Drug Interaction Classification and Mechanism



Drug interaction (drug interaction, DI) refers to the compound effect produced by the patient taking two or more drugs successively at the same time or within a certain period of time, which can enhance the efficacy of the drug, reduce the side effects, or weaken the efficacy of the drug. or undesired side effects. Enhanced effects include increased efficacy and increased toxicity, and diminished effects include decreased efficacy and decreased toxicity. Therefore, in clinical combination medication, attention should be paid to using the characteristics of various drugs to give full play to the pharmacological effects of each drug in the combination medication, so as to achieve the best curative effect and the least adverse drug reactions, thereby improving medication safety. According to the principle of occurrence, it can be divided into pharmacokinetics or/and pharmacodynamic interactions. The results of pharmacodynamic interactions include four types: irrelevant, synergistic, additive and antagonistic; pharmacokinetic interactions are mainly due to the absorption and distribution of drugs. , metabolism and excretion. The consequences of drug interactions include desirable (desirable), insignificant (inconsequential) and harmful (adverse) 3 kinds, of which insignificant accounts for the vast majority, and we are concerned about the harmful DI.

Drug Interaction Classification
1.1. Pharmacokinetic Interactions
It can occur in four stages of absorption, distribution, metabolism and excretion, among which the drug-drug interactions (DDIs) of metabolic drugs have the highest incidence, accounting for about 40% of pharmacokinetic interactions. Metabolic drug interaction refers to the interference of two or more drugs in the metabolic process when two or more drugs are administered simultaneously or sequentially, resulting in enhanced efficacy or even adverse reactions, or weakened efficacy or even treatment failure. Drugs with enzymatic action generally accelerate the metabolism of another drug and shorten the half-life. For example, phenobarbital is a liver drug enzyme inducer, which increases the metabolism of other drugs and weakens its effect. Conversely, a drug with an enzyme inhibitory effect slows the metabolism of another drug, thereby extending the half-life of the drug. For example, digoxin can be metabolized into dihydrodigoxin by normal flora in the intestinal tract. If erythromycin is used in combination, it will inhibit the normal flora and increase the blood concentration of digoxin. Clopidogrel, a prodrug that is metabolized by hepatic cytochrome P450 to an active metabolite, can significantly and irreversibly block platelet ADP P2Y12. Some drugs that inhibit CYP2C19, including some proton pump inhibitors (PPIs), reduce the production of clopidogrel’s active metabolite, thereby increasing adverse events and reducing the drug’s clinical effectiveness. For patients receiving clopidogrel, the combination of PPIs and clopidogrel should be avoided as much as possible. Studies by Ho et al and Juurlink et al have shown that the use of H2 receptor blockers does not increase the risk of recurrent cardiovascular events, so H2 receptor blockers such as Raney may be considered for patients who require acid-suppressive therapy. Ted et al. However, caution should be exercised in patients who must use PPIs and the duration of their use should be minimized. In addition, concomitant administration of lipophilic statins such as atorvastatin and simvastatin can compete with clopidogrel for CYP3A4 receptors and weaken the platelet inhibitory effect of clopidogrel. For this reason, it is clinically preferred to use clopidogrel at the same time as statins that do not affect CYP3A4 metabolism.

1.2. Pharmacodynamic interactions
It refers to the combination of drugs, one drug changes the pharmacological effect of another drug, but has no obvious effect on the blood concentration, but mainly affects the various factors that affect the drug and receptors. Hydrochlorothiazide is a commonly used drug for elderly patients with hypertension and congestive heart failure. Long-term use can cause hypokalemia to decrease. When hypokalemia occurs, myocardial stress increases, and the sensitivity of myocardium to cardiac glycosides increases, which can easily lead to rapid heart rate and arrhythmia. . Therefore, cardiac glycosides should not be used in combination with potassium-scavenging diuretics. Roxithromycin, levofloxacin, clindamycin, etc. in combination with theophylline drugs can reduce theophylline clearance rate and easily cause theophylline accumulation in the body poisoning. The blood concentration of theophylline should be monitored when combined.

