The Rawlins-Thompson classification usually classifies adverse drug reactions into two types: A and B. Type A includes reactions associated with medication dosage, with larger doses having the potential to cause more significant adverse events. Type A depends on the pharmacodynamics of a particular medication. Type B adverse drug reactions are characterized by unexpected reactions that cannot be predicted by examining the pharmacodynamics of a drug and are not dose-dependent. (1) Rarer adverse drug reactions comprise types C, D, and E. The characteristic of the chronic type, i.e. type C, is the development of the adverse reaction after the medication has been taken for a longer period. Type D (delayed type) takes place after exposure to the medication has ended. The characteristic of type E is that the adverse reaction manifests after treatment with the drug has ended. (2) This classification of adverse events during adverse drug reactions (ADR) is useful but incomplete, since the reactions can overlap. Consequently, a dose-related technique was developed, where dose dependence is defined based on a curve. ADR is considered acceptable when the dose is within treatment values. ADR and over-sensitivity are present when the dose is lower than the treatment dose, whereas drug toxicity is considered to be present when the dose is higher than the treatment value. With regard to time-dependence, we can distinguish the following types of ADR: rapid onset ADR, appearing at the first dose of the medication, early onset ADR, moderate time-to-onset, late onset, and delayed ADR. Sensitivity of patients to ADR depends on the age group, sex, drug-drug reactions (DDR), and epigenetic characteristics and comorbidities, with simultaneous use of different drugs significantly contributing to higher risk of potential drug therapy problems (DTP). (3) Potentially adverse effects or events with the use of medications are particularly common in patients with chronic kidney disease (CKD), in whom death most often has a heart-related cause, namely sudden cardiac death before the development of the final stages of CKD and before kidney replacement treatment has been initiated. The basic goal in the treatment of any chronic, non-infectious disease, including CKD, is enabling quality of life, slowing down or preventing further deterioration of organ functions, which in the case of the kidneys means monitoring glomerular filtration (GF) rate, and slowing down the progression of cardiac and renovascular remodeling. Problems arise when physicians introduce more and more different medications that are all eliminated via the kidneys, with reduced kidney function also causing pharmacological changes in the dynamics and kinetics of the drugs excreted via the kidneys. (4) Every reduction in GF should thus also result in adjustment of drug dosage in order to prevent unexpected side-effects as well as adverse events, especially in the population of patients with CKD, who are prone to DTP. (4) Chronic kidney disease is an independent risk factor not only for cardiovascular diseases but for other associated diseases as well, such as infections that often effect the older population, which additionally contributes to the development of DDR and exacerbates potential DTP, especially in combination with antimicrobial drugs, oral anticoagulant drugs, and analgesics such as non-steroidal anti-inflammatory drugs (NSAID). (5,6)
Frequency of adverse drug effects in emergency medicine and during hospitalization
Studies have found that ADR are the fifth most frequent cause of death, with an incidence between 5% and 10% in hospitalized patients. (7) The incidence of ADR in persons below the age of 18 is 0.8%, but it increases with age and is 3.2% in persons above 80 years of age. (8) Taking more and more different drugs at an older age due to comorbidities leads to polypharmacy, which is an additional factor that contributes to ADR. (7,8) It is now known that the risk factors for the development of ADR are polypharmacy (daily intake of 5 different drugs in the general population, but definition of more than 10 different medications per day is recommended for patients with heart failure and kidney disease the), older age, female sex, and comorbidities. (3) It is believed that ADR are responsible for a growing amount of unnecessary hospitalization and high treatment costs in modern society.
