So You’re Gonna… Start an Alpha-blocker

JOSEPH: Hi there and welcome. I’m Joseph Ischia. This is our new podcast series from the team at Talking Urology where we are helping doctors and allied practitioners develop a deeper understanding of the literature to ensure we apply the right evidence to the right patient.. We have heard your feedback from our Talking Urology podcasts and understand that while they have been unexpectedly popular, sometimes you just want an informative, fun and entertaining take on a common urology topic. So while the BBC News Quiz is informative and consistently makes jokes that could be considered below the belt, they are not very useful in the day to day lives of those who love Urology. Therefore, we are bringing the literature to life with our new podcast series So You’re Gonna and today I’m joined by my special co-host Rachel Esler.

RACHEL: Hello Joseph. I am a urologist from Brisbane, and we are going to tackle the topic, So You’re Gonna start an alpha blocker.  We will also be joined by international BPH expert and whose name has been attached to nearly every large trial for the medical management of LUTS, Claus Roehrborn. He is the Professor and Chairman of the Department of Urology at the University of Texas Southwestern. He has chaired committees at the WHO-sponsored Consensus Conferences on BPH, and is the current cochairman of the AUA BPH Guidelines Committee. So it’s fair to say Joseph, that Claus has forgotten more about alpha blockers than you’ve ever learned.

JOSEPH: He must have a memory like an elephant.

RACHEL: Possibly. So stay tuned while we give you all the latest news on alpha blockers for treating patients with symptomatic BPH. So sit back, relax and enjoy the show!

JOSEPH: And indeed we have a great podcast for you which we will get right on to once we get back from a quick word from our sponsor.

PODCAST SPONSOR AD.

JOSEPH: So thanks to Mayne whose support was essential to making this podcast possible but who had no editorial input in to the podcast apart from some compliance advice about Australian registered products that you will hear throughout the podcast. So back to the alpha blockers. Like a lot of urological medications, alpha blockers have an interesting history that dates back to the 1970s. In fact, in 1975, three great things happened: 1. Monty Python and the Holy Grail was released, 2. Bruce Springsteen released his album, Born to Run, and 3, a young researcher, Marco Caine from Hadassah University Hospital in Jerusalem, demonstrated that strips of human prostate tissue contracted in response to norepinephrine. Therefore, armed with his new found discovery and a Holy Hand Grenade, Marco galloped off down Thunder Road with his assistant banging two coconuts together and noticed that the norepinephrine-induced contractions could be inhibited by pre-treatment with phenoxybenzamine, a non-selective inhibitor of alpha-adrenoceptors. After this serendipitous finding the alpha blocker was born in urology! However, Born in the USA was still 9 years from release. Marco’s work was published in the British Journal of Urology in 1976 and led to the natural progression of alpha-blockers for managing patients with symptomatic BPH.

RACHEL: Two years later in 1978, the therapeutic benefit of phenoxybenzamine was confirmed by a randomised placebo-controlled study also published in the British Journal of Urology. Phenoxybenzamine was found to be superior to placebo at relieving LUTS and increasing peak flow rate. The primary limitation of phenoxybenzamine was its side effect profile, which included tiredness, dizziness, impaired ejaculation, nasal stuffiness, and hypotension. Men were fainting and dropping like flies after popping a few phenoxybenzamines but at least their flow-rates were improving!

JOSEPH:  Ok, Rachel, so we know they work, but how do they work? Let’s take a quick look at everybody’s favourite bit which is the science and try to understand how our understanding of their mechanism of action has changed over time from initially believing it was purely prostate muscle relaxation to now including more central effects that improve symptomatic LUTS.

RACHEL: Let’s start at the beginning. It is well known that BPH causes bladder obstruction by two mechanisms: firstly, mechanical compression by the prostatic adenoma on the urethra, and secondly, from dynamic obstruction of the bladder by prostatic smooth muscle compression. Alpha blockers interrupt motor sympathetic adrenergic nerve supply to the prostate, which reduces urethral pressure. Therefore, a functional predominance of alpha-one adrenoceptors in human prostatic muscle provides the rationale for using alpha blockers to treat outlet obstruction. However, the number and type of alpha receptors does not always predict therapeutic benefit.

