Reserpine

Reserpine
Reserpine
Systematic (IUPAC) name
methyl-11,17α-dimethoxy-18β-[(3,4,5-trimethoxybenzoyl)
Clinical data
AHFS/Drugs.com Consumer Drug Information
MedlinePlus a601107
Licence data US FDA:link
Pregnancy cat. D (fetotoxic)
Legal status Rx-only (some countries banned/discontinued)
Routes oral
Pharmacokinetic data
Bioavailability 50%
Metabolism gut/liver
Half-life phase 1 = 4.5h,
phase 2 = 271h,
average = 33h
Excretion 62% feces / 8% urine
Identifiers
CAS number 50-55-5 YesY
ATC code C02AA02
PubChem CID 5770
DrugBank APRD00472
ChemSpider 5566 YesY
UNII 8B1QWR724A YesY
KEGG D00197 YesY
ChEBI CHEBI:28487 YesY
ChEMBL CHEMBL772 YesY
Chemical data
Formula C33H40N2O9 
Mol. mass 608.68 g/mol
SMILES eMolecules & PubChem
 N(what is this?)  (verify)

Reserpine is an indole alkaloid[2] antipsychotic and antihypertensive drug that has been used for the control of high blood pressure and for the relief of psychotic symptoms, although because of the development of better drugs for these purposes and because of its numerous side-effects, it is rarely used today.[1] The antihypertensive actions of reserpine are a result of its ability to deplete catecholamines (among other monoamine neurotransmitters) from peripheral sympathetic nerve endings. These substances are normally involved in controlling heart rate, force of cardiac contraction and peripheral resistance.[3]

Reserpine mediated depletion of monoamine neurotransmitters in the synapses is often cited as evidence to the theory that depletion of the neurotransmitters causes subsequent depression in humans (c.f. monoamine hypothesis). However, this claim is not without controversy. The reserpine-induced depression is considered by some researchers to be 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 antidepressant.[2] 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.[3]

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).

Contents

Mechanism of Action

Reserpine irreversible blocks the vesicular monoamine transporter (VMAT).[4] This normally transports free norepinephrine, serotonin, and dopamine from the cytoplasm of the presynaptic nerve terminal into storage vesicles for subsequent release into the synaptic cleft ("exocytosis"); unprotected neurotransmitters are metabolized by MAO (as well as by COMT) in the cytoplasm and therefore never reach the synapse.

It could take days to weeks by the body to replenish the depleted VMAT and hence reserpine's effects are long-lasting.

Biosynthetic pathway

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.[5]

History

Reserpine was isolated in 1952 from the dried root of Rauwolfia serpentina (Indian snakeroot),[4] (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[1] — even Mahatma Gandhi used it as a tranquilizer.[6] 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.[7] It was introduced in 1954, two years after chlorpromazine.[5] The first total synthesis was accomplished by R. B. Woodward in 1958.[7]

Reserpine almost irreversibly blocks the uptake (and storage) of norepinephrine (i.e. noradrenaline) and dopamine into synaptic vesicles by inhibiting the Vesicular Monoamine Transporters (VMAT).[6]

Reserpine has been discontinued in the UK for some years due to its numerous interactions and side effects.

Reserpine was also highly influential in promoting the thought of a biogenic amine hypothesis of depression - see Everett & Tolman, 1959.

Uses today

Seen is the drug Reserpine in tablet form being counted out to fill a prescription in a pharmacy.

Reserpine is one of the few antihypertensive medications that have been shown in randomized controlled trials to reduce mortality: The Hypertension Detection and Follow-up Program,[8] the Veterans Administration Cooperative Study Group in Anti-hypertensive Agents,[9] and the Systolic Hypertension in the Elderly Program.[10]

Reserpine is rarely used in the management of hypertension today. Reserpine is listed as an option by the JNC 7.[11] Reserpine is a second-line adjunct agent for patients who are uncontrolled on a diuretic when cost is an issue.[12]

It is also used to treat symptoms of dyskinesia in patients suffering from Huntington's disease.[13]

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 hydralazine. 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.

Side effects

At doses of less than 0.2 mg/day, reserpine has few side effects, the most common of which is nasal congestion.[14]

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.[15][16]

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.[17] 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 hyperprolactinemia.[17]

Reserpine passes into breast milk and is harmful to breast-fed infants, and should therefore be avoided during breastfeeding if possible.[18]

