I. Drug factors, including the factors of the drug itself and market interference factors
(A) The drug itself factors
1.Isoniazid (INH).
(1) It can compete with vitamin B6 or combine with vitamin B6 and discharge to cause vitamin B6 deficiency, affect fat metabolism, lead to nerve myelin degeneration, myelin fragmentation, and peripheral neuritis, which is related to individual slow acetylation type.
(2) Hydrazine base causes vitamin B6 deficiency in central nervous tissue and affects the central nervous system.
(3) Isoniazid inhibits monoamine oxidase in some patients, causing histamine to accumulate in the body and affecting blood pressure, respiration, heart rate, and the peripheral vascular system.
(4) The metabolite acetylhydrazine is converted into reaction medium by microsomal enzymes in hepatocytes, which binds to cellular proteins and leads to hepatocyte degeneration and necrosis, causing drug-related hepatitis.
2.Rifampicin (RFP):
(1) It is a macromolecular drug, mainly excreted by bile, and its concentration in bile can be 2,000 times that of plasma. It mainly interferes with the binding and excretion of bilirubin and glucuronide, resulting in increased blood unconjugated bilirubin, jaundice and impaired excretory pigment function.
(2) Acute biliary hepatitis is particularly likely to occur in immunocompromised atopic individuals.
(3) RFP binds to plasma macromolecules to form complex antigens, which contribute to the production of anti-RFP antibodies. When a large dose of RFP causes a sudden increase in blood drug concentration and relatively few RFP antibodies, it causes a series of immune damage, involving or directly damaging liver, kidney, blood and other tissues or cells.
(4) Affects vitamin K-dependent coagulation factors and non-vitamin K-dependent coagulation factors, which may not only lead to a decrease in the synthesis of coagulation factors but also reduce the activity of coagulation factors. (5) Direct irritant effects cause gastrointestinal reactions.
3.Ethylaminebutanol (EMB).
(1) Early serious damage to vision is mainly the toxic effect of the L-isomer of EMB. Due to the chelation of copper and zinc cations by EMB affects the activity of certain enzymes and coenzymes. The incidence of side effects is directly related to the daily dose.
(2) It can also cause peripheral neuropathy.
(3) Rarely seen similar to vestibular neurotoxic reactions.
4.Pyrazinamide (PZA).
(1) The most common is hyperuricemia.
(2) May contribute to acute attacks of gout in people with pre-existing gout. The rate of joint symptoms in PZA users is 14%, which is related to individual tolerance and sensitivity.
(3) Previously, the side effects of PZA on the liver were large when used in high doses, but at present, the hepatotoxicity of PZA is extremely rare with conventional dose treatment.
(4) direct gastrointestinal irritation is still common.
(5) First-line combination drugs: with the toxicity of the first four drugs. Some reports suggest that the incidence of ADRs is higher than in bulk drug combinations due to limitations in individualization.
6, para-aminosalicylic acid (PAS).
(1) Oral administration has a greater direct irritant effect on the stomach.
(2) Compete with isoniazid and rifampicin for acetyltransferase, which can reduce the rate of acetylation of INH and RFP and increase hepatotoxicity.
7. Isoniazid para-aminosalicylate (Pa): ADR is significantly less than PAS alone or INH alone. occasional ADR such as dizziness, headache, insomnia, fever, rash, nausea, malaise, jaundice, peripheral neuritis, optic neuritis and hematocrit occur.
8. prothiouracil (Pto): excreted by kidney, may aggravate the ADR when combined with INH and other anti-tuberculosis drugs. gastrointestinal reactions are more common and may cause liver damage. A few patients may have pellagra symptoms, tongue inflammation, stomatitis, keratitis, mental depression, insomnia, polyneuritis, convulsions, diplopia, etc. and teratogenic effects. High dose application can cause postural hypotension. Occasionally can cause acne, hyperpigmentation, hair loss, rash, purpura, gynecomastia, thyroid hyperplasia, menstrual disorders, etc.
9. Aminoglycosides.
(1) Vestibular dysfunction and cochlear hearing nerve damage.
(2) Nephrotoxicity.
(3) Neuromuscular blockade. Most common after high-dose intraperitoneal or intrapleural application or intravenous injection. It can cause respiratory muscle paralysis or even respiratory arrest. It is more likely to occur in patients with reduced renal function, low blood calcium and severe myasthenia gravis.
