My watch list
my.chemeurope.com  
Login  

Sulfonamide (medicine)



  There are several sulfonamide-based groups of drugs. The original antibacterial sulfonamides (sometimes called simply sulfa drugs) are synthetic antimicrobial agents that contain the sulfonamide group. Some sulfonamides are also devoid of antibacterial activity, e.g., the anticonvulsant sultiame. The sulfonylureas (main article: sulfonylureas) and thiazide diuretics (main article thiazide) are newer drug groups based on the antibacterial sulfonamides.

Sulfa allergies are common, hence medications containing sulfonamides are prescribed carefully.It is important to make a distinction between sulfa drugs and other sulfur-containing drugs and additives, such as sulfates and sulfites, which are chemically unrelated to the sulfonamide group, and do not cause the same hypersensitivity reactions seen in the sulfonamides.

Additional recommended knowledge

Contents

Function

In bacteria, antibacterial sulfonamides act as competitive inhibitors of the enzyme dihydropteroate synthetase, DHPS. DHPS catalyses the conversion of PABA (para-aminobenzoate) to dihydropteroate, a key step in folate synthesis. Folate is necessary for the cell to synthesize nucleic acids (nucleic acids are essential building blocks of DNA and RNA), and in its absence cells will be unable to divide. Hence the sulfonamide antibacterials exhibit a bacteriostatic rather than bactericidal effect.

Folate is not synthesized in mammalian cells, but is instead a dietary requirement. This explains the selective toxicity to bacterial cells of these drugs. These antibiotics are used to treat pneumocystis jiroveci pneumonia, urinary tract infections, shigellosis, and certain protozoan infections. The sulfonamide chemical moiety is also present in other medications that are not antimicrobials, including thiazide diuretics (including hydrochorothiazide, metolazone, and indapamide, among others), sulfonylureas (including glipizide, glyburide, among others), and acetazolamide.

Sulfasalazine, in addition to its use as an antibiotic, is also utilized in the treatment of inflammatory bowel disease.

History

Sulfonamide drugs (known widely as "sulfa drugs") were the first antimicrobial drugs, and paved the way for the antibiotic revolution in medicine. The first sulfonamide was trade named Prontosil, which is a prodrug. Experiments with Prontosil began in 1932 in the laboratories of Bayer AG, at that time a component of the huge German chemical trust IG Farben. The dye-based drug was synthesized by Bayer chemist Josef Klarer and tested in animals under the direction of physician/researcher Gerhard Domagk. Domagk quickly won the 1939 Nobel Prize in Medicine and Physiology, an honor that Adolf Hitler forbade him to accept (Hitler was incensed at the awarding of a Nobel Peace Prize a few years earlier to Carl von Ossietzky, an anti-Nazi activist). Domagk's prize also caused some bad feeling between him and Klarer. The discovery was in fact a team effort in which Domagk played a central role, operating under the general direction of Heinrich Hoerlein, a Farben executive later tried (and acquitted) at Nuremberg. The first official communication about the breakthrough discovery was not published until 1935, more than two years after the drug was patented by Klarer and his research partner Fritz Mietzsch. Prontosil was the first medicine ever discovered that could effectively treat a range of bacterial infections inside the body. It had a strong protective action against infections caused by streptococci, including blood infections, childbed fever, and erysipelas, and a lesser effect on infections caused by other cocci. Perplexingly, it had no effect at all in the test tube, exerting its antibacterial action only in live animals. Later it was discovered by a French research team at the Pasteur Institute that the drug was metabolized into two pieces inside the body, releasing from the inactive dye portion a smaller, colorless, active compound called sulfanilamide. The discovery helped establish the concept of "bioactivation" and dashed the German corporation's dreams of enormous profit; the active molecule sulfanilamide (or sulfa) had first been synthesized in 1906 and was widely used in the dye-making industry; its patent had since expired and the drug was available to anyone.

