Interference of medicines in laboratory exams

Objective: Conduct a survey on the interference of drugs in laboratory tests. Methodology: To identify the interference of each medication in laboratory tests, the Municipal List of Essential Medicines (Remume) of a medium-sized municipality in the state of Minas Gerais was used along with the following sources of information: Dynamed, Micromedex ® and Nursing Reference Center. Results: We observed that the majority (67.7%) of Remume drugs can interfere in one or more laboratory tests; among them, the main classes of drugs are diuretics, beta blockers, ß-lactams, sulfonamides, macrolides, tricyclic antidepressants and selective serotonin reuptake inhibitors antidepressants. Conclusion: It is extremely important to disseminate knowledge about these interferences so that health professionals are alert and know how to identify the possible changes, reducing analytical errors and subsequently misdiagnosis and erroneous monitoring. Continued education on drug interference in laboratory tests is equally important.


INTRODUCTION
Medicines are major sources of variation in laboratory test results, and not always they can be discontinued for the conduction of those tests (1) . Some drugs can produce false-negative or falsepositive results; having access to this item of information is very important in laboratory routine, as well as in clinical practice and pharmaceutical care, because it deals with change in the clinical laboratory diagnosis and interference in the monitoring and evaluation of patient prognosis (2) .
Thus, it is essential to obtain data about medications and their time of use by the patient for the last 10 days before collecting biological material for the conduction of a laboratory test. Commonly, patients forget reporting some medicines they use to the laboratory personnel, therefore it is necessary to be attentive to any abnormality in the tests (3) .
Numerous medicines can cause biological (in vivo) and analytical (in vitro) interferences that affect laboratory tests. When a medication produces the change of a biological marker by means of a physiological or pharmacological mechanism, there is the in vivo interference or adverse drug reaction. For example, the changes in serum uric acid, which can be caused by the use of enalapril and hydrochlorothiazide (2) . On the other hand, in vitro interference of a drug or its biotransformation product can happen at an analytical step in which those tests can interact with the substances of the employed chemical reagents, producing a false result of the analysis (2) . As an example, the reduction that the ascorbic acid can cause in plasma levels of glucose when measured by the method of glucose oxidase (3) .
Given the above, it is important that both professionals working in clinical laboratories and those involved in the care of patients know how to recognize the types of interference drugs can cause on laboratory tests, as they can alter some markers and interfere in the conduct of health professionals. Besides, care must be greater with patients treated with several medicines concomitantly for a prolonged time, because the chances of interference are higher.
The objective of this work was to conduct a survey on the interference on laboratory tests by the medicines present at the Municipal List of Essential Medicines (Remume) of a mediumsized municipality of the state of Minas Gerais, in order to warn and spread this knowledge to the population and health professionals.

METHODS
The present study used the last version of Remume (130 medicines belonging to different classes) of a medium-sized municipality of the state of Minas Gerais (234,937 inhabitants (4) ), made available by the Municipal Office of Health (Semusa) in 2019. From the obtained data, we carried out a search about the interference each medication can cause in laboratory tests, by means of the site Saúde Baseada em Evidências (Evidence-Based Health), using the databases Dynamed, Micromedex ® and Nursing Reference Center. The names of medicines in English were searched as key words. Later, medicines were classified according to the Anatomical Therapeutic Chemical Code (ATC), which distributes the active substances in different groups, pursuant to the organ or system in which they act and their therapeutical, chemical and pharmacological properties (5) . From this search, a table was built to be used as a material for rapid consultation by all health professionals involved in patient care.

RESULTS
The medications present at Remume used in basic attention were distributed according to ATC classification regarding the treatment of: disorders of the digestive system and metabolism and food supplements; diseases of the blood and blood-forming organs; cardiovascular diseases; skin conditions; genitourinary tract disorders, sex hormones and immunoglobulins; inflammatory processes and hypothyroidism; systemic infectious diseases; musculoskeletal disorders; nervous system diseases and sleep disorders; parasitic diseases; respiratory diseases. The interference of those medicines in laboratory tests is represented in the We observed that most (67.7%) medicines of Remume can interfere in one or more laboratory tests. Among them, the main classes of medicines are diuretics, which change especially electrolyte balance; betablockers, which affect lipid profile; beta-lactams and sulfonamides, which cause change in blood count; macrolides and tricyclic antidepressants, which alter hepatic enzymes; and selective serotonin reuptake inhibitors antidepressants, which affect glucose and uric acid levels. e2672021 The main tests suffering interference were: liver function (46 medicines), blood glucose test (31 medicines), and electrolyte panel (29 medicines).

