Urine Luck! A Review of the Managment of BPH - FORPRINT ... file10/9/2015 1 Dana A. Brown, Pharm.D., BCPS Assistant Dean for Academics, Associate Professor of Pharmacy Practice Palm

10/9/2015

1

Dana A. Brown, Pharm.D., BCPSAssistant Dean for Academics, Associate Professor of Pharmacy PracticePalm Beach Atlantic University

1. Explain the pathophysiology of benign prostatic hyperplasia (BPH), including factors which can worsen BPH

2. Recognize the clinical presentation of BPH, including common signs and symptoms

3. Provide appropriate non‐pharmacologic and pharmacologic recommendations for a given patient with BPH based on patient‐specific parameters

4. Counsel a given patient on the appropriate administration and potential adverse effects of various BPH treatment modalities

5. Compare and contrast BPH treatment modalities pwith regards to adverse effects, role in therapy, and drug‐drug interaction considerations

6. Explain patient characteristics that would make various BPH treatment modalities inappropriate (contraindications)

10/9/2015

2

Mr. JonesMr. Jones

71 yo WM

Chief Complaint “It feels like I have to pee all of the time. I get frustrated because I just end up dribbling until the urine comes out.”

Mr. Jones, cont’dMr. Jones, cont’d

History of Present Illness

‐1 year h/o difficulty urinating that has

worsened over the past month

Reports dribbling straining weak stream‐Reports dribbling, straining, weak stream,

nocturia X 3 episodes/night, occasional bed

wetting

‐Denies hematuria, loss of urine with activity


Past Medical History

‐Hypertension ‐Dyslipidemia

‐GERD ‐Allergies

‐Type 2 diabetes

Family History

‐Mother: ↓ age 69; + HTN, Type 2 DM

‐Father: ↓ age 88 from CHF; + HTN, Type 2 DM, dyslipidemia

‐Brother: ↑ age 69; + HTN, dyslipidemia

10/9/2015

3


Social History

‐Married X 49 years

‐1 daughter aged 42

R ti d t‐Retired carpenter

‐Drinks 1 beer each evening

‐Smokes 1 pack of cigarettes/day

‐No routine physical activity


Medications: Atenolol 100 mg PO Qdaily

Lisinopril 10 mg PO Qdaily

Pravastatin 40 mg PO HS

Famotidine 20 mg PO BID

Loratadine 5 mg/Pseudoephedrine 120 mg PO BID

Aspirin 325 mg PO Qdaily

Metformin 1000 mg PO BID

Glipizide XL 10 mg PO Qdaily

Amitriptyline 25 mg PO QHS

What is BPH?What is BPH?

Benign Prostatic Hyperplasia1,2

Enlargement of the prostate resulting in compression of the urethra ultimately leading to difficulty with urinationto difficulty with urination

American Urological Association definition1

“a histologic diagnosis that refers to the proliferation of smooth muscle and epithelial cells within the prostatic transition zone.”

Signs and symptoms may be regressive

10/9/2015

4

EpidemiologyEpidemiology22

~50% of men >60yo have microscopic findings consistent with BPH; ~90% at >85yo

~50% of men with microscopic changes will~50% of men with microscopic changes will develop an enlarged prostate gland and have difficulty emptying the bladder

~50% of symptomatic patients will require treatment

Functions of the Prostate GlandFunctions of the Prostate Gland22

Two major functions of the prostate gland:

1. To secrete liquefying components of semen q y g pwhich allow sperm to move freely

2. To produce secretions which have antibacterial effects because of high zinc concentrations

Prostate Gland Growth SpurtsProstate Gland Growth Spurts22

BirthProstate weighs

~ 1 g

~40sGrowth Spurt #2

Prostate doubles/triplesin size

AdolescenceGrowth Spurt #2

Prostate weighs ~15-20 g

Age 70-80Prostate continues

to grow until this age

10/9/2015

5

Prostate Gland TissueProstate Gland Tissue22

1. Epithelial‐Produces ejaculate secretions

2. Stromal‐Contains α‐1‐adrenergic receptorsContains α 1 adrenergic receptors

‐Stromal:epithelial ratio

‐2:1 (normal), 5:1 (BPH)

