Identification

Name
Rauwolfia serpentina root
Accession Number
DB09363  (APRD00786, DB00386)
Type
Small Molecule
Groups
Investigational
Description

Rauwolfia (Rauwolfia serpentina), also spelled ravolphia, is a medicinal plant in the milkweed family. The root of the plant is ground into a powder or sold in tablets or capsules. It is a compound commonly used in Asian medicine, which includes traditional Ayurvedic medicine native to India. The active ingredients in this drug are alkaloids and about 50 have been identified through various studies, although the primary psychoactive components appear to be reserpine, rescinnamine, and deserpidine [10].

This product was approved prior to Jan 1, 1982, but since, has been discontinued due to its propensity for leading to depression [8, 20]. Reserpine is derived from Rauwolfia serpentina, and was commonly used as an antihypertensive agent in the 1950s [12]. Rauwolfia serpentina is also commonly referred to as Sarpaghanda [3]. Interestingly, the hairy root component of this plant has shown a remarkable capacity to regenerate into complete Rauwolfia plants and shows survival and unaltered biosynthetic potential during storage at decreased temperatures. For this reason, various studies into biotechnological applications of this plant have been performed. Multiple studies have been done on their biosynthetic potential and numerous biotechnological methods used to study the production of pharmaceutically important alkaloids [1, 2].

Synonyms
  • Alkaloids, rauwolfia
  • Alseroxylon
  • Rauvolfia serpentina root
  • Rauwolfia
  • Rauwolfia alkaloids
  • Rauwolfia root
  • Rauwolfia serpentina
  • Rauwolfia serpentina alseroxylon
  • Snakeroot
International/Other Brands
Sarpaghanda / Serpalan / Serpasil
Categories
Not Available
UNII
H192N84N1G
CAS number
8063-17-0
Weight
Not Available
Chemical Formula
Not Available
InChI Key
Not Available
InChI
Not Available
IUPAC Name
Not Available
SMILES
Not Available

Pharmacology

Indication

Rauwolfia alkaloids are indicated in the treatment of hypertension [6]. Rauwolfia alkaloids have been used for relief of symptoms in agitated psychotic states such as schizophrenia; however, use as antipsychotics and sedatives have been replaced with the use of more effective, safer agents [6].

Pharmacodynamics

Reserpine is used to treat high blood pressure. It also is used to treat severe agitation in patients with mental disorders. Reserpine is in a class of medications called rauwolfia alkaloids. It works by slowing the activity of the nervous system, causing the heart rate to slow and the blood vessels to dilate [9, 12].

Mechanism of action

Reserpine is an adrenergic blocking agent used to treat mild to moderate hypertension via the disruption of norepinephrine vesicular storage. The antihypertensive actions of Reserpine are a result of its ability to deplete catecholamines from peripheral sympathetic nerve endings. These substances are normally involved in controlling heart rate, the work of cardiac contraction and peripheral resistance [12]. Reserpine depletes brain (depression) and peripheral (PPH) noradrenaline (NA) storage sites, guanethidine depleted NA storage via blockade of reuptake [14].

This agent binds and inhibits catecholamine pump on the storage vesicles in central and peripheral adrenergic neurons, thereby inhibiting the uptake of norepinephrine, dopamine serotonin into presynaptic storage vesicles. This results in catecholamines and serotonin lingering in the cytoplasm where they are destroyed by intraneuronal monoamine oxidase, thereby causing the depletion of catecholamine and serotonin stores in central and peripheral nerve terminals. Depletion results in a lack of active transmitter discharge from nerve endings upon nerve depolarization, and consequently leads to a decreased heart rate and decreased arterial blood pressure as well as sedative effects [12].

TargetActionsOrganism
ASynaptic vesicular amine transporter
inhibitor
Human
Absorption

Mean maximum plasma levels of plasma concentrations after 0.5 mg of Reserpine, administered as two 0.25 mg tablets or as an aqueous solution, peaked after 2.5 hours. The mean peak level was approximately 1.1 ng/ml. Bioavailability of Reserpine, has been reported to be approximately 50% [16].

Volume of distribution
Not Available
Protein binding

Reserpine is extensively bound (95%) to plasma proteins [15].

Metabolism

Reserpine is almost completely metabolized in the body, and only about 1% is excreted as unchanged drug in the urine [15]. Hepatic metabolism accounts for less than 50% of the elimination of reserpine, with the remainder being eliminated in the faeces, and some unmetabolized reserpine and metabolites being eliminated in the urine. In man, metabolites are methylreserpate and trimethoxybenzoic acid. Metabolism may be more important with intramuscular administration [18].

Route of elimination

The elimination of reserpine and its metabolites in the feces ranges from 30% after intramuscular administration to about 60% after oral ingestion, primarily as unmetabolized reserpine, over a 4 day period after the ingestionof 0.25 mg to 0.50 mg doses. Over the same time period, about 8% of the ingested dose was recovered in the urine, primarily as the trimethoxybenzoic acid metabolite [18].

Half life

After oral ingestion, an initial half-life of approximately 5 hours is followed by a terminal half-life of approximately 200 hours [16].

Clearance

Hepatically and renally [18].

Toxicity

Ld50: 390 mg/kg oral mouse [19].

Reserpine may increase gastric acid secretion and should be used with caution in patients with a history of gastroesophageal reflux disease (GERD) and peptic ulcer. It should also not be administered to patients diagnosed with depression [15, 16].

Adverse reactions of this drug include: vomiting, diarrhea, arrhythmias , syncope, bradycardia, dyspnea, epistaxis, rare parkinsonian syndrome and other extrapyramidal tract (EPS) symptoms, dizziness, headache, paradoxical anxiety, depression, nervousness, nightmares, dull sensorium, drowsiness, muscular aches, pseudo lactation, weight gain, deafness, optic atrophy, hypersensitive reactions (pruritus) [15].

