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How do sulfonamides work?

Posted on: November 10, 2020, edit by Jason
sulfonamides
sulfonamides

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  1. Sulfonamide VS Sulfonamides
  2. Sulfonamides
    1. History
    2. How do sulfonamides work?
    3. Traits
    4. Drug resistance
  3. What are sulfa drugs?
    1. Sulfonamides for systemic infections
    2. Intestinal sulfa
    3. Topical sulfonamides
  4. The absorption reaction process of sulfa drugs
  5. Sulfa side effects
  6. Medication principle
  7. Conclusion

Sulfonamide VS Sulfonamides

1. Sulfonamide 

Sulfonamide is also called p-aminobenzene sulfonamide, p-aniline sulfonamide, p-sulfonamide aniline, and its molecular formula is C6H8N2O2S. It is white granular or powdery crystal, odorless, with slightly bitter taste. It can be used to prepare crystalline sulfa drugs for external use and anti-inflammatory, and it is also the main raw material for the synthesis of sulfa drugs.

If you eat dairy products, Ballya can also perform a sulfonamides test to tell you if there are sulfonamides residues in them.

sulfa drugs
sulfa drugs

2. Sulfonamides

Sulfonamides (SAs) are the general term for a class of drugs with a p-aminobenzenesulfonamide structure, and are a class of chemotherapeutic drugs used to prevent and treat bacterial infectious diseases. Sulfonamides are a type of antibacterial drugs commonly used in modern medicine. They have a wide antibacterial spectrum, can be taken orally, and are quickly absorbed. Some sulfonamides (such as sulfadiazine, SD) can penetrate the cerebrospinal fluid through the blood-brain barrier, which are relatively stable, and not easily deteriorated.

Sulfonamides

1. History

Sulfonamide was synthesized as an intermediate of azo dyes as early as 1908. In 1932, German scientist K. Mitch synthesized the red azo compound Bailangduoxin; from 1932 to 1935, G. Domark discovered that it had a good therapeutic effect on certain bacterial infections in experimental animals. After this epoch-making discovery was published in 1935, it caused a sensation in the world of medicine. In 1939, Domak won the Nobel Prize in Physiology and Medicine for the development of Hundred Waves. Soon, the French scientist's research clarified that the antibacterial effect of Bailangduoxi is due to the sulfonamide produced by its metabolism in the animal body.

In order to expand the antibacterial spectrum of sulfa and enhance its antibacterial activity, scientists in Europe and the United States have modified its structure in many ways, synthesized thousands of sulfa compounds (according to statistics in 1945, more than 5,000), and selected 30 of them. A variety of sulfa drugs with good efficacy and low toxicity, such as: pyridoxine, sulfadiazine (SP), sulfadiazine (SD), phthaloyl sulfathiazole (PST), sulfathiazole (ST), sulfamidine (SG), Sulfaisoxazole (SIZ), Sulfamethazine (SM2) are produced.

After the emergence of penicillin and other antibiotics, due to their higher antibacterial effects, the application of sulfa drugs was affected. However, sulfa drugs have the advantages of stable properties, easy production, low price, convenient taking, etc., so they have always played an important role in antibacterial drugs.

In 1956, the first long-acting sulfa drug that could be taken only once a day, sulfamethoxine (3-sulfa-6-methoxypyridazine), actuated new developments in the application of sulfa drugs. Later, some intermediate-acting sulfadiazines, such as sulfamethoxazole, or sulfadiazine (SMZ), which were taken twice a day, appeared, and the intermediate-acting properties of sulfadiazine were clarified. In addition, two ultra-long-acting varieties were found: 2-sulfa-3-methoxypyrazine (it can be taken once every 2 to 3 days), 2-sulfa-5,6-dimethoxypyrimidine (it is taken once a week, Therefore, it is called sulfadoxine).

In the 1960s, the antibacterial synergist trimethoprim (TMP) was discovered, which can enhance the antibacterial effect of sulfa drugs by several times to several tens of times, and expand the scope of antibacterial drugs, which strengthened the medical status of sulfa drugs. The most widely used products in clinical practice are sulfadiazine, dipyrimidine (SD+TMP), sulfamethoxazole, compound trimethoprim (SMZ+TMP), and sulfamethazine.

