Background

• Prostate: a walnut sized gland surrounding urethra at the base of bladder.
• Prostate depends on androgen for its size and function. Testosterone is metabolized to dihydrotestosterone (DHT) by 5 alpha reductases. DHT is responsible for normal and hyperplasia growth of prostate.
• Benign prostatic hyperplasia results from enlarged prostate, as the gland is enlarging, the layer of surrounding tissue prevents it from expanding, causing the gland to press against urethra like a clamp on the hose, the bladder begins to contract when it contains only small amount of urine, leading to frequent urination, and other symptoms: hesitant/interrupted/weak stream; urinary urgency and leaking.

 

Prostate cancer

• DRE (digital rectal exam) and PSA (prostate specific antigen) are used to rule out cancer.
• PSA: a protein produced by prostate cell, is increased in prostate cancer.

 

Drugs worsen BPH

• Combination cold medicines containing decongestant, antihistamine (anticholinergic property).
• Anticholinergic drugs (e.g: benztropine, TCAs): worsen urine retention and “dries up everything”, sedation, etc. review our chapter on overactive bladder for a detailed view of anticholinergic agents.
• Diuretics: worsen urine frequency.
• Caffeine, decongestant: diuretic and vasoconstrictive effect.
• SNRIs: raises BP.
• Testosterone: contributes to the overgrowth of prostate.

 

Treatment algorithm

• Alpha blockers alone or in combination with 5 alpha reductase inhibitors.
• 5 alpha reductase inhibitors are used to reduce prostate size, and should not be used in men with BPH without prostate enlargement.
• Peripheral acting anticholinergics are used for overactive bladder.
• PDE-5 inhibitor (tadalafil) can be used with or without finasteride in men with BPH alone, or with erectile dysfunction (ED).

 

Alpha blockers

• non-selective drugs: terazosin (Hytrin), doxazosin (Cardura)

• selective drugs: tamsulosin (Flomax, + dutasteride 0.5mg = Jalyn), alfuzosin (Uroxatral), silodosin (Rapaflo)
• MOA: inhibitor alpha-1 adrenergic receptors, blocking them leads to relaxation of smooth muscle of prostate and bladder neck, and improvement of urine flow.
• Common Uses: BPH, urinary obstruction, hypertension
• SE: orthostatic hypotension/syncope, dizziness, fatigue, headache, retrograde ejaculation (silodosin, tamsulosin), QT prolongation (alfuzosin), intraoperative floppy iris syndrome (IFIS) in cataract surgery.
• 1^st line in moderate to severe symptoms, they do NOT shrink prostate size nor change the PSA level.
• 3 types of alpha receptors: 1A (primarily in prostate), 1B, and 1D. Alpha 1 receptors are also located on iris dilator muscle; with alpha blockage, iris becomes floppy (IFIS) and the pupils don’t dilate well, hold alpha blocker dose before cataract surgery.
• Both non-selective and selective blockers work right away, but efficacy take weeks to months, titrate slowly.
• Risk of orthostasis higher with anon-selective alpha blockers. Usually dosed at night to minimize the risk of “first dose” effect of orthostasis.
• In the case of worsening urinary retention due to BPH after initiation of these agents, assess if your patient is on anticholinergic medications.
• You may be asked on the mechanism of tamsulosin, in an implicit way. Do not confuse this class with α₁agonist! The full name is alpha-adrenergic agonists, which have the opposite function of alpha blockers. They selectively stimulate alpha adrenergic receptors, mimic the action of epinephrine and norepinephrine, and induce smooth muscle and blood vessel constriction. (e.g: epinephrine, midodrine, oxymetazoline, as mechanism suggests, they ꝉ BP).
• Tamsulosin: 1 cap (0.4mg) 30 mins after same meal every day, women can use it for bladder outlet obstruction.
• Alfuzosin: 10mg ER QD, at risk for QT prolongation.
• DI: additive hypotensive effect with PDE5 inhibitors.

 

5-alpha reductase inhibitors

• Drugs: finasteride (Proscar, Propecia), dutasteride (Avodart): affect both types of 5-alpha receptor, may have better efficacy.
• MOA: Block conversion of testosterone to DHT, shrink prostate size and decrease PSA levels.
• Usually used in men with larger prostate size or more severe symptoms, given with alpha blocker to balance slow onset.
• SE: decreased libido, impotence.
• Pregnant women should avoid handling this drug, the pill can cause birth defect.
• finasteride 5mg QD is for BPH (Proscar). 1mg QD is used for male pattern baldness brand name is also different: Propecia.
• dutasteride affects both types of 5-alpha receptor, may have better efficacy.
• DI: They are extensively metabolized by liver, and are 3A4 substrates.

 

 PDE5 inhibitors

• Drugs: tadalafil (Cialis)
• MOA: block phosphodiesterase type 5 on cyclic GMP in the smooth muscle cells supplying the corpus cavernosum of the penis.
• SE and warnings: class effect of vasodilation (HA, flushing, sudden drop in BP, dizziness), vision loss, priapism, loss of hearing.
• Tadalafil is the only FDA approved PDE5 inhibitor in treatment of BPH.
• Absolute CI with street drug nitrates: amyl nitrate, butyl nitrate (“popper”) – may reduce BP to a dangerous level.
• DDI: If patient has angina, avoid NTG 24-hr after sidenafil/vardenafil, 48-hr after tadalafil; Caution use with alpha blocker, use a selective agent like tamsulosin, silodosin instead of non-selective agents (terazosin, doxazosin).

 

Quiz

 

A 73-year-old man with BPH has taken terazosin for 6 months with some symptom improvement. He complains of persistent urinary urgency. His prostate size is 20 g and postvoid residual volume is 50 mL. Which medication is most appropriate in combination with his current treatment to address his symptoms?

1. Tolterodine
2. Dutasteride
3. Saw palmetto
4. Sildenafil

 

A 67-year-old man with BPH has an AUA-SI score 10, prostate size 15 g, and postvoid volume of 90, with a medical history of hypertension and cataracts and is scheduled to have cataract surgery in 2 weeks. Which of the following is the best recommendation?

1. Watchful waiting for 3 months.
2. Initiate alfuzosin in 3 weeks.
3. Initiate alfuzosin today.
4. Initiate dutasteride today.

 

1. A. An anticholinergic such as tolterodine can be used in combo with alpha-blockers to treat symptoms of urinary urgency if the postvoid residual volume is below 250 mL. Dutasteride is beneficial in combo with alpha-blockers in increased prostate size (>30– 60 g), sildenafil is appropriate for ED; however, it is reserved for patients that have not responded to conventional therapies, and tadalafil is the only FDA approved agent for LUTS associated with BPH. Saw palmetto has limited evidence of benefit and would not be the best recommendation.
2. B. The patient’ s AUA-SI score (≥ 8) warrants pharmacological treatment. Alpha-blockers including alfuzosin would be the appropriate first-line therapy; however, it should only be started after the patient’ s cataract surgery. Alfuzosin has the potential to cause intraoperative floppy iris syndrome (IFIS) in patients undergoing cataract surgery. 5 alpha-reductase inhibitor like dutasteride is reserved for patients with larger prostate glands >30 mL (30 g).

 

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