3. Capsule‐Contains fibrous connective tissue & smooth muscle

‐Contains α‐1‐adrenergic receptors

Hormonal InfluenceHormonal Influence22

Testosterone

Testosterone Dihydrotestosterone

T o t pes of 5 α red ctase

5-α-reductase

Two types of 5‐α‐reductaseType I

DHT causes acne, facial hair, male pattern baldness

Type IIDHT causes prostate enlargement & growth

BPH PathophysiologyBPH Pathophysiology1,21,2

Symptoms emerge usually in 6th decade

Signs & symptoms result from static & dynamic factors

Static factorsStatic factors

Anatomical enlargement of the prostate gland leading to

direct bladder outlet obstruction (BOO)

Dynamic factors

Excessive α‐adrenergic tone of the stromal tissue of the

prostate

10/9/2015

6

Lower Urinary Tract Symptoms (LUTS)Lower Urinary Tract Symptoms (LUTS)1,21,2

ObstructiveWeak urine stream

Urinary hesitancy

Straining

bbl

IrritativeUrinary frequency

Urgency

Nocturia

Dribbling

Incomplete bladder emptying (feeling of fullness after voiding)

Enuresis

Medications and Worsening of BPH Medications and Worsening of BPH SymptomsSymptoms1,21,2

Testosterone replacement regimens

More substrate to be converted to DHT

α‐adrenergic agonists (pseudoephedrine)

Stimulate α‐adrenergic receptors

Anticholinergic agents (antihistamines, phenothiazines, TCAs)

May ↓ bladder contractility

Quiz Question #1Quiz Question #1

Which of Mr. Jones’ medications could be contributing to his current clinical presentation?

A. Atenolol

B. Amitriptyline

C. Loratadine/pseudoephedrine

D. A & B

E. B & C

10/9/2015

7


The 5‐α reductase enzyme converts dihydrotestosterone to testosterone.

A. True

B. False


Mr. Jones’ complaints of nocturia and bed wetting are examples of what type of BPH symptoms?

A. Dynamic

B. Irritative

C. Obstructive

D. Static

Clinical Clinical AssessmentAssessment1,21,2

ALWAYS assess medications!!!

Other useful parametersProstate‐specific antigen (PSA)

Age PSA (ng/mL)40‐49 0‐2.5ng/mL

/

Not specific for BPH!

50‐59 0‐3.5ng/mL

60‐69 0‐4.5ng/mL

70‐79 0‐6.5ng/mL

Digital Rectal Exam (DRE)Helps determine size of prostate gland & assesses for prostate cancer

Harder but still somewhat soft on palpation (nose cartilage)

10/9/2015

8

Back to Mr. Jones…Back to Mr. Jones…

Vital Signs: BP 106/70, P 54, RR 22, Temp 98.5◦F, Pain 0/10, Wt 263 lbs

PE: All WNL exceptPE: All WNL except

GU: Normal scrotum; prostate round, mobile and firm on palpation; penis w/o discharge or curvature

Mr. Jones, cont’dMr. Jones, cont’dLaboratory/Diagnostic Findings

Chem 8 WNL

PSA: 7.9 ng/mL

U/S findings: PVR of 264 mL and prostate weight of approximately 51 g

U/A: ‐Color: yellow ‐Leukocyte esterase: (‐)

‐SG: 1.010 ‐Nitrites: (‐)

‐Glucose: (‐) ‐Ketones: (‐)

‐Blood: (‐)


Mr. Jones’ PSA score of 7.9 ng/mL is considered elevated and likely indicates BPH.

A. True

B. False

10/9/2015

9

Complications of BPHComplications of BPH

BPH Management Options BPH Management Options 1,21,2

1. Watchful waiting

2. Pharmacotherapyα‐adrenergic antagonists5‐α‐reductase inhibitors

Type 5 phosphodiesterase inhibitorsType‐5 phosphodiesterase inhibitors Hormones (LHRH agonists & anti‐androgens)

Herbals/Complementary alternative medicine (CAM)

3. Minimally Invasive/Surgical InterventionsProstatectomy

Transurethral resection of the prostate (TURP)

Transurethral microwave thermotherapy (TUMT)

Watchful WaitingWatchful Waiting11

Indicated for patients with mild symptoms or who are asymptomatic

No specific treatment is indicated

Return for reassessment Q6‐12 months

10/9/2015

10

Patient EducationPatient Education11

Fluid restriction at bedtime

Avoid caffeine & alcohol intake

Li it lt i t kLimit salt intake

Frequent emptying of bladder

Avoid drugs that exacerbate symptoms

Categories of Drug OptionsCategories of Drug Options1,2,31,2,3

1. Interference with testosterone stimulatory effects on the prostate gland (↓ static factors)

‐5‐α‐reductase inhibitors

‐Hormones (LHRH agonists & anti‐androgens)

2. Relaxation of the prostatic smooth muscle (↓ dynamic factors)

‐ α‐adrenergic antagonists, PDE 5 inhibitors (?)

