting with drugs of abuse | journal = Annals of the New York Academy of Sciences | volume = 1216 | issue = 1 | pages = 86–98 | date = January 2011 | pmid = 21272013 | pmc = 4183197 | doi = 10.1111/j.1749-6632.2010.05906.x | bibcode = 2011NYASA1216...86E }}</ref> As it may take the body days to weeks to replenish the depleted VMATs, reserpine's effects are long-lasting.<ref>{{cite journal | vauthors = German CL, Baladi MG, McFadden LM, Hanson GR, Fleckenstein AE | title = Regulation of the Dopamine and Vesicular Monoamine Transporters: Pharmacological Targets and Implications for Disease | journal = Pharmacological Reviews | volume = 67 | issue = 4 | pages = 1005–24 | date = October 2015 | pmid = 26408528 | pmc = 4630566 | doi = 10.1124/pr.114.010397 | doi-access = free }}</ref> |
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==Side effects== |
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At doses of less than 0.2 mg/day, reserpine has few side effects, the most common of which is nasal congestion.<ref name="pmid3350594">{{cite journal |author=Curb JD, Schneider K, Taylor JO, Maxwell M, Shulman N |title=Antihypertensive drug side effects in the Hypertension Detection and Follow-up Program |journal=Hypertension |volume=11 |issue=3 Pt 2 |pages=II51–5 |year=1988 |pmid=3350594 |doi=}}</ref> |
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==Biosynthetic pathway== |
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There has been much concern about reserpine causing depression leading to suicide. However, this was reported in uncontrolled studies using doses averaging 0.5 mg per day.<ref name="pmid13629798">{{cite journal |author=QUETSCH RM, ACHOR RW, LITIN EM, FAUCETT RL |title=Depressive reactions in hypertensive patients; a comparison of those treated with Rauwolfia and those receiving no specific antihypertensive treatment |journal=Circulation |volume=19 |issue=3 |pages=366–75 |year=1959 |pmid=13629798 |doi=}}</ref><ref name="pmid13304797">{{cite journal |author=Lemieux G, Davignon A, Genest J |title=Depressive states during Rauwolfia therapy for arterial hypertension; a report of 30 cases |journal=Canadian Medical Association Journal |volume=74 |issue=7 |pages=522–6 |year=1956 |pmid=13304797 |doi= |pmc=1823144}}</ref> |
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Reserpine is one of dozens of ] ]s isolated from the plant '']''.<ref name="indole-alkaloid"> {{Webarchive|url=https://web.archive.org/web/20110902070453/http://waynesword.palomar.edu/chemid2.htm#indole |date=2011-09-02 }} ''Major Types Of Chemical Compounds In Plants & Animals Part II: Phenolic Compounds, Glycosides & Alkaloids.'' Wayne's Word: An On-Line Textbook of Natural History. 2005.</ref> In the ''Rauvolfia'' plant, tryptophan is the starting material in the biosynthetic pathway of reserpine, and is converted to tryptamine by tryptophan decarboxylase enzyme. Tryptamine is combined with secologanin in the presence of strictosidine synthetase enzyme and yields strictosidine. Various enzymatic conversion reactions lead to the synthesis of reserpine from strictosidine.<ref>Ramawat et al, 1999.{{cite book| vauthors = Ramawat KG, Sharma R, Suri SS |title=Medicinal Plants in Biotechnology- Secondary metabolites 2nd edition 2007 | veditors = Ramawat KG, Merillon JM |publisher=Oxford and IBH, India|pages=66–367|isbn=978-1-57808-428-9|date=2007-01-01 }}</ref> |
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==History== |
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Reserpine can cause: nasal congestion, nausea, vomiting, weight gain, gastric intolerance, gastric ulceration (due to increased cholinergic activity in gastric tissue and impaired mucosal quality), stomach cramps and diarrhea are noted. The drug causes hypotension and bradycardia and may worsen asthma. Congested nose and erectile dysfunction are other consequences of alpha-blockade.<ref name="Giannini">AJ Giannini,HR Black. Psychiatric, Psychogenic, and Somatopsychic Disorders Handbook. Garden City,NY. Medical Examination Publishing, 1978. Pg. 233. ISBN 0-87488596-5.</ref> Depression can occur at any dose and may be severe enough to lead to suicide. Other central effects are a high incidence of drowsiness, dizziness, and nightmares. Parkinsonism occurs in a dose dependent manner. General weakness or fatigue is quite often encountered. High dose studies in rodents found reserpine to cause fibroadenoma of the breast and malignant tumors of the seminal vesicles among others. Early suggestions that reserpine causes breast cancer in women (risk approximately doubled) were not confirmed. It may also cause ].<ref name="Giannini"/> |
