Benign prostatic hyperplasia By Lynn Gould

Benign prostatic hyperplasia By Lynn Gould Learning objectives After reading this article you should be able to: Identify symptoms suggestive of benign prostatic hyperplasia (BPH). Provide advice to customers on medicines used to treat BPH, in particular tamsulosin. Discuss complementary and non-drug therapies used in the treatment of BPH. Provide advice on lifestyle modifications which may help to alleviate the symptoms BPH. Competency standards (2010) addressed: 4.2.2, 4.3.3, 7.1.2 Accreditation number: CAP110404a Lynn Gould is a Professional Programs Pharmacist with the PSA National Office. Case study Mr Edkins, a 73-year-old customer, presents a script for tamsulosin. He has just visited his doctor because he has been getting up to urinate several times during the night and has also started having difficulty urinating. The doctor has diagnosed him with benign prostatic hyperplasia (BPH) and has given him the script for tamsulosin and a referral to a urologist. Mr Edkins has a history of hypertension and depression, for which he takes ramipril 5 mg daily, hydrochlorothiazide 12.5 mg daily and sertraline 50 mg daily. What is BPH? Benign prostatic hyperplasia (BPH) is non-malignant enlargement of the prostate gland. The prostate gland is located beneath the bladder and surrounds the top part of the urethra. It produces a fluid that is secreted into the urethra and makes up about half of the volume of seminal fluid, helping to keep the sperm alive and motile. When testosterone levels in boys begin to rise during puberty, the prostate grows about eight times in size. It then continues to grow slowly, doubling in size from ages 21 to 50, and almost doubling again between the ages of 50 and 80. 1 The causes of BPH are not well understood, but it is thought that hormonal changes associated with ageing may be involved. The hormonal changes that are thought to promote prostate enlargement include an increase in the oestrogentestosterone ratio that normally occurs as men age and an accumulation of dihydrotestosterone (DHT) in the prostate, which stimulates the growth of cells. Another theory is that BPH may develop as a result of a reawakening in adulthood of embryonic induction processes. Although not all men who have BPH are symptomatic, it is estimated that BPH is present in approximately 20% 296

Submit your answers online at www.psa.org.au and receive automatic feedback of men aged 41 50, 50% of men aged 51 60, and 90% of men over the age of 80. 1-6 What problems can BPH cause? For some men, the symptoms of BPH are quite mild or non-existent. There is a range of urinary symptoms associated with BPH which are commonly referred to as lower urinary tract symptoms, or LUTS. These symptoms are thought to occur for two reasons. Firstly, hyperplasia of the prostate can cause compression of the urethra resulting in bladder outlet obstruction (obstructive symptoms). Secondly, prolonged obstruction of the bladder outlet causes the detrusor (the muscle of the bladder wall) to increase in tone in an attempt to compensate, leading to detrusor overactivity (irritative symptoms). 1,3,6 Obstructive symptoms include: hesitancy (a longer than usual wait for the stream of urine to begin); a weak and poorly directed stream of urine; straining to urinate; posturination dribbling or an irregular stream; urinary retention; and overflow or paradoxical incontinence (urine overflows uncontrollably from a full bladder although normal urination cannot be initiated). Irritative symptoms include: urgency (an urgent desire to urinate); frequency (frequently needing to urinate); and nocturia (a need to pass urine more than twice at night). The prevalence and severity of LUTS usually increases with increasing age, although the severity of symptoms is not necessarily related to prostate size. 1,3,6,7 Straining to urinate can cause congestion of superficial veins in the prostatic urethra, which may rupture and produce haematuria. Repeated straining over a prolonged period of time may result in haemorrhoids or inguinal hernias. Sometimes a man may not realise that he has BPH until he suddenly finds himself unable to urinate at all. This is known as acute urinary retention and may be precipitated by long periods of immobility, exposure to cold, or the use of anaesthetics, anticholinergics, sympathomimetics, opioids or alcohol. Other complications that may be caused by BPH include urinary tract infections, bladder stones and renal impairment. 