Scopolamine

Scopolamine

Systematic (IUPAC) name
(–)-(S)-3-Hydroxy-2-phenylpropionic acid (1R,2R,4S,7S,9S)-9-methyl-3-oxa-9-azatricyclo[3.3.1.02,4]non-7-yl ester
Clinical data
Trade names	Transdermscop
AHFS/Drugs.com	monograph
Pregnancy cat.	C (US)
Legal status	Prescription Only (S4) (AU) ℞-only (US)
Routes	transdermal, ocular, oral, subcutaneous, intravenous, sublingual, rectal, buccal transmucousal, intramuscular
Pharmacokinetic data
Bioavailability	10 - 50%
Half-life	4.5 hours
Identifiers
CAS number	51-34-3 Y
ATC code	A04AD01 N05CM05, S01FA02
PubChem	CID 5184
IUPHAR ligand	330
DrugBank	DB00747
ChemSpider	10194106 Y
UNII	DL48G20X8X Y
KEGG	D00138 Y
ChEBI	CHEBI:16794 Y
ChEMBL	CHEMBL1201024 N
Chemical data
Formula	C17H21NO4
Mol. mass	303.353 g/mol
SMILES OC[C@H](c1ccccc1)C(=O)O[C@@H]2C[C@H]3N(C)[C@@H](C2)[C@@H]4O[C@H]34
InChI InChI=1S/C17H21NO4/c1-18-13-7-11(8-14(18)16-15(13)22-16)21-17(20)12(9-19)10-5-3-2-4-6-10/h2-6,11-16,19H,7-9H2,1H3/t11-,12-,13-,14+,15-,16+/m1/s1 Y Key:STECJAGHUSJQJN-FWXGHANASA-N Y
N (what is this?)  (verify)

Scopolamine, also known as levo-duboisine and hyoscine, sold as Scopoderm, is a tropane alkaloid drug with muscarinic antagonist effects. It is among the secondary metabolites of plants from Solanaceae (nightshade) family of plants, such as henbane, jimson weed (Datura), angel's trumpets (Brugmansia), and corkwood (Duboisia). Scopolamine exerts its effects by acting as a competitive antagonist at muscarinic acetylcholine receptors, specifically M1 receptors; it is thus classified as an anticholinergic, antimuscarinic drug. (See the article on the parasympathetic nervous system for details of this physiology.)

Although scopolamine is a dangerous drug, its anticholinergic properties give it some legitimate medical applications in very minute doses. As an example, in the treatment of motion sickness, the dose, gradually released from a transdermal patch, is only 330 micrograms (µg) per day. In rare cases, unusual reactions to ordinary doses of scopolamine have occurred, including confusion, agitation, rambling speech, hallucinations, paranoid behaviors, and delusions.

Scopolamine is named after the plant genus Scopolia. The name "hyoscine" is from the scientific name for henbane, Hyoscyamus niger.

Biosynthesis in plants

The biosynthesis of scopolamine begins with the decarboxylation of L-ornithine to putrescine by ornithine decarboxylase (EC 4.1.1.17). Putrescine is methylated to N-methylputrescine by putrescine N-methyltransferase (EC 2.1.1.53).

A putrescine oxidase (EC 1.4.3.10) that specifically recognizes methylated putrescine catalyzes the deamination of this compound to 4-methylaminobutanal, which then undergoes a spontaneous ring formation to N-methyl-pyrrolium cation. In the next step, the pyrrolium cation condenses with acetoacetic acid yielding hygrine. No enzymatic activity could be demonstrated to catalyze this reaction. Hygrine further rearranges to tropinone.

Subsequently, tropinone reductase I (EC 1.1.1.206) 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. In the final step, hyoscyamine undergoes epoxidation catalyzed by 6beta-hydroxyhyoscyamine epoxidase (EC 1.14.11.14) yielding scopolamine.