References

  1. ^ a b [1] The Columbia Encyclopedia, Sixth Edition. Copyright © 2001-05 Columbia University Press.
  2. ^ Baumeister, AA; Hawkins, MF; Uzelac, SM (2003). "The myth of reserpine-induced depression: role in the historical development of the monoamine hypothesis". Journal of the history of the neurosciences 12 (2): 207–20. PMID 12953623.  edit
  3. ^ D. L. Davies and M. Shepherd, “Reserpine in the Treatment of Anxious and Depressed Patients,” The Lancet 269 (1955): 117–20
  4. ^ Henry, J.; Scherman, D. (1989). "Radioligands of the vesicular monoamine transporter and their use as markers of monoamine storage vesicles". Biochemical pharmacology 38 (15): 2395–2404. doi:10.1016/0006-2952(89)90082-8. PMID 2667522.  edit
  5. ^ Ramawat et al, 1999.Ramawat KG, Rachnana Sharma, Suri SS. Ramawat, KG. and Merillon, JM.. ed. Medicinal Plants in Biotechnology- Secondary metabolites 2nd edition 2007. pp. 66-367. ISBN 978-1-57808-428-9. 
  6. ^ Pills for Mental Illness?, TIME Magazine, November 8, 1954
  7. ^ a b Nicolaou, K. C.; E. J. Sorensen (1996). Classics in Total Synthesis. Weinheim, Germany: VCH. p. 55. ISBN 3-527-29284-5. 
  8. ^ , (1979). "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". JAMA 242 (23): 2562–71. doi:10.1001/jama.242.23.2562. PMID 490882.  full text at OVID
  9. ^ , (1967). "Effects of treatment on morbidity in hypertension. Results in patients with diastolic blood pressures averaging 115 through 129 mm Hg". JAMA 202 (11): 1028–34. doi:10.1001/jama.202.11.1028. PMID 4862069. 
  10. ^ , (1991). "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". JAMA 265 (24): 3255–64. doi:10.1001/jama.265.24.3255. PMID 2046107. 
  11. ^ Chobanian AV, Bakris GL, Black HR, et al. (2003). "The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report". JAMA 289 (19): 2560–72. doi:10.1001/jama.289.19.2560. PMID 12748199.  summary
  12. ^ Moser M (1987). ""Cost containment" in the management of hypertension". Ann. Intern. Med. 107 (1): 107–9. PMID 3592424. 
  13. ^ Shen, Howard (2008). Illustrated Pharmacology Memory Cards: PharMnemonics. Minireview. p. 11. ISBN 1-59541-101-1. 
  14. ^ Curb JD, Schneider K, Taylor JO, Maxwell M, Shulman N (1988). "Antihypertensive drug side effects in the Hypertension Detection and Follow-up Program". Hypertension 11 (3 Pt 2): II51–5. PMID 3350594. 
  15. ^ QUETSCH RM, ACHOR RW, LITIN EM, FAUCETT RL (1959). "Depressive reactions in hypertensive patients; a comparison of those treated with Rauwolfia and those receiving no specific antihypertensive treatment". Circulation 19 (3): 366–75. PMID 13629798. 
  16. ^ Lemieux G, Davignon A, Genest J (1956). "Depressive states during Rauwolfia therapy for arterial hypertension; a report of 30 cases". Canadian Medical Association Journal 74 (7): 522–6. PMC 1823144. PMID 13304797. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1823144. 
  17. ^ a b AJ Giannini,HR Black. Psychiatric, Psychogenic, and Somatopsychic Disorders Handbook. Garden City,NY. Medical Examination Publishing, 1978. Pg. 233. ISBN 0-87488596-5.
  18. ^ kidsgrowth.org --> Drugs and Other Substances in Breast Milk Retrieved on June 19, 2009

Footnotes

  1. ^ アルカロイド (Alkaloids) (T-Z). 2004.
  2. ^ "Indole Alkaloids" 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.
  3. ^ Forney, Barbara. Reserpine for Veterinary Use Wedgewood Pharmacy. 2001-2002.
  4. ^ Rauwolfia Dorlands Medical Dictionary. Merck Source. 2002.
  5. ^ Lopez-Munoz F, Bhatara VS, Alamo C, Cuenca E. (2004): "[Historical approach to reserpine discovery and its introduction in psychiatry]" [Article in Spanish] Actas Esp Psiquiatr. 32(6):387-95. PMID 15529229 Fulltext in English and Spanish
  6. ^ Schuldiner, S. et al. (1993): J. Biol. Chem. 268(1) 29-34. PMID 8416935

External links

v · d · eSympatholytic (and closely related) antihypertensives (C02)
Sympatholytics
(antagonize α-adrenergic
vasoconstriction)
Central
Adrenergic release inhibitors
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Peripheral
Indirect
Rescinnamine • Reserpine
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dual (Bosentan) • selective (Ambrisentan, Sitaxentan)