2,3,7 Other medical conditions that can cause lower urinary tract symptoms include infections, prostate cancer, neurological disease and renal disease. Men who present with these symptoms should be promptly referred to a doctor for further investigation. 2,3,6 How does tamsulosin work? Tamsulosin works by relaxing the muscles in the bladder neck and prostate, reducing bladder outlet obstruction and improving urine flow. Tamsulosin is a selective alpha 1 - adrenergic-receptor blocking agent (other drugs in this class are alfuzosin, prazosin and terazosin). It selectively blocks the alpha 1 receptor subtypes found in the bladder and prostate, producing localised relaxation of smooth muscle. The symptoms associated with BPH may improve within 48 hours of commencing tamsulosin, with full effect usually seen within four to six weeks. 3,7,8 How should I take tamsulosin? The dose of tamsulosin is one tablet a day. The tablet needs to be swallowed whole, preferably with a glass of water. It should not be not be broken, crushed or chewed, as this will compromise its prolonged release properties. It can be taken before, with or after food. If there is no improvement in symptoms after four to six weeks of treatment, it is unlikely that it will be effective and an alternative treatment may need to be prescribed. 1,7,8 Are there any unwanted effects? Common side effects of tamsulosin include ejaculatory dysfunction (particularly retrograde ejaculation, where the semen flows backwards into the bladder during ejaculation) and dizziness. Less common side effects include weakness, constipation, diarrhoea, nausea, vomiting, headache, pruritus, rhinitis, somnolence and skin peeling-off (desquamation). Tamsulosin may also induce or aggravate stress incontinence due to sphincter relaxation. Current or previous therapy with tamsulosin may increase the risk of intra-operative floppy iris syndrome during cataract surgery. Inhibition of iris dilator smooth muscle has been suggested as a potential mechanism. Tamsulosin has also been associated with increased rates of post-operative ocular complications. 6-10 Potentially serious adverse reactions to tamsulosin may occur infrequently. They include palpitations, orthostatic hypotension, urticaria, fainting and angioedema (which may present as hoarseness, large hive-like swellings on eyelids, face, genitals, hands, feet, lips, throat, tongue, and difficulty swallowing or breathing). An extremely rare side effect of tamsulosin is priapism, a persistent, painful penile erection unrelated to sexual activity. If priapism occurs immediate medical attention should be sought as, without treatment, it can lead to permanent erectile dysfunction. 8,9 Will it affect any of my other medicines? There is limited clinical data available on interactions between tamsulosin and other drugs. Tamsulosin may cause orthostatic hypotension, and administration with other drugs that can lower blood pressure may result in additional hypotensive effects. This increases the risk of firstdose hypotension or a sharp drop in blood pressure. As Mr Edkins is taking other blood-pressure lowering medicines, it is important to warn him that he may experience some dizziness when commencing tamsulosin. Concurrent use of a phosphodiesterase 5 [PDE5] inhibitor (sildenafil, tadalafil or vardenafil) with tamsulosin may result in symptomatic hypotension. If Mr Edkins starts taking a PDE5 inhibitor while on tamsulosin therapy, he should begin with a low dose of the PDE5 inhibitor and leave at least a four-hour gap (six hours with vardenafil) between the administration of each medicine. Concurrent administration of tamsulosin with other alpha 1 -blockers is contraindicated because of the potential for hypotensive effects. 7 9 Tamsulosin is metabolised in the liver, primarily by cytochrome P450 (CYP) 3A4 and 2D6. It is therefore theoretically possible that inducers or inhibitors of CYP3A4 or CYP2D6 may affect tamsulosin plasma concentrations. CYP2D6 inhibitors include all selective serotonin reuptake inhibitors, with fluoxetine and paroxetine being 297