In addition, in the clinical application of sulfa drugs, some species have been found to inhibit carbonic anhydrase, and some have the side effects of lowering blood sugar. After systematic compound synthesis and screening, sulfa diuretics represented by hydrochlorothiazide and sulfonamide oral hypoglycemic drugs represented by tolbutamide were finally developed.

2. How do sulfonamides work?

It is a class of chemically synthesized drugs with antibacterial activity and is a derivative of p-aminobenzenesulfonamide (abbreviated as sulfonamide). Sulfonamides are bacteriostatic drugs, which inhibit the growth and reproduction of bacteria by interfering with the metabolism of bacterial folate. Unlike human and mammalian cells, bacteria that are sensitive to sulfa drugs cannot directly use folic acid in the surrounding environment.

They can only use p-aminobenzoic acid (PABA) and dihydropteridine, which are catalyzed by dihydrofolate synthase in the bacteria. Dihydrofolate is synthesized, and then tetrahydrofolate is formed by the action of dihydrofolate reductase. The activated form of tetrahydrofolate is a transfer body of one carbon unit, which plays an important role in the formation of purine and pyrimidine nucleotides. The structure of sulfa drugs is similar to that of p-aminobenzoic acid, so it can compete with p-aminobenzoic acid for dihydrofolate synthase and hinder the synthesis of dihydrofolate, thereby affecting the production of nucleic acid and inhibiting the growth and reproduction of bacteria.

3. Traits

Sulfonamide drugs are generally white or slightly yellow crystalline powders, which are easily deteriorated when exposed to light appearing a darker color. Most of these drugs have very low solubility in water and are relatively soluble in dilute alkali, but they are easily soluble in water after forming sodium salt, and its aqueous solution is strongly alkaline.

4. Drug resistance

After repeated contact between bacteria and drugs, the sensitivity to drugs decreases or even disappears. Bacteria are prone to resistance to sulfa drugs, especially when the dosage or course of treatment is insufficient. The cause of drug resistance may be that bacteria change metabolic pathways, such as producing more dihydrofolate synthase, or directly using folic acid in the environment. Intestinal flora is often transmitted through the transfer of R factor.

When combined with antibacterial synergists, it can reduce or delay the onset of drug resistance. Bacteria have cross-resistance to various sulfa drugs, that is, after bacteria develop resistance to one sulfa drug, they can also be active even with another sulfa drug. But there is no cross-resistance with other antibacterial drugs.

What are sulfa drugs?

1.Sulfonamides for systemic infections

This class of drugs can be absorbed after oral administration, but the plasma concentration of the drug lasts for a different time. According to its t1/2, it can be divided into three categories: short-acting sulfonamides (t1/2 about 6 hours), medium-acting sulfonamides (t1/2 close to 12 hours) and long-acting sulfonamides (t1/2 more than 24 hours). At present, the main clinical applications are intermediate-acting sulfamethoxazole (SMZ) and sulfadiazine (SD). Others have been used sparingly.

  • Sulfafurazole is a short-acting sulfa drug, plasma t1/2 is 5 to 7 hours. The conversion rate of acetyl is low. The highest concentration in urine can reach 1000-2000 mg/L, suitable for the treatment of urinary tract infections. Crystals are not easy to precipitate in urine. Medication is required 4 times a day, and digestive tract reactions are common.
  • Sulfadiazine (SD) is an intermediate-acting sulfa drug that is easily absorbed after oral administration. The plasma concentration reaches its peak 3 to 4 hours after administration, and the plasma t1/2 is 10 to 13 hours. It has strong antibacterial power, the lowest plasma protein binding rate is about 25%, and it easily penetrates the blood-brain barrier. The concentration of cerebrospinal fluid can reach 40% to 80% of plasma concentration. It is the drug of choice for the treatment of epidemic cerebrospinal meningitis, and it is also suitable for the treatment of urinary tract infections. But it is easy to precipitate crystals in the urine, so attention should be paid to the damage to the kidney.
  • Sulfamethoxazole (sinomin, SMZ), also known as sinomin, is a moderately effective sulfa drug with a plasma t1/2 of 10 to 12 hours. The antibacterial effect is similar to SIZ. The protein binding rate is high (60% to 80%), and the concentration of cerebrospinal fluid is lower than that of SD. Although the concentration in urine is lower than SIZ but close to SD, it is also suitable for the treatment of urinary tract infections. Crystals can precipitate in acidic urine and damage the kidneys. Pay attention to alkalinizing urine.
  • Sulfamethoxydiazine (SMD) is a long-acting sulfa drug with a plasma t1/2 of 30-40 hours. The antibacterial power is weak. It lasts longer in the body and can be taken once a day. It has low acetylation rate, high solubility in urine, and is not easy to precipitate crystals.
  • Sulfadoxine (SDM'), also known as weekly sulfa, is a long-acting sulfa drug with a plasma t1/2 of 150 to 200 hours. It can be maintained in the body for the longest time and can be taken once every 3 to 7 days. It has weak antibacterial power, suitable for mild infections and prevention of streptococcal infections, and also effective for malaria.

