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Current
Drug Safety
ISSN: 1574-8863
Current Drug Safety
Volume 3, Number 3, September 2008
Contents
Editorial Pp. 167
Changes in Bone Turnover, Bone Mineral and Fracture Risk Induced
by Drugs Used to Treat Epilepsy Pp. 168-172
Peter Vestergaard
[Abstract]
Skeletal Effects of Drugs to Treat Cancer
Pp. 173-177
Peter Vestergaard
[Abstract]
Cardiovascular Drugs and Bone Pp.
178-184
Lars Rejnmark
[Abstract]
Skeletal Effects of Central Nervous System
Active Drugs: Anxiolytics, Sedatives, Antidepressants, Lithium
and Neuroleptics Pp. 185-189
Peter Vestergaard
[Abstract]
Skeletal Effects of Systemic and Topical
Corticosteroids Pp. 190-193
Peter Vestergaard
[Abstract]
Bone Effects of Glitazones and Other
Anti-Diabetic Drugs Pp. 194-198
Lars Rejnmark
[Abstract]
Pain-Relief Medication and Risk of Fractures
Pp. 199-203
Peter Vestergaard
[Abstract]
Proton Pump Inhibitor Therapy and Osteoporosis
Pp. 204-209
Yu-Xiao Yang
[Abstract]
General Articles
Combination of Aripiprazole and Other Psychopharmacological
Treatments in Resistant and Multi-Resistant Patients Pp.
210-215
Jesús Vicente Cobo Gómez,
Gideoni Fuste, Ramón Coronas, Nagore Benito, Juan-David
Barbero, Cristina Domenech and Gemma García-Parés
[Abstract]
Developmental Immunotoxicity (DIT) in
Drug Safety Testing: Matching DIT Testing to Adverse Outcomes
and Childhood Disease Risk Pp. 216-226
Rodney R. Dietert
[Abstract]
Improving Medication Reconciliation in
the 21st Century Pp.
227-229
Daniel P. Dunham and Gregory Makoul
[Abstract]
Clinical Strategies for Preventing Postoperative
Nausea and Vomiting After Middle Ear Surgery in Adult Patients
Pp. 230-239
Yoshitaka Fujii
[Abstract]
Abstracts
[Back to top]
Editorial: Fracture Risk Associated with Prescribed Medication
Bone fractures are a source of considerable morbidity
that is likely to increase as the age of the general population
rises. Physicians should avoid additional fracture risk that
might result from choosing inappropriate drugs or failing
to attend to other important factors such as vitamin D or
nutritional status.
This collection of papers on the bone changes and fracture
risk associated with prescribed medication is both fascinating
and informative. The conclusions of some of the contributions
are contrary to traditional views, implying that a re-examination
of practice may be warranted. Other reviews in the collection
make it clear that a drug that can reduce one public health
problem may increase fracture risk, leading to a different
public health concern.
Some of the salient points from the review papers in this
series follow.
Oral corticosteroids are associated with an increased fracture
risk from effects on sex steroids, vitamin D, calcium balance,
bone cells and the bone matrix. However, the increase in fracture
risk with oral administration seems to be more linked to daily
than to cumulative dose. Inhaled and topical steroids are
generally not associated with an increased fracture risk unless
higher than recommended doses are used. Proton pump inhibitors
may increase fracture risk, implying that the lowest doses
together with maintenance of good vitamin D and calcium status
are advisable. Some drugs used to treat cardiovascular conditions
might actually increase bone mineral density (BMD) but loop
diuretics and amiodarone appear to decrease it and to increase
fracture risk. There is not sufficient evidence for many of
the cardiovascular drugs to allow firm conclusions to be drawn.