The mechanism of drug interaction
Most drugs are metabolized by cytochrome P450 enzymes in the intestine and 1 or liver. The inhibition or induction of P450 enzymes is the main cause of metabolic DI. The clinical significance of enzyme inhibition is far greater than enzyme induction. effect, accounting for about 70% of metabolic interactions, and DI caused by enzymatic induction accounted for about 23%. Drug transporters are also an important factor in the production of DI.
2.1 Cytochrome P450
Drug metabolism in the body includes two-phase reactions: Phase I reaction is a redox reaction, mainly involving the CYP enzyme family; Phase II reaction is a binding reaction, involving glutathione, glucuronic acid, sulfate, and glycine. Usually, a drug is metabolized by multiple subtypes of CYP enzymes, and only a few drugs are metabolized by a single drug enzyme. It is estimated that about 60% of prescription drugs are metabolized by CYP enzymes. The cytochrome P450 family that has been identified is 18 families and 42 subfamilies. The CYP enzymes involved in metabolism are mainly CYP3A4, CYP1A2, CYP2C9, CYP2C19, and CYP2D6, accounting for 95% of the CYP enzymes. About 55% of the drug is metabolized by CYP3A4, 20% by CYP2D6, and 15% by CYP2C9 and CYP2C19.
2.2 P protein
Effects on absorption The effect of protein P on drug absorption is due to its mediated drug interactions. P protein has a wide range of substrates, and the drug efflux mediated by it is a major cause of differences in oral drug absorption and bioavailability. The absorption of P protein substrates such as digoxin, cyclosporine, tacrolimus, etc. is easily affected by P protein inhibitors (such as verapamil, quinidine) or inducers (such as rifampicin) effects, resulting in an increase or decrease in bioavailability. For some drugs with a narrow therapeutic index, changes in bioavailability can lead to corresponding changes in plasma concentrations, resulting in toxicity or ineffective treatment. P protein inhibitors mainly include verapamil, valsartan, quinidine, etc., but the affinity is low, and when the desired inhibitory effect is achieved, it will produce great toxicity. Some components in fruits and vegetables, herbs and other foods such as flavonols and coumarins can modulate the activity of protein P, which in turn affects the disposition of drugs in the body. Flavonoids mainly inhibited the activity of P protein ATPase and increased the absorption of substrates; furanocoumarins in grapefruit juice simultaneously inhibited CYP3A4 enzyme and P protein, and significantly increased the absorption of drugs.

Prevention of drug interactions
3.1 Implement individualized drug delivery
For children, the elderly, and special populations with impaired liver and kidney function, special attention should be paid to drug interactions during clinical medication. Due to the reduced metabolism and excretion of the drug in the body, it will cause an increase in the blood concentration of the drug, which is prone to adverse reactions. Try to avoid the combined use of drugs that make treatment more difficult to control or drugs that are likely to cause serious adverse interactions, and it is better to choose safer alternatives.

3.2 Pay attention to drug instructions
When a drug is not effective, it is necessary to change the drug or select other drugs for reasonable compatibility. But not all compatibility is reasonable, some compatibility will weaken the therapeutic effect of the drug, leading to treatment failure; some compatibility will increase adverse reactions or toxicity, causing serious adverse reactions; some compatibility will increase the therapeutic effect excessively, beyond the body tolerance can also cause adverse reactions. These are all contraindications. The solvent selection and interactions of the drug are detailed in the drug insert. Physicians and pharmacists should read it carefully before using it, so as to be aware of it and avoid possible adverse interactions.

3.3 Pay attention to the use of drugs in high-risk groups who are prone to drug interactions
The study reported that the incidence of bleeding events in patients aged 65 years and above was significantly higher than that in patients under the age of 65. Therefore, for the elderly suffering from various chronic diseases, patients who need long-term drug maintenance treatment, patients with multiple organ dysfunction, and patients who have been treated by multiple hospitals or multiple doctors, they should be asked in detail about their drug history, and comprehensive consideration should be given to them. Disease, and strive to use less and more precise.

