Sulfonamides are synthetic antibacterial drugs, which have been used clinically for nearly 50 yearsAntibacterial spectrumIt has the advantages of wide range, stable property, simple use, and no consumption of grain during production.Especially in 1969Antibacterial synergist——After the discovery of trimethoprim (TMP), the combination of trimethoprim (TMP) and sulfonamides can enhance its antibacterial effect and expand the scope of treatment. Therefore, although a large number of antibiotics have come out, sulfonamides are still important chemotherapeutic drugs.
Artificial synthesisA class of antibacterial drugs.In 1932, GJ. P. Domark found that Bailangduoxi can control
Sulfonamides
Streptococcus infection.In 1935, sulfonamides were officially used in clinical practice.haveAntibacterial spectrumIt is wide, stable in nature, widely distributed in the body, does not need food as raw materials for manufacturing, has the advantages of large output, many varieties, low price, simple use, and adequate supply.Although there are many effective antibiotics, sulfonamides are used to control variousBacterial infectionIn the treatment of acute diseasesurinary tract infection It still has important value.Sulfonamides are easy to produceDrug resistanceAcetylated sulfonamide, a metabolite in the liver, has low solubility and is easy to precipitate crystals in the urine, causing renaltoxicityTherefore, the dosage and time should be strictly controlled, and sodium bicarbonate should be taken with more water.
Basic structure
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The commonly used sulfonamides in clinic are derivatives with p-aminobenzenesulfonamide (sulfa for short) as the basic structure
The hydrogen on the sulfonamide group can be replaced by different heterocycles to form different kinds of sulfonamides.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 isantibacterial activitySome, if replaced, will lose antibacterial effect.The amino acid must be released again after decomposition in the body to restore its activity.
classification
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According to the clinical use, it can be divided into three categories: ① Sulfonamides that are easily absorbed in the intestine.Mainly used for systemic infection, such assepticemiaUrinary tract infection, typhoid fever, osteomyelitis, etc.according toDrug actionThe duration is divided into short effect, medium effect and long effect categories.Short acting species absorb and excrete quickly in the intestinal tract,half life5~6 hours, 4 times a day, such asSulfamethazine(SM2), sulfamethoxazole (SIZ);The half-life of medium effect drugs is 10-24 hours, and they are taken twice a day, such as sulfadiazine (SD), sulfamethoxazole (SMZ);The half-life of long-acting drugs is more than 24 hours, such as sulfamethoxine (SMD), sulfamethoxine (SDM), etc. ②Sulfonamides that are difficult to absorb in the intestine.It can maintain high drug concentration in the intestinal tract.It is mainly used for intestinal infection, such as bacillary dysentery, enteritis, etc., such as phthalein sulfathiazole (PST). ③Sulfonamides for external use.It is mainly used for burn infection, suppurative wound infection, ophthalmic diseases, etc., such as sulfacetamide (SA), sulfadiazine silver salt (SD Ag), and methanesulfonate suppurative (SML).
Antibacterial effect
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Sulfonamides are effective against many gram-positive bacteria and someGram negative bacteria、Nocardia、chlamydiaGenus and someprotozoan(such as plasmodium andAmoeba）All of them have inhibitory effect.Among the positive bacteria, the highly sensitive ones arestreptococcusAnd pneumococcus;Staphylococcus and Clostridium perfringens were moderately sensitive.Sensitive persons among negative bacteriaMeningococci, Escherichia coliProteus、Shigella、Pneumonia、Yersinia pestis。For virusesSpirochete, Trypanosoma is invalid.Opposite kettsia is not only ineffective, but can promote its reproduction.It is generally believed that the difference in the antibacterial power of different sulfonamides is in quantity, not in quality.The compounds with the highest potency for one type of bacteria also have high potency for other types of bacteria.
