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GHENT UNIVERSITY FACULTY OF PHARMACEUTICAL SCIENCES Department of Bioanalysis Pharmaceutical Care Unit Academic year 2014-2015 QT-PROLONGING AND ANTICHOLINERGIC MEDICATION IN OLDER BELGIAN POLYPHARMACY PATIENTS Eline CHRISTIAEN 1ST master pharmaceutical care Promoter: Prof. dr. K.Boussery Commissioners: Prof. dr. J.Van Bocxlaer Prof. dr. A.Somers GHENT UNIVERSITY FACULTY OF PHARMACEUTICAL SCIENCES Department of Bioanalysis Pharmaceutical Care Unit Academic year 2014-2015 QT-PROLONGING AND ANTICHOLINERGIC MEDICATION IN OLDER BELGIAN POLYPHARMACY PATIENTS Eline CHRISTIAEN 1ST master pharmaceutical care Promoter: Prof. dr. K.Boussery Commissioners: Prof. dr. J.Van Bocxlaer Prof. dr. A.Somers COPYRIGHT “The author and the promoters give the authorization to consult and to copy parts of this thesis for personal use only. Any other use is limited by the laws of copyright, especially concerning the obligation to refer to the source whenever results from this thesis are cited.” June 2, 2015 Promoter Prof. dr. K. Boussery author Eline Christiaen SUMMARY Polypathology and polypharmacy are a growing problem in our aging society. Consequently, older adults are at greater risk of ADEs due to physiological, pharmacokinetic and pharmacodynamic changes. ADEs are potentially dangerous and can lead to hospitalization and even death. In this study we focus on two types of ADEs; QT-prolongation and anticholinergic (side-)effects. QT-prolongation in itself is not a large problem but can possibly lead to fatal TdP. Anticholinergic (side-) effects on the other hand can include for example (further) deterioration of the aging brain, dry mouth and gastrointestinal problems. Recently there has been increasing research on both of these topics. In this thesis, the general drug use of 1016 community-dwelling and 400 institutionalized older adults in Belgium was evaluated. Besides that, a literature search was conducted for existing evidencebased risk scales to determine the risk of QT-prolongation and anticholinergic (side-) effects. Consequently the use of QT-prolonging drugs and drugs with anticholinergic properties was evaluated for both subpopulations and a comparison between the subpopulations was made. There is only one risk scale for QT-prolongation and TdP useful for estimating an individual community-dwelling or institutionalized patient’s risk of TdP available in literature, the one described on the credible meds website. This risk scale was used to evaluate the use of QT-prolonging drugs for the 1016 community-dwelling and 400 institutionalized older Belgian polypharmacy patients. Anticholinergic risk scales on the other hand exist in abundance but the risk scale described by Duran et al. was chosen because it is the most evidence-based risk scale in the literature. The use of drugs with anticholinergic properties was also evaluated with the risk scale described by Rudolph et al. because it is the most commonly used anticholinergic risk scale. Generally, the community-dwelling older adults in this study take an average of 11 ± 4 drugs (mean ± SD), while the institutionalized older adults take an average of 12 ± 5 drugs (mean ± SD). In this study, 63.4% of the community-dwelling older adults and 85.8% of the institutionalized older adults used one or more QT-prolonging drugs. The top 10 most commonly used drugs are largely comparable, but institutionalized older adults relatively use these drugs more. Besides that, 42.0% of the community-dwelling older adults and 72.9% of the institutionalized older adults used a drug with anticholinergic properties according to Duran et al. while this is 24.6% and 60.0% respectively according to Rudolph et al. The top 10 most commonly used drugs according to Duran et al. and Rudolph et al. were largely comparable but some drugs included by Duran et al. were not included by Rudolph et al. Here as well the percentages in the top 10 were considerably higher for the population of institutionalized older adults. SAMENVATTING Polypathologie en polyfarmacie zijn een groeiend probleem in onze verouderende maatschappij. Daarnaast hebben ouderen een groter risico op bijwerkingen door fysiologische, farmacokinetische en farmacodynamische veranderingen. Bijwerkingen kunnen gevaarlijk zijn en leiden tot hospitalisatie en mogelijks zelfs tot de dood. In deze studie werden QT-verlenging en anticholinerge (bij-)werkingen bestudeerd. QT-verlenging op zich is geen groot probleem, maar het kan leiden tot het mogelijks dodelijke TdP. Anticholinerge (bij-)werkingen daarentegen kan leiden tot de (verdere) achteruitgang van de verouderende hersenen, droge mond en gastro-intestinale problemen. De laatste tijd wordt er meer onderzoek verricht naar deze onderwerpen. In deze thesis werd het algemeen medicatiegebruik van 1016 thuiswonende en 400 geïnstitutionaliseerde oudere polyfarmacie patiënten in België geëvalueerd. Daarnaast werd in de literatuur gezocht naar risicoschalen voor QT-verlenging en anticholinerge (bij-) werkingen. Het gebruik van deze medicatie werd ook geëvalueerd. Er was slechts één risicoschaal voor QT-verlenging en TdP bruikbaar voor de individuele patiënt, degene beschreven door AZCERT. Deze risicoschaal werd gebruikt om het gebruik van QTverlengende medicatie in de subpopulaties te evalueren. Er bestaan meerdere anticholinerge risicoschalen, maar de risicoschaal beschreven door Duran et al. werd gebruikt omdat deze de hoogste graad van evidentie heeft. Daarnaast evalueerden we het gebruik van geneesmiddelen met anticholinerge eigenschappen ook a.d.h.v. de risicoschaal beschreven door Rudolph et al. omdat deze in de literatuur het meest gebruikt wordt. In het algemeen nemen de thuiswonende ouderen in deze studie een gemiddelde van 11 ± 4 geneesmiddelen (gemiddelde ± SD), terwijl dit 12 ± 5 geneesmiddelen (gemiddelde ± SD) was bij de geïnstitutionaliseerde patiënten. In deze studie gebruikte 63.4% van de thuiswonende ouderen en 85.8% van de geïnstitutionaliseerde ouderen een of meerdere QT-verlengend geneesmiddelen. De top 10 meest gebruikte geneesmiddelen was grotendeels hetzelfde, maar deze geneesmiddelen werden meer gebruikt door de geïnstitutionaliseerde ouderen. Daarnaast gebruikte 42.0% van de thuiswonende ouderen en 72.9% van de geïnstitutionaliseerde ouderen een of meerdere geneesmiddelen met anticholinerge eigenschappen volgens Duran et al. Dit was respectievelijk 24.6% and 60.0% volgens Rudolph et al. De top 10 meest voorkomende geneesmiddelen met anticholinerge eigenschappen waren voor beide subpopulaties grotendeels gelijk maar het procentueel voorkomen was hoger voor de geïnstitutionaliseerde ouderen. ACKNOWLEDGMENTS I would like to thank the following people for helping me realize this thesis. First of all I Prof.dr. Boussery for this very interesting study and the advice he gave when I was stuck. Eline Tommelein for her inspiring ideas, correcting this thesis, her patience... I really couldn’t have wished for a better mentor. Simon Capiau for helping me order the database of community-dwelling older adults. And finally, An Mestach for reading and correcting this thesis. TABLE OF CONTENTS PART 1: INTRODUCTION ............................................................................................................... 1 1.1 PHYSIOLOGICAL CHANGES AND ADVERSE DRUG EVENTS (ADEs) IN OLDER ADULTS ............. 1 1.2 QT-PROLONGATION AND TORSADES DE POINTES (TdP) ........................................................ 3 1.2.1 Physiology ............................................................................................................. 3 1.2.2 Types of QT-prolongation ....................................................................................... 7 1.2.2.1 Congenital Long QT Syndrome (cLQTS) ....................................................................... 7 1.2.2.2 Drug-induced Long QT Syndrome (diLQTS) ................................................................. 8 1.2.3 Risk factors for QT-prolongation and TdP ................................................................ 9 1.2.4 Prevention ........................................................................................................... 10 1.2.5 Treatment ............................................................................................................ 11 1.3 DRUGS WITH ANTICHOLINERGIC (SIDE-) EFFECTS ................................................................ 12 1.3.2 Pharmacology ...................................................................................................... 12 1.3.3 Anticholinergic (side-) effects in older patients...................................................... 13 PART 2: OBJECTIVES ................................................................................................................... 14 PART 3: REVIEW OF QT-PROLONGING RISK SCALES IN OLDER ADULTS ......................................... 15 3.1 METHODS ............................................................................................................................... 15 3.2 RESULTS ................................................................................................................................. 15 PART 4: REVIEW OF ANTICHOLINERGIC RISK SCALES IN OLDER ADULTS ........................................ 17 4.1 METHODS .............................................................................................................................. 17 4.2 RESULTS ................................................................................................................................. 17 PART 5: DRUG USE OF BELGIAN OLDER POLYPHARMACY PATIENTS ............................................. 19 5.1 METHODS .............................................................................................................................. 19 5.1.1 Study design, setting and participants .................................................................. 19 5.1.2 Data-analysis........................................................................................................ 19 5.1.3 Evaluation of use of QT-prolonging drugs in our populations ................................. 20 5.1.4 Evaluation of use of drugs with anticholinergic properties in our populations ........ 20 5.2 RESULTS ................................................................................................................................. 21 5.2.1 Basic characteristics ............................................................................................. 21 5.2.2 General drug use of the included population ......................................................... 22 5.2.3 Evaluation of the individual use of QT-prolonging drugs and drugs with anticholinergic properties ................................................................................................... 23 PART 6: DISCUSSION................................................................................................................... 33 6.1 RISK SCALES ........................................................................................................................... 33 6.1.1 QT-prolonging risk scales in older adults .............................................................. 33 6.1.2 Anticholinergic risk scales in older adults ............................................................. 34 6.2 GENERAL DRUG USE OF THE INCLUDED POPULATIONS ....................................................... 36 6.3 EVALUATION OF THE INDIVIDUAL USE OF QT-PROLONGING DRUGS .................................. 37 6.4 EVALUATION OF THE INDIVIDUAL USE OF DRUGS WITH ANTICHOLINERGIC PROPERTIES .. 39 6.5 STRENGHTS AND LIMITATIONS ............................................................................................. 41 PART 7: CONCLUSION ................................................................................................................. 42 LIST OF USED ABBREVIATIONS ADE: Adverse Drug Event ADECA: Adverse Drug Event Causality Analysis ADR: Adverse Drug Reaction ADS: Anticholinergic Drug Scale ARS: Anticholinergic Risk Scale ATC: Anatomical Therapeutic Chemical AZCERT: Arizona Center for Education and Research on Therapeutics cLQTS: congenital Long QT Syndrome CNK: Code National(e) Kodenummer diLQTS: drug-induced Long QT Syndrome ECG: electrocardiogram ICD: Implantable Cardioverter-Defibrillator LQTS: Long QT Syndrome QoL: quality of life Pts: patients QTc: heart rate corrected QT-interval SA: sino-atrial TdP: Torsades de Pointes WHO: World Health Organization PART 1: INTRODUCTION 1.1 PHYSIOLOGICAL CHANGES AND ADVERSE DRUG EVENTS (ADEs) IN OLDER ADULTS The World Health Organization (WHO) defines adverse drug reactions (ADR) as “a response to a drug that is noxious and unintended and occurs at doses normally used in men for the prophylaxis, diagnosis or therapy of disease, or for modification of physiological function”.1 Because this is an old and rather vague definition, many people have attempted to formulate a different definition of ADR. An example of such a definition was formulated by Edwards et al.2 and states that an ADR is “an appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which predicts hazard from future administration and warrants prevention of specific treatment, or alteration of the dosage regimen, or withdrawal of the product”. This means that contaminants or inactive excipients can cause ADRs as well as active components and are thus not always inherent to the drug’s pharmacology. Besides that, the terms ‘adverse drug reaction’ and ‘adverse drug effect’ are more or less interchangeable but they don’t necessarily imply the same thing as ‘adverse drug events’ (ADE). ADEs also include those adverse outcomes for which no causality of drug-use has been found. 2 Older adults are more at risk for ADEs due to changes in their physiology, pharmacokinetics and pharmacodynamics. For example, the kidney and liver functions in older adults may be reduced, possibly deteriorated by heart failure. Because of that, the first-pass clearance in the liver and the renal elimination are reduced which means dosage of medication should be adapted accordingly. Besides, drug distribution may change as well because older adults have a different ratio of body weight to body fat. 3 Furthermore, older people may concomitantly use several different chronic medications. This is called polypharmacy. In this thesis we defined polypharmacy as the concomitant use of 5 or more different chronic medications. When drugs are combined, they can influence each other’s pharmacokinetics and/or pharmacodynamics leading to higher or lower clearance of a drug, causing either less or toxic effects. The toxic effect of some drugs may however be synergistic. In other words, due to chronic comorbid conditions and the use of multiple medications, the risk of adverse events increases. This is a growing problem in our aging society. 4, 5, 6 1 For some medical conditions, there is an association between ADE rate and increasing age. The bigger part of the ADEs that cause hospital admission can however be prevented. Yet, ADEs are a great cost to health care and one of the largest causes of death in older people worldwide. Studies showed that in American hospitals, serious ADEs occurred with an incidence of 6.7% and were fatal in 0.32% of the patients. 6-8 Recently more research has been done considering two types of ADEs: QT-prolongation and anticholinergic (side-) effects. This thesis focuses on the use of QT-prolonging and anticholinergic drugs in institutionalized and community dwelling older adults. 6 2 1.2 QT-PROLONGATION AND TORSADES DE POINTES (TdP) 1.2.1 Physiology A person’s heart cycle can be subdivided in 3 phases. During the first phase, the depolarization, voltage-gated fast Na+ channels open which allows extracellular Na+ to enter the cardiac muscle cells. Because of a positive feedback cycle, many Na+ channels open causing a reversal of the membrane potential. This phase is followed by a plateau phase (second phase) during which Ca2+ flows in the cell through slow Ca2+ channels. This keeps the cell depolarized because there are few K+ channels open. The third phase is called the repolarization. During this phase the Ca2+ channels are inactivated and the K+ channels are open, allowing K+ to flow out of the cells. Because of this, the membrane potential returns to its resting voltage. 9 This electrical activity spreads from the sino-atrial node (SA node) in the right atrium past the left atrium to the ventricles and can be graphically represented by an electrocardiogram (ECG). On a normal ECG there are 3 waves which are called the P-wave, the QRS-complex and the T-wave. Each of these zones depicts a certain event in either the atria or the ventricles (Figure 1.2.1a). The P-wave depicts the atrial depolarization initiated by the SA node. The QRS complex depicts the ventricular depolarization which begins at the apex of the heart. The atrial repolarization occurs at the same moment but this is obscured by the ventricular depolarization and thus not visible on an ECG. Because the current direction of depolarization through the ventricles changes continuously, the QRS-complex has a complicated shape. Finally, the T-wave depicts ventricular repolarization, which begins at the apex of the heart as well. The ventricular repolarization is slower than the ventricular depolarization. This means that the T-wave has a lower amplitude and spreads out more than the QRS-complex. 9 Figure 1.2.1a: Normal ECG: adopted from: 10 3 Usually, the size, duration and timing of the waves are consistent and so are the various intervals. This means that changes in the timing or pattern of the ECG may lead to the discovery of a problem with the heart’s conduction system. Here, we will discuss QT-prolongation. The QT-interval depicts the period from the beginning of ventricular depolarization to ventricular repolarization and is usually quite constant in a certain moment. 9 QT-prolongation occurs when the repolarization of the cardiac ventricular cells is reduced. This is most commonly caused by an insufficient outflow of potassium and on an ECG a prolongation of the QT-interval can be seen. As shown in Figure 1.2.1b, the time between the start of the Q-wave and the end of the T-wave is longer compared to Figure 1.2.1a. 11 Figure 1.2.1b: ECG with prolonged QT-interval: adopted from: 10 There are some factors that influence the QT-interval and the interpretation thereof such as diurnal effects, processing of ECG recording and intra- of inter-observer variability. The main factor however is the patient’s heart rate. Because the time needed for repolarization depends on the heart rate, the QT-interval must be corrected accordingly (corrected QT = QTc). If not, patients’ QT-intervals are not comparable and it is hard to find out whether there is QT-prolongation or not. There are several formulas available to correct the QT-interval for heart rate. However, there is a lot of criticism because these formulas are only useful within a narrow interval of resting heart rates. There is no formula that can calculate the QTc for every heart rate. The most commonly used formula is Bazett’s formula. 12, 13, 14 𝐵𝑎𝑧𝑒𝑡𝑡 ′ 𝑠 𝑓𝑜𝑟𝑚𝑢𝑙𝑎: 𝑄𝑇𝑐 = 𝑄𝑇 𝑖𝑛𝑡𝑒𝑟𝑣𝑎𝑙 √𝑅 − 𝑅 𝑖𝑛𝑡𝑒𝑟𝑣𝑎𝑙 Additionally, there is no consensus on what QT- interval is regarded as safe. The normal value for a QTc is <450 ms for adult women and <430 ms for men. Usually a QTc of over 500 ms or an increase of 60 ms or more compared to what is normal in that same person, is considered a higher risk of developing of a specific arrhythmia, called Torsades de Pointes (TdP). Yet, there is no limit to what is regarded as safe. 15 4 11 Table 1.2.1: QTc values for normal and prolonged QT interval by age and sex in ms: adopted from 1-15 years (ms) Adult males (ms) Adult females (ms) Normal <440 <430 <450 Borderline 440-460 430-450 450-470 Prolonged (top 1%) >460 >450 >470 QT-prolongation in itself is not a large problem. Nevertheless, in some cases it can lead to a polymorphic ventricular tachycardia also known as TdP, which literally means “twisting of points”. TdP is rarely recorded on an ECG since it mostly lasts only a few seconds. However, it does show some very characteristic features (Figure 1.2.1c). TdP usually begins with a short-long-short sequence of the R-R cycles. This induces TdP by creating heterogeneity of repolarization. This is followed by changes in the morphology and amplitude of the QRS complexes which is also known as the “twisting of points”. Besides that, the rate of the first couple of beats of ventricular tachycardia varies between 160 and 240 beats per minute which is slower than that of ventricular fibrillation. This is called the “warm-up phenomenon”. Finally, the heart rate can spontaneously return to sinus rhythm. As opposed to ventricular fibrillation, defibrillation is not always necessary.10, 16 Figure 1.2.1c: ECG strip in a patient with drug induced TdP: adopted from 11 5 If the TdP only lasts a couple of seconds, the heart rhythm can spontaneously return to sinus rhythm without loss of consciousness. The patient may then experience dizziness, lightheadedness, shortness of breath or he may have palpitations. If the arrhythmia however continues, the patient can collapse after a few seconds due to an ineffective cardiac output, possibly associated with tonicclonic seizures because of brain hypoxia. If this does not stop within about two minutes, it can lead to ventricular fibrillation and sudden death. Return to sinus rhythm leads however to repair of consciousness quite quickly. 11, 12 There are nevertheless some practical issues that need consideration. Due to its rareness, TdP is difficult to notice in study populations or to detect in post-marketing surveillance. Prevalence in use of certain drugs that block potassium or sodium channels may be as high as 1 to 10%. Examples of such drugs are sotalol and quinidine. Besides, there are drugs, proarrhythmics, that cause an arrhythmia similar to that of TdP but without a QT-prolongation. This is not called TdP by definition which means TdP is always accompanied by QT-prolongation but not vice versa. 12,16 6 1.2.2 Types of QT-prolongation QT-prolongation can be subdivided in two main categories. The QT-prolongation is either caused by a genetic defect, in which case we consider it a congenital Long QT syndrome (cLQTS), or either by the use of certain drugs, in which case we call it drug-induced LQTS (diLQTS). 12 1.2.2.1 Congenital Long QT Syndrome (cLQTS) The cLQTS can be caused by mutations in 13 different genes and may lead to unusual electrical activity in the heart. These 13 genes can be divided in 2 main categories. Six genes code for a pore-forming protein, functioning as a voltage-gated ion channel. Specific ions such as potassium pass across the cardiac cell membrane through these channels. The remaining 7 genes encode proteins that modulate ion channel function. All of these channel dysfunctions are known as “channelopathies”. 12 Because the action potentials and the QT interval depend on the ion current, a defect in ionic flow of potassium, sodium or calcium ions can cause major arrhythmias possibly leading to sudden death. In less dramatic cases it can lead to loss of consciousness. 