A, the harmful effects of drugs and their classification drugs can produce therapeutic effects, can also produce harmful reactions, people tend to pay attention to its therapeutic effects and ignore its harmful reactions, harmful reactions are divided into two categories: 1, Adverse Drug Reaction (ADR), refers to the normal dosage, the appearance of harmful reactions. It does not include reactions caused by overdose of drugs, etc. 2, adverse drug event Lishui County People’s Hospital Orthopedic Surgery Department Gu Xiang Adverse Drug Event (ADE) adverse drug reaction refers to the reaction whose causality has been determined, while adverse drug event refers to the reaction whose causality has not been determined. This reaction is not certain to be caused by the drug and needs to be further evaluated. Therefore, adverse drug events are adverse clinical events that occur in the course of drug therapy, it is not necessarily causally related to the drug. Second, the classification of adverse drug reactions and classification 1, the classification of adverse drug reactions In 1977 Rawlins and other designed a simple ADR typing method, the adverse reactions into two types, namely, type A and type B. Type A reaction refers to the reaction caused by the normal pharmacological effect of a drug is too strong, such as propranolol caused by bradycardia. type A reaction can be predicted according to the pharmacological properties of the drug, usually dose dependent. type A reaction is more common, the incidence is higher but the mortality rate is lower. Type B reaction refers to the normal pharmacological effects of drugs, new or abnormal adverse reactions, such as penicillin-induced allergic reactions, usually unpredictable and uncommon, the incidence is low but the mortality rate is relatively high. 2, the classification of adverse drug reactions Because the typing method is easy to remember, has been widely used for more than 20 years, but the actual application process is subject to some limitations, so some people will be divided into six categories or nine categories of adverse reactions. Classification of common adverse reactions of antimicrobial drugs Classification Type Classification Examples Main relevant factors Type A Toxic reaction Aminoglycoside ototoxicity Related to the dose and regimen of the drug Secondary reaction Broad-spectrum antibacterial drugs cause dysbiosis Irritant reaction Gastrointestinal irritation symptoms Type B Metabolic reaction Beta-lactam metabolic reaction Specificity related to the human body Familial reaction Glucose-6-phosphate dehydrogenase deficiency caused by flavopiridol Hemolytic anemia in people The common adverse reactions of antimicrobial drugs classification comparison of antimicrobial drugs Type B adverse reactions Type A adverse reactions Metabolic reactions Hepatotoxicity Nephrotoxicity Hematotoxicity Neurotoxicity Common A-type adverse reactions of antimicrobial drugs A. Toxic effect (Toxic effect) Toxic reactions of antimicrobial drugs generally refers to the drug to human tissue, organs of different degrees of damage, generally correlated with the dose and duration of antimicrobial drugs, toxic reactions Toxic reactions are the most common type of adverse reactions of antimicrobial drugs. Toxic reactions are generally predictable and have less individual variation than type B adverse reactions. In most cases, they can be eliminated by discontinuation of the drug. There are many types of toxic reactions, such as: nephrotoxicity, neurotoxicity, hepatotoxicity, hematotoxicity, cardiotoxicity, abnormal coagulation mechanism and gastrointestinal reactions, etc. 1, nephrotoxic reactions The kidney is the main excretory organ of most antibacterial drugs, and the drug can accumulate in high concentration in the renal cortex, therefore, nephrotoxicity is quite common. The main antibacterial drugs that cause nephrotoxicity are aminoglycosides, β-lactams and amphotericin B, etc. (1) Aminoglycosides: Aminoglycosides and the brush-border membrance of the renal tubules (brush-border membrance) are easy to combine, and the local tissues, especially the renal cortex, often have a much higher concentration of drugs than the blood accumulation, and some species have a half-life of more than 100h; nephrotoxicity is proportional to the amount of drug accumulation. The drug directly damages renal tubular epithelial cells, causing tubular necrosis and acute renal failure in severe cases, especially in elderly people, dehydrated people, and people who use more than two nephrotoxic drugs in combination. Gentamicin is more likely to cause nephrotoxicity than amikacin. (Other first generation cephalosporins such as cefothiophene and cefazolin also have certain nephrotoxicity when used in large dosage, especially when combined with other nephrotoxic drugs such as aminoglycosides and strong diuretics. (3) Amphotericin B Amphotericin B can cause a variety of kidney damage, the incidence of high, almost every application of the people have it. It can change the permeability of renal tubular epithelial cells, leading to impaired hydrogen excretion and increased urinary potassium excretion, and can also affect the concentration function and develop nephrogenic uremia. More importantly, amphotericin B can also cause renal vasoconstriction, leading to renal cortical ischemia and reduced glomerular filtration rate. At higher doses, it may lead to irreversible acute renal failure. 