Bone problems and fracture risk have long been associated
with antiepileptic drugs but it appears that the risk attributable
to the medication may have been overestimated. Good control
of seizures and attention to vitamin D/nutritional status
may be much more important factors. Benzodiazepines are associated
with a small increase in fracture risk, possibly because of
increased falls. Tricyclic antidepressants and SSRIs are associated
with an increased fracture risk; it is of particular interest
to note that the SSRIs might be worse in this regard, probably
both through effects on BMD and on balance. Neuroleptics appear
to be associated with a small increase in fracture risk but
lithium, in contrast, appears to decrease fracture risk. Antineoplastic
drugs that decrease sex steroid effects increase fracture
risk but tamoxifen, which is a partial oestrogen agonist,
increases BMD and may reduce the risk. Diabetes appears to
increase fracture risk through a number of mechanisms and
glitazones may increase the risk further but metformin and
the sulphonylureas decrease fracture risk. With regard to
analgesic medication, paracetamol (acetaminophen) increases
fracture risk but aspirin (acetylsalicylic acid) does not.
Some non-steroidal anti-inflammatory drugs (NSAIDs) appear
to increase BMD but this potentially beneficial effect on
fracture risk might be lost because of an increase in adverse
effects leading to falls; fracture risk is increased with
some but not all NSAIDs. Opiates have been shown to decrease
BMD but effects on falls might be of greater importance.
There are many factors affecting fracture risk, implying that
research in this field needs to be meticulous in analysing
the importance of each of these factors if misleading conclusions
are to be avoided.
This is the first in the Current Drug Safety “Hot Topics”
series. It is unusual, in that most of the papers come from
one centre, a practice that, as Editor-in-Chief, I should
not generally encourage. However, the centre concerned specialises
in the area and the quality of the reviews from experienced
workers in the field speaks for itself. I hope that other
readers of these papers will find them as interesting as I
have.
Frank M.C. Besag
(Editor-in-Chief)
Specialist Medical Department
Twinwoods Health Resource Centre
Bedfordshire, MK41 6AT
UK
E-mail: FBesag@aol.com
[Back to top]
Changes in Bone Turnover, Bone Mineral and Fracture Risk Induced
by Drugs Used to Treat Epilepsy
Peter Vestergaard
Antiepileptic drugs (AEDs) have traditionally been associated
with osteoporosis. However, recent studies have only shown
a very limited increase in the risk of fractures with the
use of some but not all AEDs. Patients with epilepsy have
an increased risk of fractures, but this increase is mainly
linked to fractures sustained during seizures. Patients with
epilepsy may also have a decreased bone mineral density but
this decrease is far too small to explain the increase in
fracture risk. The decrease in bone mineral density is seen
mainly in children with complicating diseases and developmental
disorders that lead to vitamin D deficiency. Much of the increase
in fracture risk may be due to the underlying disorder and
the severity of seizures rather than to the drugs used to
treat epilepsy. The prevention of seizures seems to be of
greater importance than any potential detrimental effects
of the AEDs on the skeleton, provided that vitamin D status
is kept at an optimal level. From a fracture point of view
most AEDs seem to be relatively safe.
[Back to top]
Skeletal Effects of Drugs to Treat Cancer
Peter Vestergaard
Drugs used to treat cancer may affect the skeleton in
several ways, the most important being a decrease in sex steroid
levels. This may induce rapid bone loss. Tamoxifen is a partial
oestrogen receptor agonist and antagonist (classified as a
selective oestrogen receptor modulator or SERM). As it has
agonistic effects on oestrogen receptors of bone it increases
bone mineral density and thus may potentially prevent fractures.
In contrast aromatase inhibitors such as anastrozole lead
to a decrease in bone mineral density and an increased risk
of fractures. Most high-dose intravenous chemotherapeutic
regimens induce rapid bone loss from effects on the gonads
with induction, for example, of premature menopause. Low-dose
oral agents such as methotrexate are not associated with an
increased risk of fractures. Androgen deprivation therapies
such as LHRH agonists in breast cancer are also associated
with an increase in bone loss and an increased risk of fractures.
With the increasing long-term survival of patients with cancer,
preventive measures against osteoporosis must be considered.
[Back to top]
Cardiovascular Drugs and Bone
Lars Rejnmark
Cardiovascular diseases are common and occur mainly in
the elderly in whom osteoporotic fractures also are very common.