History

One of the earlier alkaloids isolated from plant sources, scopolamine has been in use in its purified forms (such as various salts, including hydrochloride, hydrobromide, hydroiodide and sulfate), since its isolation by the German scientist Albert Ladenburg in 1880, and as various preparations from its plant-based form since antiquity and perhaps prehistoric times. Following the description of the structure and activity of scopolamine by Ladenburg, the search for synthetic analogues of and methods for total synthesis of scopolamine and/or atropine in the 1930s and 1940s resulted in the discovery of diphenhydramine, an early antihistamine and the prototype of its chemical subclass of these drugs, and pethidine, the first fully synthetic opioid analgesic, known as Dolatin and Demerol amongst many other trade names.

Scopolamine was used in conjunction with morphine, oxycodone, or other opioids from before 1900 into the 1960s to put mothers in labor into a kind of "twilight sleep". The analgesia from scopolamine plus a strong opioid is deep enough to allow higher doses to be used as a form of anaesthesia.

Scopolamine mixed with oxycodone (Eukodal) and ephedrine was marketed by Merck as SEE (from the German initials of the ingredients) and Scophedal starting in 1928, and the mixture is sometimes mixed on site on rare occasions in the area of its greatest historical usage, namely Germany and Central Europe.

Scopolamine was also one of the active ingredients in Asthmador, an over-the-counter (OTC) smoking preparation marketed in the 1950s and '60s claiming to combat asthma and bronchitis. In November 1990, the US Food and Drug Administration forced OTC products with scopolamine and several hundred other ingredients that had allegedly not been proved effective off the market. Scopolamine shared a small segment of the OTC sleeping pill market with diphenhydramine, phenyltoloxamine, pyrilamine, doxylamine, and other first-generation antihistamines, many of which are still used for this purpose in drugs such as Sominex, Tylenol PM, NyQuil, etc.

Methods of administration

Scopolamine can be administered orally, subcutaneously, ophthalmically and intravenously, as well as via a transdermal patch. The transdermal patch (e.g., Transderm Scōp) for prevention of nausea and motion sickness employs scopolamine base, and is effective for up to three days. The oral, ophthalmic, and intravenous forms have shorter half-lives and are usually found in the form scopolamine hydrobromide (for example in Scopace, soluble 0.4 mg tablets or Donnatal).

NASA is currently developing a nasal administration method. With a precise dosage, the NASA spray formulation has been shown to work faster and more reliably than the oral form.

Medical use

Scopolamine has a number of uses in medicine:

• Primary uses:
  • Its primary use is for the treatment of postoperative nausea and vomiting and sea sickness, leading to its use by scuba divers.
  • Treatment of intestinal cramping
  • For ophthalmic purposes
  • As a general depressant and adjunct to narcotic painkillers

• Secondary uses:
  • As a preanesthetic agent
  • As a drying agent for sinuses, lungs, and related areas: In otolaryngology, it is used to dry the upper airway (antisialogogue action) prior to instrumentation of the airway.
  • To reduce motility and secretions in the GI tract—most frequently in tinctures or other belladonna or stramonium preparations, often used in conjunction with other drugs as in Donnagel original forumulation, Donnagel-PG (with paregoric), Donnabarb/Barbadonna/Donnatal (with phenobarbital), and a number of others
  • Uncommonly, for some forms of Parkinsonism
  • As an adjunct to opioid analgesia, such as the proprietary fixed-ratio product Twilight Sleep and the technique after which it was named which contained morphine and scopolamine, Scophedal (oxycodone, ephedrine and scopolamine), some of the original formulations of Percodan, and some European brands of methadone injection^{[citation needed]}
  • As an over-the-counter sedative, (until November 1990, scopolamine in minute doses could be purchased OTC in the United States): It can be used as a depressant of the central nervous system, and was formerly used as a bedtime sedative.

Scopolamine is an ingredient of Schlesinger's Analgesic Solution, invented in the first decade of the previous century for use as a general-purpose analgesic, as well as drops for painful eye conditions, and an antitussive. The combination, as given in the 1913 US Pharmacopoeia and other national formularies, is 15 mg dionine hydrochloride, 10 mg morphine sulfate, and 125 µg scopolamine hydrobromide per cc. Some sources give the recipe as ¹/₄ grain dionine, ¹/₆ grain morphine, and ~²⁹/₈₁₀ grain of scopolamine; in some cases the salts of morphine and dionine may differ.