3. Combination therapy

‐ α‐adrenergic antagonist + 5‐α‐reductase inhibitor

Drug InitiationDrug Initiation2,32,3

Initiate with a single agent

α‐adrenergic antagonistFaster acting & more effective

Less sexual adverse effects

5‐α‐reductase inhibitor Prostates > 40g

Cannot tolerate the CV effects of α‐antagonists

PDE5 inhibitorFDA‐approved for BPH or BPH + ED

Combination therapy Prostates ≥50g + ↑ PSA levels

10/9/2015

11

αα‐‐Adrenergic AntagonistsAdrenergic Antagonists1,2,4,5,6,7,8,9,101,2,4,5,6,7,8,9,10

MOA: Relax prostatic smooth muscle by α1‐adrenergic receptor blockade (α1A [tamsulosin & silodosin])

Examples:First generation: phenoxybenzamine

Second generation: alfuzosin (Uroxatral®) doxazosinSecond generation: alfuzosin (Uroxatral®), doxazosin(Cardura®/Cardura XL®), terazosin (Hytrin®)

Third generation: Tamsulosin (Flomax®), silodosin (Rapaflo®)

↓ BPH symptoms but do not ↓ prostate size or volume

Do not affect PSA levels

TamsulosinTamsulosin v. Silodosinv. Silodosin1111

955 pts with t ti BPH

Silodosin 8 mg/dX 12 weeks

Tamsulosin 0.4 mg/dX 12 k

∆ from baseline in t t l f

Silodosin and tamsulosin significantly improved total scores of IPSS questionnaire, storage/voiding scores and QOL as compared to placebo

symptomatic BPH X 12 weeks

PlaceboX 12 weeks

total score ofIPSS questionnaire

TamsulosinTamsulosin v. v. SilodosinSilodosin, cont’d, cont’d1111

Only silodosin significantly ↓ nocturia v. placebo

Improvements in Qmax were noted in ALL t t ttreatment groups

A high placebo response

Most common ADR was absent or ↓ ejaculation

14% with silodosin, 2% with tamsulosin

10/9/2015

12

αα‐‐Adrenergic Adrenergic Antagonists, Antagonists, cont’dcont’d1,2,4,5,6,7,8,9,121,2,4,5,6,7,8,9,12

Relief of symptoms usually within 3 weeks of initiation

DosesAlfuzosin XR 10mg PO with same meal Qdaily

Doxazosin 1mg PO QHS, up to 4‐8mg/dayg Q , p g/ y

Doxazosin XL 4mg PO Qam w/breakfast, up to 8mg PO Qam over 3‐4 weeks

Terazosin 1mg PO QHS, up to 2‐10mg/day

Tamsulosin 0.4mg PO Qdaily, up to 0.8mg/day if no resolution of symptoms within 2 weeks of initiation; Take 30 min after the same meal

Silodosin 8mg PO with same meal Qdaily

αα‐‐Adrenergic Antagonists, cont’dAdrenergic Antagonists, cont’d99

Renal Dosage Adjustment for SilodosinCrCl > 50 ml/min: No dosage adjustment is needed.

CrCl 30—50 ml/min: 4 mg PO once daily.

CrCl < 30 ml/min: Not recommended.

αα‐‐Adrenergic Antagonists, cont’dAdrenergic Antagonists, cont’d1,2,4,5,6,7,8,91,2,4,5,6,7,8,9

Adverse EffectsOrthostatic hypotension (2nd generation)

Dizziness (2nd generation)

First dose syncope (2nd generation)

Fatig e (3rd generation)Fatigue (3rd generation)

Ejaculatory dysfunction (3rd generation)

Nasal congestion (3rd generation)

Flu‐like symptoms (3rd generation)

↑ risk for complications with cataract surgery (3rd generation)13

10/9/2015

13


Drug‐Drug InteractionsAlfuzosin is a substrate for CYP 3A4

Tamsulosin clearance is ↓ by cimetidine (avoid use)