Antibacterial mechanism
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Bacteria can not directly use folic acid in their growth environment, but use para aminobenzoic acid (PABA), dihydropteridine and glutamic acid in the bacteriasynthetaseDihydrofolate was synthesized under catalysis.Dihydrofolate inDihydrofolate reductaseTetrahydrofolate, as the coenzyme of one carbon unit transferase, participates in the synthesis of nucleic acid precursors (purine and pyrimidine) (Figure 2).Nucleic acid is an essential component for bacterial growth and reproduction.The chemical structure of sulfonamides is similar to that of PABA, which can compete with PABA for dihydrofolate synthetase and affect the synthesis of dihydrofolate, thus inhibiting the growth and reproduction of bacteria.As sulfa drugs can only inhibit bacteria without killing bacteria, the elimination of pathogenic bacteria in the body ultimately depends on the body's defense ability.In order to ensure that sulfonamides are dominant in the competition, attention should be paid to: ① sufficient dosage, the first dosage must be doubled, so that the concentration of sulfonamides in blood greatly exceeds the amount of PABA. ②The pus and necrotic tissue contain a large amount of PABA, which should be washed before use. ③It should be avoided to use with drugs that can decompose PABA in the body, such as procaine.
Drug resistance
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After repeated contact with drugs, the sensitivity of bacteria to drugs decreases or even disappears.Bacteria are easy to produce sulfonamidesDrug resistance, especially when the dosage or course of treatment is insufficient.The reason for drug resistance may be bacterial changeMetabolic pathwayIf more dihydrofolate synthase is produced or folic acid in the environment can be directly used, intestinal flora is often transmitted through the transfer of R factor.When andAntibacterial synergistWhen used together, it can reduce or delay the occurrence of drug resistance.Bacteria have cross resistance to various sulfonamides, that is, when bacteria are resistant to one sulfonamide, they are also ineffective to another sulfonamide.But there was no cross resistance with other antibiotics.Absorption, distribution, metabolismexcretionSince the effect of sulfonamides is bacteriostasis rather than sterilization, to ensure the antibacterial effect of sulfonamides, effective blood concentration must be maintained for a long enough time.
Oral sulfa drugs are mainly absorbed in the small intestine, and the blood concentration reaches its peak within 4-6 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 penetratecerebrospinal fluidMedium.After the drug is absorbed into the blood, a considerable part ofPlasma proteinThe combined sulfa drug temporarily loses its antibacterial effect, cannot penetrate into cerebrospinal fluid, is not metabolized by liverRenal excretion。However, the combination is relatively loose, sometimes with a small amount of release, so it does not affect the efficacy.Long acting sulfa andPlasma protein binding rateHigh, so it lasts for a long time in the body.Sulfonamides can penetrateMeningesFluid accumulation and other fluid accumulation, as well as entering the fetal circulation through the placenta, so pregnant women should be cautious in using sulfanilamide treatment.
Sulfonamides are mainly metabolized in the liver, and some are related toGrapeThe glucuronic acid is bound to lose efficacy, and some of them are acetylated to form acetylated sulfonamide, which loses efficacy.After sulfonamide acetylation, the solubility is reduced, especially in acidic urine. It is easy to precipitate crystals in urine and damage the kidney.The degree of acetylation of various sulfonamides is different.
The main excretory organ of sulfonamides (except those difficult to absorb) is the kidney.Excretion from urine as prototype and acetylated sulfa and a small amount of glucuronic acid conjugates>
Toxic reaction
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InabsorbableSulfonamidesIt rarely causes adverse reactions.The incidence of easily absorbed adverse reactions was about 5%. ①Anaphylactic reaction。The most common arerash. Drug fever.It usually occurs 5-9 days after medication, especially in children.There is cross allergy between sulfonamides, so it is unsafe for patients to switch to other sulfonamides when they are allergic to one.In case of allergic reaction, the drug should be stopped immediately.Long acting sulfa drugs have high binding rate with plasma protein, and there are still drugs in the blood for several days after drug withdrawal, so the risk is very high. ②Kidney damage。Because of the low solubility of acetylated sulfonamide, especially when the urine is slightly acidic, it is easy toRenal tubulePrecipitation and crystallization inhematuria, pain in urination, urination and other symptoms.To prevent thisToxic reactionThe following measures can be taken to prevent the occurrence of: taking bicarbonate or citrate to alkalize the urine and increase the solubility of the effluent;Drinking a lot of water can increase urine output and also reduce the concentration of excreta;The elderly andrenal functionThose with defects should be used with caution. ③Hematopoietic system.Sulfonamides can inhibit the formation of white blood cells in bone marrow, causingLeukopenia。Granulocyte deficiency was occasionally seen, which could be recovered after drug withdrawal.Blood picture should be checked after long-term treatment with sulfonamides.Congenital deficiency of glucose-6-phosphate dehydrogenase can cause hemolytic anemia.Sulfonamides can enter the fetal circulation through the motherbilirubinCompeting for the binding site of plasma protein increases the concentration of free bilirubin, causing nuclear jaundice.Especially for pregnant women and newbornspremature infantNot suitable for use. ④central nervous systemAnd gastrointestinal reactions.Most of them are due to sufficient sulfa.
