Durante mucho tiempo no había principios uniformes para la Atribución de nombres a los antibióticos https://antibioticos-wiki.es . Más a menudo se les llama por el nombre genérico o especie del producto, con menos frecuencia-de acuerdo con la estructura química. Algunos antibióticos se nombran de acuerdo con el lugar donde se asignó el producto.
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Eur J Clin PharmacolDOI 10.1007/s00228-007-0394-1
Identification of severe potential drug-drug interactionsusing an Italian general-practitioner database
L. Magro & A. Conforti & F. Del Zotti & R. Leone &M. L. Iorio & I. Meneghelli & D. Massignani & E. Visonà &U. Moretti
Received: 9 July 2007 / Accepted: 27 September 2007
number of different types of severe potential DDIs was 119,
Objective To analyze prescriptions in a general-practitioner
which occurred 1,037 times in 758 patients (4.7% of the total
database over 1 year to determine the frequency, the
number of patients). More than 80% of drugs involved in
characteristics, and the monitoring of the severe potential
severe potential DDIs were cardiovascular drugs. Digoxin was
the most frequently involved drug. Electrolyte disturbances,
Methods We retrospectively analyzed the clinical records from
increase in serum digoxin levels, risk of hemorrhage, severe
16 general practitioners in the Veneto region, an area in northern
myopathy or rhabdomyolysis, and cardiac arrhythmias were
Italy. The study covered the period from January 1 to December
the most commonly implicated potential risks. When consid-
31, 2004. We selected all severe and well-documented
ering patients using digoxin with loop or thiazide diuretics for
interactions according to the book Drug Interaction Facts by
more than 5 months, 72% had at least one test to monitor
David S. Tatro (Facts and Comparisons, St. Louis, MO,
potential digoxin toxicity, whereas 28% had no tests. Sixty-
2006). We grouped severe potential DDIs according to their
four percent of patients using digoxin with amiodarone,
specific potential risk, and for the most frequently interacting
verapamil, or propafenone had an ECG and/or digoxin
drug pairs, we investigated whether some specific tests had
monitoring, and 36% of them did not have any tests.
been prescribed by physicians for safety monitoring.
Conclusions The present study revealed that, in a group of
Results During the study period, 16,037 patients (55% female)
Italian general practitioners, the risks of severe potential
with at least one drug prescription were recorded, and a total of
drug interactions are relatively low and the drugs concerned
185,704 prescriptions relating to 1,020 different drugs were
are few. Analyses of specific tests showed that physicians
analyzed. Ramipril was the most frequently prescribed drug
are generally aware of the potential risks caused by digoxin
followed by acetylsalicylic acid and atorvastatin. The final
drug associations. However not all patients were closelymonitored and this should be improved.
L. Magro A. Conforti R. Leone M. L. Iorio
I. Meneghelli U. MorettiClinical Pharmacology Unit, University of Verona,
Severe potential drug-drug interactions . Monitoring
European General Practice Research Network (EGRPN),Verona, Italy
In the broadest sense, a drug-drug interaction (DDI) may be
defined as the pharmacological or clinical response to the
Società Italiana Medicina Generale (SIMG),
administration of a drug combination that is different from
that anticipated from the known effects of the two agents
when given alone and that can result in reduced effective-
Clinical Pharmacology Unit, Policlinico G.B. Rossi,
ness or increased toxicity []. A DDI can be the
consequence of various situations that reflect the growing
37134 Verona, Italye-mail: aconforti@sfm.univr.it
number of drugs available on the market. The increasing
complexity of polytherapy is a major source of DDIs. The
three levels of severity—major, moderate, and minor—and
very widespread practice of self-medication makes the
five categories of degree of documentation—established,
situation more severe and difficult.
probable, suspected, possible, and unlikely. Based on a
In the literature, most studies on drug interactions have
combination of these two elements, he assigns a signifi-
analyzed patients in hospitals, and it has been estimated that
cance rating (from 1 to 5) to each DDI.
drug interactions may affect up to 63% of all hospitalized
By excluding drugs not used in primary care and not
patients Data about outpatients exposed to drug
available in the Italian market, a list of 895 DDIs with
interactions are limited, and a few studies set in the context
significance rating of 1 (major severity and established or
of general practice have generated a wide range of
probable or suspected documentation) were selected. In the
estimates. In primary health care, from 9 to 70% of patients
database, we looked for patients who were concomitantly
are reported to use concomitant drugs with the risk of a
potential DDI ], even if these are serious only in a
We assumed that consumption of a drug started the same
fraction of these patients (from 0.5 to 2%) [,
day the drug was prescribed, and for each patient we
According to the literature, many factors contribute to
calculated the period of exposure to each interacting drug
these wide ranges, either in a hospital or an outpatient
by multiplying the number of defined daily doses (DDD)
setting, including the target population, the number of
by the number of prescribed packs. Severe potential DDIs
prescribed drugs, or the differences in methods used.
