Hyoscyamine (also known as daturine) is a naturally occurring tropane alkaloid and plant toxin. It is a secondary metabolite found in certain plants of the family Solanaceae, including henbane (Hyoscyamus niger), mandrake (Mandragora officinarum), angel's trumpets (Brugmansia spp.), jimsonweed (Datura stramonium), tomato (Solanum lycopersicum) the sorcerers' tree ( Latua pubiflora ) and deadly nightshade (Atropa belladonna). It is the levorotary isomer of atropine (third of the three major nightshade alkaloids) and thus sometimes known as levo-atropine.
Brand names for hyoscyamine include Symax, HyoMax, Anaspaz, Egazil, Buwecon, Cystospaz, Levsin, Levbid, Levsinex, Donnamar, NuLev, Spacol T/S and Neoquess.
|Trade names||Anaspaz, Levbid, Levsin|
|Bioavailability||50% Protein binding|
|Elimination half-life||3–5 hrs.|
|Chemical and physical data|
|Molar mass||289.375 g/mol g·mol−1|
|3D model (JSmol)|
|(what is this?)|
Hyoscyamine is used to provide symptomatic relief of spasms caused by various lower abdominal and bladder disorders including peptic ulcers, irritable bowel syndrome, diverticulitis, pancreatitis, colic, and interstitial cystitis. It has also been used to relieve some heart problems, control some of the symptoms of Parkinson's disease, as well as for control of abnormal respiratory symptoms and "hyper-mucus secretions" in patients with lung disease.
It is also useful in pain control for neuropathic pain, chronic pain and palliative care – "comfort care" – for those with intractable pain from treatment resistant, untreatable, and incurable diseases. When combined with opioids it increases the level of analgesia (pain relief) obtained. Several mechanisms are thought to contribute to this effect. The closely related drugs atropine and hyoscine and other members of the anticholinergic drug group like cyclobenzaprine, trihexyphenidyl, and orphenadrine are also used for this purpose. When hyoscyamine is used along with opioids or other anti-peristaltic agents, measures to prevent constipation are especially important given the risk of paralytic ileus.
Side effects include dry mouth and throat, increased appetite leading to weight gain, eye pain, blurred vision, restlessness, dizziness, arrhythmia, flushing, and faintness. An overdose will cause headache, nausea, vomiting, and central nervous system symptoms including disorientation, hallucinations, euphoria, sexual arousal, short-term memory loss, and possible coma in extreme cases. The euphoric and sexual effects are stronger than those of atropine but weaker than those of Hyoscine, as well as dicycloverine, orphenadrine, cyclobenzaprine, trihexyphenidyl, and ethanolamine antihistamines like phenyltoloxamine.
Hyoscyamine is an antagonist of muscarinic acetylcholine receptors (antimuscarinic). It blocks the action of acetylcholine at parasympathetic sites in sweat glands, salivary glands, stomach secretions, heart muscle, sinoatrial node, smooth muscle in the gastrointestinal tract, and the central nervous system. It increases cardiac output and heart rate, lowers blood pressure and dries secretions. It may antagonize serotonin. At comparable doses, hyoscyamine has 98 per cent of the anticholinergic power of atropine. The other major belladonna-derived drug Hyoscine (known in the United States as Scopolamine) has 92 per cent of the antimuscarinic potency of atropine.
Hyoscyamine can be extracted from plants of the Solanaceae family, notably Datura stramonium. As hyoscyamine is a direct precursor in the plant biosynthesis of hyoscine, it is produced via the same metabolic pathway.
The biosynthesis of hyoscine begins with the decarboxylation of L-ornithine to putrescine by ornithine decarboxylase (EC 18.104.22.168). Putrescine is methylated to N-methylputrescine by putrescine N-methyltransferase (EC 22.214.171.124).
A putrescine oxidase (EC 126.96.36.199) that specifically recognizes methylated putrescine catalyzes the deamination of this compound to 4-methylaminobutanal which then undergoes a spontaneous ring formation to N-methylpyrrolium cation. In the next step, the pyrrolium cation condenses with acetoacetic acid yielding hygrine. No enzymatic activity could be demonstrated that catalyzes this reaction. Hygrine further rearranges to tropinone.