12 There are three major ion currents that need consideration: IKs, IKr and INa (Figure 1.2.2.1). Ikr symbolizes the rapid component of the potassium outflow and IKs the slow component. The potassium components are responsible for repolarization while activation of the inward INa induces longer depolarization and thus QT-prolongation. cLQTS can be caused by the blockage of any of these three ion channels. There are subdivisions depending on the cause of the cLQTS such as the ion channel malfunctions. They are numbered LQT1, LQT2, LQT3... The cLQTS can be diagnosed with an ECG. 12 7 Figure 1.2.2.1: The ion channels in a cardiac cell: adopted from 17 1.2.2.2 Drug-induced Long QT Syndrome (diLQTS) In diLQTS, the QT-prolongation is caused by the use of certain drugs. Here, QT-prolongation is associated with the development of TdP as well. This however is just an association because not all drugs that cause QT-prolongation lead to TdP. For example: amiodarone can cause QT-prolongation but hardly ever induces TdP. Of course there are many drugs that cause both, such as disopyramide. 12 Where cLQTS can be caused by either one of three deficiencies in ion flow (IKr, IKs or INa), diLQTS is almost always caused by blockage of IKr. There are many different classes of drugs that may block these channels including antibiotics, antipsychotics, antihistamines and antiarrhythmics. Some of those, such as diuretics and antidepressants, are often prescribed for older patients. The other two types of ion channels are far less prone to medication. This ability of drugs blocking ion channels and thus possibly leading to certain arrhythmias has had an important effect on the development of new medicines. During the clinical stages of drug development new drugs are now screened for QTprolongation. 12, 18 8 1.2.3 Risk factors for QT-prolongation and TdP Blockage of merely Ikr is often not sufficient to create QT-prolongation. In an analogous manner, QTprolongation is not always followed by TdP. The presence of other risk factors is necessary in both cases. The most common risk factors for both QT-prolongation and TdP are hypokalemia, atrioventricular block or other bradyarrhythmias (Table 1.2.3). Female sex and hypokalemia increase the risk of arrhythmias in both the congenital and the drug-induced variants of LQTS. Hypokalemia can be caused by many factors such as diarrhea and is a risk in malnutrition and chronic alcohol abuse. There are however some risk factors specific for diLQTS such as pharmacokinetic and pharmacodynamic effects. There are studies examining the genetic predisposition to risk as well. 11, 12 12 Table 1.2.3: Risk factors for QT-prolongation and TdP: adopted from Risk factor Mechanism of increased risk Female sex Sex hormonal regulation of repolarization especially by testosterone Bradycardia Pause-dependent QT-prolongation with typical short-long-short cycle Electrolyte disturbances Hypokalemia Decreases IKr by enhanced inactivation or exaggerated competitive block of sodium potentiation of drug blockade of residual IKr Hypomagnesemia Modulation of L-type calcium channel Recent conversion from atrial fibrillation especially with Reduced heart rate after conversion to sinus QT remodeling QT-prolonging drugs in AF High drug concentrations and rapid infusion of QT- Dose- or concentration- dependent QT-prolongation (except prolonging drugs quinidine) Digitalis Intracellular calcium overload with delayed afterdepolarizations and inhibition of KCNH2 trafficking Subclinical (congenital) LQTS QT prolonging upon exposure to Ikr -blocking drugs Ion channel polymorphisms Minor effects at baseline but compounded with QT-prolonging drug leading to TdP Additional risk factors for TdP are old age, various cardiovascular diseases such as bundle branch block and ischemia, and a family history of LQTS. 19 9 1.2.4 Prevention There are a number of measures that can be taken into account to prevent QT-prolongation and TdP. First of all, QT-prolonging medication should be avoided in both patients with cLQTS or diLQTS. There is no consensus on whether these medicines should not be used. Different sources suggest different QTc-values as a limit for risk of QT-prolongation as depicted in the table below. However, all researchers agree that use of QT-prolongating drugs should be precluded in case of a QTc-interval above 500 ms or a rise of over 60 ms. 20 Table 1.2.4: When to avoid QT-prolonging drugs Men QTc 14 Al-Khatib et al. (2003) >450 ms 19 Li et al. (2010) >460 ms 21 AZCERT >420 ms Women QTc >460 ms >460 ms >440 ms When to avoid? In the absence of intraventricular conduction defects In the absence of identifiable risk factors If possible The patient’s risk factors should be considered as well as the risk-benefit of the drug in that specific patient. Certain combinations of drugs, such as the combination of two QT-prolonging drugs are to be avoided. Besides that, some antiarrhythmics, especially those belonging to class IA (disopyramide, quinidine), are to be avoided in case of QT-prolongation or a high risk thereof. If such a drug does need to be used, it is better to start in a hospital environment under constant cardiac monitoring. Finally, all patients treated with QT-prolonging medication must be warned about symptoms associated with arrhythmia including dizziness, palpitations and syncope. In case one of these symptoms occurs, it is the physician’s responsibility to stop the use of the QT-prolonging drug at once. In this case the ECG should be checked and other factors should be corrected. 10 20 1.2.5 Treatment In most cases, QT-prolongation or TdP disappears within 1 to 5 minutes after administrating 2g MgSO4 intravenously (IV). Standard antiarrhythmics, except most beta-blockers, cannot be used. Beta-blockers inhibit the occurrence of extrasystoles but may lead to bradycardia. If treatment with MgSO4 is inadequate, isoproterenol, dobutamine or atropine IV can be considered. Potassium is also an option in case of low serum K+ but this should only be considered in a clinical environment after careful consideration of additional risk factors such as renal failure. Alternatively, lidocaine and phenytoin can be used. In case of ventricular fibrillation, cardiac pacing or shocking may be necessary. 20, 22-23 Re-use of the drug molecule leading to QT-prolongation or TdP must be avoided at all cost and normal K+, Mg2+ and HCO-3 serum values must be maintained. 24 Treatment of TdP depends on the risk of sudden death. High-risk patients are more likely to receive an implantable cardioverter-defibrillator (ICD) or beta-blockers (not sotalol). Usually, these patients already survived a cardiac arrest. 10 Patients who haven’t had a cardiac arrest before are started on beta-blockers too, but are urged to change their lifestyle. If this does not suffice, an ICD is implanted after all. 10 Currently “personalized” pharmacotherapy is being developed because more is known about the pathophysiology of TdP and the various mutations. Genetic testing has improved and has become cheaper. For some variants of cLQTS, specific therapy has been developed. For example potassium supplements are prescribed to patients with LQTS 2 while the therapy of patients with LQTS 3 may include mexiletine. In both LQTS 2 and LQTS 3 patients early ICD placement is considered as well. 10 11 1.3 DRUGS WITH ANTICHOLINERGIC (SIDE-) EFFECTS 1.3.1 Pharmacology Acetylcholine is a neurotransmitter in both the central and peripheral nervous system. It mainly binds two types of receptors which are known as nicotinic and muscarinic receptors. There are five subtypes of muscarinic receptors of which M1, M2 and M3 are the most commonly present. Stimulation of these receptors leads to stimulation of the parasympathetic nervous system. There are a lot of drugs that interact with these receptors but drugs that interact with nicotinic receptors are less commonly used due to the extensive occurrence of side effects. There are two main types of medicines that interact with the muscarinic receptors; those that block (parasympatholytic or anticholinergic drug) and those that stimulate these receptors (parasympathomimetics). Because both the sympathetic and the parasympathetic nervous system lead to a wide variety of effects (Appendix 1), these drugs are used for the symptomatic treatment of a wide variety of conditions in older people (Table 1.3.1). 4, 25, 26 4, 25 Table 1.3.1: The most common symptoms and diseases treated with anticholinergic drugs: Symptoms or diseases Examples of drugs with anticholinergic properties Parkinsonism Bromocriptine, entacapone, procyclidine, trihexyphenidyl Urinary incontinence and urge incontinence Flavoxate, oxybutynin, tolterodine Psychoses Haloperidol, olanzapine, pimozide, quetiapine Depression Amitriptyline, clomipramine, doxepin, imipramine, nortriptyline, pimozide… Allergy Chlorphenamine, fexofenadine, loratadine Obstructive lung diseases Ipratropium, theophylline Peptic ulcer Cimetidine, ranitidine Sleep disorders Paroxetine Cardiac arrhythmias Atropine, disopyramide, Travel sickness Diphenhydramine, meclozine, scopolamine 12 1.3.2 Anticholinergic (side-) effects in older patients A patient’s anticholinergic burden can be calculated by adding all the anticholinergic effects of the medication the patient takes. In other words, to calculate a patient’s anticholinergic burden, one must add the scores given to all individual drugs the patient uses. This is possible because anticholinergic effects are additive.4, 27 A higher anticholinergic burden is not always caused by the use of a few drugs with a high anticholinergic activity. This means that how small the contribution of several medicines may be, the patient might still have a heavy anticholinergic burden. Older women may use multiple drugs with a lower anticholinergic activity. Therefore adverse effects are less likely to be attributed to the use of medications with anticholinergic effects.4, 27 The therapeutic indications of anticholinergic drugs, such as sleep disorders and urinary incontinence, are more common in older patients who are more at risk for ADEs. Drugs with anticholinergic (side-) effects can cause both peripheral and central adverse effects. The most common peripheral adverse effects are dry mouth, dry eyes, constipation, blurred vision and tachycardia. The most frequent central adverse effects are dizziness, sedation, confusion, delirium and cognitive impairment.6,28 Many studies show that a higher anticholinergic burden is related to a higher risk of falls, impulsive behavior, loss of independence and delirium. In other words, a higher anticholinergic burden is associated with the loss of functional skills necessary for everyday life such as balance, gait and mobility. 4,29 Older adults with some type of dementia have an additional problem. The use of medication with anticholinergic properties can further deteriorate their memory due to antagonistic effects of anticholinergic medication and acetylcholinesterase-inhibitors. Patients with dementia or Alzheimer’s disease and older people already have a central cholinergic deficiency which is only exacerbated by the use of anticholinergic medication. Even though this may cause complications, studies show that concomitant use of these drugs is common in nursing homes. 30 Although a high anticholinergic burden can cause a lot of adverse effects in older patients, this problem can easily be diminished by a reduction of anticholinergic medications. There are many alternatives available that do not have anticholinergic (side-) effects. For example second-generation antihistamines have fewer anticholinergic side-effects than first-generation antihistamines. Revising a patient’s medication taking into account his or her anticholinergic burden can possibly prevent many complications. 30, 31 13 PART 2: OBJECTIVES Polypathology and polypharmacy are a growing problem in our aging society. Consequently, older adults are at greater risk of ADEs due to physiological, pharmacokinetic and pharmacodynamic changes. ADEs are potentially dangerous and can lead to hospitalization and even death. In this study we focus on two types of ADEs; QT-prolongation and anticholinergic (side-) effects. QT-prolongation in itself is not a large problem but can possibly lead to fatal TdP. Anticholinergic (side-) effects on the other hand can include for example (further) deterioration of the aging brain, dry mouth and gastrointestinal problems. Recently there has been increasing research on both of these topics. The overall goal of this thesis was to get a better insight in the use of QT-prolonging drugs and drugs with anticholinergic properties by older Belgian polypharmacy patients. To obtain this goal we: 1. Objective 1: reviewed the existing evidence-based risk scales to determine the risk of QTprolongation. The results of this literature search are described in part 3. 2. Objective 2: reviewed the existing evidence-based risk scales to determine anticholinergic (side-) effects. The results of this literature search are described in part 4. 3. Objective 3: evaluated the drug use of 1016 community-dwelling and 400 institutionalized older adults in Belgium. We evaluated the drug use in general as well as the use of QT-prolonging drugs and drugs with anticholinergic properties. In order to evaluate the use of QT-prolonging drugs, we used one of the methods as described in part 3. For the evaluation of the use of drugs with anticholinergic properties, we used two of the scales as described in part 4. A comparison between both subpopulations was made as well. These evaluations are described in part 5 of this thesis. 14 PART 3: REVIEW OF QT-PROLONGING RISK SCALES IN OLDER ADULTS 3.1 METHODS We used the Credible Meds website as a starting point for the literature search on risk scales for QTprolongation and TdP. We then used the MEDLINE database to search for alternative risk scales using key words such as “QT-prolongation AND older patients”, “TdP AND older patients”, “TdP AND risk scale”, “QT-prolongation AND risk scale”. For TdP, the whole word as well as the abbreviation was used. After reading the most relevant manuscripts, we scanned the reference lists of these manuscripts for other potentially useful manuscripts (“snowballing”). When these manuscripts were not available in Pubmed, we also used Google Scholar and Web of Science. We also used the “related citation” method in Pubmed on the most relevant manuscripts. 3.2 RESULTS During the literature search approximately 1073 manuscripts were found. A first selection was made based on title and abstract after which the most interesting manuscripts were screened. Eventually one manuscript and the credible meds website was included in this thesis; one by Tisdale et al. and one by the Arizona Center for Education and Research on Therapeutics (AZCERT). Tisdale et al. researched possible risk factors for TdP in hospitalized patients. They examined the administered medication and the outcome by analyzing patients’ ECGs. Besides, they determined the risk factors with the largest effect on the QT-interval. The factors with the lowest risk were appointed 1 point, medium risk 2 points and factors with the largest risk were appointed 3 points (Table 3.2a). A patient presenting with all risk factors is consequently given a total score of 21. 32 They also determined cut-off points to estimate the severity of the risk. A patient with a risk score of 6 or lower had a low risk of QT-prolongation, patients with a risk score from 7 to 10 a medium risk while patients with a score ranging from 11 to 21 had a high risk for the development of QTprolongation and TdP. The Tisdale-scale is very useful in hospital settings because all necessary information is available. 21, 32 15 Table 3.2a: Calculation of Risk Score for QTc-interval prolongation: adopted from Risk factors Age > 67 y Female Use of loop diuretic + Serum K ≤3.5 mEq/L Admission QTc ≥450 ms Acute myocard infarct in the past ≥2 QTc-prolonging drugs Sepsis Heart failure One QTc-prolonging drug Maximum risk score 32 Points 1 1 1 2 2 2 3 3 3 3 21 Where the screening method of Tisdale et al. calculates an individual risk per hospitalized patient the people of AZCERT took the drugs themselves as a starting point. They developed a process to divide all drugs with a potential risk of QT-prolongation or TdP into 4 categories (Table 3.2b) which is called the Adverse Drug Event Causality Analysis (ADECA)-process. 21 21 1 2 3 4 Table 3.2b: the 4 categories for risk of TdP Drugs to avoid for people with cLQTS This list also contains all medication in the other three lists Conditional risk of TdP There is a risk in certain circumstances such as excessive dosage, bradycardia, hypokalemia, cLQTS or other risk factors Possible risk of TdP There is insufficient evidence that these drugs cause TdP, they do however prolong the QT-interval Risk of TdP Drugs that cause TdP under normal conditions ADECA includes research on the following three sources: cases posted on their website (credible meds), medical literature search and drugs labeled QT-prolonging by the FDA. They categorize drugs according to the Bradford Hill criteria (Figure 3.2, Appendix 4) and based on the expert opinion of the Credible Meds team and an advisory board. 21 Figure 3.2: The Bradford Hill criteria: adopted from 21 16 PART 4: REVIEW OF ANTICHOLINERGIC RISK SCALES IN OLDER ADULTS 4.1 METHODS We used the MEDLINE database for the study on anticholinergic risk scales. We used key words such as “anticholinergic AND elderly”, “anticholinergic burden AND older patients”, “anticholinergic risk (scale)”. After reading the most relevant manuscripts, we scanned the reference lists of these manuscripts for other potentially useful manuscripts (“snowballing”). When these manuscripts were not available in Pubmed, we used Google Scholar and Web of Science. We also used the “related citation” method in Pubmed on the most relevant manuscripts. 4.2 RESULTS During the literature search approximately 5246 manuscripts were found. A first selection was made based on title and abstract after which the most interesting manuscripts were screened. Eventually 10 manuscripts were included in this thesis. Until now, several scales to evaluate anticholinergic (side-) effects have been developed. These scales measure or calculate the anticholinergic burden of an individual patient. There is a great heterogeneity between the various scales with regard to the examined outcome. Some scales predict peripheral effects such as the Anticholinergic Drug Scale (ADS - Carnahan et al.33), other scales include both peripheral and central effects (ARS - Rudolph et al.31) and/or cognitive performance (Anticholinergic Cognitive Burden Scale - Hilmer et al.34). 27 Most of these scales are based on expert opinion and rank drugs according to their presumed anticholinergic activity. An overview is given in Table 4.2. 27 The majority of the developed scales provided the most commonly prescribed drugs with an anticholinergic activity score from 0 (no anticholinergic activity) to 3 or 4 (strong anticholinergic activity). In 2013 Duran et al. provided a systematic review of seven of these scales and divided these drugs into two categories: drugs with a high anticholinergic potency and drugs with a low anticholinergic potency (Appendix 5). 28, 27 17 Table 4.2: The nine scales to estimate the anticholinergic burden for an individual patient: adopted from and adapted: Study ID (author, year, country) Carnahan 2006 USA (AnticholinergicDrugScale) Grading system and methodology Outcome studied Scores: 4-point scale (0 to 3) Basis: Expert opinion Number of drugs: 117 Serum anticholinergic activity Ancelin 2006 France Scores: 4-point scale (0 to 3) Basis: serum anticholinergic activity and expert opinion Number of drugs: 27 Cognitive performance and mild cognitive impairment Kouladijan 2014, Kashyap 2014, Kersten 2014 Scores: 3-point scale Basis: expert opinion Number of drugs: not mentioned Physical and cognitive performance Kouladijan 2014, Kashyap 2014, Tay 2014 Han 2008 USA Scores: 4-point scale (0 to 3) Basis: previous published anticholinergic scale and expert opinion Number of drugs: 60 Memory performance and executive function Kouladijan 2014, Tay 2014, Kersten 2014 Rudolph 2008 USA (Anticholinergic Risk Scale ARS) Scores: 4-point scale (0 to 3) Basis: detailed literature review and expert opinion Number of drugs: 49 Frequency of anticholinergic adverse effects Kouladijan 2014, Kashyap 2014, Kersten 2014 Chew 2008 USA Scores: 4-point scale (0 to 3) Basis: radioreceptor assay Number of drugs: 22 Anticholinergic activity in vitro Kouladijan 2014, Kersten 2013, Cetinel 2013 35 Scores: 3-point scale (1 to 3) Basis: expert opinion Number of drugs: 88 Long-term cognitive decline Campbell 2015, Kersten 2013, Cai 2013 Ehrt 2010 Norway Scores: 5-point scale (0 to 4) Basis: Chew 2008 and expert opinion Number of drugs: 29 Long-term cognitive decline Kouladijan 2014, Wojtalik 2012 Sittironnarit 2011 Australia (Anticholinergic Loading Scale) Scores: 4-point scale (0 to 3) Basis: Ancelin 2006, Han 2008, Chew 2008, Rudolph 2008 and expert opinion Number of drugs: 49 Psychomotor speed and executive function Kouladijan 2014, Puustinen 2012, Thorpe 2012 Hilmer 2007 USA Boustani 2008 34 18 Other researchers that used this method Kouladijan 2014, Kashyap 2014, Kersten 2014 28 PART 5: DRUG USE OF BELGIAN OLDER POLYPHARMACY PATIENTS 5.1 METHODS 5.1.1 Study design, setting and participants From December 2013 until July 2014, an observational study was conducted in 1016 Belgian older adults with polypharmacy (≥70 years and chronic ≥5 drugs). These patients were recruited in 204 community-pharmacies in Belgium (142 in Flanders – 62 in Wallonia). Each pharmacy recruited a maximum of 5 patients. The goal of this observational study was to identify potential drug-related problems in older polypharmacy patients in Belgium. Participating patients were interviewed by a pharmacist-intern through a structured questionnaire. The patient was questioned about his or her demographic data, alcohol consumption, functional status, cognitive status, fall incidents and hospitalizations in the past year, self-scored quality of life and current medication use. At the same time, a second dataset, containing all dispensed chronic medication to 400 institutionalized patients, randomly selected from 10 different Flemish nursing homes, was obtained. Analogously, institutionalized patients could only be included if they were 70 years or older and were chronically prescribed 5 or more different drugs. 