JOSEPH: That’s right, Rachel. For example, tamsulosin actually has a lower affinity for some alpha-receptor subtypes compared with most of the other alpha blockers but has good efficacy in the management of BPH. Therefore, when medically managing BPH, the goal is to achieve the trifecta of maximum improvement in urinary flow rate, reduction in lower urinary tract symptoms, and do this while producing minimal adverse effects. So Rachel, let’s quickly touch on those different alpha-receptor subtypes in a little bit more detail.

RACHEL: Sure. There are three alpha_–one-adrenergic receptor subtypes (α_1A, α_1B, and α_1D) in human tissue.

JOSEPH: Wait on, what happened to the α_1C receptor?

RACHEL: At one time, there was a subtype known as α1C, but it was found to be identical to the previously discovered α1A receptor subtype so to avoid confusion, naming was continued with the letter D.

JOSEPH: Nice.

RACHEL: Approximately 75% of α₁-adrenergic receptors in the prostate belong to the α_1A subtype. This means that antagonism of this receptor can lead to an improvement in LUTS via relaxation of the lower urinary tract smooth muscle and this is the predominant rationale for α- blocker treatment for symptomatic BPH. Now the α_1B subtype is widely found in vascular smooth muscle, thus blocking it can cause orthostatic hypotension. It’s also found in human prostate epithelium. The α_1D subtype is functional in human epicardial coronary arteries and its inhibition might mediate coronary vasodilation. To reduce these cardiovascular side effects, α₁-adrenergic receptor inhibitors with high selectivity for the α_1A subtype, such as silodosin, have been developed and these are often favoured in the elderly for very obvious reasons.

JOSEPH: Ok , so it’s pretty simple so far. Alpha receptors in the smooth muscle of the bladder neck and prostate are responsible for increased tone and can be inhibited with alpha-blockers. And until recently, that was where we thought the story ended. But not anymore, the plot thickens.

RACHEL: Correct. As well as lower urinary and vascular tissues, all 3 alpha one receptor subtypes have been found in the human spinal cord particularly in the sacral ventral motor neurons and parasympathetic pathways. The main differences among alpha-one receptor antagonists appear to relate to their potential to cause adverse effects, due to their action at extra-urinary receptors like those in the central nervous and cardiovascular systems. The rate of adverse side effects varies by the type of alpha blocker but some ball park figures were determined in a meta-analysis in European Urology in 1999 and include dizziness (12%), asthenia (7.5%), chest pain (3%), postural hypotension (1-8%), rhinitis (or a stuffy nose) (2%) and abnormal ejaculation (1.4%). Obviously the newer selective alpha blockers have less vascular side effects, but more retrograde ejaculation and we will come back to that in a minute. A good number to know is that 11% of patients discontinue alpha blockers due to their side-effects as demonstrated by Kirby in the PREDICT trial.

JOSEPH: Thanks Rachel. I just want to pick up on this side effect of sexual dysfunction that is quoted in the product information sheets. Some patients actually read those Iliad length epics that come with the tablets and it is important to note that patients can get confused about what sexual dysfunction means in these brochures. We can distinguish between the retrograde ejaculation associated with alpha blockers and the loss of libido and erectile dysfunction we occasionally see with the 5-alpha reductase inhibitors. It is an important point to consider when counselling patients. But I digress. Back to the selectivity of the alpha receptors.

RACHEL: Looking at the more common α-blockers, alfuzosin, doxazosin and terazosin are non-subtype-selective. Tamsulosin has roughly equal selectivity for α_1A and α_1D and less so for α_1B. Silodosin has very high selectivity for α_1A, with decreasing selectivity for α_1D and then for α_1B.

Some people have very early starts, and we don’t want them falling asleep at the wheel with too much science, so it is time to chat to our international expert, Claus Roehrborn, for his take on the practicalities of using these drugs.

JOSEPH: I thought we would start with the big question. At risk of ruining all future sponsorship and making this the last podcast ever, we asked him if there was any difference in the efficacy between the different generations of alpha blockers, because the newer selective alpha blockers are certainly more expensive than the older non-selective alpha blockers.

