Speaker 1 00:05 Hi. Welcome to HelixTalk, a podcast presented by the Rosalind Franklin University College of Pharmacy. Narrator - Dr. Abel 00:11 This podcast is produced by pharmacy faculty to supplement study material and provide relevant drug and professional topics. Speaker 1 00:19 We're hoping that our real life clinical pearls and discussions will help you stay up to date and improve your pharmacy knowledge. Narrator - Dr. Abel 00:27 This is an educational production copyright Rosalind Franklin, University of Medicine and Science. Speaker 1 00:32 This podcast contains general information for educational purposes only. This is not professional advice and should not be used in lieu of obtaining advice from a qualified health care provider. Narrator - Dr. Abel 00:47 And now on to the show. Dr. Sean Kane 00:51 Welcome to Episode 17 of HelixTalk. I'm your co host, Dr. Kane. Unknown Speaker 00:55 I'm Dr. Schuman, and I'm Dr. Patel, and Dr. Sean Kane 00:57 today we're talking about overactive bladder, or OAB. So what exactly is overactive bladder? Speaker 2 01:03 Well, overactive bladder consists of four different types of cardinal symptoms or components. It could be manifest in terms of urgency, increased frequency of urination, increased frequency at nighttime, which we call nocturia or urgency incontinence, meaning, you know, by the time patient is going to the bathroom, there would be a leakage or an accident. Speaker 3 01:26 And this is something that you know not a lot of people always talk about at the open it's one of those kind of taboo topics, but it's fairly well represented in the population. There's a prevalence at any point in the time you have seven to 27% in men, and then a little bit higher, nine to 43% in women. And again, there's a lot of variance in studies, because this is something that not a lot of people are going to admit or self report. Dr. Sean Kane 01:51 And even on top of that, you know, symptoms can get better within, let's say, a year, but many patients will need lifelong therapy because of their overactive bladder symptoms. So before we get to the direct therapy, we have to kind of understand the pathophysiology of why these patients have overactive bladder. And it really all boils down to the parasympathetic nervous system, specifically acetylcholine. So we Speaker 3 02:12 kind of have that fight or flight system, where you you have that sympathetic nervous system, and we come back, we have that kind of rest and digest system, parasympathetic and so that parasympathetic tone is what manages the bladder. Tone the contractions. Again, as Dr. Kane mentioned, you mentioned, acetylcholine hits the muscarinic receptors of the bladder. And so we're looking at, in cases of an overactive bladder, there's too much of that acetylcholine stimulating the muscarinic receptors. And so then, as a result, we see that compression, that urinary frequency urgency, or that urge incontinence, where you actually cannot make it to the restroom at that point. So you do have Speaker 2 02:48 an accident, and when we say muscarinic receptors, you know there's m1 m2 m3 but most of the treatment that we have available that targets m3 subtype of the receptors. And so the side effects that come are also associated with blocking the m3 subtype of receptors, and mainly those kind of revolve around the anticholinergic type of Dr. Sean Kane 03:12 side effects. Great. So we've established that we have this pathophysiology of too much acetylcholine, specifically muscarinic activity in the bladder. We can block that with an m3 antagonist. Turns out, though, that we also have an m3 receptor elsewhere in the body, primarily in the salivary gland. So when we take the drugs that work on decreasing the parasympathetic tone in the bladder, that also means that we're going to have symptoms of dry mouth, which is a very common anticholinergic effect, but also specific to these m3 antagonists. So Dr. Patel, what do we actually see pharmacologically when we give these agents? What effect will a patient have when they have when they're given an agent that works on the m3 receptor? Speaker 2 03:50 The efficacy results by these drugs acting as anti spasmodic so basically what we are trying to do with using these agents is increasing bladder capacity, reducing those acetylcholine mediated contractions of the bladder, and then thus, we delay the desire to void. And then this also results in less urgency and frequency of urination. Dr. Sean Kane 04:13 So as we said, the adverse effect profile is mediated by the fact that this is an anticholinergic agent. So aside from xerostomia or dry mouth, we can see fairly less frequently, but still seeing constipation, blurred vision, drowsiness, urinary retention, which might be saying to yourself, well, that's kind of the goal, right? Urinary retention, but in patients who have, let's say, benign prostatic hypertrophy, that's a problem where they can't pee. And if they take these