Benzylpenicillin/penicillin
brief introduction
Penicillin refers to a kind of antibiotic containing penicillin in its molecule, which can destroy the cell wall of bacteria and play a bactericidal role in the reproductive period of bacterial cells.
Penicillin is also called penicillin G, penicillin G, penicillin, penicillin sodium, benzylpenicillin sodium, benzylpenicillin potassium and benzylpenicillin potassium.
Penicillin is a kind of antibiotic, which refers to an antibiotic extracted from Penicillium culture solution. It contains penicillin, which can destroy the cell wall of bacteria and play a bactericidal role in the reproductive period of bacterial cells. It is the first antibiotic that can treat human diseases. Penicillin antibiotics are the general name of a large class of β -lactams antibiotics, but they can not tolerate the enzymes produced by drug-resistant strains (such as drug-resistant Staphylococcus aureus), and are easily destroyed by them, and their antibacterial spectrum is narrow, which is mainly effective against Gram-positive bacteria. Penicillin g can be divided into potassium salt and sodium salt. Potassium salt cannot be directly injected intravenously, and the amount of potassium ion should be carefully calculated during intravenous drip to avoid the death caused by injecting hyperkalemia into human body to inhibit heart function.
Penicillin antibiotics have little toxicity, because β -lactams act on the cell wall of bacteria, while human beings only have cell membranes without cell walls, so they are less toxic to human beings. Except for severe allergic reaction, the toxicity is not obvious at general dose. They are the antibiotics with the largest chemotherapy index. The common allergic reaction of penicillin antibiotics ranks first among all kinds of drugs, and the highest incidence rate can reach 5% ~ 10%, which is a skin reaction, manifested as rash and vascular edema. The most serious is anaphylactic shock, which usually occurs within a few minutes after injection. Symptoms are dyspnea, cyanosis, blood pressure drop, coma, limb stiffness, and finally convulsions, which can lead to death if not rescued in time. Various routes of administration or the application of various preparations can cause anaphylactic shock, but the incidence of injection is the highest. The occurrence of allergic reaction has nothing to do with drug dosage. Even a small amount of people who are highly allergic to this product can cause shock. Injection into the body can cause seizures. Large-dose long-term injection is toxic to the central nervous system (such as convulsion and coma), which can be recovered by stopping the drug or reducing the dose.
To use this product, intradermal test must be carried out first. Penicillin allergy test includes skin test and in vitro test, in which intradermal injection is more accurate. Skin test itself has certain risks. About 25% of patients who died of anaphylactic shock died of skin test. Therefore, skin test or injection should be fully prepared for rescue. When you switch to different batches of penicillin, you also need to do a skin test again. Injection and skin test solution are unstable, so fresh preparation is better. Moreover, for patients with renal excretion and poor renal function, the dose should be adjusted appropriately. In addition, local application has many sensitization opportunities, and bacteria are prone to drug resistance, so it is not recommended.
Introduction to English
Penicillin (sometimes abbreviated as PCN) refers to a group of β -lactam antibiotics used to treat bacterial infections caused by sensitive (usually Gram-positive) organisms. The name "penicillin" can also be used to refer to a specific member of the Penicillin group Penam skeleton, and its molecular formula is R-C9H 1 1N2O4S, where R is a variable side chain.
classify
According to its characteristics can be divided into:
Penicillin G: such as penicillin G potassium, penicillin G sodium, benzathine benzylpenicillin for injection, etc.
Enzyme-resistant penicillins: such as oxacillin (Xinqing Ⅱ) and oxacillin.
Broad-spectrum penicillin: such as ampicillin, amoxicillin, etc.
Broad-spectrum penicillin against Pseudomonas aeruginosa: such as carbenicillin, piperazine, furbenicillin and so on.