Because of this, it is of importance to establish whether
drugs used in the treatment of cardiovascular diseases affect
bone, in order to minimise any possible adverse effects. In
the majority of studies, treatment with thiazide diuretics,
statins, digoxin, angiotensin-converting enzyme (ACE)-inhibitors,
and organic nitrates have not been associated with harmful
effects on bone. On the contrary, treatment with these drugs
may improve bone strength but because there is a lack of randomised
controlled trials (RCTs) with fracture as a primary outcome
measure, these drugs should not be pre-scribed for fracture
prevention. In RCTs, treatment with loop diuretics have been
shown to increase plasma levels of parathyroid hormone and
decrease bone mineral density. In epidemiological studies,
treatment with loop diuretics as well as treatment with amiodarone
has been associated with an increased risk of fracture. In
view of the conflicting results from published studies, no
conclusions can be drawn on potential bone effects of treatment
with oral anticoagulants, β-blockers,
and calcium channel blockers.
[Back to top]
Skeletal Effects of Central Nervous System Active Drugs: Anxiolytics,
Sedatives, Antidepressants, Lithium and Neuroleptics
Peter Vestergaard
Many central nervous system active drugs can alter postural
balance, increasing the risk of fractures. Anxiolytics and
sedatives include the benzodiazepines, and these have been
associated with a limited increase in the risk of fractures,
even at low doses, probably from an increased risk of falls.
No systematic differences have been shown between benzodiazepines
with long and short half-lives. Although the increase in risk
of fractures was limited, care must still be taken when prescribing
for older fall-prone subjects at risk of osteoporosis. Neuroleptics
may be associated with a decrease in bone mineral density
and a very limited increase in fracture risk. Antidepressants
are associated with a dose-dependent increase in the risk
of fractures. The increase in relative risk of fractures seems
to be larger with selective serotonin reuptake inhibitors
(SSRIs) than with tricyclic antidepressants. The reason for
this is not known but may be linked to serotonin effects on
bone cells and the risk of falls. With the wide use of SSRIs,
more research is needed. Lithium is associated with a decrease
in the risk of fractures. This may be linked to its effects
on the Wnt glycoprotein family, which is a specialised signalling
system for certain cell types.
[Back to top]
Skeletal Effects of Systemic and Topical
Corticosteroids
Peter Vestergaard
Oral corticosteroids are associated with an increased
risk of fractures from negative effects on sex steroids and
vitamin D with a negative calcium balance, together with negative
effects on the bone cells and the bone matrix. However, the
increase in fracture risk with oral corticosteroids seems
more linked to daily than to cumulative dose. A small daily
dose may consequently be more detrimental than a large cumulative
dose given as intermittent doses. Topical corticosteroids
administered locally in the eyes, ears, in the mouth, on the
skin, and rectally are not associated with an increased risk
of fractures. Inhaled corticosteroids are not associated with
an increased risk of fractures, except at very high doses
that are much higher than the doses usually administered.
With regard to the prevention of fractures, the use of topical
corticosteroids may be preferred over oral administration
where feasible. More research is needed to determine practically
applicable intermittent dosing regimens for corticosteroids,
replacing daily administration, to assess if this can have
the same beneficial clinical effect but avoid, or at least
reduce, the risk of osteoporosis and fractures.
[Back to top]
Bone Effects of Glitazones and Other Anti-Diabetic Drugs
Lars Rejnmark
Several lines of evidence suggest that diabetes causes
harmful effects on bone. This may be due to the diabetic disease
per se i.e., high as well as low insulin and glucose
levels may cause direct effects on bone metabolism. Moreover,
diabetes associated co-morbidity, including impaired vision
and neuropathy may affect physical activity and postural stability
with effects on bone mineral density (BMD) and fracture risk.
In type 1 diabetes, a 7-fold increase in risk of fracture
has been reported but there is controversy about whether risk
of fracture can be reduced by tight glycaemic control. However,
the increased fracture risk seems at least in part to be associated
with complications of diabetes, and therefore good metabolic
control may reduce the risk of fracture in the long term.
