A. Harmful reactions to 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 reactions (Adverse Drug Reaction, abbreviated as 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 Reaction Gu Xiang, Department of Orthopedic Surgery, Lishui County People’s Hospital
Adverse Drug Event (ADE, abbreviated as ADE) Adverse drug reaction is a reaction whose causality has been determined, while adverse drug event is a reaction whose causality has not been determined. This reaction is not certain to be caused by the drug and needs to be further evaluated. So adverse drug events are adverse clinical events that occur in the course of drug therapy, it is not necessarily causal relationship with the drug.
Second, the classification of adverse drug reactions and classification
1, the typology of adverse drug reactions
In 1977 Rawlins, etc. 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 unusual 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 to antibacterial drugs
Type Classification Examples Main relevant factors
Type A Toxic reactions Aminoglycoside ototoxicity Related to the dose and course of the drug
Secondary reactions Broad-spectrum antimicrobials cause dysbiosis
Irritant reaction Gastrointestinal irritation
Type B Metabolic reaction β-lactam metabolic reaction Associated with human specificity
Familial reactions Flavopiridol-induced hemolytic anemia in glucose-6-phosphate dehydrogenase deficient individuals
Comparison of the classification of common adverse reactions to antimicrobial drugs
Antimicrobial drugs Type B adverse reactions Type A adverse reactions
Metabolic reactions Hepatotoxicity Nephrotoxicity Hematotoxicity Neurotoxicity
Common type A adverse reactions of antimicrobial drugs
I. Toxic effect (Toxic effect)
Toxic reaction of antimicrobial drugs generally refers to the drug to human tissue and organs of different degrees of damage, generally correlated with the dose and duration of antimicrobial drugs, toxic reactions are the most common type of adverse reactions to 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 more types of toxic reactions, such as: nephrotoxicity, neurotoxicity, hepatotoxicity, hematotoxicity, cardiotoxicity, abnormal coagulation mechanism and gastrointestinal reactions.
1.Nephrotoxic reactions
The kidney is the main excretory organ of most antibacterial drugs, and the drugs 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 renal tubules (brush-border membrance) are easy to combine, and local tissues, especially the renal cortex, often have a much higher accumulation of drugs than the blood concentration, 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 those who use more than two nephrotoxic drugs in combination. Gentamicin is more likely to cause nephrotoxicity than amikacin.
(2)β-lactams
Other first generation cephalosporins such as cefothiophene and cefazolin also have certain nephrotoxicity when used in large dosages, and should be used in combination with other nephrotoxic drugs such as aminoglycosides and strong diuretics.
(3) Amphotericin B
Amphotericin B can cause a variety of kidney damage, and the incidence is high, almost every application has it. It can change the permeability of renal tubular epithelial cells, resulting in 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.Nervous system toxic reactions
Toxicity of the nervous system caused by antibacterial drugs mainly include aminoglycosides, fluoroquinolones, β-lactams, as well as chloramphenicol, ethambutol and isoniazid.
(1) Aminoglycosides: Eighth to brain nerve damage is the most serious toxic reaction of aminoglycosides. All aminoglycosides have certain ototoxicity, such as hearing loss, tinnitus or a sense of fullness in the ear, and the occurrence of ototoxicity is related to the drug concentration and longer half-life in the lymphatic fluid of the inner ear, where T1/2 is 10-15 times longer than T1/2 in 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 tested, and 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. 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 2 g daily. 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) Other drugs that cause neurological reactions are isoniazid and ethambutol, which can cause peripheral neuritis and can be prevented by giving vitamin B6.
3. Hepatotoxicity
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 most frequently reported macrolide antibiotic causing liver injury is erythromycin, which is 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. Cardiotoxicity of antibacterial drugs
The risk factors for Tdp and QT interval prolongation 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.
Secondary effict
Secondary reaction is an adverse effect that occurs after the antimicrobial 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 due to antimicrobial agents.
Application of antimicrobial drugs during Gram-negative bacterial infections can lead to the release of endotoxin, and the amount and rate of release is related to the type of antimicrobial drug 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 antibacterial drugs can reduce the release of endotoxin, such as cefuroxime can induce a large release of endotoxin, but adding tobramycin to the combination can significantly inhibit.
2.Bacterial flora dysbiosis
Dysbiosis or dichotomous infection, also known as bacterial alternans, is a new infection that occurs during the application of antibacterial drugs. Dysbiosis includes oral infections, intestinal infections, pneumonia, urinary tract infections, sepsis. Intestinal infections are illustrated as an example, as shown in the following table.
Various manifestations of antibiotic-associated intestinal flora dysbiosis
Degree of dysbiosis Clinical manifestations Pathological changes Name
First degree: mild, reversible, recoverable after drug discontinuation Mild diarrhea or constipation Mild congestion of intestinal mucosa, no inflammation Antibiotic-associated diarrhea
Second degree: Long-term, chronic, not automatically recoverable Long-term chronic diarrhea, constipation, or other intestinal dysfunction Inflammatory areas of varying degrees and sizes in the colonic mucosa Antibiotic-associated enteritis
Third degree: Extremely severe, there are called bacterial alternans. The intestinal flora all disappears and is replaced by one kind of bacteria such as Staphylococcus, Candida albicans, mainly by Clostridium difficile Diarrhea 10-20 times/day, stool up to several liters, with abdominal distension, abdominal pain, intestinal paralysis, severe dehydration, systemic symptoms are obvious, even shock Large intestinal mucosa inflammation, bleeding, ulceration, necrosis, even intestinal perforation and cause peritonitis, the surface is covered with large pseudomembrane pseudomembranous enteritis
Intestinal flora dysbiosis is most easily triggered by antibiotics such as lincomycin and broad-spectrum β-lactams, mainly caused by Clostridium difficile, which produces two kinds of exotoxins, A and B, with exotoxin A having powerful toxicity.
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 may be given orally again. When oral administration with metronidazole is ineffective, vancomycin may be given orally instead at 125-500 mg every 6 hours.
Third, side effects
Side effects (side effact): Generally refers to the effects that occur outside the therapeutic purpose under the range of commonly used amount. Side effects can be converted into therapeutic effects when needed for therapeutic purposes. The side effect of antimicrobial drugs is very rare, because antimicrobial drugs generally have only antibacterial effects, unlike non-antimicrobial 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 gastrointestinal irritation side effects while exerting antibacterial effects, and this side effect can have the effect of a gastrointestinal motility drug when treating gastroparesis.
Antimicrobial drugs common type B adverse reactions
I. Metabolic reactions: drug metabolic reactions can be divided into type I to type Ⅳ, now take the metabolic reactions caused by penicillin as an example.
Penicillin-induced metabolic reaction types and characteristics
Immunity type metabolic reaction type clinical adverse reactions examples involved in immune active ingredients
Humoral immunity I tachyphylaxis Anaphylaxis Ig E, mast cells, eosinophils
Urticaria
Cytotoxic type II Hemolytic anemia IgG, IgM, complement
Cellular immunity III immune complex type Seropathic reaction IgG or IgM, IgA, complement, neutrophils
IV late 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. Antibacterial drugs with similar adverse effects include sulfonamides, furans and berberine.