(4) Rarely see rash, fever, angioneurotic edema and exfoliative dermatitis and other metabolic reactions.
10, quinolones: can have allergic reactions including polymorphic erythema, photosensitivity dermatitis and anaphylaxis. Can pass the blood-brain barrier, neurological and (or) psychiatric system damage is more prominent. Can cause damage to the skin and its adnexa, with sparfloxacin being the most prominent. It can cause crystalluria, hematuria, and renal damage. Levofloxacin causes muscle pain more commonly.
11.Clofazimine (Cf).
(1) Lipophilic, easy to deposit in fatty tissue, 75% to 100% of patients can be discolored skin and conjunctiva.
(2) Anticholinergic effect can make sweat and tears decrease. Some patients may have gastrointestinal reactions.
(3) Pigmentation may also occur in infants who take breast milk containing the drug.
12. Clarithromycin (Ct).
(1) May cause pseudomembranous enteritis. Nausea, indigestion, abdominal pain, vomiting and diarrhea are common in adults.
(2) May cause transient elevation of hepatic transaminases, hepatocellular and/or cholestatic hepatitis.
(3) Other neuropsychiatric symptoms include headache, abnormal taste, etc.
(4) Allergic reactions, tooth discoloration, etc. may occur.
13. Amoxicillin-potassium clavulanate (Amx-Clv) Cross-allergic reactions with penicillin G. Gastrointestinal reactions are higher than with amoxicillin alone. Abnormal liver function and jaundice occurred in individual patients. Positive anti-human globulin test (Coomb test) has been reported. Candida albicans secondary infection has been reported in about 1% of patients after using this agent.
14.Linazolamide (Lzd)
(1) The common ADRs of linezolid are gastrointestinal symptoms, headache and skin rash.
(2) Myelosuppression (including anemia, various types of thrombocytopenia and thrombocytopenia, etc.), neurological ADRs (peripheral neuropathy and optic neuropathy and even blindness), and cardiac arrhythmias.
(3) It can inhibit mitochondrial protein synthesis and lead to lactic acidosis.
(4) May cause oral and vaginal candidiasis, fungal infection and itching.
(5) 5-Hydroxytryptamine syndrome has been reported in combination with 5-hydroxytryptamine drugs.
15, Cycloserine (Cycloserine): Cycloserine ADR is mainly in the neurological and psychiatric aspects, serious cases may have schizophrenia and suicidal tendencies. It can cause gastrointestinal reactions: nausea, vomiting, loss of appetite, abdominal distention, diarrhea and drug fever. ADR increases when combined with other neurotoxic drugs (isoniazid, ethionamide).
16, Bedaquiline (Bedaquiline): In phase II clinical trials, Bedaquiline was found to have only mild ADRs such as nausea. the instructions warn that the drug may cause abnormal and potentially fatal heart rhythms. It can increase hepatic transaminases and can cause hepatic decompensation at high doses.
17, rifapentine (Rft): 1998 that was included in the United States anti-tuberculosis chemotherapy drugs. The ADR ratio is much lower than that of RFP, and a few patients may experience leukocytosis, thrombocytopenia, elevated alanine aminotransferase, rash, dizziness, insomnia, etc. Gastrointestinal reactions are rare. Gastrointestinal reactions are rare, and only 4 or 8% of allergic reactions occur when patients with RFP allergy are switched to RFT. It has a strong hepatic enzyme-inducing effect, which may reduce the efficacy of other drugs used at the same time or even fail and induce the corresponding ADR.
18.Rifabutin (Rfb): local tissue blood drug concentration of lung lesion is more than 5 times higher than plasma concentration, with lipophilic, easy to permeate the cell wall characteristics, ADR less than RFP, may have neutropenia, drug hepatitis and ocular uveitis and gastrointestinal discomfort. The induction of hepatic drug enzymes is much lower than that of RFP and Rft. If Rfb is used to replace RFP and/or Rft, the ADR caused by RFP and Rft can be greatly reduced.
(ii) Drug dose
It is related to the blood concentration, free concentration of drugs, and the concentration of drugs in liver, kidney, nerve and other tissues.