DISCUSSION
We verified that the medicines atenolol, propranolol, carvedilol, hydrochlorothiazide, carbamazepine, haloperidol, clopidogrel, medroxyprogesterone, prednisolone, and prednisone can cause alteration of the lipid profile as the major biological interference. Thus, it is important to monitor the lipid profile of the patients taking those drugs, as the increased serum levels of triglycerides and the low-density lipoprotein cholesterol (LDL-c) and the reduced serum levels of the high-density lipoprotein cholesterol (HDL-c) are associated with the increased risk of development of cardiovascular diseases (6) .
Acetylsalicylic acid, atenolol, carvedilol, clonidine, furosemide, hydrochlorothiazide, propranolol, simvastatin, prednisolone, prednisone, amoxicillin, amoxicillin + clavulanic acid, azithromycin, benzathine penicillin, cefalexin, nitrofurantoin, baclofen, ibuprofen, amitriptyline, clomipramine, phenytoin, fluoxetine, imipramine, levodopa + benserazide, levodopa + carbidopa, nortriptyline, paracetamol, promethazine, ciprofloxacin, and carbamazepine are associated with alterations in the metabolism of glucose by means of decreased insulin secretion or action. As they increase blood glucose as a biological interference, it is important to monitor the glycemic levels of patients who use them. Besides, in case patients suffer from diabetes mellitus, it may be necessary to adjust the dose of the antidiabetic agent (7) .
The medicines that cause biological interference in renal function, with the risk of increased levels of urea and creatinine and reduction of creatinine clearance, are: clopidogrel, atenolol, captopril, carvedilol, spironolactone, furosemide, hydrochlorothiazide, losartan, methyldopa, propranolol, acyclovir, azithromycin, cefalexin, clarithromycin, nitrofurantoin, sulfamethoxazole + trimethoprim, allopurinol, diclofenac sodium, ibuprofen, carbamazepine, fluoxetine, levodopa + carbidopa, mebendazole, acyclovir, ceftriaxone, and sulfadiazine. Some of these medications are nephrotoxic (9) , consequently, for prevention of chronic kidney disease it is relevant to monitor renal function by means of the assessment of glomerular filtration rate and albuminuria (10) . Besides, some of those medications are contraindicated or must have the dose adjusted in patients who already present kidney disease (9) .
Linagliptin, acetylsalicylic acid, clopidogrel, atenolol, carvedilol, spironolactone, furosemide, hydrochlorothiazide, methyldopa, and propranolol have as biological interference the increased levels of uric acid, being important to monitor serum levels of this analyte in patients who use those medications due to the risk of development of gout -a disease characterized by accumulation of crystals of urate in joints, synovial tissue, bones, skin, and kidneys -, regardless of the presence or absence of clinical manifestations (11) .
Electrolytes are essential for basic life functioning, such as maintenance of electrical neutrality of cells, generation and conduction of action potentials in nerves and muscles (12) . The drugs that alter the levels of electrolytes (sodium, potassium, magnesium, calcium) are aluminum hydroxide + magnesium hydroxide, recombinant human insulin (NPH), regular human insulin, omeprazole, enoxaparin, heparin, atenolol, captopril, carvedilol, enalapril, spironolactone, furosemide, hydrochlorothiazide, losartan, methyldopa, propranolol, prednisolone, azithromycin, benzathine penicillin, sulfamethoxazole + trimethoprim, ibuprofen, carbamazepine, lithium carbonate, fluoxetine, oxcarbazepine, topiramate, salbutamol, and itraconazole. High or reduced levels of electrolytes can cause an imbalance in the body, interrupting the normal body functions, with risk of complications such as death; therefore, it is important to monitor serum levels in patients who are treated with these medications (12) .
Acetylsalicylic acid, amiodarone, phenytoin, and medroxyprogesterone are able to interfere biologically in the levels of hormones triiodothyronine (T3) and thyroxine (T4), responsible for metabolism regulation, and also in the levels of the thyroid stimulating hormone (TSH), produced and released by the anterior pituitary gland and responsible for regulating the secretion of thyroid hormones (13) . Thus, it is of utmost importance to monitor thyroid hormones of patients in use of the mentioned drugs. Besides, dose adjustment can be necessary in patients with hypothyroidism who are treated with levothyroxine (14) . Some drugs can even cause blood count alterations: dabigatran, hydralazine, amoxicillin, amoxicillin + clavulanic acid, benzathine penicillin, diclofenac sodium, ibuprofen, chlorpromazine, clomipramine, levodopa + carbidopa, thioridazine, mebendazole, ceftriaxone, ciprofloxacin, and silver sulfadiazine. They reduce the levels of hemoglobin, causing anemia. Metformin, pyridoxin, pyrimethamine can also cause reduction in the levels of vitamin B12 and/or folic acid, resulting in megaloblastic anemia (15) . Captopril, enalapril, hydralazine, silver sulfadiazine, amoxicillin, amoxicillin + clavulanic acid, azithromycin, benzathine penicillin, cefalexin, ibuprofen, valproic acid, alprazolam, carbamazepine, clomipramine, chlorpromazine, phenytoin, haloperidol, levodopa + carbidopa, thioridazine, albendazole, ivermectin, mebendazole, promethazine, ceftriaxone, ciprofloxacin, and pyrimethamine can cause interference in the leukocyte levels. If patients use any of these drugs, it is important to monitor them by means of blood count (16) .
Regarding blood clotting, medications that interfere with the levels of platelets are heparin, hydralazine, silver sulfadiazine, amoxicillin, amoxicillin + clavulanic acid, azithromycin, cefalexin, allopurinol, ibuprofen, valproic acid, carbamazepine, clomipramine, chlorpromazine, phenytoin, levodopa + carbidopa, thioridazine, mebendazole, ceftriaxone, ciprofloxacin, pyrimethamine. As the acetylsalicylic acid, methyldopa, azithromycin, paracetamol, and ceftriaxone can cause alterations in prothrombin time, it is fundamental to monitor patients that use these drugs by means of laboratory assessment of coagulation panel. Besides, in case the patient uses the oral anticoagulant, drug dose adjustment may be necessary (17) .

CONCLUSION
Laboratory tests are essential for clinical diagnosis to be correctly established by the physician and the therapeutic choice to be appropriate. An incorrect test involves erroneous treatment, what can cause complications in patients' health in the future. Besides, some drugs can promote alterations in laboratory tests due to adverse effects; that is why it is so important to monitor laboratorial the patients who use them.
In this study we observed that most (67.7%) medications of Remume interfere in one or more laboratory tests. Therefore, this survey bears great relevance, because it promotes dissemination of knowledge about the interference medications cause in laboratory tests, so that pharmacists, physicians and other health professionals are attentive and learn how to identify possible interference during analysis, leading to reduction of wronged diagnoses and unsuccessful monitoring.