What Is Sulfanilamide?
Sulfonamides are synthetic antibacterials that have been used in the clinic for nearly 50 years. They have the advantages of a broad antibacterial spectrum, stable properties, easy use, and no food consumption during production. Especially after the discovery of the antimicrobial synergist trimethoprim (TMP) in 1969, the combined application with sulfa drugs can enhance its antibacterial effect and expand the scope of treatment. Therefore, although there are a large number of antibiotics, sulfa drugs are still Is an important chemotherapy drug.
- Drug Name
- Sulfa drugs
- Whether prescription drugs
- prescription
- Main indications
- Antibacterial
- Drug type
- Chemotherapy drugs
- Advantages
- Broad antibacterial spectrum and stable properties
- For clinical time
- 1935
- Sulfonamides are synthetic antibacterials that have been used in the clinic for nearly 50 years. They have the advantages of a broad antibacterial spectrum, stable properties, easy use, and no food consumption during production. Especially after the discovery of the antimicrobial synergist trimethoprim (TMP) in 1969, the combined application with sulfa drugs can enhance its antibacterial effect and expand the scope of treatment. Therefore, although there are a large number of antibiotics, sulfa drugs are still Is an important chemotherapy drug.
Brief introduction of sulfa drugs
- sulfa drugs
- A class of synthetic antibacterial drugs. In 1932, GJP Dommark discovered that hundreds of waves could be controlled.
- Sulfa drugs
Basic structure of sulfa drugs
- Sulfonamides commonly used in clinical practice are derivatives with para-aminobenzenesulfonamide (sulfonamide for short) as the basic structure
- The hydrogen on the sulfonamide group can be substituted by different heterocycles to form different kinds of sulfa drugs. Compared with the parent sulfa, they have the advantages of high potency, low toxicity, broad antibacterial spectrum, and easy absorption by oral administration. The free amino group in the para position is an antibacterially active part, and if substituted, the antibacterial effect is lost. The amino group must be re-released after being decomposed in vivo to restore activity.
Classification of sulfa drugs
- According to clinical use, it can be divided into three categories: sulfa drugs that are easily absorbed by the intestine. Mainly used for systemic infections, such as sepsis, urinary tract infections, typhoid fever, osteomyelitis, etc. According to the duration of drug action, it is divided into short-acting, medium-acting and long-acting. Short-acting class absorbs quickly in the intestine and excretes quickly. Its half-life is 5 to 6 hours, and it needs to be taken 4 times a day, such as sulfamethazine (SM2) and sulfisoxazole (SIZ). 24 hours, take medication twice daily, such as sulfadiazine (SD), sulfamethoxazole (SMZ); long-acting half-life is more than 24 hours, such as sulfadiazine (SMD), sulfadimethoxine ( SDM) and so on. Intestinal sulfa drugs are difficult to absorb. Can maintain high drug concentration in the intestine. It is mainly used for intestinal infections, such as bacillary dysentery, enteritis, etc., such as phthalazide (PST). topical sulfa drugs. It is mainly used for burn infections, purulent wound infections, and ophthalmic diseases, such as sulfacetamide (SA), silver sulfadiazine (SD-Ag), and mesosulfuric acid (SML).
Antibacterial effect of sulfa drugs
- Sulfonamides inhibit many Gram-positive and some Gram-negative bacteria, Nocardia, Chlamydia, and certain protozoa (such as Plasmodium and Amoeba). Among those who are highly sensitive among positive bacteria are streptococcus and pneumococcus; those who are moderately sensitive are staphylococcus and perfringens. Among the negative bacteria were meningococcus, E. coli, proteus, dysentery, pneumococcus, and plague. Ineffective against viruses, treponema and trypanosomes. Not only is rickettsia body ineffective, but it can promote its reproduction. It is generally believed that the difference in antibacterial power of different sulfa drugs is in terms of quantity, not quality. The compound with the highest titer against one type of bacteria is also high against other types of bacteria.