Nausea

It is used as an antiemetic in the form of a transdermal patch (applied behind the external ear).

Ophthalmic

The drug is used in eye drops to induce mydriasis (pupillary dilation) and cycloplegia (paralysis of the eye focusing muscle), primarily in the treatment of eye disorders that benefit from its prolonged effect, e.g. uveitis, iritis, iridocyclitis, etc.

Memory research

Because of its anticholinergic effects, scopolamine has been shown to prevent the activation of medial temporal lobe structures for novel stimuli during spatial memory tasks. It has also been shown to impair memory in humans to mimic the cognitive deficits found in Alzheimer's dementia.

Adverse effects

The common side effects are related to the anticholinergic effect on parasympathetic postsynaptic receptors: dry mouth, throat, and nasal passages in overdose cases progressing to impaired speech, thirst, blurred vision, sensitivity to light, constipation, difficulty urinating, and tachycardia. Other effects of overdose include flushing and fever, as well as excitement, restlessness, hallucinations, or delirium. These side effects are commonly observed with oral or parenteral uses of the drug and generally not with topical ophthalmic use.

Use in scuba diving to prevent sea sickness has led to the discovery of another side effect. In deep water, below 50–60 feet, some divers have reported pain in the eyes that subsides quickly if the diver ascends to a depth of 40 feet or less.^{[citation needed]} Mydriatics can precipitate an attack of glaucoma in susceptible patients, so the medication should be used with extra caution among divers who intend to go below 50 feet.^{[citation needed]}

Drug interactions

When combined with morphine, scopolamine is useful for premedication for surgery or diagnostic procedures, and was widely used in obstetrics in the past; the mixture also produces amnesia and a tranquillised state known as twilight sleep, also the name of a proprietary drug available in the past in ampoules of injectable fluid containing morphine sulfate and scopolamine hydrobromide (and in some cases the phenothiazine antinauseants prochlorperazine or promethazine as a third ingredient). Although originally used in obstetrics, it is now considered dangerous for that purpose for both mother and baby.^{[citation needed]}

Toxicity

Physostigmine is an anticholinesterase that regularly crosses the blood-brain barrier, and has been used to treat the CNS depression symptoms of scopolamine toxicity.

Recreational use

While it is occasionally used recreationally for its hallucinogenic properties, the experiences are often extremely mentally and physically unpleasant, and frequently physically dangerous, so repeated use is rare.

The use of medical scopolamine/opioid combination preparations for euphoria is uncommon, but does exist and can be seen in conjunction with opioid use. Doses of scopolamine by itself near the therapeutic range can create euphoria and anxiolysis of anticholinergic origin, similar to that of some first-generation antihistamines and similar drugs.^{[citation needed]}

Another separate group of users prefer dangerously high doses, especially in the form of datura preparations, for the deliriant and hallucinogenic effects. The hallucinations produced by scopolamine, in common with other potent anticholinergics, are especially realistic, with many users reporting hallucinations such as spiders crawling on walls and ceilings, especially in the dark. While some users find this pleasant, often the experience is not one the user would want to repeat. An overdose of scopolamine is also exceedingly unpleasant physically, and can be fatal, unlike the effect of other more commonly used hallucinogens. For these reasons, naturally occurring anticholinergics are rarely used for recreational purposes.

Scopolamine in transdermal, oral, sublingual, and injectable formulations can produce a cholinergic rebound effect when high doses are stopped. This is the opposite of scopolamine's therapeutic effects: sweating, runny nose, abdominal cramps, nausea, vomiting, vertigo, dizziness, irritability, and diarrhea. Psychological dependence is also possible when the drug is taken for its tranquilizing effects.^{[citation needed]}

Scopolamine related hospitalizations

Nevertheless, about one in five emergency room admissions for poisoning in Bogotá, Colombia, have been attributed to scopolamine. In June 2008, more than 20 people were hospitalized with psychosis in Norway after ingesting counterfeit Rohypnol tablets containing scopolamine.