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Reserpine was isolated in 1952 from the dried root of '']'' (Indian snakeroot),<ref name="mercksource"> Dorlands Medical Dictionary. Merck Source. 2002.</ref> which had been known as ''Sarpagandha'' and had been used for centuries in India for the treatment of insanity, as well as fever and snakebites<ref name="Columbia">{{cite encyclopedia | title = Reserpine | url = http://www.bartleby.com/65/re/reserpin.html | archive-url = https://web.archive.org/web/20090212221725/http://www.bartleby.com/65/re/reserpin.html | archive-date=2009-02-12 | encyclopedia = The Columbia Encyclopedia | edition = Sixth | date = 2005 | publisher = Columbia University Press }}</ref> — ] used it as a ].<ref>, '']'', November 8, 1954</ref> It was first used in the United States by ] in 1950. Its molecular structure was elucidated in 1953 and natural ] published in 1955.<ref name="Nicolaou">{{cite book |title= Classics in Total Synthesis| vauthors = Nicolaou KC, Sorensen EJ | author-link1 = K. C. Nicolaou |year= 1996|publisher= VCH|location= Weinheim, Germany|isbn= 978-3-527-29284-4|page= |url=https://archive.org/details/classicstotalmet00kcni_087|url-access= limited}}</ref> It was introduced in 1954, two years after ].<ref name="history1">{{cite journal | vauthors = López-Muñoz F, Bhatara VS, Alamo C, Cuenca E | title = | journal = Actas Españolas de Psiquiatría | volume = 32 | issue = 6 | pages = 387–95 | year = 2004 | pmid = 15529229 | url = http://www.arsxxi.com/Revistas/mostrararticulo.php?idarticulo=411106110 }}</ref> The first ] was accomplished by ] in 1958.<ref name="Nicolaou"/> |
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Reserpine was influential in promoting the thought of a ] hypothesis of depression.<ref>{{cite journal | vauthors = Everett GM, Toman JE | date =1959 | title = Mode of action of Rauwolfia alkaloids and motor activity | journal = Biol Psychiat | volume = 2 | pages = 75–81 }}</ref><ref>{{cite book | vauthors = Govindarajulu M | veditors = Agrawal D | title = Medicinal herbs and fungi : neurotoxicity vs. neuroprotection | publisher = Springer | location = Singapore | year = 2021 |chapter=Reserpine-Induced Depression and Other Neurotoxicity: A Monoaminergic Hypothesis. | isbn = 978-981-334-140-1 }}</ref> Reserpine-induced depletion of monoamine ]s in the ] allegedly caused depression and was cited as evidence that a "chemical imbalance", namely low levels of monoamine neurotransmitters, is what causes ] in humans. A 2003 review showed barely any evidence that reserpine actually causes depression in either human patients or animal models.<ref>{{cite journal | vauthors = Baumeister AA, Hawkins MF, Uzelac SM | title = The myth of reserpine-induced depression: role in the historical development of the monoamine hypothesis | journal = Journal of the History of the Neurosciences | volume = 12 | issue = 2 | pages = 207–20 | date = June 2003 | pmid = 12953623 | doi = 10.1076/jhin.12.2.207.15535 | s2cid = 42407412 }}</ref> Notably, reserpine was the first compound ever to be shown to be an effective antidepressant in a randomized placebo-controlled trial.<ref>{{cite journal | vauthors = Davies DL, Shepherd M | title = Reserpine in the treatment of anxious and depressed patients | journal = Lancet | volume = 269 | issue = 6881 | pages = 117–20 | date = July 1955 | pmid = 14392947 | doi = 10.1016/s0140-6736(55)92118-8 }}</ref><ref>{{cite book | author=Healy, David|title=The Antidepressant Era|publisher=Harvard University Press|year=1997|isbn=978-0-674-03958-2}}</ref> A 2022 ] found that studies of the influence of reserpine on mood were highly inconsistent, with similar proportions of studies reporting depressogenic effects, no influence on mood, and antidepressant effects.<ref name="pmid36000248">{{cite journal | vauthors = Strawbridge R, Javed RR, Cave J, Jauhar S, Young AH | title = The effects of reserpine on depression: A systematic review | journal = J Psychopharmacol | volume = 37| issue = 3| pages = 248–260 | date = August 2022 | pmid = 36000248 | doi = 10.1177/02698811221115762 | s2cid = 251765916 | url = | pmc = 10076328 }}</ref> The ] was limited, and only a subset of studies were ]s.<ref name="pmid36000248" /> Although reserpine itself cannot provide good evidence for the ] of depression, other lines of evidence support the idea that boosting serotonin or norepinephrine can effectively treat depression, as shown by ]s, ]s, and ]. |
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Reserpine passes into ] and is harmful to breast-fed infants, and should therefore be avoided during breastfeeding if possible.<ref name=kidsgrowth> Retrieved on June 19, 2009</ref> |
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==References== |
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==Veterinary use== |
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Reserpine is used as a long-acting tranquilizer to subdue excitable or difficult horses and has been used illicitly for the sedation of show horses, for-sale horses, and in other circumstances where a "quieter" horse might be desired.<ref>Forney B. Reserpine for veterinary use. Available at http://www.wedgewoodpetrx.com/learning-center/professional-monographs/reserpine-for-veterinary-use.html.</ref> |
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{{reflist}} |
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It is also used in ]s. |
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==Footnotes== |
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# {{note|iupac}} . 2004. |
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# {{note|indole-alkaloid}} ''Major Types Of Chemical Compounds In Plants & Animals Part II: Phenolic Compounds, Glycosides & Alkaloids.'' Wayne's Word: An On-Line Textbook of Natural History. 2005. |