Azithromycin: such as methicillin and its ester Pimeticillin. , which is characterized by enzyme resistance, is effective for some negative bacilli (such as Escherichia coli, Klebsiella pneumoniae and Salmonella), but ineffective for Pseudomonas aeruginosa.
trait
Penicillin antibiotics are the general name of a large class of β -lactam antibiotics. Because β -lactams act on the cell wall of bacteria, while human beings only have cell membranes without cell walls, they are less toxic to human beings. Except for severe allergic reaction, the toxicity is not obvious in general dosage, but it can not tolerate the enzyme produced by drug-resistant strains (such as drug-resistant Staphylococcus aureus), is easy to be destroyed by it, and has a narrow antibacterial spectrum, which is mainly effective against Gram-positive bacteria. Penicillin g can be divided into potassium salt and sodium salt. Potassium salt cannot be directly injected intravenously, and the amount of potassium ion should be carefully calculated during intravenous drip to avoid the death caused by injecting hyperkalemia into human body to inhibit heart function.
Penicillins have little toxicity and are the antibiotics with the largest chemotherapy index. The common allergic reaction of penicillin antibiotics ranks first among all kinds of drugs, and the highest incidence rate can reach 5% ~ 10%, which is a skin reaction, manifested as rash and vascular edema. The most serious is anaphylactic shock, which usually occurs within a few minutes after injection. Symptoms are dyspnea, cyanosis, blood pressure drop, coma, limb stiffness, and finally convulsions, which can lead to death if not rescued in time. Various routes of administration or the application of various preparations can cause anaphylactic shock, but the incidence of injection is the highest. The occurrence of allergic reaction has nothing to do with drug dosage. Even a small amount of people who are highly allergic to this product can cause shock. Injection into the body can cause seizures. Large-dose long-term injection is toxic to the central nervous system (such as convulsion and coma), which can be recovered by stopping the drug or reducing the dose.
Ethnicity
Before the 1940s, humans had not mastered a drug that could effectively treat bacterial infections with little side effects. At that time, if someone got tuberculosis, it meant that the person was going to die soon. In order to change this situation, researchers have made a long-term exploration, but the breakthrough in this respect stems from an unexpected discovery. Alexander fleming was lucky to find penicillin. When Xia Fleming was on vacation on 1928, he forgot that bacteria were growing in the Petri dish in the laboratory. Three weeks later, when he returned to the laboratory, he noticed a group of turquoise molds growing in a staphylococcus aureus Petri dish that was accidentally exposed to the air. When observing the Petri dish with a microscope, Fleming found that the staphylococcus colonies around the mold had dissolved. This means that some secretions of mold can inhibit staphylococcus. Subsequent identification showed that the above mold was Penicillium punctatum, so Fleming called its antibacterial substance penicillin. Unfortunately, Fleming couldn't find a way to extract high-purity penicillin, so he cultured Penicillium strains on his behalf and provided them to the British pathologist Flory and biochemist Ernst Boris ernst boris chain who were preparing to study penicillin systematically in 1939.
After a period of intense experiments, Flory and ernst boris chain finally extracted penicillin crystals by freeze-drying. Later, Flory discovered a mold that could extract penicillin from a melon in large quantities, and prepared the corresponding culture solution with corn flour. Flory and Ernst Boris ernst boris chain re-experimented with penicillin in 1940. They injected eight mice with a lethal dose of Streptococcus, and then only four of them were injected with penicillin. Within a few hours, only four mice treated with penicillin were still alive and well. "This is really like a miracle!" Flory said. Since then, a series of clinical experiments have confirmed the efficacy of penicillin on streptococcus, diphtheria and other bacterial infections. Penicillin can kill bacteria without damaging human cells, because penicillamine contained in penicillin can hinder the synthesis of bacterial cell walls, leading to the dissolution and death of bacteria, while human and animal cells have no cell walls. However, penicillin can cause allergic reactions in individuals, so skin tests must be done before application. Driven by these research results, American pharmaceutical companies began to produce penicillin in large quantities in 1942. By 1943, pharmaceutical companies had discovered the method of mass production of penicillin. At that time, Britain and the United States were at war with Nazi Germany. This new medicine is very effective in controlling wound infection. By 1944, the supply of medicine was enough to treat all allied soldiers who participated in the war during World War II.
1945, Fleming, Flory and Qian En all won the Nobel Prize in Physiology or Medicine for "discovering penicillin and its clinical effects".
