GU: benign prostatic hyperplasia

prostate

• a small, walnut sized organ found in men that sits around the bladder and encompasses the urethra

• as men age, this organ naturally gets enlarged

  • since it is so close to the urethra, the larger size can impinge on the urethra, potentially causing symptoms like difficulty voiding (urinating) as well as irritation

5-alpha-reductase (5-AR)

• converts testosterone to dihydrotestosterone (DHT)

dihydrotestosterone (DHT)

• responsible for prostate growth and enlargement

• it’s made when testosterone is converted by the enzyme 5-α-reductase inside tissues like the prostate, hair follicles, and skin

  • it binds more strongly to androgen receptors than testosterone and drives prostate cell growth and differentiation (more potent than testosterone)

• as men age, systemic testosterone declines, but the activity of 5-α-reductase in the prostate actually increases or becomes more efficient

  • this means even with less testosterone circulating, more of it is being converted to it locally in the prostate

• this can cause local concentrations to be 10× higher than plasma levels, even if serum levels stays normal

  • this chronic local androgen exposure leads to stromal and epithelial cell proliferation, which enlarges the prostate and contributes to BPH

benign prostatic hyperplasia (BPH)

• an enlargement of the prostate due to local (within the prostate) activity and elevation of DHT

  • includes hyperplasia, lower urinary tract symptoms, and bladder outlet obstruction

factors relating to disease progression of BPH

• anatomical hyperplasia (thickening) of prostate cells

• physical obstruction in the urinary tract

• detrusor muscle response to obstruction

• signs and symptoms of prostatism

  • inflammation of the prostate

detrusor muscle

• the muscle that sits over the bladder and its responsible for contracting and expelling urine from the bladder

types of clinical findings for BPH

• obstructive symptoms

• irritative symptoms

signs and symptoms of obstructive BPH

• difficulties with voiding:

  • stream weakness

  • hesitancy

  • inability to stop the action of peeing abruptly

  • post-void dribbling

  • sensation of bladder fullness

  • urinary retention

signs and symptoms of irritative BPH

• difficulties with storage of urine:

  • changes in frequency or urgency

  • nocturia (peeing too much at night)

  • pain with urination

  • urge incontinence

• caused by bladder muscle hypertrophy from working harder to push urine out

medications that aggravate the prostate → drugs

• diuretics

• sympathomimetics

  • OTC decongestants (eg Sudafed: alpha-1 agonist → can cause constriction in the nose but also in the prostate, and this constriction can make it more difficult to pass urine)

• anticholinergics

  • antihistamines

  • antidepressants

  • antipsychotics

  • GI antispasmodics

prostate specific antigen (PSA)

• useful for screening for prostate cancer

• it’s FDA approved for use in conjunction with a digital rectal exam (DRE) to help detect prostate cancer in men > 50 yrs and for monitoring cancer patients after treatment

• it’s useful for estimating the prostate size and selecting individualized therapy

normal PSA levels

• 0 - 4 ng/mL

  • 2.5 ng/mL is considered the “upper limit of normal”

treatment goals for BPH

• improve symptoms

• relieve obstruction

• improve bladder emptying

• prevent acute urinary retention

treatment options for BPH

• watchful waiting

• drug therapy

• non-surgical invasive procedures

• surgery

watchful waiting

• indicated for:

  • patients with mild symptoms (AUA score <7)

  • patients with minimal bother and no complications (e.g., no urinary retention, infections, or bladder stones)

• discussion should be held with patients on the risks and benefits of pharmacotherapy

• keep in mind that 1/3 of patients deteriorate to moderate or severe stages

indications for pharmacotherapy for BPH

• patients who have:

  • moderate or severe symptoms (AUA score ≥ 8)

  • severe symptoms, but refuses surgery

  • severe symptoms and is not a candidate for surgery

  • severe symptoms with no evidence of complications

algorithm for pharmacotherapy for BPH

1. a patient presents with moderate-severe symptoms (IPSS AUA score ≥ 8)

2. first-line: alpha-1 blockers

   • work both in the prostate and urethra to induce relaxation of smooth muscles and make it easier to pass urine

   • used for symptomatic relief

3. if a patient has an enlarged prostate:

   • initiate 5-ARI

4. if a patient has predominantly irritative symptoms:

   • initiate an anticholinergic agent or mirabegron

5. if a patient has ED

   • can initiate tadalafil

signs of an enlarged prostate

• prostate volume > 30 cc on imaging

• PSA > 1.5 ng/dL

• palpable prostate enlargement on DRE

MOA of alpha-1 blockers

• since the receptors (1A, 1B, 1D) are found in the prostate, they inhibit the contraction of smooth muscles and therefore help to smooth muscle relaxation at the prostate

  • this reduces bladder outlet obstruction and improves urinary flow and voiding symptoms (like hesitancy, weak stream, and incomplete emptying) and makes it easier for urine to flow into the urethra

  • they don’t help with shrinking the prostate, only relieving muscle-tone related obstruction

• they provide rapid symptomatic relief (within as little as a week)