3.4 Keep in mind high-risk drugs that are prone to drug interactions
Such as antiepileptic drugs (phenytoin), cardiovascular drugs (quinidine, propranolol, digoxin), oral anticoagulants (warfarin, dicoumarin), oral hypoglycemic drugs (glib Benurea), antibiotics and antifungal drugs (erythromycin, rifampicin, ketoconazole) and gastrointestinal drugs (cimetidine, cisapride). Warfarin is a commonly used anticoagulant in clinical practice, with high anticoagulation efficacy and low price, but the disadvantage is that it will interact with many drugs. For example, the combination of cephalosporin antibiotics (cefoperazone, cefotaxime, etc.), macrolide antibiotics, amiodarone, etc. can enhance the anticoagulant effect of warfarin, which is related to the competition with vitamin K, oral contraceptives and estrogen. Enzyme protein, promote the production of coagulation factors II, VII, IX, X, antagonize the effect of warfarin, and weaken the anticoagulant effect.

3.5 It is not advisable to change the medicine frequently
In the process of treating or treating the disease, if it is necessary to change the drug and there is a drug interaction, since the time, course and degree of the drug interaction varies with the drug and the patient, the therapeutic effect after the drug change and the degree of the drug interaction should be closely observed. Adverse reactions.

3.6 Timely monitoring of therapeutic drugs
For example, in patients with vital organ failure, when the disease itself affects the metabolism and excretion of drugs, therapeutic drug monitoring should be carried out to adjust the drug dosage and drug treatment plan in time to avoid serious adverse reactions and iatrogenic diseases.

3.7 The interaction between Chinese and Western medicines cannot be ignored
Licorice is a very commonly used Chinese medicine, and most Chinese medicine prescriptions contain licorice. However, in patients taking digoxin, taking licorice may increase the toxicity of digoxin. Additionally, ginseng can increase the bleeding effects of heparin, aspirin, and NSAIDs such as ibuprofen, naproxen, and ibuprofen. Zhang Yu reported a patient with coronary heart disease and atrial fibrillation who suffered from urinary tract bleeding due to overdose of safflower decoction while taking warfarin. Ginkgo biloba and simvastatin are commonly used cardiovascular drugs in combination. Experiments show that when 20mg/kg Ginkgo biloba preparation and simvastatin are used in combination, there is no significant interaction. When the dose is 200mg/kg, it can induce the activity of CYP 3A and promote the in vitro metabolism of simvastatin. When used together, they should be taken separately.

3.8 Taking into account the effects of food on drugs
Drug interaction mainly refers to the interaction between drugs and drugs, but also includes the interaction between drugs and tobacco, alcohol, and food. There are also many examples of food affecting the efficacy of drugs. For example, drinking alcohol while taking phenobarbital drugs may increase drug absorption and enhance the inhibitory effect of the nervous system. Grape juice should not be used concomitantly with certain antihypertensive drugs and cyclosporine, which prevents organ transplant rejection, because grape juice can increase the concentration of these drugs in the body, thereby increasing the adverse effects of these drugs. Grape juice also interacts with the anti-anxiety drug buspirone, the anti-malarial drug cyclohexanediol, and the hypnotic drug Oxymetholone to increase blood pressure. The caffeine in chocolate can also interact with stimulant drugs such as Ritalin, increasing the effects of the drugs or reducing the effects of sedative-hypnotic drugs such as Zolpidem.

3.9 Utilizing the Rational Drug Use Monitoring System
Use the rational drug use monitoring system to improve the safe drug use level in the hospital. The system is a standardized and automated management system, based on the basic characteristics and requirements of clinical rational drug use professional work, using computer database organization principles and technologies, through the scientific, authoritative and updated knowledge of medicine, pharmacy and related disciplines. After standardized processing, it can be applied to doctor’s order review and medical information query, so as to prevent the occurrence of adverse drug events and realize rational drug use. This system can provide real-time warning information about in vitro compatibility, in vivo interactions, adverse drug reactions and other warning information between drugs in the clinical drug treatment process. Develop and implement a reasonable drug treatment plan for clinical medical staff.
Paying attention to drug interactions is extremely important for improving the quality of medical care and for safe and effective combination drugs. An in-depth understanding of the absorption, distribution, metabolism and excretion of drugs in the body, as well as the interaction of various drugs in the body, can help avoid disadvantages, reduce adverse drug reactions, and ensure medication safety.

Bioanalytical Service – PK Studies