madman
Super Moderator
Abstract: The number of compounds used in the pharmacological treatment of lower urinary tract symptoms (LUTS) of patients who do not respond to conservative measures has been relatively stable during the last decade, with the exception of the introduction of the new class of β3 adrenoceptor agonists. However, different combinations have been investigated, and the long-term use of these compounds has raised new concerns about adherence and safety. This review summarizes the current state of pharmacology for LUTS, and presents a thorough discussion of the possible challenges concerning their future use. In this narrative review, we analyze the most recent articles related to LUTS pharmacotherapy, after an initial review of mechanisms of bladder function relevant in present clinical practice. The main problems with pharmacotherapy in LUTS are associated with its moderate efficacy, low persistence on treatment, and the incidence of short- and long-term adverse events (AE) associated with some compounds. The long-term AE, such as cognitive impairment in the elderly vulnerable patients associated with antimuscarinic drugs or persistent erectile dysfunction in sexually active men after treatment with 5-α-reductase inhibitors (5-ARI), are some of the problems addressed in this review. Combination therapy taking advantage of the synergistic mechanisms of action between some classes of compounds may overcome AE associated with dose escalation. LUTS pharmacotherapy offers moderate results to most patients but not a full cure. The use of combination drugs to achieve better clinical results, reduce AE and improve both efficacy and adherence, will be used more frequently in the future. The recently raised concern on potential long-term irreversible AE associated with some of these drugs, like antimuscarinics and 5-ARI, are critically important and require further investigation.
5α-reductase inhibitors
Only two 5-ARI available for clinical use; these two differ in their activity against 5-AR isoenzymes. Finasteride inhibits preferentially type II 5-AR isoenzymes and prevents, by 70%, the conversion of testosterone to DHT. Dutasteride inhibits both types I and II isoenzymes, preventing 95% conversion of testosterone to DHT. Despite these different profiles, there are no relevant clinical differences between them. In a head-to-head comparative trial between the two drugs, the conclusion was that, in terms of LUTS improvement, Qmax, and prostate volume variation, the drugs had similar efficacy at 1year follow up.
Clinical effects of 5-ARI are seen after a minimum treatment duration of at least 6– 12months. After 2–4years of treatment, 5-ARI reduce IPSS by 15–30%, increase Qmax by 1.5–2.0ml/s, and reduce prostate volume by 18–28% 5-ARIs decrease prostatic specific antigen (PSA) by 50% within 6–12months. 5-ARIs show little efficacy in patients with prostates smaller than 40ml.
A very important feature of the 5-ARI is that, contrary to α-blockers, these drugs can change the natural history of BPH, reducing the risk of long-term complications like AUR and BPE-related surgery. This is particularly evident in patients with large prostate glands and high total serum PSA. Reflecting this information, EAU guidelines recommend 5-ARI in men with moderate-to-severe LUTS, prostate volume over 40ml, and an increased risk of disease progression.
Regarding AE profile, both finasteride and dutasteride exhibit similar profiles. Up to 10% of patients report sexually related events, like erectile dysfunction (ED), decreased libido, and decreased volume of ejaculate. In placebo-controlled trials, the incidence of these AE in the active arm was nearly twice the incidence in the placebo arms.74 Some alarms concerning the nonreversibility of sexual AE were recently raised. A study in 2017 evaluated the risk of developing persistent ED (ED for more than 90days after stopping 5-ARI) in men undergoing medical therapy with 5-ARI. In this study, persistence ED affected one-third of the men who complained of ED during exposure to the 5ARIs. This percentage represents 1.4% of men with 5-ARI exposure (0.1mg of finasteride, 5mg of finasteride or Dutasteride) who developed de novo persistent ED. The long duration of exposure to 5-ARI was the most accurate predictor of persistent ED, from all the risk factors accessed. Interestingly, a recent pre-clinical study, in rats, also concluded that long-term 5-ARI medication can result in persistent ED. Further prospective studies are warranted, since they may restrict the use of these drugs in the future. A critical aspect of the efficiency of 5ARIs is long-term adherence to the medication. EAU guidelines strongly highlight discussion of this aspect with candidates for the medication to obtain the ideal effect. However, in real life, long-term adherence is low. An Italian database shows that the proportion of patients who continued 5ARIs up to 10months does not reach 60%, and is only 18% at 1year.
