The number of prescription drugs, but not age, was significantly different between
users (12.13?±?6.70) and nonusers (5.67?±?5.24) of medicines that can cause urinary
symptoms.
Polypharmacy, inappropriate prescribing, and adverse drug events are highly prevalent
in elderly patients 23]. The characteristics of patients with LUTS included old age (average age, 70.52?±?14.60)
and male sex. Voiding symptoms was noted in 57.9% of women, presumably because of
declines in muscle strength, such as pelvic floor muscle strength, with age. In men,
the prevalence of high outlet obstruction (91.5%) predominated as a result of prostate
enlargement with age.
The typical elderly patient with LUTS typically receives medication for other comorbidities.
Elderly patients taking five to eight drugs were reported to be at greater risk of
adverse drug reaction related hospitalization than those taking zero to four drugs
23]. However, a meaningful correlation was not found between age and the number of the
prescription drugs used by patients with LUTS (data not shown) in this study. This
result may be responsible for the findings that patients with LUTS were old (average
age, 70.52?±?14.60) and presented with several comorbid conditions requiring medication
(average number of prescription drugs, 6.16?±?5.38).
In total, 7.7% of patients were prescribed medications potentially contributing to
urinary symptoms. Donepezil (14.1%), antiparkinson drugs (13.7%), antidepressants
(13.8%), and antipsychotics (13.3%) were frequently prescribed, reflecting the rate
of complications in older people. Patients who used medicines that can cause storage
symptoms, such as donepezil, were older than nonusers. In contrast, patients who used
medicines that can cause voiding symptoms, such as antiparkinson drugs (13.7%), antidepressants
(13.8%), and antipsychotics, were younger than their nonusing counterparts. The prevalence
of incontinence in the elderly with dementia is higher than that of persons without
dementia. Multiple comorbid diseases, such as depression, Parkinson’s disease, psychotic
disorders, and medications are possible risk factors for voiding symptoms.
In this study, we demonstrated that the side effects of donepezil, cyclophosphamide,
amantadine, levodopa/benserazide, paroxetine, fluvoxamine,milnacipran, diazepam, risperidone,levomepromazine,sulpiride,
cimetidine, scopplamine butylbromide, tiotropium bromide, and opioids were associated
with LUTS. Risperidone therapy has been associated with storage symptoms (28% in some
cases) 24]. Risperidone primarily acts as an antagonist of serotonin type 2A (5HT2a) and D2-dopamine
receptors, and it has a strong blockade effect on ?-1 and ?-2 adrenergic receptors.
It may be that the antagonizing effect of risperidone on the ?-1 receptors of the
internal bladder sphincter causes urinary retention 25]. Levomepromazine also may affect the ?-1 receptors of the internal bladder sphincter.
Sulpiride, a D2-selective dopaminergic receptor antagonist, increased bladder capacity
in rats 26]. Dopaminergic systems have also been implicated in the control of the micturition
reflex. D1-like dopaminergic receptors mediate forebrain-inhibitory effects on the
micturition reflex, whereas D2-like dopaminergic receptors appear to be involved in
excitatory regulation of the micturition reflex at the level of the brainstem. The
prevalence of LUTS in patients with Parkinson disease (PD) is reported to be 27%–39%
27]. Levodopa is well established as the most effective drug for the symptomatic treatment
of idiopathic or Lewy body PD. Amantadine is known to increase dopamine release, inhibit
dopamine reuptake, and stimulate dopamine receptors, and it may possibly exert central
anticholinergic effects 27].
Anticholinergic agents such as biperiden and trihexyphenidyl did not display meaningful
peripheral antimuscarinic side effects. In contrast, the dopamine-related drugs levodopa
and amantadine exerted side effects, suggesting that LUTS caused by such drugs is
dependent on dopaminergic activity.
Milnacipran, a dual-action antidepressant that acts as a serotonin and norepinephrine
reuptake inhibitor (SNRI), and paroxetine, a selective serotonin reuptake inhibitor
(SSRI), have been linked to voiding symptoms. Animal studies suggested that incontinence
secondary to serotonergic antidepressants could be mediated by 5HT4 receptors found
on the bladder 28],29]. These drugs may affect serotonin uptake by 5HT receptors found on the bladder. Recently,
experiments in cats illustrated that SNRIs suppress parasympathetic activity and increase
sympathetic and somatic neural activity in the lower urinary tract 30]. The inhibition of serotonin and norepinephrine reuptake during bladder storage is
believed to increase pudendal nerve output, resulting in increased tone of the rhabdosphincter
and subsequently improved urethral closure. The SNRI duloxetine can significantly
improve the quality of life of patients with stress urinary incontinence. In this
study, voiding symptoms was caused by milnacipran, suggesting that milnacipran-associated
voiding symptoms may have beneficial effects on urinary incontinence.
The most common medication class potentially contributing to LUTS is benzodiazepines
(17.4%) 31]. The mechanism by which other medicines cause incontinence is the activation of N-methyl-D-aspartate receptors in pontine micturition center (PMC) that are involved in the
facilitation of voiding 32].
Men with LUTS or BPH who are treated with inhaled anticholinergic agents may develop
acute urinary retention, but this cannot be quantified on the basis of the limited
information available. Inhaled anticholinergic agents should be used when indicated
in men with LUTS or BPH but close monitoring and patient education should be implemented
33]. Inhaled anticholinergic medication use in older men with chronic obstructive pulmonary
disorder is associated with an increased risk of acute urinary retention 34].
The prevalence of opioid-induced dysuria in patients with advanced cancer-associated
pain was 14.9% 35]. Urinary retention induced by systematically injected morphine was considered to
result from the inhibition of bladder function mediated via ?-opioid receptors of
the micturition centers in the supraspinal and spinal regions 36].
Dementia and storage symptoms are common, and often coexisting, problems in older
people. Anticholinergic drugs are used to treat urinary instability 37]-39]. In this study, storage symptoms is expected to occur in patients treated with donepezil.
The potential for worsened urinary continence is an important consideration when starting
cholinesterase treatment in Alzheimer disease (AD).
Cyclophosphamide is metabolized to several moieties, including acrolein, which collects
in the urinary bladder, leading to urothelial damage 40]. Cyclophosphamide causes cellular damage in bladder tissue that triggers an inflammatory
response. Therefore, cyclophosphamide is commonly used in noninvasive rodent models
of acute bladder pain 41].
The current study has highlighted the potential for the initiation of commonly used
medicines to be associated with the subsequent initiation of drug treatment for LUTS
and has provided an estimate of the risk of LUTS associated with these medicines.
Prescribers should be aware of LUTS that occurs shortly after the initiation of new
medicines, and the potential for an adverse event should be considered. For this reason,
before the treatment for LUTS is started, the possible side effects of medications
currently used for the patient should be reviewed and the planned treatment for LUTS
should be adjusted if necessary.