agents and it works too well. Then, instead of having overactive bladder, they have a problem where they actually can't urinate at all. Speaker 3 04:46 Another thing to plan is there are a large number of medications that do have the systemic effect of drying your eyes, drowsiness, constipation. You know, in general, a lot of these are anticholinergic agents, but these in particular. It's the m3 selectivity of the hallmark of this compared to something like glycopyrrolate or Benadryl. And so we do see overall fewer systemic side effects than we would with Benadryl, but again they can still be problematic, Speaker 2 05:14 and especially at higher doses, that selectivity kind of reduces too. So we get to see higher side effects as well, in terms of contraindication, like we mentioned, because of the anticholinergic side effect, people who have uncontrolled narrow angle glaucoma, these drugs are not to be used. And if they have any gastric or urinary retention, like Dr. Kane you mentioned just earlier, this agent should not be used. Dr. Sean Kane 05:39 So there's a number of different m3 selective anticholinergics on the market. So we're going to go over a number of different agents very briefly. Historically, the most used one was oxybutynin. It had a couple different brand names, Ditropan, Ditropan XL, and then actually newly approved as an over-the-counter product, Oxytrol, which is a patch. This is the oldest agent in the category of m3 selective anticholinergics. Speaker 2 06:05 And as the years passed by, and the IR formulation and the extended release formulation of oxymutin is getting old, they're coming up with various products, like patches. There's also a 3% and 10% topical gel available called gel leak. The only difference with the topical agents is that, you know, because of the formulation issues, we associate higher cost with those agents. Dr. Sean Kane 06:27 So a few of the other m3 selective anticholinergic agents on the market. One is tolterodine (Detrol). Speaker 2 06:34 following tolterodine, trospium (brand name Sanctura), was approved in 2004. Speaker 3 06:40 and then, along in that same time frame, we also had solifenacin (Vesicare) come out, and then darifenacin (Enablex) come out right around 2004 as well, within the last of those agents within that class, fesoterodine (Toviaz), which came out a little bit later in about 2013. Speaker 2 06:59 so instead of going over the older agents in detail, we're going to actually talk about the couple new agents that are out in the market just recently, and then some of the older agents and the new agents. We're going to discuss the new guidelines they came out and how they all play a role in treatment of overactive bladder. So the newest agent in the market is not an antimuscarinic; the new agent brand name is Myrbetriq. Generic is mirabegron. And this is, again, not an antimuscarinic agent, but it is a beta-3 adrenergic agonist. So how does it work? Dr. Schuman, well, Speaker 3 07:33 again, this one's a little bit different. So it's still working on that kind of system of sympathetic parasympathetic, but this one causes a relaxation of the bladder through that beta three adrenergic agonism, and then that promotes an increased storage volume. And it's fairly selective for beta three as compared to some of the other receptors. Because one thing you would want to consider is, what are we doing for those the beta one or the beta two receptors that exist? You know, we think of in the lungs for some of our drugs, for COPD asthma, as well as in the heart for some of our cardiac medications. But this one is fairly selective for beta three. That is, some in vitro studies that had a little stimulation of either beta one or beta two. You're really at normal doses, yes, at a dose of about four times the maximum study dose, if you could get some beta one stimulation. But again, as taken at the approved doses, you're really not gonna see any at all. Dr. Sean Kane 08:22 So thinking about dosing, the dose is pretty simple. It's 25 milligrams once a day. After eight weeks, that can be doubled to 50 milligrams a day. It is renally eliminated, so it does have renal adjustments and considerations and those with renal impairment. Speaker 2 08:36 So then, if it is a beta three adrenergic agonist, what kind of side effect would we experience with this medication? Speaker 3 08:44 Well, I think one thing we'd have to be concerned with is, as we said, it's fairly selective for the beta three receptors, but you can see a dose dependent hypertension as you get up higher, and so because of that, there's a recommendation that you do not use this medication in patients with uncontrolled hypertension. So again, if you have somebody who has history of hypertension that is well controlled in other medications, this is something that just needs to be monitored. But if somebody you know that it's up high, they're not taking medications, there still seems to be going up