REVIEW ARTICLE Vol. 47 (4): 747-752, July - August, 2021 doi: 10.1590/S1677-5538.IBJU.2021.99.06
Otorhinolaryngological adverse effects of urological drugs ______
Nathalia de Paula Doyle Maia 1, Karen de Carvalho Lopes 2, Fernando Freitas Ganança 2
1 Programa de Pós-Graduação em Medicina, Otorrinolaringologia da Universidade Federal de São Paulo - Escola Paulista de Medicina - UNIFESP, São Paulo, SP, Brasil; 2 Departamento de Otorrinolaringologia e Cirurgia de Cabeça e Pescoço da Universidade Federal de São Paulo - Escola Paulista de Medicina - UNIFESP, São Paulo, SP, Brasil
ABSTRACT ARTICLE INFO
Purpose: To describe the otorhinolaryngological adverse effects of the main drugs used Fernando Gananca in urological practice. http://orcid.org/0000-0002-8703-9818 Materials and Methods: A review of the scientific literature was performed using a combination of specific descriptors (side effect, adverse effect, scopolamine, Keywords: sildenafil, tadalafil, vardenafil, oxybutynin, tolterodine, spironolactone, furosemide, Cholinergic Antagonists; hydrochlorothiazide, doxazosin, alfuzosin, terazosin, prazosin, tamsulosin, Adrenergic alpha-1 Receptor desmopressin) contained in publications until April 2020. Manuscripts written in Antagonists; Deamino Arginine Vasopressin English, Portuguese, and Spanish were manually selected from the title and abstract. The main drugs used in Urology were divided into five groups to describe their Int Braz J Urol. 2021; 47: 747-52 possible adverse effects: alpha-blockers, anticholinergics, diuretics, hormones, and phosphodiesterase inhibitors. Results: The main drugs used in Urology may cause several otorhinolaryngological ______adverse effects. Dizziness was most common, but dry mouth, rhinitis, nasal congestion, Submitted for publication: epistaxis, hearing loss, tinnitus, and rhinorrhea were also reported and varies among June 24, 2020 drug classes. ______Conclusions: Most of the drugs used in urological practice have otorhinolaryngological Accepted after revision: July 15, 2020 adverse effects. Dizziness was most common, but dry mouth, rhinitis, nasal congestion, ______epistaxis, hearing loss, tinnitus, and rhinorrhea were also reported. Therefore, doctors Published as Ahead of Print: must be aware of these adverse effects to improve adherence to the treatment and to August 25, 2020 minimize damage to the health of patients.
INTRODUCTION to treatment, the adverse effects may generate serious risks to the health of patients and hinder the mana- The treatment of urological disorders such as gement of urological diseases. Researchers are always urinary tract infection and erectile dysfunction has looking for new drugs with better efficacy, safety, spread to several medical specialties besides Urology, and tolerability (2). However, doctors must know the including among others, general practitioners. It is adverse effects of drugs to contraindicate their use important to emphasize that drugs, especially when or at least detect them promptly aiming minimizing administered orally, may have effects on other parts the damage to the patient’s health. This study aims to of the human body besides the genitourinary tract describe the otorhinolaryngological adverse effects of (1). In addition to reducing the adherence of patients the main drugs used in urological practice.