the most potent. CYP3A4 inducers include phenytoin and St John s wort, and CYP3A4 inhibitors include clarithromycin, diltiazem, verapamil and ketoconazole. 7 9 Tamsulosin also binds extensively to plasma proteins and may displace other protein-bound drugs. However, this is unlikely to be clinically significant, as most drugs which are extensively bound to plasma proteins (e.g. warfarin, phenytoin, sodium valproate, methotrexate) have lowextraction ratios and any increase in the free fraction should be rapidly metabolised and cleared. 8,11 If tamsulosin doesn t work, are there any other medicines the doctor can prescribe? If Mr Edkins symptoms do not improve with tamsulosin therapy, the use of a 5-alpha-reductase inhibitor (finasteride or dutasteride) may be considered. These medicines inhibit the enzyme 5-alpha-reductase, which converts testosterone to dihydrotestosterone (DHT). 5-alphareductase inhibitors are indicated for use in symptomatic BPH when the prostate size is >30 40 cm 3. They reduce prostate size, thereby improving urinary symptoms and urinary flow rate, and reducing the risk of acute urinary retention and the need for surgery. It may take six months or longer for symptoms to improve and 12 18 months before the full effect is seen. Adverse effects may include impotence, decreased libido, ejaculation disorder (including decreased ejaculate volume) and breast tenderness or enlargement. 7,12 Combination treatment with alpha 1 - blockers and 5-alpha-reductase inhibitors medicines may be considered when prostate size is >30 40 cm 3 and rapid relief of troublesome symptoms is required as alpha 1 -blockers relieve symptoms more rapidly than 5-alphareductase inhibitors. 7 A promising new treatment that is still under investigation is botulinum toxin type-a (BTX-A) which can be injected directly into the prostate. Although the mechanism of action is not yet fully understood, it appears to reduce the size of the prostate as well as relaxing the smooth muscle of the prostate and urethral sphincter. Clinical trials are being carried out to investigate its efficacy and safety. 1,13 Are there any complementary and alternative treatments for BPH? The herbal medicine most commonly used for BPH is saw palmetto (Serenoa repens). Cochrane reviews carried out in 1998 and 2002 concluded that saw palmetto provided mild improvement of symptoms in BPH. However, a review carried out in 2008 found that saw palmetto did not provide noticeable relief of urinary symptoms and was no better than placebo for the treatment of BPH. The most common adverse effects of saw palmetto are gastrointestinal and include abdominal discomfort, nausea, vomiting and diarrhoea. Headaches, sexual dysfunction and two cases of severe bleeding have also been reported. Based on the proposed antiandrogenic activity of saw palmetto, it is possible that additive effects may occur if it is used concomitantly with 5-alpha-reductase inhibitors. Because there have been reports of bleeding with saw palmetto, it should be used cautiously with anticoagulants. 14,15 Another herbal medicine which has been used to treat BPH is an extract from the bark of the African prune tree Pygeum africanum. A 1998 Cochrane review found that Pygeum africanum is well tolerated and provides moderate relief from the symptoms of BPH. However, the authors caution that the reviewed studies were small and of short duration, used varied doses and preparations and rarely reported outcomes using standardised validated measures of efficacy. They conclude that additional well-designed trials are needed before definitive recommendations can be made. 16 Are there any non-drug treatments for BPH? Men with severe BPH symptoms which have not responded to pharmacotherapy may require surgery. The standard surgical therapy is transurethral resection of the prostate (TURP). It involves removing part of the prostate via an endoscope through the urethra. If the prostate is greatly enlarged (>80 cm 3 ) an open prostatectomy, via an incision in the lower abdominal area, may be considered. Possible complications of these procedures include TUR syndrome (a dilutional hyponatraemia caused by absorption of irrigating solution into the bloodstream), erectile dysfunction, urinary incontinence, retrograde ejaculation, bladder neck contracture, urinary tract infections and haematuria. 