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# {{note|veterinary1}} Forney, Barbara. Wedgewood Pharmacy. 2001-2002. |
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# {{note|mercksource}} Dorlands Medical Dictionary. Merck Source. 2002. |
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# {{note|history1}} Lopez-Munoz F, Bhatara VS, Alamo C, Cuenca E. (2004): "" ''Actas Esp Psiquiatr.'' 32(6):387-95. PMID 15529229 |
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# {{note|VMAT}}Schuldiner, S. et al. (1993): ''J. Biol. Chem.'' 268(1) 29-34. PMID 8416935 |
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==External links== |
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==Research== |
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===Animal model of depression and amotivation=== |
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Similarly to ], reserpine, via ], produces ]-like effects and lack of ] or ]-like symptoms in animals.<ref name="StutzGolaniWitkin2019">{{cite journal | vauthors = Stutz PV, Golani LK, Witkin JM | title = Animal models of fatigue in major depressive disorder | journal = Physiol Behav | volume = 199 | issue = | pages = 300–305 | date = February 2019 | pmid = 30513290 | doi = 10.1016/j.physbeh.2018.11.042 | url = | quote = In a study performed by Sommer et al. (2014), healthy rats treated with the selective dopamine transport (DAT) inhibitor MRZ-9547 (Fig. 1) chose high effort, high reward more often than their untreated matched controls.}}</ref><ref name="SalamoneYohnLópez-Cruz2016">{{cite journal | vauthors = Salamone JD, Yohn SE, López-Cruz L, San Miguel N, Correa M | title = Activational and effort-related aspects of motivation: neural mechanisms and implications for psychopathology | journal = Brain | volume = 139 | issue = Pt 5 | pages = 1325–1347 | date = May 2016 | pmid = 27189581 | pmc = 5839596 | doi = 10.1093/brain/aww050 | url = | quote = Several recent studies have focused on the effort-related effects of . TBZ inhibits VMAT-2 (i.e. vesicular monoamine transporter type 2, encoded by Slc18a2), which results in reduced vesicular storage and depletion of monoamines. The greatest effects of TBZ at low doses have been reported to be on dopamine in the striatal complex, which is substantially depleted relative to norepinephrine and 5- HT (Pettibone et al., 1984; Tanra et al., 1995). Originally developed as a reserpine-type antipsychotic, TBZ has been approved for use as a treatment for Huntington’s disease and other movement disorders, but its major side effects include depressive symptoms (Frank, 2009, 2010; Guay, 2010; Chen et al., 2012). Like reserpine, TBZ has been used in studies involving classical animal models of depression (Preskorn et al., 1984; Kent et al., 1986; Wang et al., 2010). Low doses of TBZ that decreased accumbens dopamine release and dopamine-related signal transduction altered effort-related choice behaviour as assessed by concurrent lever pressing/chow feeding choice procedures (Nunes et al., 2013b; Randall et al., 2014).}}</ref> This can be useful in evaluating new ]s and ]-like agents.<ref name="StutzGolaniWitkin2019" /><ref name="SalamoneYohnLópez-Cruz2016" /> |
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* National Center for Biotechnology Information. |
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===Antibacterial effects=== |
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Reserpine inhibits formation of biofilms by ''Staphylococcus aureus'' and inhibits the metabolic activity of bacteria present in biofilms.<ref>{{cite journal | vauthors = Parai D, Banerjee M, Dey P, Mukherjee SK | title = Reserpine attenuates biofilm formation and virulence of Staphylococcus aureus | journal = Microbial Pathogenesis | volume = 138 | pages = 103790 | date = January 2020 | pmid = 31605761 | doi = 10.1016/j.micpath.2019.103790 | doi-access = }}</ref> |
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==References== |
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{{Reflist}} |
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== External links == |
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* National Center for Biotechnology Information. |
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{{Antihypertensives and diuretics}} |
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{{Antihypertensives and diuretics}} |
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{{Antipsychotics}} |
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{{Antipsychotics}} |
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{{Monoamine reuptake inhibitors}} |
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{{Adrenergics}} |
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{{Xenobiotic-sensing receptor modulators}} |
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{{Dopaminergics}} |
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{{Histaminergics}} |
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{{Tryptamines}} |
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{{Authority control}} |
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{{Serotonergics}} |
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