5.1.2 Data-analysis All data was entered digitally via an electronic platform by the interns who conducted the study. The results were then extracted into Excel (Microsoft, 2010, Redmond, WA) and double checked using the paper version by Eline Christiaen and Simon Capiau. Chronic and acute medication was listed per patient. Each drug or supplement was linked to an ATC-code as well as the content of pharmaceutical compounded drugs. The basic characteristics of the population, drug- and alcohol use were mainly statistically described by frequency tables and center sizes. Descriptives were displayed as counts with percentages and means with standard deviations or medians with interquartile ranges as appropriate. To analyze the interactions between drugs and the use of QT-prolonging drugs as well as drugs with anticholinergic properties, cross tables were used. Here, the ATC codes of the drugs used in the elderly population were compared with the ATC codes in the listed risk scales. All analyses were carried out using Microsoft Excel of SPSS Statistics (IBM Corp, 2013, IBM SPSS Statistics for Windows, Version 22.0. Armonk, NY). 19 5.1.3 Evaluation of use of QT-prolonging drugs in our populations Two different risk scales to evaluate the risk for QT-prolongation and TdP were retrieved. Only the one by credible meds is however useful for the purpose of this research as an individual score per drug used was given. The risk score developed by Tisdale et al. is specific for hospitalized patients and laboratory and clinical data are needed that are not available in this research. The ATC codes corresponding to the drugs on the credible meds list were added to a Microsoft Excel table (Appendix 2 and 3) and the patients of both subpopulations were scanned for use of drugs that may cause TdP as described by AZCERT. Consequently, prevalence of use of QT-prolonging drugs in the general population was calculated. A custom table that lists the number of drugs with and without interactions of every patient was created. 17, 21 5.1.4 Evaluation of use of drugs with anticholinergic properties in our populations There is a wide variety of anticholinergic risk scales. In this research the method described by Duran et al. will be used because it has the highest level of evidence (systematic review, level A). Duran et al. grouped all medication described in the nine scales to estimate the anticholinergic burden for an individual patient (Table 1.3.1) and divided them into two groups: high and low anticholinergic activity. However, the nine anticholinergic scales where it was based on divided them in 4 or 5 groups, assigning them a score from 0 to 3 or 4. Because these scales are more commonly used, we also briefly compared the method described by Duran et al. and the one developed by Rudolph et al. with regard to the outcome as Rudolph’s scale is the most widely used. The ATC codes corresponding to the drugs with anticholinergic properties as described by Duran et al. and Rudolph et al. were added to a Microsoft Excel table (Appendix 5 and 6) and the patients of both subpopulations were scanned for use of drugs with anticholinergic properties. Consequently, prevalence of use of drugs with anticholinergic properties in the general population was calculated. A custom table that lists the number of drugs with and without anticholinergic (side-) effects of every patient was created. 28, 31 20 5.2 RESULTS 5.2.1 Basic characteristics As displayed in Table 5.2.1, the institutionalized population is markedly older than the communitydwelling population (mean vs mean) and significantly more women were included. Table 5.2.1: Basic characteristics Age, Mean (SD) Age ≥ 85j, # (%) Gender, # women (%) BMI, Mean (SD) BMI < 22, # (%) Smoker, # (%) Living situation Alone With partner/family Nursing home Need help to Wash Dress Toileting Go outside the house Eat Clean Minicog Minicog 0 t.e.m. 2 (=positive diagnosis) Minicog 3 t.e.m. 5 Description health condition, # (%) Excellent Very good Good Average Bad Pts with fall incident in the past year, # (%) Number fall incidents, Med (IQL) Community-dwelling (n=1016) 78.8 5.5 162 16 592 58 26.6 4.3 131 13 57 6 Institutionalized (n=400) 86.2 6.3 250 63 298 75 NA NA NA NA NA NA 434 582 0 43 57 0 0 0 400 0 0 100 110 54 19 117 38 382 11 5 2 12 4 38 NA NA NA NA NA NA NA NA NA NA NA NA 335 33 NA NA 681 67 NA NA 19 104 497 343 53 333 1 2 10 49 34 5 33 1-3 NA NA NA NA NA NA NA NA NA NA NA NA NA NA 21 5.2.2 General drug use of the included population The community-dwelling older adults take an average of 11 ± 4 drugs (mean ± SD). The population as a whole (1016 patients) used 635 different molecules and 10705 drugs in total. The institutionalized older adults taken an average of 12 ± 5 drugs (mean ± SD). The population as a whole (400 patients) uses 486 different molecules and 4647 drugs in total. Table 5.2.2 displays all drug classes that contain more than 2% of the 10705 drugs and the 4647 drugs. We used the short ATC version of the frequency table and gave as example the three most frequently used drugs of this class. The complete list of drugs used by the population of community-dwelling and institutionalized older adults are presented in the appendix (Appendix 7 and 8). Table 5.2.2: Most frequently used drugs by community-dwelling and institutionalized older adults in Belgium Community-dwelling (n= 1016) 1 2 3 ATC code Drug (group) name No. of pts % ATC code Drug (group) name No. of pts % B01A B01AC06 B01AA03 B01AC04 C10A C10AA01 C10AA05 C10AA07 Antithrombotic agents Acetylsalicylic acid Warfarin Clopidogrel Lipid modifying agents, plain Simvastatin Atorvastatin Rosuvastatin 806 500 65 65 719 289 165 133 7.5 4.7 0.6 0.6 6.7 2.7 1.5 1.2 B01A B01AC06 B01AB05 B01AA03 A06A A06AD65 A06AD11 A06AG10 295 158 38 26 276 153 54 24 6.3 3.4 0.8 0.6 5.9 3.3 1.2 0.5 J07B J07BB02 Viral vaccines Influenza, inactivated, split virus or surface antigen Hepatitis B, purified antigen 686 685 6.4 6.4 A02B 212 4.6 1 0.0 A02BC02 A02BC01 A02BA02 118 46 36 2.5 1.0 0.8 Beta blocking agents Bisoprolol Nebivolol Sotalol Drugs for peptic ulcer and gastor-oesophageal reflux disease (GORD) Pantoprazole Omeprazole Ranitidine Blood glucose lowering drugs, excl. insulins Metformin Gliclazide Repaglinide Anxiolytics Lorazepam Alprazolam Bromazepam Other analgesics and antipyretics Paracetamol 586 317 64 49 469 5.5 3.0 0.6 0.5 4.4 N06A N06AX05 N06AB10 N06AX11 N02B 211 55 51 25 166 4.5 1.2 1.1 0.5 3.6 221 151 42 431 2.1 1.4 0.4 4.0 N02BE01 N02BE51 N02BA01 Antithrombotic agents Acetylsalicylic acid Enoxaparin Warfarin Drugs for constipation Macrogol, combinations Lactulose Docusate sodium, incl. combinations Drugs for peptic ulcer and gastoroesophageal reflux disease (GORD) Pantoprazole Omeprazole Ranitidine Antidepressants Trazodone Escitalopram Mirtazapine Other analgesics and antipyretics Paracetamol Paracetamol, combinations ASA 159 5 2 3.4 0.1 0.0 245 66 27 330 121 98 44 329 2.3 0.6 0.3 3.1 1.1 0.9 0.4 3.1 C07A C07AB07 C07AB02 C07AA05 Beta blocking agents Bisoprolol Metoprolol Propranolol 163 112 10 9 3.5 2.4 0.2 0.2 C03C C03CA02 C03CA01 High-ceiling diuretics Bumetanide Furosemide 148 74 73 3.2 1.6 1.6 303 2.8 N05C N05CD06 N05CF02 Hypnotics and sedatives Lormetazepam 144 76 45 3.1 1.6 1.0 J07BC01 4 5 C07A C07AB07 C07AB12 C07AA07 A02B 6 A02BC02 A02BC01 A02BA02 A10B 7 8 Institutionalized (n= 400) A10BA02 A10BB09 A10BX02 N05B N05BA06 N05BA12 N05BA08 N02B N02BE01 22 N02BE51 9 10 11 N02BA01 N05C N05CD06 N05CF02 N05CF01 N06A N06AX05 N06AB10 N06AA09 A11C 12 A11CC05 A11CC03 A11CC04 C09A C09AA04 C09AA03 C09AA05 13 C08C 14 C08CA01 C08CA13 C08CA12 M01A 15 M01AX05 M01AE01 M01AB05 A12A A12AX A12AA04 A12AA12 5.2.3 Paracetamol, combinations excl. psycholeptics Acetylsalicylic acid Hypnotics and sedatives Lormetazepam Zolpidem Zopiclone Antidepressants Trazodone Escitalopram Amitriptyline Vitamin A and D, incl. combinations of the two Colecalciferol Alfacalcidol Calcitriol Ace inhibitors, plain Perindopril Lisinopril Ramipril 16 0.1 6 315 122 104 23 273 49 41 30 253 0.1 2.9 1.1 1.0 0.2 2.6 0.5 0.4 0.3 2.4 246 6 1 236 105 70 43 2.3 0.1 0.0 2.2 1.0 0.7 0.4 Selective calcium channel blockers with mainly vascular effects Amlodipine Lercanidipine Barnidipine Antiinflammatory and antirheumatic products, nonsteroids Glucosamine Ibuprofen Diclofenac Calcium Calcium, combinations with vitamin D and/or other drugs Calcium carbonate Calcium acetate anhydrous 225 2.1 114 55 33 225 1.1 0.5 0.3 2.1 56 40 26 213 117 0.5 0.4 0.2 2.0 1.1 87 6 0.8 0.1 N05CD03 Zolpidem Flunitrazepam 5 0.1 N05A N05AH04 N05AX08 N05AD01 N05B N05BA06 N05BA12 N05BA08 N02A N02AX02 N02AB03 N02AX52 Antipsychotics Quetiapine Risperidone Haloperidol Anxiolytics Lorazepam Alprazolam Bromazepam Opioids Tramadol Fentanyl Tramadol, combinations Calcium Calcium with vitamin D Calcium carbonate Calcium acetate anhydrous Blood glucose lowering drugs, excl. insulins Metformin Gliquidone Gliclazide 131 36 34 19 121 43 35 16 111 36 30 22 2.8 0.8 0.7 0.4 2.6 0.9 0.8 0.3 2.4 0.8 0.6 0.5 106 95 9 3 2.3 2.0 0.2 0.1 98 2.1 57 17 16 1.2 0.4 0.3 Adrenergics, inhalants Fenoterol and ipratropium bromide Salmeterol and fluticasone Salbutamol Lipid modifying agents, plain Simvastatin Atorvastatin Rosuvastatin 96 28 2.1 0.6 23 0.5 14 93 0.3 2.0 46 26 10 1.0 0.6 0.2 A12A A12AX A12AA04 A12AA12 A10B A10BA02 A10BB08 A10BB09 R03A R03AL01 R03AK06 R03AC02 C10A C10AA01 C10AA05 C10AA07 Evaluation of the individual use of QT-prolonging drugs and drugs with anticholinergic properties We also compared the relative occurrence of the top 10 most commonly used drugs by the community-dwelling and the institutionalized older adults. We used the same colors in the figures below in case the same drug appeared in the top 10 for the community-dwelling older adults as well as for the institutionalized older adults. We used analogue techniques for all tables below. 23 5.2.3.1 Individual use of QT-prolonging medication disregarding the risk scores In the population of community-dwelling older adults 634 of the 1016 patients (62.4%) uses one or more drugs with risk for QT-prolongation or TdP. In the population of institutionalized older adults this is 343 out of 400 or 85.8% and thus remarkably higher. The top 10 most commonly used drugs that can lead to QT-prolongation and TdP by older polypharmacy patients in Belgium is listed below (Table 5.2.3.1). The complete tables for communitydwelling older adults and institutionalized older adults are presented in Appendix 9 and 10. Table 5.2.3.1: Top 10 drugs with risk for QT-prolongation and TdP used by older adults disregarding the risk score Community-dwelling (n=1016) Drug name ATC code 1 Pantoprazole 2 Institutionalized (n=400) No. of pts 221 % A02BC02 Risk score 2 Drug name ATC code A02BC02 Risk score 2 No. of pts 118 21.8 Pantoprazole C03CA01 2 3 Furosemide (frusemide) Formoterol 76 7.5 R03AK07 4 Salmeterol R03AK06 1 65 1 59 5 Sotalol C07AA07 4 6 Trazodone N06AX05 7 Amiodarone 8 % 29.5 C03CA01 2 73 18.3 6.4 Furosemide (frusemide) Trazodone N06AX05 2 55 13.8 5.8 Escitalopram N06AB10 4 51 12.8 49 4.8 Domperidone A03FA03 4 38 9.5 2 49 4.8 Quetiapine N05AH04 3 36 9.0 C01BD01 4 46 4.5 Risperidone N05AX08 3 34 8.5 Escitalopram N06AB10 4 41 4.0 Moxifloxacin J01MA14 4 29 7.3 9 Indapamide C03BA11 2 40 3.9 Mirtazapine N06AX11 3 25 6.3 10 Domperidone A03FA03 4 35 3.4 Salmeterol R03AK06 1 23 5.8 Six drugs appear in both the top 10’s but formoterol, sotalol, amiodarone and indapamide only appear in that of the community-dwelling population while quetiapine, risperidone, moxifloxacin and mirtazapine only appear in that of the institutionalized older adults. Figure 5.2.3.1: Top 10 drugs with risk for QT-prolongation and TdP used by older adults disregarding the risk score Community-dwelling (n=1016) (%) Institutionalized (n=400) (%) 3.9 3.4 21.8 4.0 4.5 4.8 4.8 7.5 5.8 6.4 Pantoprazole Furosemide Formoterol Salmeterol Sotalol Trazodone Amiodarone Escitalopram Indapamide Domperidone Quetiapine Risperidone Moxifloxacin Mirtazapine 24 6.3 5.8 7.3 29.5 8.5 9.0 18.3 9.5 12.8 13.8 5.2.3.2 Individual use of QT-prolonging medication with high risk of TdP (risk score 4) In the population of community-dwelling older adults 257 of the 1016 patients (25.3%) uses one or more drugs with risk for QT-prolongation or TdP. In the population of institutionalized older adults this is 206 out of 400 or 51.5% and thus remarkably higher. Remark however that it is possible here that a single patient took two or more drugs with risk score 4. The complete tables for communitydwelling older adults and institutionalized older adults are presented in Appendix 11 and 12. The top 10 most commonly used drugs with a known risk for QT-prolongation and TdP (risk score 4) by older polypharmacy patients in Belgium is listed below (Table 5.2.3.2). Table 5.2.3.2: Top 10 drugs with risk for QT-prolongation and TdP used by older adults with risk score 4 Community-dwelling (n=1016) Drug name ATC code 1 Sotalol 2 Institutionalized (n=400) No. of pts 49 % Drug name ATC code C07AA07 Risk score 4 No. of pts 51 % N06AB10 Risk score 4 4.8 Escitalopram Amiodarone C01BD01 4 46 4.5 Domperidone A03FA03 4 38 9.5 3 Escitalopram N06AB10 4 41 4.0 Moxifloxacin J01MA14 4 29 7.3 4 Domperidone A03FA03 4 35 3.4 Amiodarone C01BD01 4 19 4.8 5 Flecainide C01BC04 4 29 2.9 Haloperidol N05AD01 4 19 4.8 6 Sulpiride 7 Citalopram N05AL01 4 23 2.3 Citalopram N06AB04 4 13 3.3 N06AB04 4 16 1.6 Azithromycin J01FA10 4 10 2.5 8 Azithromycin J01FA10 4 9 0.9 Sotalol C07AA07 4 9 2.3 9 Clarithromycin J01FA09 4 5 0.5 Levofloxacin J01MA12 4 7 1.8 10 Moxifloxacin J01MA14 4 3 0.3 Sulpiride N05AL01 4 7 1.8 12.8 Eight drugs appear in both the top 10’s but flecaïnide and clarithromycin only appear in that of the community-dwelling population while haloperidol and levofloxacin only appear in that of the institutionalized older adults. Figure 5.2.3.2: Top 10 drugs with risk score 4 for QT-prolongation and TdP Community-dwelling (n=1016) (%) Institutionalized (n=400) (%) 0.9 0.5 Sotalol 0.3 1.6 1.8 Amiodarone 4.8 1.8 2.3 Escitalopram 2.5 12.8 Domperidone 2.3 Flecainide 3.3 Sulpiride 2.9 4.5 Citalopram 4.8 Azithromycin Clarithromycin Moxifloxacin 3.4 4.0 9.5 4.8 Haloperidol Levofloxacin 25 7.3 5.2.3.3 Number of QT-prolonging drugs per patient In the population of community-dwelling older adults the number of QT-prolonging drugs per patient varies between 0 and 6 with a median (IQR) of 1 ± 2 drugs. In the population of institutionalized older adults on the other hand the number of QT-prolonging drugs per patient varies between 0 and 8 with a median (IQR) of 2 ± 2 drugs. We compared the distribution of the number of QT-prolonging drugs per patient of the communitydwelling older adults and the institutionalized older adults. This is presented in Figure 5.2.3.3. The yaxis depicts the number of QT-prolonging drugs a patient might take and the X-axis depicts the number of patients in per cent. 8 0.0 7 0.0 6 0.2 5 0.3 4 1.5 3 5.9 2 18.1 1 36.4 0 37.6 0 10 20 30 40 Number of QT-prolonging drugs Number of QT-prolonging drugs Figure 5.2.3.3: Comparison of the number of QT-prolonging drugs per patient between community-dwelling older adults and institutionalized older adults in percentage of patients Community-dwelling (n=1016) Institutionalized older adults (n=400) 8 0.2 7 0.2 6 0.5 5 3.8 4 8.2 3 16.8 2 26.2 1 29.8 0 14.2 0 Percentage of patients (n=1016) (%) 10 20 30 Percentage of patients (n=400) (%) 26 40 5.2.3.4 Individual use of drugs with anticholinergic properties according to Duran et al., disregarding the risk scores In the population of community-dwelling older adults 427 of the 1016 of the patients (42.0%) uses one or more drugs with anticholinergic properties. In the population of institutionalized older adults this is 291 out of 400 patients or 72.9% and thus remarkably higher. The top 10 drugs most commonly used drugs with anticholinergic properties drugs according to Duran et al. by older polypharmacy patients in Belgium is listed below (Table 5.2.3.4). The complete tables are presented in Appendix 13 and 14. Table 5.2.3.4: Top 10 drugs with anticholinergic properties according to Duran et al. used by older adults, disregarding the risk scores Community-dwelling (n=1016) Institutionalized (n=400) Drug name ATC code No. of pts 91 % Drug name ATC code N02AX02 Risk score L No. of pts 56 % R03AL01 Risk score H 1 Tramadol 9.0 Ipratropium* 2 Trazodone N06AX05 L 49 4.8 Trazodone N06AX05 L 55 13.8 3 Ipratropium* R03AL01 H 47 4.6 Domperidone A03FA03 L 38 9.5 4 Ranitidine A02BA02 L 5 N02AX52 L 6 Combinations with tramadol or methadone Domperidone 42 4.1 Quetiapine N05AH04 L 36 9.0 36 3.5 Ranitidine A02BA02 L 36 9.0 A03FA03 L 35 3.4 Tramadol N02AX02 L 36 9.0 7 Amitriptyline 8 Fentanyl N06AA09 H 30 3.0 Risperidone N05AX08 L 34 8.5 N02AB03 L 29 2.9 Fentanyl N02AB03 L 30 7.5 9 Paroxetine N06AB05 L 27 2.7 Mirtazapine N06AX11 L 25 6.3 10 Loperamide A07DA03 L 26 2.6 Combinations with Tramadol or methadone N02AX52 L 22 5.5 14.0 Figure 5.2.3.4: Top 10 drugs with anticholinergic (side-) effects according to Duran et al. disregarding the risk score Community-dwelling (n=1016) (%) Institutionalized (n=400) (%) Tramadol 5.5 Trazodone 2.6 14.0 6.3 5.2 Ipratropium 2.7 Ranitidine 7.5 2.8 Domperidone 4.7 Comb. with tramadol or methadone Amitriptyline 3.0 13.8 8.5 Fentanyl Paroxetine 4.6 3.4 Loperamide 9.0 9.5 Quetiapine (fumarate) 3.4 4.1 9.0 Risperidone 9.0 Mirtazapine *: Ipratropium is usually not considered for the calculation of the anticholinergic burden because it works locally after 36 inhalation and is barely absorbed systemically. 27 5.2.3.5 Individual use of drug with a high anticholinergic activity according to Duran et al. In the population of community-dwelling older adults 117 of the 1016 of the patients (11.5%) uses a drug with a high anticholinergic activity. In the population of institutionalized older adults this is 117 out of 400 patients or 29.3% and thus remarkably higher. Remark however that here it is possible that a single patient took 2 or more drugs with a high anticholinergic activity. The top 10 most commonly used drugs with a high anticholinergic activity according to Duran et al. by older polypharmacy patients in Belgium is listed below (Table 5.2.3.5). The complete tables are presented in Appendix 15 and 16. Table 5.2.3.5: Top 10 drugs with anticholinergic properties according to Duran et al. used by older adults with high anticholinergic activity Community-dwelling (n=1016) Institutionalized (n=400) Drug name ATC code No. of pts 47 % Drug name ATC code R03AL01 Risk score H No. of pts 56 % R03AL01 Risk score H 1 Ipratropium* 4.6 Ipratropium* 2 Amitriptyline N06AA09 H 30 3.0 Oxybutynin G04BD04 H 19 4.8 3 Oxybutynin G04BD04 H 17 1.7 Amitriptyline N06AA09 H 14 3.5 4 Hydroxyzine N05BB01 H 5 Meclozine R06AE05 H 7 0.7 Clozapine N05AH02 H 6 1.5 3 0.3 Hydroxyzine N05BB01 H 5 1.3 6 Diphenhydramine R06AA02 H 2 0.2 Trihexyphenidyl N04AA01 H 3 0.8 7 Doxepin N06AA12 H 2 0.2 Promethazine R06AD02 H 3 0.8 8 Nortriptyline N06AA10 H 2 0.2 Levomepromazine N05AA02 H 2 0.5 9 Tolterodine G04BD07 H 2 0.2 Nortriptyline N06AA10 H 2 0.5 10 Belladona alkaloids A03BA04 H 1 0.1 Diphenhydramine D04AA32 H 2 0.5 Scopolamine N05CM05 H 2 0.5 Figure 5.2.3.5: Top 10 drugs with high anticholinergic activity according to Duran et al. Community-dwelling (n=1016) (%) Institutionalized (n=400) (%) 0.2 0.3 0.2 0.2 0,2 0.1 4.6 0.7 1.7 3.0 Ipratropium* Amitriptyline Oxybutynin Hydroxyzine Meclozine Diphenhydramine Doxepin Nortriptyline Tolterodine Belladona alkaloids Clozapine Trihexyphenidyl Promethazine Levomepromazine Scopolamine (hyoscine) 0.5 0.5 0.8 0.5 0.5 0.8 1.3 1.5 14.0 3.5 4.8 *: Ipratropium is usually not considered for the calculation of the anticholinergic burden because it works locally after 36 inhalation and is barely absorbed systemically. 28 14.0 5.2.3.6 Number of drugs with anticholinergic properties according to Duran et al. per patient In the population of community-dwelling older adults the number of drugs with anticholinergic properties according to Duran et al. varies between 0 and 6 with a median (IQR) of 0 ± 1 drug. In this population of institutionalized older adults on the other hand the number of drugs with anticholinergic properties according to Duran et al. varies between 0 and 6 with a median (IQR) of 1 ± 2 drugs. We compared the distribution of the number of drugs with anticholinergic properties per patient of the community-dwelling older adults and the institutionalized older adults. This is presented in Figure 5.2.3.6. The y-axis depicts the number of drugs with anticholinergic properties a patient might take and the X-axis depicts the number of patients in per cent. 6 0.1 5 0.2 4 Number of drugs with anticholinergic properties Number of drugs with anticholinergic properties Figure 5.2.3.6: Comparison of the number of drugs with anticholinergic properties according to Duran et al. per patient between community-dwelling older adults and institutionalized older adults in per cent Community-dwelling (n=1016) Institutionalized older adults (n=400) 1.1 3 2.5 2 8.4 1 29.7 0 58.0 0 20 40 60 6 0.2 5 2.8 4 3.8 3 12,5 2 21.2 1 32.2 0 27.3 0 80 10 20 30 Percentage of patients (n=400) (%) Percentage of patients (n=1016) (%) 29 40 5.2.3.7 Individual use of drugs with anticholinergic properties according to Rudolph et al., disregarding the risk scores In the population of community-dwelling older adults 250 of the 1016 patients (24.6%) uses one or more drugs with anticholinergic properties. In the population of institutionalized older adults this is 240 (60.0%) out of the patients or 60.0% and thus remarkably higher. The top 10 most commonly used drugs with anticholinergic properties according to Rudolph et al. by older polypharmacy patients in Belgium is listed below (Table 5.2.3.7). The complete tables are presented in Appendix 17 and 18. Table 5.2.3.7: Top 10 drugs with anticholinergic properties according to Rudolph et al. used by older adults disregarding the risk score Community-dwelling (n=1016) Institutionalized (n=400) Drug name ATC code Risk No. % Drug name ATC code Risk No. of % score of pts score pts 1 Trazodone N06AX05 1 49 4.8 Trazodone N06AX05 1 55 13.8 2 Ranitidine A02BA02 1 42 4.1 N04BA02 1 44 11.0 3.1 Carbidopalevodopa Quetiapine 3 N04BA02 1 31 4 Carbidopalevodopa Amitryptyline N05AH04 1 36 9.0 N06AA09 3 30 3.0 Ranitidine A02BA02 1 36 9.0 5 Paroxetine N06AB05 6 Loperamide A07DA03 1 27 2.7 Risperidone N05AX08 1 34 8.5 2 26 2.6 Mirtazapine N06AX11 1 25 6.3 7 Cetirizine R06AE07 2 25 2.5 Cetirizine R06AE07 2 21 5.3 8 Oxybutynin G04BD04 3 17 1.7 Loperamide A07DA03 2 20 5.0 9 Mirtazapine N06AX11 1 15 1.5 Oxybutynin G04BD04 3 19 4.8 10 Metoclopramide A03FA01 1 9 0.9 Haloperidol N05AD01 1 19 4.8 Seven drugs appear in both the top 10’s but amitriptyline, paroxetine and metoclopramide only appear in that of the community-dwelling population while quetiapine, risperidone and haloperidol only appear in that of the institutionalized older adults. Figure 5.2.3.7: Top 10 drugs with anticholinergic properties according to Rudolph et al. disregarding the risk score 1.7 Community-dwelling (n=1016) (%) Trazodone 0.9 1.5 Ranitidine 4.8 Carbidopa-levodopa Institutionalized (n=400) (%) 4.8 4.8 13.8 5.0 Amitryptyline Paroxetine 2.5 Loperamide 5.3 Cetirizine 2.6 4.1 Oxybutynin 11.0 6.3 Mirtazapine Metoclopramide 2.7 3.1 3.0 Quetiapine Risperidone Haloperidol 30 9.0 8.5 9.0 5.2.3.8 Individual use of drugs with risk score 3 for anticholinergic (side-) effects according to Rudolph et al. In the population of community-dwelling older adults 59 of the 1016 patients (5.8%) uses one or more drugs with anticholinergic properties. In the population of institutionalized older adults this is 43 out of 400 patients or 10.8% and thus