Antibacterial mechanism of sulfa drugs
- Bacteria cannot directly use folic acid in the environment in which they grow. Instead, they use p-aminobenzoic acid (PABA), dihydropyridine, and glutamic acid in the environment to synthesize dihydrofolate under the catalysis of dihydrofolate synthetase in the bacteria. Dihydrofolate forms tetrahydrofolate under the action of dihydrofolate reductase. As a coenzyme of one-carbon unit transferase, tetrahydrofolate is involved in the synthesis of nucleic acid precursors (purines, pyrimidines) (Figure 2). Nucleic acid is an essential component of bacterial growth and reproduction. The chemical structure of sulfa drugs is similar to that of PABA, and it can compete with PABA for dihydrofolate synthase, which affects the synthesis of dihydrofolate, thereby inhibiting the growth and reproduction of bacteria. Because sulfa drugs can only inhibit bacteria without bactericidal effect, the elimination of pathogenic bacteria in the body ultimately depends on the defense ability of the body. In order to ensure the superiority of sulfa drugs in the competition, it should be noted in clinical use: the amount is sufficient, the first dose must be doubled, so that the concentration of sulfa in the blood greatly exceeds the amount of PABA. There is a large amount of PABA in pus and necrotic tissue, and it should be used after washing. should be avoided in combination with drugs that can decompose PABA in the body, such as procaine.
Sulfa drug resistance
- After repeated exposure of bacteria to the drug, the sensitivity to the drug decreases or even disappears. Bacteria are prone to develop resistance to sulfa drugs, especially when the dosage or course of treatment is insufficient. The reason for the resistance may be that the bacteria change the metabolic pathway, such as the production of more dihydrofolate synthase, or the direct use of folic acid in the environment. The intestinal flora is often transmitted through the transfer of R factors. When combined with antibacterial synergists, the occurrence of resistance can be reduced or delayed. Bacteria have cross-resistance to various sulfa drugs, that is, after bacteria become resistant to one sulfa drug, they are not effective against another sulfa drug. But there is no cross-resistance with other antibacterials. Absorption, distribution, metabolism, and excretion are due to the effect of sulfa drugs on bacteriostatic rather than sterilization. Therefore, to ensure the antibacterial effect of sulfa drugs, it is necessary to maintain an effective blood concentration for a sufficient period of time.
- Oral sulfa drugs are mainly absorbed in the small intestine, and the blood concentration reaches a peak within 4 to 6 hours. The drug is distributed in all tissues of the body after absorption, with the highest blood, liver, and kidney contents. Most sulfa drugs penetrate the cerebrospinal fluid. After being absorbed into the blood, a considerable part of the drug is bound to plasma proteins. The combined sulfa drug temporarily loses its antibacterial effect, cannot penetrate into the cerebrospinal fluid, is not metabolized by the liver, and is not excreted by the kidneys. However, the combination is relatively loose and sometimes released in small amounts, so it does not affect the efficacy. Long-acting sulfonamide has a high binding rate to plasma proteins, so it can be maintained in the body for a long time. Sulfa drugs can also penetrate into meningeal effusion and other effusions, as well as enter the fetal circulation through the placenta, so pregnant women should be treated with sulfa.
- Sulfonamides are mainly metabolized in the liver, and some of them fail by combining with glucuronic acid, and some of them fail by acetylation to form acetylated sulfonamide. After sulfa acetylation, the solubility is reduced, especially in acid urine, which is less soluble, and it is easy to precipitate crystals in the urine, which will damage the kidneys. The degree of acetylation of various sulfa drugs is different.
- The main excretory organ of sulfa drugs (except those that are difficult to absorb) is the kidney. Excreted from urine with prototype and acetylated sulfa and a small amount of glucuronide conjugate>
Sulfonamide toxicity
- Difficult to absorb sulfa drugs rarely cause adverse reactions. The incidence of easily absorbed adverse reactions accounts for about 5%. Allergic reactions. The most common are rash and fever. It usually occurs 5 to 9 days after medication, and is more common in children. There is cross-allergy between sulfa drugs, so it is not safe to switch to another sulfa drug when the patient is allergic to one sulfa drug. Once an allergic reaction occurs, the drug should be discontinued immediately. Long-acting sulfa drugs are very dangerous because of the high rate of binding to plasma proteins. Kidney damage. Due to the low solubility of acetylated sulfonamide, especially when the urine is acidic, crystals are easily precipitated in the renal tubules, causing symptoms such as hematuria, dysuria, and urination. In order to prevent this toxic reaction, the following measures can be taken to prevent: adding bicarbonate or citrate to alkalinize urine and increase the solubility of the excretion; drinking a lot of water to increase the amount of urine can also reduce the Concentration; the elderly and those with renal dysfunction should be used with caution. Influence of hematopoietic system. Sulfa drugs can inhibit the formation of white blood cells in the bone marrow, causing leukopenia. Occasionally, granulocyte deficiency can be recovered after drug withdrawal. Hematology should be checked for long-term application of sulfa drugs. Hemolytic anemia can be caused by those born with a deficiency of glucose 6-phosphate dehydrogenase. Sulfa drugs can enter the fetal circulation through the mother's body and compete with free bilirubin for plasma protein binding sites, increasing the concentration of free bilirubin and causing nuclear jaundice. Not suitable for pregnant women, newborns, especially premature babies. Central nervous system and gastrointestinal reactions. Mostly due to the sufficient amount of sulfonamide.