CLAUS: Well, as you know there have been comparative studies done, even randomised trials, comparing the various alpha blockers and most of them did not show a big difference in terms of efficacy, and the later analysis didn’t show any difference in terms of efficacy either. Now there are some trials and people will bring them up which show and advantage of one versus the other. But, be careful. Most of these trials were rigged to show one particular aspect of one alpha-blocker be better than the other. Across the board I think there is not a big difference.

JOSEPH: Oh well. This podcast gig was good while it lasted but Claus and his level 1 evidence has skewered us.

RACHEL: Wait, Joseph, just before you start crying in to your flowmeter, let’s look at the efficacy you can quote to your patients when starting alpha blockers.  The headline numbers you need to know are that 40% of men will say they feel a symptomatic improvement from an alpha blocker. The meta-analysis show that Alpha blockers decrease the IPSS by 35-40% and increase maximum urinary flow rate (Qmax) by 20-25%. They also increase bladder capacity and decrease detrusor overactivity.

JOSEPH: This is where I like to dig below the surface of the headlines and look at a very interesting point. In fact, the meta-analysis in European Urology in 2008 found that when you compared them to placebo, the alpha-blockers improved the Qmax by 1.3ml/min and IPSS by 1.9 points more than placebo. I think this is one interesting case where the clinical benefit is actually greater than the statistically significant benefit. You won’t often hear me say that. This is a key point because we know that placebo has a larger than normal effect in men with lower urinary tract symptoms and hence why many patients have will claim that their latest herb or snake oil seems to work.

RACHEL: That is a good number to work with. It is also interesting to note at this point that the studies also showed that while alpha blockers help with the day to day symptoms associated with LUTS, they did not reduce the risk of acute urinary retention nor the need for surgery. This is considered one of the major differences in the long term efficacy between the alpha blockers and the 5-alpha reductase inhibitors, but that is the topic of whole another podcast.

JOSEPH: Ok. Let’s get to the practicalities of prescribing alpha-blockers. We asked Claus what he thought were some of the commonest mistakes that urologists make when prescribing these drugs?

CLAUS: Well there’s a couple of common mistakes that are being made. The first one is those urologists’ switch alpha-blockers for efficacy reason. They argue with the patient to go from one to another to improve efficacy, and the reality is that the efficacy is just about the same across the board. The second mistake is that they don’t respect too much the patient’s baseline presentation, age, sexual activity etc, and being careful what they select. So, for example; in a young, very sexually active patient, I think it is not appropriate to select Silodosin because the patients will call in with an ejaculation and an elderly patient with cardiac condition, I feel you should choose Alfuzosin because it’s cardiac wise extremely safe, so is Silodosin. Alfuzosin on the other hand doesn’t cause any ejaculation problems. So I don’t think urologists differentiate enough based on adverse events and they seem to want to differentiate based on efficacy which I don’t think is relevant.

JOSEPH: So monitoring and preparing for side effects is the key to using alpha blockers. Great. We might be back in the podcast business. I also just want to clarify the terminology where Claus refers to anejaculation, alpha blockers actually cause retrograde ejaculation where the sperm go back up in to the bladder on ejaculation. Not great for making babies, sure, but most of my men don’t seem to mind… except this one 75yo guy: a new father at 76 and very proud of himself!

RACHEL: We asked him if he had any tips for commencing alpha blockers or dealing with the side effects.

CLAUS: I grew up in the 90s with the Doxazosin and Terazosin and those will have to be titrated and so we wrote a titration pack, you know, start with 2 and go to 4 or 5, and then from 4-5 go to 8, and that is definitely very important with those drugs. With the other drugs it’s important to tell the patient to watch for certain side effects, be aware that with Tamsulosin there is an 8-20% risk of an ejaculation depending on the dose, with Silodosin there is a 30% risk – make the patients aware of that. Then I tell the patient to expect a beneficial effect on their symptoms within 3-7 days. Please remember, another important point – the shortest time period for which the symptoms score was validated was 7 days. So the shortest time period of measurement is 7 days, in other words the IPSS score was validated to ask the question, you know – over the last week or so – “how did your symptoms change”. But that doesn’t mean that the effect is not sooner, so I tell patients to expect that after 3-7 days when the drug reaches a steady stage. Side effects – well I tell the patient to basically look out for anything that is out of the ordinary from a stuffy nose to stomach upset to dizziness and light-headedness, to ejaculatory problems or anything else long that line, and report it to me.