remarkably higher. Remark however that here it is possible that a single patient took 2 or more drugs with risk score 3. There are only 5 drugs with anticholinergic properties according to Rudolph et al. taken by older polypharmacy patients in Belgium. This is listed in Table 5.2.3.8. Table 5.2.3.8: Top 10 drugs with risk score 3 for anticholinergic (side-) effects used by older adults according to Rudolph et al. Community-dwelling (n=1016) Institutionalized (n = 400) Drug name ATC code No. of pts 30 % Drug name ATC code N06AA09 Risk score 3 1 Amitryptyline 2 No. of pts 19 % G04BD04 Risk score 3 3.0 Oxybutynin Oxybutynin G04BD04 3 17 1.7 Amitryptyline N06AA09 3 14 3.5 3 Hydroxyzine N05BB01 3 7 0.7 Hydroxyzine N05BB01 3 5 1.3 4 Meclozine R06AE05 3 5 Diphenhydra mine R06AA02 3 3 0.3 Promethazine R06AD02 3 3 0.8 2 0.2 Diphenhydrami ne D04AA32 3 2 0.5 4.8 Four of the drugs appear in both the top 5’s but meclozine only appears in that of the communitydwelling population while promethazine only appears in that of the institutionalized older adults. Figure 5.2.3.8: Top 10 drugs with risk score 3 for anticholinergic (side-) effects according to Rudolph et al. Community-dwelling (n=1016) (%) Institutionalized (n=400) (%) 0.3 0.7 0.2 0.8 3.0 0.5 Amitryptyline Oxybutynin 1.3 Hydroxyzine 4.8 Meclozine Diphenhydramine 1.7 Promethazine 31 3.5 5.2.3.9 Number of drugs with anticholinergic properties according to Rudolph et al. per patient In the population of community-dwelling older adults the number of drugs with anticholinergic properties according to Rudolph et al. varies between 0 and 4 per patient with a median (IQR) of 0 ± 0 drugs. In the population of institutionalized older adults on the other hand the number of drugs with anticholinergic properties varies between 0 and 6 with a median (IQR) of 1 ± 2 drugs. We compared the distribution of the number of drugs with anticholinergic properties per patient of the community-dwelling older adults and the institutionalized older adults. This is presented in Figure 5.2.3.9. The y-axis depicts the number of drugs with anticholinergic properties a patient might take and the X-axis depicts the number of patients in per cent. 6 0.0 5 0.0 4 0.1 3 1.2 2 3.2 1 20.1 0 75.4 0 20 40 60 Number of drugs with anticholinergic properties Number of drugs with anticholinergic properties Figure 5.2.3.9: Comparison of the number of drugs with anticholinergic properties according to Rudolph et al. per patient between community-dwelling older adults and institutionalized older adults in per cent Community-dwelling (n=1016) Institutionalized (n=400) 80 6 0,5 5 0.2 4 1.3 3 4.2 2 22.0 1 31.8 0 40.0 0 20 40 60 Percentage of patients (n=400) (%) Percentage of patients (n= 1016) (%) 32 PART 6: DISCUSSION 6.1 RISK SCALES 6.1.1 QT-prolonging risk scales in older adults Drug induced QT-prolongation and TdP is currently a topic receiving a lot of attention by researchers37 as well as the media38, 39. However, during the literature search we only found two existing risk scales for QT-prolongation and TdP and only one of them includes a list of drugs with a risk for TdP.21, 32 A possible explanation for this lack of risk scales is that the occurrence of TdP is very hard to measure because it usually only lasts a couple of seconds.12 The credible meds list is however updated monthly and currently remains the largest available database of QT-research.21 It is likely that this new interest by researchers and the media will lead to new and improved scales to predict QT-prolongation and TdP. The credible meds lists in itself are quite clear but a log-in must be made for the website.21 In the community-pharmacy, however, these lists are not practical because the pharmacist would have to scan the lists for every drug the patient uses which is a time-consuming activity. Here the top 10 most commonly used QT-prolonging drugs as found in this research might be useful because then the physician or pharmacist would only have to look for the 10 most commonly used drugs. Further research could also focus on what pharmacists might find useful in every day practice. 33 6.1.2 Anticholinergic risk scales in older adults Scales to predict the anticholinergic burden of an individual patient exist in abundance.28 There are many scales that predict more or less the same, so we made an evidence-based decision on what scales would be used in this thesis.28 The results of the evaluation of the drugs with anticholinergic properties according to Duran et al. and Rudolph et al. were largely the same because the list by Duran et al. includes some drugs that Rudolph et al. did not include, even the top 10 most commonly used drugs by both subpopulations varies. It is reasonable to conclude that the other anticholinergic risk scales would have led to even other outcomes. An Australian study evaluated the use of drugs with anticholinergic properties in a communitydwelling population of older men using four different anticholinergic risk scales (Table 6.1.2).40 40 Table 6.1.2: Use of drugs with anticholinergic properties, an Australian study: adopted from Anticholinergic risk scale % of patients with at least one drug with anticholinergic properties ARS 13.0 ADS 39.0 ACB 39.0 DBI-Ach 18.0 Pont et al. concluded that there is little agreement between the four anticholinergic risk scales included in their study and conclusions regarding anticholinergic risk should be made with great care due to the great variations between the existing scales.40 Besides that, even though the anticholinergic risk scale designed by Duran et al. includes all medication included by earlier scales as well as Martindale, it is a lot harder for pharmacists to calculate a patient’s anticholinergic burden because the drugs are not graded.28 It also contains drugs such as ipratropium which, when used properly, are barely absorbed in the blood stream and do not lead to systemic ADE’s.36 The list composed by Rudolph et al. on the other hand does not include some of the most commonly used drugs with anticholinergic properties by either of the subpopulations in this thesis.31 Because the drugs are graded, as in most existing anticholinergic risk scales, it is possible for the pharmacist to calculate the anticholinergic burden for the individual patient.28, 31 34 However, there is no consensus on the grades given to these drugs so further research is necessary.28 Besides that, the score of the anticholinergic burden leading to ADE’s such as deterioration of the aging brain, falls etc. was not found, possibly because here there is no consensus either.4, 28, 29 This means that a pharmacist can calculate a patient’s anticholinergic burden taking into account the fact that there are many possibilities depending on what scale was used. However, it is impossible for the pharmacist to then predict the actual risk of ADE’s for that patient. This is especially important because the risk of ADE’s depends on the anticholinergic burden and anticholinergic effects are additive.4, 27 Hopefully further research will lead to an unambiguous anticholinergic risk scale that includes all drugs with anticholinergic properties that may lead to ADE’s and that is useful for calculating a patient’s risk of ADE’s by physicians or pharmacists. 35 6.2 GENERAL DRUG USE OF THE INCLUDED POPULATIONS Generally, the expected result was that institutionalized older adults use more medication than community-dwelling older adults. This turned out to be right, but the average difference was smaller than expected. A possible explanation for this small difference might for example be that the drugs of the community-dwelling older adults included flu vaccines and all sorts of supplements where that was not included for the institutionalized population. The average number of drugs used by the Belgian older population was then compared to that of foreign older populations. However, the general drug use in older polypharmacy patients has not been described before. The general drug use of institutionalized older adults has only been described a few times and not in polypharmacy patients. This means that the results as described in Table 6.2 are not comparable to those in this study because they also or mainly included non-polypharmacy patients. Generally, the number of drugs used by the older adults in other countries are more or less comparable but can vary depending on for example age and the relative number of polypharmacy patients. The drug use as described by Felton et al. (United-States) is considerably lower, but they only included prescription drugs.41 Table 6.2: General use of medication in various countries Community-dwelling Belgium (this study) 11 ± 4 42 France 8.3 ± 4.2 43 Spain 4.6 ± 2.9 43 Cognitive impaired: 5.2 ± 3.2 43 Not cognitive impaired: 4.0 ± 2.7 41 United-States 1.7 ± 1.9 (prescription drugs) 36 Institutionalized 12 ± 5 6.5 ± 2.9 44 6.3 EVALUATION OF THE INDIVIDUAL USE OF QT-PROLONGING DRUGS As expected, a large difference between community-dwelling and institutionalized older adults was found regarding the percentage of patients taking one or more QT-prolonging drugs as well as the number of QT-prolonging drugs per patient. This is possibly because institutionalized older adults have more comorbidities and generally are in a worse medical condition than community-dwelling older adults. Especially the institutionalized older adults in general use a lot of QT-prolonging drugs with known risk of TdP (risk score 4). Because two of the risk factors for TdP are old age and female sex and this is a population with a lot of female older adults (75%), many of them are possibly at risk for TdP.12 We compared this use of QT-prolonging drugs with other studies. Four interesting studies regarding QT-prolonging drugs were found but none of them included older polypharmacy patients. This is the first research for older polypharmacy patients. Vandael et al. studied the use of QT-prolonging drugs in Belgian psychiatry. However, they focused on drug interactions including a QT-prolonging drug. Vandael et al. used the credible meds lists as well but only included antipsychotics and antidepressants, probably because these are the only relevant classes in psychiatry. The drug use of 43 patients (7.3%) contains one or more interactions with a severe or very severe risk for QT-prolongation. Remark however that they did not include the use of QT-prolonging drugs of other classes, the use of QT-prolonging drugs without interactions or QT-prolonging drugs with a small or medium risk for QT-prolongation. Besides that, the psychiatric patients are considerably younger than the community-dwelling and institutionalized patients and the population also includes non-polypharmacy patients. This might explain the big difference in the use of QT-prolonging drugs between the psychiatric patients and the patients in this study (Table 6.3a). 45 Table 6.3a: The use of QT-prolonging drugs in Belgium: a comparison between the use in psychiatric, communitydwelling and institutionalized patients 45 Adopted from This study Population Psychiatric Community-dwelling Institutionalized No. of pts 592 1016 400 % female 46 58 75 Age (mean ± SD) in years 52.4 ± 17.3 78.8 ± 5.5 86.2 ± 6.3 1 QTPD or more (%) 7.3 62.4 85.8 Vandael et al. also listed the most commonly used antipsychotics and antidepressants by Belgian psychiatry patients. We compared this to the Belgian community-dwelling and institutionalized older adults (Table 6.3b) and found that the use of antipsychotics was considerably lower in communitydwelling older adults but considerably higher in institutionalized older adults. The use of antidepressants in community-dwelling as well as institutionalized older adults was lower than in 37 psychiatric patients except for Amitriptyline. This might be explained by comments as described for Table 6.3a.45 Table 6.3b: Most commonly used antipsychotics and antidepressants in Belgian psychiatry: a comparison with Belgian community-dwelling and institutionalized older adults 45 Adopted from This study Psychiatric (n=592) Community-dwelling (n=1016) Institutionalized (n=400) No. of pts % No. of pts % No. of pts % Antipsychotics Risperidone 15 2.5 1 0.1 34 8.5 Olanzapine 14 2.4 1 0.1 13 3.3 Quetiapine 14 2.4 5 0.5 36 9.0 Venlafaxine Dosulepine Amitriptyline 15 11 11 Antidepressants 20 16 30 2.5 1.9 1.9 2.0 1.6 3.0 7 0 14 1.8 0.0 3.5 The three remaining studies researched the use of QT-prolonging drugs or interactions involving QTprolonging drugs (Table 6.3c). First of all, the difference in use of QT-prolonging drugs might be explained by the fact that Baptista et al., Curtis et al. and Allen LaPointe et al. also included nonpolypharmacy patients. Further, Curtis et al. recruited a considerably younger population, while this is not known for the research by Allen La Pointe et al. Besides that, Allen LaPointe et al. only searched for interactions including QT-prolonging drugs and Baptista et al. only screened for 19 different QT-prolonging drugs. This might explain the big difference in the use of QT-prolonging drugs between the populations in these studies and ours.46-48 Table 6.3c: Evaluation of the individual use of QT-prolonging drugs: a comparation with other studies 46 47 48 This study Baptista et al. Curtis et al. Allen LaPointe et al. Country Belgium Portugal United-States United-States Population Community- Institutionalized Hospitalized CommunityCommunity-dwelling dwelling dwelling No. of pts 1016 400 108,045 4,825,345 2,000,000 Age (Mean ± SD) in 78.8 ± 5.5 86.2 ± 6.3 74.2 ± 12.5 49.0 ± 16 years No. of drugs 175 175 19 76 researched 1 QTPD or more (%) 2 QTPD 3 QTPD 4 QTPD 5 QTPD 62.4 18.1 5.9 1.5 0.3 85.8 26.2 16.8 8.2 3.8 17.5 2.6 % 0.3 % 0.025 % 0.009 % 22.8 8.7 0.7 (3 or more) 11.4 (high-risk use) 4.6 There are many patients in both subpopulations who take one or more QT-prolonging drugs and physicians and pharmacists should consider the risks of these drugs when prescribing or delivering them in daily practice. The problem and a possible solution are described in 6.1.1. Besides that, further research could focus on the effect of reduced use of QT-prolonging drugs on the patient’s quality of life (QoL). When exactly a patient is at risk for drug-induced TdP, is being researched.49 38 6.4 EVALUATION OF THE INDIVIDUAL USE OF DRUGS WITH ANTICHOLINERGIC PROPERTIES The expected differences between community-dwelling older adults and institutionalized older adults were found as well as a slight difference between the use of drugs with anticholinergic properties as described by Duran et al. and Rudolph et al.28, 31 The literature was searched for comparable researches. The two most interesting studies are discussed below. An American study by Felton et al. compared the use of drugs with anticholinergic properties between black and white older Americans spread over 10 years. They started with a population of 1266 black (41.4%) and 1789 white (58.6%) community-dwelling Americans aged 70 to 79 years in year one and researched the evolution of the use of drugs with anticholinergic properties over 10 years. The manuscript does not state how many of them became institutionalized over the years.41 The use of drugs with anticholinergic properties in year 1, year 5 and year 10 are presented in Table 6.4a. The general use of drugs with anticholinergic properties is much lower in both American subpopulations than in either of our subpopulations this might be explained by the fact that Felton et al. also included non-polypharmacy patients.41 41 Table 6.4a: American anticholinergic use by type and race over time: adopted from Anticholinergic Year 1 Year 5 use Blacks Whites Blacks Whites (n=1266) (%) (n=1789) (%) (n=1035) (%) (n=1610) (%) Prescription 8.8 11.4 11.4 11.9 Non-prescription 5.4 6.9 2.7 4.9 Any 13.4 17.8 13.9 16.3 Year 10 Blacks (n=537) (%) 5.0 3.4 8.0 Whites (n=1001) (%) 7.0 6.1 12.5 Felton et al. also created a top 10 most commonly used drugs with anticholinergic properties for these subpopulations but they used the 2012 American Geriatrics Society Beers Criteria (Table 6.4b).41 41 Table 6.4b: Top 10 most commonly used anticholinergic drugs by white older adults in the United-States: adopted from Year 1 (n=1789) Year 5 (n=1610) Year 10 (n=1001) Drug name No. of % Drug name No. of % Drug name No. of % pts pts pts Diphenhydramine 82 4.6 Diphenhydramine 51 3.2 Meclozine 13 1.3 Chlorpheniramine 41 2.3 Tolterodine 40 2.5 Oxybutynin 12 1.2 Amitriptyline 32 1.8 Paroxetine 32 2.0 Tolterodine 9 0.9 Meclozine 28 1.6 Meclozine 29 1.8 Paroxetine 6 0.6 Paroxetine 19 1.1 Oxybutynin 26 1.6 Diphenhydramine 3 0.3 Hydroxyzine 15 0.8 Amitriptyline 22 1.4 Nortriptyline 3 0.3 Hyoscyamine 14 0.8 Hydroxyzine 10 0.6 Atropine 3 0.3 Clemastine 12 0.7 Chlorpheniramine 10 0.6 Dicyclomine 2 0.2 Atropine 11 0.6 Olanzapine 7 0.4 Hyoscyamine 2 0.2 Nortriptyline 10 0.6 Dicyclomine 7 0.4 Solifenacin 2 0.2 39 Compared to the top 10 most commonly used drugs with anticholinergic properties found in the American study, some drugs do not appear in our top 10 such as dicyclomine and clemastine because they are not available in Belgium. Solifenacin does not appear in either of the lists we used. Compared to year 1 and 10, 6 drugs appear in both the American study as in our top 10 for drugs with a high anticholinergic activity according to Duran et al. 41 A British study by Fox et al. researched the use of drugs with anticholinergic properties in a population of community-dwelling as well as institutionalized older adults living in England and Wales (Table 6.4c). However, Fox et al. also included non-polypharmacy patients and 21% of the older adults did not use any drug. We excluded the older adults who did not take any drug and estimated the use of drugs with anticholinergic properties. Fox et al. their population included both community-dwelling and institutionalized older adults and the use of anticholinergic drugs lays somewhere between that of the community-dwelling and the institutionalized older adults in this study. This means it is reasonable to say that the use of drugs with anticholinergic properties in Fox et al. their study and ours is very comparable.50 Table 6.4c: Evaluation of the use of drugs with anticholinergic properties in a British population of community-dwelling and institutionalized older adults 50 adopted from This study Community-dwelling CommunityInstitutionalized + institutionalized dwelling No. of pts 13,004 1016 400 Age (mean ± SD) in years 75.2 ± 6.8 78.8 ± 5.5 86.2 ± 6.3 pts taking any drug (%) 9,850 (79) pts using one or more drug(s) with anticholinergic 6010 (48) properties (%) % of pts using one or more drug(s) with 61 42.0 72.8 anticholinergic properties when excluding those who don’t use any drug Analogue to the research on QT-prolongation, physicians and pharmacists should consider avoiding the use of drugs with anticholinergic properties where possible. They should also take a patient’s cognitive status into account because drugs with anticholinergic properties can (further) deteriorate the aging brain.30 However, as described in 6.1.2 the lists of drugs with anticholinergic (side-) effects are not readily usable in daily practice. Besides that, drugs with anticholinergic properties have some large adverse effects such as (further) deterioration of the aging brain, falls and decreasing abilities to live independently. So further research could focus on the effects on patients’ QoL with and without reduced use of drugs with anticholinergic properties and on the absolute risk of ADE’s with anticholinergic drugs in order to be able to estimate the individual patient’s risk of large anticholinergic ADE’s and therefor his QoL.6 40 6.5 STRENGHTS AND LIMITATIONS This study includes a large group of patients and focuses on community-dwelling older adults as well as institutionalized older adults. In this study, the general drug use as well as the use of QTprolonging drugs and drugs with anticholinergic properties were evaluated. This means that multiple aspects of drug use in Belgian older polypharmacy patients were evaluated for community-dwelling older adults as well as institutionalized older adults. A comparable study for the use of QT-prolonging drugs and drugs with anticholinergic properties has never been conducted for older polypharmacy patients. Because the same methods were used for both subpopulations, the results could easily be compared. Besides that, the Strengthening the Reporting of Observational studies in Epidemiology (STROBE)-guidelines were followed for this observational study.51 Because of the choice of population, the information obtained in this study may not apply to similar but slightly different populations such as hospitalized older adults or foreign older patients. Besides that, this is a retrospective observational study so it doesn’t have the highest level of evidence. Consequently, only associations can be made following the results found in this thesis and no causality. We didn’t evaluate the severity of the drug use. For QT-prolongation we didn’t take the risk factors as described in Table 1.2.3 into account. 41 PART 7: CONCLUSION Generally, community-dwelling older adults in this study take an average of 11 ± 4 drugs (mean ± SD), while institutionalized older adults take an average of 12 ± 5 drugs (mean ± SD). Firstly, there is only one risk scale to estimate an individual patient’s risk of TdP available in the literature; the one described by AZCERT. This risk scale was used to evaluate the use of QTprolonging drugs for the 1016 community-dwelling and 400 institutionalized older Belgian polypharmacy patients. In this first part of our research, we found that 63.4% of the communitydwelling older adults and 85.8% of the institutionalized older adults used one or more QT-prolonging drugs. There is a considerable difference between community-dwelling older adults and institutionalized older adults in the number of QT-prolonging drugs per patient as well. The top 10 most commonly used drugs are largely comparable, but institutionalized older adults use these drugs more. Finally, further research is necessary to estimate the individual risk of TdP for these patients and to estimate the increase in QoL in case the use of QT-prolonging drugs is reduced. Subsequently the existence of anticholinergic risk scales was researched and these seemed to exist in abundance. The risk scale described by Duran et al. was chosen because it is the most evidencebased risk scale in the literature. The use of drugs with anticholinergic properties was also evaluated with the risk scale described by Rudolph et al. because it is the most commonly used anticholinergic risk scale. In the population of community-dwelling older adults 42.0% of the patients used a drug with anticholinergic properties according to Duran et al. while this is 72.9% in the population of institutionalized older adults. Here as well there is a considerable difference between communitydwelling older adults and institutionalized older adults regarding the number of drugs with anticholinergic properties per patient as well. The results for the evaluation using Rudolph et al. were comparable to those using Duran et al. However, the percentage of patients using one or more drugs with anticholinergic properties was much lower: 24.6% of the community-dwelling older adults and 60.0% of the institutionalized older adults. 