Penicillin is an important antibiotic with high efficiency, low toxicity and wide clinical application. Its successful development greatly enhanced the ability of human beings to resist bacterial infection, and led to the birth of antibiotic family. Its appearance ushered in a new era of treating diseases with antibiotics. After decades of improvement, penicillin injection and oral penicillin have been able to treat pneumonia, tuberculosis, meningitis, endocarditis, diphtheria, anthrax and other diseases respectively. After penicillin, antibiotics such as streptomycin, chloramphenicol, oxytetracycline and tetracycline are constantly produced, which enhances the ability of human beings to treat infectious diseases. But at the same time, the drug resistance of some bacteria is gradually increasing. In order to solve this problem, researchers are currently developing more effective antibiotics, exploring how to prevent bacteria from acquiring drug resistance genes, and developing plant-based antibacterial drugs.
pharmacology
Oral administration is easily destroyed by gastric acid and digestive enzymes. It is absorbed quickly after intramuscular injection or subcutaneous injection, and reaches the peak of blood drug concentration within 15 ~ 30 min. Penicillin has a short half-life in the body and is mainly excreted from urine in its original form.
Chloramphenicol has broad-spectrum antibacterial effect, and its effect on gram-negative bacteria is stronger than that on gram-positive bacteria, and its effect on typhoid, influenza and pertussis is stronger than other antibiotics, and it has good curative effect on rickettsia infection (such as typhus) and virus infection (such as trachoma). It also has a strong antibacterial effect on Brucella, Escherichia coli, aerogenes, pneumonia, dysentery, Vibrio cholerae, meningococcus and Neisseria gonorrhoeae. This product belongs to bacteriostatic agent, and its mechanism of action is mainly to inhibit the synthesis of bacterial protein. It acts on the 50S subunit of ribonucleoprotein, inhibiting the action of peptidyl transferase and preventing the growth of peptide chain. Clinically, it is mainly used for typhoid fever, paratyphoid fever and other salmonella infections, with good curative effect, and it is still the first choice for treating these diseases.
function
Penicillin has a good antibacterial effect on Streptococcus, Streptococcus pneumoniae and Staphylococcus which does not produce penicillin enzyme. It has moderate antibacterial effect on Enterococcus, and Neisseria meningitidis, Corynebacterium diphtheriae, Bacillus anthracis, Actinomyces bovis, Streptococcus moniliforme, Listeria monocytogenes, Leptospira and Treponema pallidum are sensitive to this product. This product also has certain antibacterial activity against Haemophilus influenzae and Bordetella pertussis, and other gram-negative aerobic or facultative anaerobic bacteria are less sensitive to this product. This product has good antibacterial activity against Clostridium, anaerobic bacteria of peptic streptococcus and Bacteroides melanogenesis, but poor antibacterial activity against Bacteroides fragilis. Penicillin plays a bactericidal role by inhibiting the combination of tetrapeptide chain and pentapeptide cross-linking bridge of bacterial cell wall and hindering the synthesis of cell wall. It is effective for gram-positive bacteria, but penicillin has little effect on gram-negative bacteria because they lack pentapeptide cross-linking bridge.
Among them, penicillin is the first choice for the following infections:
1. hemolytic streptococcus infections, such as pharyngitis, tonsillitis, scarlet fever, erysipelas, cellulitis and puerperal fever.
2. Streptococcus pneumoniae infections, such as pneumonia, otitis media, meningitis and bacteremia.
3. Staphylococcus infection that does not produce penicillinase
4. Anthrax
Clostridium infection, such as tetanus and gas gangrene.
6. Syphilis (including congenital syphilis)
7. Leptospirosis
8. relapsing fever
9.diphtheria
10. Penicillin combined with aminoglycosides is used to treat streptococcal endocarditis.
Penicillin can also be used to treat:
1. Epidemic cerebrospinal meningitis
2. Actinomycosis
3. Gonorrhea
4. Finson angina pectoris
5. Lyme disease
6. Kill more Pasteurella infection.
7. Rat bite fever
8. Listeria infection
9. Many anaerobic infections except Bacteroides fragilis.
Penicillin can be used to prevent infective endocarditis in patients with rheumatic heart disease or congenital heart disease before oral, dental, gastrointestinal or urogenital surgery and operation.
manufacturing method
The production methods of natural penicillin and semi-synthetic penicillin are completely different.
