Sweatman - BPH

Question 1

What is BPH?

Answer 1

• Originates in transition zone of the prostate, surrounding the proximal urethra
• Untreated enlargement can block urine flow and cause bladder, urinary tract, or kidney problems

Question 2

What are the 2 short-acting selective alpha-1 blockers?

Answer 2

• Prazosin
• Alfuzosin

Question 3

What are the 2 long-acting selective alpha-1 blockers?

Answer 3

• Terazosin
• Doxazosin

Question 4

What are the alpha-1 partially selective blockers?

Answer 4

• Tamsulosin
• Silodosin

Question 5

What are the drug targets for BPH and lower urinary tract symptoms (image)?

Answer 5

Question 6

Why is the alpha-receptor hierarchy important?

Answer 6

• Sub-divided by structure and, when expressed in the target tissue, can represent potential therapeutic advantage for specifically targeted drugs
• Alpha-1a overwhelmingly predominant in the normal human prostatic stroma
  1. Alpha-1d present to a lesser extent

Question 7

Where in the urinary tract/prostate do alpha-1a and alpha-1d predominate (image)?

Answer 7

• Alpha-1a: predominates in lower GI tract
• Alpha-1d: predominates in detrussor muscle of the urinary bladder
• NOTE: alpha-1 blockers cause relaxation of the smooth muscle in the prostatic and penile urethra, permitting easier urination

Question 8

Describe the metab/elim, half-life, and bioavailability of the 6 alpha-1 blockers.

Answer 8

• All oral drugs with extensive CYP metabolism, so there is always an issue for drug-drug interactions
• Generally have a long duration of action, so less frequent dosing and better compliance
  1. Except Prazosin: great variability from pt to pt, so dose titration necessary (Q12h dosing)
• Tamsulosin: DEC bioavailability with food
• REMEMBER: Tamsulosin (9-18%), Silodosin (<=28%) partially selective

Question 9

What are the issues with the alpha-1 blockers?

Answer 9

• All have comparable efficacy, and common AE’s include: GI (xerostomia, nausea), CNS (dizziness, somnolence, asthenia, headache, insomnia)
• Selective (alpha-1a) agents:
  1. Advantage: no need for dose titration (diminished effects on CV func)
  2. Disadvantage: abnormal (retrograde, or no) ejaculation, block of Dopa and other regulatory CNS transmitters
• Floppy iris syndrome

Question 10

What is the best alpha blocker currently available for treating BPH? Why?

Answer 10

• Alfuzosin 10mg
• Achieves clinically significant improvements in LUTS and has no significant effects on dizziness, asthenia, and ejaculatory dysfunction
• NOTE: this is just the conclusion in one paper

Question 11

What is floppy iris syndrome?

Answer 11

• Occasional AE during cataract sx in pts on alpha-1 blockers (mechanism unknown)
• Characteristics: flaccid iris that billows in response to intraoperative irrigation
  1. Progressive intraoperative miosis (excessive constriction of pupil) despite dilation with std mydriatic drugs
  2. Potential prolapse of the iris toward pharmacoemulsification incisions
• No apparent benefit of stopping alpha-1 blocker therapy prior to cataract surgery
• May necessitate possible modifications to sx technique

Question 12

Describe the molecular pathway PDE5 is involved in. What do PDE5 INH do?

Answer 12

• NOS produces NO, which is released from endo cells and cavernous nerves in the smooth muscle of the urethra
• NO stimulates guanylyl cyclase, leading to INC levels of cGMP
• Subsequent phosphorylation of cellular mem proteins via PKG results in efflux of Ca, and smooth muscle relaxation, vasodilation of penile arteries and sinus, and erection
• PDE5 INH DEC breakdown of cGMP by INH of PDE5, resulting in prolonged high levels of cGMP necessary for erections

Question 13

Tadalafil use, metab, AEs

Answer 13

• Relief of BPH via smooth muscle relaxation -> comparable to corpus cavernosum effect in erectile dysfunction
• Hepatic metabolism (3A4); mainly fecal elim
• Well tolerated, and AE’s uncommon: headache, nausea, indigestion, nasopharyngitis, URTIs
  1. RARE: non-arteritic ischemic optic neuropathy, retinal artery occlusion, hearing loss
• Contraindication: concurrent organic nitrates
  1. Profound hypotension
  2. Exacerbated by alcohol consumption
• This is the ONLY PDE5 INH approved for this use (probably due to its long duration of action: <35-hr half-life)

Question 14

What is the role of 5-alpha reductase in smooth muscle tone? INH?

Answer 14

• Catalyzes conversion of T to DHT, which binds the AR w/higher affinity, and activates gene expression more efficiently
  1. Type 1: predominantly in non-genital skin, liver, and bone
  2. Type 2: mainly in urogenital tissue in men, and genital skin in men and women
• 5-alpha reductase INH reduce DHT-driven proliferation of the prostate, providing relief for urinary evacuation

Question 15

Finasteride, Dutasteride

Answer 15

• Finasteride: type 2 (comparable drugs, outside of this difference in specificity)
• Dutasteride: types 1 and 2 -> competitive, long binding time, slow reversal (extensive 3A4 hepatic metabolism)
• Both Cat X, but not carried in semen
• Well tolerated; low incidence of AE’s: ejaculation and erectile dysfunction, DEC libido, gynecomastia
  1. DEC PSA levels: problem if being used to monitor prostate cancer, INC rate of prostate cancer reported (1.8 vs. 1.1%)

Question 16

What are the beta-sitosterols? Do they work?