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Medicinale chemie deel 1. 2013. 44 Appendix 52 Appendix 1: Sympathic and parasympathic effect on various organs: adopted from Organ Sympatic stimulation Parasympathic stimulation Eye - Iris - Stimulates radial fibers (dilates - Stimulates circular fibers pupil) (constricts pupil) - Ciliary muscle - Inhibits (flattens lens- weak action) - Stimulates (bulges lens) Salivary glands (parotid, sublingual, Vasoconstriction may diminish Stimulates copious secretion high in submaxillary) secretion enzym content Lacrimal glands Stimulates secretion Sweat glands Copious sweating (cholinergic) Heart - SA node - Increased rate - Decreased rate - Muscle - Increased force of contraction Lungs - Bronchi - Dilatation - Constriction Stomach - Wall - Decreased motility and tone - Increased motility and tone - Glands - Stimulates secretion of alkaline juice - Stimulates secretion of acid juice with with low enzym activity high enzym activity Intestine - Wall - Decreased motility and tone - Increased motility and tone - Anal sphincter - Contraction - Inhibition Pancreas Vasoconstriction may diminish Stimulates secretion of pancreatic secretion enzymes Suprarenal gland - Medulla - Secretion of epinephrine Urinary bladder - Wall - Inhibition - Excitation - Sphincter - Excitation - Inhibition Penis Ejaculation Erection (vasodilatation) Arrector pili muscles of hair follicles Contraction Arterioles - Splanchnic region and skin skeletal - Constriction muscles - Baro- and chemoreceptor response - Constriction - Response to exercise and alarm - Dilatation 45 Appendix 2: Alphabetical list of QT-prolonging 21 medication: adopted from and adapted ATC code Drug name ATC combination R03AC12 Albuterol R03CC02 (salbutamol) R03AL02 R03AK04 G04CA01 Alfuzosin G04CA51 Risk score 1 3 ATC code Drug name ATC combination A03FA03 Domperidone Risk score 4 N06AA12 Doxepin 2 N05AD08 Droperidol 4 C01CA26 Ephedrine R01AA03 Ephedrine 1 R01AB05 Ephedrine 1 R03CA02 Ephedrine 1 S01FB02 Ephedrine 1 A01AD01 A08AA56 1 C01BD01 Amiodarone 4 N05AL05 Amisulpride 2 N06AA09 Amitriptyline L01XX35 Anagrelide 4 G04BE07 Apomorphine 3 N04BC07 Apomorphine 3 B02BC09 Epinephrine (adrenaline) Epinephrine N05AX12 Aripiprazole 3 C01CA24 Epinephrine 1 Epinephrine 1 N06CA01 2 R03AK01 S01EA51 1 1 L01XX27 Arsenic trioxide 4 R01AA14 J05AE08 Atazanavir 3 R03AA01 Epinephrine 1 N06BA09 Atomoxetine 1 S01EA01 Epinephrine 1 J01FA10 Azithromycin 4 L01XX41 Eribulin 3 S01AA26 Azithromycin 4 D10AF02 Erythromycin J04AK05 Bedaquiline 3 J01FA01 Erythromycin 4 L01XX32 Bortezomib 3 S01AA17 Erythromycin 4 L01XE14 Bosutinib 3 N06AB10 Escitalopram 4 Felbamate 3 J01RA07 D10AF52 4 N05CC01 Chloral hydrate 2 N03AX10 P01BA01 Chloroquine 4 L04AA27 Fingolimod 3 S01AE03 Ciprofloxacin 2 C01BC04 Flecainide 4 J02AC01 Fluconazole D01AC15 Fluconazole N06AB03 Fluoxetine N06CA03 2 R03AC13 Formoterol R03AL05 R03AK08 R03AK07 R03AK11 R03AK09 1 J05AD01 Foscarnet C03CA01 J01RA10 J01RA12 J01RA11 S03AA07 Ciprofloxacin 2 S02AA15 Ciprofloxacin 2 J01MA02 Ciprofloxacin 2 N06AB04 Citalopram 4 J01FA09 Clarithromycin A02BD06 A02BD07 A02BD09 A02BD05 A02BD04 4 J01RA07 2 2 3 N06AA04 Clomipramine 2 N06DA04 Furosemide (frusemide) Galantamine N05AH02 Clozapine 3 A04AA02 Granisetron 3 L01XE16 Crizotinib 3 N05AD01 Haloperidol 4 L01XE23 Dabrafenib 3 C03AA03 Hydrochlorothiazide L01XE06 Dasatinib 3 N05CM18 Dexmedetomidine 3 P01BF05 3 D04AA32 Dihydroartemisinin + piperaquine Diphenhydramine P01BA02 Hydroxychloroquine R06AA02 Diphenhydramine 2 N05BB01 Hydroxyzine N05BB51 2 C01BA03 Disopyramide 4 N06AA02 2 Dobutamine 1 Imipramine (melipramine) N06AA03 C01CA07 D04AA33 R06AA52 2 46 C03CB01 C03EB01 2 2 C09XA52 C09XA54 C03AB03 C03EA01 C03AX01 C09DX03 C09DX01 2 2 ATC code Drug name ATC combination C09BX01 Risk score 2 ATC code Drug name C03BA11 Indapamide C01CA02 R03AB02 Isoproterenol (isoprenaline) Isoproterenol H01BB02 Oxytocin R03AK02 R03CB51 1 N05AX13 Paliperidone A02BC02 Pantoprazole R03CB01 Isoproterenol 1 N06AB05 Paroxetine 2 C08CA03 Isradipine 3 L01XE11 Pazopanib 3 P01CX01 Pentamidine J02AC02 Itraconazole 2 4 C01EB17 Ivabradine 2 V08DA04 3 C01CA06 Perflutren lipid microspheres Phenylephrine D01AC08 Ketoconazole 2 G01AF11 Ketoconazole 2 J02AB02 Ketoconazole 2 R01AA04 Phenylephrine 1 L01XE07 Lapatinib 3 R01AB01 Phenylephrine 1 J01MA12 Levofloxacin 4 R01BA03 Phenylephrine 1 S01AE05 Levofloxacin S01FB01 Phenylephrine 1 N07BC02 Methadone S01GA05 Phenylephrine 1 N06BA04 Methylphenidate 1 N05AG02 Pimozide 4 A03FA01 Metoclopramide 2 N05AD05 Pipamperone 3 J02AC04 Posaconazole A01AB17 Metronidazole 2 D04AA10 Promethazine R06AD02 Promethazine R01BA02 Pseudoephedrine N05AH04 Quetiapine 3 J05AG05 Rilpevirine 3 N05AX08 Risperidone 3 J05AE03 Ritonavir J01FA06 Roxithromycin R03AC12 Salmeterol J05AE01 Saquinavir 3 N05AE03 Sertindole 3 N06AB06 Sertraline 2 N01AB08 Sevoflurane 4 G04BD08 Solifenacin L01XE05 Sorafenib C07AA07 Sotalol N05AL01 Sulpiride 4 L01XE04 Sunitinib 3 L02BA01 Tamoxifen 3 J05AE11 Telaprevir 2 J01FA15 Telithromycin 3 N07XX06 Tetrabenazine 3 M03BX02 Tizanidine 3 G04BD07 Tolterodine 3 N06AX05 Trazodone 2 1 A02BD10 J01RA05 4 N02AC52 A02BD08 J01RA03 J01RA10 A02BD03 A02BD02 P01AB51 A02BD01 J01RA04 4 2 D06BX01 Metronidazole 2 G01AF01 Metronidazole 2 J01XD01 Metronidazole 2 P01AB01 Metronidazole 2 G03XB01 Mifepristone G03XB51 G04BD12 Mirabegron 3 N06AX11 Mirtazapine 3 C09AA13 Moexipril/HCTZ J01MA14 Moxifloxacin 4 S01AE07 Moxifloxacin 4 C08CA04 Nicardipine 3 L01XE08 Nilotinib 3 C01CA03 1 J01MA06 Norepinephrine (noradrenaline) Norfloxacin S01AE02 Norfloxacin 3 N06AA10 Nortriptyline 2 J01MA01 Ofloxacin S01AE01 Ofloxacin C09BA13 J01RA13 J01RA09 3 3 3 3 3 S02AA16 Ofloxacin 3 N05AH03 Olanzapine 3 A04AA01 Ondansetron 4 47 ATC combination G02AC01 Risk score 3 3 A02BD04 R01BA53 S01GA55 V03AB05 R06AD52 2 1 3 3 R01BA52 J05AR10 1 2 3 R03AK06 G04CA53 1 2 3 C07BA07 C07AA57 4 ATC code Drug name L01XE12 G04BE09 L01XE15 ATC combination ATC code Drug name Vandetanib Risk score 4 N06AX16 Venlafaxine Risk score 3 Vardenafil Vemurafenib 3 3 J02AC03 Voriconazole 2 N05CC01 Chloral hydrate 2 S01AE03 Ciprofloxacin S03AA07 Ciprofloxacin 2 S02AA15 Ciprofloxacin 2 J01MA02 Ciprofloxacin 2 N06AA04 Clomipramine 2 1 D04AA32 Diphenhydramine 1 Appendix 3: Categorical list of QT-prolonging medication: 20 adopted from and adapted ATC Drug name ATC Risk combination score R03AC12 Albuterol R03CC02 1 (salbutamol) R03AL02 R03AK04 N06BA09 Atomoxetine 1 ATC combination J01RA10 J01RA12 J01RA11 D04AA33 R06AA52 2 2 C01CA07 Dobutamine C01CA26 Ephedrine R06AA02 Diphenhydramine 2 R01AA03 Ephedrine 1 N06AA12 Doxepin 2 R01AB05 Ephedrine 1 J02AC01 Fluconazole R03CA02 Ephedrine 1 D01AC15 Fluconazole S01FB02 Ephedrine 1 N06AB03 Fluoxetine N06CA03 2 A01AD01 1 C03CA01 1 C03CB01 C03EB01 N06DA04 Furosemide (frusemide) Galantamine 2 B02BC09 Epinephrine (adrenaline) Epinephrine C01CA24 Epinephrine 1 C03AA03 Hydrochlorothiazide R01AA14 Epinephrine 1 R03AA01 Epinephrine 1 S01EA01 Epinephrine 1 R03AC13 Formoterol C09XA52 C09XA54 C03AB03 C03EA01 C03AX01 C09DX03 C09DX01 P01BA02 Hydroxychloroquine N05BB01 Hydroxyzine N05BB51 2 N06AA02 N06AA03 2 C03BA11 Imipramine (melipramine) Indapamide C09BX01 2 J02AC02 Itraconazole 2 C01EB17 Ivabradine 2 D01AC08 Ketoconazole 2 C01CA02 A08AA56 R03AK01 S01EA51 R03AL05 R03AK08 R03AK07 R03AK11 R03AK09 R03AK02 R03CB51 1 R03AB02 Isoproterenol (isoprenaline) Isoproterenol R03CB01 Isoproterenol 1 N06BA04 Methylphenidate 1 C01CA03 C01CA06 Norepinephrine (noradrenaline) Phenylephrine R01AA04 1 1 1 J01RA07 2 2 2 2 2 G01AF11 Ketoconazole 2 1 J02AB02 Ketoconazole 2 Phenylephrine 1 A03FA01 Metoclopramide 2 R01AB01 Phenylephrine 1 A01AB17 Metronidazole R01BA03 Phenylephrine 1 S01FB01 Phenylephrine 1 S01GA05 Phenylephrine 1 R01BA02 Pseudoephedrine R01BA52 1 R03AC12 Salmeterol R03AK06 1 N05AL05 Amisulpride D06BX01 Metronidazole 2 N06AA09 Amitriptyline G01AF01 Metronidazole 2 R01BA53 S01GA55 2 N06CA01 2 48 A02BD08 J01RA03 J01RA10 A02BD03 A02BD02 P01AB51 A02BD01 J01RA04 2 J01XD01 Metronidazole 2 H01BB02 Oxytocin P01AB01 Metronidazole 2 N05AX13 Paliperidone 3 N06AA10 Nortriptyline 2 L01XE11 Pazopanib 3 A02BC02 Pantoprazole 2 V08DA04 3 N06AB05 Paroxetine 2 J02AC04 Posaconazole 2 N05AD05 Perflutren lipid microspheres Pipamperone J05AE03 Ritonavir D04AA10 Promethazine N06AB06 Sertraline 2 R06AD02 Promethazine 3 G04BD08 Solifenacin 2 N05AH04 Quetiapine 3 J05AE11 Telaprevir 2 J05AG05 Rilpevirine 3 N06AX05 Trazodone 2 N05AX08 Risperidone 3 J02AC03 Voriconazole 2 J01FA06 Roxithromycin 3 G04CA01 Alfuzosin 3 J05AE01 Saquinavir 3 Sertindole 3 A02BD04 J05AR10 G04CA53 G04CA51 2 G02AC01 3 3 V03AB05 R06AD52 3 G04BE07 Apomorphine 3 N05AE03 N04BC07 Apomorphine 3 L01XE05 Sorafenib 3 N05AX12 Aripiprazole 3 L01XE04 Sunitinib 3 J05AE08 Atazanavir 3 L02BA01 Tamoxifen 3 J04AK05 Bedaquiline 3 J01FA15 Telithromycin 3 L01XX32 Bortezomib 3 N07XX06 Tetrabenazine 3 L01XE14 Bosutinib 3 M03BX02 Tizanidine 3 N05AH02 Clozapine 3 G04BD07 Tolterodine 3 Vardenafil 3 L01XE16 Crizotinib 3 G04BE09 L01XE23 Dabrafenib 3 L01XE15 Vemurafenib 3 L01XE06 Dasatinib 3 N06AX16 Venlafaxine 3 P01BF05 3 C01BD01 Amiodarone 4 L01XX41 Dihydroartemisinin + piperaquine Eribulin L01XX35 Anagrelide 4 N03AX10 Felbamate 3 L01XX27 Arsenic trioxide 4 L04AA27 Fingolimod 3 J01FA10 Azithromycin J05AD01 Foscarnet 3 S01AA26 Azithromycin 4 A04AA02 Granisetron 3 P01BA01 Chloroquine 4 C08CA03 Isradipine 3 N06AB04 Citalopram 4 L01XE07 Lapatinib 3 J01FA09 Clarithromycin G03XB01 Mifepristone 3 G04BD12 Mirabegron N06AX11 Mirtazapine 3 C01BA03 Disopyramide 4 C09AA13 Moexipril/HCTZ 3 A03FA03 Domperidone 4 C08CA04 Nicardipine 3 N05AD08 Droperidol 4 L01XE08 Nilotinib 3 D10AF02 Erythromycin J01MA06 Norfloxacin 3 J01FA01 Erythromycin 4 S01AE02 Norfloxacin 3 S01AA17 Erythromycin 4 J01MA01 Ofloxacin 3 N06AB10 Escitalopram 4 S01AE01 Ofloxacin 3 C01BC04 Flecainide 4 S02AA16 Ofloxacin 3 N05AD01 Haloperidol 4 N05AH03 Olanzapine 3 J01MA12 Levofloxacin 3 G03XB51 C09BA13 J01RA13 J01RA09 3 49 J01RA07 A02BD06 A02BD07 A02BD09 A02BD05 A02BD04 D10AF52 A02BD10 J01RA05 4 4 4 4 S01AE05 Levofloxacin 4 N07BC02 Methadone J01MA14 Moxifloxacin 4 S01AE07 Moxifloxacin 4 A04AA01 Ondansetron 4 P01CX01 Pentamidine 4 N05AG02 Pimozide 4 N01AB08 Sevoflurane 4 N02AC52 4 50 C07AA07 Sotalol C07BA07 C07AA57 4 N05AL01 Sulpiride 4 L01XE12 Vandetanib 4 Appendix 4: AZCERT diagram for QT risk scores adopted from 21 51 Appendix 5: High potency (H) and low potency (L) 28 anticholinergic drugs: adopted from and adapted ATC Drug name ATC Risk combination score N06AA09 Amitriptyline N06CA01 H A03BA01 Atropine A03BA04 R06AB04 Belladonna alkaloids Chlorphenamine N06AA04 Clomipramine N05AH02 Clozapine R06AA02 Diphenhydramine S01FA01 A03CB03 A03CB02 A06AB30 R06AB54 ATC Drug name N05AH03 Olanzapine N02AA05 Oxycodone N06AB05 Paroxetine L N05AH04 L A02BA02 Quetiapine (fumarate) Ranitidine R03DA04 Theophylline H N05CD05 Triazolam L H R06AD01 Alimemazine L M03BX01 Baclofen L H N04BC01 Bromocriptine H H H H D04AA32 D04AA33 R06AA52 ATC combination Risk score L N02AA55 L A02BA07 L R03DB04 R03DA54 R03DA74 L N06AA12 Doxepin N05BB01 Hydroxyzine N05BB51 H N03AF01 Carbamazepine L N06AA02 Imipramine N06AA03 H R06AE07 Cetirizine L N05AA02 H N06AB04 Citalopram L R06AE05 Levomepromazin e Meclozine R05DA04 Codeine N06AA10 Nortriptyline H C01BA03 Disopyramide L G04BD04 Oxybutynin H A03FA03 Domperidone L A04AD01 Scopolamine (hyoscine) H N06AA16 Dosulepin L N04BX02 Entacapone L R06AE55 N05CM05 S01FA02 A04AD51 H G02CB01 N02AA59 N02AA79 L L G04BD07 Tolterodine H R06AX26 Fexofenadine L N04AA01 Trihexyphenidyl H N05AD01 Haloperidol L G04BD10 Darifenacin H M01AB15 Ketorolac S01BC05 L H A07DA03 Loperamide A07DA05 A07DA53 L R06AX13 Loratadine L N07BC02 Methadone L N06AX11 Mirtazapine L N02AA01 Morphine R06AA02 Dimenhydrinate G04BD02 Flavoxate R03BB01 Ipratropium N04AA04 Procyclidine R06AD02 Promethazine R06AC01 Pyrilamine H N06AX06 Nefanzodone L M03BX02 Tizanidine H N03AF02 Oxcarbazepine L A02BA01 Cimetidine L N06AF03 Phenelzine L Pimozide L L H R03AL01 R01AX03 R03AL02 H H D04AA10 R06AD52 V03AB05 A02BA51 H N03AE01 Clonazepam L N05AG02 N05BA01 Diazepam L N05AX08 Risperidone N02AB03 Fentanyl L N02AX02 Tramadol N06AB03 Fluoxetine N06AX05 Trazodone N06AB08 Fluvoxamine N01AH01 N01AH51 N06CA03 L L 52 N02AG01 A07DA52 N02AA51 R05DA05 N02AX52 L L L Appendix 6: ical list of drugs with anticholinergic (side-) effects by Rudolph et al. (available in Belgium): 31 adopted and adapted from ATC Drug name ATC combination Risk factor N06AA09 Amitriptyline hydrochloride N06CA01 3 A03BA01 Atropine producten S01FA01, A03CB03 3 R06AB02 Chlorpheniramine maleate R06AA02 Diphenhydramine hydrochloride D04AA32, D04AA33, R06AA52 3 N05BB01 Hydroxyzine hydrochloride N05BB51 3 N05BB01 Hydroxyzine pamoate 3 N06AA02 Imipramine hydrochloride 3 R06AE05 Meclozine hydrochloride 3 G04BD04 Oxybutynin chloride 3 R06AD02 Promethazine hydrochloride M03BX02 Tizanidine hydrochloride 3 M03BX01 Baclofen 2 R06AE07 Cetirizine hydrochloride 2 A02BA01 Cimetidine N05AH02 Clozapine A07DA03 Loperamide hydrochloride R06AX13 Loratadine 2 N06AA10 Nortriptyline hydrochloride 2 N05AH03 Olanzapine 2 R01BA02 Pseudoephedrine hydrochloride G04BD07 Tolterodine tartrate N04BA01 Carbidopa-levodopa N04BX02 Entacapone 1 N05AD01 Haloperidol 1 A03FA01 Metoclopramide hydrochloride 1 N06AX11 Mirtazapine 1 N06AB05 Paroxetine hydrochloride 1 N04BC05 Pramipexole dihydrochloride 1 N05AH04 Quetiapine fumarate 1 A02BA02 Ranitidine hydrochloride 1 N05AX08 Risperidone 1 N04BD01 Selegiline hydrochloride 1 N06AX05 Trazodone hydrochloride 1 3 D04AA10, R06AD52, V03AB05 A02BA51 3 2 2 A07DA05, A07DA53 R01BA52 2 2 2 N04BA02, N04BA03 53 1 Appendix 7: Complete drug list community-dwelling older adults ATC Drug name Freq % B01A B01AC06 B01AA03 B01AC04 B01AF01 B01AA07 B01AA04 B01AE07 B01AC07 B01AC30 B01AC05 B01AF02 B01AC24 B01AB06 B01AB05 B01AC22 C10A C10AA01 C10AA05 C10AA07 C10AB05 C10AA03 C10AX09 C10AX06 C10AA04 C10AB08 C10AA02 J07B J07BB02 J07BC01 C07A C07AB07 C07AB12 C07AA07 C07AG02 C07AB02 C07AA05 C07AB03 C07AB08 C07AB04 C07AA03 A02B A02BC02 A02BC01 A02BA02 A02BC05 A02BC03 A02BX13 A02BA01 A10B A10BA02 A10BB09 A10BX02 Antithrombotic agents Acetylsalicylic acid Warfarin Clopidogrel Rivaroxaban Acenocoumarol Phenprocoumon Dabigatran etexilate Dipyridamole Combinations Ticlopidine Apixaban Ticagrelor Nadroparin Enoxaparin Prasugrel Lipid modifying agents, plain Simvastatin Atorvastatin Rosuvastatin Fenofibrate Pravastatin Ezetimibe Omega-3-triglycerides incl. other esters and acids Fluvastatin Ciprofibrate Lovastatin Viral vaccines Influenza, inactivated, split virus or surface antigen Hepatitis B, purified antigen Beta blocking agents Bisoprolol Nebivolol Sotalol Carvedilol Metoprolol Propranolol Atenolol Celiprolol Acebutolol Pindolol Drugs for peptic ulcer and gastro-oesophageal reflux disease (GORD) Pantoprazole Omeprazole Ranitidine Esomeprazole Lansoprazole Alginic acid Cimetidine Blood glucose lowering drugs, excl. insulins Metformin Gliclazide Repaglinide 806 500 65 65 39 30 29 26 12 10 9 8 7 3 2 1 719 289 165 133 43 42 18 11 7.5 4.7 0.6 0.6 0.4 0.3 0.3 0.2 0.1 0.1 0.1 0.1 0.1 0.0 0.0 0.0 6.7 2.7 1.5 1.2 0.4 0.4 0.2 0.1 7 6 5 0.1 0.1 0.0 686 685 6.4 6.4 1 586 317 64 49 48 33 27 26 16 4 2 469 0.0 5.5 3.0 0.6 0.5 0.4 0.3 0.3 0.2 0.1 0.0 0.0 4.4 221 151 42 35 10 9 2 431 2.1 1.4 0.4 0.3 0.1 0.1 0.0 4.0 245 66 27 2.3 0.6 0.3 A10BB08 A10BH01 A10BB12 A10BB01 A10BD08 A10BH02 A10BH03 A10BH05 A10BX07 A10BD02 A10BD10 A10BG03 A10BX04 N05B N05BA06 N05BA12 N05BA08 N05BA11 N05BA01 N05BA21 N05BA05 N05BB01 N05BA04 N05BA09 N05BA22 N05BA18 N05BA16 N05BC01 N02B N02BE01 N02BE51 N02BA01 N02BA51 N05C N05CD06 N05CF02 N05CF01 N05CD01 N05CD09 N05CD05 N05CD11 N05CM09 N05CD03 N05CH01 N05CD02 N05CA06 N05CX N05CA02 N05CM N06A N06AX05 N06AB10 N06AA09 N06AB05 N06AX16 54 Gliquidone Sitagliptin Glimepiride Glibenclamide Metformin and vildagliptin Vildagliptin Saxagliptin Linagliptin Liraglutide Metformin and sulfonamides Metformin and saxagliptin Pioglitazone Exenatide Anxiolytics Lorazepam Alprazolam Bromazepam Prazepam Diazepam Clotiazepam Potassium clorazepate Hydroxyzine Oxazepam Clobazam Cloxazolam Ethyl loflazepate Nordazepam Meprobamate Other analgesics and antipyretics Paracetamol Paracetamol, combinations excl. psycholeptics Acetylsalicylic acid Acetylsalicylic acid, combinations excl. psycholeptics Hypnotics and sedatives Lormetazepam Zolpidem Zopiclone Flurazepam Brotizolam Triazolam Loprazolam Valerianae radix Flunitrazepam Melatonin Nitrazepam Secobarbital Hypnotics and sedatives in combination, excl. barbiturates Amobarbital Other hypnotics and sedatives Antidepressants Trazodone Escitalopram Amitriptyline Paroxetine Venlafaxine 25 21 11 6 6 6 6 6 2 1 1 1 1 0.2 0.2 0.1 0.1 0.1 0.1 0.1 0.1 0.0 0.0 0.0 0.0 0.0 330 121 98 44 15 12 12 8 7 4 3 3 2 1 1 329 3.1 1.1 0.9 0.4 0.1 0.1 0.1 0.1 0.1 0.0 0.0 0.0 0.0 0.0 0.0 3.1 303 16 2.8 0.1 6 4 0.1 0.0 315 122 104 23 13 11 10 7 7 6 4 3 2 2 2.9 1.1 1.0 0.2 0.1 0.1 0.1 0.1 0.1 0.1 0.0 0.0 0.0 0.0 1 1 0.0 0.0 273 49 41 30 27 20 2.6 0.5 0.4 0.3 0.3 0.2 N06AA16 N06AB04 N06AB06 N06AX11 N06AX21 N06AB03 N06AX03 N06AX12 N06AA10 N06AA12 N06AA04 N06AB08 N06AX25 A11C A11CC05 A11CC03 A11CC04 C09A C09AA04 C09AA03 C09AA05 C09AA06 C09AA01 C09AA02 C08C C08CA01 C08CA13 C08CA12 C08CA05 C08CA03 C08CA09 C08CA02 C08CA07 M01A M01AX05 M01AE01 M01AB05 M01AC01 M01AH01 M01AC06 M01AB16 M01AX01 M01AE02 M01AH05 M01AB14 M01AX25 M01AE12 M01AE52 M01AB01 M01AC02 M01AX26 A12A A12AX A12AA04 A12AA12 Dosulepin Citalopram Sertraline Mirtazapine Duloxetine Fluoxetine Mianserin Bupropion Nortriptyline Doxepin Clomipramine Fluvoxamine Hyperici herba Vitamin A and D, incl. combinations of the two Colecalciferol Alfacalcidol Calcitriol Ace inhibitors, plain Perindopril Lisinopril Ramipril Quinapril Captopril Enalapril Selective calcium channel blockers with mainly vascular effects Amlodipine Lercanidipine Barnidipine Nifedipine Isradipine Lacidipine Felodipine Nisoldipine Anti-inflammatory and antirheumatic products, non-steroids Glucosamine Ibuprofen Diclofenac Piroxicam Celecoxib Meloxicam Aceclofenac Nabumetone Naproxen Etoricoxib Proglumetacin Chondroitin sulfate Oxaprozin Naproxen and esomeprazole Indometacin Tenoxicam Avocado and soyabean oil, unsaponifiables Calcium Calcium, combinations with vitamin D and/or other drugs Calcium carbonate 16 16 16 15 15 9 8 4 2 2 1 1 1 253 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.0 0.0 0.0 0.0 0.0 0.0 2.4 246 6 1 236 105 70 43 8 6 4 225 2.3 0.1 0.0 2.2 1.0 0.7 0.4 0.1 0.1 0.0 2.1 114 55 33 12 5 3 2 1 225 1.1 0.5 0.3 0.1 0.0 0.0 0.0 0.0 2.1 A12AA A12AA12 A12AA20 R03A R03AK06 R03AK07 R03AL01 R03AC18 R03AK08 R03AC02 R03AL02 R03AC13 R03AC12 C03C C03CA02 C03CA01 C03CA04 A06A A06AD65 A06AD11 A06AC01 A06AD15 A06AB02 A06AB06 A06AB08 A06AG11 A06AX01 A06AA01 A06AB52 A06AB56 A06AC51 A06AB20 56 40 26 21 18 14 12 11 10 4 3 3 2 2 0.5 0.4 0.2 0.2 0.2 0.1 0.1 0.1 0.1 0.0 0.0 0.0 0.0 0.0 1 1 1 0.0 0.0 0.0 213 117 2.0 1.1 87 6 0.8 0.1 A06AC03 A06AC05 A06AD18 A06AG01 H03A H03AA01 N02A N02AX02 N02AX52 N02AB03 N02AA59 N02AE01 N02AA05 N02AX01 N02AA01 N02AA55 M04A M04AA01 M04AC01 M04AA03 C09C 55 Calcium acetate anhydrous Calcium Calcium acetate anhydrous Calcium (different salts in combination) Adrenergics, inhalants Salmeterol and fluticasone Formoterol and budesonide Fenoterol and ipratropium bromide Indacaterol Formoterol and beclometasone Salbutamol Salbutamol and ipratropium bromide Formoterol Salmeterol High-ceiling diuretics Bumetanide Furosemide Torasemide Drugs for constipation Macrogol, combinations Lactulose Ispaghula (psylla seeds) Macrogol Bisacodyl Senna glycosides Sodium picosulfate Laurilsulfate, incl. combinations Glycerol Liquid paraffin Bisacodyl, combinations Senna glycosides, combinations Ispaghula, combinations Contact laxatives in combination Sterculia Linseed Sorbitol Sodium phosphate Thyroid preparations Levothyroxine sodium Opioids Tramadol Tramadol, combinations Fentanyl Codeine, combinations excl. psycholeptics Buprenorphine Oxycodone Tilidine Morphine Oxycodone, combinations Antigout preparations Allopurinol Colchicine Febuxostat Angiotensin II antagonists, plain 1 1 1 0.0 0.0 0.0 194 59 47 33 1.8 0.6 0.4 0.3 15 14 0.1 0.1 12 9 0.1 0.1 4 1 193 116 76 1 170 72 25 13 13 12 9 7 3 0.0 0.0 1.8 1.1 0.7 0.0 1.6 0.7 0.2 0.1 0.1 0.1 0.1 0.1 0.0 3 2 2 2 0.0 0.0 0.0 0.0 2 1 0.0 0.0 1 1 1 1 168 168 161 55 36 29 15 0.0 0.0 0.0 0.0 1.6 1.6 1.5 0.5 0.3 0.3 0.1 9 8 7 1 1 160 138 16 6 144 0.1 0.1 0.1 0.0 0.0 1.5 1.3 0.1 0.1 1.3 C09CA01 C09CA06 C09CA08 C09CA03 C09CA04 C09CA07 C09CA02 S01E S01EE01 S01ED51 S01ED01 S01ED05 S01EC04 S01EE04 S01ED02 S01EA05 S01EE03 S01ED03 S01EA03 S01EC01 S01EC03 C01D C01DX12 C01DA02 C01DA08 C09D C09DA01 C09DA04 C09DB02 C09DA03 C09DA07 C09DA08 C09DA06 C09DX03 C09DB01 C09DX01 C09DA02 A11A A11AA03 A11AA04 A11AH02 G04C G04CA02 G04CA03 G04CA52 G04CX02 G04CA04 G04CB01 G04CB02 S01X Losartan Candesartan Olmesartan medoxomil Valsartan Irbesartan Telmisartan Eprosartan Antiglaucoma preparations and miotics Latanoprost Timolol, combinations Timolol Carteolol Brinzolamide Travoprost Betaxolol Brimonidine Bimatoprost Levobunolol Apraclonidine Acetazolamide Dorzolamide Vasodilators used in cardiac diseases Molsidomine Glyceryl trinitrate Isosorbide dinitrate Angiotensin II antagonists, combinations Losartan and diuretics Irbesartan and diuretics Olmesartan medoxomil and amlodipine Valsartan and diuretics Telmisartan and diuretics Olmesartan medoxomil and diuretics Candesartan and diuretics Olmesartan medoxomil, amlodipine and hydrochlorothiazide Valsartan and amlodipine Valsartan, amlodipine and hydrochlorothiazide Eprosartan and diuretics Multivitamins, combinations Multivitamins and other minerals, incl. combinations Multivitamins and trace elements Multivitamins, combinations Drugs used in benign prostatic hypertrophy Tamsulosin Terazosin Tamsulosin and dutasteride Sabalis serrulatae fructus Silodosin Finasteride Gutasteride Other ophthalmologicals 44 23 23 22 12 11 9 139 0.4 0.2 0.2 0.2 0.1 0.1 0.1 1.3 37 29 15 15 11 10 7 5 5 2 1 1 1 121 0.3 0.3 0.1 0.1 0.1 0.1 0.1 0.0 0.0 0.0 0.0 0.0 0.0 1.1 89 19 13 115 0.8 0.2 0.1 1.1 20 15 15 0.2 0.1 0.1 10 10 10 0.1 0.1 0.1 9 9 0.1 0.1 8 5 0.1 0.0 4 113 109 0.0 1.1 1.0 2 0.0 2 0.0 102 1.0 47 20 13 13 4 4 1 94 0.4 0.2 0.1 0.1 0.0 0.0 0.0 0.9 S01XA20 M05B M05BA04 M05BX04 M05BB03 M05BA06 M05BA07 M05BA08 M05BB04 M05BX03 R03B R03BB04 R03BA02 R03BA01 R03BB01 R03BA05 R03BB06 A10A A10AD05 A10AE04 A10AD01 A10AB05 A10AC01 A10AD04 A10AB01 A10AB04 A10AB06 A10AE05 C01B C01BD01 C01BC04 C01BC03 C01BA03 C01BG07 C09B C09BB04 C09BA03 C09BA04 C09BB05 C09BB02 C09BA02 C09BA08 N07C N07CA01 N07CA02 N07CA03 N07CA52 C03D C03DA01 C07B C07BB07 C07BB12 C07BB04 56 Artificial tears and other indifferent preparations Drugs affecting bone structure and mineralization Alendronic acid Denosumab Alendronic acid and colecalciferol Ibandronic acid Risedronic acid Zoledronic acid Risedronic acid, calcium and colecalciferol, sequential Strontium ranelate Other drugs for obstructive airway diseases, inhalants Tiotropium bromide Budesonide Beclometasone Ipratropium bromide Fluticasone Glycopyrronium bromide Insulines and analogues Insulin aspart Insulin glargine Insulin (human) Insulin aspart Insulin (human) Insulin lispro Insulin (human) Insulin lispro Insulin glulisine Insulin detemir Antiarrhythmics, class I and III Amiodarone Flecainide Propafenone Disopyramide Cibenzoline Ace inhibitors, combinations Perindopril and amlodipine Lisinopril and diuretics Perindopril and diuretics Ramipril and felodipine Enalapril and lercanidipine Enalapril and diuretics Cilazapril and diuretics Antivertigo preparations Betahistine Cinnarizine Flunarizine Cinnarizine, combinations Potassium-sparing agents Spironolactone Beta blocking agents and thiazides Bisoprolol and thiazides Nebivolol and thiazides Acebutolol and thiazides 94 0.9 93 0.9 30 24 18 0.3 0.2 0.2 7 6 5 2 0.1 0.1 0.0 0.0 1 0.0 91 0.9 60 15 5 5 4 2 86 22 19 12 10 6 5 4 4 3 1 84 0.6 0.1 0.0 0.0 0.0 0.0 0.8 0.2 0.2 0.1 0.1 0.1 0.0 0.0 0.0 0.0 0.0 0.8 46 29 7 1 1 84 31 23 20 4 3 2 1 0.4 0.3 0.1 0.0 0.0 0.8 0.3 0.2 0.2 0.0 0.0 0.0 0.0 83 71 10 1 1 78 78 74 0.8 0.7 0.1 0.0 0.0 0.7 0.7 0.7 69 4 1 0.6 0.0 0.0 N03A N03AE01 N03AX12 N03AX16 N03AF01 N03AG01 N03AX09 N03AA03 N03AA02 N03AX11 N03AX14 N03AB02 A12C A12CC10 A12CB01 A12CB02 A12CC03 A12CC04 A12CE R05C R05CB01 R05CB02 R05CB03 R05CB15 R05CA03 R05CA10 R06A R06AE07 R06AE09 R06AX27 R06AX22 R06AE05 R06AB03 R06AX28 R06AX29 R06AA02 R06AA52 R06AD01 R06AX13 R06AX17 R06AX25 R06AX26 R01A R01AD09 R01AD12 R01AA07 R01AD08 R01AA05 R01AA09 R01AD52 R01AA03 R01AA08 R01AB01 R01AB06 R01AX10 R01AB02 Antiepileptics Clonazepam Gabapentin Pregabalin Carbamazepine Valproic acid Lamotrigine Primidone Phenobarbital Topiramate Levetiracetam Phenytoin Other mineral supplements Magnesium oxide Zinc sulfate Zinc gluconate Magnesium gluconate Magnesium citrate Selenium Expectorants, excl. combinations with cough suppressants Acetylcysteine Bromhexine Carbocisteine Erdosteine Guaifenesin Combinations (expectorants) Antihistamines for systemic use Cetirizine Levocetirizine Desloratadine Ebastine Meclozine Dimetindene Rupatadine Bilastine Diphenhydramine Diphenhydramine, combinations Alimemazine Loratadine Ketotifen Mizolastine Fexofenadine Decongestantsand other nasal preparations for topical use Mometasone Fluticasone furoate Xylometazoline Fluticasone Oxymetazoline Tramazoline Prednisolone, combinations Ephedrine Naphazoline Phenylephrine Xylometazoline Other nasal preparations Naphazoline 74 20 19 9 6 5 5 3 2 2 2 1 73 66 3 1 1 1 1 71 0.7 0.2 0.2 0.1 0.1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.7 0.6 0.0 0.0 0.0 0.0 0.0 0.7 R01AD05 R01AD53 55 5 5 4 1 1 0.5 0.0 0.0 0.0 0.0 0.0 C03EA04 71 0.7 25 15 11 4 3 2 2 2 1 1 0.2 0.1 0.1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1 1 1 1 1 69 0.0 0.0 0.0 0.0 0.0 0.6 C05C C05CA53 C05CA04 C05CX C05CX02 C05CA03 H02A H02AB04 H02AB06 H02AB09 H02AB01 H02AA02 H02AB02 H02AB08 C03E C03EA01 V06X V06XX02 N04B N04BA02 N04BD02 N04BC05 N04BA03 N04BC04 N04BB01 N04BC01 M02A M02AA15 M02AC M02AA06 M02AA10 M02AX10 M02AA13 C02A 22 13 7 6 3 3 3 2 2 2 2 2 1 0.2 0.1 0.1 0.1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 C02AC05 C02AC01 A03F A03FA03 A03FA01 A03FA05 A11D A11DB A11DA01 57 Budesonide Dexamethasone, combinations Capillary stabilizing agents Diosmin, combinations Troxerutin Other capillary stabilizing agents Naftazone Diosmin Corticosteroids for systemic use, plain Methylprednisolone Prednisolone Hydrocortisone Betamethasone Fludrocortisone Dexamethasone Triamcinolone Diuretics and potassiumsparing agents in combination Altizide and potassiumsparing agents Hydrochlorothiazide and potassium-sparing agents General nutrients Dopaminergic agents Levodopa and decarboxylase inhibitor Rasagiline Pramipexole Levodopa, decarboxylase inhibitor and COMT inhibitor Ropinirole Amantadine Bromocriptine Topical products for joint and muscular pain Diclofenac Preparations with salicylic acid derivatives Etofenamate Ketoprofen Other topical products for joint and muscular pain Ibuprofen Antiadrenergic agents, centrally acting Moxonidine Clonidine Propulsives Domperidone Metoclopramide Alizapride Vitamin B1, plain and in combination with vitamin B6 and B12 Vitamin B1 in combination with vitamin B6 and/or Vitamin B12 1 1 0.0 0.0 66 35 21 7 0.6 0.3 0.2 0.1 2 1 66 0.0 0.0 0.6 37 14 7 4 2 1 1 59 0.3 0.1 0.1 0.0 0.0 0.0 0.0 0.6 49 0.5 10 0.1 57 57 53 27 0.5 0.5 0.5 0.3 9 6 4 0.1 0.1 0.0 4 2 1 52 0.0 0.0 0.0 0.5 26 8 0.2 0.1 7 7 3 0.1 0.1 0.0 1 50 0.0 0.5 49 1 47 35 9 3 47 0.5 0.0 0.4 0.3 0.1 0.0 0.4 43 0.4 4 0.0 thiamine (vit B1) N05A N05AL01 N05AX07 N05AH04 N05AF01 N05AA02 N05AD01 N05AH02 N05AH03 N05AL05 N05AN01 N05AX08 N05AX13 G04B G04BD04 G04BD06 G04BD08 G04BD11 G04BX G04BD07 G04BE09 G04BD12 G04BE01 G04BE03 G04BE08 G04BX06 C01A C01AA05 C01AA08 C03B C03BA11 C03BA04 L04A L04AX03 L04AA13 L04AB04 L04AD02 L04AX01 L04AA06 L04AC07 L04AD01 L04AB01 L04AB02 L04AB06 L04AX02 R03D R03DC03 R03DA04 C08D C08DB01 C08DA01 B03B B03BB01 B03BA01 A02A A02AD01 Antipsychotics Sulpiride Prothipendyl Quetiapine Flupentixol Levomepromazine Haloperidol Clozapine Olanzapine Amisulpride Lithium Risperidone Paliperidone Urologicals Oxybutynin Propiverine Solifenacin Fesoterodine Other urologicals Tolterodine Vardenafil Mirabegron Alprostadil Sildenafil Tadalafil Phenazopyridine Cardiac glucosides Digoxin Metildigoxin Low-ceiling diuretics, excl. thiazides Indapamide Chlortalidone Immunosuppressants Methotrexate Leflunomide Adalimumab Tacrolimus Azathioprine Mycophenolic acid Tocilizumab Ciclosporin Etanercept Infliximab Golimumab Thalidomide Other systemic drugs for obstructive airway diseases Montelukast Theophylline Selective calcium channel blockers with direct cardiac effects Diltiazem Verapamil Vitamin B12 and folic acid Folic acid Cyanocobalamin Antacids Ordinary salt combinations A02AH 47 23 9 5 2 1 1 1 1 1 1 1 1 46 17 8 6 3 3 2 2 1 1 1 1 1 45 40 5 45 0.4 0.2 0.1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.4 0.2 0.1 0.1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.4 0.4 0.0 0.4 40 5 44 19 4 4 4 3 2 2 2 1 1 1 1 39 0.4 0.0 0.4 0.2 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.4 21 18 38 0.2 0.2 0.4 33 5 36 32 4 35 23 0.3 0.0 0.3 0.3 0.0 0.3 0.2 A02AD02 G03C G03CA04 G03CA03 G03CX01 A07F A07FA02 A07FA51 A07FA01 A07FA B03A B03AA07 B03AA03 B03AB02 B03AC B03AD02 B03AE02 N06C N06CA02 A03A A03AB06 A03AA04 A03AD01 D07A D07AC01 D07AB02 D07AD01 D07AC13 D07AC06 D07AC14 J07A J07AL01 J07AM51 J07AX N06D N06DX02 N06DA02 N06DA03 N06DX01 A07D A07DA03 D01A D01AC02 D01AA20 D01AC08 D01AC20 58 Antacids with sodium bicarbonate Magaldrate Estrogens Estriol Estradiol Tibolone Antidiarrheal microorganisms Saccharomyces boulardii Lactic acid producing organisms, combinations Lactic acid producing organisms Antidiarrheal microorganisms Iron preparations Ferrous sulfate Ferrous gluconate Saccharated iron oxide Iron, parenteral preparations Ferrous fumarate Iron, multivitamins and folic acid Psycholeptics and psychoanaleptics in combination Melitracen and psycholeptics Drugs for functional gastrointestinal disorders Otilonium bromide Mebeverine Papaverine Corticosteroids, plain Betamethasone Hydrocortisone butyrate Clobetasol Mometasone Diflucortolone Methylprednisolone aceponate Bacterial vaccines Pneumococcus, purified polysaccharides antigen tetanus toxoid, combinations with Diphtheria toxoid Other bacterial vaccines Anti-dementia drugs Ginkgo folium Donepezil Rivastigmine Memantine Antipropulsives Loperamide Antifungals for topical use Miconazole Antibiotics combinations Ketoconazole Imidazole and triazole derivatives, combinations 10 0.1 2 32 19 9 4 31 0.0 0.3 0.2 0.1 0.0 0.3 14 10 0.1 0.1 4 0.0 3 0.0 31 23 3 2 1 0.3 0.2 0.0 0.0 0.0 1 1 0.0 0.0 29 0.3 29 0.3 27 0.3 14 11 2 27 9 6 6 4 1 1 0.1 0.1 0.0 0.3 0.1 0.1 0.1 0.0 0.0 0.0 27 19 0.3 0.2 4 0.0 4 27 17 7 2 1 26 26 25 11 4 3 3 0.0 0.3 0.2 0.1 0.0 0.0 0.2 0.2 0.2 0.1 0.0 0.0 0.0 D01AC52 D01AA01 R05D R05DA R05DA09 R05DA04 R05DB13 R05DB R05DB21 J01X J01XX01 J01XE01 J01XE02 L02B L02BB03 L02BG04 L02BA01 L02BG03 L02BG06 A11J A11JA A11JC J01C J01CR02 J01CA04 J01CF05 S01A S01AA12 S01AA13 S01AA30 S01AA02 S01AD03 S01AE01 J01F J01FA10 J01FA09 J01FF01 N06B N06BX03 N06BC01 N06BX18 V03A V03AE01 V03AN01 V03AE02 V03AE04 R05F Miconazole, combinations Nystatin Cough suppressants, excl. combinations with expectorants Opium alkaloids and derivatives Dextromethorphan Codeine Butamirate Other cough suppressants Cloperastine Other antibacterials Fosfomycin Nitrofurantoin Nifurtoinol Hormone antagonists and related agents Bicalutamide Letrozole Tamoxifen Anastrozole Exemestane Other vitamin products, combinations Combinations of vitamins Vitamins, other combinations Beta-lactam antibacterials, penicillins Amoxicillin and enzyme inhibitor Amoxicillin Flucloxacillin Anti-infectives Tobramycin Fusidic acid Combinations of different antibiotics Chlortetracycline Aciclovir Ofloxacin Macrolides, lincosamides and streptogramins Azithromycin Clarithromycin Clindamycin Psychostimulants, agents used for ADHD and nootropics Piracetam Caffeine Vinpocetine All other therapeutic products Polystyrene sulfonate Oxygen Sevelamer Calcium acetate and magnesium carbonate Cough suppressants and expectorants, combinations 3 1 24 0.0 0.0 0.2 R05FA02 8 0.1 7 5 2 1 1 23 13 5 5 23 0.1 0.0 0.0 0.0 0.0 0.2 0.1 0.0 0.0 0.2 7 6 5 3 2 18 0.1 0.1 0.0 0.0 0.0 0.2 11 7 0.1 0.1 17 0.2 9 0.1 7 1 17 6 4 3 0.1 0.0 0.2 0.1 0.0 0.0 A01AB12 A01AB09 A01AB11 2 1 1 16 0.0 0.0 0.0 0.1 C10B 9 5 2 16 0.1 0.0 0.0 0.1 14 1 1 16 0.1 0.0 0.0 0.1 7 5 3 1 0.1 0.0 0.0 0.0 15 0.1 S01B S01BC01 S01BA01 S01BC03 S01BA04 M09A M09AA01 M09AX01 S01C S01CA01 S01CC01 A03B A03BB01 A03BA04 A03BB01 C05B C05BA01 C07C C07CB03 C07CA03 A01A A01AD11 C10BA02 C04A C04AX21 C04AE01 C04AD03 D06A D06AX01 D06AX09 D06AA03 D06AX05 H03B H03BB02 H03BA02 L02A L02AE02 L02AE04 L02AE03 L02AB02 C01E C01EB09 C01EB09 59 Opium derivatives and expectorants Antiinflammatory agents Indometacin Dexamethasone Diclofenac Prednisolone Other drugs for disorders of the musculo-skeletal system Hydroquinine Hyaluronic acid Antiinflammatory agents and antiinfectives in combination Dexamethasone and antiinfectives Diclofenac and antiinfectives Belladonna and derivates, plain Butylscopolamine Belladonna total alkaloids Butylscopolamine Antivaricose therapy Organo-heparinoid Beta blocking agents and other diuretics Atenolol and other diuretics Pindolol and other diuretics Stomatological preparations Hexetidine Miconazole Various anti-infectives and antiseptics for local oral treatment Various (Other agents for local oral treatment) Lipid modifying agents, combinations Simvastatin and ezetimibe Peripheral vasodilators Naftidrofuryl Ergoloid mesylates Pentoxifylline Antibiotics for topical use Fusidic acid Mupirocin Oxytetracycline Bacitracin Antithyroid preparations Thiamazole Propylthiouracil Hormones and related agents Leuprorelin Triptorelin Goserelin Medroxyprogesterone Other cardiac preparations Ubidecarenone Ubidecarenone 15 0.1 15 10 2 2 1 14 0.1 0.1 0.0 0.0 0.0 0.1 13 1 14 0.1 0.0 0.1 13 0.1 1 0.0 13 0.1 11 1 1 12 12 12 0.1 0.0 0.0 0.1 0.1 0.1 10 2 11 0.1 0.0 0.1 5 3 2 0.0 0.0 0.0 1 0.0 11 0.1 11 10 7 2 1 10 5 3 1 1 10 9 1 10 0.1 0.1 0.1 0.0 0.0 0.1 0.0 0.0 0.0 0.0 0.1 0.1 0.0 0.1 4 3 2 1 9 4 3 0.0 0.0 0.0 0.0 0.1 0.0 0.0 C01EB04 C01EB17 C05A C05AA04 C05AA12 C05AX03 C05AE01 A05A A05AX A05AA02 A05AX02 C09X C09XA02 C09XA52 G03X G03XC01 J01M J01MA14 J01MA06 J01MA12 J01MA01 A11G A11GA01 G03D G03DA04 L01X L01XX05 L01XE02 L01XE08 A07E A07EA06 A07EC02 A14A A14AB01 A14AA07 R02A R02AA20 R02AA05 R02AB03 D07C D07CC01 D07CA01 D08A D08AG02 D08AC02 D08AC52 D08AX02 Crataegus glycosides Ivabradine Agents for treatment of hemorrhoids and anal fissures for topical use Prednisolone Triamcinolone Other preparations, combinations Glyceryl trinitrate Bile therapy Other drugs for bile therapy Ursodeoxycholic acid Hymecromone Other agents acting on the renin-angiotensin system Aliskiren Aliskiren and hydrochlorothiazide Other sex hormones and modulators of the genital system Raloxifene Quinolone antibacterials Moxifloxacin Norfloxacin Levofloxacin Ofloxacin Ascorbic acid (vitamin C), incl. combinations Ascorbic acid (vit C) Progestogens Progesterone Other antineoplastic agents Hydroxycarbamide Gefitinib Nilotinib Intestinal antiinflammatory agents Budesonide Mesalazine Anabolic steroids Nandrolone Prasterone Throat preparations Antiseptics Chlorhexidine Fusafungine Corticosteroids, combinations with antibiotics Betamethasone and antibiotics Hydrocortisone and antibiotics Antiseptics and disinfectants Povidone-iodine Chlorhexidine Chlorhexidine, combinations Eosin 1 1 9 0.0 0.0 0.1 L01B L01BA01 L01BC02 N02C N02CC01 N02CC02 N02CX02 R01B 3 3 2 0.0 0.0 0.0 1 8 5 2 1 8 0.0 0.1 0.0 0.0 0.0 0.1 6 2 0.1 0.0 8 0.1 8 8 3 2 2 1 7 0.1 0.1 0.0 0.0 0.0 0.0 0.1 7 7 7 7 0.1 0.1 0.1 0.1 5 0 0 6 0.0 0.0 0.0 0.1 5 1 6 4 2 6 3 2 1 5 0.0 0.0 0.1 0.0 0.0 0.1 0.0 0.0 0.0 0.0 4 0.0 D06BB03 D06BA01 J01A J01AA02 J01E 1 0.0 J01EE01 5 0.0 M03B 2 1 1 0.0 0.0 0.0 M03BB03 M03BB53 1 0.0 R01BA52 R01BA02 R01BA53 A09A A09AA02 A11H A11HA03 A11HA04 J02A J02AC01 J05A J05AB01 N07A N07AA02 N07AB02 P01B P01BA02 A07A A07AA06 B03X B03XA02 C02D C02DB01 C07F C07FB02 D02A D02AE01 D02AB D06B 60 Antimetabolites Methotrexate Fluorouracil Antimigraine preparations Sumatriptan Naratriptan Clonidine Nasal decongestants for systemic use Pseudoephedrine, combinations Pseudoephedrine Phenylephrine, combinations Digestives, incl.enzymes Multienzymes (lipase, protease etc.) Other plain vitamin preparations Tocopherol (vit E) riboflavin (vit B2) Antimycotics for systemic use Fluconazole Direct acting antivirals Aciclovir Parasympathomimetics Pyridostigmine Bethanechol Antimalarials Hydroxychloroquine Intestinal anti-infectives Paromomycin Other antianemic preparations Darbepoetin alfa Arteriolar smooth muscle, agents acting on Dihydralazine Beta blocking agents and other antihypertensives Metoprolol and other antihypertensives Emollients and protectives Carbamide Zinc products Chemotherapeutics for topical use Aciclovir Silver sulfadiazine Tetracyclines Doxycycline Sulfonamides and trimethoprim Sulfamethoxazole and trimethoprim Muscle relaxants, centrally acting agents Chlorzoxazone Chlorzoxazone, combinations excl. psycholeptics 5 4 1 5 3 1 1 5 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 3 0.0 1 1 0.0 0.0 4 4 0.0 0.0 4 0.0 2 2 4 0.0 0.0 0.0 4 4 4 4 3 1 4 4 3 3 3 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 3 3 0.0 0.0 3 3 0.0 0.0 3 0.0 3 2 1 3 0.0 0.0 0.0 0.0 2 1 3 3 3 0.0 0.0 0.0 0.0 0.0 3 0.0 3 0.0 1 1 0.0 0.0 M03BX01 Baclofen 1 0.0 D03BA52 Collagenase, combinations 1 0.0 S01G Decongestants and antiallergics Levocabastine Azelastine Intestinal adsorbents Medicinal charcoal Attapulgite Potassium Potassium chloride Potassium citrate Tonics 3 0.0 D04A 1 0.0 2 1 2 1 1 2 1 1 2 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1 1 0.0 0.0 1 1 1 1 0.0 0.0 0.0 0.0 Other alimentary tract and metabolism products Anethole trithione Antipsoriatics for topical use Calcipotriol, combinations Other gynecologicals Cimicifugae rhizoma Antiandrogens Cyproterone Anti-parathyroid agents Calcitonin (salmon synthetic) Cinacalcet Alkylating agents Chlorambucil Busulfan Anesthetics, general 2 0.0 1 1 0.0 0.0 2 2 2 0.0 0.0 0.0 2 2 2 2 2 1 1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1 1 0.0 0.0 1 1 0.0 0.0 1 1 0.0 0.0 2 1 1 2 2 2 0.0 0.0 0.0 0.0 0.0 0.0 1 1 1 0.0 0.0 0.0 1 0.0 2 2 0.0 0.0 1 1 0.0 0.0 2 0.0 2 1 1 1 1 1 1 1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1 1 1 1 1 1 1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1 1 1 0.0 0.0 0.0 1 0.0 1 0.0 1 1 1 1 0.0 0.0 0.0 0.0 1 1 0.0 0.0 Antipruritics, incl. antihistamines, anesthetics, etc. Lidocaine Corticosteroids, other combinations Betamethasone Medicated dressings Fusidic acid Anti-acne preparations for systemic use Isotretinoin Anti-infectives and antiseptics, excl. combinations with corticosteroids Miconazole Progestogens and estrogens in combination Norgestrel and estrogen Posterior pituitary lobe hormones Desmopressin Parathyroid hormones and analogues Teriparatide Amphenicols Thiamphenicol, combinations Other beta-lactam antibacterials Cefuroxime Drugs for treatment of tuberculosis Isoniazid Immunostimulants BCG vaccine Anticholinergic agents Trihexphenidyl Adrenergics for systemic use Salbutamol Mydriatics and cycloplegics Tropicamide Ocular vascular disorder agents Ranibizumab Anti-infectives Ciprofloxacin Corticosteroids and antiinfectives in combination Hydrocortisone and antiinfectives 1 0.0 1 1 0.0 0.0 107 05 100 S01GX02 S01GX07 A07B A07BA01 A07BC04 A12B A12BA01 A12BA02 A13A A16A A16AX02 D05A D05AX52 G02C G02CX04 G03H G03HA01 H05B H05BA01 H05BX01 L01A L01AA02 L01AB01 N01A N01AX25 N07B N07BA01 S02C S02CA07 S02D S02DA01 S02DC A05B A05BA03 A11B A11BA A11E A11EB C01C C01CA01 D01B D01BA02 D03B Drugs used in addictive disorders Nicotine Corticosteroids and antiinfectives in combination Fludrocortisone and antiinfectives Other otologicals Lidocaine Indifferent preparations Liver therapy, lipotropics Silymarin Multivitamins, plain Multivitamins, plain Vitamin B-complex, incl. combinations Vitamin B-complex with vitamin C Cardiac stimulants excl. cardiac glycosides Etilefrine Antifungals for systemic use Terbinafine Enzymes D04AB01 D07X D07XC01 D09A D09AA02 D10B D10BA01 G01A G01AF04 G03F G03FB01 H01B H01BA02 H05A H05AA02 J01B J01BA52 J01D J01DC02 J04A J04AC01 L03A L03AX03 N04A N04AA01 R03C R03CC02 S01F S01FA06 S01L S01LA04 S03A S03AA07 S03C S03CA04 Total 61 Appendix 8: complete drug list institutionalized older adults ATC code Drug name Freq % B01A B01AC06 B01AB05 B01AA03 B01AB06 B01AC04 B01AF01 B01AA04 B01AA07 B01AE07 B01AB10 B01AC05 B01AC07 B01AC24 B01AC30 A06A A06AD65 A06AD11 A06AG10 A06AG01 A06AD15 A06AB08 A06AB02 A06AG11 A06AX01 A06AD17 A06AD18 A06AA01 A06AB52 A06AB56 A02B A02BC02 A02BC01 A02BA02 A02BC05 A02BC03 A02BX13 N06A N06AX05 N06AB10 N06AX11 N06AB06 N06AA09 N06AB04 N06AX16 N06AX21 N06AB05 N06AX12 Antithrombotic agents Acetylsalicylic acid Enoxaparin Warfarin Nadroparin Clopidogrel Rivaroxaban Phenprocoumon Acenocoumarol Dabigatran etexilate Tinzaparin Ticlopidine Dipyridamole Ticagrelor Platelet aggregation inhibitors excl. Heparin combinations Drugs for constipation Macrogol, combinations Lactulose Docusate sodium, incl. combinations Sodium phosphate Macrogol Sodium picosulfate Bisacodyl Laurilsulfate, incl. combinations Glycerol Sodium phosphate Sorbitol Liquid paraffin Bisacodyl, combinations Senna glycosides, combinations Drugs for peptic ulcer and gastro-oesophageal reflux disease (GORD) Pantoprazole Omeprazole Ranitidine Esomeprazole Lansoprazole Alginic acid Antidepressants Trazodone Escitalopram Mirtazapine Sertraline Amitriptyline Citalopram Venlafaxine Duloxetine Paroxetine Bupropion 295 158 38 26 21 21 10 5 5 3 2 2 2 1 1 63 3.4 0.8 0.6 0.5 0.5 0.2 0.1 0.1 0.1 0.0 0.0 0.0 0.0 0.0 276 153 54 24 5.9 3.3 1.2 0.5 11 9 5 4 4 0.2 0.2 0.1 0.1 0.1 4 2 2 1 1 1 0.1 0.0 0.0 0.0 0.0 0.0 212 4.6 118 46 36 10 1 1 211 55 51 25 16 14 13 7 7 5 4 2.5 1.0 0.8 0.2 0.0 0.0 4.5 1.2 1.1 0.5 0.3 0.3 0.3 0.2 0.2 0.1 0.1 N06AB03 N06AA10 N06AX03 N02B N02BE01 N02BE51 N02BA01 C07A C07AB07 C07AB02 C07AA05 C07AA07 C07AB12 C07AB03 C07AB08 C07AG02 C03C C03CA02 C03CA01 N05C N05CD06 N05CF02 N05CD03 N05CF01 N05CM09 N05CD05 N05CD01 N05CM05 N05CD09 N05CD11 N05CM N05CX N05A N05AH04 N05AX08 N05AD01 N05AH03 N05AL01 N05AD05 N05AH02 N05AA02 N05AD07 N05AH06 N05AL05 N05AN01 N05AX12 N05B N05BA06 N05BA12 N05BA08 N05BA05 N05BB01 N05BA01 N05BA11 62 Fluoxetine Nortriptyline Mianserin Other analgesics and antipyretics Paracetamol Paracetamol, combinations Acetylsalicylic acid Beta blocking agents Bisoprolol Metoprolol Propranolol Sotalol Nebivolol Atenolol Celiprolol Carvedilol High-ceiling diuretics Bumetanide Furosemide Hypnotics and sedatives Lormetazepam Zolpidem Flunitrazepam Zopiclone Valerianae radix Triazolam Flurazepam Scopolamine Brotizolam Loprazolam Other hypnotics and sedatives Hypnotics and sedatives in combination, excl. barbiturates Antipsychotics Quetiapine Risperidone Haloperidol Olanzapine Sulpiride Pipamperone Clozapine Levomepromazine Benperidol Clotiapine Amisulpride Lithium Aripiprazole Anxiolytics Lorazepam Alprazolam Bromazepam Potassium clorazepate Hydroxyzine Diazepam Prazepam 3 2 1 166 0.1 0.0 0.0 3.6 159 5 2 163 112 10 9 9 9 6 2 2 148 74 73 144 76 45 5 4 4 3 2 2 1 1 1 3.4 0.1 0.0 3.5 2.4 0.2 0.2 0.2 0.2 0.1 0.0 0.0 3.2 1.6 1.6 3.1 1.6 1.0 0.1 0.1 0.1 0.1 0.0 0.0 0.0 0.0 0.0 1 0.0 131 36 34 19 13 7 6 6 2 2 2 2 1 1 121 43 35 16 9 5 4 3 2.8 0.8 0.7 0.4 0.3 0.2 0.1 0.1 0.0 0.0 0.0 0.0 0.0 0.0 2.6 0.9 0.8 0.3 0.2 0.1 0.1 0.1 N05BA04 N05BA21 N05BA09 N05BA22 N02A N02AX02 N02AB03 N02AX52 N02AE01 N02AA01 N02AA05 N02AA59 N02AX01 N02AA03 A12A A12AX A12AA04 A12AA12 A12AA20 A10B A10BA02 A10BB08 A10BB09 A10BH01 A10BX02 A10BB12 A10BB01 R03A R03AL01 R03AK06 R03AC02 R03AL02 R03AK07 R03AC18 R03AK08 R03AC13 C10A C10AA01 C10AA05 C10AA07 C10AA03 C10AB08 C10AA04 C10AX09 J01C J01CR02 J01CA04 J01CF05 J01CA01 J01CE08 Oxazepam Clotiazepam Clobazam Cloxazolam Opioids Tramadol Fentanyl Tramadol, combinations Buprenorphine Morphine Oxycodone Codeine, combinations excl. psycholeptics Tilidine Hydromorphone Calcium Calcium with vitamin D Calcium carbonate Calcium acetate anhydrous Calcium (different salts) Blood glucose lowering drugs, excl. insulins Metformin Gliquidone Gliclazide Sitagliptin Repaglinide Glimepiride Glibenclamide Adrenergics, inhalants Fenoterol and ipratropium bromide Salmeterol and fluticasone Salbutamol Salbutamol and ipratropium bromide Formoterol and budesonide Indacaterol Formoterol and beclometasone Formoterol Lipid modifying agents, plain Simvastatin Atorvastatin Rosuvastatin Pravastatin Ciprofibrate Fluvastatin Ezetimibe Beta-lactam antibacterials, penicillins Amoxicillin and enzyme inhibitor Amoxicillin Flucloxacillin Ampicillin Benzathine benzylpenicillin 2 2 1 1 111 36 30 22 9 8 3 3 0.0 0.0 0.0 0.0 2.4 0.8 0.6 0.5 0.2 0.2 0.1 0.1 2 1 106 95 9 3 1 98 0.0 0.0 2.3 2.0 0.2 0.1 0.0 2.1 57 17 16 4 3 2 1 96 28 1.2 0.4 0.3 0.1 0.1 0.0 0.0 2.1 0.6 23 14 13 0.5 0.3 0.3 9 5 5 0.2 0.1 0.1 1 93 0.0 2.0 46 26 10 7 3 1 1 88 1.0 0.6 0.2 0.2 0.1 0.0 0.0 1.9 41 0.9 40 5 1 1 0.9 0.1 0.0 0.0 C08C C08CA01 C08CA13 C08CA12 C08CA05 C08CA07 C08CA09 C08CA02 C09A C09AA03 C09AA04 C09AA05 C09AA06 C09AA01 C09AA02 D01A D01AC02 D01AC52 D01AA20 D01AC08 D01AC20 R05C R05CB01 R05CB03 R05CB06 R05CA03 R05CB15 R05CA10 R05CB02 A11C A11CC05 A11CC03 N04B N04BA02 N04BA03 N04BD02 N04BC05 N04BC04 N04BD01 D02A D02AB D02AE01 A03F A03FA03 A03FA01 A03FA05 J01M J01MA14 63 Selective calcium channel blockers with mainly vascular effects Amlodipine Lercanidipine Barnidipine Nifedipine Nisoldipine Lacidipine Felodipine Ace inhibitors, plain Lisinopril Perindopril Ramipril Quinapril Captopril Enalapril Antifungals for topical use Miconazole Miconazole, combinations Antibiotics combinations Ketoconazole Imidazole and triazole derivatives combinations Expectorants, excl. combinations with cough suppressants Acetylcysteine Carbocisteine Ambroxol Guaifenesin Erdosteine Combinations expectorantia Bromhexine Vitamin A and D, incl. combinations of the two Colecalciferol Alfacalcidol Dopaminergic agents Levodopa and decarboxylase inhibitor Levodopa, decarboxylase inhibitor and COMT inhibitor Rasagiline Pramipexole Ropinirole Selegiline Emollients and protectives Zinc products Carbamide Propulsives Domperidone Metoclopramide