Natural penicillin
The production of penicillin G can be divided into two steps: strain fermentation and extraction refining. (1) strain fermentation: Huang Qing-producing mold was inoculated on solid culture medium and cultured at 25℃ for 7- 10 days to obtain Penicillium spore culture. Inoculating spores with sterile water into a sterile culture medium in a seed tank, and introducing sterile air; Gas, stirring, and culturing at 27℃ for 24-28 hours, then inoculating the seed culture solution into the sterilized culture medium containing phenylacetic acid precursor in the fermentor, introducing sterile air, and stirring and culturing at 27℃ for 7 days. In the process of fermentation, phenylacetic acid precursor and suitable culture medium should be added. (2) extraction and refining: cooling and filtering the penicillin fermentation liquid. Under the condition of pH 2 ~ 2.5, the filtrate and butyl acetate were extracted in an extractor by multistage countercurrent extraction to obtain butyl ester extract, which was transferred to a buffer solution with pH 7.0 ~ 7.2, and then transferred to butyl ester. Decolorizing butyl ester extract with activated carbon, adding salt forming agent, and boiling distillation to obtain potassium salt of penicillin G. The sodium salt of penicillin G is prepared by passing the potassium salt of penicillin G through ion exchange resin (sodium type).
Semi-synthetic penicillin
6APA can be acylated with various chemically synthesized organic acids to prepare various types of semi-synthetic penicillin.
6APA is obtained by cracking penicillin G or V with penicillin acylase produced by microorganisms. Enzymatic reaction is usually carried out at 40 ~ 50℃ and pH 8 ~ 10. In recent years, enzyme immobilization technology has been applied to 6APA production, which simplifies the cracking process. 6APA can also be prepared from penicillin G by chemical cracking, but the cost is higher. The introduction of side chain is that the corresponding organic acid is first made into acyl chloride with chlorinating agent, and then, according to the stability of acyl chloride, inorganic or organic base is used as condensing agent in water or organic solvent for acylation with 6APA. The condensation reaction can also be carried out directly in the pyrolysis liquid, without separation of 6APA.
Dosage form, usage and dosage
Tablets: 0.25g each. Capsule: 0.25g per capsule. Injection: 2ml each, containing 0.25g of medicine. Eye drops: 8 mg: 0.02 g orally, adult 1 ~ 2g/ day; Children take 50 ~ 100 mg per kilogram of body weight every day, divided into 2 ~ 4 times. Adult intramuscular injection, 0.5 ~ 1g each time, twice a day; Children take 25 ~ 50mg per kilogram of body weight twice a day. Intravenous drip with the same dose as intramuscular injection. Because propylene glycol is used as the solvent for the injection, it should be diluted to 2.5 mg: ml with isotonic glucose injection or physiological saline for later use, that is, 2 mg (0.25 g) should be diluted with 100 ml infusion and extracted with a dry empty needle to avoid crystallization. After dilution, carefully check that there is no crystallization before use.
counteraction
1. The main toxic reaction is to inhibit the hematopoietic function of bone marrow, causing granulocytopenia and thrombocytopenia. If mild leukopenia or thrombocytopenia is found during medication, the drug should be stopped immediately and generally recovered. Aplastic anemia caused by chloramphenicol is rare, but it is difficult to reverse and often fatal. It mostly happens in children who use chloramphenicol repeatedly for a long time, and occasionally it happens in a small amount.
2. Allergic reaction is rare, but it can also cause rash and drug fever. A few can cause jaundice, and those with original liver disease can even cause acute liver necrosis.
3. It can cause hallucinations, delirium and other mental symptoms, which usually appear 3-5 days after taking the medicine and disappear within two days after stopping taking the medicine.