In a study by Giardina et al., the number of complications caused by ADR during hospitalization (in-hospital ADR) and the number of emergency hospitalizations due to ADR were compared to patients who did not have ADR. (7) The prevalence of in-hospital ADR was 3.2%, while the prevalence of ADR in emergency services which were the reason for hospitalization was 6.2%. Polypharmacy and female sex were factors associated with ADR in both groups. In the population of hospitalized patients, ADR were classified based on clinical manifestations from the least to the most common as follows: cardiac (11.5%), general (13.4%), vascular (13.4%), and skin disorders (27.0%) as the most common. The medications that caused ADR ranged from those that were least common (cardiovascular drugs, antidiabetic drugs), drugs from the antihypertensive group (renin-angiotensin-aldosterone system / RAAS inhibitors and diuretics), to those that resulted in ADR much more often, which included antiplatelet medication with a frequency of 21.7% and antimicrobial drugs with the highest ADR frequency of 38.2%. In the antimicrobial drug group, the most commonly applied drugs were quinolones and penicillin. Classification of serious ADR was present in 46% of cases, among which 95% of patients fully recovered. Of the patients admitted to the emergency room, ADR were most frequently the consequence of improper drug intake due to misunderstanding, accidental intake of an overly large dose (mistake in drug application), and patients deliberately taking a dose that was too large due to misuse. The most common newly-developed clinical conditions and disorders manifested in the gastrointestinal (27.7%) and hematological system (26.5%). 18.1% newly-developed metabolic disorders and 16.1% new neurological disorders were also found. Based on ADR frequency, the medications were from the antiplatelet group (39%), RAAS inhibitors (13.9%), NSAID (11.9%), and diuretics (9%). Total recovery was achieved in 87% of patients, but 2.9% had long-term lingering effects. The study states it would have been possible to prevent 69.4% of the total in-hospital ADR, 24.2% could not have been predicted or prevented in any way, and 6.4% were preventable. Among patients admitted to emergency services due to ADR, ADR likely could have been prevented in 63.9%, while 23.2% of ADR cases could have certainly been predicted and prevented. (7) Other authors have reported that most patients examined in emergency services were admitted due to bleeding, in 8.6% of cases, followed by ADR (3.6%), hypoglycemia (3.1%), elevated body temperature in 2.8% cases, agranulocytosis in 2.2% cases, and finally dehydration in 2.1% of cases. (8) The medications that caused ADR were from the group of anticoagulant drugs (17.8%), cytostatics (14.8%), diuretics (8.0%), antidiabetics (4.4%), salicylates (4.2%), and antirheumatics (4.1%). Studies have reported different incidence rates for ADR and fatal adverse drug reactions (FADR), depending on whether the study examined patients admitted through emergency services or those who were in hospital treatment. FADR incidence in the population admitted through emergency services was between 0.05% and 0.44%, whereas in-hospital FADR was 0.05 and 0.19%. (9) A study conducted in Sweden reported a FADR frequency of 3.1% and that most of these cases were caused by bleeding. In this study, antiplatelet drugs and NSAIDs were the most commonly used drugs among ADR cases. (9) The results of a study in Croatia conducted by Marušić et al. on the incidence of ADR after discharge from the clinic showed an incidence of ADR of 30% (72 out of 209 patients). In this study, the most common manifestations were bleeding due to oral anticoagulant drugs (warfarin) and low glucose levels (hypoglycemia) caused by antidiabetic drugs, with 5 patients presenting a severe clinical picture. (10) All the studies described above examined the incidence of ADR in the general population, but what happens in the population of patients with CKD? A study by Hellden et al. examined the effects of ADR in a group of patients with CKD. (11) The study included 1425 persons receiving home care aged 65 and above. 16.0% were examined at the hospital and 10.8% (154) were hospitalized. Among the hospitalized patients, ADR was the primary cause of hospitalization in 14% (22). In 7 of the 22 patients with ADR (32%), medications had been administered that are not recommended for CKD, indicating medical error. (11) The most common symptoms and causes of hospitalization were orthostatic hypotension as well as vertigo with accidental falls in 5 patients. Incidence of bleeding was found in 4 patients, and a confused state and sedation was observed in 3 patients, with the most frequently administered drug being tramadol. It is important to know that tramadol and metabolites (as active compounds) are excreted through the kidneys. CKD thus increases excretion half-life and plasma concentrations of tramadol, as well as incidence of ADR. The study showed that female sex, polypharmacy, age over 80, and CKD are risk factors that contribute to the development of ADR. (11) The average number of prescribed medications in the group of patients with ADR was seven, which emphasizes the problem of polypharmacy that should be considered in treatment, especially in the population of older patients. Average GF was 40 mL/min/1.73 m2, which means it was in stage G3b. (11) Most ADR belonged to type A, but one type B reaction was described, an anaphylactoid reaction to the application of drugs from the angiotensin converting enzyme inhibitors (ACEI). An additional problem indicated by this study is that the older population has diminished renal reserve, which should be considered when selecting medication. Another fact stemming from this study is that the majority of patients treated in emergency services as well in ambulance service for primary, secondary, and tertiary care are of increasingly advanced age. (11)