M: VAS

anat(a:h/u/t/a/l,v:h/u/t/a/l)/phys/devp/cell/prot

noco/syva/cong/lyvd/tumr, sysi/epon, injr

proc, drug(C2s+n/3/4/5/7/8/9)
v · d · eAntipsychotics (neuroleptics) (N05A)
Typical
Benzamides: Levosulpiride • Nemonapride • Sulpiride • Sultopride • Tiapride • Veralipride; Butyrophenones: Azaperone • Benperidol • Bromperidol • Droperidol • Fluanisone • Haloperidol • Lenperone • Moperone • Pipamperone • Spiperone • Timiperone • Trifluperidol; Diphenylbutylpiperidines: Clopimozide • Fluspirilene • Penfluridol • Pimozide; Phenothiazines: Acepromazine • Acetophenazine • Butaperazine • Carphenazine • Chloracizine • Chlorproethazine • Chlorpromazine • Cyamemazine • Dixyrazine • Fluacizine • Fluphenazine • Levomepromazine/Methotrimeprazine • Mesoridazine • Perazine • Pericyazine • Perphenazine • Piperacetazine • Pipotiazine • Prochlorperazine • Promazine • Promethazine • Propiomazine • Sulforidazine • Thiethylperazine • Thiopropazate • Thioproperazine • Thioridazine • Trifluoperazine • Triflupromazine; Thioxanthenes: Chlorprothixene • Clopenthixol • Flupentixol • Thiothixene • Zuclopenthixol; Tricyclics: Amoxapine • Butaclamol • Fluotracen • Loxapine • Metitepine/Methiothepin • Octoclothiepin • Trimipramine; Others: Prothipendyl
Atypical
Benzamides: Amisulpride • Remoxipride; Butyrophenones: Cinuperone • Setoperone; Benzo(iso)oxazolepiperidines: Iloperidone • Ocaperidone • Paliperidone • Risperidone; Benzo(iso)thiazolepiperazines: Lurasidone • Perospirone • Revospirone • Tiospirone • Ziprasidone; Diphenylbutylpiperazines: Amperozide; Phenylpiperazines: Aripiprazole • Bifeprunox • Elopiprazole • Umespirone; Tricyclics: Asenapine • Carpipramine • Clocapramine • Clotiapine • Clozapine • Fluperlapine • Gevotroline • Metitepine/Methiothepin • Mosapramine • NDMC • Olanzapine • Piquindone • Quetiapine • Tenilapine • Zotepine; Others: Blonanserin • Cariprazine • Molindone • Pimavanserin • Roxindole • Sarizotan • Sertindole • Spiramide
Others
Azacyclonol • Cannabidiol • D-Cycloserine • Lithium • Mifepristone • Oxypertine • Reserpine • Rimcazole • Secretin • Talnetant • Tetrabenazine • Vabicaserin

M: PSO/PSI

mepr

dsrd (o, p, m, p, a, d, s), sysi/epon, spvo

proc(eval/thrp), drug(N5A/5B/5C/6A/6B/6D)


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  • Reserpine — Réserpine Réserpine Général Nom IUPAC 11,17α diméthoxy 18β (3,4,5 triméthoxybenzoyloxy) 3β,20α yohimban 16β carboxylate de méthyl ou (1R,15S,17R,18R,19S,20S) 6,18 diméthoxy 17 [(3,4,5 triméthoxyphenyl) …   Wikipédia en Français

  • Réserpine — Général Nom IUPAC 11,17α diméthoxy 18β (3,4,5 triméthoxybenzoyloxy) 3β,20α yohimban 16β carboxylate de méthyle ou (1R,15S,17R,18R,19S,20S) 6,18 diméthoxy 17 [(3,4,5 triméthoxyphenyl)carbonyloxy] 3,13 d …   Wikipédia en Français

  • reserpine — [ri sʉr′pin, ri sʉr′pēn; res′ər pēn΄] n. [Ger reserpin, prob. arbitrary contr. < ModL Rauwolfia serpentina + Ger in, INE3] a crystalline alkaloid, C33H40N2O9, extracted from the root of various rauwolfias (esp. Rauwolfia serpentina), used in… …   English World dictionary

  • reserpine — /res euhr pin, peen , reuh serr pin, peen/, n. Pharm. an alkaloid, C33H40N2O9, obtained from the root of the rauwolfia, Rauwolfia serpentina, used in the treatment of hypertension. [1950 55; < G Reserpin, equiv. to reserp (prob. irreg. < NL… …   Universalium

  • Reserpine, an Early Psychiatry Drug —    (from 1954)    Although Ayurvedic practitioners in India had used the roots of the Rauwolfia plant for centuries in the treatment of mental illness, it was only in the early 1950s that the drug became part of the revolution in… …   Historical dictionary of Psychiatry

  • reserpine — noun Etymology: German Reserpin, probably irregular from New Latin Rauwolfia serpentina, a species of rauwolfia Date: 1952 an alkaloid C33H40N2O9 extracted especially from the root of rauwolfias and used as a tranquilizer especially in psychotic… …   New Collegiate Dictionary

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  • reserpine — noun An alkaloid, isolated from the snakeroot plant, that is used as an antipsychotic and antihypertensive drug …   Wiktionary

  • reserpine — An ester alkaloid isolated from the root of certain species of Rauwolfia; it decreases the 5 hydroxytryptamine and catecholamine concentrations in the central nervous system and in peripheral tissues; used in conjunction with other hypotensive… …   Medical dictionary

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