2, neurotoxic reactions The main neurotoxic reactions caused by antimicrobial drugs are aminoglycosides, fluoroquinolones, β-lactams and chloramphenicol, ethambutol and isoniazid, etc. (1) Aminoglycosides: Eighth to brain nerve damage is the most serious toxic reaction of aminoglycosides. All aminoglycosides have some ototoxicity, such as hearing loss, tinnitus or a sense of fullness in the ear, and the occurrence of ototoxicity is related to the concentration and longer half-life of the drug in the lymphatic fluid of the inner ear, where T1/2 is 10-15 times longer than T1/2 in the blood. Among the commonly used aminoglycosides, the incidence of ototoxicity is lower with naftifloxacin. Ear vestibular damage is manifested by vertigo, headache, and in severe cases, balance disorders. In the treatment of tuberculosis with streptomycin, to ensure patient safety, ① monitor audiogram and monitor high frequency hearing damage; ② test vestibular toxicity; ③ test blood concentration. ④monitor renal function. During treatment with gentamicin and amikacin, etc., blood concentration should be detected. When blood concentration cannot be monitored, the dose should be adjusted according to the patient’s creatinine clearance. (2) Fluoroquinolones Fluoroquinolones bind to GABA receptors of intracellular inhibitory neurons, thus blocking GABA and causing central nervous excitation, which can be manifested as insomnia, hallucinations and convulsions in a dose-dependent manner. 7-position non-substituted piperazines have strong central adverse reactions, such as enrofloxacin, norfloxacin and ciprofloxacin, which are more likely to occur when administered intravenously, while 7-position piperazine methylation or 7-position pyrrolidine have weak central adverse reactions. Adverse reactions are very weak, such as sparfloxacin, gatifloxacin, ofloxacin and levofloxacin. In the presence of central adverse reactions, benzodiazepines may be administered and fluoroquinolones may be discontinued. GABA receptors: (3) Carbapenems of imipenem also inhibit GABA neurons and cause central excitatory adverse reactions such as dizziness, convulsions, myoclonus and psychiatric symptoms, mainly in patients with dosage above 2g per day. The central adverse reactions of panipenem are lower than those of imipenem and lowest in meropenem, which is why the US FDA approved meropenem for the treatment of meningitis. When central system symptoms such as convulsions occur, benzodiazepines may be given and carbapenems may be discontinued. (4) Drugs that cause other neurological reactions include isoniazid and ethambutol, which can cause peripheral neuritis and can be prevented by giving vitamin B6. 3. Hepatotoxicity The liver is the main organ of drug metabolism in the body, especially for oral drugs. Antibacterial drugs that can cause liver damage are mainly azole antifungals and macrolide antibiotics. (1) azole antifungal drugs: azole antifungal drugs such as fluconazole can cause changes in liver function, generally <5%, and can generally recover after discontinuing the drug. However, both ketoconazole and itraconazole can cause serious liver damage (including liver failure, liver transplantation or even death). As of March 2001, the FDA had received 24 cases of liver failure possibly related to itraconazole, including 11 deaths. (2) Macrolide antibiotics The macrolide antibiotic causing liver injury is more frequently reported as erythromycin, mainly caused by intravenous drip. However, according to the WHO data in 1995, reports from 4 countries including the United States, erythromycin caused liver function damage up to 157 cases. 4, antimicrobial cardiotoxicity antimicrobial-induced QT interval prolongation and tip-twisting tachycardia (Tdp), has gradually attracted the attention of clinicians, in many cases, Tdp is self-limiting, but sometimes will turn into ventricular fibrillation, and even cause cardiac arrest. tdp and QT interval prolongation susceptibility factors include hyperkalemia, hypomagnesemia, sinus bradycardia, class II-III AV block and Concomitant use of P450 enzyme inhibitors. The main antimicrobial agents that can cause prolongation of Tdp and QT interval are macrolide antibiotics and fluoroquinolones. (1) Fluoroquinolones are mainly gepafloxacin and sparfloxacin, especially for intravenous injection. And levofloxacin and moxifloxacin have not been found. (2) Macrolides are mainly erythromycin (especially intravenous injection), clarithromycin and spiramycin are less common, but they can also occur. 5.Hematologic toxicity (1)Chloramphenicol can cause aplastic anemia and anemia due to inhibition of erythropoiesis. (2)Chloramphenicol can cause leukopenia and thrombocytopenia. (3) Abnormal coagulation mechanism: cephalosporin antibiotics with 7-position carboxyl group make ADP-induced platelet aggregation dysfunction, such as laxative cephalosporin. In cephalosporins, the 3-position thiametetrazole side chain interferes with the carboxylation reaction in which vitamin K is involved, so it affects coagulation, such as laxative cephalosporin, cefoperazone and cefamandole, etc. Second, secondary reactions (Secondary effict) secondary reactions are the adverse consequences secondary to the antibacterial effect of antibacterial drugs. Related to the pharmacological effects of antibacterial drugs. There are two main types of secondary reactions to antimicrobial drugs. 