1,6 Alternative, less invasive procedures include: 1,6 Laser therapy, which uses laser energy to produce a variety of effects within prostate tissue including coagulation necrosis and vaporisation. This treatment causes less bleeding than TURP and is generally recommended for men taking anticoagulants. However, because of the cost of the laser machine, it is not available in all hospitals. Transurethral microwave thermotherapy (TUMT), in which the prostate is heated using a microwave antenna mounted on a urethral catheter. Although this treatment has fewer and less serious side-effects than TURP, it is not commonly used as it has lower success rates than TURP. Can I do anything else to help relieve my symptoms? Certain lifestyle modifications may help to alleviate symptoms of BPH. These may include: 1,12,17 limiting daily fluid intake to less than 2,000 ml and avoiding drinking after the evening meal; reducing intake of caffeine, alcohol and spicy foods; avoiding constipation eat plenty of fruit, vegetables and fibre-containing foods; staying active immobility may increase the risk of urine retention; avoiding activities that involve vibration or trauma to the perineum (e.g. bike riding, tractor driving, long-distance driving); after urinating, waiting for a short time and trying to urinate again ( double-voiding ); trying to urinate at least once every three hours; avoiding medicines that may worsen urinary incontinence (e.g. decongestants, antihistamines); doing pelvic floor exercises; learning how to do urethral milking, which helps to expel any residual urine by physically pressing the urinary tract. A doctor or continence nurse can show men how to do this. 298

Where can I find more information on BPH? The following websites contain useful information about BPH and urinary incontinence: Andrology Australia: www.andrologyaustralia.org (Tel: 1300 303 878) Australian Government Bladder & Bowel Website: www.bladderbowel.gov.au Department of Health and Ageing continence information: www.health.gov.au/internet/main/ publishing.nsf/content/continence-2 Continence Foundation of Australia: www.continence.org.au (Tel: 1800 330 066) The National Kidney and Urologic Diseases Information Clearinghouse (NKUDIC); National Institutes of Health: http://kidney. niddk.nih.gov/kudiseases/pubs/ prostateenlargement/ University of Maryland Medical Center (UMMC): www.umm.edu/ patiented/articles/benign_prostatic_ hyperplasia_000071.htm Case study continued Mr Edkins should be offered a tamsulosin CMI and provided with advice on how to take the tablets and possible side effects. He should be warned about potentially serious side effects which require medical attention (e.g. angioedema, priapism, palpitations and skin rashes). He should be cautioned that the tamsulosin may initially cause him to feel faint or dizzy, and that the combination of tamsulosin and his blood pressure medicines may increase the risk of dizziness and lightheadedness. To minimise this effect, he should get up slowly from a sitting or lying position and, if he feels faint on standing up, he should lie down for a short while. Taking the tamsulosin at bedtime may be helpful, but he should be careful if he gets up during the night as he might feel dizzy. He should avoid driving a car or operating machinery if he feels dizzy. If the dizziness or light-headedness persists, he should see his doctor and have his blood pressure checked. He can be reassured that the tamsulosin is unlikely to affect his sertraline. He should be warned that, if he needs to have cataract surgery in the future, he must inform his ophthalmologist that he is taking, or has taken, tamsulosin. Lifestyle modifications which may help to alleviate his symptoms can also be suggested. Key learning points BPH becomes increasingly common as men get older, and is present in approximately 90% of men over the age of 80. For some men the symptoms are quite mild or nonexistent, however, many men experience a range of lower urinary tract symptoms (LUTS). These can include hesitancy, urinary