were identified when the exposure periods to two interact-
Some studies have quantified the outcome of specific
ing drugs overlapped. Severe potential DDIs were grouped
interactions , however little or nothing is known
according to their specific potential risk, as described in
about the actual number of patients with serious conse-
We considered the most frequently interacting drug pairs
quences resulting from potential DDIs in primary health
and investigated whether some specific tests had been
care [The few published studies are related to hospital
prescribed by physicians for safety monitoring of poten-
settings. Some authors suggest that even if many patients
use potentially interacting drugs, the real risk related tothese associations seems to be low or modest , Onthe other hand, other authors suggest that DDIs are a major
The purpose of this study was to analyze prescriptions in
During the study period, 16,037 patients with at least one drug
a general-practitioner database over 1 year to determine the
prescription were recorded by 16 GPs. Every physician had
frequency, the characteristics, and the monitoring of the
approximately the same number of patients. Table shows the
general characteristics of the patients in the database. Themean age was 53.1 years; the majority of individuals (66%)fell in the age range between 15 and 64 years, and there was
an evident prevalence of women in older age groups (61%were female in the patients >75 years). A total of 185,704
We retrospectively analyzed the clinical records from 16
prescriptions relating to 1,020 different drugs (available as
general practitioners (GPs) in the Veneto region, an area in
single or combined formulations) were analyzed.
northern Italy. The study covered the period from January 1
As shown in Fig. , most patients (48%) received two to
to December 31, 2004. During this year every physician
five different drugs, whereas 35% of them had prescriptions
used the same software to record all drug prescriptions,
for more than five drugs. Seventeen percent of patients
medical tests and the most important clinical events foreach patient in a personal clinical record. Data from all
Table 1 Characteristics of general-practice patient database (16 GPs)
computerized clinical records were pooled in a singledatabase. Patients with at least one drug prescription during
All drugs prescribed to each patient in the study period
were registered, since in Italy a prescription by the GP is
necessary to have the drug or the medical test reimbursed
by the National Health System, which covers the majority
To define severe DDIs, we used the book Drug
Interaction Facts by David S. Tatro, one of the primary
sources for drug information [, The author defines
895 different types of severe DDIsa researched in 16,037 patients
119 different types of severe potential DDIs found in
758 patients (4.7% of the total number of patients)
% of patients
- 559 patients with one DDI- 144 patients with 2 different DDIs
- 36 patients with 3 different DDIs- 13 patients with 4 different DDIs
Number of different drugs
Fig. 1 Number of different drugs per patient
could not have DDIs because they received prescriptions
Fig. 2 Flow chart showing identification of severe potential DDIs
for only one drug. The median number of different drugsper patient was three (range 1–35).
interactions). Diuretics, amiodarone, warfarin, verapamil, and
Table shows the 10 most frequently prescribed drugs,
ACE inhibitors were also frequently involved.
expressed as total DDDs during the study year, and their
Among the antibacterial drugs, the macrolide azithro-
ranking in the national consumption database in the same
mycin was associated with atorvastatin (18 patients) and
period. Ramipril was the most frequently prescribed drug
simvastatin (13), and the fluoroquinolone levofloxacin was
followed by acetylsalicylic acid and atorvastatin. All drugs
associated with amiodarone (17 patients). In 15 patients
were present in the national top 10 list except for atenolol
treated with acetylsalicylic acid, the nonsteroidal anti-
and the association ramipril-hydrochlorothiazide ].
inflammatory ketorolac was also used.
As shown in Fig. , we found 119 different severe potential
Table lists the 1,037 severe potential DDIs grouped
DDIs (out of 895), which occurred 1,037 times in 758
according to the potential risk as described in [].
patients (4.7% of the total number of patients). The majority
Electrolyte disturbances, increase in serum digoxin levels,
of patients (74%) had only one potential DDI, but in six
risk of hemorrhage, severe myopathy or rhabdomyolysis,
patients (0.04%), five different potential DDIs were detected.
