November 1999

TAYSIDE PRESCRIBER Issue 69

Produced by: Mr Kevin Rothnie (Practice Pharmacist), Mr Keith Baxby (Consultant Urologist) and Mr Angus MacConnachie (Tayside Drug Information Service)

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DRUG TREATMENT OF BENIGN PROSTATIC HYPERPLASIA: IMPROVING THE FLOW OF BEST PRACTICE IN TAYSIDE

Benign prostatic hyperplasia (BPH) is a common condition affecting older men. Given that the proportion of elderly in the population is steadily growing, the treatment of this group has increasing significance for the drug budget. The following, which is based on recent national reviews of treatment,1,2 is intended to define the role of drug therapy and best practice in the management of BPH. Recommendations in the following text reflect the initial choice of treatment in the Tayside Area Drug Formulary.

FIRST- STOP!! - ARE THE SYMPTOMS REALLY DUE TO BPH?

There is a temptation to blame all urinary symptoms in a man over 55 years on the prostate. Many elderly men have urinary symptoms: most will have a degree of prostatic enlargement, which may be nothing to do with their complaints. Frequency, urgency and nocturia are not symptoms of an enlarged prostate: they are symptoms of an irritable (‘unstable’) bladder, of which BPH is only one cause. If infection is ruled out, these symptoms are often due to inability to inhibit bladder activity at cortical level. The prostate is likely to be a cause only if there is also hesitancy and a poor flow. To make matters more complicated, a poor flow may occur without obstruction when frequency is so bad that the patient cannot hold enough urine to produce a good stream. If in doubt, refer the patient for open access uroflow and residual urine measurement, or for a urological consultation, before prescribing.

Nocturia is commonly blamed on BPH but is often due to other causes: on its own it is never suggestive of a prostate problem. In this age group it is commonly due to nocturnal re- absorption of accumulated tissue fluid caused by mild CCF, or to early renal impairment or to absence of the normal night-time increase in ADH secretion. These conditions (as well as undiagnosed diabetes!) cause nocturnal polyuria (an increase in the total urine volume passed at night) which in turn causes nocturnal frequency. Nocturnal polyuria does not respond to drugs aimed at the prostate! It is easily identified by asking the patient to measure each voided urine volume over 3 or 4 days and nights. This painless and cheap ‘test’ may save the cost of months of treatment with drugs, which have no chance of helping.

Before commencing drug treatment, all patients should have urinalysis (for blood, protein, glucose, nitrites and leucocytes) and measurement of plasma creatinine and electrolytes. Although there is no consensus on screening asymptomatic men for prostate cancer, it is now considered wise to do a rectal examination and PSA in men who present with urinary symptoms. ROLE OF DRUG THERAPY IN BPH

Drug therapy is generally reserved for men with moderate symptoms or for those with more severe disease for whom surgery is not an option because of cardio-respiratory problems, anticoagulation or other contraindications to surgery of this nature.

Drugs reduce the symptoms of BPH by relieving urinary outflow obstruction by one of two mechanisms:

· Directly by reducing tone in the prostatic urethra (alpha-blockers). · Indirectly by reducing benign prostatic enlargement (5-alpha reductase inhibitors).

Alpha-adrenergic receptor blocking drugs (alpha-blockers)

Drugs of this type (originally marketed for the treatment of hypertension but now largely superseded in this role) remain a cost-effective treatment for the majority of cases. They relieve symptoms by reducing resistance to flow through the bladder neck and prostatic urethra, the tone of which is under alpha-adrenergic control. Relaxation of these areas improves urine flow and bladder emptying, and reduces residual volume. Reduced outflow resistance allows the bladder to empty at lower pressure which, in turn, improves the ‘irritable’ symptoms of frequency, urgency and nocturia. These drugs do not reduce prostate volume, so eventually an increase in prostate size may negate the effect of reduced tone. Older drugs of this type are used initially at low dosage, taken at bedtime, in order to minimise the risk of early dose hypotension, then the dosage is increased gradually according to the response. Alpha-blockers have a rapid onset of action (within 36 hours) and a full clinical response often occurs after 4-6 weeks. Apart from inappropriate hypotension, the alpha blockers can cause flushing, dizziness and sedation. Of the older drugs, indoramin (DoraleseÔ ) is a cost-effective treatment for many patients. However side effects are a problem for some, for whom the newer, more selective agent alfuzosin (XatralÔ ) is recommended. Tamsulosin (FlomaxÔ ), for which a high degree of selectivity is claimed (but not necessarily proven3), should be reserved for the relatively few patients who cannot tolerate even alfuzosin. Choice of alpha-blocker is summarised in the table below. Suggested use of alpha-blockers for BPH First consider Indoramin (DoraleseÔ ) initially 20mg twice daily £6-12/month (20mg at night if elderly) If side effects are a problem Alfuzosin (XatralÔ ) 5mg M/R twice daily £12-24/month (5mg M/R at night if elderly) If side effects are still a problem Tamsulosin (Flomax MRÔ ) 400micrograms each morning £24/month