Risk of fracture is also increased in type 2 diabetes, but
there are no good-quality studies comparing effects on bone
of insulin with oral anti-diabetic agents. However, there
are differences between bone effects of different oral anti-diabetic
drugs. From a bone perspective, metformin and sulphonylureas
should be chosen rather than glitazones, as randomised trials
have shown that glitazones decrease BMD and increase fracture
risk. The mechanism of action is probably through decreased
bone formation. Conversely, metformin and sulphonylureas may
counter the harmful bone effects of diabetes, as risk of fracture
in patients treated with these drugs seems to be reduced compared
with the general population. Studies are needed to elucidate
mechanisms of action by which metformin and sulphonylureas
may affect bone.
[Back to top]
Pain-Relief Medication and Risk of Fractures
Peter Vestergaard
Medications to treat pain are in widespread use and any
change in the risk of fracture may consequently have a significant
impact at a population level. Strong analgesics of the opiate
and opiate-like group are associated with an increased risk
of fractures probably from an increased risk of falls resulting
from the dizziness induced by these drugs. However, not all
strong analgesics are associated with an increased risk of
fractures. The differences are not readily explained from
variations in pharmacokinetic properties. Weak analgesics
mainly interact with the prostaglandin system; these drugs
include non-steroidal anti-inflammatory drugs (NSAIDs), acetylsalicylic
acid and acetaminophen. Acetaminophen is associated with an
increased risk of fractures while acetylsalicylic acid is
not. Some but not all NSAIDs are associated with an increased
fracture risk, and the differences are not explained by variations
in pharmacokinetic properties. More research is needed to
determine if some analgesics are safer than others with respect
to fracture risk.
[Back to top]
Proton Pump Inhibitor Therapy and Osteoporosis
Yu-Xiao Yang
Osteoporotic fractures, particularly hip fractures, can
have a devastating impact on the well-being of the elderly
population. Recently, two population-based observational studies
reported a highly important association between the use of
potent acid suppressive therapy and an increased risk of hip
fractures. The mechanisms underlying such an association are
not clear. However, a careful review of the existing evidence
seems to suggest that the main physiologic consequences of
proton pump inhibitor therapy may each have a theoretical
influence on bone metabolism. Specifically, inhibition of
the osteoclastic proton pumps may reduce bone resorption,
while profound acid suppression could potentially hamper intestinal
calcium absorption, and secondary hypergastrinemia may enhance
bone resorption through the induction of parathyroid gland
hyperplasia. However, the existing data are clearly too limited
for us to draw any definitive conclusions, and more studies
are urgently needed to delineate the physiologic relevance
of these theoretical mechanistic links, individually and collectively.
[Back to top]
Combination of Aripiprazole and Other Psychopharmacological
Treatments in Resistant and Multi-Resistant Patients
Jesús Vicente Cobo Gómez,
Gideoni Fuste, Ramón Coronas, Nagore Benito, Juan-David
Barbero, Cristina Domenech and Gemma García-Parés
Introduction: Aripiprazole is a new antipsychotic agent
that has proven safe and efficacious in controlled clinical
trials. However, few published data on its effectiveness and
safety when used in augmentation and combination are available.
Methods: Our study aimed to determine the functional
effectiveness and safety of different combinations of aripiprazole
with other psychotropics in resistant patients. All acute
not selected (15) patients treated with aripiprazole and other
psychotropics between February 2005 and May 2007 are included.
Results: Mean follow-up 20.4 days. Main diagnosis
was schizophrenia (40%) and mean dose of aripiprazole was
25 mg/d. Resistant patients received initially multiple psychotropics
(mean 3.3) and their functional status was very low. A significant
functional improvement was observed after admission in most
(12) of them. Only three patients experienced mild to moderate
improvement; another three patients showed extrapyramidal
symptoms. No dermatological reactions or adverse effects were
observed with lamotrigine association.