4. Gastrointestinal reactions may occur after oral administration, such as nausea, vomiting, diarrhea and loss of appetite.
side effect
1 penicillin has low toxicity, but it is prone to allergic reactions, with an incidence of about 5%? 10%。 The most common diseases are rash, asthma, drug fever and severe anaphylactic shock, which may lead to death.
When high-dose penicillin is used for anti-infection, neuropsychiatric symptoms appear, such as hyperreflexia, perceptual disturbance, convulsion, drowsiness and so on. Can be recovered by stopping the drug or reducing the dose.
Skin allergy test must be done before using penicillin. In case of anaphylactic shock, 0. 1% adrenaline 0.5 ml ~ 1 ml should be injected subcutaneously or intramuscularly immediately, and oxygen should be given at the same time, and antihistamines and adrenocortical hormones should be used.
Local pain is obvious when potassium salt is injected into muscle, and the pain can be eliminated by dissolving it with benzyl alcohol solution as diluent.
Bacteria are resistant to penicillin.
There are three main mechanisms of bacterial resistance to penicillin:
1. Bacteria produce β -lactamase to hydrolyze and inactivate penicillin;
2. pbps, the target of penicillin in bacteria, has changed;
3. The permeability of cell wall to penicillin is decreased. Among them, the first mechanism is the most common and important.
Penicillins have good water solubility, and the half-life of blood elimination is mostly less than 2 hours, which is mainly excreted by the kidneys, and most varieties can be eliminated by hemodialysis.
According to the regulations of China's Ministry of Health, penicillin skin test should be done before using penicillin antibiotics, and those who are positive are prohibited.
Matters needing attention
1. Avoid compatibility with alkaline drugs when taking orally or injecting, so as to avoid decomposition failure.
2. This product should not be mixed with tetracycline hydrochloride, kanamycin, polymyxin E, sulfadiazine sodium, adenosine triphosphate, coenzyme A, etc. To avoid precipitation or degradation.
3. Chloramphenicol and penicillin should not be used together in general, because chloramphenicol is a bacteriostatic agent and penicillin is a bactericide during the breeding period, and the combination will affect the antibacterial activity of penicillin and reduce its efficacy. However, this problem is still controversial, and there are different opinions, because the combination of the two has a good clinical effect on gram-positive bacteria, mixed infection of negative bacteria and intracranial infection. Solution, if necessary, should be penicillin 2 ~ 3 hours after chloramphenicol.
4. Because this product can inhibit the activity of some liver enzymes, it can interfere with the biotransformation of tolbutamide, phenytoin sodium and dicoumarin in human body, enhance the effects of tolbutamide and phenytoin sodium, and enhance the anticoagulant effects of dicoumarin and warfarin.
5. Infants, patients with liver and renal insufficiency should use it with caution, pregnant women should use it with caution at the end of pregnancy, and lactating women should not use it.
In addition to skin test before using penicillin, the following points should also be noted:
1. Inject penicillin in a regular medical unit with rescue equipment. Once an allergic reaction occurs, you can get timely and effective rescue treatment. If you feel dizzy, flustered, sweaty or have difficulty breathing at any time during the injection, please tell the doctor and nurse immediately.
2. After injecting penicillin, observe in the hospital for at least 20 minutes, and leave without discomfort.
3. Don't use penicillin when you are extremely hungry, so as not to reduce your body's tolerance to drugs when you are hungry and induce adverse reactions such as needle sickness.
4, two injections should not be too close together, with 4-6 hours as well. When injecting penicillin intravenously, the initial speed should not be too fast, and it should not exceed 40 drops per minute. Observe 10-20 minutes, and then adjust the infusion speed.
5. If you have a history of penicillin injection that day and feel dizzy, flustered, sweaty, and have difficulty breathing at home, you should be sent to the hospital for treatment in time.
Interaction in the application of penicillin compatibility;
In recent years, the problem of drug abuse in clinic has caused some adverse reactions, especially the interaction and adverse reactions caused by the compatibility of penicillin with other drugs.
1 penicillin should not be used with similar antibiotics.
Because their antibacterial spectrum and antibacterial mechanism are mostly similar, the combined action does not accumulate. On the contrary, combined medication will aggravate renal damage and cause dyspnea or respiratory arrest. There is cross-resistance between them, so it is not recommended to use two kinds of β -lactam antibiotics in combination.