no matter what. This may not be the first medication you'd want to go for. Dr. Sean Kane 09:17 We can also see a few less common adverse effects, like tachycardia or an increase in heart rate, which you would expect from that beta one, very minimal stimulation and then even headache. But these are fairly uncommon, really. The hypertension is the main thing that we worry about with these agents, and Speaker 2 09:32 because it doesn't have any antimuscarinic action or anticholinergic type of adverse effect, we can use in patients who are intolerable to other agents because of dry mouth or can't use because they have, you know, worsening glaucoma. So this is where we can consider Myrbetriq (mirabegron). Speaker 3 09:50 And again, one thing to think about with those older agents as anticholinergics as a class, and particularly with Ditropan (oxybutynin), there's the issue of their inclusion on the Beers List. So that's a list of medications that we need to use caution with in the elderly, and that's primarily due to dry mouth, which can impact the ability to swallow, and so you can have a risk of choking or aspiration, as well as significant constipation, which could then lead to problems with gut motility, bowel perforations, things like that. So for those reasons, it could be a strong argument to consider this class of medication. Dr. Sean Kane 10:24 Then finally, the last thing in terms of adverse effects to think about is in the packaging, it does mention Qt prolongation, which again, is that EKG rhythm. If that Qt segment is too prolonged, it can predispose patients to arrhythmias clinically, this is probably not terribly relevant, because we only saw Qt prolongation with extremely high doses of the drug. That would be very uncommon unless a patient were to overdose on the medication. As an example, Speaker 2 10:52 some of the kinetic issues to be considered is that this medication is formulated to be a longer release tablet, Excel tablet, so it should not be crushed. And also, it is a moderate inhibitor of CIP, 2d six, but a weak inhibitor of three, a four. So you kind of have to consider those 2d six substrates, such as codeine, Tramadol, tamoxifen, cut, commit and use. Also, metabolism of some of the beta blocker is also 2d six pathway dependent. So you have to be careful there. And also, the manufacturer recommends to monitor dish levels in patients who are using those concomitantly, because, again, the 2e six inhibition. Dr. Sean Kane 11:28 So before we get to the overactive bladder guidelines, we'd be remiss if we didn't talk about Botox and its role in overactive bladder. Botox is the brand name on a botulinum toxin. A is the generic Speaker 2 11:41 name, and actually this was recently approved in January 2013 for the treatment of OAB. Again, this is not a common practice, so this should be reserved for patients who have tried other oral medications we discussed earlier, and failed or cannot tolerate those medications. Speaker 3 11:57 And like with other indications, it's done via local prevention of the release of acetylcholine, and again, without that acetylcholine, the detrusor muscle, which is the main muscle located within the bladder, has difficulty creating some of that frequent contraction, so you block some of its effect, so you hopefully don't see a lot of the systemic effects you would see if you were to somehow take that kind of medication systemically. Dr. Sean Kane 12:19 That kind of makes sense, too. That just like you would see decreasing in wrinkles by relaxing the face, you're decreasing the contractions by relaxing the muscle in the bladder with this toxin, Speaker 2 12:29 sounds fantastic. So if patients are using Botox for their wrinkle treatment, we can just tell them if they have overactive bladder, they can inject some in their bladder muscle, right? Dr. Sean Kane 12:40 Not exactly. So this is one of those things that's going to be done, either in an outpatient surgical setting or potentially in an outpatient clinic setting for probably someone like a urologist. And the reason is that they actually have to do a cystoscopy, where they're actually sticking a probe or a camera through the urethra into the urinary bladder in order to inject the medication through that cystoscope. So this isn't exactly the most elegant way to treat overactive bladder, but it is an FDA approved indication. So help me understand you know, where our m3 specific anticholinergics, our Botox and our mirabegron, really fit in? Is there a preferred agent? Do we have guidelines on overactive bladder? Where do these really fit into practice? Speaker 3 13:26 So one thing we do, the advantage we have is, though some of these agents have come out fairly recently, within the last few years, we do have new guidelines that came out within May of 2014 so very new, and they came from the American urology Association, or the AUA, as well as society for your dynamics and female urology or su Fu. And what