Subsequently, tropinone reductase I (EC 188.8.131.52) converts tropinone to tropine which condenses with phenylalanine-derived phenyllactate to littorine. A cytochrome P450 classified as Cyp80F1 oxidizes and rearranges littorine to hyoscyamine aldehyde.
Anisodamine, also known as 7β-hydroxyhyoscyamine, is an anticholinergic and α1 adrenergic receptor antagonist used in the treatment of acute circulatory shock in China. It is given orally or by injection, as a racemic mixture (racanisodamine) or as a hydrobromide salt. Eye drops at 0.5% concentration for slowing the progression is also available in China.Anisodamine is a naturally occurring tropane alkaloid found in some plants of the Solanaceae family. Its Mandarin Chinese name 山莨菪碱 is given after Anisodus tanguticus (Chinese: 山莨菪; pinyin: shān làng dàng).Anticholinergic
An anticholinergic agent is a substance that blocks the action of the neurotransmitter acetylcholine at synapses in the central and the peripheral nervous system. These agents inhibit parasympathetic nerve impulses by selectively blocking the binding of the neurotransmitter acetylcholine to its receptor in nerve cells. The nerve fibers of the parasympathetic system are responsible for the involuntary movement of smooth muscles present in the gastrointestinal tract, urinary tract, lungs, and many other parts of the body. Anticholinergics are divided into three categories in accordance with their specific targets in the central and peripheral nervous system: antimuscarinic agents, ganglionic blockers, and neuromuscular blockers.Apoatropine
Apoatropine is a member of class of tropane alkaloids. Apoatropine can be found in plants of Solanaceae family. It is a bitter crystalline alkaloid. Examples of related tropane alkaloids include atropine, hyoscyamine, and hyoscine. Though apoatropine is found in various plants, it can also be prepared by the dehydration of atropine using nitric acid . Apoatropine is used as a pigment.Asthmador
Asthmador was a nonprescription treatment for the relief of bronchial asthma made by the R. Schiffmann Company.
It consisted of a mixture of belladonna, stramonium and potassium perchlorate, and was a fine powder intended to be burned and the smoke inhaled. The primary alkaloid present in the mixture was hyoscyamine, and when the powder was ingested rather than burned, could be used to induce hallucinations. In severe overdose it could hospitalize the patient or cause death.
Prior to the introduction of rescue inhalers in the mid-1950s this was an effective over-the-counter remedy for asthma attacks. Asthmador was sold in packets like cigarettes, in tins like pipe tobacco, or as an incense. The paroxysms would abate after a few minutes of the victim inhaling the mixture.Atropa belladonna
Atropa belladonna, commonly known as belladonna or deadly nightshade, is a perennial herbaceous plant in the nightshade family Solanaceae, which includes tomatoes, potatoes, and eggplant (aubergine). It is native to Europe, North Africa, and Western Asia. Its distribution extends from Great Britain in the west to western Ukraine and the Iranian province of Gilan in the east. It is also naturalised or introduced in some parts of Canada and the United States.
The foliage and berries are extremely toxic when ingested, containing tropane alkaloids. These toxins include atropine, scopolamine and hyoscyamine, which cause delirium and hallucinations, and are also used as pharmaceutical anticholinergics. These tropane alkaloids appear to be common in the Solanaceae family, as they are also present in plants of the Brugmansia, Datura and Hyoscyamus genera, of the same family but in different subfamilies and tribes to the nightshade.
