Objective; To carry out an overview of the medical treatment of the benign prostatic hyperplasia using the combination drugs of alpha adrenagic uro selective blockers( Tamsulocin, Alfuzocin) and 5 Alpha reductase iso enzyme 1&2 inhibitor - dutasteride.
Data Source; Review of literature of multicenter international control trials, plus those in the local scene.
Data Selection; Selected articles from international papers on BPH from international research groups (See Appendix) and the Mater Hospital Study.
Data Extraction; Selection of research conclusion from various researches tested for clinical use by international researchers, those locallyâ€¦â€¦.?
Data Synthesis; From various advantages and drug compliance the weighted clinical use of the drug in reducing benign prostatic hyperplasia ( BPH) symptoms in reducing prostate size, in reducing BPH progression , acute retention of urine and surgical indications for BHP.
Conclusion; BPH symptom reduction and shrinkage of prostate size by the use of these two groups of drugs lead to a treatment method that stands out as a first priority in the management of BPH especially in those cases that are surgical risks or those patients who are in the category of mild to moderate (International prostate symptom score)IPSS scores.
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Benign prostatic hyperplasia (BPH) is the most common cause of urinary bladder outflow obstruction (BOO) in men aged 50 years and above. The incidence and prevalence increases with advancing age. Men 40 years to 49 years have incidence of 14% and those 60 years and above have incidence of 43% (1). Other studies have given prevalences as follows;- 51years to 60 years, 50%; 71 years to 80 years, 79% and above 80 years, 85% (2).
The men with BPH who develop symptoms vary from different groups, country and environmental conditions. The moderate to severe symptoms of lower urinary tract (LUTS) occurs in 19% of men of 50 years and above. This increases to 30% of men 70 years and above and increases with age (3).
Using the definition of BPH as a prostate size greater than 30cc in volume and International prostate symptom score (IPSS) greater than 7, the men aged 55-74 years have prevalence of 19% (4) but this definition of BPH is often based on symptoms alone if on both prostate volume and symptoms. There is also international variation of prevalence of symptoms in men aged 40-79 years (5). Across sectional survey of BPH in United Kingdom (UK), France, The Netherlands and Korea gave results that moderate to severe symptoms (LUTS of IPSS 8-35) was common in men 70-79 years by 40.4% and that of men 40-49 years by 10.6%. The greatest bothersome symptoms and BPH impact symptom score (B11) rating was 7-13 in the same age groups. (5)
The etiology of BPH has now been linked to advancing age 40 years onwards and the hormonal control on prostatic cell growth. The active form of testosterone, the dihydrotestosterone (DHT) is the main stimulant. Other factors are genetic and environmental. There is prostatic cell proliferation that results in increased size with reduction in programmed cell death (apoptosis) (6). The cell proliferation is concentrated in the peri - urethral and transitional zones. The increase in prostate size and the stromal content in the growth involving the smooth muscles results in symptoms of bladder outlet obstruction. The symptoms are voiding/obstructive (weak urinary stream, prolonged voiding time, hesitancy, intermittency, incomplete bladder emptying, terminal or post voiding dribbling) and storage/irritative (frequency, nocturia, urgency, incontinence) in various combinations. Other associated symptoms are abdominal pain, haematuria, haemospermia, and erectile dysfunction.
FACTORS THAT LEAD TO SYMPTOMS OF BPH
Progression of BPH (continued growth) and worsening of symptoms results in acute retention of urine (AUR) and demand for BPH related surgery (7). The risk AUR is 23% in a 60 year old by the time he becomes 80 years old. This also increases morbidity and mortality of BPH. It is therefore necessary to treat and prevent BPH progression by identifying the predictors to AUR which are increased in prostatic volume (>30cc) and serum prostatic specific antigen >1.5ng/ml and <10.0ng/m.
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COMBINATION DRUG TREATMENT OF BPH
The discussion on medical therapy centres on the value and advantages of combination drug therapy rather than monotherapy. The drugs researched on are alpha-adrenergic uroselective blockers (tamsulosin and alfuzosin) and 5-alpha reductase inhibitors (finasteride and dutasteride).
Abbreviations should be written in full especially the first time they appear in the text
Medical therapy is one of the best first optional mode to treat patients with mild to moderate LUTs due to BPH. (9) There are various international papers on the prevention of BPH progression into AUR and BPH related surgery.
Alfuzocin and tamsulocin are uroselective, (acts only on Î±1a and Î±1d).