RACHEL: They are some great tips from Claus, but we just have to do our Australian registered products public announcement here. In the Australian product information, the quoted rates of retrograde ejaculation are 1.7% for Tamsulosin, and 23% for Silodosin, perhaps correlating with their α1A receptor selectivity which we know is only one component of their efficacy in LUTS. Also, we must note that terazosin is no longer registered in Australia.

JOSEPH: Claus has been the first or senior author or an investigator on most of the alpha blocker trials to come out over the last 2 decades. MTOPS and COMBAT to name a few. We asked him what is the biggest mistake you see in interpretation of the alpha blocker trials you’ve been involved with and therefore do we need to have any caution when referencing them?

CLAUS: I think there are two ways of miss-interpreting that. The first way of miss-interpreting it is that, 90% of alpha-blockers trials with the exception of the trial and one trial with Alfuzosin, they are all 12-week trials as a rule. And the 12 week trial result in terms of symptom improvement are taken as gospel, and people then forget that the prostate will grow, that the detrusor muscle will deteriorate, and then a year or two down the road things will change and the effect will not be as good. I think that is the number 1 error. To assume that the 12-week trial will project a 12-year outcome which by no means does it do that. The second problem is not unique to alpha blocker but to all medical treatment trials, and that is, medical treatment trials get ___, because the patients have a placebo lead in, in those groups the active and the placebo, and after the placebo lead in, they do another symptoms core and that symptoms score is then used to assess the efficacy from baseline to end point. And that is a faulty assumption because a patient in practice, he will give credit to both the placebo effect and the drug effect. So, when doctors tell patients “well you can expect about a 4-5 point improvement” I think that is wrong. They can expect a 7-9 point improvement because they also roll in this placebo effect. Often overlapped, poorly understood, but definitely a case in all medical treatment trials that, that placebo effect is not credited to the alpha-blocker in real life practice.

RACHEL:  Obviously men present with a constellation of lower urinary tract symptoms. We asked him if there were any symptoms that responded best to alpha blockers?

CLAUS: This is sort of a resident’s project. So if you have a data set of a large trial with IPSS score, it’s acute product to say “hey let’s look how the individual symptoms responded” or the storage vs voiding. And the universal answer is – the alpha-blockers work for both storage and voiding. And the universal answer is also – it is rare to improve nocturia by more than 1 number, ie from 3 to 2, from 4 to 3 etc. To go to 0 is nearly impossible. So I would say across the board the same nocturia week response, and you know that that’s the case with all drugs.

JOSEPH: One final caveat with the use of α-blockers we should mention is floppy iris syndrome (FIS). It seems to be relatively controversial as to its significance. I first asked Claus what he thought of it.

CLAUS: Floppy iris syndrome was reported first with Flomax and by far the highest number of reports and spontaneous events reporting is with Flomax. I, and others believe this has to do with the fact that Flomax is widely used, and since doctors are aware, they are more in tune with it and report it more often. I think that it is likely a phenomenon with all alpha blockers, and there is a book, a journal it’s called “S___ Archive of Physiology”, and in that particular magazine an article was published some years ago that showed that all alpha blockers have the same effect on the ciliary muscle, and now come the shocker. That effect sets in within a few hours or days from the first dose and that effect is universally gone after a few days as well. I say shocker because, as you know, some eye doctors claim that the effect doesn’t go away for weeks or it doesn’t go away ever. This seems incredible to me because, we know in urology that the effect on the receptors is temporary and if we stop it it’s gone, so I don’t understand it and my recommendation to patients is to a) tell their eye doctor or talk to both the eye doctor and urologist, b) stop it for 2 weeks and resume it 2 weeks later, except if the ophthalmologist has a very specific reason to query this or question this, or ask for something different.