Atropa belladonna has unpredictable effects. The antidote for belladonna poisoning is physostigmine or pilocarpine, the same as for atropine.It has a long history of use as a medicine, cosmetic, and poison. Before the Middle Ages, it was used as an anesthetic for surgery; the ancient Romans used it as a poison — the Roman empresses Livia Drusilla and Agrippina the Younger both were rumored to have used it for murder; and, predating this, it was used to make poison-tipped arrows. The genus name Atropa comes from Atropos ("unable to be turned aside"), one of the three Fates from Greek mythology, who cut the thread of life after her sisters had spun and measured it. The name belladonna is derived from Italian for "beautiful woman", as during the Renaissance, the herb was used in eyedrops by women to dilate the pupils of the eyes to make them appear seductive.Atropine
Atropine is a medication used to treat certain types of nerve agent and pesticide poisonings as well as some types of slow heart rate and to decrease saliva production during surgery. It is typically given intravenously or by injection into a muscle. Eye drops are also available which are used to treat uveitis and early amblyopia. The intravenous solution usually begins working within a minute and lasts half an hour to an hour. Large doses may be required to treat some poisonings.Common side effects include a dry mouth, large pupils, urinary retention, constipation, and a fast heart rate. It should generally not be used in people with angle closure glaucoma. While there is no evidence that its use during pregnancy causes birth defects, it has not been well studied. It is likely safe during breastfeeding. It is an antimuscarinic (a type of anticholinergic) that works by inhibiting the parasympathetic nervous system.Atropine occurs naturally in a number of plants of the nightshade family including deadly nightshade, Jimson weed, and mandrake. It was first isolated in 1833. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. It is available as a generic medication and is not very expensive. A one-milligram vial costs between US$0.06 and US$0.44, wholesale, in the developing world.Donnatal
Donnatal is a combination medication which provides natural belladonna alkaloids in a specific fixed ratio combined with phenobarbital to provide peripheral anticholinergic/antispasmodic action and mild sedation,. Donnatal is manufactured for Concordia Pharmaceuticals by IriSys, LLC. It is distributed by RedHill Biopharma, Inc. It is available as tablets and 5 mL elixir. Active ingredients are listed as: phenobarbital (16.2 mg), hyoscyamine sulfate (0.1037 mg), atropine sulfate (0.0194 mg), and scopolamine hydrobromide (0.0065 mg). The latter two ingredients are found in plants of the Solanaceae family such as Belladonna.
Based on a review of this drug by the National Academy of Sciences–National Research Council and/or other information, FDA has classified the indications as follows: “Possibly” effective: For use as adjunctive therapy in the treatment of irritable bowel syndrome (irritable colon, spastic colon, mucous colitis) and acute enterocolitis. May also be useful as adjunctive therapy in the treatment of duodenal ulcer.,History
Clinical Research with Combinations of Belladonna Alkaloids and Phenobarbital. Clinical studies have been performed on different combinations of belladonna alkaloids and phenobarbital over the last 70 years. For example, Steigmann et al evaluated a combination of 0.25 mg belladonna alkaloids and 50 mg phenobarbital on gastrointestinal symptoms in 93 patients. The population included 33 IBS patients. Eighteen out of 33 patients reported complete relief of symptoms and 13 reported fair response with partial relief within 24 hours. Only 2 IBS patients reported no response. A small assessment of sustained release of 0.4 mg belladonna alkaloids and ~60 mg phenobarbital (1 grain) was performed in patients with functional GI disorders (i.e., gastric hyperacidity, dyspepsia, pyrosis, gas pains and epigastric distress. Overall, 23 of 25 patients reported complete or significant relief of symptoms. Hock also examined the effect of 0.25 mg belladonna alkaloids and 50 mg phenobarbital sustained release formulation in 82 clinical practice patients with various gastrointestinal disturbances including “functional distress” over 27 months. Of the 82 total patients, 33 patients reported a 50%-75% and 20 reported a 75%-100% improvement. There were specific reports of improvements in pain and bowel habits in over half of the patients.