(iii) Drug combination factors
1, the effect of the combination of anti-tuberculosis drugs: INH, RFP, PAS in the liver metabolism need acetyltransferase, metabolism to form amide compounds, there is enzyme competition between each other, PAS can reduce the rate of INH acetylation, increasing hepatotoxicity; RFP is a liver microsomal enzyme inducer, can increase liver microsomal enzyme activity, accelerate INH metabolism, increasing INH toxicity.
2. Effects of combined use of non-tuberculosis drugs: Combination of INH, RFP and acetaminophen (paracetamol) is a potential cause of significantly increased liver damage. Combined use of other drugs that are mainly metabolized in the liver or affect liver metabolism, such as general anesthetics or other drugs that can induce liver microsomal enzymes such as Valium and Barbiturate, etc., increase the burden on the liver and have a more pronounced effect on women.
3, the drug dose is too large: the current conventional dose treatment, INH and PZA rarely appear hepatotoxic reactions.
4.Anti-tuberculosis treatment with unreasonably large amounts of multiple antimicrobials and other drugs.
5.Inappropriate use of immune enhancers: it can increase the probability of drug allergic reactions or Hepatitis-like reactions.
(D) Drug market interference factors
Including drug quality, unreasonable combination of each component ratio.
Second, the patient factors
1, genotype relevance: hepatic drug enzyme characteristics are related to the patient’s genotype, allergy specific, immune hypo-specific and metabolic specific are related to the patient’s genotype.
2. Underlying diseases: Patients with neurological, gastrointestinal, hepatobiliary, renal, hematological and other organ or system-related diseases and malnutrition are more likely to have ADR of the corresponding organ or system during anti-tuberculosis treatment.
3.Living habits: Bad living habits are also one of the causes of ADR. For example, alcoholics are prone to liver injury, and those who prefer high protein, seafood and river food are prone to hyperuricemia.
Third, class Hirschsprung’s reaction
It is neither a toxic reaction of drugs to human body, nor an allergic reaction of the body to drugs, but also belongs to the category of allergic reaction. “Hirschsprung’s reaction” is a persistent type I allergic reaction (some scholars call it allergic inflammation or delayed type I allergic reaction) to mycobacterium tuberculosis breakdown products – allergens.
Fourth, health care personnel factors
1.Lack of understanding or insufficient understanding of ADR-related risk factors, laboratory items that should be examined, diagnosis and prevention methods.
2.Inability to correctly grasp the scale of reducing medical costs and reasonable examination. Abandoned the necessary testing and monitoring.
3.There is a misunderstanding of the concept of standardized treatment. Not knowing that the combination of general principles and individualization must be followed, and one-sidedly treating general principles as standardized principles.
4.Failure to detect and treat the underlying diseases and systemic diseases in a timely manner.
5. The use of immunomodulators is unreasonable. The use of immunomodulators before the peak inflammatory response to TB is effectively controlled can increase the occurrence of Hirschsprung-like reactions and allergic inflammatory injury.
V. Policy and management measures factors
1, the lack of control of anti-tuberculosis ADR in the control strategy.
2. The lack of standardized guidance on the examination items before the use of anti-tuberculosis drugs and the items that should be monitored during treatment leaves a hidden danger of possible ADR in anti-tuberculosis treatment.
3.Insufficient training for medical personnel.
4. Combination of drugs: The current concept of “standardization” needs to be re-understood. In fact, there is a problem of combining “general principles” and “individualized principles” for the treatment of any patient. The combination of “general principles” and “individualized principles” is a more complete standardization. Combination drug formulations create obstacles for individualized treatment. Moreover, there are many kinds of existing drug combinations, and some of them have an inappropriate configuration ratio, which may not only increase the incidence of ADR, but also lay the groundwork for the formation of drug-resistant tuberculosis.
5, the drug instructions are not reasonable: such as INH instructions indicate that the maximum dose should not exceed 300 mg/day, quinolones and some new clinical TB drugs do not indicate that they can be used for TB treatment, and aminoglycosides instructions indicate that they can only be used for a short period of time. However, due to the lipophilic nature of Rft, it is recommended abroad that the product be given after breakfast with a high fat content and a small amount of carbohydrate to improve bioavailability. In some cases, the use according to the instructions is not conducive to the treatment of patients, which can interrogate the professional conscience of doctors, and the use of the instructions to break through the instructions brings great medical pressure and risk to clinicians, and it is an important new responsibility to provide and review the instructions in a realistic manner.
6. There is no compensation mechanism for ADR in anti-tuberculosis treatment.