Alizapride Quinolone antibacterials Moxifloxacin 79 1.7 59 6 5 3 3 2 1 79 34 27 10 3 2 2 77 56 15 2 1 1 1.3 0.1 0.1 0.1 0.1 0.0 0.0 1.7 0.7 0.6 0.2 0.1 0.0 0.0 1.7 1.2 0.3 0.0 0.0 0.0 72 1.5 52 12 4 2 2 1 1.1 0.3 0.1 0.0 0.0 0.0 1 68 0.0 1.5 68 2 66 44 1.5 0.0 1.4 0.9 7 0.2 4 3 2 2 57 48 7 56 38 15 5 54 29 0.1 0.1 0.0 0.0 1.2 1.0 0.2 1.2 0.8 0.3 0.1 1.2 0.6 J01MA02 J01MA12 J01MA01 J01MA06 N03A N03AG01 N03AX14 N03AE01 N03AX09 N03AA03 N03AB02 N03AX16 N03AB52 N03AX12 N03AF01 N06D N06DA02 N06DA04 N06DA03 N06DX01 N06DX02 R06A R06AE07 R06AE09 R06AX27 R06AB03 R06AD02 R06AB04 R06AX22 R06AX28 C01D C01DX12 C01DA02 C01DA08 R03B R03BA02 R03BB01 R03BA05 R03BB04 H03A H03AA01 C03D C03DA01 M01A M01AB05 M01AE01 M01AC01 M01AC06 M01AB16 M01AX01 M01AH01 M01AX05 M01AE02 Ciprofloxacin Levofloxacin Ofloxacin Norfloxacin Antiepileptics Valproic acid Levetiracetam Clonazepam Lamotrigine Primidone Phenytoin Pregabalin Phenytoin, combinations Gabapentin Carbamazepine Anti-dementia drugs Donezepil Galantamine Rivastigmine Memantine Ginkgo folium Antihistamines for systemic use Cetirizine Levocetirizine Desloratadine Dimetindene Promethazine Chlorphenamine Ebastine Rupatadine Vasodilators used in cardiac diseases Molsidomine Glyceryl trinitrate Isosorbide dinitrate Other drugs for obstructive airway diseases, inhalants Budesonide Ipratropium bromide Fluticasone Tiotropium bromide Thyroid preparations Levothyroxine sodium Potassium-sparing agents Spironolactone Antiinflammatory and antirheumatic products, non-steroids Diclofenac Ibuprofen Piroxicam Meloxicam Aceclofenac Nabumetone Celecoxib Glucosamine Naproxen 14 7 3 1 53 15 10 9 4 3 3 3 2 2 1 52 30 10 6 3 2 52 0.3 0.2 0.1 0.0 1.1 0.3 0.2 0.2 0.1 0.1 0.1 0.1 0.0 0.0 0.0 1.1 0.6 0.2 0.1 0.1 0.0 1.1 21 13 9 4 3 1 1 1 51 0.5 0.3 0.2 0.1 0.1 0.0 0.0 0.0 1.1 28 21 5 51 0.6 0.5 0.1 1.1 30 14 7 2 46 46 45 43 45 0.6 0.3 0.2 0.0 1.0 1.0 1.0 0.9 1.0 12 10 5 5 4 4 3 2 1 0.3 0.2 0.1 0.1 0.1 0.1 0.1 0.0 0.0 M01AE03 M01AE09 A10A A10AD05 A10AB01 A10AD01 A10AB05 A10AC01 A10AE04 A10AE05 H02A H02AB04 H02AB01 H02AB06 S01E S01ED01 S01EE01 S01ED02 S01ED51 S01EC04 S01ED05 S01EE03 S01EA05 S01ED03 S01EE04 B03A B03AA07 B03AA03 B03AE01 B03AB02 B03AD B03AD02 M02A M02AA15 M02AC M02AA06 M02AA10 M02AA M02AA13 R05D R05DA09 R05DB13 R05DB05 R05DA R05DA04 R05DB27 R05DB 64 Ketoprofen Flurbiprofen Insulins and analogues Insulin aspart Insulin (human) Insulin (human) Insulin aspart Insulin (human) Insulin glargine Insulin detemir Corticosteroids for systemic use, plain Methylprednisolone Betamethasone Prednisolone Antiglaucoma preparations and miotics Timolol Latanoprost Betaxolol Timolol, combinations Brinzolamide Carteolol Bimatoprost Brimonidine Levobunolol Travoprost Iron preparations Ferrous sulfate Ferrous gluconate Iron, vitamin B12 and folic acid Saccharated iron oxide Iron in combination with folic acid Ferrous fumarate Topical products for joint and muscular pain Diclofenac Preparations with salicylic acid derivatives Etofenamate Ketoprofen Antiinflammatory preparations, non-steroids for topical use Ibuprofen Cough suppressants, excl. combinations with expectorants Dextromethorphan Butamirate Pentoxyverine Opium alkaloids and derivatives Codeine Levodropropizine Other cough suppressants 1 1 43 14 8 8 5 5 4 1 42 0.0 0.0 0.9 0.3 0.2 0.2 0.1 0.1 0.1 0.0 0.9 34 6 3 41 0.7 0.1 0.1 0.9 12 8 5 5 2 2 2 1 1 1 40 14 12 8 0.3 0.2 0.1 0.1 0.0 0.0 0.0 0.0 0.0 0.0 0.9 0.3 0.3 0.2 5 1 0.1 0.0 1 38 0.0 0.8 17 9 0.4 0.2 7 3 1 0.2 0.1 0.0 1 37 0.0 0.8 17 8 6 5 0.4 0.2 0.1 0.1 2 2 1 0.0 0.0 0.0 B03B B03BB01 B03BA01 A07F A07FA02 A07FA01 R01A R01AD52 R01AD53 R01AX02 R01AA05 R01AA07 R01AD08 R01AD09 R01AD12 R01AC01 R01AX03 J01X J01XX01 J01XE01 J01XE02 M05B M05BA04 M05BX03 M05BB03 M05BX04 M05BA07 G04B G04BD04 G04BD11 G04BD06 G04BD08 G04BD02 G04BD07 G04BX M04A M04AA01 M04AC01 A11D A11DB A11DA01 S01X S01XA20 S01XA15 D07A Vitamin B12 and folic acid Folic acid Cyanocobalamin Antidiarrheal microorganisms Saccharomyces boulardii Lactic acid producing organisms Decongestants and other nasal preparations for topical use Prednisolone, combinations Dexamethasone, combinations Retinol Oxymetazoline Xylometazoline Fluticasone Mometasone Fluticasone furoate Cromoglicic acid Ipratropium bromide Other antibacterials Fosfomycin Nitrofurantoin Nifurtoinol Drugs affecting bone structure and mineralization Alendronic acid Strontium ranelate Alendronic acid and colecalciferol Denosumab Risedronic acid Urologicals Oxybutynin Fesoterodine Propiverine Solifenacin Flavoxate Tolterodine Other urologicals Antigout preparations Allopurinol Colchicine Vitamin B1, plain and in combination with vitamin B6 and B12 Vitamin B1 in combination with Vitamin B6 and/or vitamin B12 Thiamine (vit B1) Other ophthalmologicals Artificial tears and other indifferent preparations Ascorbic acid Corticosteroids, plain 36 29 3 33 0.8 0.6 0.1 0.7 D07AC01 D07AB02 D07AA02 D07AC06 D07AC13 D07AC14 30 3 0.6 0.1 32 0.7 11 4 0.2 0.1 4 3 3 3 3 2 1 1 31 20 7 5 31 0.1 0.1 0.1 0.1 0.1 0.0 0.0 0.0 0.7 0.4 0.2 0.1 0.7 21 4 3 0.5 0.1 0.1 R05FA02 3 1 30 19 3 2 2 1 1 1 27 23 3 26 0.1 0.0 0.6 0.4 0.1 0.0 0.0 0.0 0.0 0.0 0.6 0.5 0.1 0.6 G04C 24 0.5 D07AD01 D08A D08AG02 D08AC52 D08AX02 D08AC02 N07C N07CA01 N07CA03 C09C C09CA01 C09CA03 C09CA06 C09CA08 C09CA04 C09CA07 R05F R05FB02 G04CA02 G04CX02 G04CB01 G04CA03 A07D A07DA03 C01A C01AA05 C01B C01BD01 C01BC04 C03E C03EA04 2 26 23 0.0 0.6 0.5 C03EA01 3 25 0.1 0.5 A11AA03 A11A 65 Betamethasone Hydrocortisone butyrate Hydrocortisone Diflucortolone Mometasone Methylprednisolone aceponate Clobetasol Antiseptics and desinfectants Povidone-iodine Chlorhexidine, combinations Eosin Chlorhexidine Antivertigo preparations Betahistine Flunarizine Angiotensin II antogonists, plain Losartan Valsartan Candesartan Olmesartan medoxomil Irbesartan Telmisartan Cough suppressants and expectorants, combinations Opium derivatives and expectorants Cough suppressants and expectorants Drugs used in benign prostatic hypertrophy Tamsulosin Sabalis serrulatae fructus Finasteride Terazosin Antipropulsives Loperamide Cardiac glycosides Digoxin Antiarrhythmics, class I and III Amiodarone Flecainide Diuretics and potassiumsparing agents in combination Altizide and potassiumsparing agents Hydrochlorothiazide and potassium-sparing agents Multivitamins, combinations Multivitamins and other minerals, incl. combinations 12 6 2 2 2 1 0.3 0.1 0.0 0.0 0.0 0.0 1 24 0.0 0.5 12 8 0.3 0.2 2 1 24 22 1 23 0.0 0.0 0.5 0.5 0.0 0.5 8 4 4 4 3 3 23 0.2 0.1 0.1 0.1 0.1 0.1 0.5 22 0.5 1 0.0 22 0.5 17 3 2 1 21 20 20 19 20 0.4 0.1 0.0 0.0 0.5 0.4 0.4 0.4 0.4 19 1 20 0.4 0.0 0.4 14 0.3 5 0.1 17 0.4 10 0.2 A11AA04 A11AA01 S01C S01CA01 S01CC01 J01F J01FA10 J01FF01 J01FA09 A12C A12CC A12CC03 A12CC10 C05C C05CA53 C05CA04 C05CX C05CX02 C07B C07BB07 C07BB02 C07BB04 C09D C09DA01 C09DA03 C09DA04 C09DA06 C09DA07 C09DA08 C09DX03 S01A S01AA13 S01AE01 S01AA12 S01AA30 S01AX03 S01B S01BC01 S01BC03 S01BA01 S01BA04 S01BA07 S01BC05 S01BC09 C03B Multivitamins and trace elements Multivitamins and iron Antiinflammatory agents and antiinfectives in combination Dexamethasone and antiinfectives Diclofenac and antiinfectives Macrolides, lincosamides and streptogramins Azithromycin Clindamycin Clarithromycin Other mineral supplements Magnesium Magnesium gluconate Magnesium oxide Capillary stabilizing agents Diosmin, combinations Troxerutin Other capillary stabilizing agents Naftazone Beta blocking agents and thiazides Bisoprolol and thiazides Metoprolol and thiazides Acebutolol and thiazides Angiotensin II antagonists, combinations Losartan and diuretics Valsartan and diuretics Irbesartan and diuretics Candesartan and diuretics Telmisartan and diuretics Olmesartan medoxomil and diuretics Olmesartan medoxomil, amlodipine and hydrochlorothiazide Antiinfectives Fusidic acid Ofloxacin Tobramycin Combinations of different antibiotics Zinc compounds Antiinflammatory agents Indometacin Diclofenac Dexamethasone Prednisolone Fluorometholone Ketorolac Pranoprofen Low-ceiling diuretics, excl. 5 0.1 2 16 0.0 0.3 16 0.3 C03BA11 C03BA04 H03B H03BB02 J07A J07AL01 1 0.0 J07AM51 15 0.3 J07AX 10 4 3 14 8 4 3 13 6 5 1 0.2 0.1 0.1 0.3 0.2 0.1 0.1 0.3 0.1 0.1 0.0 R03D 1 13 0.0 0.3 11 1 1 13 0.2 0.0 0.0 0.3 3 2 2 2 2 1 0.1 0.0 0.0 0.0 0.0 0.0 1 0.0 R03DA04 R03DC03 R03DC01 S03C S03CA04 J01D 13 5 4 2 2 0.3 0.1 0.1 0.0 0.0 2 13 5 3 1 1 1 1 1 12 0.0 0.3 0.1 0.1 0.0 0.0 0.0 0.0 0.0 0.3 J01DC02 J01DB04 A11J A11JA A11JC C02A C02AC05 C02AC01 C05B C05BA01 C09B C09BA04 C09BB04 C09BA03 L02B L02BA01 L02BG03 L02BG04 S02D S02DC D06A D06AX09 D06AX01 D06AX05 A01A A01AB03 A01AB09 66 thiazides Indapamide Chlortalidone Antithyroid preparations Thiamazole Bacterial vaccines Pneumococcus, purified polysaccharides antigen Tetanus toxoid, combinations with diphtheria toxoid Other bacterial vaccines Other systemic drugs for obstructive airway diseases Theophylline Fenspiride Zafirlukast Corticosteroids and antiinfectives in combination Hydrocortisone and antiinfectives Other beta-lactam antibacterials Cefuroxime Cefazolin Other vitamin products, combinations Combinations of vitamins Vitamins, other combinations Antiadrenergic agents, centrally acting Moxonidine Clonidine Antivaricose therapy Organo-heparinoid Ace inhibitors, combinations Perindopril and diuretics Perindopril and amlodipine Lisinopril and diuretics Hormone antagonists and related agents Tamoxifen Anastrozole Letrozole Other otologicals Indifferent preparations Antibiotics for topical use Mupirocin Fusidic acid Bacitracin Stomatological preparations Chlorhexidine Miconazole 11 1 12 11 11 9 0.2 0.0 0.3 0.2 0.2 0.2 1 0.0 1 0.0 11 0.2 10 2 1 11 0.2 0.0 0.0 0.2 11 0.2 10 0.2 7 4 9 0.2 0.1 0.2 5 3 0.1 0.1 9 0.2 6 2 9 8 9 0.1 0.0 0.2 0.2 0.2 4 4 1 9 0.1 0.1 0.0 0.2 4 2 2 9 8 8 4 2 2 7 0.1 0.0 0.0 0.2 0.2 0.2 0.1 0.0 0.0 0.2 4 1 0.1 0.0 A01AD B05B B05BA03 B05BC01 C05A C05AA04 C05AA12 D07C D07CC01 D07CA01 J01E J01EE01 S01K S01KA01 S01KA51 N06B N06BX03 A03B A03BB01 A12B A12BA05 A12BA01 G03C G03CA04 J02A J02AC01 M03B M03BX01 M03BB53 N06C N06CA02 R02A R02AA05 R02AA03 R02AB02 A02A A02AD02 A02AD01 Other agents for local oral treatment I.V. solutions Carbohydrates Mannitol Agents for treatment of hemorrhoids and anal fissures for topical use Prednisolone Triamcinolone Corticosteroids, combinations with antibiotics Betamethasone and antibiotics Hydrocortisone and antibiotics Sulfonamides and trimethoprim Sulfamethoxazole and trimethoprim Surgical aids Hyaluronic acid Hyaluronic acid, combinations Psychostimulants, agents used for ADHD and nootropics Piracetam Belladonna and derivatives, plain Butylscopolamine Potassium Potassium gluconate Potassium chloride Estrogens Estriol Antimycotics for systemic use Fluconazole Muscle relaxants, centrally acting agents Baclofen Chlorzoxazone, combinations excl. psycholeptics Psycholeptics and psychoanaleptics in combination Melitracen and psycholeptics Throat preparations Chlorhexidine Dichlorobenzyl alcohol Tyrothricin Antacids Magaldrate Ordinary salt combinations 1 0.0 A03A 7 5 2 7 0.2 0.1 0.0 0.2 A03AB06 A03AA04 A07B A07BA01 A07BC05 A07E 4 3 7 0.1 0.1 0.2 A07EA 6 0.1 1 0.0 A07EA06 A07EC01 C04A C04AE01 D04A 7 0.2 6 0.1 7 7 1 0.2 0.2 0.0 6 0.1 6 5 0.1 0.1 6 5 3 2 5 4 5 0.1 0.1 0.1 0.0 0.1 0.1 0.1 5 5 0.1 0.1 3 1 0.1 0.0 5 0.1 5 0.1 5 3 1 1 4 3 1 0.1 0.1 0.0 0.0 0.1 0.1 0.0 D04AA32 D04AB01 L04A L04AX03 L04AB01 L04AD01 N04A N04AA01 N04AA02 A07X A07XA04 A11H A11HA01 A11HA04 C07C C07CB03 D06B D06BA01 D06BX01 G01A G01AF04 G01AF07 H04A H04AA01 J01A J01AA02 J01AA08 N01B N01BB02 N07A N07AA02 V03A V03AE01 67 Drugs for functional gastrointestinal disorders Otilonium bromide Mebeverine Intestinal adsorbents Medicinal charcoal Diosmectite Intestinal antiinflammatory agents Corticosteroids acting locally Budesonide Sulfasalazine Peripheral vasodilators Ergoloid mesylates Antipruritics, incl. antihistamines, anesthetics, etc. Diphenhydramine Lidocaine Immunosuppressants Methotrexate Etanercept Ciclosporin Anticholinergic agents Trihexyphenidyl Biperiden Other antidiarrheals Racecadotril Other plain vitamin preparations Nicotinamide Riboflavin (vit B2) Beta blocking agents and other diuretics Atenolol and other diuretics Chemotherapeutics for topical use Silver sulfadiazine Metronidazole Antiinfectives and antiseptics, excl. combinations with corticosteroids Miconazole Isoconazole Glycogenolytic hormones Glucagon Tetracyclines Doxycycline Minocycline Anethetics, local Lidocaine Parasympathomimetics Pyridostigmine All other therapeutic products Polystyrene sulfonate 4 0.1 3 1 4 2 2 4 0.1 0.0 0.1 0.0 0.0 0.1 2 0.0 1 1 4 4 4 0.0 0.0 0.1 0.1 0.1 2 1 4 2 1 1 4 3 1 3 3 3 0.0 0.0 0.1 0.0 0.0 0.0 0.1 0.1 0.0 0.1 0.1 0.1 1 1 3 0.0 0.0 0.1 3 3 0.1 0.1 2 1 3 0.0 0.0 0.1 2 1 3 3 3 2 1 3 2 3 2 3 0.0 0.0 0.1 0.1 0.1 0.0 0.0 0.1 0.0 0.1 0.0 0.1 1 0.0 V03AE02 V03AE03 V06X V06XX02 B02A B02AA02 C08D C08DB01 C10B C10BA02 D05A D05AX52 D11A D11AC03 D11AH02 L02A L02AE02 M09A M09AA01 M09AX01 R01B R01BA52 R01BA53 S01G S01GA01 S01GA02 S02C S02CA07 A05A A05AX02 A07A A07AA02 A11B A11BA A11E A11EB Sevelamer Lanthanum carbonate General nutrients Other combinations of nutrients Antifibrinolytics Tranexamic acid Selective calcium channel blockers with direct cardiac effects Diltiazem Lipid modifying agents, combinations Simvastatin and ezetimibe Antipsoriatics for topical use Calcipotriol, combinations Other dermatological preparations Selenium compounds Pimecrolimus Hormones and related agents Leuprorelin Other drugs for disorders of the musculo-skeletal system Hydroquinine Hyaluronic acid Nasal decongestants for systemic use Pseudoephedrine, combinations Phenylephrine, combinations Decongestants and antiallergics Naphazoline Tetryzoline Corticosteroids and antiinfectives in combination Fludrocortisone and antiinfectives Bile therapy Hymecromone Intestinal antiinfectives Nystatin Multivitamins, plain Multivitamins, plain Vitamin B-complex, incl. combinations Vitamin B-complex with vitamin C 1 1 3 3 0.0 0.0 0.1 0.1 B05C B05CB01 B05X B05XA02 C01C 2 2 2 0.0 0.0 0.0 3 2 0.1 0.0 2 2 0.0 0.0 2 2 0.0 0.0 1 1 2 0.0 0.0 0.0 2 2 0.0 0.0 1 1 2 0.0 0.0 0.0 H01BA02 H05B H05BA01 1 0.0 1 0.0 J05A J05AB01 J07B J07BB02 2 0 1 1 2 0 0 0.0 2 0.0 1 1 1 1 1 1 1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 S03A S03AA07 V07A V07AB 1 0.0 Total C01CA01 C02C C02CA01 C02D C02DB01 C09X C09XA02 D03B D03BA52 D05B D05BB02 G03X G03XC01 H01B L01X L01XX05 N02C N02CX02 R05 R05 68 Irrigating solutions Sodium chloride I.V. solution additives Sodium bicarbonate Cardiac stimulants excl. cardiac glycosides Etilefrine Antiadrenergic agents, peripherally acting Prazosin Arteriolar smooth muscle, agents acting on Dihydralazine Other agents acting on the renin-angiotensin system Aliskiren Enzymes Collagenase, combinations Antipsoriatics for systemic use Acitretin Other sex hormones and modulators of the genital system Raloxifene Posterior pituitary lobe hormones Desmopressin Anti-parathyroid agents Calcitonin (salmon synthetic) Direct acting antivirals Aciclovir Viral vaccines Influenza, inactivated, split virus or surface antigen Other antineoplastic agents Hydroxycarbamide Antimigraine preparations Clonidine Cough and cold preparations Cough and cold preparations Antiinfectives Ciprofloxacin All other non-therapeutic products Solvents and diluting agents, incl. irrigating solutions 1 1 1 1 1 0.0 0.0 0.0 0.0 0.0 1 1 0.0 0.0 2 1 0.0 0.0 1 1 0.0 0.0 1 1 1 1 0.0 0.0 0.0 0.0 1 1 0.0 0.0 1 1 0.0 0.0 1 1 1 0.0 0.0 0.0 1 1 1 1 0.0 0.0 0.0 0.0 1 0.0 1 1 1 1 0.0 0.0 0.0 0.0 1 0.0 1 1 1 0.0 0.0 0.0 1 0.0 4647 100 Appendix 9: Complete list of QT-prolonging drugs community-dwelling older adults Drug name ATC code Risk No. of score pts Pantoprazole 2 221 A02BC02 221 A02BD04 0 Furosemide (frusemide) 2 C03CA01 C03CB01 C03EB01 Formoterol Salmeterol 1 R03AK07 R03AK08 R03AC13 R03AL05 R03AK11 R03AK09 R03AK06 Sotalol N06AX05 % 4 49 49 0 0 4.8 4.8 0.0 0.0 2 49 4.8 1 Fluoxetine Metoclopramide 0.5 0.5 Tamoxifen L02BA01 3 5 0.5 2 4 4 0 0 4 0.4 0.4 0.0 0.0 0.4 4 3 1 3 0.4 0.3 0.1 0.3 3 3 0 3 2 1 0 0 0 0 0 0 0.3 0.3 0.0 0.3 0.2 0.1 0.0 0.0 0.0 0.0 0.0 0.0 2 2 0.2 1 2 2 0 0 0 2 2 0 0 0 0.2 0.2 0.0 0.0 0.0 0.2 0.2 0.0 0.0 0.0 3.4 Hydroxychloroquine 2 3.0 3.0 0.0 2.9 Pseudoephedrine Moxifloxacin 2 2.6 1.0 0.9 0.5 0.2 0.0 0.0 0.0 0.0 2.3 Fluconazole Ketoconazole Sulpiride C03EA01 C09DX03 C09DX01 C09XA52 C09XA54 C03AB03 C03AX01 C03AA03 N05AL01 4 Venlafaxine N06AX16 3 20 2.0 Citalopram N06AB04 4 16 1.6 Doxepin Sertraline N06AB06 2 16 1.6 Ephedrine Mirtazapine N06AX11 3 15 1.5 1 11 9 1 1 0 1.1 0.9 0.1 0.1 0.0 R03AL02 R03CC02 R03AC12 R03AK04 J02AC01 J01RA07 D01AC15 P01BA02 2 1 R01BA52 R01BA02 D01AC08 2 4 J01MA14 S01AE07 26 10 9 5 2 0 0 0 0 23 Albuterol (salbutamol) 0.5 0.5 0.0 0.0 0.0 0.0 0.0 5 35 Hydrochlorothiazide 5 5 0 0 0 0 0 5 4 2.7 4 3 3.9 3.9 0.0 27 0.7 0.7 0.0 0.6 0.6 0.0 3 40 40 0 2 7 7 0 6 6 0 N05AH04 2 N06AB05 2 C08CA03 4.0 Paroxetine 0.9 Quetiapine 41 4 9 Isradipine 4 Flecainide 2 J01FA09 A02BD06 A02BD07 A02BD09 A02BD05 A02BD04 N06AB10 30 30 0 29 0.9 0.9 0.0 0.9 0.9 0.0 2 Clarithromycin Escitalopram N06AA09 N06CA01 C01BC04 9 9 0 9 9 0 G04BD08 G04CA53 4.5 Amitriptyline A03FA01 Solifenacin 46 A03FA03 4 N05BB01 N05BB51 4 Domperidone % 2 Hydroxyzine C01BD01 C03BA11 C09BX01 No. of pts N06AB03 N06CA03 Amiodarone Indapamide Risk score J01FA10 J01RA07 7.5 7.5 0.0 0.0 6.4 4.6 1.4 0.4 0.0 0.0 0.0 5.8 ATC code Azithromycin 21.8 21.8 0.0 65 47 14 4 0 0 0 59 C07AA07 C07BA07 C07AA57 Trazodone 76 76 0 0 Drug name Phenylephrine 1 R01AB01 R01BA53 S01GA55 R01AA04 C01CA06 R01BA03 S01FB01 S01GA05 N06AA12 R01AA03 R01AB05 R03CA02 S01FB02 Levofloxacin 4 J01MA12 A02BD10 J01RA05 S01AE05 69 Drug name ATC code Norfloxacin Risk score 3 No. of pts 2 2 0 0 % Drug name ATC code 0.2 0.2 0.0 0.0 Bosutinib 2 2 3 J01MA06 S01AE02 J01RA13 Nortriptyline N06AA10 Ofloxacin J01MA01 S01AE01 J01RA09 S02AA16 No. of pts 0 % L01XE14 Risk score 3 Chloral hydrate N05CC01 2 0 0.0 Chloroquine P01BA01 4 0 0.0 0.2 Crizotinib L01XE16 3 0 0.0 2 1 1 0 0 0.2 0.1 0.1 0.0 0.0 Dabrafenib L01XE23 3 0 0.0 Dasatinib L01XE06 3 0 0.0 Dexmedetomidine N05CM18 3 0 0.0 P01BF05 3 0 0.0 C01CA07 1 0 0.0 N05AD08 4 0 0.0 1 0 0 0 0.0 0.0 0.0 1 0 0 0 0 0 0 0 0 0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 3 0 0.0 4 0.0 0.0 0.0 0.0 0.0 0.0 Tolterodine G04BD07 3 2 0.2 Dihydroartemisinin + piperaquine Dobutamine Vardenafil G04BE09 3 2 0.2 Droperidol Amisulpride N05AL05 2 1 0.1 Ephedrine 2 0.1 0.1 0.0 0.0 0.0 0.0 0.0 0.0 0.1 Ciprofloxacin Clomipramine S03AA07 S01AE03 J01RA10 J01RA12 J01RA11 S02AA15 J01MA02 N06AA04 2 1 1 0 0 0 0 0 0 1 Clozapine N05AH02 3 1 0.1 2 2 1 1 0 0 0.2 0.1 0.1 0.0 0.0 Diphenhydramine R06AA52 R06AA02 D04AA32 D04AA33 C01CA26 A08AA56 Epinephrine (adrenaline) Eribulin A01AD01 R03AK01 S01EA51 B02BC09 C01CA24 R01AA14 R03AA01 S01EA01 L01XX41 Erythromycin 3 0 0 0 0 0 0 0.0 Disopyramide C01BA03 4 1 0.1 Haloperidol N05AD01 4 1 0.1 Felbamate D10AF02 D10AF52 J01FA01 S01AA17 N03AX10 Ivabradine C01EB17 2 1 0.1 Fingolimod L04AA27 3 0 0.0 Mirabegron G04BD12 3 1 0.1 Foscarnet J05AD01 3 0 0.0 Nilotinib L01XE08 3 1 0.1 Galantamine N06DA04 2 0 0.0 Olanzapine N05AH03 3 1 0.1 Granisetron A04AA02 3 0 0.0 Paliperidone N05AX13 3 1 0.1 N05AX08 3 1 0.1 Imipramine (melipramine) 2 Risperidone 3 0 0 0 0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0 0 0 0 0 0 0 0 0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Itraconazole 2 0 0.0 Ketoconazole 2 0 0 0 0.0 0.0 0.0 3 0 0.0 4 0 0 0 0 0.0 0.0 0.0 0.0 Alfuzosin Anagrelide G04CA01 G04CA51 L01XX35 Apomorphine 4 3 Isoproterenol (isoprenaline) Aripiprazole G04BE07 N04BC07 N05AX12 3 0 0 0 0 Arsenic trioxide L01XX27 4 0 0.0 Atazanavir J05AE08 3 0 0.0 Atomoxetine N06BA09 1 0 0.0 Lapatinib Azithromycin S01AA26 4 0 0.0 Methadone Bedaquiline J04AK05 3 0 0.0 Bortezomib L01XX32 3 0 0.0 N06AA02 N06AA03 1 C01CA02 R03AK02 R03CB51 R03AB02 R03CB01 J02AC02 G01AF11 J02AB02 Methylphenidate 70 L01XE07 N07BC02 N02AC52 N06BA04 1 Drug name ATC code Metronidazole Risk score 2 A01AB17 A02BD08 J01RA03 J01RA10 A02BD03 A02BD02 P01AB51 A02BD01 J01RA04 D06BX01 G01AF01 J01XD01 P01AB01 Mifepristone 3 G03XB01 G03XB51 Moexipril/HCTZ 3 C09AA13 C09BA13 No. of pts 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 % Drug name ATC code No. of pts 0 % N05AD05 Risk score 3 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Pipamperone Posaconazole J02AC04 2 0 0.0 3 0 0 0 0 0 0.0 0.0 0.0 0.0 0.0 3 0 0.0 2 0.0 0.0 0.0 0.0 0 0 0 0.0 0.0 0.0 Promethazine D04AA10 V03AB05 R06AD52 R06AD02 Rilpevirine J05AG05 Ritonavir 0.0 Roxithromycin J05AE03 J05AR10 J01FA06 3 0 0 0 0 Saquinavir J05AE01 3 0 0.0 Sertindole N05AE03 3 0 0.0 Sevoflurane N01AB08 4 0 0.0 Sorafenib L01XE05 3 0 0.0 Sunitinib L01XE04 3 0 0.0 Telaprevir J05AE11 2 0 0.0 Telithromycin J01FA15 3 0 0.0 Nicardipine C08CA04 3 0 0.0 Norepinephrine (noradrenaline) Ondansetron C01CA03 1 0 0.0 A04AA01 4 0 0.0 Tetrabenazine N07XX06 3 0 0.0 3 0 0 0 0.0 0.0 0.0 Tizanidine M03BX02 3 0 0.0 Vandetanib L01XE12 4 0 0.0 Vemurafenib L01XE15 3 0 0.0 Voriconazole J02AC03 2 0 0.0 Oxytocin H01BB02 G02AC01 Pazopanib L01XE11 3 0 0.0 Pentamidine P01CX01 4 0 0.0 Perflutren lipid microspheres Pimozide V08DA04 3 0 0.0 N05AG02 4 0 0.0 71 Appendix 10: Complete list QT-prolonging drugs institutionalized older adults Drug name ATC code Risk No. score of pts Pantoprazole 2 118 A02BC02 118 A02BD04 0 Furosemide (frusemide) 2 C03CA01 C03CB01 C03EB01 Drug name Formoterol 29.5 29.5 0.0 73 73 0 0 18.0 18.0 0.0 0.0 Sotalol 4 Venlafaxine N06AX16 3 7 1.8 3 7 4 3 0 0 1.8 1.0 0.8 0.0 0.0 N05AH02 3 6 1.5 N05AD05 3 6 1.5 2 6 5 1 0 0 0 0 0 0 1.5 1.3 0.3 0.0 0.0 0.0 0.0 0.0 0.0 2 5 5 0 0 1.3 1.3 0.0 0.0 2 5 5 0 1.3 1.3 0.0 N06AB10 4 51 12.8 Domperidone A03FA03 4 38 9.5 Quetiapine N05AH04 3 36 9.0 Risperidone N05AX08 3 34 8.5 4 29 29 0 7.3 7.3 0.0 3 25 6.3 1 5.8 5.8 0.0 4.8 Clozapine Levofloxacin S01AE01 J01MA01 S02AA16 J01RA09 Amiodarone 4 23 23 0 19 Haloperidol N05AD01 4 19 4.8 Pipamperone Sertraline N06AB06 2 16 4.0 Hydrochlorothiazide A03FA01 2 15 3.8 2 14 14 0 3.5 3.5 0.0 2 14 13 1 0 0 0 0 0 13 13 0 0 0 3.5 3.3 0.3 0.0 0.0 0.0 0.0 0.0 3.3 3.3 0.0 0.0 0.0 N06AA09 N06CA01 Ciprofloxacin J01MA02 S03AA07 S02AA15 J01RA10 J01RA12 J01RA11 S01AE03 Albuterol (salbutamol) 1 R03AL02 R03CC02 R03AK04 R03AC12 Citalopram N06AB04 4 13 3.3 Olanzapine N05AH03 3 13 3.3 2 11 11 0 10 10 0 0 10 2.8 2.8 0.0 2.5 2.5 0.0 0.0 2.5 Indapamide C03BA11 C09BX01 Azithromycin Galantamine 4 J01FA10 S01AA26 J01RA07 N06DA04 2 4 Ofloxacin R03AK06 R03AC12 C01BD01 Amitriptyline C03EA01 C09DX03 C03AA03 C09XA52 C09XA54 C03AB03 C03AX01 C09DX01 Fluconazole J02AC01 D01AC15 J01RA07 Hydroxyzine N05BB01 N05BB51 Paroxetine N06AB05 2 5 1.3 Tamoxifen L02BA01 3 4 1.0 4 3 3 0 0 0 0 0 3 3 0 2 0.8 0.8 0.0 0.0 0.0 0.0 0.0 0.8 0.8 0.0 0.5 Clarithromycin J01FA09 A02BD06 A02BD07 A02BD09 A02BD05 A02BD04 Fluoxetine Amisulpride 72 2.3 2.3 0.0 0.0 1.8 1.8 0.0 0.0 0.0 1.8 3.8 2.3 0.3 0.0 1.3 0.0 0.0 Sulpiride Escitalopram Metoclopramide % J01MA12 S01AE05 A02BD10 J01RA05 N05AL01 13.8 Salmeterol No. of pts 15 9 1 0 5 0 0 9 9 0 0 7 7 0 0 0 7 55 N06AX11 4 C07AA07 C07BA07 C07AA57 2 Mirtazapine 1 R03AK07 R03AC13 R03AL05 R03AK08 R03AK11 R03AK09 N06AX05 J01MA14 S01AE07 Risk score % Trazodone Moxifloxacin ATC score 2 N06AB03 N06CA03 N05AL05 2 Drug name ATC code Diphenhydramine Nortriptyline Risk score 2 D04AA32 R06AA02 D04AA33 R06AA52 N06AA10 Solifenacin 2 2 G04BD08 G04CA53 No. of pts 2 2 