RACHEL: That is some fantastic practical advice but may I remind our Australian audience that floppy Iris syndrome is a cautious adverse event that requires special monitoring in Australia and all BPH alpha blockers have this precaution. This can even be a single dose of an alpha blocker in a man’s life can cause floppy iris syndrome.

JOSEPH: We should note that this only occurs intraoperatively if they go on to have cataract surgery. You can rest assured that there is not an epidemic of old men wandering the earth with floppy irises. But what is it, and what do the ophthalmologists have to say about it? I chatted to a colleague of mine, an ophthalmologist in Melbourne, Dr Jonathon Ruddle,  to get his take on floppy iris syndrome.

JON: Thanks, Joseph. Intra-operative floppy iris syndrome was first described in 2005, but it only takes one difficult cataract case to imprint the effect of alpha-blockers in the mind of a cataract surgeon. In short, to perform safe cataract surgery, it is necessary to have a stable large pupil. This is achieved by pharmacological contraction of the iris dilator muscle with phenylephrine and inhibition of parasympathetic iris sphincter.

JOSEPH: So it’s not the ciliary muscle as we may have mentioned earlier. And considering the eye could be considered almost as important as some of the urological organs, we will graciously accept the correction.  

JON: So kind of you. Theory goes that alpha-blockers you use on the urinary tract also block the α1-adrenergic receptors supplying the iris dilator muscle. Their long half-life and constant receptor blockade may result in diffuse atrophy of the iris dilator smooth muscle. This causes the stoma or opening of the iris to billow with fluid currents during cataract surgery, and to prolapse through normal wounds. These chronically alpha-blocked iris also tend to constrict as surgery continues, risking further complications during the case.

JOSEPH: So it is actually an issue of atrophy of the muscle with chronic inhibition by alpha blockers. Fascinating.

JON: It seems prospective data shows that selective α1-adrenergic receptor antagonists such as Tamsulosin and silodosin, are notorious for causing IFIS more than non-selective blockers. The reported incidence of IFIS associated with the selective alpha blockers ranges from 43% to 100% .  The effects of adrenergic antagonists on iris behaviour are not correlated with the dose or duration of therapy, and discontinuing the medication seems to have no effect on the degree of IFIS . Non selective blockers such as prazosin, terazosin, doxazosin and alfuzosin can cause IFIS, but at perhaps half the rate.

JOSEPH: How do cataract surgeons handle this complication?

JON: To be forewarned is all important. Cataract surgeons when prepared, can give greater preoperative medication, alter their techniques, and counsel patients about the slightly greater risks involved in their surgery

 JOSEPH: Alright then, so if Urologists are gonna prescribe alphablockers, what can they do?

JON: I suggest asking the patient about any planned or possible cataract surgery. If he has already had both cataracts removed, then there is no need to avoid or worry about any alpha-1 antagonist. If the patient says he has a cataract and also his vision has been getting worse, then he may want to have an eye exam to see if cataract surgery is a consideration before starting on chronic alpha-1 antagonist treatment.

If there is a history of early cataract, but surgery is not yet needed, starting with a nonselective alpha-1 antagonist may be preferable. If the nonselective drug is ineffective, however, silodosin or tamsulosin use need not be discouraged.

RACHEL: Thank you, Jon. That was fantastic. Claus had a very interesting tip on how to bridge the cataract surgery for the patient that just can’t stop the alpha blocker:

CLAUS: Some patients feel without the alpha-blocker, they say, “if I don’t take Flomax, I really can’t urinate at all, I’m nervous”. So, I say, well you can bridge that by taking Cialis 5mg daily, you can almost switch. One day you take Flomax and the next day you take Cialis, and it has almost the same effect. It immediately kicks in, and it is immediately in and out of the system. So for those patients I use that particular approach.

JOSEPH: That is a great tip from Claus, and just a quick compliance note for here in Australia that Cialis is registered for continuous use for LUTS.

RACHEL: OK. But what about the man with mixed LUTS:  with both voiding and storage LUTS?