and cardiac arrhythmias were the most commonly impli-
Table shows the severe potential DDIs occurring in more
than 10 patients. The drug pairs listed in the table represent
We focused on digoxin toxicity since it was the most
69% of total potential interactions and the digoxin/furosemide
frequently involved drug and looked for medical tests
pair was the most frequent one (23%). Forty-three severe
Table 3 Drug pairs causing severe potential DDIs concomitantly used
potential DDIs occurred only once. More than 80% of
in more than 10 patients and cumulative percentages
involved drugs were cardiovascular drugs, and digoxin wasthe most frequently implicated drug (47% of total potential
Table 2 The top 10 prescribed drugs among study patients expressed
Table 4 Severe potential DDIs (1,037) grouped according to their potential risk
Furosemide (243) or thiazide diuretics (142)
disturbances may predisposeto digitalis-induced arrhythmias
ACE-inhibitors (178), angiotensin II-receptor
antagonists (53), or potassium preparations (19)
Amiodarone (57), verapamil (28), propafenone (7),
clarithromycin (5), doxycycline (1), or quinidine (1)
increase in the pharmacologicand toxic effects of digoxin
Amiodarone (59), cotrimoxazole (5), sulfinpyrazone (1),
macrolide antibiotics (8), fibric acids (5), azole
antifungal agents (3), or metronidazole (1)
Macrolide antibiotics (48), cyclosporine (7),
Antiarrhythmic agents (21), tricyclic antidepressants
NSAIDS (14), sulfasalazine (4), or amoxicillin (3)
Risperidone (7) or selective 5-HT1-receptor
indicating physician awareness of potential risks. We
followed by a careful evaluation of the patient in order to
investigated whether electrocardiograms were carried out
consider possible risk factors, concomitant pathologies, and
or serum potassium or digoxin concentration levels were
measured by physicians in patients treated for at least
In the present study, the analysis of prescriptions by 16
5 months with digoxin in association with diuretics (165
GPs over 1 year showed that, in general practice, 4.7% of
patients) and anti-arrhythmics (53 patients). Tables and
the patients concomitantly used drugs that could cause a
show the patients who underwent specific tests after the
severe potential DDI. Previous studies showed that 0.5–2%
beginning of these drug associations. Thirty-five percent of
of patients are exposed to serious potential drug interactions
patients had one test, 26% had two tests and 11% had threetests. However 28% of them were treated with the
Table 5 Number of tests [ECG, digoxin level, potassium (K) serum
combination for more than 5 months without any testing.
level] in 165 patients with at least 5 months of co-administration ofdigoxin and diuretics
Sixty-four percent of patients using digoxin with amiodar-one, verapamil, or propafenone had an ECG, digoxin
monitoring or both, but 36% of them did not have any tests.
The correct use of a drug is determined by several
or ECG + K serum level, or digoxin +K serum level)
important factors, including the awareness of product
All (ECG + digoxin level + K serum level)
characteristics, such as contraindications and warnings,
Table 6 Number of tests (ECG, digoxin level) in 53 patients with at
effects of digoxin, particularly in patients with cardiac
least 5 months of co-administration of digoxin and amiodarone,
The administration of amiodarone, verapamil, or propafe-
none to patients on stable doses of digoxin results in increaseddigoxin serum levels. The increase in serum digoxin level
after the addition of amiodarone has been reported in the
literature as between 69 and 800% , ]. Verapamil and
digoxin have additional effects to slow atrio-ventricularconduction; investigations in healthy volunteers and cardiac
in primary health care However differences in the
patients indicated that verapamil raises plasma digoxin
selection of interactions or in the target population could
concentrations 60–75% In addition, verapamil
explain these discrepancies. In our study, the most
decreased digoxin elimination and total body digoxin
commonly interacting drugs were cardiovascular drugs
clearance was reduced by approximately 35% []. There
(more than 80%). Bjerrum and colleagues showed that in
was an increase in premature ventricular contraction fre-
primary health care most of the potential interactions
quency in 1 out of 10 patients on the combination [] and
emerged in patients treated with cardiovascular drugs
another study reported digoxin toxicity in 7 out of 49
(diuretics, ACE inhibitors, digoxin, beta-blockers and
patients treated with verapamil [], but it is still unclear if
calcium channel blockers), NSAIDs, oral antidiabetics,
an increased risk of digoxin-induced arrhythmias exists.
and anticoagulants. Considering only major potential
Due to the considerable risk of the above-mentioned
interactions, the most frequently involved drugs were
interactions, many authors agree that some relevant
potassium-sparing diuretics and anticoagulants []. A study
parameters should be closely monitored and that the dosage
relating to multiple-drug prescribing by GPs in Germany
of digoxin should be individualized and reduced when
concluded that the most frequently found drug pairs
patients receive these medications concurrently ,
implicated in potential DDIs were digitalis/diuretics, digi-
In our study, 72% of patients using digoxin with loop or
talis/calcium channel blockers, and theophylline/quinolones
thiazide diuretics for at least 5 months had some tests
]. Other authors, looking at elderly outpatients, found
relating to the monitoring of digoxin. On the other hand, in
that the most common potential interactions were between
28% no tests of any kind related to the risk of interaction
beta-adrenergic blockers and anti-diabetics, followed by
were done, showing inadequate monitoring. General practi-
potassium-sparing diuretics and potassium preparations [].