  • full therapeutic benefit seen within 2-3 months

  • average 4-6 point improvement in AUA symptom index

• more uroselective blockers act mainly on the prostate and bladder neck (alpha-1A), causing fewer systemic side effects (like hypotension) than nonselective blockers

  • recall that alpha receptors are mediated by norepinephrine

alpha-1 blockers → drugs

• terazosin

• doxazosin

• prazosin

• alfuzosin

• tamsulosin

• silodosin

non-uroselective alpha-1 blockers → drugs

• binds to alpha-1A, 1B, and 1D receptors → more likely to cause orthostasis:

  • terazosin

  • prazosin

  • doxazosin

uroselective alpha-1 blockers → drugs

• binds to alpha-1A receptors only → more likely to cause problems with ejaculation:

  • silodosin

  • tamsulosin

  • alfuzosin

brand name for terazosin

• brand name

  • Hytrin

brand name for prazosin

• brand name

  • Minipress

brand name for doxazosin

• brand name

  • Cardura

brand name for alfuzosin

• brand name

  • Uroxatral

brand name for silodosin

• brand name

  •  Rapaflo

brand name for tamosulosin

• brand name

  • Flomax

considerations for all alpha-1 blockers

1. first dose effect:

   • a sudden, pronounced drop in blood pressure (orthostatic hypotension) that can occur after the very first dose (or after a dose increase)

   • it usually causes dizziness, lightheadedness, or fainting when the patient stands up (syncope)

   • it happens because this blockade prevents normal vasoconstriction when standing, so blood pools in the lower extremities and venous return decreases

   • to prevent it, you can take at bedtime with the lowest possible dose, titrate up slowly over several days to weeks, and avoid concurrent diuretic or antihypertensive initiation at the same time

     • can also counsel the patient to get up slowly after sitting down or getting out of bed

     • START LOW GO SLOW!

2. drug-drug interactions with PDE5 inhibitors:

   • these medications increase cGMP in smooth muscle (by preventing its breakdown), enhancing nitric oxide–mediated vasodilation

   • in combination with alpha-blockers, this can cause excessive hypotension (syncope, dizziness, lightheadedness, reflex tachycardia)

   • they carry precautions when used in combination, but they’re not contraindicated

3. floppy iris syndrome:

   • especially seen in patients undergoing cataract and glaucoma surgery, including in patients who had discontinued the drug more than 5 weeks up to 9 months prior to surgery

   • initiation NOT recommended in patients scheduled for cataract or glaucoma surgery

4. however, these considerations are more profound or have a higher risk of occurring with non-selective alpha blockers

considerations for terazosin and doxazosin

• efficacy → increases urinary flow rates by 2-3 mL/sec in 60% of patients

• onset of effects → 2-4 weeks

• adverse effects:

  • orthostasis

  • nasal congestion

  • asthenia → abnormal physical weakness or lack of energy

  • dizziness

• DDIs → PDE5 inhibitors

dosing for terazosin (Hytrin)

• starting dose (days 1-3):

  • 1 mg at bedtime

• target dose (week 7):

  • 10 mg at bedtime

dosing for doxazosin (Cardura)

• starting dose:

  • 0.5 - 2 mg at bedtime

• target dose:

  • 8 mg at bedtime

considerations for prazosin

• efficacy → avoid use due to CNS side effects

  • it’s more lipophilic, so it can cross the BBB more easily

  • once in the CNS, it can interfere with signaling, causing effects like dizziness, drowsiness, headache, weakness, fatigue, or vivid dreams

  • these effects make it a less preferred agent

• onset of effects → 2-4 weeks

• adverse effects:

  • CNS

  • orthostasis

  • nasal congestion

  • asthenia → abnormal physical weakness or lack of energy

  • dizziness

• DDIs → PDE5 inhibitors

dosing for prazosin (Minipress)

• starting dose:

  • 1 mg BID

• target dose:

  • 2 mg BID

considerations for alfuzosin

• efficacy → similar to other alpha-blockers

• onset of effects → weeks

• adverse effects:

  • dizziness

  • headache

  • fatigue

  • less likely to cause orthostasis

contraindications + precautions for alfuzosin

• moderate to severe hepatic impairment

• QTc prolongation

• concomitant use of CYP 3A4 inhibitors → can increase blood levels

• use caution in patients with severe renal impairment (CrCl < 30 mL/min

dosing for alfuzosin (Uroxatral)

• 10 mg once daily after the same meal

considerations for tamsulosin

• efficacy → similar to other alpha-1 blockers

• onset of effects → days-weeks

• adverse effects:

  • dizziness

  • lack of energy (asthenia)

  • decreased libido (sex drive)

  • insomnia

  • rhinitis

  • abnormal ejaculation

• DDIs → CYP3A4 and 2D6 inhibitors

dosing for tamsulosin (Flomax)

• 0.4 mg daily 30 mins after the same meal

  • dose may be increased to 0.8 mg after 2-4 weeks

considerations for silodosin

• efficacy → similar to other alpha-1 blockers

• has the highest incidence of abnormal ejaculation among its drug class

dosing for silodosin (Rapaflo)