they have done is they have periodically been updating, and they went ahead and compiled about 70 or 80 new articles that have come out even in the last year or two, and added those, including some about mirabegron as well, Speaker 2 13:58 and it's a fairly easy read as far as the guidelines go, fairly nicely organized. Dr. Sean Kane 14:02 Dr. Schuman, can I ask, Did you renew your su fu membership this year, the Society for urodynamic and female Urology? Speaker 3 14:09 Not this year, I figured I'd let it lapse for about a year, collect a little bit more data, and then really get the most bang for my buck. Sounds like a good plan. So yeah, within those guidelines, they determine the first line therapy is something you consider is going to be behavioral therapy, actually, things like bladder training, bladder control strategies, pelvic floor muscle training and fluid management, not medication. So with bladder training, again, it's going to be timed voiding, so giving your your body a chance to instead of accumulating large volumes of urine, doing timing it out. So every couple of hours, I'm going to go to the restroom, being careful that we're not just letting it all hold until nighttime, as well as doing those exercises that can strengthen those muscles there and again, allowing them to either hold more urine or be able to have more strength so that they can they can, again, keep it from voiding when you're not ready. Speaker 2 14:57 And I think the pelvic floor muscle. Training, the Kegel exercises are really to strengthen the sphincters that open up the bladder neck muscles to the urethra. Speaker 3 15:07 I think for some individuals, there may be the false idea that something like behavior can't really do that. That seems, you know, silly or pointless when we have great medications. But what's interesting is most studies have shown these behavioral techniques to be as good or even better than the pharmacologic interventions. Granted, many of these studies were older and only looking at comparison to the oxybutynin products, not to the newer agents, but it still is something we can educate them that, you know, we're not just saying this because we don't want to give medications with which to avoid cost, but really can, for avoidance of side effects, recommend this as a very strong therapy early on, Dr. Sean Kane 15:40 weight loss is important with diet and exercise, and some studies do indicate that. So even with moderate amounts of weight loss, like 8% we can see somewhere in the 40% reduction range in terms of symptoms, like having incontinence episodes with moderate amounts of weight loss compared to no weight loss at all. Speaker 2 15:58 So then the first line is all behavior modification and those exercises and weight loss, the second line then becomes our pharmacologic agent that we discussed earlier. But then the committee, or the group also discusses those further in detail, and they recommend one over the other. Can you shed some light on that? Speaker 3 16:17 Drummond, yes. So what they recommended, again, medications because of the potential for side effects. You know, these are unpleasant, but not life threatening. These medications are relegated to second line. And what they stated is that, with Grade B evidence, so again fairly robust, either the oral antimuscarinics, those m3 blockers, or the oral beta-3 adrenergic receptor agonists, such as mirabegron, either one of those can be used. And one thing that they said is overall, across the overall body of evidence, no single agent has shown better efficacy over another, with the one exception being the NICE study, which gave a slight edge to solifenacin. But again, therefore its efficacy is not the place to initially select one agent versus another; tolerability is. And the one thing to look at is that extended release formulations may be better than immediate release formulations. And then they also pointed out that the side effects, interestingly enough, because, again, this thing we're focusing on, are not dose dependent, but they did depend upon that formulation, again, immediate release being more problematic than extended release. And then there seemed to be an overall low risk of dry mouth compared to those older Benadryl type of agents that are not selected for. Dr. Sean Kane 17:32 M3 then, as you'd expect, mirabegron does have a lower incidence of dry mouth. And we don't have direct comparative studies, but you'd expect that just based on the pharmacology alone, and that was pretty similar in terms of dry mouth compared to placebo. So in patients who have issues with dry mouth, this would be a really good agent to consider, and Speaker 3 17:53 there were a few other agents that they recommended as well further down the line, again, especially the non oral m3 antagonist, so the oxybutynin gel or the patch could be used with a little bit lower level of evidence, Level C. Speaker 2 18:07 And so what to do if patient, you