Discusions: The combination of aripiprazole with
other psychotropics was well tolerated. No significant new
adverse reactions were observed. In a short term follow-up,
our results show a good tolerability of aripiprazole in combination
with other psychotropics of different groups.
[Back to top]
Developmental Immunotoxicity (DIT) in Drug Safety Testing:
Matching DIT Testing to Adverse Outcomes and Childhood Disease
Risk
Rodney R. Dietert
Developmental immunotoxicity (DIT) recently emerged as
a significant concern for drug safety and was the topic of
several recent scientific forums in Europe, North America
and Asia. The heightened concern is based on several observations:
1) many childhood diseases with recent increases in prevalence,
such as asthma, allergic disease, leukemia and certain infections,
have clear linkages to the immune system and immune dysfunction,
2) the developing immune system has been shown to be a particularly
sensitive target for xenobiotic-induced adverse outcomes,
3) immunotoxicity as-sessment following adult exposure to
xenobiotics is ineffective for predicting immunotoxic risk
in the non-adult and 4) in several cases developmental immunotoxicity
to low-level xenobiotic exposure can take the form of immune
dysfunction in the absence of readily detected morphometric/histological
alterations. The present review examines harmonized pre-clinical
drug safety guidelines for immunotoxicity in light of environmentally-mediated
childhood disease trends as well as research-based mechanisms
for DIT. Because none of the guidelines was designed to address
risk of DIT, suggestions are offered for closing the earlylife
immune dysfunction data gap. A longer-term goal is to help
narrow the difference between current guideline expectations
and the known sensitivity of the developing immune system
for potential adverse outcomes.
[Back to top]
Improving Medication Reconciliation in the 21st
Century
Daniel P. Dunham and Gregory Makoul
Approximately 7000 deaths occur yearly in the United
States as a result of medication errors, and 1.5 million people
are harmed by adverse drug events at a cost of $3.5 billion
per year. Computerized order entry has been shown to decrease
the number of medication errors by 55% to 80 % in the hospital.
This has led many to advocate the use of electronic medical
records in both the inpatient and outpatient setting. However,
there is little evidence at present that electronic medical
records reduce adverse drug events in the outpatient setting.
This may be largely due to the quality of medication lists
in the medical record: Among complicated patients, complete
agreement between the medication list and what the patient
is actually taking occurs in only 5% of patients. Unless there
is improved medication reconciliation, it will be difficult
to realize the potential safety benefits of information technology.
An accurate medication list requires a healthcare team dedicated
to obtaining and maintaining this information.
[Back to top]
Clinical Strategies for Preventing Postoperative Nausea and
Vomiting After Middle Ear Surgery in Adult Patients
Yoshitaka Fujii
Middle ear surgery (tympanoplasty and mastoidectomy)
performed under general or local anesthesia is associated
with a high incidence of postoperative nausea and vomiting
(PONV). Between 50% and 80% of patients who undergo these
surgical procedures experience PONV. Numerous antiemetics
have been studied for the prevention of PONV after middle
ear surgery. Traditional antiemetics, including anticholinergics
(e.g., scopolamine), phenothiazines (e.g., promethazine),
butyrophenones (e.g., droperidol), and benzamide (e.g., metoclopramide),
are used for the prevention of PONV during 0-24 h after anesthesia.
The available nontraditional antiemetics that have been shown
to be effective for the prophylaxis against PONV are propofol,
dexamethasone, tandospirone, and midazolam. Antiserotinins
(ondansetron, granisetron, and ramosetron) are highly effective
in decreasing the incidence of PONV for 24 h postoperatively,
compared with traditional antiemetics. Ramosetron is effective
for the long-term (up to 48 h) prevention of PONV. None of
the available antiemetics is entirely effective, perhaps because
most of them act through the blockade on one type of receptor.
There is a possibility that combined antiemetics with different
sites of activity would be more effective than one drug alone
for preventing PONV. Nonpharmacological technique is acustimulation
at P6 (Nei-Kuwan) point.
Clinicians should consider these clinical strategies as mentioned
above for preventing PONV after middle ear surgery in adult
patients.
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