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MATERIALS AND METHODS vous system effects and can be safely prescribed in contrast to their predecessors (doxazosin, tera- A review of the scientific literature was zosin, prazosin) (7, 8). Dizziness and rhinitis have performed using a combination of specific des- been described as adverse effects of tamsulosin (9). criptors (side effect, adverse effect, scopolamine, sildenafil, tadalafil, vardenafil, oxybutynin, tolte- Anticholinergics rodine, spironolactone, furosemide, hydrochloro- Scopolamine is the main non-selective an- thiazide, doxazosin, alfuzosin, terazosin, prazosin, tagonist drug of acetylcholine muscarinic recep- tamsulosin, desmopressin) contained in publi- tors used in Urology (10, 11). In the genitourinary cations until April 2020. Manuscripts written in tract, it promotes an increase in bladder capacity, English, Portuguese, and Spanish were manually decreasing the frequency of contractions of the selected from the title and abstract. Studies that detrusor muscle, and delaying the initial desire to did not provide information sufficient for analysis urinate (12). In otorhinolaryngology, this drug can were excluded. Additional bibliographical resear- be used transdermal in some patients to prevent ch was carried out to provide specific information and treat motion sickness (10). It is also useful in on the drugs used in urological practice. The ne- suppressing pendular nystagmus and downbeat cessary information and data were extracted from nystagmus since the drug acts on the muscarinic the selected studies. The main drugs used in urolo- receptors present in the medial vestibular nucleus, gy were divided into five groups: alpha-blockers, a structure responsible for maintaining the eyes in anticholinergics, diuretics, hormones, and phos- an eccentric position (13). phodiesterase inhibitors. The main adverse effects of anticholiner- gics, especially scopolamine, are increased in- RESULTS traocular pressure, xerostomia, dizziness, visual clouding, and decreased concentration, mictu- Alpha-blockers rition dysfunction, tachycardia, and sleepiness Alpha-1 adrenergic receptor blockers (14, 15). Transdermal administration of scopo- (α-blockers) are widely used in the management lamine was developed to reduce serious adverse of patients with benign prostatic hyperplasia but effects and maintain the action of the drug over were originally developed for the treatment of an extended time (approximately 72 hours), with systemic arterial hypertension (3). Examples of xerostomia being the main adverse effect when drugs in this group are doxazosin, terazosin, pra- administered by this route (11). After transder- zosin, alfuzosin, and tamsulosin. The blocking of mal administration, adverse effects on the central alpha-1 adrenergic receptors in the genitourinary nervous system (disorientation, memory disor- tract promotes relaxation of the smooth muscle of ders, dizziness, restlessness, hallucinations, con- the prostate, urethra, and neck of the bladder with fusion, and insomnia) have been reported with a consequent decrease in pressure in the prostate low frequency (16). No significant influence on urethra and facilitating urinary flow (3). the sense of smell was identified after the syste- Because of the distribution of alpha-1 mic administration of scopolamine hydrobromi- adrenergic receptors in various organs and sys- de (17). tems, the adverse effects that may occur during Oxybutynin and tolterodine are powerful treatment with these drugs involve, but are not antagonists of muscle receptors (18) and have limited to, postural dizziness, lethargy, fatigue, been used in the treatment of overactive bladder fluid retention, rhinitis, sexual dysfunction, as- for over 40 years (19, 20). The adverse effects thenia, syncope, headache, visual clouding, nasal of these drugs differ little from those associated congestion and xerostomia (3-6). Third-generation with scopolamine; xerostomia, visual clouding, alpha-1 adrenergic blockers (alfuzosin, tamsulosin) constipation, erythema, fatigue, sweating, dizzi- are considered “uro-selective” and are rarely asso- ness, cognitive changes, sleepiness, and urinary ciated with adverse cardiovascular or central ner- retention have been reported in the literature (18,
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19, 21, 22). Epistaxis, characterized by the nasal- Aqueous rhinorrhea adverse effect was observed -mucosa dryness as the main factor, was reported during an otorhinolaryngological physical exa- as an adverse effect of oxybutynin but was seen mination that coincided with the use of spiro- in one patient only (23). Facial flushing is another nolactone (30). The clear aspect of nasal fluid, frequent adverse effect due to vasodilation that can chemo-cytological analysis, and glucose levels play a role in triggering epistaxis (23). In compari- ruled out the differential diagnosis of cerebros- son to oxybutynin that acts mainly on the subtypes pinal fluid. Moreover, rhinorrhea ceased after the M1 and M3 of muscle receptors and is more present suspension of the drug and recurred after repe- in the parotid than in the bladder, tolterodine acts ated introduction (30). One possible explanation on subtypes M2 and M3 muscle receptors and has is that spironolactone may decrease the vascular fewer adverse effects because it reaches the bladder response to norepinephrine, with the consequent more than any other areas of the body (20). The stu- nasal vasodilator effect triggering aqueous rhi- dy by Paquette et al. evaluated the cognitive perfor- norrhea (30). mance of patients who used anticholinergic drugs; Hydrochlorothiazide is the most widely dizziness was the most frequently reported adverse used thiazide-type diuretic (31). Common adverse effect that was observed in 3% of people who used effects of this class of drugs include nausea, dizzi- oxybutynin, 1.8% who used tolterodine, and 1.6% ness, headache, polyuria, dehydration, hyponatre- on placebo (24). mia, hypokalemia, and hypomagnesemia (32).