know, tried one agent and didn't work? So the committee is recommending here that you know, if the patient fails an initial agent or has any intolerable side effect, either we can try to increase the dose, obviously not in the setting of intolerable side effect, but you know, if the medication wasn't efficacious enough, or we can try to change it to other anti muscarinic or beta three agonist agent, Dr. Sean Kane 18:31 things really get bad. Our third line agents are things like Botox that we talked about, that would be done in a physician's office, even nerve stimulation and a very select group of patients, and that nerve stimulation can either be with peripheral tibial nerve or the sacral nerve itself. And again, that would be a very, very third, maybe even fourth line option for patients with very severe symptoms. Speaker 3 18:55 And then one other one that was not as discussed in the guidelines, but just in a practice setting you may come across, is going to for those individuals, especially who may, you know there may be contraindications to medications in general or of advanced age, and you want to avoid some of the more invasive techniques, such as Botox. We have the availability of couple different cut types of undergarments or diapers. We have the traditional tab diapers, which can be problematic for some for individuals who maybe are post stroke or have some difficulties with motor movement, it's going to be very difficult to use the tabs and to try to put together these these diapers, unless you have, you know, a caregiver. So we do have the availability of some elastic or pull on style adult diapers or adult undergarments, which can be a little bit more easily used by the individual. Can just just pull them on and they kind of cinch up that way for the last stick, rather than having to kind of tape them together. So they can be something else to consider, again, somewhat potentially costly as well, but for as an alternative for somebody who needs the medication, just don't seem to be appropriate. Work, and Speaker 2 20:00 depending on the insurance, it could be also covered as a medical equipment or durable equipment on patients insurance as well. So it's worth checking that region area as well. So according to the American urology Association and society for urodynamic and female urology, the recent guidelines that were published in May 2011 the first line of therapy should be always behavioral modification, such as bladder training, Kegel exercises and weight loss. Dr. Sean Kane 20:28 And then another thing to keep in mind is with Myrbetriq, it has a completely different adverse effect profile than what we saw with our m3 antagonists. So with this, we're worried more about hypertension, maybe tachycardia. We don't see things like dry mouth, which is extremely common with our m3 antagonists. Speaker 3 20:45 And then one other final point to make is that for a second line, we do have the medications as our option, both Myrbetriq or mirabegron as our beta-3 agonist, or our traditional oral muscarinics. Any of those agents may be used. And at this point again until maybe we have more time to assess mirabegron, we currently have the option to use any of them, since there's no one agent that's shown efficacy over another. So we can choose the one agent for that individual, potentially keeping in mind the side effect profiles, which would be something that we could use to determine maybe where we go, and if there is a tolerability issue with one agent, then we can safely either adjust the dose or move to another agent. Dr. Sean Kane 21:25 So to review, we talked about a number of m3 antagonists. The first was oxybutynin. We had a couple different brand names, detropan, ditropan XL, and then the patch, which is over the counter, called oxytrol. Speaker 3 21:37 Then we also had tolterodine (Detrol), which was the first of these newer agents to come out, Speaker 2 21:44 and following tolterodine in 2004, three agents came out: trospium (brand name Sanctura), solifenacin (brand name Vesicare), and darifenacin (brand name Enablex). Dr. Sean Kane 21:54 And then in 2013 a fairly newer agent, fesoterodine (brand name Toviaz), came out, that's, again, another m3 antagonist. Speaker 2 22:04 And lastly, the very recent two products out in the market are mirabegron (brand name Myrbetriq), which is not an antimuscarinic but is a beta-3 adrenergic agonist. And we also have botox (brand name onabotulinumtoxinA), and that was approved in January 2013. Dr. Sean Kane 22:24 so if you haven't done so already, we would really appreciate a five star review in iTunes. If you want to visit us online, we're at HelixTalk.com With that, I'll sign off. I'm Dr. Kane, Unknown Speaker 22:33 I'm Dr. shoeman, Unknown Speaker 22:34 and I'm Dr. Patel, and as always, study hard. Narrator - Dr. Abel 22:39 Thank you for listening to this episode of HelixTalk. For more information about the show, please visit us at HelixTalk.com you.