retention, overflow incontinence, urgency, frequency and nocturia. Drugs used for BPH include selective alpha 1 -adrenergic blockers (tamsulosin, alfuzosin, prazosin and terazosin) and 5-alphareductase inhibitors (finasteride and dutasteride). Men with severe symptoms which have not responded to drug therapy may require surgical intervention. Non-drug therapies which are available include transurethral resection of the prostate (TURP), laser therapy, transurethral microwave thermotherapy (TUMT) and open prostatectomy. Men can also try certain lifestyle modifications which may help to alleviate the symptoms of BPH. Because LUTS can also be caused by other disorders, including infections, prostate cancer, neurological disease or renal disease, men with these symptoms should be referred to a doctor for investigation. References 1. Gardiner RA. Fact sheet: prostate enlargement (BPH) [online]. Andrology Australia. Mar 2006. At: www.andrologyaustralia.org/pagecontent. asp?pagecode=prostateproblems 2. Benign Prostatic Hyperplasia (BPH). Merck Manual for Healthcare Professionals [online]; last updated Oct 2008. At: www.merckmanuals.com/professional/sec17/ ch240/ch240b.html 3. Prostate Enlargement: Benign Prostatic Hyperplasia [online]. National Kidney and Urologic Diseases Information Clearinghouse (NKUDIC); National Institutes of Health US. Jun 2006. At: http://kidney.niddk.nih.gov/ kudiseases/pubs/prostateenlargement/ 4. Rohrmann S, Platz EA, Giovannucci E. Lifestyle and benign prostatic hyperplasia in older men: What do we know? J Men s Health Gend. Jun 2005; 2(2):230 5. 5. Djavan B, Eckersberger E, Finkelstein J, et al. Benign prostatic hyperplasia: current clinical practice. Primary Care: Clinics in Office Practice. Sept 2010; 37(3):583 97. 6. American Urological Association. Guideline on the management of benign prostatic hyperplasia (BPH) [online]. American Urological Association of Education and Research, Inc. 2010. At: www.auanet.org/content/ guidelines-and-quality-care/clinical-guidelines. cfm?sub=bph 7. Rossi S, ed. Australian Medicines Handbook [online]. Adelaide: Australian Medicines Handbook; 2011. 8. Approved product Information. emims [CD-ROM]. St Leonards: CMPMedica Australia, Nov 2010. 9. Bicopoulos D, ed. AusDI Advanced Feb 2011 [online]. Phoenix Medical Publishing; 2011. 10. Sansom L, ed. Australian pharmaceutical formulary and handbook (APF). 21 st edn. Canberra: Pharmaceutical Society of Australia; 2009. 11. Baxter K, ed. Stockley s drug interactions. 8 th edn. London: Pharmaceutical Press; 2008. 12. Andrology Australia. Clinical summary guide 7: prostate disease [online]. May, 2010. At: www.andrologyaustralia.org/docs/clinicalsummary-guide07_may2010.pdf 13. Goldstraw MA, Kirby RS, Dasgupta P. The role of botulinum toxin in benign prostatic hyperplasia [online]. British Journal of Urology International. Dec 2006; 98(6):1147 8. At: http://onlinelibrary.wiley.com/ doi/10.1111/j.1464-410x.2006.06565.x/pdf 14. Tacklind J, MacDonald R, Rutks I, et al. Serenoa repens for benign prostatic hyperplasia [online]. Cochrane Database of Systematic Reviews 2009, Issue 2. At: http://onlinelibrary.wiley.com/o/cochrane/clsysrev/ articles/cd001423/frame.html 15. Ulbricht CE, Basch EM, eds. Natural Standard Herb & Supplement Reference: Evidence-based Clinical Reviews. Elsevier Mosby; 2005. 16. Wilt T, Ishani A. Pygeum africanum for benign prostatic hyperplasia [online]. Cochrane Database of Systematic Reviews 1998, Issue 1. At: http://onlinelibrary.wiley.com/o/cochrane/clsysrev/ articles/cd001044/frame.html 17. Benign prostatic hyperplasia: lifestyle changes [online]. University of Maryland Medical Center (UMMC). 2011. At: www.umm.edu/patiented/articles/ what_tests_used_evaluate_lower_urinary_tract_ symptoms_000071_7.htm 300