clinical application
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After long-term high selection, some highly toxic sulfonamides are gradually eliminated, such as sulfathiazole (ST)Sulfamethazine(SM), sulfamethoxydazine (SMP).There are only 3-4 kinds (SD, SIZ, SMZ, SA) actually used in clinic. Although many bacteria are resistant to sulfonamides, sulfonamides are cheap, easy to use, and do not produce symptomsBroad-spectrum antibioticFrequently causedDysfunction of intestinal floraTherefore, sulfa sensitive bacteria are still mainly treated with sulfa drugs, whose potency is equal to or higher than that of antibiotics.The common administration method of sulfonamides is to take them orally at regular intervals. In order to reach sufficient effective blood concentration as soon as possible, the dosage should be doubled at the beginning.And because of these drugsexcretionFaster. To maintain the blood concentration, the drug must be administered repeatedly.Clinically, it is mainly used in the following aspects: ①Epidemic cerebrospinal meningitis。Among various sulfonamides, SD has the highest concentration in cerebrospinal fluid, so treatmentmeningitisSD is preferred.Mild illnessOral administration。In severe cases, use its sodium salt for intravenous injection. ②urinary-tract infection。Generally, sulfa drugs with large solubility and more excretion from urine are selected.SIZ and SMZ are commonly used.SMZ is usually made with antibacterial synergist (TMP) in a ratio of 5:1Compound sulfamethoxazoleTablets, the antibacterial effect can be increased several times to dozens of times. ③Respiratory and pharyngeal infections.Acute symptoms caused by bacterialower respiratory tract infection。SMZ+TMP is commonly used in clinic. ④Intestinal infection.Sulfonamides that are difficult to absorb in the gastrointestinal tract are generally selected.However, the intestinal bacteria of anti sulfa drugs have increased, so some easily absorbed sulfa drugs, such as SMZ+TMP, can be used in treatment. ⑤Local infection。Sulfonamides for external use are selected.SA is commonly used for eye diseases, and SD Ag and SML can be used for burns and wound infections, both of which are resistant toPseudomonas aeruginosaeffect.The chemical structure of SML is not exactly the same as that of sulfa, so it is not affected by PABA.The antibacterial spectrum of TMP is similar to that of sulfanilamide, and it is effective against both gram-positive and negative bacteria.Its antibacterial effect is bacteriostasis rather than sterilization.It is mainly used as antibacterial synergist in clinic.The antibacterial mechanism of TMP is to inhibit dihydrofolate reductase and hinder the synthesis of tetrahydrofolate.Therefore, when TMP is used in combination with sulfanilamide, 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 development of sulfonamides in antibacterial treatment.TMP is completely absorbed orally and distributed throughout the bodybileMedium high concentration, can penetrate into cerebrospinal fluid, and most of them are discharged from the kidney in original form, with a half-life of 10 hours.In clinical practice, TMP and SMZ are often used as a mixed preparation of compound sulfamethoxazole. Because their in vivo processes and half-life are relatively consistent, they can always maintain a relatively stable concentration in the body, and play a synergistic role.It is often used clinically to treat acute and chronic diseasesurethraOr respiratory tract infection.yesgonorrhea, severe intestinal infection andendocarditisIt also has curative effect.TMP has low toxicity. Although the human body also needs dihydrofolate reductase in the process of synthesizing tetrahydrofolate, experiments show that the affinity of TMP to mammalian dihydrofolate reductase is 10000 to tens of thousands times less than that of bacterial dihydrofolate reductase.It is possible for TMP to exert a significant inhibitory effect on bacteria, but it is not toxic to human and mammalian body, so the general treatment dose does not cause folic acid deficiency.A small number of patients may have white blood cells andThrombocytopenia, can be treated with tetrahydrofolate.The animal experiment found that TMP had teratogenic effect, so it was forbidden for pregnant women.