Finasteride (Proscar) - a 5-alpha reductase inhibitor

Finasteride blocks the conversion of testosterone to dihydrotestosterone, the form of the hormone found in prostatic tissue and thought to be responsible for BPH. It therefore relieves outflow obstruction by “shrinking down” the gland and not by reducing tone in and around the prostate. The dose of finasteride is 5 mg once daily at a cost of £25 per month. There is no rationale for increasing dosage in non-responders.

2 Finasteride should be reserved for patients with larger prostates or for those who do not respond to, or are intolerant of, alpha-blockers (despite use of newer selective agents). It may require to be taken for several months before symptomatic relief is noticed. Treatment should be reviewed after 6 months and discontinued if there is no benefit by this time.

Finasteride has been shown to be less effective where the prostate is relatively small. A comparison was made between placebo, terazosin (an alpha-blocker), finasteride, and terazosin plus finasteride in patients with an average prostate volume of 37 ml. (which is about 3 times normal). Terazosin was effective, finasteride was not, and the combination was no more effective than terazosin alone.4 In a four year study5 on men with larger glands (average 55ml), the use of finasteride was associated with a 55% reduction in the need for elective prostatic surgery and a similar reduction in the incidence of acute retention of urine, as well as significant improvements in symptoms, urine flow rates and prostate size. Finasteride is (predictably) associated with decreased libido and erectile dysfunction in about 3% of treated men but is otherwise well tolerated. PSA may be reduced by as much as 50% during treatment with finasteride. This should be taken into account when interpreting levels.

Current Practice in Tayside

Analysis of prescriptions for alpha-blockers is difficult since some (e.g. doxazosin) are still used to treat hypertension. Indoramin, which is listed in the Tayside Formulary, appears to be most popular with over 5,300 prescriptions dispensed at a cost of £77,700 in the last financial year. The use of the newer selective agents alfuzosin and tamsulosin has increased dramatically by 68% last year, with around 5,100 prescriptions at a cost of £155,000. In contrast, prescriptions for finasteride during the same period amounted to £250,000 or 0.53% of the total drug bill for Tayside. This seems excessive for what is essentially a second line therapy and is high in comparison with the Scottish average where finasteride prescribing amounts to 0.34% of total prescribing costs.

Summary of key points for prescribing in BPH

· An alpha-blocker is an appropriate first choice for many patients · There is no convincing evidence that any one of the older alpha-blockers is more or less likely to be better tolerated than another. However, one of the newer agents may be considered for patients who develop unwanted side effects. · Indoramin 20 mg and alfuzosin M/R 5 mg at a dosage of once or twice daily according to age are economic choices from the older and newer alpha-blockers respectively. · Finasteride should be reserved for non-responders, those who experience troublesome side effects with any alpha-blocker, or where the prostate is known to be considerably enlarged. · The clinical use of finasteride should be reviewed after 6 months. If no relief of symptoms at this stage, further benefit is unlikely.

References 1 Management of benign prostatic hyperplasia. MeRec Bulletin 1998; 9: 1-4 2 Benign prostatic hypertrophy. SMRC Bulletin 1998; 49: 191-194 3 Buzelin JM, Ronteyne E, et al. Comparison of tamsulosin with alfuzosin in the treatment of patients with lower urinary symptoms suggestive of bladder outlet obstruction (symptomatic benign prostatic hyperplasia). Br J Urol 1997; 80: 597-605 4 Lepor H, Williford WO, Barry MJ, et al. The efficacy of terazosin, finasteride, or both in benign prostatic hyperplasia. N Eng J Med 1998; 335: 533-539 5 McConell JD, Bruskewitz R, Walsh P et al. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. N Eng J Med 1998; 338: 557-563

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