JOSEPH: Let’s be honest, Rachel, no one really wants to hear what I think. So let’s ask Claus.

CLAUS: I was part of several trials. I was part of the very first trial published in JAMA called the time study that was a parallel trial with Detrol vs Tamsulosin vs placebo vs combination. It showed a benefit in all storage symptoms in 24hr voiding frequency and urgency with a combination therapy. My personal practice is that if a patient presents with dominant storage symptoms, I go for it. I give them both drugs at the same time, and I will tell them why and how, and then I will just wait to see what happens. Now there are patients who come back after a month and say “ I still have urgency and frequency”, then I say well, add this drug. So, I’ll do both, I’ll do a antimuscarinic add on, and I will also start patients at the same time. What I rarely do is, I rarely start men only on an antimuscarinic. I have concerns a little bit in elderly patients with bad detrusor’s. There have been studies done, Paul Abrems did it, Steve Caplin did it, showing no effect on urodynamics, but I maintain some nervousness and so I either do both at the same time, or stagger it, alpha blocker – antimuscarinic, but I rarely give an antimuscarinic alone.

JOSEPH: So while it was beyond the scope of this podcast to delve deep in to the 5-alpha reductase inhibitors, we asked Claus what he thought of combination therapy.

CLAUS: If there is a patient who fits the bill and has a big prostate or an elevated PSA and you know that from an MRI or an ultrasound and you know that already, just jump in with a combination with a 5-ARI, that’s the most time honoured and studies combination medicine in all of urology in trials of 20,000 men showing a substantial benefit. And don’t try to get away with just an alpha-blocker because those patients, rather sooner than later, will deteriorate and not have a long-term benefit.

RACHEL: That is well and good but there are so many things you can use to surgically treat BPH such as cut it, steam it, vapourise it, laser it, microwave it, freeze it, cook it, pin it, etc and really the only thing in the kitchen you can’t do to it is throw the sink at it. So where does Claus see alpha blockers fitting in in this future?

CLAUS: I think the alpha-blockers have a role at the present time, and they had a role for 25 years and they will have a role in the future. There are many men who don’t want to go minimally invasive surgical treatment, many men shy away from any time of anaesthetic. They like to take a medication trial for a while, and the majority of men at least in numerical as you know, have a prostate size of under 40gms, the majority have a PSA of under 2, let’s say; and in those patients the alpha blocker’s at least for a year or 2 years provide excellent benefit. I mentioned earlier you do want to monitor the long-term consequences and make the patient aware that after 2,3,4 years the prostate may grow, the detrusor may weaken and so, it may not be the treatment for the long term.

JOSEPH: Well that has been absolute gold from Claus, silver to you, Rachel, and I’ll take home the bronzed walnut; the analogous size and shape of the normal prostate before it grows in to the mythologised grapefruit. To summarise, alpha blockers were developed in the 1970s during the era of disco fever! The established role for alpha-blockers as monotherapy or as combination therapy is based on large scale randomised controlled trials (RCTs) such as the MTOPS and CombAT trials. And now for our fast five facts you can quote to your patients tomorrow:

1. alpha blockers will improve their Qmax by 25%
2. they decrease the IPSS by 40%
3. 40% of men will have significant improvement in their symptoms
4. 11% of men will need to cease an alpha blocker due to side effects
5. Don’t forget to mention floppy iris syndrome.

And I think that’s everything on alpha-blockers for the moment ladies and gentlemen. Hopefully, you’ve learned a thing or two about starting patients with BPH on alpha-blocker therapy and thanks again for listening. And thanks to Claus Roehrborn who has shared his invaluable expertise and insights with us today. And thank you Rachel for joining me.

You can now get all our podcasts on Apple podcasts, Soundcloud or on twitter @talking_urology. Remember to send all feedback to Talkingurology@gmail.com.

You’ve been listening to Joseph Ischia, Rachel Esler, and Claus Roehrborn. Written by Mark Quinlan, Niall Davis, and Joseph Ischia. Produced by Joseph Ischia and Cara Webb. And a special thanks to our sponsor of this episode Mayne, the alpha dogs of Pharma.