Penicillin should not be combined with sulfanilamide and tetracycline.
Penicillin is a "bactericide" in the breeding period, which hinders the synthesis of bacterial cell walls, while tetracycline is a "bacteriostatic agent" that affects the synthesis of protein. The combined effect of penicillin and tetracycline is antagonistic, so it is generally not suitable for use. Clinical data show that the antibacterial efficacy of penicillin alone is 90%, that of sulfonamides alone is 8 1%, and that of the two drugs combined is 75%. Unless there are special circumstances, they should not be combined.
Penicillin should not be combined with aminoglycosides.
The mixture of penicillin and gentamicin is the same as the infusion set used by patients. Because the β -lactams of penicillin can inactivate gentamicin, the mechanism is the chemical interaction between them, so it is forbidden to mix them. Penicillin should be injected intravenously and gentamicin should be injected intramuscularly.
To sum up, improper compatibility of penicillin and adverse drug reactions caused by drug interaction should not be underestimated. Penicillin is the most commonly used antibiotic to treat various infectious diseases. Strictly grasp the indications, rationally combine and take effective measures to reduce unnecessary adverse reactions.
Penicillin family
Penicillin was used in clinic in the early 1940s. After a lot of research on penicillin, some penicillins were found. Some effective semi-synthetic penicillins were obtained by chemical modification of penicillin. In 1970s, some penicillins with mother nuclei similar to penicillin and containing β -lactam ring but not tetrahydrothiazole ring structure were found, which can be divided into three generations: the first generation of penicillins refers to natural penicillins, such as penicillin G (benzylpenicillin); The second generation penicillin refers to semi-synthetic penicillin obtained by changing the side chain of 6- aminopenicillanic acid (6-APA), such as trimethoprim, carbenicillin, ampicillin, etc. The third generation penicillin is the mother nucleus, which has the same β -lactam ring as penicillin, but no tetrahydrothiazole ring, such as thiomycin and Nocardiamycin.
Penicillin concentration method
The method of killing wild-type cells specifically with penicillin and retaining auxotrophic cells. Penicillin can inhibit the synthesis of bacterial cell walls, so it can only kill bacteria that are growing and reproducing, but not bacteria that stop dividing. In the selective liquid medium which can only make the wild type grow but not the mutant type, the wild type is killed by penicillin, but the mutant type is not killed, thus eliminating the wild type and concentrating the mutant type. It can be applied to bacteria and actinomycetes, and is one of the common methods for screening auxotrophic mutants.
Island penicillin
If rice is not threshed and dried in time after harvest, it is easy to cause mildew when piled up. Moldy grains turn into "yellow rice" or "retted yellow rice" after threshing, which is mainly caused by Penicillium.islandicum pollution. Yellow rice is common in tropical and subtropical areas such as South China and Japan. Mice can die of liver hypertrophy in about a week after taking 200g of yellow rice contaminated by Penicillium islandicum orally every day. If you feed 0.05g yellow rice every day for two consecutive years, you can induce liver cancer. Epidemiological investigation shows that the incidence of liver cancer is related to excessive consumption of moldy rice by residents. People who eat yellow rice will be poisoned (liver necrosis, liver coma) and liver cirrhosis. Penicillium islandicum can not only produce penicillium islandicum, but also produce many mycotoxins, such as cyclosporin, Luteoskyrin and erythrocin.
Both island penicillin and xanthophyllum have strong carcinogenic activity. The structure of xanthophyllum is similar to that of aflatoxin, and its toxicity and carcinogenic activity are also equivalent to that of aflatoxin. Taking 7mg/kg huangtianjing daily for several weeks can lead to liver necrosis in mice, and long-term low-dose intake can lead to liver cancer. Cyclin is a kind of peptide with chlorine ring structure. The oral LD50 of mice is 6.55mg/kg body weight, which has strong acute toxicity. Circulating intake of chloride can cause necrotic lesions in the liver of mice in a short time, and long-term low dose can cause cancer.