The mechanism of reserpine's toxic effects is found to be in parallel with the mechanism of its pharmacologic effects. Reserpine inhibits sympathetic activity in the central nervous system and peripheral nervous system by binding to catecholamine storage vesicles. This prevents the normal storage of catecholamines and serotonin in the nerve, resulting in catecholamine depletion. This drug has also been described as inhibiting catecholamine synthesis by blocking the uptake of dopamine into the storage vesicles [18].

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

General References
  1. Mehrotra S, Goel MK, Srivastava V, Rahman LU: Hairy root biotechnology of Rauwolfia serpentina: a potent approach for the production of pharmaceutically important terpenoid indole alkaloids. Biotechnol Lett. 2015 Feb;37(2):253-63. doi: 10.1007/s10529-014-1695-y. Epub 2014 Oct 18. [PubMed:25326172]
  2. Madhusudanan KP, Banerjee S, Khanuja SP, Chattopadhyay SK: Analysis of hairy root culture of Rauvolfia serpentina using direct analysis in real time mass spectrometric technique. Biomed Chromatogr. 2008 Jun;22(6):596-600. doi: 10.1002/bmc.974. [PubMed:18205139]
  3. Mehrotra S, Srivastava V, Goel MK, Kukreja AK: Scale-Up of Agrobacterium rhizogenes-Mediated Hairy Root Cultures of Rauwolfia serpentina: A Persuasive Approach for Stable Reserpine Production. Methods Mol Biol. 2016;1391:241-57. doi: 10.1007/978-1-4939-3332-7_17. [PubMed:27108322]
  4. Rauwolfia in the Treatment of Hypertension [Link]
  5. Rauwolfia [Link]
  6. Rauwolfia serpentina [Link]
  7. Human kidney proximal tubule cells are vulnerable to the effects of Rauwolfia serpentina. [Link]
  8. Hyserpin/rauwolfia [Link]
  9. Reserpine [Link]
  10. Review of Rauwolfia [Link]
  11. Prospecting for Novel Plant-Derived Molecules of Rauvolfia serpentina as Inhibitors of Aldose Reductase, a Potent Drug Target for Diabetes and Its Complications [Link]
  12. Rauwolfia Serpentina in the Treatment of High Blood Pressure A Review of the Literature [Link]
  13. Reserpine, Pub chem [Link]
  14. Sympatholytic therapy in primary hypertension: a user friendly role for the future [Link]
  15. Reserpine [Link]
  16. Reserpine, Drugs.com [Link]
  17. Differential Network Analysis Reveals Evolutionary Complexity in Secondary Metabolism of Rauvolfia serpentina over Catharanthus roseus [Link]
  18. Reserpine [Link]
  19. MSDS [Link]
  20. Severe depression caused by reserpine [Link]
  21. Reserpine-induced Reduction in Norepinephrine Transporter Function Requires Catecholamine Storage Vesicles [Link]
External Links
PubChem Substance
347910447

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedPreventionCardiovascular Disease (CVD) / Heart Diseases / High Blood Pressure (Hypertension) / Vascular Diseases1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Not Available
Experimental Properties
PropertyValueSource
melting point (°C)265http://www.bio.vu.nl/~microb/Protocols/chemicals/MSDS/reserpine.pdf
water solubilitysoluble http://www.bio.vu.nl/~microb/Protocols/chemicals/MSDS/reserpine.pdf
Predicted Properties
Not Available
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Taxonomy

Classification
Not classified

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Monoamine transmembrane transporter activity
Specific Function
Involved in the ATP-dependent vesicular transport of biogenic amine neurotransmitters. Pumps cytosolic monoamines including dopamine, norepinephrine, serotonin, and histamine into synaptic vesicles...
Gene Name
SLC18A2
Uniprot ID
Q05940
Uniprot Name
Synaptic vesicular amine transporter
Molecular Weight
55712.075 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423]
  3. FORD RV, MOYER JH: Rauwolfia toxicity in the treatment of hypertension; comparative toxicity of reserpine and alseroxylon. Postgrad Med. 1958 Jan;23(1):41-8. [PubMed:13505370]
  4. SCHLAGEL CA, NELSON JW: Rauwolfia hypotension. II. Action of the alseroxylon alkaloids and epinephrine on the carotid pressoreceptors. J Am Pharm Assoc Am Pharm Assoc. 1957 Feb;46(2):103-9. [PubMed:13438725]
  5. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]

Enzymes

Kind
Protein group
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Serotonin binding
Specific Function
Catalyzes the oxidative deamination of biogenic and xenobiotic amines and has important functions in the metabolism of neuroactive and vasoactive amines in the central nervous system and peripheral...

Components:
References
  1. Review of Rauwolfia [Link]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Norepinephrine:sodium symporter activity
Specific Function
Amine transporter. Terminates the action of noradrenaline by its high affinity sodium-dependent reuptake into presynaptic terminals.
Gene Name
SLC6A2
Uniprot ID
P23975
Uniprot Name
Sodium-dependent noradrenaline transporter
Molecular Weight
69331.42 Da
References
  1. Reserpine-induced Reduction in Norepinephrine Transporter Function Requires Catecholamine Storage Vesicles [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Not Available
Specific Function
Not Available
Gene Name
VMAT2
Uniprot ID
Q99870
Uniprot Name
Vesicle monoamine transporter type 2
Molecular Weight
17291.525 Da
References
  1. Reserpine-induced Reduction in Norepinephrine Transporter Function Requires Catecholamine Storage Vesicles [Link]

Drug created on November 30, 2015 12:10 / Updated on November 02, 2018 07:02