Drug accumulation refers to the repeated or long-term continuous use of drugs with slow metabolism, relatively narrow safety range and high toxicity, which are too late to be metabolized and excreted after reaching the body, or the metabolism and excretion of drugs are impaired due to poor liver and kidney function of patients, thus causing drugs to accumulate in the body. When the concentration exceeds the safe range, the patient will have a series of poisoning symptoms that are only present when the drug is overdosed, and this type of poisoning is called drug accumulation poisoning.
Because drug accumulation is a repeated and long-term process, there is a certain degree of insidiousness, unlike acute drug poisoning, which is easier to detect and ignored, but often causes irrecoverable damage to liver and kidney and other organs, and even endangers life, therefore, it is very important to master the “fire” of drug use and prevent drug accumulation for patients who use drugs for a long time. Therefore, it is very important for patients to master the “fire” of medication and prevent drug accumulation for long-term medication.
The main factors that cause drug accumulation are human physiology, liver and kidney function, and drug factors.
The liver is the main organ for drug metabolism, and when the drug user has poor liver function or liver disease (acute or chronic disease affecting the ultrastructure of the liver), it can significantly affect the metabolism of certain drugs in the liver, including fatty liver, liver cancer, alcoholic hepatitis or cirrhosis, hemochromatosis, chronic active hepatitis, biliary cirrhosis, acute viral or drug-related hepatitis.
The degree of damage to hepatic drug metabolizing enzymes varies with the severity of the disease, especially the particulate oxidase enzymes are most likely to be damaged and thus can significantly affect the clearance of the drug drug in question.
The kidney is the main excretory organ of drugs, when the renal function is low, the elimination of drugs mainly excreted by the kidney is slowed down, for example, gentamicin, the plasma half-life is prolonged. The drug accumulates in the body, resulting in enhanced drug effects and even toxic reactions. When renal function is low, not only the excretion of the original drug is slowed, but also the excretion of its metabolites is slowed and causes accumulation. If the metabolites are active, pharmacological effects will occur. For example, the accumulation of N-acetyl-procaine amine in patients who have been administered with procainamide enhances the effect of the original drug.
Accumulation of active metabolites can also cause adverse reactions. The metabolites of clobetamine (Antomin) are excreted slowly in renal hypofunction. It is also toxic to skeletal muscle, so it is likely to cause severe muscle weakness and muscle tenderness in renal failure. In addition, furantoin is prone to peripheral neuritis, which is also related to the accumulation of its active metabolites.
The kidney also has the function of metabolizing drugs, for example, 50% of insulin elimination is metabolized by the kidney, therefore, patients with renal failure are prone to insulin accumulation.
Because most drugs are metabolized in the liver and excreted through the kidneys, patients with liver and kidney dysfunction (including the elderly and infants) are prone to accumulation in the body with long-term or repeated medication. However, daily medication should pay special attention to drugs with slow metabolism, relatively narrow safety range and high toxicity. These drugs are not metabolized and excreted in time after they reach the body, or the metabolism and excretion of the drugs are impaired due to poor liver and kidney function of the patient, thus making the drugs accumulate in the body continuously.
And it is easy to exceed the safe range of concentration, so that patients produce a series of toxic symptoms only when overdose. In the case of poor liver and kidney function, the dose of these drugs needs to be adjusted appropriately according to the liver and kidney function, or the time interval between doses needs to be adjusted appropriately.
Streptomycin, Tobramycin, Etimicin, Netilmicin, etc.), polymyxin, vancomycin, antiarrhythmics (including quinidine, procainamide, lidocaine, digoxin, digitalis toxin, etc.), psychoactive drugs (including chloral hydrate, diazepam, chlordiazepoxide, promethazine, amitriptyline, lithium, etc.), colistin, cimetidine, diuretics (hydrochlorothiazide, furosemide), warfarin, etc. Farin, etc.
There are also some diseases that can affect the metabolism of drugs, so that the half-life of drugs is prolonged, and if the dose or interval of administration is not adjusted, the drugs can easily accumulate in the body and even become toxic. Heart disease, for example, can affect hepatic blood flow, and for some (such as alprenolol, propranolol, dulcolax, morphine, isoniazid, etc.) can be rapidly metabolized by the liver, which actually affects the rate of metabolism and prolongs the half-life. The half-life of antipyrine is prolonged in cancer patients. Hypothyroidism can affect the metabolism of some drugs (e.g., antipyrine, digoxin, methimazole, and propranolol) and endogenous substances, which can prolong their half-lives.