Submit your answers online at www.psa.org.au and receive automatic feedback Questions A score of 4 out of 5 attracts 1 CPD credit. 1. Regarding the symptoms of benign prostatic hyperplasia (BPH), which of the following statements is CORRECT? a) The severity of symptoms increases with increasing prostate size. b) Lower urinary tract symptoms (LUTS) are specifically diagnostic of BPH. c) Acute urinary retention may be precipitated by strenuous activity. d) Irritative symptoms of BPH may include urgency, frequency and nocturia. 2. Which of the following counselling points regarding tamsulosin is CORRECT? a) Tamsulosin may have to be taken for up to six months before symptoms start to improve. b) Concurrent use of tamsulosin and alfuzosin is contraindicated because of the potential for additive hypotensive effects. c) Priapism and angioedema are common side effects of tamsulosin therapy. d) Ceasing tamsulosin 48 hours before cataract surgery will remove the risk the risk of intraoperative floppy iris syndrome. 3. Which of the following statements regarding the treatment of BPH is CORRECT? a) Unlike alpha 1 -blockers, 5-alphareductase inhibitors reduce prostate size in addition to relieving LUTS. b) Concurrent use of an alpha 1 -blocker and a 5-alpha-reductase inhibitor is not recommended because of the potential for additive effects on ejaculation dysfunction. c) If symptoms of BPH are not relieved by monotherapy with an alpha 1 -blocker, combination therapy with a PDE5 inhibitor and an alpha 1 -blocker may be considered. d) Botulinum toxin injection has recently been approved by the TGA for the treatment of severe BPH. 4. Which of the following recommendations regarding complementary and non-drug therapies for BPH is CORRECT? a) Laser therapy carries a greater risk of bleeding than transurethral resection of the prostate (TURP) and is not recommended for men taking anticoagulants. b) Open prostatectomy is generally only considered if the prostate size is greater than 80 cm 3. c) The most recent Cochrane review on saw palmetto concluded that it provides mild improvement of symptoms in BPH. d) Transurethral microwave thermotherapy (TUMT) has higher success rates than TURP and is commonly used for BPH. 5. Which of the following lifestyle modifications IS APPROPRIATE to recommend for alleviating the symptoms of BPH? a) Train the bladder by waiting as long as possible (at least five hours) between one urination and the next. b) Try and drink at least 2,000 ml of fluid each day. c) Try and avoid drinking tea, coffee and alcohol. d) To minimise the risk of urinary incontinence, do as little exercise as possible. Combination therapy for BPH approved Duodart (dutasteride/tamsulosin hydrochloride) has been approved for use in Australia as a new, convenient option for men diagnosed with moderate to severe symptomatic benign prostatic hyperplasia (BPH). It combines a 5-alpha reductase inhibitor (dutasteride) and an alpha blocker (tamsulosin) into a single treatment. A recent study has shown that combination therapy where dutasteride is used in combination with tamsulosin provides rapid, superior and sustained symptom improvement in BPH compared to tamsulosin or dutasteride alone (as measured by International Prostate Symptom Score (IPSS), p<0.001 for both comparisons at 4 years). 1 Combination therapy also significantly reduced the relative risk of BPH clinical progression over four years compared to either monotherapy. The primary end point, time to acute urinary retention or BPH related surgery, was also significantly longer with combination therapy versus tamsulosin (p<0.001) but there was no significant difference between combination therapy and dutasteride monotherapy (p=0.18). 1 While the occurrence of drug-related adverse events was significantly greater in those patients receiving combination therapy in this study, withdrawal rates due to drug related adverse events were similar across the treatment groups. 1 Dutasteride/ tamsulosin is not PBS listed. According to the Minimum Product Information, dutasteride/tamsulosin is indicated for the management of moderate to severe symptomatic benign prostatic hyperplasia (BPH). Contraindications include: Hypersensitivity to dutasteride, other 5-alpha reductase inhibitors, tamsulosin hydrochloride, or any component of the preparation; use in women and children; pregnancy (Category X); lactation; history of orthostatic hypotension; severe hepatic impairment; severe renal impairment; combination with another alpha-blocker. GlaxoSmithKline s registration of Duodart follows the PBS listing of Avodart (dutasteride), in combination with an alpha blocker, from February 2011. Reference 1. Roehrborn CG, et al. European Urology 2010; 57:123 31. 301