Reserpine

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| _datapage = Reserpine (data page) | _vaccine_target={{#ifeq: | vaccine | | _type_not_vaccine }} | _legal_all=Rx-only (banned/discontinued in some countries) | _ATC_prefix_supplemental=C02 | _has_EMA_link = | CAS_number=50-55-5 | PubChem=5770 | ChemSpiderID=5566 | ChEBI=28487 | ChEMBL=772 | DrugBank=DB00206 | KEGG=D00197 | _hasInChI_or_Key={{#if: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/s1QEVHRUUCFGRFIF-MDEJGZGSSA-N |yes}} | UNII=8B1QWR724A | _hasJmol02 = |_hasMultipleCASnumbers = |_hasMultiplePubChemCIDs = |_hasMultipleChEBIs =

| _countSecondIDs={{#invoke:ParameterCount |main |CAS_number2 |ATC_prefix2 |PubChem2 |PubChemStructure2 |IUPHAR_ligand2 |DrugBank2 |ChemSpiderID2 |UNII2 |KEGG2 |ChEBI2 |ChEMBL2 |PDB_ligand2 |NIAID_ChemDB2 |SMILES2 |smiles2 |StdInChI2 |StdInChIKey2 |DTXCID2}} | _countIndexlabels={{#invoke:ParameterCount |main |index_label |index2_label}} | _trackListSortletter= |QID = |QID2 = |Verifiedfields= |Watchedfields=changed |verifiedrevid=460779417}} Reserpine is a drug that is used for the treatment of high blood pressure, usually in combination with a thiazide diuretic or vasodilator.<ref>Template:Cite journal</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>{{#invoke:citation/CS1|citation |CitationClass=web }}</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>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> The reserpine-hydrochlorothiazide combo pill was the 17th most commonly prescribed of the 43 combination antihypertensive pills available in 2012.<ref>Template:Cite journal</ref>

The antihypertensive actions of reserpine are largely due to its antinoradrenergic effects, which 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 vascular resistance.<ref name="veterinary1">Forney, Barbara. Reserpine for Veterinary Use Wedgewood Pharmacy. 2001-2002.</ref>

At doses of 0.05 to 0.2 mg per day, reserpine is well tolerated;<ref>Template:Cite journal</ref> the most common adverse effect being nasal stuffiness.

Reserpine has also been used for relief of psychotic symptoms.<ref>Template:Cite journal</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 chlorpromazine for improving a person's global state.<ref>Template:Cite journal</ref>

Medical uses

Reserpine is recommended as an alternative drug for treating hypertension by the JNC 8.<ref>Template:Cite journal</ref> A 2016 Cochrane review found reserpine to be as effective as other first-line antihypertensive drugs for lowering of blood pressure.<ref>Template:Cite journal</ref> 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,<ref name="pmid490882">Template:Cite journal full text at OVID</ref> the Veterans Administration Cooperative Study Group in Anti-hypertensive Agents,<ref name="pmid4862069">Template:Cite journal</ref> and the Systolic Hypertension in the Elderly Program.<ref name="pmid2046107">Template:Cite journal</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">Template:Cite journal</ref>

It was previously used to treat symptoms of dyskinesia in patients with Huntington's disease,<ref name="pharmnemonics">Template:Cite book</ref> but alternative medications are preferred today.<ref>Template:Cite journal</ref>

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.

Adverse effects

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">Template:Cite journal</ref>

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. Template:ISBN.</ref>

Central nervous system effects at higher doses (0.5 mg or higher) include drowsiness, dizziness, nightmares, Parkinsonism, general weakness and fatigue. <ref name="Barcelos 2010">Template:Cite journal</ref>

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.<ref name="Giannini" />

Reserpine passes into breast milk and is harmful to breast-fed infants, and should therefore be avoided during breastfeeding if possible.<ref name="kidsgrowth">Template:Usurped Retrieved on June 19, 2009</ref>

It may produce an excessive decline in blood pressure at doses needed for treatment of anxiety, depression, or psychosis.<ref>Template:Cite book</ref>

Mechanism of action

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.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref> As it may take the body days to weeks to replenish the depleted VMATs, reserpine's effects are long-lasting.<ref>Template:Cite journal</ref>

Biosynthetic pathway

Reserpine is one of dozens of indole alkaloids isolated from the plant Rauvolfia serpentina.<ref name="indole-alkaloid">"Indole Alkaloids" Template:Webarchive 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.Template:Cite book</ref>

History

Reserpine was isolated in 1952 from the dried root of Rauvolfia serpentina (Indian snakeroot),<ref name="mercksource">Rauwolfia 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">Template:Cite encyclopedia</ref> — Mahatma Gandhi used it as a tranquilizer.<ref>Pills for Mental Illness?, TIME Magazine, November 8, 1954</ref> 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.<ref name="Nicolaou">Template:Cite book</ref> It was introduced in 1954, two years after chlorpromazine.<ref name="history1">Template:Cite journal</ref> The first total synthesis was accomplished by R. B. Woodward in 1958.<ref name="Nicolaou"/>

Reserpine was influential in promoting the thought of a biogenic amine hypothesis of depression.<ref>Template:Cite journal</ref><ref>Template:Cite book</ref> 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.<ref>Template:Cite journal</ref> Notably, reserpine was the first compound ever to be shown to be an effective antidepressant in a randomized placebo-controlled trial.<ref>Template:Cite journal</ref><ref>Template:Cite book</ref> 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.<ref name="pmid36000248">Template:Cite journal</ref> The quality of evidence was limited, and only a subset of studies were randomized controlled trials.<ref name="pmid36000248" /> 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.

Veterinary use

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>

It is also used in dart guns.

Research

Animal model of depression and amotivation

Similarly to tetrabenazine, reserpine, via depletion of monoamine neurotransmitters, produces depression-like effects and lack of motivation or fatigue-like symptoms in animals.<ref name="StutzGolaniWitkin2019">Template:Cite journal</ref><ref name="SalamoneYohnLópez-Cruz2016">Template:Cite journal</ref> This can be useful in evaluating new antidepressants and psychostimulant-like agents.<ref name="StutzGolaniWitkin2019" /><ref name="SalamoneYohnLópez-Cruz2016" />

Antibacterial effects

Reserpine inhibits formation of biofilms by Staphylococcus aureus and inhibits the metabolic activity of bacteria present in biofilms.<ref>Template:Cite journal</ref>

External links

• NLM Hazardous Substances Databank – Reserpine
• PubChem Substance Summary: Reserpine National Center for Biotechnology Information.
• The Stork Synthesis of (−)-Reserpine

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