Diuretics Hormones Diuretics are widely used for the treat- Desmopressin (DDAVP) is an analog of ment of systemic arterial hypertension and ede- vasopressin and is a potent agonist of the vaso- matous states. There are several classes of diure- pressin-2 receptor (VR2) used in the management tics drugs that act through various mechanisms of diabetes insipidus, night enuresis, and hema- of action (25). There are three main classes of tological disorders (33). DDAVP increases water diuretics drugs routinely used in clinical practice reabsorption by acting on the renal tubules, with that have adverse effects - loop diuretics such as the consequent increase in urinary osmolality furosemide, potassium-sparing diuretics such as and a decrease in urinary volume (34). spironolactone, and thiazide such as hydrochlo- Vasopressin type 2 receptors are also rothiazide. found in other sites besides the kidney such as Furosemide is the main representative of the inner ear and vascular endothelium (35). The loop diuretics (26). Common adverse effects of use of desmopressin may be associated with a this class of drugs include headache, gastroin- worsening of endolymphatic hydrops in the in- testinal disorders, hypernatremia, hypokalemia, ner ear through the presence of VR2 in the en- and dehydration (27). Its otorhinolaryngological dolymphatic sac (36-39). These receptors are also effects include hearing loss, tinnitus, and dizzi- associated with increased levels of clotting factor ness/vertigo (28). Ototoxicity is a relevant adver- VIII, von Willebrand factor, and tissue plasmi- se effect that can be transient or permanent (29). nogen activator in endothelial cells (35). A sys- Several investigations to elucidate the ototoxici- tematic review suggested the use of DDAVP in ty mechanisms of furosemide have been perfor- otorhinolaryngological surgical procedures as a med, but they are still unknown (29). Methods prophylactic agent in the perioperative period to avoid ototoxicity include slow and continuous and as an intervention agent in postoperative infusion instead of bolus injection, use of frac- bleeding (40). tionated oral doses, and even the quantification Desmopressin has few adverse effects of blood levels to avoid the serum concentration with the most common being facial flushing. of furosemide above 50µg/mL (29). Other adverse effects include headache, decrea- Spironolactone is a diuretic aldosterone sed blood pressure, tachycardia, fatigue, and di- antagonist and potassium-sparing diuretic (26). zziness (33, 41, 42).
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Phosphodiesterase inhibitors tly associated with tinnitus, dizziness, or vertigo Initially developed for the control of sys- (44), epistaxis has also been observed with some temic arterial hypertension and angina pectoris, patients (6). phosphodiesterase-5 inhibitors (iPDE5) are now The main otorhinolaryngological adverse widely used for the management of penile erec- effects of drugs most commonly used in urologi- tion when this action has been observed as an cal practice are listed in Table-1. adverse effect of a drug (43). Sildenafil, tadala- fil, and vardenafil are the main representatives CONCLUSIONS of iPDE5. The most frequently reported adverse effects associated with the use of these drugs are Most of the drugs used in urological prac- headache, facial flushing, dyspepsia, nasal con- tice have otorhinolaryngological adverse effects. gestion, rhinitis, visual disorders, and myalgia Dizziness was most common, but dry mouth, rhi- (44). Otorhinolaryngological adverse effects as- nitis, nasal congestion, epistaxis, hearing loss, sociated with the use of iPDE5 include sudden tinnitus, and rhinorrhea were also reported. The- hearing loss, usually unilateral, occurring in the refore, doctors must be aware of these adverse first three days after using the drug and frequen- effects and identify them early to minimize pos-
Table 1 - The main otorhinolaryngological adverse effects of drugs most commonly used in urological practice.
Class Drug Adverse effects
Doxazosin Rhinitis, nasal congestion, xerostomia
Terazosin Rhinitis, nasal congestion, xerostomia
Alpha-blocker Prazosin Rhinitis, nasal congestion, xerostomia
Alfuzosin Rhinitis, nasal congestion, xerostomia
Tamsulosin Dizziness, rhinitis
Xerostomia, dizziness, suppression Scopolamine of pendular nystagmus and downbeat nystagmus Anticholinergic Oxybutynin Xerostomia, dizziness, epistaxis
Tolterodine Xerostomia, dizziness
Furosemide Hearing loss, tinnitus, dizziness/vertigo
Diuretic Spironolactone Rhinorrhea
Hydrochlorothiazide Dizziness
Endolymphatic hydrops, dizziness, Hormone Desmopressin procoagulant effects
Sildenafil Nasal congestion, rhinitis, sudden Phosphodiesterase inhibitor Tadalafil hearing loss, tinnitus, dizziness/vertigo, epistaxis Vardenafil
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