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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. This is because Duran et al. included all drugs considered
to have anticholinergic properties while Rudolph et al. did not. The top 10 most commonly used
drugs according to Duran et al. and Rudolph et al. were largely comparable. Here as well the
percentages in the top 10 were considerably higher for the population of institutionalized older
adults. These numbers were lower in other studies but they also included non-polypharmacy
patients. Finally, further research is necessary to create an unambiguous risk scale for estimating the
individual risk of ADE’s and to estimate the increase in QoL in case the use of drugs with
anticholinergic properties is reduced.
42
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levels in the elderly: a population based study in a French region. Archives of gerontology and geriatrics 2014;59(3):630-5.
Epub 2014/09/07. DOI 10.1016/j.archger.2014.08.006
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2010/10/23. DOI
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home admission. Journal of the American Medical Directors Association 2012;13(1):83.e9-15. Epub 2012/01/03. DOI
10.1016/j.jamda.2011.02.009
45.
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Belgium. International journal of clinical pharmacy 2014;36(4):757-65. Epub 2014/05/09. DOI 10.1007/s11096-014-9953-6
46.
Baptista R, Silva S, Dias P, Monteiro P, Feio J, Providência LA. In-hospital prescription of QT-prolonging drugs in a
cohort of more than 100,000 patients. International Journal of Cardiology 2011;147(1):165-6.
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outpatients. The American journal of medicine 2003;114(2):135-41. Epub 2003/02/15. DOI
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49.
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Herdewijn P VCS. 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