One of the earliest randomized double-blind clinical trials of belladonna alkaloids + phenobarbital was in 1959 by Lichstein et al. The study involved 75 patients with unstable bowel (whose symptoms are typical or similar to a current diagnosis of IBS) to investigate the combination therapy of an anticholinergic with the addition of phenobarbital against placebo over 15 months. Of these patients, 20 were treated with placebo, 43 were treated with 50 mg phenobarbital in combination with 0.25 mg Belladonna alkaloids, and 12 received both therapies (patients who lacked a response were switched therapy). Of those receiving the belladonna alkaloids / phenobarbital only, 75.6% reported a mean improvement (2+ or better) in all categories. Among the placebo patients only, only 29.8% reported mean improvement in symptoms. When improvement was clinically assessed, 69% of belladonna alkaloids/phenobarbital patients were reported to improve compared to 24% of placebo patients. For the 12 patients who were switched therapies, it was found that they were originally given placebo and switched to treatment therapy. While on placebo, 11.1% of patients reported a mean improvement, whereas 55.5% reported mean improvement on treatment therapy. The authors noted that the response for patients on placebo was rather quick with immediate effects. Further they noted that among patients with diarrhea, 100% reported an improvement while 53.2% of those with constipation reported an improvement. In several patients with constipation, fiber and laxatives were also provided. In patients where constipation was the chief complaint, the authors noted that they failed to respond.
Several office-belladonna alkaloids ed case series also presented positive outcomes for almost 1000 patients on the effect of belladonna alkaloids and phenobarbital formulations in irritable colon, other functional disorders, and gastric/duodenal.Donnatal® Clinical Research. A.H. Robins developed and began marketing Donnatal® in the 1940s. Two studies have been performed over the years specifically with the Donnatal® formulation. Steigmann and Kaminski examined the antisecretory effect of 0.1296 mg belladonna alkaloids + 16.2 mg phenobarbital (Donnatal®) in peptic ulcer patients, motility in a subgroup of patients and clinical effects in all patients (N =176). Of the IBS patients (n =66), a reported good response with complete relief was found in 53% of male patients and 58% of female patients. Fair response with partial improvement was noted in 37% of male patients and 34% of female patients. No response was reported in 10% of male and 8% of female IBS patients. There were few side effects noted with 8% reporting dry mouth. Dosages were reduced in patients who reported drowsiness (10%) as well as 1 patient who reported visual disturbance. Otherwise, the formulation was well-tolerated.
Donnatal is also a common component of a GI cocktail used in emergency rooms. In 1976, Donnatal was one of the 25 most widely prescribed drugs in the U.S. It has since been displaced by H2 antagonists and proton pump inhibitors, which are more effective and lack many of the adverse effects of phenobarbital.A 4-week multicenter, randomized placebo-controlled trial by Turner et al compared Donnatal® tablets (hyoscyamine sulfate - 0.1037 mg; atropine sulfate - 0.0194 mg; scopolamine hydrobromide - 0.0065 mg and phenobarbital - 16.2 mg) to belladonna alkaloids alone (hyoscyamine sulfate - 0.1037 mg; atropine sulfate - 0.0194 mg; scopolamine hydrobromide - 0.0065 mg), phenobarbital alone (16.2 mg) and placebo. The intent-to-treat population of 204 IBS patients was evaluated for pain (cramping), nighttime and daytime pain severity, bowel movement frequency and with a clinician global evaluation of improvement in response to treatment. The response for improvement of pain was mixed for all groups after 1 day. After 1 day, patients exhibited significant improvement in day and night pain as well as clinician global evaluation when taking Donnatal® tablets and belladonna alkaloids, but the phenobarbital group was also statistically better for day and night pain and the placebo for day pain. Females taking Donnatal® tablets were 4-times more likely to experience weeks free of daytime pain compared to phenobarbital alone and 2-times as likely to experience weeks free of nighttime pain compared to belladonna alkaloids. Only the phenobarbital group demonstrated a significant change in pain type compared to belladonna alkaloids at the end of the study with an approximate 48% response rate. Patients on Donnatal® tablets, belladonna alkaloids, and placebo all had non-significant (p > 0.149) shifts to dull pain, 39.5%, 52.3%, and 40.4%, respectively compared to belladonna alkaloids eline. Males also showed a greater response for pain free weeks on phenobarbital in comparison to Donnatal® tablets. All groups demonstrated an improvement in bowel movement frequency.
Status at FDA. Donnatal® is considered part of the DESI drug category and is currently listed as one of 14 drugs still under evaluation by the FDA. In response to FDA questions about Donnatal® efficacy, A.H. Robins Co. filed abbreviated new drug applications for Donnatal® tablets (ANDA 86-676), capsules (ANDA 86-677) and Elixir (ANDA 86-661). These ANDAs, with the exception of the capsule formulation, are still in force today and the FDA has not changed the review status of Donnatal® as being conditionally approved for its indication.