A study conducted in Italy examined the association between CKD and ADR during hospitalization. (12) The study divided older patients into 3 groups depending on GF and serum creatinine (C) values. The first group of participants had GF and C within reference values. The second group had GF within reference values, but elevated C values, and was classified as the group with concealed kidney problems. The third group had lowered GF values and elevated C, and was classified as the CKD group. Medications dissolvable in water (hydrosoluble) caused 301 cases of ADR, while non-hydrosoluble medications caused 640 cases of ADR. The most common ADR due to hydrosoluble medications were low blood pressure or hypotension (caused by drugs from the RAAS group at 17.9% and diuretics at 15.3%), bradycardia (caused by digitalis, 16.3%), hypoglycemia due to treatment with antidiabetics in 13.9% of cases, and hypokalemia due to treatment with diuretics. These were followed by drugs causing gastrointestinal symptoms (antithrombotic medications, 8.0%), sluggishness and drowsiness (with psycholeptics, 7.6%), and headache and hypotension due to nitrate treatment (13.7%). The authors demonstrated that medications soluble in water increase risk of ADR in the group of patients with concealed kidney disease with a OR of 1.78 for hydrosoluble medications, in comparison with OR 0.92 for other medications. This indicated that hydrosoluble medications increase risk of ADR in this group of patients. (12) Age groups were not a statistically significant factor for incidence of ADR. The authors emphasized the importance of GF assessment with dose adjustment, which can prevent the majority of ADR. (12)
Individual studies have emphasized the importance of adjusting and reducing drug dosage by almost 30% of the typically prescribed doses in older populations with CKD. (13) But is there a way to adequately assess which patient would be in an at-risk group for ADR? A study from Dubai assessed the risk that would allow timely diagnosis of CKD and reduce the likelihood of ADR. (13) The study examined the following patient characteristics: age, sex, and comorbidities, and included a physical examination and laboratory parameters as well as the medications the patients were taking. ADR incidence was 12.1% (95% CI, 9.2-14.9), which means ADR was the underlying cause in 62 hospitalization complications among 512 patients. The most common ADR was bleeding due to anticoagulant medication (70% of all ADR), followed by heparin (28%), enoxaparin (26%), and warfarin (13%). The next most frequent ADR was hypoglycemia due to sulphonylurea treatment (6% of cases). Polypharmacy was once again shown to be the most important risk factor for ADR development, especially if the patient was taking more than 8 medications, and the study graded the polypharmacy data with four points. Age above 65 and female sex were graded with one point. End-stage CKD, serum albumin <3.5 g/dL, elevated high-sensitivity C-reactive protein (hsCRP) >10 mg/L, and cardiovascular diseases were graded with two points each. Data analysis determined that almost 47% of patients with ADR had ten or more points. These data could be used to conduct a routine assessment of patients with increased ADR risk with complicated treatment, extended hospital treatment, and increased additional costs for the healthcare system in general. (14)
Options for diagnosis, treatment, and prevention of adverse drug effects
The current treatment approach to patients in emergency rooms (airway, breathing, circulation, disability, and exposure, i.e. ABCDE) for the assessment of the patient’s clinical condition does not include assessment of kidney function. If ADR is the reason that the patient presented to emergency services, it is important to suspect and recognize drugs that might be the cause of ADR and know the exact time when the last dose was taken. If there is an option to apply an antidote for the drug that caused ADR, it is important to administer it immediately. In case of acute kidney damage or progression of previously diagnosed CKD into the acute phase, clearance of medications excreted via the kidneys will be reduced, which should be taken into consideration, adjusting medication dosage with diuresis monitoring and preventing electrolyte imbalances (especially hyperkalemia) and acidosis. Today, new insights have allowed simpler and safer drug prescription, especially in comparison with the time before Internet literacy, with additional individual adjustment of the medications to patients, considering their comorbidities and monitoring not only ADR but also different DDRs, usually caused by medical error resulting from the application of two or more medications that have an adverse reaction with one another or which cause toxic metabolites. We now have the capacity to select medications that are associated with less ADR at a dose adjusted to kidney function, which should be applied to individual patients in as short a timeframe as possible, which in turn represents a daily challenge in patient care. (15,16) The cooperation of different medical fields is thus paramount in the care for patients with comorbidities such as CKD and heart failure, where the inclusion of a clinical pharmacist can significantly reduce the issue of polypharmacy and unadjusted drug dosage at all levels of healthcare, starting with the primary level, and indicate timely referral for ADR treatment at secondary and tertiary healthcare levels, as demonstrated in the paper by Brajković et al. (17)
Conclusion
Unwanted ADR range from minimal to life-threatening conditions. Polypharmacy significantly contributes to higher incidence of ADR. Combining multiple different medications also increases the incidence of DDR. Considering the global aging of the population and the continuous rise in chronic non-infectious diseases, it is important to be aware of the growing issue of DRR and recognize unwanted events associated with the application of different medications. One of the measures that can be introduced in order to improve quality of care and prevent ADR is the inclusion of clinical pharmacists in everyday patient care, especially for older patients with comorbidities.