Clinical application of sulfa drugs
- After a long period of high selection, some toxic sulfa drugs such as sulfamethoxazole (ST), sulfamethazine (SM), and sulfamethazine (SMP) have gradually been phased out. Actually used in clinical only 3 ~ 4 kinds (SD, SIZ, SMZ, SA). Although many bacteria have resistance to sulfa drugs, but because sulfa drugs are cheap, easy to use, and do not produce broad-spectrum antibiotics. Due to the intestinal flora imbalance caused, sulfa-sensitive bacteria are still mainly treated with sulfa drugs, and their titers are comparable to or higher than antibiotics. The general administration method of sulfa drugs is oral administration at regular intervals. In order to reach a sufficient effective blood concentration as soon as possible, the dose should be doubled at the beginning. And because these drugs are excreted faster, to maintain blood concentration, repeated administration must be repeated. Clinically, it is mainly used in the following aspects: epidemic cerebrospinal meningitis. Among the various sulfa drugs, SD penetrates into the cerebrospinal fluid at the highest concentration, so SD is preferred when treating meningitis. Mild can be administered orally. Severely use its sodium salt for intravenous injection. Urinary tract infection. Generally, sulfa drugs with a large solubility and a large amount excreted from the urine are selected. Commonly used SIZ, SMZ. SMZ is often compounded with antibacterial synergist (TMP) at a ratio of 5: 1 to make compound Xin Nuoming tablets, and the antibacterial effect can be multiplied to dozens of times. Respiratory and pharynx infections. Acute upper and lower respiratory infections caused by bacteria. SMZ + TMP is commonly used in clinical practice. Intestinal infection. Generally, sulfa drugs that are difficult to absorb in the gastrointestinal tract are used. However, intestinal strains of anti-sulfa drugs have increased, so during treatment, some easily absorbed sulfa drugs such as SMZ + TMP can be used. Local infection. Select topical sulfa drugs. Eye diseases are commonly used in SA. SD-Ag and SML can be used for burns and wound infections. Both have anti-Pseudomonas aeruginosa effect. The chemical structure of SML is not exactly the same as that of sulfa, so it is not affected by PABA. TMP's antibacterial spectrum is similar to that of sulfa and is effective against both Gram-positive and negative bacteria. Its antibacterial effect is antibacterial rather than bactericidal. Clinically, it is mainly used as an antibacterial synergist. The antibacterial mechanism of TMP is to inhibit dihydrofolate reductase and hinder the synthesis of tetrahydrofolate. Therefore, when TMP and sulfa are used in combination, the folic acid synthesis of bacteria can be double-blocked, which not only enhances the antibacterial power, but also reduces the generation of drug resistance. Therefore, the discovery of TMP has led to new developments in sulfa drugs in antibacterial treatment. TMP is completely absorbed orally and is distributed throughout the body. It has a high concentration in lung, liver, and bile, and can penetrate into the cerebrospinal fluid. Most of it is excreted from the kidney in its original form, with a half-life of 10 hours. Clinically, TMP is often used in combination with SMZ to form a compound formulation of Novozymes. Due to the consistent in vivo processes and half-life of the two, they can always maintain a relatively stable concentration in the body and play a synergistic effect. It is commonly used clinically to treat acute and chronic urethral or respiratory infections. It is also effective for gonorrhea, severe intestinal infections and endocarditis. TMP has low toxicity. Although the human body also needs dihydrofolate reductase during the synthesis of tetrahydrofolate, experiments have shown that TMP has a lower affinity for mammalian dihydrofolate reductase than for bacteria. 10,000 to tens of thousands of times. When TMP is likely to exert a significant inhibitory effect on bacteria, it is not very toxic to humans and mammals, so the general therapeutic amount does not cause folic acid deficiency. Large doses and long-term administration, a few patients may develop leukocytes and thrombocytopenia, which can be treated with tetrahydrofolate. Animal experiments have found that TMP has teratogenic effects, so pregnant women are contraindicated.