1, endotoxin release caused by antimicrobial drugs: the application of antimicrobial drugs in Gram-negative bacterial infections can lead to the release of endotoxin, the amount and rate of release is related to the type of antimicrobial drugs and the rate of administration. In general, β-lactams and quinolones can lead to rapid lysis of bacterial cells resulting in a rapid rise in endotoxin, while aminoglycosides cause slow death of bacteria, resulting in a slow release of endotoxin. Animal experiments on E. coli meningitis have shown that a single intravenous injection of cefotaxime, cefpirome, Tylenol, chloramphenicol, and gentamicin can cause a 2- to 10-fold increase in endotoxin in the cerebrospinal fluid within 2 hours. Appropriate combination of antimicrobial drugs can reduce the release of endotoxin, such as cefuroxime can induce a large release of endotoxin, but the combination of tobramycin can be significantly inhibited. 2, dysbiosis dysbiosis or dichotomous infection, also known as bacterial alternans, is the application of antibacterial drugs in the process of new infections. Dysbiosis includes oral infections, intestinal infections, pneumonia, urinary tract infections, sepsis. The following table shows the various manifestations of antibiotic-associated intestinal dysbiosis degree of dysbiosis clinical manifestations pathological changes name first degree: mild, reversible, recoverable after drug withdrawal mild diarrhea or constipation mild congestion of intestinal mucosa, no inflammation antibiotic-associated diarrhea second degree: long-term, chronic, not automatically recovered long-term chronic diarrhea, constipation or other intestinal dysfunction colonic mucosa with varying degrees of inflammatory areas of varying sizes Antibiotic-associated enterocolitis Third degree: extremely severe, with alternating bacterial disease. The intestinal flora is completely lost and replaced by one kind of bacteria such as Staphylococcus, Candida albicans, mainly Clostridium difficile Diarrhea 10-20 times/day, stool up to several liters, bloating, abdominal pain, intestinal paralysis, severe dehydration, systemic symptoms, even shock Large intestinal mucosa inflammation, bleeding, ulceration, necrosis, even intestinal perforation and peritonitis, the surface is covered with large pseudomembranes Pseudomembranous enteritis Intestinal Dysbiosis is most easily triggered by antibiotics such as lincomycin and broad-spectrum β-lactams, and is mainly caused by Clostridium difficile, which produces two kinds of exotoxins, A and B. Exotoxin A is powerfully toxic. Treatment of pseudomembranous enteritis caused by lincomycin antibiotics: mild cases can generally be effective with discontinuation of the drug alone, and moderate to severe cases should be given metronidazole 250-500 mg orally three times a day when it is ineffective after discontinuation of the drug and regulation of hydroelectric balance. In case of relapse, metronidazole can be used again orally. When oral administration with metronidazole is ineffective, vancomycin can be used orally instead, 125-500mg every 6 hours. iii. Side effects (side effact): generally refers to the effects occurring outside the therapeutic purpose under the commonly used range of dosage. Side effects can be converted into therapeutic effects when needed for therapeutic purposes. The side effect of antibacterial drugs is very rare, because antibacterial drugs generally have only antibacterial effects, unlike non-antibacterial drugs and other drugs with several pharmacological effects at the same time, so the case can be converted is very rare. Very few examples can be given such as: erythromycin has a gastrointestinal irritation side effect while exerting an antibacterial effect, and this side effect can have the effect of a gastrointestinal motility drug in the treatment of gastroparesis. Antimicrobial drugs common type B adverse reactions A. Metabolic reactions: drug metabolic reactions can be divided into type I to Ⅳ, now take penicillin-induced metabolic reactions as an example. Penicillin-induced metabolic reaction types and characteristics Immunity type Metabolic reaction type Examples of clinical adverse reactions Involved in immune active components Humoral immunity I rapid type Anaphylaxis Ig E, mast cells, eosinophils Urticaria II cytotoxic type Hemolytic anemia IgG, IgM, complement Cellular immunity III immune complex type Serum sickness type reaction IgG or IgM, IgA, complement, neutrophils IV late-onset contact dermatitis Lymphocytes II. Familial abnormal reactions: chloramphenicol can induce hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency. This is due to the fact that G-6-PD is involved in the anaerobic glycolytic pathway of erythrocytes and maintains the stability of erythrocytes through reduced glutathione. When G-6-PD is deficient, erythrocytes are already in an unstable state, and chloramphenicol can cause oxidation of reduced glutathione, thus easily inducing hemolytic anemia. Antibacterial drugs with similar adverse effects include sulfonamides, furans and berberine.