The mechanism of action of these drugs is the reduction of muscle tone, thereby relieving the due to muscle tone to the bladder outlet obstruction in patients with BPH. This principle relies on the proportion of the stromal tissue to the epithelial glandular tissue related to the development of symptoms of BPH (11). The Î±-adrenergic blockade in BPH is dependent on the percentage area density of the prostate smooth muscle (12). Study on tissue strips from prostatic capsule, prostatic smooth muscle, bladder neck smooth muscle here revealed Î±-adrenoreceptors subtypes Î±1a and Î±1d the dominant forming 70% of all Î±1 receptors. (13) The number of receptors increase in the prostate as it enlarges with age such that BPH has more receptors compared to normal sized prostate (14). The clinical application of this uroselectivity has resulted in the use of alfuzocin and tamsulocin.
Revise underlined sentence above
Reference number 10 is missing
Figure II is incomplete and has several errors
PREDOMINANCE OF ALPHA 1 RECEPTOR SUBTYPES IN BPH/BLADDER NECK.
PROSTATE CAPSULE AND SM.M. M
BLADDER BASE AND NECK
Ref. Drugs 2002; 62 (1): 135-37
MECHANISM OF ACTION OF UROSELECTIVE Î±1-BLOCKERS
SELECTIVE BLOCKADE Î±1a and Î±1d RECEPTORS
Reduced Detrusor muscle instability Prostate Sm-m relaxation
Bladder neck sm.m. relaxation
Decreases urgency, frequency incontinence Relief of bladder outlet obstruction
Improvement of urinary flowrate
IMPROVED SYMPTOM OF BPH
Tamsulocin has a rapid onset of action of one week while alfuzocin works within 2-3 weeks. Alfuzocin improves sex drive and is valuable to elderlymen who are sexually active. Erectile dysfunction resulting from BPH is a bothersome and worrying symptom. Both drugs are effective in treatment of symptoms (LUTS) improving peak urinary flow rate (Q max) by causing relaxation of the smooth muscles of the prostate gland and bladder neck.(15). This effect is greater the younger the patient (<60yrs), the smaller the prostate volume (<30cc). The maximum improvement is felt at 6 months (24 weeks) but may continue to 18 months (64 weeks). The risk of treatment failure with Î±-blockers have been shown to be related to baseline prostate volumes (larger than 40cc) and PSA levels. These have resulted in drug withdrawals.
The growth of the prostate gland is dependent on advancing age above 40 years, and the role of dihydrotestosterone (DHT) on the proliferation of the prostate cells. (see diagram below) which one?
5 Alpha reductase isoenzyme type 1 is less concentrated in the prostate cells but abundant in liver and skin while 5 Alpha reductase isoenzyme type 2 is in abundance in the prostate and genital tissues (15).
FINASTERIDE suppresses total DHT by 70% within the first month, it has adverse effects include erectile dysfunction, decreased libido and gynaecomastia amongst others. Its combination with doxazocin (PLESS study) and terazocin (VACOOP study) have yielded important effective reduction in prostatic volume, Qmax and IPSS symptoms improvement better than monotherapy with adverse effects similar in both treatment groups.
The second 5-alpha reductase inhibitor dutasteride inhibits the isoenzyme type 1 and type 2. It is referred to as the dual inhibitor because of this role. It was launched in 2002 and since then has been studied extensively as follows; MTOPS 2003-2006 (Medical Therapy of Prostatic Symptoms). Mc Connel et al NEJM 2003; 349:2387-98. Roehrborn C G et al BJU Vol. 2006; 97; 734-41 should be referenced at references
Phase III a dutasteride study 2003 (2year study) 0.5mg/day Vs placebo in USA and Europe. Randomized double blind placebo controlled.
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Dutasteride 4 year data study (2004-2008). Debruyne F, Barkin J, Van Erps P, et al. Efficacy and Safety of long-term treatment with dual 5ARI dutasteride in men with symptomatic BPH. Eur Urol 2004; 46: 488-95 (Dutasteride D/D n=1152), (Placebo P/D - n-1188) references should be in the reference section
This study showed sustained and continued improvement in symptoms and flow rate 4 years Vs 2 year longer therapy which resulted in greater improvements.
CombAT study of 2007 (on going now 4th year) 4 years end point
The suppression of DHT by dutasteride is 95% within the first month of its use. This suppression is reversible when dutasteride is discontinued (16).
Intra prostatic DHT suppression has been given as follows by studies of Andriole et al and Gleare et al (12) Reference number 12 is Lepor H et al
Could better read as: Andriole et al and Gleare et al reported intraprostatic DHT as 89.3% at 2 weeks, 92.4% at 4 weeks and 98.9% at 4 months
At 2 weeks it is 89.3%
4 weeks it is 92.4%
4 months it is 98.9%
Due to the dual inhibition effect of dutasteride on 5AR isoenzymes 1 and 2, it produces a rapid potent 0.5mg dose - dependent reduction of serum DHT up to 95% within 1 month and intra prostatic DHT reduction by over 98% with 4 month. This reduction of DHT levels has a significant effect on prostatic volume (PV) as early as 1 month and by six (6) months it reaches 95% reduction in blood. The prostatic volume shrinkage is about 24-25%. This leads to symptoms and flow rate improvement by over 65% with effect maintained over 4 years.