Use in interrogation

The effects of scopolamine were studied by criminologists in the early 20th century. However, scopolamine as a "truth drug" was not seriously tested for this purpose until the 1950s, when it was experimented on by various intelligence agencies, including the CIA as part of Project MKULTRA. In 2009, it was proved that Czechoslovak communist secret police used scopolamine at least three times to obtain confessions from alleged anti-state conspirators. Because of a number of undesirable side effects, scopolamine was shortly disqualified as a truth drug.

Criminal use

In 1910, it was detected in the remains believed to be those of Cora Crippen, wife of Dr. Hawley Harvey Crippen, and was accepted at the time as the cause of her death, since her husband was known to have bought some at the start of the year.

In 2008, Vice News aired an episode called "Colombian Devil's Breath" recounting the use of scopolamine by Colombian criminals as a suggestion drug. The two-part investigation contains multiple first-hand accounts of its use.

A 2012 example claims small amounts are blown into victims' faces on the street to turn the victims into "mindless zombies".

Scopolamine has been used under the name burundanga in Venezuelan and Thailand resorts in order to drug and then rob tourists. While there are unfounded rumors that delivery mechanisms include using pamphlets and flyers laced with the drug, not enough is readily absorbed through the skin to have an effect. However, spiked alcoholic drinks are occasionally used.

In recent years the criminal use of scopolamine has become an epidemic. Approximately half of emergency room admissions for poisoning in Bogotá have been attributed to scopolamine.

Victims of this crime are often admitted to a hospital in police custody, under the assumption that the patient is experiencing a psychotic episode.^{[citation needed]} A telltale sign is a fever accompanied by a lack of sweat.^{[citation needed]}

Scopolamine is used criminally as a date rape drug and as an aid to robbery, the most common act being the clandestine drugging of a victim's drink. It is preferred because it induces anterograde amnesia, or an inability to recall events a certain amount of time after its administration or during the time of intoxication.^{[citation needed]}

Per the United States State Department (March 4, 2012):

• "One common and particularly dangerous method that criminals use in order to rob a victim is through the use of drugs. The most common has been scopolamine. Unofficial estimates put the number of annual scopolamine incidents in Colombia at approximately 50,000. Scopolamine can render a victim unconscious for 24 hours or more. In large doses, it can cause respiratory failure and death. It is most often administered in liquid or powder form in foods and beverages. The majority of these incidents occur in night clubs and bars, and usually men, perceived to be wealthy, are targeted by young, attractive women. To avoid becoming a victim of scopolamine, one should never accept food or beverages offered by strangers or new acquaintances or leave food or beverages unattended. Victims of scopolamine or other drugs should seek immediate medical attention."

Witchcraft and sorcery

Scopolamine was one of the active principles in many of the "flying ointments" used by witches^{[citation needed]}, sorcerers, and fellow travellers of many countries and cultures from millennia ago, ostensibly to the late 19th century or even to the present day. Scopolamine and related tropanes contributed both to the flying sensations and hallucinations sought by users of these compounds. Potions, solids of various types, and other forms were also used in some cases.

These ointments could contain any number of ingredients^{[citation needed]} with belladonna, henbane, and other plants of the belladonna and datura families being present almost invariably; they were applied to large areas of the skin with the objective being to see the gods or spirits, and/or be transported to the Sabbat.

The hallucinations, sensation of flying, often a rapid increase in libido, and other characteristic effects of this practice are largely attributable^{[citation needed]} to the CNS and peripheral effects of scopolamine and other active drugs present in the ointments, such as atropine, hyoscyamine, mandragorine, scopoline, solanine, optical isomers of scopolamine, and other tropane alkaloids.

The inclusion of belladonna- and datura]-type plants amongst the dozens of ingredients in the Haitian zombie drug is thought by some authorities to be at least somewhat likely, although scopolamine-bearing plant matter is almost certainly not the main active ingredient, which has been theorised to possibly be tetrodotoxin or a related substance.