tioners are probably aware of the risk of digoxin combina-
In our results the most frequently interacting drug was
tions and made the prescriptions because they thought the
digoxin, involved in almost half of total severe potential DDIs.
benefits of the drugs outweighed the risks. However our
Although this drug has been used for more than two centuries,
findings strengthen the need to improve their knowledge of
its role in the management of chronic heart failure has been
the proviso that all patients should be monitored. It should
more precisely defined by recent clinical trials showing that
be underlined that 322 out of 385 patients treated with
digoxin therapy was associated with no beneficial effects on
digoxin and diuretics received concomitant administration
mortality, but only with a reduction in clinical symptoms and
of ACE inhibitors, sartans, potassium, or potassium-sparing
in the frequency of heart failure-related hospitalization
diuretics, known to induce hyperkalemia. In this group, 162
]. Therefore digoxin, even at low doses, is currently
patients (∼50%) had at least one potassium serum level test,
considered most beneficial in symptomatic patients who are
showing hyperkalemia (K>5.3 mEq/l) in 17 patients, and in
already undergoing adequate diuretic therapy and taking
only one case hypokalemia (K<3.5 mEq/l).
ACE inhibitors with or without beta blockers [, ].
Physicians seem to be less aware of the risk from the
The relationship between diuretic-induced electrolyte
combination of digoxin with amiodarone, verapamil, or
depletion and digitalis-induced arrhythmia, as well as the
propafenone; 36% of patients using these drug associations
connection between the toxic effects of digoxin and the use
for at least 5 months had no related tests in the period
of anti-arrhythmic drugs, is known and widely accepted
, In an intensive-care study, patients treated with
Potassium-sparing diuretics were commonly prescribed
digitalis and diuretics had an approximately 1.5-fold higher
along with either ACE inhibitors, sartans, or potassium
risk of digoxin toxicity compared to those treated with
preparations by the physicians participating in this study. The
digitalis alone ]. In a review on digoxin, the association
risk of hyperkalemia due to this association is well documented
between digoxin and loop and thiazide diuretics proved
in the literature. Many authors reported life-threatening hyper-
among the most important drug interactions, causing a
kalemia in patients treated with spironolactone associated with
dose-dependent reduction in serum potassium and magne-
ACE inhibitors or sartans [, –even if in other
sium [This reduction increases the arrhythmogenic
published studies this risk has been reported as infrequent ].
In our study, 250 potential DDIs occurred between
potassium-sparing diuretics and ACE inhibitors, sartans, orpotassium supplements, although in all but four patients,
The present study revealed that, in a group of Italian
loop or thiazide diuretics were concomitantly prescribed.
general practitioners, the numbers of severe potential drug
This co-prescription could have reduced the risk of hyper-
interactions are relatively low and the drugs concerned are
few. The monitoring of patients treated with digoxin and
Many patients with cardiac arrhythmias in our database
other cardiovascular drugs should be improved. The use of
received concomitant therapy with warfarin and amiodar-
concomitant drugs to compensate for hyperkalemia or
one. This association requires a significant warfarin dose
hypokalemia induced by some cardiovascular drugs seems
reduction, due to the risk of hemorrhage. Moreover thyroid
to indicate physicians′ awareness of potential electrolyte
disorders may affect warfarin sensitivity, with hypothyroid-
disturbances. Moreover precise and updated information on
ism and thyrotoxicosis resulting in increased or decreased
interacting drugs could prevent the occurrence of known
warfarin requirements, respectively ].
interactions, particularly when therapeutic alternatives exist.
In the present study, about 50 patients were treated
concomitantly with statins and macrolides, mainly repre-
We thank all general practitioners involved in
sented by atorvastatin and azithromycin. The risk of
this study for collecting the clinical records. The authors have no
myopathy and rhabdomyolysis, well documented in statin
conflicts of interest directly relevant to the content of this study.
users, increases in cases of concomitant prescription withcytochrome P450 (CYP) inhibitors such as macrolides ]. Simvastatin and atorvastatin are mostly metabolized by the
Azithromycin shows a lower affinity to this isoenzyme
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ADR-Merkblatt Transport von Stihl-Akku-Packs ADR-Merkblatt für STIHL-Händler Transport von Stihl-Akku-Packs (Lithium-Ionen-Batterien) 1. VORWORT ACHTUNG! Das folgende Merkblatt beschreibt zum einen den Transport von Stihl-Akku-Packs der Serie AP ohne und mit Geräten und zum anderen den Transport von gebrauchten Akku-Packs und Batterien für den Versand im Rücknahmesystem. Wer