Answer 16

• Derived from South African star grass (Hypoxis rooperi), or species of Pinus and Picea
• Improved urinary symptom scores and flow measures, but NO significant reduction in prostate size compared to placebo in a 4-trial Cochrane review
• Long-term effectiveness, safety, and ability to prevent BPH complications not known

Question 17

Does saw palmetto work?

Answer 17

• Not enough scientific evidence to support its use for BPH or any other conditions
• Does not appear to affect PSA levels

Question 18

What is the MOA of Alprostadil?

Answer 18

• Synthetic mimic of naturally occurring PDE1
• Activates adenylate cyclase, which synthesizes cAMP from ATP
• cAMP acts as a 2nd messenger, activating PKA
• Efflux of IC Ca -> SM. M. RELAXATION and erection

Question 19

What are the options for delivery of Alprostadil?

Answer 19

• Intra-urethral suppository: placed to dissolve in residual urine and be absorbed across urethral wall
• Direct injection into the corpus cavernosum, avoiding the top and bottom of the penis (to avoid systematization via deep and dorsal arteries of penis)
• Minimal systematization

Question 20

Alprostadil onset, duration, AE’s

Answer 20

• Rapid onset: minutes; durable effect: 1/2 - several hours -> both vary by patient
• Pain the most common AE: penile (36%), urethral (13%), testicular (5%)
• Rarely, adverse CV effects reported: prudent to monitor and initially dose-titrate in pts with pre-existing CV disorders
• Delivery methods generally avoid systemic effects

Question 21

Compare the pharmacology of the PDE5-INH.

Answer 21

• Oral drugs, w/peak plasma levels achieved quickly
• Hepatically processed, so drug-drug interactions possible
• Common and rare AE’s similar, with HEADACHE being the most common
• All are associated with: CV issues, and sudden loss of hearing and sight
• THINGS TO NOTE:
  1. Sildenafil/Vardenafil bioavailability DEC by high-fat meals
  2. No CV effects listed for Sildenafil
  3. Avanafil has fewest AE’s listed
  4. Resp effects only listed for Tadalafil
• Remember: Tadalafil used for BPH (probably due to long 1/2-life)

Question 22

What are the drug interactions of the PDE5 INH?

Answer 22

• Absolute contraindication: NITRATES -> severe and life-threatening hypotension
• Potential interactions with:
  1. Alpha-blockers: INC hypotension (prolonged)
  2. Drugs affecting CYP activity
• Vardenafil: interaction with >70 drugs -> INC risk of QT prolongation (cardiac arrhythmias)
• NOTE: adulterated herbal supplements may contain these products, and lead to some of these AE’s too

Question 23

How is T replacement used to tx erectile dysfunction?

Answer 23

• May improve the response rate of hypogonadal men to PDE5 INH like Sildenafil citrate
• About 65% of hypogonadal men may have improvement in erectile dysfunction w/T replacement therapy
• NOTE: minimal circulating level of T necessary to maintain an erection unknown, but levels below lower limit of normal may be sufficient to retain normal erection in most men
  1. Evidence suggests T plays important role in erectile dysfunction

Question 24

Yohimbine MOA, effectiveness

Answer 24

• Alpha-2 adrenergic antagonist formerly used to tx erectile dysfunction -> replaced by PDE5 INH
• MOA complex:
  1. POST-junc smooth m cells: INH E/NE-activated phosphorylation of myosin light chain kinase, INH vascular sm m contraction
  2. Non-adrenergic, non-cholinergic nerves (NANC): blocks INH action of PRE-junc heteroreceptors, leading to INC NO production and vascular sm m relaxation
• Pts may take this as a supplement to improve sex performance, promote weight loss, curb appetite
  1. Effectiveness for ANY health condition unknown bc NO clinical trials on bark/extract
  2. Highly refined product used in some supplements, which may INC the potency of the product and INC the risk of drug-drug interactions

Question 25

Yohimbine metabolism, AE's

Answer 25

- Rapid (variable) absorption; complete and rapid metabolism - Crosses BBB easily, potentially producing: 1. Anxiety, _antidiuresis_, dizziness, flushing, HTN, INC motor activity, irritability, _sinus tachy_, nervousness, restlessness, tremor - MAOI action at supra-clinical doses: _tyramine and caffeine interactions_ possible - **Worsens renal function in failure, dysfunction** - NOTE: high placebo effect; drug \> placebo in only a minority of trials (34-86% efficacy in pts with ED)

Question 26

What is a "hidden risk" in taking herbal supplements for ED?

Answer 26

- Many of these products contain varying amounts of _illicitly synthesized PDE-5 INH_ - **Potential for fatal interaction** b/t the product and a nitrate is very real (nitrates often taken by pts with diabetes, high BP, high cholesterol, or heart disease) - Virility Max recall example

Question 27

How many drugs can cause ED? Why is this important?

Answer 27

- 280 have ED listed as an AE: drugs with a wide range of clinical utilities and pharmacologic actions - Often not known how/why this AE is produced - When evaluating ED, physician should _ask about drug history to rule out this possibility_ 1. Might be appropriately managed by removing, or substituting the offending drug