Introduction
Consulting the print edition of the Canadian Compendium of Pharmaceuticals and Specialties1 (CPS) for the product monograph of the drug Bisoprolol, my attention strayed to the immediately preceding entry Bismutal:2
Alchemical symbol, Bismuth, used by Torbern Bergman, 17751.
Bismutal
bismuth camphocarbonate-guaifenesin
Sore Throat Treatment
Rougier Pharma
SUPPLIED: Each white to creamy white opaque rectal suppository contains: bismuth camphocarbonate 150 mg and guaifenesin 250 mg. Non-medicinal ingredients: semisynthetic glycerides. Boxes of 2.”
Guaifenesin1 is an expectorant1 present in many cough syrups.
How does a drug containing the heavy metal bismuth,1 administered as a rectal suppository,1 act on a sore throat?!! Read on. The CPS contains a section cross-referencing all chemical names and generic names to trade names, indicating which entry is most informative. In addition to bismuth camphocarbonate in Bismutal®, two other bismuth compounds are listed as pharmaceuticals: bismuth dipropylacetate in Neo-Laryngobis® and bismuth subsalicylate1 in Pepto-Bismol®.1
Bismuth and bismuth compounds
Bismuth, element 83, is a heavy metal in the same chemical family as nitrogen, phosphorus, arsenic and antimony. According to Greenwood and Earnshaw, Chemistry of the Elements,3 world production and use of bismuth and its compounds hovered around 4000 metric tonnes per annum in the years up to 1997. The major uses are in pharmaceuticals, in fusible low-melting alloys (e.g., in fire sprinklers) and in metallurgical additives. In common with the elements arsenic, antimony, cobalt and zinc, bismuth metal was first produced from its ores during the 13th to 15th centuries. These were the first elements to be produced since those known to the ancient world. In 1450, a bismuth alloy was used to cast type for Gutenberg presses.1 No industrial poisoning by bismuth has ever been reported — suggesting that this element is not highly toxic.
Bismuth compounds are known in both the +3 and the +5 oxidation states; the +3 state is far more stable. For example, the Bi(III) halides BiF3, BiCl3, BiBr3 and BiI3 are all stable and are produced commercially, while of the Bi(V) halides only BiF5 is known. BiF5 is extremely reactive; it converts paraffin oil to fluorocarbons, and UF4 to UF6. The bismuth pharmaceutical compounds are all Bi(III) compounds.
Historical use of bismuth pharmaceuticals
The Wikipedia article on Pepto-Bismol states that the use of bismuth subsalicylate as an oral remedy for gastric upset dates to at least 1901. A web search for information on bismuth pharmaceuticals turned up a useful source from the British Journal of General Practice. In a 1955 article4 describing various treatments for tonsillitis1 author W. J. H. Lord summarizes the history of the use of bismuth in treating oral infections, dating from 1923 in Brazil for the treatment of infections by Vincent’s organisms, which cause ulcerative gingivitis.1 The administration of bismuth drugs in suppositories dates to the early 1940s. For tonsillitis, Lord recommends the use of bismuth sodium tartrate in cocoa butter suppositories, compounded by the local pharmacist.
Bismuth pharmaceutical compounds
Bismuth subsalicylate and bismuth subgallate1,5
Bismuth subsalicylate1.
Bismuth subsalicylate (pink bismuth) is the active ingredient of Pepto-Bismol. It is administered orally, is extremely insoluble and is not absorbed from the digestive tract. It acts in the digestive tract to relieve digestive upset. According to the Wikipedia article, which lists references, bismuth subsalicylate exists as at least two very large, highly water-insoluble, multi-bismuth-atom cluster complexes. Bismuth subgallate1 is chemically similar to bismuth subsalicylate and has similar uses.
Bismuth camphocarbonate
Bismuth subgallate1.
This compound, which is the medicinal ingredient of Bismutal, is apparently widely used around the world. A web search turned up a listing of four vendors,6 numerous synonyms and two MSDS pages.6 Two of the vendors’ webpages6 state elemental analysis percentages and propose structures for the compound. These two analyses and structures are different: one structure contains a single bismuth atom, the other two. In both, the bismuth atoms are shown bonded to three oxygen atoms. Both structures contain three camphor1 residues.
The wide usage of bismuth camphocarbonate suggests that this compound is an effective treatment for bacterial infections of the mouth and throat.
Bismuth dipropylacetate.