On September 29, 2011, the FDA issued new guidance with regard to the DESI category. This effectively disallowed any new DESI formulations to enter the market. The FDA has also stated that DESI drugs do not have any therapeutic equivalent drugs listed in the “Orange Book”. In their description of therapeutic equivalence, the FDA specifically cites Donnatal®. Therefore, any so-called generic drugs on the market with similar formulation to DESI drugs are considered illegal drugs as the FDA has not reviewed their composition or therapeutic equivalence.Duboisia
The orchid genus described by Karsten as Duboisia is now included in Myoxanthus. For the prehistoric antelope genus, see Duboisia (antelope).
Duboisia (commonly called corkwood tree) is a genus of small perennial shrubs and trees up to 14 metres (46 feet) tall, with extremely light wood and a thick corky bark. There are four species; all occur in Australia, and one also occurs in New Caledonia.
The alternate, glabrous leaves are narrow and elliptical. The inflorescence is an open cymose panicle of apically small white flowers, sometimes with a purple or mauve striped tube. They flower profusely in spring. The fruit is a small, globular, black, juicy berry.
Aboriginal Australians sometimes chew the nicotine-containing leaves of Duboisia hopwoodii (see entry on pituri) mixed with wood ash for their stimulant and, after extended use, depressant effects. The leaves of Duboisia leichhardtii and Duboisia myoporoides also contain scopolamine and hyoscyamine, along with some other pharmaceutically important alkaloids. A derivative of scopolamine is the drug butylscopolamine, a potent peripherally acting antispasmodic. These trees are commercially grown for the pharmaceutical industry.
The genus was named by Robert Brown in honour of Louis DuBois who wrote Méthode éprouvée, avec laquelle on peut parvenir facilement et sans maître à connaître les plantes de l'intérieur de la France et en particulier celles des environs d'Orléans, par M. Dubois, théologal de l'église d'Orléans, ancien démonstrateur du Jardin des plantes (1803).Hyoscyamine/hexamethylenetetramine/phenyl salicylate/methylene blue/benzoic acid
The drug combination hyoscyamine/hexamethylenetetramine/phenyl salicylate/methylene blue/benzoic acid (trade names Methylphen, Prosed DS) is used for the treatment of urinary tract infections.Hyoscyamine (6S)-dioxygenase
In enzymology, a hyoscyamine (6S)-dioxygenase (EC 184.108.40.206) is an enzyme that catalyzes the chemical reaction
The 3 substrates of this enzyme are L-hyoscyamine, 2-oxoglutarate, and O2, whereas its 3 products are (6S)-hydroxyhyoscyamine, succinate, and CO2.
This enzyme belongs to the family of oxidoreductases, specifically those acting on paired donors, with O2 as oxidant and incorporation or reduction of oxygen. The oxygen incorporated need not be derived from O2 with 2-oxoglutarate as one donor, and incorporation of one atom o oxygen into each donor. The systematic name of this enzyme class is L-hyoscyamine,2-oxoglutarate:oxygen oxidoreductase ((6S)-hydroxylating). Other names in common use include hyoscyamine 6beta-hydroxylase, hyoscyamine 6beta-dioxygenase, and hyoscyamine 6-hydroxylase. This enzyme participates in alkaloid biosynthesis ii. It has 2 cofactors: iron, and Ascorbate.Hyoscyamus
Hyoscyamus — known as the henbanes — is a small genus of flowering plants in the nightshade family, Solanaceae. It comprises 11 species, all of which are toxic. It, along with other genera in the same family, is a source of the drug hyoscyamine (daturine).Littorine
Littorine is a tropane alkaloid found in a variety of plants including Datura and Atropa belladonna. It is closely related in chemical structure to atropine, hyoscyamine, and scopolamine, which all share a common biosynthetic pathway.Muscarinic acetylcholine receptor
Muscarinic acetylcholine receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled receptor complexes in the cell membranes of certain neurons and other cells. They play several roles, including acting as the main end-receptor stimulated by acetylcholine released from postganglionic fibers in the parasympathetic nervous system.