Conclusion
The high prevalence of LUTS in the population above the age of 40years requires the frequent prescription of drugs. Therefore, functional urologists and physicians, in general, require a solid knowledge of LUT pharmacology, and on the efficacy and safety of licensed drugs.
The introduction of β3-AR will progressively challenge the use of antimuscarinics in monotherapy. The use of combined pharmacotherapy will slowly increase to enhance efficacy and reduce potential AE related to dose escalation.
Strategies to improve adherence need to be implemented in clinical practice, taking into consideration the low persistence seen in most drugs in use for LUTS treatment. In this context, phenotyping patients may help select the ideal treatment for the right patient.
The development of new drugs to treat LUTS is major proof that innovation and better solutions are needed for the pharmacological treatment of LUTS.
5α-reductase inhibitors
Only two 5-ARI available for clinical use; these two differ in their activity against 5-AR isoenzymes. Finasteride inhibits preferentially type II 5-AR isoenzymes and prevents, by 70%, the conversion of testosterone to DHT. Dutasteride inhibits both types I and II isoenzymes, preventing 95% conversion of testosterone to DHT. Despite these different profiles, there are no relevant clinical differences between them. In a head-to-head comparative trial between the two drugs, the conclusion was that, in terms of LUTS improvement, Qmax, and prostate volume variation, the drugs had similar efficacy at 1year follow up.
Clinical effects of 5-ARI are seen after a minimum treatment duration of at least 6– 12months. After 2–4years of treatment, 5-ARI reduce IPSS by 15–30%, increase Qmax by 1.5–2.0ml/s, and reduce prostate volume by 18–28% 5-ARIs decrease prostatic specific antigen (PSA) by 50% within 6–12months. 5-ARIs show little efficacy in patients with prostates smaller than 40ml.
A very important feature of the 5-ARI is that, contrary to α-blockers, these drugs can change the natural history of BPH, reducing the risk of long-term complications like AUR and BPE-related surgery. This is particularly evident in patients with large prostate glands and high total serum PSA. Reflecting this information, EAU guidelines recommend 5-ARI in men with moderate-to-severe LUTS, prostate volume over 40ml, and an increased risk of disease progression.
Regarding AE profile, both finasteride and dutasteride exhibit similar profiles. Up to 10% of patients report sexually related events, like erectile dysfunction (ED), decreased libido, and decreased volume of ejaculate. In placebo-controlled trials, the incidence of these AE in the active arm was nearly twice the incidence in the placebo arms.74 Some alarms concerning the nonreversibility of sexual AE were recently raised. A study in 2017 evaluated the risk of developing persistent ED (ED for more than 90days after stopping 5-ARI) in men undergoing medical therapy with 5-ARI. In this study, persistence ED affected one-third of the men who complained of ED during exposure to the 5ARIs. This percentage represents 1.4% of men with 5-ARI exposure (0.1mg of finasteride, 5mg of finasteride or Dutasteride) who developed de novo persistent ED. The long duration of exposure to 5-ARI was the most accurate predictor of persistent ED, from all the risk factors accessed. Interestingly, a recent pre-clinical study, in rats, also concluded that long-term 5-ARI medication can result in persistent ED. Further prospective studies are warranted, since they may restrict the use of these drugs in the future. A critical aspect of the efficiency of 5ARIs is long-term adherence to the medication. EAU guidelines strongly highlight discussion of this aspect with candidates for the medication to obtain the ideal effect. However, in real life, long-term adherence is low. An Italian database shows that the proportion of patients who continued 5ARIs up to 10months does not reach 60%, and is only 18% at 1year.
Conclusion
The high prevalence of LUTS in the population above the age of 40years requires the frequent prescription of drugs. Therefore, functional urologists and physicians, in general, require a solid knowledge of LUT pharmacology, and on the efficacy and safety of licensed drugs.
The introduction of β3-AR will progressively challenge the use of antimuscarinics in monotherapy. The use of combined pharmacotherapy will slowly increase to enhance efficacy and reduce potential AE related to dose escalation.
Strategies to improve adherence need to be implemented in clinical practice, taking into consideration the low persistence seen in most drugs in use for LUTS treatment. In this context, phenotyping patients may help select the ideal treatment for the right patient.
The development of new drugs to treat LUTS is major proof that innovation and better solutions are needed for the pharmacological treatment of LUTS.