2. Intestinal sulfa

This type of sulfonamides is poorly absorbed after oral administration, and mainly plays a bacteriostatic effect in the intestines. There are sulfaguanidine (SG), succinthiazole (SST), phthalosulfothiazole (PST), and phthalosulfonamide (siramide, PSA) Wait.

Sulfasalazine is less absorbed orally, has a special affinity for connective tissues, and releases sulfapyridine from the connective tissues of the intestinal wall to activate antibacterial, anti-inflammatory and immunosuppressive effects. It is uitable for the treatment of non-specific colitis. Due to the long course of treatment, reactions such as nausea, vomiting, skin rash and drug fever are prone to occur.

3. Topical sulfonamides

mainly include sulfacetamide sodium (SA: SC-Na), methanesulfadiazine (SML), and silver sulfadiazine (SD-Ag). 

  • Sulfadiazine silver can exert the antibacterial effects of both SD and silver nitrate. It has a broad antibacterial spectrum, a strong inhibitory effect on Pseudomonas aeruginosa, and has astringent effect. It can promote wound healing and is suitable for second- or third-degree burns.
  • Sulfamylon (SML), also known as methanesulfonate, is a para-aminomethyl sulfa drug, so its antibacterial effect is not affected by pus and necrotic tissue. It is effective against Pseudomonas aeruginosa, Staphylococcus aureus and Tetanus bacillus. It can quickly penetrate into the wound surface and eschar, and can promote the growth and healing of the wound surface and increase the survival rate of skin grafts. It is suitable for burns and large-area post-traumatic infections.
  • Sulfacetamide (SA) is a sodium salt aqueous solution (15%-30%) close to neutral. It is almost non-irritating for topical application and has strong penetrating power. It is used to treat trachoma, conjunctivitis and keratitis.

The absorption reaction process of sulfa drugs

Since sulfa drugs are antibacterial rather than sterilizing, so if to ensure the antibacterial effect of sulfa drugs, effective blood concentration must be maintained for a long enough time.

Oral sulfa drugs are mainly absorbed in the small intestine, and the plasma concentration reaches a peak within 4 to 6 hours. After absorption, the drug is distributed in various tissues of the body, with the highest content in blood, liver, and kidney. Most sulfa drugs can penetrate into the cerebrospinal fluid. After the drug is absorbed into the blood, a considerable part of it is combined with plasma proteins.

The combined sulfa drug temporarily loses its antibacterial effect, cannot penetrate into the cerebrospinal fluid, and cannot be metabolized by the liver and excreted by the kidney. But the combination is relatively loose, and there is a small amount of release from time to time, so it does not affect the efficacy. Long-acting sulfonamides have a high binding rate to plasma proteins, so they can maintain a long time in the body. Sulfonamides can also penetrate into meningeal effusions and other effusions, and enter the fetal circulation through the placenta, so pregnant women should be cautious when using sulfa treatments.

Sulfonamides are mainly metabolized in the liver, some of which are combined with glucuronic acid and become ineffective, and some of them become acetylated sulfonamides through acetylation. After acetylation of sulfonamides, the solubility decreases, especially in acidic urine. It is easy to precipitate crystals in the urine and damage the kidneys. The degree of acetylation of various sulfa drugs varies.

The main excretory organ of sulfa drugs (except those that are difficult to absorb) is the kidney. It is excreted in the urine as the prototype and acetylated sulfonamide and a small amount of glucuronic acid conjugate. Part of it is excreted from the bile and intestines, and re-absorbed through the liver and intestines.

