reserpine

Reserpine is recommended as an alternative drug for treating hypertension by the JNC 8.{{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 = }} A 2016 Cochrane review found reserpine to be as effective as other first-line antihypertensive drugs for lowering of blood pressure.{{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 }} The reserpine–thiazide diuretic combination is one of the few drug treatments shown to reduce mortality in randomized controlled trials: The Hypertension Detection and Follow-up Program,{{cite journal | vauthors = | 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 }} [http://gateway.ovid.com/ovidweb.cgi?T=JS&PAGE=linkout&SEARCH=490882.ui full text at OVID] the Veterans Administration Cooperative Study Group in Anti-hypertensive Agents,{{cite journal | vauthors = | 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 }} and the Systolic Hypertension in the Elderly Program.{{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 }} Moreover, reserpine was included as a secondary antihypertensive option for patients who did not achieve blood pressure lowering targets in the ALLHAT study.{{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 | url-access = subscription }}

It was previously used to treat symptoms of dyskinesia in patients with Huntington's disease,{{Cite book|author=Shen, Howard|title=Illustrated Pharmacology Memory Cards: PharMnemonics|publisher=Minireview|year=2008|isbn=978-1-59541-101-3|page=11}} but alternative medications are preferred today.{{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 }}

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.

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.

At doses of less than 0.2 mg/day, reserpine has few adverse effects, the most common of which is nasal congestion.{{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 }}

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.AJ Giannini, HR Black. Psychiatric, Psychogenic, and Somatopsychic Disorders Handbook. Garden City, NY. Medical Examination Publishing, 1978. Pg. 233. {{ISBN|0-87488-596-5}}.

Central nervous system effects at higher doses (0.5 mg or higher) include drowsiness, dizziness, nightmares, Parkinsonism, general weakness and fatigue.

{{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 }}

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 hyperprolactinemia.

Reserpine passes into breast milk and is harmful to breast-fed infants, and should therefore be avoided during breastfeeding if possible.{{usurped|1=[https://archive.today/20070623011707/http://www.kidsgrowth.org/resources/articledetail.cfm?id=471 kidsgrowth.org Drugs and Other Substances in Breast Milk]}} Retrieved on June 19, 2009

It may produce an excessive decline in blood pressure at doses needed for treatment of anxiety, depression, or psychosis.{{cite book| vauthors = Pinel JP |title=Biopsychology|date=2011|publisher=Allyn & Bacon|isbn=978-0-205-83256-9|edition=8th|location=Boston|pages=469}}

{{See also|Monoamine-depleting agent}}

Reserpine irreversibly blocks the H⁺-coupled vesicular monoamine transporters, VMAT1 and VMAT2. VMAT1 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 monoamine neurotransmitters norepinephrine, dopamine, serotonin and histamine in the synaptic vesicles of neurons.{{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 }} VMAT2 normally transports free intracellular norepinephrine, serotonin, and dopamine in the presynaptic nerve terminal into presynaptic vesicles for subsequent release into the synaptic cleft ("exocytosis"). Unprotected neurotransmitters are metabolized by MAO (as well as by COMT), 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.{{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 }} As it may take the body days to weeks to replenish the depleted VMATs, reserpine's effects are long-lasting.{{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 }}

Reserpine is one of dozens of indole alkaloids isolated from the plant Rauvolfia serpentina.[http://waynesword.palomar.edu/chemid2.htm#indole "Indole Alkaloids"] {{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. 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.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 }}

Reserpine was isolated in 1952 from the dried root of Rauvolfia serpentina (Indian snakeroot),[http://www.mercksource.com/pp/us/cns/cns_hl_dorlands.jspzQzpgzEzzSzppdocszSzuszSzcommonzSzdorlandszSzdorlandzSzdmd_r_03zPzhtm#1093125 Rauwolfia] Dorlands Medical Dictionary. Merck Source. 2002. 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{{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 }} — Mahatma Gandhi used it as a tranquilizer.[https://web.archive.org/web/20080627161307/http://www.time.com/time/magazine/article/0,9171,857672,00.html Pills for Mental Illness?], TIME Magazine, November 8, 1954 It was first used in the United States by Robert Wallace Wilkins in 1950. Its molecular structure was elucidated in 1953 and natural configuration published in 1955.{{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= [https://archive.org/details/classicstotalmet00kcni_087/page/n80 55] |url=https://archive.org/details/classicstotalmet00kcni_087|url-access= limited}} It was introduced in 1954, two years after chlorpromazine.{{cite journal | vauthors = López-Muñoz F, Bhatara VS, Alamo C, Cuenca E | title = [Historical approach to reserpine discovery and its introduction in psychiatry] | 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 }} The first total synthesis was accomplished by R. B. Woodward in 1958.

Reserpine was influential in promoting the thought of a biogenic amine hypothesis of depression.{{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 }}{{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 }} Reserpine-induced depletion of monoamine neurotransmitters in the synapse allegedly caused depression and was cited as evidence that a "chemical imbalance", namely low levels of monoamine neurotransmitters, is what causes clinical depression in humans. A 2003 review showed barely any evidence that reserpine actually causes depression in either human patients or animal models.{{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 }} Notably, reserpine was the first compound ever to be shown to be an effective antidepressant in a randomized placebo-controlled trial.{{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 }}{{cite book | author=Healy, David|title=The Antidepressant Era|publisher=Harvard University Press|year=1997|isbn=978-0-674-03958-2}} A 2022 systematic review 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.{{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 }} The quality of evidence was limited, and only a subset of studies were randomized controlled trials. Although reserpine itself cannot provide good evidence for the monoamine hypothesis of depression, other lines of evidence support the idea that boosting serotonin or norepinephrine can effectively treat depression, as shown by SSRIs, SNRIs, and tricyclic antidepressants.

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.Forney B. Reserpine for veterinary use. Available at http://www.wedgewoodpetrx.com/learning-center/professional-monographs/reserpine-for-veterinary-use.html.

It is also used in dart guns.

Similarly to tetrabenazine, reserpine, via depletion of monoamine neurotransmitters, produces depression-like effects and lack of motivation or fatigue-like symptoms in animals.{{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.}}{{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 [tetrabenazine (TBZ)]. 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).}} This can be useful in evaluating new antidepressants and psychostimulant-like agents.

Reserpine inhibits formation of biofilms by Staphylococcus aureus and inhibits the metabolic activity of bacteria present in biofilms.{{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 = }}

{{Reflist}}

• [http://toxnet.nlm.nih.gov/cgi-bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+50-55-5 NLM Hazardous Substances Databank – Reserpine]
• [https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=148558&namedisopt=&ncount=165#Synonyms PubChem Substance Summary: Reserpine] National Center for Biotechnology Information.
• [https://www.organic-chemistry.org/Highlights/2006/01May.shtm The Stork Synthesis of (−)-Reserpine]

{{Antihypertensives and diuretics}}

{{Antipsychotics}}

{{Monoamine reuptake inhibitors}}

{{Xenobiotic-sensing receptor modulators}}

{{Tryptamines}}

{{Authority control}}

Category:Alkaloids found in Rauvolfia

Category:Antihypertensive agents

Category:Benzoate esters

Category:Fetotoxins

Category:Heterocyclic compounds with 5 rings

Category:Tryptamine alkaloids

Category:Indole ethers at the benzene ring

Category:Indoloquinolizines

Category:Isoquinoline alkaloids

Category:Monoamine-depleting agents

Category:Plant toxins

Category:VMAT inhibitors

Category:Depressogens