0 0 0 2 % Drug name 0.5 0.5 0.0 0.0 0.0 0.2 Ephedrine 2 2 0 0.5 0.5 0.0 Foscarnet D10AF02 J01FA01 S01AA17 D10AF52 J05AD01 3 No. of pts 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Granisetron A04AA02 3 0 0.0 Hydroxychloroquine P01BA02 2 0 0.0 Imipramine (melipramine) N06AA02 N06AA03 2 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Epinephrine (adrenaline) N05AX12 3 1 0.3 Flecainide C01BC04 4 1 0.3 2 1 1 0 0 1 1 0 0 0.3 0.3 0.0 0.0 0.3 0.3 0.0 0.0 Erythromycin 3 1 0.3 3 0 0 0 0.0 0.0 0.0 4 0 0.0 3 0 0 0 0.0 0.0 0.0 D01AC08 G01AF11 J02AB02 Norfloxacin 3 J01MA06 S01AE02 J01RA13 Tolterodine G04BD07 Alfuzosin G04CA01 G04CA51 Anagrelide L01XX35 Apomorphine G04BE07 N04BC07 Risk score 1 C01CA26 A08AA56 R01AA03 R01AB05 R03CA02 S01FB02 Aripiprazole Ketoconazole ATC code 1 A01AD01 R03AK01 S01EA51 B02BC09 C01CA24 R01AA14 R03AA01 S01EA01 4 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Isradipine C01CA02 R03AK02 R03CB51 R03AB02 R03CB01 C08CA03 3 0 0 0 0 0 0 0 0 0 0 Itraconazole J02AC02 2 0 0.0 Ivabradine C01EB17 2 0 0.0 Lapatinib L01XE07 3 0 0.0 4 0 0 0 0 0.0 0.0 0.0 0.0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0.3 0.3 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Isoproterenol (isoprenaline) Arsenic trioxide L01XX27 4 0 0.0 Atazanavir J05AE08 3 0 0.0 Atomoxetine N06BA09 1 0 0.0 Bedaquiline J04AK05 3 0 0.0 Bortezomib L01XX32 3 0 0.0 Bosutinib L01XE14 3 0 0.0 Chloral hydrate N05CC01 2 0 0.0 Chloroquine P01BA01 4 0 0.0 Clomipramine N06AA04 2 0 0.0 Crizotinib L01XE16 3 0 0.0 Methylphenidate Dabrafenib L01XE23 3 0 0.0 Metronidazole Dasatinib L01XE06 3 0 0.0 Dexmedetomidine N05CM18 3 0 0.0 Dihydroartemisinin + piperaquine Disopyramide P01BF05 3 0 0.0 C01BA03 4 0 0.0 Dobutamine C01CA07 1 0 0.0 Doxepin N06AA12 2 0 0.0 Droperidol N05AD08 4 0 0.0 Eribulin Felbamate L01XX41 N03AX10 3 3 0 0 0.0 0.0 Fingolimod L04AA27 3 0 0.0 1 Methadone N07BC02 N02AC52 N06BA04 1 2 D06BX01 A01AB17 A02BD08 J01RA03 J01RA10 A02BD03 A02BD02 P01AB51 A02BD01 J01RA04 G01AF01 J01XD01 P01AB01 73 % Drug name ATC code Mifepristone Mirabegron Risk score 3 G03XB01 G03XB51 G04BD12 Moexipril/HCTZ 3 3 No. of pts 0 0 0 0 % Drug name ATC code Risk score 0.0 0.0 0.0 0.0 Posaconazole J02AC04 2 0.0 0.0 0.0 0.0 Nicardipine C09AA13 C09BA13 C08CA04 3 0 0 0 0 Nilotinib L01XE08 3 0 0.0 Norepinephrine (noradrenaline) Ondansetron C01CA03 1 0 0.0 A04AA01 4 0 0.0 3 0.0 0.0 0.0 0.0 Paliperidone H01BB02 G02AC01 N05AX13 3 0 0 0 0 Pazopanib L01XE11 3 0 0.0 Pentamidine P01CX01 4 0 0.0 Perflutren lipid microspheres Phenylephrine V08DA04 3 0 0.0 1 R01BA53 C01CA06 R01AA04 R01AB01 R01BA03 S01FB01 S01GA05 S01GA55 N05AG02 4 1 1 0 0 0 0 0 0 0 0 % 3 3 3 0 0 0 0.8 0.8 0.0 0.0 0.0 1 1 0 1 0.3 0.0 0.3 3 0 0.0 2 0.0 0.0 0.0 0.0 R06AD02 D04AA10 V03AB05 R06AD52 Pseudoephedrine R01BA02 R01BA52 Rilpevirine J05AG05 Ritonavir Oxytocin Pimozide Promethazine No. of pts 0 0.3 0.3 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 74 0.0 Roxithromycin J05AR10 J05AE03 J01FA06 3 0 0 0 0 Saquinavir J05AE01 3 0 0.0 Sertindole N05AE03 3 0 0.0 Sevoflurane N01AB08 4 0 0.0 Sorafenib L01XE05 3 0 0.0 Sunitinib L01XE04 3 0 0.0 Telaprevir J05AE11 2 0 0.0 Telithromycin J01FA15 3 0 0.0 Tetrabenazine N07XX06 3 0 0.0 Tizanidine M03BX02 3 0 0.0 Vandetanib L01XE12 4 0 0.0 Vardenafil G04BE09 3 0 0.0 Vemurafenib L01XE15 3 0 0.0 Voriconazole J02AC03 2 0 0.0 Appendix 11: Complete list QT-prolonging drugs with risk score 4 community-dwelling older adults Drug name ATC code Risk No. of % score pts Sotalol 4 49 4.8 C07AA07 49 4.8 C07BA07 0 0.0 C07AA57 0 0.0 Amiodarone C01BD01 4 46 4.5 Escitalopram N06AB10 4 41 4.0 Domperidone A03FA03 4 35 3.4 Flecainide C01BC04 4 29 2.9 Drug name ATC code Risk score No. of pts % Disopyramide C01BA03 4 1 0.1 Haloperidol N05AD01 4 1 0.1 Anagrelide L01XX35 4 0 0.0 Arsenic trioxide L01XX27 4 0 0.0 Azithromycin S01AA26 4 0 0.0 Chloroquine P01BA01 4 0 0.0 Droperidol N05AD08 4 0 0.0 Sulpiride Citalopram Azithromycin Erythromycin 4 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 N05AL01 N06AB04 4 4 4 J01FA10 J01RA07 Clarithromycin 4 J01FA09 A02BD06 A02BD07 A02BD09 A02BD05 A02BD04 Moxifloxacin 4 J01MA14 S01AE07 Levofloxacin 4 J01MA12 A02BD10 J01RA05 S01AE05 23 16 9 9 0 5 5 0 0 0 0 0 3 3 0 2 2 0 0 0 2.3 1.6 0.9 0.9 0.0 0.5 0.5 0.0 0.0 0.0 0.0 0.0 0.3 0.3 0.0 0.2 0.2 0.0 0.0 0.0 Ondansetron N07BC02 N02AC52 A04AA01 4 0 0 0 0 0 0 0 0 0 Pentamidine P01CX01 4 0 0.0 Pimozide N05AG02 4 0 0.0 Sevoflurane N01AB08 4 0 0.0 Vandetanib L01XE12 4 0 0.0 D10AF02 D10AF52 J01FA01 S01AA17 Methadone 75 4 Appendix 12: Complete list QT-prolonging drugs with risk score 4 institutionalized older adults Drug name ATC code Risk No. % score of pts Escitalopram N06AB10 4 51 12.8 Domperidone A03FA03 Moxifloxacin 4 38 9.5 4 7.3 7.3 0.0 4.8 Drug name ATC code Risk score No. of pts % Flecainide C01BC04 4 1 0.3 Anagrelide L01XX35 4 0 0.0 Arsenic trioxide L01XX27 4 0 0.0 Chloroquine P01BA01 4 0 0.0 Amiodarone J01MA14 S01AE07 C01BD01 4 29 29 0 19 Disopyramide C01BA03 4 0 0.0 Haloperidol N05AD01 4 19 4.8 Droperidol N05AD08 4 0 0.0 Citalopram N06AB04 4 13 3.3 Erythromycin 4 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Azithromycin 4 10 10 0 0 2.5 2.5 0.0 0.0 4 9 9 0 0 7 7 0 0 0 2.3 2.3 0.0 0.0 1.8 1.8 0.0 0.0 0.0 7 3 3 0 0 0 0 0 1.8 0.8 0.8 0.0 0.0 0.0 0.0 0.0 J01FA10 S01AA26 J01RA07 Sotalol C07AA07 C07BA07 C07AA57 Levofloxacin 4 J01MA12 S01AE05 A02BD10 J01RA05 Sulpiride Clarithromycin N05AL01 J01FA09 A02BD06 A02BD07 A02BD09 A02BD05 A02BD04 4 4 Ondansetron N07BC02 N02AC52 A04AA01 4 0 0 0 0 0 0 0 0 0 Pentamidine P01CX01 4 0 0.0 Pimozide N05AG02 4 0 0.0 Sevoflurane N01AB08 4 0 0.0 Vandetanib L01XE12 4 0 0.0 D10AF02 J01FA01 S01AA17 D10AF52 Methadone 76 4 Appendix 13: Complete list of drugs with anticholinergic properties according to Duran et al. community-dwelling older adults Drug name ATC code Risk No. % score of pts Tramadol N02AX02 L 91 9.0 Drug name Trazodone Quetiapine (fumarate) Meclozine N06AX05 Ipratropium L 49 4.8 H 47 33 9 5 0 4.6 3.2 0.9 0.5 0.0 R03AL01 R03AL02 R03BB01 R01AX03 Ranitidine Combinations with tramadol or methadone Domperidone L A02BA02 A02BA07 N02AX52 A03FA03 Amitriptyline Loperamide H 0.3 0.3 0.0 0.2 0.1 0.1 0.0 0.0 0.2 Doxepin R06AA02 R06AA52 D04AA32 D04AA33 N06AA12 H 3 3 0 2 1 1 0 0 2 R06AE05 R06AE55 Dimenhydrinate/ diphenhydramine H N06AA10 H 2 0.2 Tolterodine G04BD07 H 2 0.2 H 30 30 0 29 29 0 0 3.0 3.0 0.0 2.9 2.9 0.0 0.0 Cimetidine L 2 2 0 0.2 0.2 0.0 H L 27 2.7 1 1 0 0 0.1 0.1 0.0 0.0 L 26 26 0 0 2.6 2.6 0.0 0.0 25 2.5 Clonazepam N03AE01 L 20 2.0 L 20 15 5 0 2.0 1.5 0.5 0.0 1.8 1.8 0.0 0.0 0.0 1.7 N02AA59 R05DA04 N02AA79 L A02BA01 A02BA51 Belladona alkaloids A03BA04 A03CB02 A06AB30 Clomipramine N06AA04 H 1 0.1 Clozapine N05AH02 H 1 0.1 Levomepromazine N05AA02 H 1 0.1 Trihexyphenidyl N04AA01 H 1 0.1 Fluvoxamine N06AB08 L 1 0.1 Olanzapine N05AH03 L 1 0.1 Alimemazine R06AD01 L 1 0.1 Baclofen M03BX01 L 1 0.1 L 0.1 0.1 0.0 0.1 Bromocriptine Disopyramide N04BC01 G02CB01 C01BA03 L 1 1 0 1 Fexofenadine R06AX26 L 1 0.1 Haloperidol N05AD01 L 1 0.1 R06AX13 L 1 0.1 L 1 1 0 0 0 0 1 0.1 0.1 0.0 0.0 0.0 0.0 0.1 0 0 0 0 0.0 0.0 0.0 0.0 Oxybutynin R03DA04 R03DB04 R03DA54 R03DA74 G04BD04 H 18 18 0 0 0 17 Citalopram N06AB04 L 16 1.6 Loratadine Dosulepin N06AA16 L 16 1.6 Morphine Mirtazapine N06AX11 L 15 1.5 Diazepam N05BA0F1 L 12 1.2 Triazolam N05CD05 L 10 1.0 L 9 9 0 0.9 0.9 0.0 N06AB03 N06CA03 L N02AA05 N02AA55 0.5 Nortriptyline L Oxycodone 5 3.4 R06AE07 Fluoxetine L 35 Cetirizine Theophylline N05AH04 L A07DA03 A07DA05 A07DA53 Codeine L 0.7 0.7 0.0 0.6 L L N06AB05 Carbamazepine H % 4.1 4.1 0.0 3.5 N02AB03 N01AH01 N01AH51 Paroxetine N05BB01 N05BB51 N03AF01 No. of pts 7 7 0 6 Hydroxyzine Risk score 42 42 0 36 N06AA09 N06CA01 Fentanyl ATC code 9 8 1 Risperidone N02AA01 N02AG01 A07DA52 N02AA51 R05DA05 N05AX08 Atropine H A03BA01 S01FA01 A03CB03 0.9 0.8 0.1 77 L Drug name ATC code Chlorphenamine Risk score H R06AB04 R06AB54 Imipramine H N06AA02 N06AA03 Scopolamine (hyoscine) H A04AD01 N05CM05 S01FA02 A04AD51 No. of pts 0 0 0 % Drug name ATC code Risk score 0.0 0.0 0.0 Tizanidine M03BX02 Entacapone N04BX02 0 0 0 0 0 0 0 0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Darifenacin G04BD10 H 0 0.0 Flavoxate G04BD02 H 0 0.0 Procyclidine N04AA04 H 0 0.0 Pyrilamine R06AC01 H 0 0.0 Promethazine % H No. of pts 0 L 0 0.0 H 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Methadone M01AB15 S01BC05 N07BC02 L 0 0 0 0 0 0 0 0 0 Nefanzodone N06AX06 L 0 0.0 Oxcarbazepine N03AF02 L 0 0.0 Phenelzine N06AF03 L 0 0.0 Pimozide N05AG02 L 0 0.0 R06AD02 D04AA10 R06AD52 V03AB05 Ketorolac 78 0.0 L Appendix 14: Complete list of drugs with anticholinergic properties according to Duran et al. institutionalized older adults Drug name ATC code Risk No. % score of pts Ipratropium H 56 14.0 R03AL01 28 7.0 R03BB01 14 3.5 R03AL02 13 3.3 R01AX03 1 0.3 Trazodone N06AX05 L 55 13.8 Domperidone A03FA03 L 38 9.5 Quetiapine (fumarate) Ranitidine N05AH04 L 36 9.0 L 36 36 0 9.0 9.0 0.0 A02BA02 A02BA07 Tramadol N02AX02 L 36 9.0 Risperidone N05AX08 L 34 8.5 L 30 30 0 0 7.5 7.5 0.0 0.0 Fentanyl Drug name ATC code Risk score % L No. of pts 5 Paroxetine N06AB05 Diazepam N05BA01 L 4 1.0 Trihexyphenidyl N04AA01 H 3 0.8 H 3 3 0 0 0 3 3 0 0.8 0.8 0.0 0.0 0.0 0.8 0.8 0.0 0.8 0.8 0.0 0.8 Promethazine R06AD02 D04AA10 R06AD52 V03AB05 Fluoxetine L N06AB03 N06CA03 Oxycodone L Triazolam N02AA05 N02AA55 N05CD05 L 3 3 0 3 Baclofen M03BX01 L 3 0.8 L 1.3 0.8 0.5 0.0 0.5 Codeine Levomepromazine N02AA59 R05DA04 N02AA79 N05AA02 Mirtazapine N06AX11 L 25 6.3 Nortriptyline N06AA10 Combinations with tramadol or methadone Cetirizine N02AX52 L 22 5.5 Diphenhydramine N02AB03 N01AH01 N01AH51 R06AE07 Loperamide L 21 5.3 L 5.0 5.0 0.0 0.0 4.8 Oxybutynin A07DA03 A07DA05 A07DA53 G04BD04 H 20 20 0 0 19 Haloperidol N05AD01 L 19 4.8 H 3.5 3.5 0.0 3.3 Amitriptyline Olanzapine N06AA09 N06CA01 N05AH03 L 14 14 0 13 Citalopram N06AB04 L 13 L Theophylline Clonazepam R03DA04 R03DB04 R03DA54 R03DA74 N03AE01 Morphine Clozapine L L N02AA01 N02AG01 A07DA52 N02AA51 R05DA05 N05AH02 Hydroxyzine H H N05BB01 N05BB51 1.3 H 5 3 2 0 2 H 2 0.5 H 2 2 0 0 0 0.5 0.5 0.0 0.0 0.0 H 2 2 0 0 0 1 1 0 0.5 0.5 0.0 0.0 0.0 0.3 0.3 0.0 D04AA32 R06AA02 D04AA33 R06AA52 Scopolamine (hyoscine) N05CM05 A04AD01 S01FA02 A04AD51 Chlorphenamine H R06AB04 R06AB54 Tolterodine G04BD07 H 1 0.3 3.3 Flavoxate G04BD02 H 1 0.3 10 10 0 0 0 9 2.5 2.5 0.0 0.0 0.0 2.3 Carbamazepine N03AF01 L 1 0.3 L 1 1 0 0.3 0.3 0.0 H 8 8 0 0 0 0 6 2.0 2.0 0.0 0.0 0.0 0.0 1.5 0 0 0 0 0.0 0.0 0.0 0.0 H 0.0 0.0 0.0 0.0 0.0 5 5 0 1.3 1.3 0.0 0.0 Ketorolac S01BC05 M01AB15 Atropine A03BA01 S01FA01 A03CB03 Belladona alkaloids 79 Clomipramine A03BA04 A03CB02 A06AB30 N06AA04 H 0 0 0 0 0 Doxepin N06AA12 H 0 Drug name ATC code Imipramine Risk score No. of pts % Drug name ATC code Risk score H 0 0 0 0.0 0.0 0.0 Alimemazine R06AD01 L 0.0 0.0 0.0 0.0 N06AA02 N06AA03 Meclozine Darifenacin R06AE05 R06AE55 G04BD10 H H 0 0 0 0 Dimenhydrinate R06AA02 H 0 0.0 Procyclidine N04AA04 H 0 0.0 Pyrilamine R06AC01 H 0 0.0 Tizanidine M03BX02 H 0 0.0 L 0 0 0 0.0 0.0 0.0 L 0 0.0 Cimetidine A02BA01 A02BA51 Fluvoxamine N06AB08 Appendix 15: Complete list of drugs with a high anticholinergic activity according to Duran et al. community-dwelling older adults Drug name ATC code Risk No. of score pts Ipratropium H 47 R03AL01 33 R03AL02 9 R03BB01 5 R01AX03 0 Amitriptyline H Oxybutynin G04BD04 Hydroxyzine H 17 1.7 H 7 7 0 3 3 0 0.7 0.7 0.0 0.3 0.3 0.0 2 1 1 0 0 0.2 0.1 0.1 0.0 0.0 N05BB01 N05BB51 Meclozine H R06AE05 R06AE55 Dimenhydrinate/ diphenhydramine 4.6 3.2 0.9 0.5 0.0 3.0 3.0 0.0 H R06AA02 R06AA52 D04AA32 D04AA33 Doxepin N06AA12 H 2 0.2 Nortriptyline N06AA10 H 2 0.2 Tolterodine G04BD07 H 2 0.2 H 1 1 0 0 0.1 0.1 0.0 0.0 Belladona alkaloids A03BA04 A03CB02 A06AB30 % L 0 0 0 0.0 0.0 0.0 N04BC01 G02CB01 % 30 30 0 N06AA09 N06CA01 Bromocriptine No. of pts 0 Disopyramide C01BA03 L 0 0.0 Dosulepin N06AA16 L 0 0.0 Entacapone N04BX02 L 0 0.0 Fexofenadine R06AX26 L 0 0.0 Loratadine R06AX13 L 0 0.0 Methadone N07BC02 L 0 0.0 Nefanzodone N06AX06 L 0 0.0 Oxcarbazepine N03AF02 L 0 0.0 Phenelzine N06AF03 L 0 0.0 Pimozide N05AG02 L 0 0.0 Drug name ATC code N06AA04 No. of pts 1 % Clomipramine Risk score H Clozapine N05AH02 H 1 0.1 Levomepromazine N05AA02 H 1 0.1 Trihexyphenidyl N04AA01 H 1 0.1 H 0 0 0 0 0.0 0.0 0.0 0.0 H 0 0 0 0 0 0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Atropine A03BA01 S01FA01 A03CB03 Chlorphenamine R06AB04 R06AB54 Imipramine H N06AA02 N06AA03 Scopolamine (hyoscine) H 0.1 Darifenacin A04AD01 N05CM05 S01FA02 A04AD51 G04BD10 H 0 0 0 0 0 0 Flavoxate G04BD02 H 0 0.0 Procyclidine N04AA04 H 0 0.0 H 0 0 0 0 0 0.0 0.0 0.0 0.0 0.0 Promethazine R06AD02 D04AA10 R06AD52 V03AB05 80 0.0 Pyrilamine R06AC01 H 0 0.0 Tizanidine M03BX02 H 0 0.0 Appendix 16: Complete list of drugs with a high anticholinergic activity according to Duran et al. institutionalized older adults Drug name ATC code Risk No. score of pts Ipratropium H 56 R03AL01 28 R03BB01 14 R03AL02 13 R01AX03 1 Oxybutynin G04BD04 Amitriptyline Clozapine N06AA09 N06CA01 N05AH02 Hydroxyzine Trihexyphenidyl Promethazine 14.0 7.0 3.5 3.3 0.3 H 1 1 0 0.3 0.3 0.0 G04BD07 H 1 0.3 G04BD02 H 1 0.3 H 0 0 0 0 0.0 0.0 0.0 0.0 H 0 0 0 0 0.0 0.0 0.0 0.0 Atropine A03BA01 S01FA01 A03CB03 14 14 0 6 3.5 3.5 0.0 1.5 5 5 0 3 1.3 1.3 0.0 0.8 3 3 0 0 0 0.8 0.8 0.0 0.0 0.0 Meclozine R06AD02 D04AA10 R06AD52 V03AB05 % Flavoxate H H No. of pts Tolterodine 4.8 H Risk score R06AB04 R06AB54 19 H ATC code Chlorphenamine % H H N05BB01 N05BB51 N04AA01 Drug name Belladona alkaloids A03BA04 A03CB02 A06AB30 Clomipramine N06AA04 H 0 0.0 Doxepin N06AA12 H 0 0.0 H 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Imipramine H 0 0 0 0 0 0 0 N06AA02 N06AA03 H Levomepromazine N05AA02 H 2 0.5 Darifenacin R06AE05 R06AE55 G04BD10 Nortriptyline N06AA10 H 2 0.5 Dimenhydrinate R06AA02 H 0 0.0 H 2 2 0 0 0 0.5 0.5 0.0 0.0 0.0 Procyclidine N04AA04 H 0 0.0 Pyrilamine R06AC01 H 0 0.0 Tizanidine M03BX02 H 0 0.0 2 2 0 0 0 0.5 0.5 0.0 0.0 0.0 Diphenhydramine D04AA32 R06AA02 D04AA33 R06AA52 Scopolamine (hyoscine) H N05CM05 A04AD01 S01FA02 A04AD51 81 Appendix 17: Complete list of drugs with anticholinergic properties according to Rudolph et al. communitydwelling older adults Drug name ATC code Risk No. % score of pts Trazodone N06AX05 1 49 4.8 hydrochloride Ranitidine A02BA02 1 42 4.1 hydrochloride Carbidopa-levodopa 1 31 3.1 N04BA02 27 2.7 N04BA01 0 0.0 N04BA03 4 0.4 Amitryptyline 3 30 3.0 hydrochloride N06AA09 30 3.0 N06CA01 0 0.0 Drug name Paroxetine hydrochloride Loperamide hydrochloride N06AB05 1 2 A07DA03 A07DA05 A07DA53 27 2.6 2.6 0.0 0.0 Cetirizine hydrochloride Oxybutynin chloride R06AE07 2 25 2.5 G04BD04 3 17 1.7 Mirtazapine N06AX11 1 15 1.5 Metoclopramide hydrochloride Hydroxyzine A03FA01 1 9 0.9 3 7 7 0 0.7 0.7 0.0 N05BB01 N05BB51 Pramipexole dihydrochloride Quetiapine fumarate Pseudoephedrine hydrochloride Meclizine hydrochloride N04BC05 1 6 0.6 N05AH04 1 5 0.5 2 4 3 1 0.4 0.3 0.1 3 0.3 R01BA52 R01BA02 R06AE05 3 2 G04BD07 2 2 0.2 Baclofen M03BX01 2 1 0.1 Clozapine N05AH02 2 1 0.1 Loratadine R06AX13 2 1 0.1 Olanzapine N05AH03 2 1 0.1 Haloperidol N05AD01 1 1 0.1 Risperidone N05AX08 1 1 0.1 3 0 0 0 0 0.0 0.0 0.0 0.0 R06AB02 3 0 0.0 N06AA02 3 0 0.0 3 0.0 0.0 0.0 0.0 0.0 0.0 Nortriptyline hydrochloride Tolterodine tartrate Risk score 3 R06AA02 R06AA52 D04AA32 D04AA33 Cimetidine 2.7 26 26 0 0 A02BA01 A02BA51 N06AA10 No. of pts 2 1 1 0 0 2 2 0 2 Diphenhydramine hydrochloride ATC code 2 Atropine producten A03BA01 S01FA01 A03CB03 Chlorpheniramine maleate Imipramine hydrochloride Promethazine hydrochloride Tizanidine hydrochloride Entacapone Selegiline hydrochloride 82 % 0.2 0.1 0.1 0.0 0.0 0.2 0.2 0.0 0.2 R06AD02 D04AA10 R06AD52 V03AB05 M03BX02 3 0 0 0 0 0 0 N04BX02 1 0 0.0 N04BD01 1 0 0.0 Appendix 18: Complete list of drugs with anticholinergic properties according to Rudolph et al. institutionalized older adults Drug name ATC code Risk No. % score of pts Trazodone N06AX05 1 55 13.8 hydrochloride Carbidopa-levodopa 1 51 12.8 N04BA02 44 11.0 N04BA01 0 0.0 N04BA03 7 1.8 Quetiapine fumarate N05AH04 1 36 9.0 Ranitidine hydrochloride Risperidone A02BA02 1 36 9.0 N05AX08 1 34 8.5 Mirtazapine N06AX11 1 25 6.3 Cetirizine hydrochloride Loperamide hydrochloride R06AE07 2 21 5.3 2 20 20 0 0 5.0 5.0 0.0 0.0 A07DA03 A07DA05 A07DA53 Oxybutynin chloride G04BD04 3 19 4.8 Haloperidol N05AD01 1 19 4.8 Metoclopramide hydrochloride Amitryptyline hydrochloride A03FA01 1 15 3.8 3 14 14 0 3.5 3.5 0.0 Olanzapine N05AH03 2 13 3.3 Clozapine N05AH02 2 6 1.5 3 5 5 0 1.3 1.3 0.0 N06AA09 N06CA01 Hydroxyzine N05BB01 N05BB51 Paroxetine hydrochloride Baclofen N06AB05 1 5 1.3 M03BX01 2 3 0.8 Drug name Promethazine hydrochloride Pramipexole dihydrochloride Diphenhydramine hydrochloride Nortriptyline hydrochloride Selegiline hydrochloride Tolterodine tartrate Pseudoephedrine hydrochloride ATC code Risk score No. of pts 3 3 0 0 0 3 % 3 2 2 0 0 0 0.5 0.5 0.0 0.0 0.0 N06AA10 2 2 0.5 N04BD01 1 2 0.5 G04BD07 2 1 0.3 2 3 1 0 1 0 0 0 0 0.3 0.0 0.3 0.0 0.0 0.0 0.0 R06AB02 3 0 0.0 N06AA02 3 0 0.0 R06AE05 3 0 0.0 M03BX02 3 0 0.0 2 0 0 0 0.0 0.0 0.0 3 R06AD02 D04AA10 R06AD52 V03AB05 N04BC05 1 D04AA32 R06AA02 D04AA33 R06AA52 R01BA02 R01BA52 Atropine producten A03BA01 S01FA01 A03CB03 Chlorpheniramine maleate Imipramine hydrochloride Meclizine hydrochloride Tizanidine hydrochloride Cimetidine A02BA01 A02BA51 83 0.8 0.8 0.0 0.0 0.0 0.8 Loratadine R06AX13 2 0 0.0 Entacapone N04BX02 1 0 0.0 LECTURES 1. March 4, 2015: Research on the causes of human cancer and scientific strategies for cancer prevention and control by Dr. Inge Huybrechts There are about 200 types of cancer, leading to about 7.6 million deaths annually worldwide and most of them occur in low- and middle- income countries. This prevalence is still increasing. There are many risk factors for cancer but eight of them account for 50% of all cancer deaths. These risk factors are more common in low- and middle- income countries and smoking is the most common of them. Apparently there is a genetic predisposition as well as a geographical influence either. There are however some UN organizations researching cancer and striving for cancer control such as the WHO, the International Agency for Research on Cancer (IARC) as well as government cancer institutions such as the National Cancer Institute (NCI) and local initiatives. Dr. Huybrechts, who works for IARC, then explained IARC’s process for classifying potential cancer hazards. IARC mainly researches the literature on cancer research and classifies those cancer hazards in five categories depending on the scientific evidence. These monographs include chemicals, complex mixtures, occupational exposures, physical and biological agents and lifestyle factors. Over the years, they created an “Encyclopaedia of carcinogens” with over 400 possibly carcinogenic agents. I thought this was an interesting presentation on cancer and cancer research, but the explanation on how IARC reaches a verdict for a certain cancer hazard and how they work was a little long. In my opinion, a more general presentation on cancer research would have been more interesting. 2. March 19, 2015: The evolution of microbiology in cystic fibrosis: Prof.dr. Li Puma In this lecture the definition and evolution of microbiology and cystic fibrosis (CF) and the evolution of thinking about the microbiology of CF were discussed. There are different parts in microbiology. In this lecture, infectious diseases were the focus. CF is multiple system disease causing problems mainly in the patient’s lungs possibly leading to death at a very young age. In the 1940’s the main therapy for CF was inhalation of penicillin but children died before the age of 40 months due to S. aureus infections in the lungs. The treatment of CF between the ’40s and 1967 was mainly to, without any evidence-based studies, give the patient various antibiotics and see what happens. This approach seemed to work and overall survival increased to 5 years and older. Thanks to antibiotic susceptibility testing, the antibiotics were adapted and overall survival increased even more. Because of this, the population of patients with CF changed into an older population in need of social support but CF in itself changed as well and a mutated P. aeruginosa became the most 84 prevalent bacterium in the lungs. More research showed that resistance against the antibiotics was transmissible between the patients and soon the summer camps and specialized clinics were closed or adapted. To avoid resistance, antibiotics are first tested before they are administered to the patients and the FDA specifically asks for documents on how active the new medicines are against P. aeruginosa. There is however a wide variety of bacteria present in the lungs of CF patients who seem to communicate with each other. Current research focuses on the different bacteria: which are present, which communicate and is this communication positive or negative, what is the relative abundance and how can we best eradicate them? These questions allow for an exciting future. In my opinion, this was a very fascinating lecture most of which I will definitely remember for quite some time. Prof. Dr. Li Puma kept me interested throughout the entire lecture and made me very excited about this topic. I can’t wait what the future holds for the microbiology of CF and it’s medication. 3. April 22, 2015: Are management skills in pharmaceutical care important for the future? A view from “Nether-Belgian” perspective: Hendrik De Rocker Recently there has been some evolutions in pharmaceutical care. The patient became the main focus in community-pharmacies instead of the drug. Besides that, preventing diseases is becoming more important than curing them. Because of changes in society and the patients’ expectations, the pharmacists their main activity is evaluating as well. Patients are becoming more empowered and they should be approached with an integrated vision. The pharmacist’s activities are based on three pillars: drug use, prevention and ‘referral center’. The second part of the lecture focused on management in community-pharmacies. Mr. De Rocker started by explaining the definition and evolution of management as well as the different levels of management in the pharmaceutical cares system. Management is also important in the daily operation of community-pharmacies. The pharmacist should look for the most effective, appropriate and safe combination of drugs for the patient while also taking the patients’ wishes into account. The goal of this is the improvement of the patient’s quality of life. This is called Pharmaceutical patient care (FPZ). Mr. De Rocker continued by giving some examples and challenges in the Netherlands and Belgium. The conclusion of this lecture was that pharmacists will have to limit the impact of chronic diseases on the population in the future. He will have to cooperate with physicians and patients, acquire specific skills, offer preventive care and focus on the patient in order the reach this goal. In my opinion, this was a very interesting lecture on what we can expect in the future and how pharmaceutical care should evolve to meet the changing needs and to still be valuable in the future. Unfortunately, the lecture stayed very theoretical and didn’t focus on daily life examples. 85