In conclusion, for this group of patients, especially those with low liver and kidney function, the metabolism and excretion of drugs are affected to some extent due to low liver and kidney function, which prolongs the half-life and can easily cause the accumulation of drugs in the body and even produce toxicity. These patients, according to the situation of liver and kidney function, appropriate adjustment of the dose used, or appropriate adjustment of the time interval of taking. Of course, the best should be used in accordance with the doctor’s instructions, do not blindly use their own drugs.
In addition to patients with liver and kidney diseases, some special groups of people, due to physiological characteristics, are also prone to accumulation of drugs in the body.
For example, the fetal liver is immature and lacks the enzymes that catalyze the formation of glucuronide, so the fetal liver glucuronidation is weak and the detoxification function of drugs is insufficient, and the fetal glomerular filtration area and renal tubular volume are relatively insufficient and the renal tubular excretion function is immature, so many drugs are excreted slowly in the fetus, which can easily cause drug accumulation and poisoning. Pregnant women should pay special attention when using drugs.
Infants and children have incomplete internal organs, high sensitivity to drug action, slow metabolism of drugs, and poor excretion function of the kidneys, which can easily cause accumulation. In the elderly, there are different degrees of organ function degeneration, slow drug metabolism, lower plasma protein content in the blood and lower binding rate of plasma protein. This increases the concentration of free drugs, which continuously accumulates beyond the safe dose and triggers poisoning.
For example, the binding rate of phenytoin sodium and plasma protein is 26% lower in elderly people than in people under 45 years of age, and if the drug is taken according to the regular dose, it will easily cause drug accumulation poisoning.
Some drugs have their own characteristics, long half-life and slow metabolism in the body. The application of this type of treatment of chronic diseases of some drugs generally need to be taken for a long time, because the metabolism of drugs in the body takes ~ time, and the amount taken does not change, the blood concentration of drugs in the body gradually increases after long-term use, beyond the safe dose, resulting in human poisoning. For example, drugs containing the ingredients of Stilbene, whose elimination speed in the body is slow, need to be taken for a long time in the treatment of lumbar disc herniation and other diseases, and a little carelessness will lead to the accumulation of poisoning symptoms in the body.
Some modern speed-controlled dosage forms, such as slow-release tablets, controlled-release tablets, long-acting injections and so on, use modern preparation technology to make the drug released slowly, prolonging the half-life of the drug, reducing the number of times the drug is used, so that patients can take it conveniently. It is easy to cause drug accumulation poisoning.
Some drug interactions can also affect the absorption, distribution, metabolism, excretion and clearance rate of drugs, etc. Unreasonable combination of drugs can also cause drug accumulation and even poisoning symptoms. For example, some drugs can compete with plasma protein binding when used in combination, and different drugs have different plasma protein binding rates, so when 2 or more drugs are used in combination, the drug with the stronger binding rate will displace the other drug, increasing its free concentration in the blood, which can lead to the accumulation of drug concentrations in the blood and accidents.
For example, chloral hydrate, etanercept, indomethacin, aspirin, botrytisine, clofibrate, etc. are strong plasma protein binding ability, when combined with these drugs, especially oral hypoglycemic drugs, oral anticoagulants, antineoplastic drugs (such as methotrexate), it should be cautious and careful, if not pay attention, can cause accidents.
Some drugs have strong inhibition of liver drug enzyme activity, which can block the metabolism of other drugs, slow down the elimination, blood concentration accumulation and higher than normal, the drug effect is enhanced, and also has the risk of causing poisoning. For example, when chloramphenicol is combined with bicoumarin, because chloramphenicol is a strong inhibitor of hepatic enzyme activity, resulting in the metabolism of bicoumarin is blocked, thus causing adverse reactions of bleeding. There are also drugs such as chlorpromazine, cimetidine, ciprofloxacin, propranolol, verapamil, and protamine, all of which have strong pharmacological enzyme inhibitory effects.
To prevent drug accumulation poisoning, you should stop administering or give a smaller maintenance amount when applying slower metabolizing drugs after a certain amount. The drug should be used in patients with hepatic and renal insufficiency, and the blood concentration should be tested when applied, and a certain number of consecutive doses or a certain period of time should be specified as a course of treatment, and after a course of treatment, if repeated doses are needed, full consideration should be given to the need to stop the drug for a certain period of time before starting the next course of treatment. For infants and the elderly, start with a small dose, minimize the duration of the drug and reduce the variety of drugs used.
In case of adverse reactions, the drug should be stopped immediately, and for different symptoms and characteristics of the poisoned drug, symptomatic treatment should be taken quickly, or first-aid measures such as accelerating the discharge of the drug, and hemodialysis can be performed when conditions permit or if necessary, to minimize the consequences of adverse reactions.