Bismuth dipropylacetate is the medicinal ingredient of Neo-Laryngobis, for the treatment of sore throat. A product monograph is available online from Health Canada.7
Neo-Laryngobis is available over-the-counter in Canada from Teva Canada/Rougier Pharma. Bismutal is not. A sample package of Neo-Laryngobis was obtained by special order through Shoppers Drug Mart® in Toronto.
Bismuth camphocarbonate structure from ChemSpider8.
The CPS product monograph for Neo-Laryngobis is very informative:
“Neo-Laryngobis
bismuth dipropylacetate
Sore Throat- Loss of Voice Treatment
Rougier Pharma
Dipropylacetate ion8.
PHARMACOLOGY: Bismuth dipropylacetate has both anti-bacterial and anti-inflammatory activity. Once absorbed, it distributes into the lymph ducts and is eliminated from the tonsils into the saliva. Once in the saliva, it acts to disinfect the pharyngeal area. ……………………
INDICATIONS: For the treatment of throat infections, more particularly for non-diphtheritic anginas, pharyngitis, tonsillitis, laryngitis and gingivostomatitis. Also recommended as an adjuvant to the treatment of tonsil phlegmons, Vincent's angina, otitis and sinusitis.
CONTRAINDICATIONS: In the presence of chronic nephritis, albumin deficiency, congestive heart failure, rectal lesions and intolerance towards bismuth……
DOSAGE: Adults: One 135 mg rectal suppository daily. …..
SUPPLIED: Each white to creamy white opaque rectal suppository contains: bismuth dipropylacetate 135 mg (bismuth octanoate). Non-medicinal ingredients: semisynthetic glycerides.Boxes of 2. …….”
Bismuth camphocarbonate structure from Chemical Book6.
Discussion
My take on the above information is as follows:
- Bismuth camphocarbonate and bismuth dipropylacetate are neutral complexes which are at least somewhat soluble in water, but probably more soluble in lipid. They are not absorbable from the digestive tract and thus cannot be administered orally. Instead, they are mixed with lipid and administered as a rectal suppository. The absorption process is probably similar to the way emulsified lipids in food move passively from the small intestine into the lymph ducts called lacteals.1
- The bismuth complex from the suppository enters the lymphatic ducts passively, and is transported passively by the lymphatic system, entering the bloodstream at the thoracic duct.1
Neo-Laryngobis
Suppositories
(The ruler scale shown
is in cm units). Photo: D. Cash 2014.
-
The blood circulation takes the bismuth complex throughout the body. It is selectively removed from the blood by the tonsils,1 which are lymph glands. It enters the saliva, taking its effect in the throat.
- Excretion of the bismuth compound from the blood is via the kidneys, hence the precaution that chronic nephritis1 is a contraindication for use.
Questions for students
- Have students verify the oxidation state of bismuth in both online structures proposed for bismuth camphocarbonate.
- Draw the structural formulas of and give the IUPAC names and common names of the acids corresponding to the salicylate anion, the gallate anion and the dipropylacetate anion. Is octanoate an acceptable common or IUPAC name for dipropylacetate anion? Explain.
- What are the source, formula and structure of camphor? What are the uses of camphor? Why is camphor used in a pharmaceutical?
- (Food for thought.) Many elements near bismuth in the periodic table are very toxic: e.g., mercury, thallium, lead, arsenic. Propose reasons why bismuth is not also very toxic.
References
- www.wikipedia.org: Compendium of Pharmaceuticals and Specialties; guaifenesin; expectorant (mucokinetics); bismuth; suppository; bismuth subsalicylate; Pepto-Bismol; Gutenberg press; tonsillitis; ulcerative gingivitis; bismuth subgallate; camphor; lacteals; thoracic duct; tonsil; nephritis.
- Compendium of Pharmaceuticals and Specialties, Canadian Pharmacists Association, 2011 print edition: Bismutal, page 418; Neo-Laryngobis, page 1638.
- N.N. Greenwood and A. Earnshaw, Chemistry of the Elements, 2nd Edition, Butterworth Heinemann, 1997, Chapter 13, pages 547-549.
- BJGP November 1, 1955, os-3/9/pages 140-146: http://bjgp.org/content/os-3/9/140.full.pdf.
- What body noises really mean, Consumer Reports on Health, Consumers Union, April 2015, page 11.
- Bismuth camphocarbonate information from following websites:
Chemical Handbook, http://www.chemicalbook.com/
PubChem, https://pubchem.ncbi.nlm.nih.gov/
American Custom Chemical Corporation, http://acccorporation.com.
- Health Canada: search Drug Product Database under Neo-Laryngobis or DIN 00065927, www.hc-sc.gc.ca.
- ChemSpider, www.chemspider.com.