Once an enlarged prostate becomes symptomatic then BPH progression continues to worsen resulting AUR and BPH related surgery. Above 70 years of age the serum testosterone remains normal or may drop but once the cellular proliferation has started it progresses on.. Receptors are not down regulated with advancing age (19).
Because of this reason, the objectives of medical therapy are;
early diagnosis before symptoms progress to severe forms and avoid AUR/BPH related surgery
to slow down the progression if any
to avoid complications resulting from surgery for the BPH
to deal with sympathetic over activity persisting after BPH surgery
to allow patients choices when they demand medical therapy as an alternative.
Medical therapy becomes the best option to control symptoms of BPH and disease progression. The men at risk of disease progression are screened and identified for treatment. The predictors for disease progression are prostatic volume > 30cc, PSA of >1.5ng/ml and <10.0 ng/ml, Qmax of less than 12mls/second, ages over 60 years and symptoms severity greater than 7 (19).
Table 2. BENEFITS PROFILE OF 5 ARIs AND ALPHA-BLOCKERS AND COMBINATION OF THE TWO
COMBINATIONOF THE TWO
Improvement of symptoms flow rate
Onset of symptom relief in 1-2 weeks
Maintenance of symptoms and flow rate improvements
Prevention of symptom progression
Reduction in PV
Maintaining reduction in PV
Reduce long-term risk of A|UR and surgery
Combination drugs medical therapy is the best of the two worlds of monotherapy (5ARIs and alpha-blockers). Combining the mode of action of 5 alpha reductase dual inhibition and alpha-adrenergic blockade for BPH treatment is the best; 5 alpha reductase inhibition decreases the levels of DHT, thereby reducing the androgenic drive stimulants to the prostate leading to reduction in prostate volume and reduces the outflow obstruction, improving the peak urine flow rate (Qmax) and improves symptoms. The Î±1a and Î±1d adrenergic blockage in the smooth muscles of the prostate, the bladder neck and urethra gives rise to relaxation of these muscular tones resulting in improved urinary flow and symptoms. They may also have an effect on the spinal cord receptors. The combination of these two "worlds" have a marked benefit in symptoms and flow rate improvements in short term and in long-term. The prostate volume reduction, the reduction of BPH progression, risks to AUR/BPH related surgery by 50-60% are worthwhile benefits with minimal adverse effects (AEs) compared to monotherapy. (15)
The key factors in combination drug therapy are the duration of treatment, (over 4 years for dutasteride 6/12 for Î±-blockers): the prostatic volume at onset of treatment (>25cc). From symptom management after reducing therapy drug (SMART-1) study, it is possible to withdraw Î±-blocker drugs after 6/12 without affecting the progressive improvement of symptoms.
This allows one drug to be continued for longer time. The therapeutic impact of withdrawing Î±-blocker was assessed by Barkin (42). He found that majority of patients (over 77%) require Î±-blocker withdrawal but a small proportion may need combination treatment for a longer duration.
Combination of the two drugs( combined AB and 5RI)offers the best treatment for
BPH. It is better than monotherapy. It has best long-term effects.
At the onset of treatment, the 5ARIs and Î±-blockers have a combined effect on the symptoms severity reduction, the peak flow rate (Qmax), the prostate volume reduction (>30cc). Further benefits long-term use are reduction of risk factors for BPH progressing to AUR and BPH-related surgery. The low adverse effects (AE's) in long-term use of dutasteride as a dual inhibitor of 5 Î± reductase iso enzymes (1,2) makes it to be tolerable and acceptable to patients economically and with good compliance, it gives good quality of life according to IPSS QOL score and BII score index.
BPH is a universal problem in elderly men. It affects quality of life, it is a burden on health budget, and patients are now aware of nonsurgical management. With the increase of urbanization literacy and availability of health services to the community, increase of life expectancy increased of a better quality of life in chronic conditions, drug combination medical therapy for BPH is the best first line treatment choice . Surgery is left for those that have not benefited well from drug therapy or those in severe symptom presentations of BPH.
Watson et al, studied patient's wishes and gave the summary below;
Patient's preferences for BPH medical therapy. Watson et al J Urol 2003; 172:2321-5 please use a uniform method of referencing
Prostate size reduction (the most preferred)
Reduction in risk of surgery
Reduction in risk of AUR
Time to symptom improvements (immediate relief)
Side effects attributes
Impotence (least preferred)
Decreased sex drive (libido)
Reasons for patients consultation to a doctor for LUTS
Fear that it may be cancerous
Disturbed sleep (nocturia, frequency)
Embarrassment from symptoms (e.g. incontinence)
Frustration with symptoms
Impact of symptoms on work/professional life
Impact on social activities/life
Patient choice for medical therapy:
Majority chose medical therapy over 50-70%