Scopolamine

Scopolamine is a drug used to treat motion sickness and in ophthalmology as a diagnostic agent. Chemically, scopolamine is a so-called tropane alkaloid, which is naturally found in some plants of the nightshade family(lat. Solanaceae). These include mainlybelladonna (Atropa belladonna), henbane(Hyoscamus niger), datura(Datura stramonium) and the genus of angel's trumpet(Burgmansia). In pharmacology, the substance is classified as an anticholinergic.

Scopolamine is available only on prescription.

Indications and uses

Scopolamine is used therapeutically usually for treatment of postoperative nausea and motion sickness. In the former, it is administered in the form of a transdermal patch. Furthermore, it is often used in ophthalmology. Here it is used to dilate the pupils in order to examine the refractive power of the eye.

In addition, scopolamine can be used in palliative medicine to alleviate the so-called death rattle, which often occurs in the last hours of life of the seriously ill. It is administered either subcutaneously or as a transdermal patch. Although scopolamine has not yet been approved for this use in most countries, intensive research is still underway. There are already some studies indicating efficacy in this area, which could potentially lead to future approval.

History

In ancient and medieval times, potions and preparations made from plants now known to contain scopolamine were used. Nevertheless, widespread use of analgesic drugs probably did not occur, probably because of side effects and unpredictable dose-response relationships. The word "scopolamine" is derived from "Scopolia carniolica," a nightshade plant so named by Carl von Linné in honor of its presumed discoverer, J. A. Scopoli. Although scopolamine was first fully synthesized in 1959, the synthesis is still less efficient than the extraction of scopolamine from plants.

Pharmacology and mechanism of action

Acetylcholine (ACh) is a neurotransmitter that transduces signals through G-protein-coupled muscarinic receptors (mAChRs). These receptors, which are present in the central nervous system (CNS) and periphery, regulate various physiological processes such as smooth muscle contraction, glandular secretion, heart rate, and neurological processes such as learning and memory. Muscarinic receptors can be divided into five subtypes (M1-M5) and are found at various levels throughout the brain. In addition, M2 receptors are found in the heart and M3 receptors in smooth muscle. This receptor system is also involved, in part, in the development of nausea and the urge to vomit.

Scopolamine acts as a non-selective competitive inhibitor of M1-M5 mAChRs, with much weaker inhibition of M5. As an anticholinergic, scopolamine has a very narrow therapeutic range and therefore highly dose-dependent therapeutic and adverse effects. An advantage of scopolamine over the other representatives of anticholinergics (e.g., atropine) is its good penetration of the blood-brain barrier. Therefore, it is well suited for the treatment of nausea and motion sickness. Administration to the eyes results in inhibition of muscarinic receptors in the ciliary muscles, causing dilation of the pupils (mydriasis). However, due to its extremely long half-life, scopolamine is now only second choice for use in ophthalmology.

Pharmacokinetics

The pharmacokinetics of scopolamine are highly dependent on the route of administration. Oral administration of 0.5 mg scopolamine to healthy volunteers results in an absolute bioavailability of only 13%. Due to the dose-dependent adverse effects of oral administration, a transdermal patch formulation was developed to achieve therapeutic plasma concentrations over a longer period of time and minimize side effects. Following patch application, scopolamine is detectable in the blood within four hours and reaches peak concentrations within 24 hours. Thereby, the average drug release is approximately 1.0 mg/ 72h.

The volume of distribution of scopolamine is not precisely known. In rats, scopolamine shows a relatively low plasma protein binding of 30 ± 10%. The exact values in humans are not known. Little is known about the metabolism of scopolamine in humans. Numerous metabolites have been detected in animal studies. In general, scopolamine is metabolized primarily in the liver, and the primary metabolites are various glucuronide and sulfide conjugates. After oral administration, approximately 2.6% of unchanged scopolamine is excreted in the urine. After transdermal application, this value is approximately 10%. The half-life of scopolamine varies depending on the route of administration. For intravenous, oral, and intramuscular administration, the half-life is approximately 70 minutes. For subcutaneous administration, the half-life is approximately 213 minutes. After removal of the transdermal patch system, scopolamine plasma concentration decreases in a log-linear fashion with a half-life of approximately 9.5 hours.

Drug Interactions

Concomitant use of scopolamine and H2 receptor blockers may result in increased inhibition of gastric acid secretion.

If belladonna preparations, antihistamines, tricyclic antidepressants (such as amitriptyline and imipramine), amantadine, or quinidine are taken concomitantly, there is a possibility of increased anticholinergic effects. In this case, the dosage of these drugs should be adjusted accordingly

It is not recommended to use scopolamine together with other agents against motion sickness

Consumption of alcohol should be avoided during the use of scopolamine.

Contraindications

Scopolamine must not be taken/used if:

• There is an allergy to the substance
• glaucoma (green cataract) is present

Side effects

Very common and frequent side effects:

• Dry mouth
• dizziness
• blurred vision
• Irritation of the eyelids
• Skin irritation

Rare and very rare side effects

• difficulty urinating
• poor concentration and memory
• Skin rash

Pregnancy and lactation

In pregnancy, scopolamine may be used throughout pregnancy if strictly indicated.

With single use of scopolamine, breastfeeding appears to be acceptable with careful observation of the infant for anticholinergic symptoms.