The result was a sulfa craze. For several years in the late 1930s hundreds of manufacturers produced tens of thousands of tons of myriad forms of sulfa. This and nonexistent testing requirements lead to the Elixir Sulfanilamide disaster in the fall of 1937, wherein at least 100 people were poisoned with diethylene glycol. This led to the passage of the Federal Food, Drug, and Cosmetic Act in 1938. As the first and only effective antibiotic available in the years before Penicillin, sulfa drugs continued to thrive through the early years of World War II. They are credited with saving the lives of tens of thousands of patients including Franklin Delano Roosevelt, Jr. (son of President Franklin Delano Roosevelt) (in 1936) and Winston Churchill. Sulfa had a central role in preventing wound infections during the war. American soldiers were issued a first aid kit containing sulfa powder and were told to sprinkle it on any open wound. During the years 1942 to 1943, Nazi doctors conducted sulfanilamide experiments on prisoners in concentration camps.

The sulfanilamide compound is more active in the protonated form, which in case of the acid works better in a basic environment. The solubility of the drug is very low and sometimes can crystalize in the kidneys, due to its first pKa of around 10. This is a very painful experience so patients are told to take the medication with copious amounts of water. Newer compounds have a pKa of around 5-6 so the problem is avoided.

Many thousands of molecules containing the sulfanilamide structure have been created since its discovery (by one account, over 5400 permutations by 1945), yielding improved formulations with greater effectiveness and less toxicity. Sulfa drugs are still widely used for conditions such as acne and urinary tract infections, and are receiving renewed interest for the treatment of infections caused by bacteria resistant to other antibiotics.

Sulpha is an alternate (British English) spelling of the common name for sulfonamide antibiotics.

Preparation

Sulfonamides are prepared by the reaction of a sulfonyl chloride with ammonia or an amine. Certain sulfonamides (sulfadiazine or sulfamethoxazole) are sometimes mixed with the drug trimethoprim, which acts against dihydrofolate reductase. Also known as Sulfa Powder. Used largely in WWII to treat any wound.

List of Sulfonamides

Side effects

Sulfonamides have the potential to cause a variety of untoward reactions, including urinary tract disorders, haemopoietic disorders, porphyria and hypersensitivity reactions. When used in large dose, it may develop a strong allergic reaction. One of the most serious is Stevens Johnson syndrome(or toxic epidermal necrolysis). Some of the original sulfonamide drugs were derived from azo dyes and had the interesting effect of temporarily turning the patient red.[citation needed]

Adverse reactions

Approximately 3% of the general population have adverse reactions when treated with sulfonamide antimicrobials. Of note is the observation that patients with HIV have a much higher prevalence, at about 60%[1]. People who have a hypersensitivity reaction to one member of the sulfonamide class are likely to have a similar reaction to others.

Hypersensitivity reactions are less common in non-antibiotic sulfonamides, and, though controversial, the available evidence suggests those with hypersensitivity to sulfonamide antibiotics do not have an increased risk of hypersensitivity reaction to the non-antibiotic agents[2].

Two regions of the sulfonamide antibiotic chemical structure are implicated in the hypersensitivity reactions associated with the class.

  • The first is the N1 heterocyclic ring, which causes a type I hypersensitivity reaction.
  • The second is the N4 amino nitrogen that, in a stereospecific process, forms reactive metabolites that cause either direct cytotoxicity or immunologic response.

The non-antibiotic sulfonamides lack both of these structures[3].

The most common manifestation of a hypersensitivity reaction to sulfa drugs are rash and hives. However, there are several life-threatening manifestations of hypersensitivity to sulfa drugs, including Stevens-Johnson syndrome, toxic epidermal necrolysis, agranulocytosis, hemolytic anemia, thrombocytopenia, and fulminant hepatic necrosis, among others[4].

See also

References

  1. ^ SA Tilles (Aug 2001). "Practical issues in the management of hypersensitivity reactions: sulfonamides". Southern Medical Journal 94 (8): 817-24.
  2. ^ CG Slatore (Aug 2004). "Sulfonamide hypersensitivity". Immunology and Allergy Clinics of North America 24 (3): 477-90,vii.
  3. ^ CC Brackett (Jul 2004). "Likelihood and mechanisms of cross-allergenicity between sulfonamide antibiotics and other drugs containing a sulfonamide functional group". Pharmacotherapy 24 (7): 856-70.
  4. ^ (1994) Harrison's Principles of Internal Medicine, 13th Ed.. McGraw-Hill Inc., 604. 


 
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Sulfonamide_(medicine)". A list of authors is available in Wikipedia.
Your browser is not current. Microsoft Internet Explorer 6.0 does not support some functions on Chemie.DE