• 8 mg once daily with a meal

  • renal-dose adjustment (CrCl <50 mL/min): 4 mg daily

ALLHAT trial

• looked at the therapeutic efficacy of doxazosin

  • found that in patients who had prematurely discontinued doxazosin, there was an increased incidence of CHF and combined CV disease

  • this is why alpha-1 blockers are not really used for hypertension despite their BP lowering effects

MOA of 5-alpha-reductase (5-AR) inhibitors

• inhibits 5-AR, preventing the conversion of testosterone to dihydrotestosterone (DHT), aka the more potent androgen in the prostate, leading to significant reduction in serum and tissue DHT and contributing to prostate shrinkage 

5-alpha-reductase inhibitors → drugs

• finasteride

• dutasteride

brand name for finasteride

• brand name

  • Proscar

brand name for dutasteride

• brand name

  • Avodart

considerations for finasteride

• efficacy → decreases prostate volume by 40 mL

  • reduces the need for surgery

  • reduces urinary retention

  • reduction in prostate volume

• onset of effects → 6 months

• adverse effects:

  • erectile dysfunction

  • problems with ejaculation

  • nausea

  • abdominal pain

  • asthenia → abnormal physical weakness or lack of energy

  • dizziness

  • gynecomastia

• DDIs → CYP3A4 inhibitors

• inhibits 5-alpha-reductase type 2

contraindications + precautions for finasteride

• pregnancy category X

  • do NOT give during pregnancy

• can decrease PSA levels by half → should be mindful when monitoring patients’ PSA levels

  • after ≥6 months of therapy, double the measured PSA value to estimate the “true” baseline level

dosing for finasteride (Proscar)

• 5 mg daily

considerations for dutasteride

• efficacy → inhibits both type 1 and type 2 5-alpha-reductase

  • had a 6.1 point reduction in AUA

• onset of effects → 6 weeks - 6 months

• adverse effects:

  • erectile dysfunction

  • problems with ejaculation

  • decreased libido

  • breast tenderness and enlargement

• DDIs → CYP3A4 inhibitors

contraindications + precautions for dutasteride

• pregnancy category X

  • do NOT give during pregnancy

• can decrease PSA levels by half → should be mindful when monitoring patients’ PSA levels

  • after ≥6 months of therapy, double the measured PSA value to estimate the “true” baseline level

• avoid blood donations for 6 months after discontinuing medication → due to potential fetal risk if transfusion recipient is pregnant

dosing for dutasteride (Avodart)

• 0.5 mg daily

medical therapy of prostatic symptoms (MTOPS)

• a study that aimed to find the efficacy of alpha blockers and 5-alpha-reducatase inhibitors when used to treat BPH and its symptoms, as well as disease progression

  • it found that clinical progression of BPH was much lower when using doxazosin + finasteride in combination!

  • however, this combination increased the risk of side effects, primarily erectile dysfunction

CombAT study

• a study of the combination of tamsulosin with dutasteride 

  • found that there was reduced risk of acute urinary retention and BPH-related surgery by 66% compared to monotherapy with tamsulosin

  • there was also reduced risk of clinical deterioration of symptoms

  • improvements in symptoms scores were significantly greater with combination therapy

brand name for tamsulosin/dutasteride

• brand name

  • Jalyn

considerations for PDE-5 inhibitors

• clinical trials have shown a consistent improvement in IPSS scores in men with erectile dysfunction or lower urinary tract symptoms (LUTS)

• its MOA is not really understood for BPH

• tadalafil was approved in 2011 for BPH treatment

  • 5 mg daily → not recommended for pts with CrCl < 30 mL/min

considerations for finasteride + tadalafil combination product

• for patients with a significantly enlarged prostate:

  • prostate volume > 30 mL

  • PSA > 1.5 ng/dL

  • palpable prostate enlargement on digital rectal exam (DRE)

• not recommended in severe hepatic impairment

• counseling points:

  • take on an empty stomach around the same time each day

brand name for finasteride/tadalafil

• brand name

  • Entadfi

dosing for finasteride/tadalafil (Entadfi)

• 5 mg/5 mg once daily for up to 26 weeks

  • CrCl < 50 mL/min or on hemodialysis → not recommended

  • not recommended in severe hepatic impairment either

considerations for saw palmetto

• used extensively in Europe for symptomatic relief for BPH

• MOA? → probably anti-androgenic

• efficacy:

  • a meta-analysis did show improvement when compared to placebo

  • similar improvements in symptoms and flow rates when compared with finasteride

• adverse effects:

  • minor GI upset

  • lower incidence of adverse effects when compared to finasteride

• AUA statement says: phytotherapeutic agents and other dietary supplements cannot be recommended for treatment of BPH at this time

dosing for saw palmetto

• 160 mg BID

follow-up

• should monitor for severity score (AUA index) and post-void residuals (PVR)

  • watchful waiting → q6mos

  • 5-AR inhibitors → at 12 weeks, then 6 months, then 1 year of treatment

  • alpha blockers → at 6 weeks, then 6 months, then 1 year of treatment