Muscarinic receptors are so named because they are more sensitive to muscarine than to nicotine. Their counterparts are nicotinic acetylcholine receptors (nAChRs), receptor ion channels that are also important in the autonomic nervous system. Many drugs and other substances (for example pilocarpine and scopolamine) manipulate these two distinct receptors by acting as selective agonists or antagonists.Muscarinic acetylcholine receptor M2
The muscarinic acetylcholine receptor M2, also known as the cholinergic receptor, muscarinic 2, is a muscarinic acetylcholine receptor that in humans is encoded by the CHRM2 gene. Multiple alternatively spliced transcript variants have been described for this gene.Scopolia
Scopolia is a genus of four species of flowering plants in the family Solanaceae, native to Europe and Asia. The genus is named after Giovanni Scopoli (1723–88), a Tyrolean naturalist.
Scopolia carniolica is a creeping perennial plant, with light green leaves and pale yellow to dull red flowers. It is sometimes cultivated as a decorative plant. Scopolia's extract (which contains a form of the alkaloid scopolamine) is used in at least one commercial stomach remedy (Inosea, produced by Sato Pharmaceutical). The extract is an anti-spasmodic in low doses and may be used to relax smooth muscle tissue or prevent motion-sickness induced nausea; in higher doses it is a poison having hallucinogenic and memory-inhibiting effects.
Other alkaloids found in Scopolia carniolica include cuscohygrine and hyoscyamine.
Alkaloids found in Scopolia tangutica include hyoscyamine, scopolamine, anisodamine, and anisodine.
Alkaloids found in Scopolia atropoides (possibly just a synonym for Scopolia carniolica) include atroscine.
The coumarin phenylpropanoids umbelliferone and scopoletin have been isolated from the roots of Scopolia japonica.
The related species Atropanthe sinensis is sometimes included in Scopolia as Scopolia sinensis.Scopolia japonica
Scopolia japonica, also Japanese belladonna or Korean scopolia, is a flowering plant species in the genus Scopolia.
The coumarins umbelliferone and scopoletin have been isolated from the roots of Scopolia japonica. The hairy roots technique has also been used to produce the alkaloids scopolamine and hyoscyamine.Solanum seaforthianum
Solanum seaforthianum, the Brazilian nightshade, is a flowering evergreen vine of the Solanaceae family native to tropical South America. As a member of the Solanum genus, it is related to such plants as the tomato and potato. It is characterized by clusters of four to seven leaves and can climb to a height of 6 m (20 ft) given enough room. It blooms in the mid to late summer with clusters of star-shaped purple inflorescence followed by scarlet marble-sized berries. The plant is highly heat resistant, but cannot tolerate frost conditions. The plant contains modest amounts of various tropane alkaloids such as atropine, scopolamine and hyoscyamine and should be considered mildly toxic and inedible.
Promising molluscicidal and schistosomicidal activities were displayed for the S. seaforthianum extracts and fractions which are attributed to the glycoalkaloid content. The species has become widely naturalised outside its native range and is an invasive species in Australia, Africa, Indochina, the Pacific Islands and India, choking native vegetation and poisoning livestock.Tropane alkaloid
Tropane alkaloids are a class of bicyclic [3.2.1] alkaloids and secondary metabolites that contain a tropane ring in their chemical structure. Tropane alkaloids occur naturally in many members of the plant family Solanaceae. Some tropane alkaloids have pharmacological properties and can act as anticholinergics or stimulants.Tropic acid
Tropic acid is a chemical with IUPAC name 3-hydroxy-2-phenylpropanoic acid and condensed structural formula HOCH2CHPhCOOH. It is a laboratory reagent used in the chemical synthesis of atropine and hyoscyamine. Tropic acid is a chiral substance, existing as either a racemic mixture or as a single enantiomer.
|Plants / animals|
See also: Receptor/signaling modulators • Nicotinic acetylcholine receptor modulators • Acetylcholine metabolism/transport modulators