Mechanism of action and selectivity
The action of sulfonamides is based on their structural similarity to para-aminobenzoic acid (PABA). Normally, bacteria use PABA and dihydropteridine to synthesize dihydropteroic acid with the help of the enzyme dihydropteroate synthase.
Sulfonamides engage in competitive antagonism with PABA, taking its place on the enzyme. As a result, the formation of dihydropteroic acid and subsequently dihydrofolic acid is blocked. The bacterium loses the ability to synthesize purines, pyrimidines, and certain amino acids (e.g., methionine), which halts DNA and RNA assembly. A bacteriostatic effect occurs—microorganisms stop growing and multiplying, but do not die immediately.
The drugs are highly selective and safe for the macroorganism. Human cells lack dihydropteroate synthase, as we do not synthesize folic acid de novo, but instead uptake preformed vitamins from the blood via specific membrane carriers.
Pharmacokinetic classification
The main criterion for dividing these drugs is their ability to be absorbed and excreted from the body.
- For systemic (resorptive) action (well absorbed in the gastrointestinal tract):
- Short-acting (half-life up to 10 h): sulfanilamide, sulfathiazole, sulphaethidole. Require frequent administration (4–6 times a day).
- Intermediate-acting (10–24 h): sulfadiazine, sulfamethoxazole.
- Long-acting (24–48 h): sulfadimetoxine, sulfamonomethoxine. Prescribed 1–2 times a day.
- Ultra-long-acting (more than 48 h): sulfalene.
- Acting within the intestinal lumen (poorly absorbed, creating high concentrations in the GI tract):
- Phthalylsulfathiazole.
- Sulfaguanidine.
- For topical use (ointments, creams, eye drops):
- Sulfacetamide.
- Silver sulfadiazine.
Spectrum of activity and resistance
Initially, the group had a broad spectrum of action, but due to prolonged use, most staphylococci, pneumococci, and gonococci have acquired resistance.
How bacteria adapt to the drugs:
- Begin synthesizing PABA in huge amounts (substrate hyperproduction).
- Mutate the structure of the target enzyme, reducing its affinity for the drug.
- Decrease the permeability of their cell wall.
Today, sulfonamides remain drugs of first choice for nocardiosis, toxoplasmosis, and tropical malaria (in combinations). They also retain activity against Chlamydia, Pneumocystis, and Actinomyces.
Pharmacokinetics and interactions
Systemic drugs have high bioavailability (70–100%) and penetrate all tissues, including the blood-brain barrier, serous cavities, and placenta.
- Protein binding: Long-acting drugs bind firmly to plasma albumins. If the patient is taking other medications (NSAIDs, warfarin, phenytoin), they can displace sulfonamides from protein binding, sharply increasing their free fraction and the risk of toxicity.
- Metabolism: Occurs in the liver via acetylation. Acetylated metabolites lose antimicrobial activity and are extremely poorly soluble in an acidic environment.
- Excretion and complications: Excreted by the kidneys. Upon urine acidification (e.g., due to ascorbic acid intake), metabolites can precipitate, causing crystalluria. This is especially typical for short-acting drugs.
- Antagonism: In purulent wounds and tissue breakdown foci, there are many preformed purine and pyrimidine bases—bacteria use them, bypassing the blocked pathway, so drug efficacy drops. Furthermore, their action is neutralized by local anesthetics (procaine, benzocaine), which release PABA upon hydrolysis.
Briefly: answers to topical questions
What side effects are typical for sulfonamides?
Sulfonamides are characterized by a wide range of adverse reactions affecting various organ systems.
- Allergic and skin reactions — fever, pruritus, rash, photosensitization, lupus-like syndrome, anaphylactic shock, Stevens-Johnson syndrome.
- Dyspeptic disorders — nausea, vomiting, diarrhea.
- Hepatotoxicity — cholestatic jaundice, chronic hepatitis.
- Hematological disorders — anemia (including hemolytic), leukopenia, thrombocytopenia, granulocytopenia.
- Kidney damage — crystalluria (drug precipitation in acidic urine).
- Neurotoxicity — headache, dizziness, asthenia, peripheral polyneuropathies.
- Specific complication in newborns — kernicterus due to bilirubin displacement from albumin binding.
What is the fixed combination of sulfamethoxazole and trimethoprim called?
The fixed combination of sulfamethoxazole and trimethoprim is called co-trimoxazole. This drug is also known under the brand names bactrim and biseptol. The combination of these two components provides potentiation of action and leads to a bactericidal effect, unlike the bacteriostatic effect of each substance individually. Resistance of microorganisms develops significantly slower to this combination because the drugs block different enzymes of the folic acid metabolic pathway.
Which drugs belong to the salazosulfonamide group?
Drugs representing combinations of sulfonamides with salicylic acid include sulfasalazine, salazopyridazine, and salazodimethoxine. These medications are used as anti-inflammatory drugs in the intestine.
- Sulfasalazine is an azo compound of sulfapyridine and 5-aminosalicylic acid; taken orally (per os).
- Salazopyridazine and salazodimethoxine are analogues of sulfasalazine with similar properties.
- Reported side effects for sulfasalazine include dyspepsia, burning sensation in the rectum, leukopenia, agranulocytosis, ataxia, seizures, tinnitus, hallucinations, photosensitization, and interstitial pneumonitis.
To remember the mechanism: SULFAanilamides Successfully Compete with PABA for the enzyme, depriving the bacterium of folic acid.
Class and exam questions
Why don't sulfonamides affect human cells?
Mammalian cells do not synthesize folic acid, but obtain preformed vitamins externally. Humans simply lack the dihydropteroate synthase enzyme that these drugs block.
Why does procaine reduce the efficacy of sulfonamides?
Local anesthetics, such as procaine (novocaine), are esters of PABA. During their breakdown in tissues, PABA is released, which displaces the sulfonamide and restores folic acid synthesis in bacteria.
Why are sulfonamides combined with trimethoprim?
This provides a "double hit" to bacterial metabolism. Sulfonamide blocks the first step (synthesis of dihydrofolic acid), and trimethoprim blocks the second (the work of dihydrofolate reductase), which sharply enhances the antibacterial effect.
What else to study on this topic
- Features of sulfonamide use in urinary tract infections.
- Combination drugs with salicylic acid in gastroenterology.
- Use of sulfones in the treatment of leprosy.
- The historical significance of the discovery of prontosil by Gerhard Domagk.
- Detailed analysis of the folic acid cycle and nucleotide synthesis.
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