Sulfa side effects

Sulfa drugs that are difficult to absorb rarely cause adverse reactions. The incidence of easily absorbed adverse reactions is about 5%.

1. Allergic reaction

The most common includes skin rash and drug fever. It usually occurs 5 to 9 days after medication, especially in children. There are cross allergies between sulfa drugs, so when a patient is allergic to one sulfa drug, it is not safe to switch to another sulfa drug. Once an allergic reaction occurs, the drug should be stopped immediately. Long-acting sulfa drugs have a high binding rate to plasma proteins, and there are still drugs individuals in the blood for a few days after stopping the drug, so they are very dangerous.

2. Kidney damage

Due to the low solubility of acetylsulfonamide, especially when the urine is acidic, crystals are easily precipitated in the renal tubules, causing symptoms such as hematuria, dysuria, and urinary obstruction. In order to prevent the occurrence of this toxic reaction, the following measures can be taken to prevent: adding bicarbonate or citrate to alkalinize the urine and increase the solubility of the discharge; drinking a lot of water can increase the urine output and also reduce the discharge Concentration; the elderly and those with poor renal function should be used with caution.

3. The influence of hematopoietic system

Sulfonamides can inhibit the formation of bone marrow white blood cells and cause leukopenia. Occasionally a lack of granulocytes can be seen and will recover after stopping the drug. Long-term use of sulfa drugs should check blood. Congenital deficiency of glucose 6-phosphate dehydrogenase can cause hemolytic anemia. Sulfonamides can enter the fetal circulation through the mother and compete with free bilirubin for plasma protein binding sites, increasing higher concentration of free bilirubin and causing kernicterus. It is not suitable for pregnant women, newborns, especially premature babies.

4. Central nervous system and gastrointestinal reactions

These symptoms are mostly due to superabundant sulfa drugs.

Medication principle

  1. It is necessary to strictly follow the indications and contraindications of the medication. Those who are allergic to sulfa drugs and patients with megaloblastic anemia should not use it. Pregnant women and breastfeeding women should avoid using it. Babies younger than 2 months are also absolutely prohibited from eating it. Elderly patients should avoid using it. If there are urgent needs, they must weigh the pros and cons before applying.
  2. The first dose of sulfa drugs should be doubled in order to achieve the purpose of rapid antibacterial, and then use the maintenance dose (normal dose), and after the symptoms disappear, give the minimum dose 2-3 times in order to maintain the efficacy of the medicine for a long time and prevent the rebound of bacteria. During medication, remember not to arbitrarily increase the dosage and the frequency of medication or extend the course of treatment to prevent poisoning due to accumulation of medication.
  3. During the medication period, the patient's blood picture and urine should also be closely monitored; liver and kidney functions should be checked regularly; the patient's blood drug concentration can be measured when necessary to avoid adverse drug reactions. In addition, patients are advised to drink plenty of water and maintain a high urine flow. Those who have taken sulfa drugs for more than a week should check their urine regularly to reduce the possibility of crystaluria. If necessary, they can take sodium bicarbonate to alkalize their urine.
  4. Sulfonamide drugs can inhibit the synthesis of B vitamins in the intestine. Therefore, those who use sulfa drugs for more than one week should also be given vitamin B to prevent their deficiency.
  5. Since sulfa drugs can cause dizziness, headache, fatigue, malaise and insomnia in a few patients, they should not engage in high-altitude operations and driving during the medication period.
  6. Although sulfa drugs have a good effect on bacteria such as streptococcus, they are helpless against other bacteria. Moreover, some bacteria that could be subdued will soon develop drug resistance after a period of time. Once the drug resistance occurs, all sulfa drugs will fail. At this time, it is necessary to quickly change to other antibacterial drugs.
  7. Sulfonamides are often used in combination with antibiotics. For severe systemic infections, antibiotics should be the first choice, and sulfa drugs can only be taken as a secondary choice. Sulfa drugs, especially compound synergistic sulfa preparations, cannot be combined with multiple drugs such as penicillins, tetracyclines, sodium bicarbonate, calcium chloride, chlorpromazine, vitamin C, vitamin B1, compound sodium chloride solution, etc.

Conclusion

Sulfanilamide drugs have their own unique advantages over antibiotics, but once bacteria develop resistance, all sulfanilamide drugs become ineffective. In addition, you ought to follow doctor's advice when you need to use this kind of drugs.

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