Phosphodiesterase‐5 inhibitorsProduce systemic hypotension

Coadministration: stable dose of α‐adrenergic antagonist before initiation of PDE5 inhibitor


Avoid use:Hepatic insufficiency (no use in severe hepatic dysfunction)

Strong CYP 3A4 inhibitors (tamsulosin & silodosin)

CAD/angina

V l d l ti T l i &Volume depletion

Cardiac arrhythmias

Multiple antihypertensives

NOTE: Monotherapy with α‐adrenergic antagonists for the management of HTN in men with BPH is inappropriate therapy for HTN14

Tamsulosin & Silodosin arebetter options

αα‐‐Adrenergic Antagonists, cont’dAdrenergic Antagonists, cont’d1,8,91,8,9

Monitoring Parameters

Symptom improvement

BP and HR checks at every visit

10/9/2015

14

55‐‐αα‐‐ReductaseReductase InhibitorsInhibitors1,15,16,171,15,16,17

MOA: Blockade of 5‐α‐reductase enzyme to inhibit conversion of testosterone to DHT (finasteride – Type II only)

Examples:

Finasteride (Proscar®)

Dutasteride (Avodart®)

Best used in patients with LUTS and enlarged prostates (≥50 grams)

Adequate trial is 6‐12 months

55‐‐αα‐‐ReductaseReductase Inhibitors, cont’dInhibitors, cont’d1,15,16,171,15,16,17

DosesFinasteride 5mg PO Qdaily

Dutasteride 0.5mg PO Qdaily

Maximal reductions in prostate size seen ~12 monthsmonths

Adverse EffectsEjaculation disorders

Erectile dysfunction/↓ libido

Gynecomastia

Nausea, abdominal pain, flatulence

Rash (finasteride only)


Contraindications/PrecautionsHepatic dysfunction (caution)

Pregnancy Category XWomen of childbearing age or who are pregnant should NOT

Handle 5‐α‐reductase inhibitor tablets

Have contact with semen from men treated with 5‐α‐reductase inhibitors

Drug‐Drug InteractionsDutasteride only: cautious use with CYP 3A4 inhibitors/inducers

10/9/2015

15


Monitoring ParametersObtain baseline PSA & DRE

↓ PSA levels by 50%

Follow up with PSA in 6 months, then PSA & DRE annually

PDE5 InhibitorsPDE5 Inhibitors1188

MOA: Inhibition of PDE5 in prostate to cause vasodilation and prostatic and bladder neck relaxation

Example: Tadalafil (Cialis®)

FDA approved in Oct 2011

Approved for BPH as well as BPH + ED as studies show improvement in urinary symptoms

Dose5 mg PO Qdaily

Combination Combination TherapyTherapy19,2019,20

5‐α‐reductase inhibitor + α‐adrenergic antagonistJalyn® (0.5 mg dutasteride + 0.4 mg tamsulosin)

Ideal for patients with

Severe symptomsSevere symptoms

Enlarged prostates (>40 grams)

↑ PSA levels

Has been shown to prevent symptom progression & ↓ the risk for developing urinary retention, UTIs, & need for surgery

10/9/2015

16

Combination Therapy, cont’dCombination Therapy, cont’d1,19,201,19,20

↑ adverse effects and expensive

Can consider d/c’ing α‐blocker after 6‐9 mos

α‐adrenergic antagonist + anticholinergicConsidered for patients with BOO symptoms + symptoms of overactive bladder

Urinary frequency, urgency, enuresis


Silodosin provides quick symptom relief in the management of BPH as well as reduces prostate size and volume.

A. True

B. False


As part of the management of his BPH symptoms, Mr. Jones may be counseled to:

A. Avoid alcohol at bedtime

B. Discontinue using loratadine/pseudoephedrine

C. Limit fluid intake at bedtime

D. All of the above

10/9/2015

17


A common adverse effect associated with terazosin therapy is:

A E il d f iA. Erectile dysfunction

B. Gynecomastia

C. Orthostatic hypotension

D. Rash


Which of the following treatment options is appropriate for initiating today to manage Mr. Jones’ BPH symptoms?

A. Finasteride 5 mg PO Qdaily

B. Tadalafil 5 mg PO Qdaily

C. Tamsulosin 0.8 mg PO Qdaily

D. Terazosin 10 mg PO QHS

Herbals/CAM, cont’dHerbals/CAM, cont’d

Saw palmetto21,22,23Earlier evidence suggests modest efficacy on treated LUTS

Newer data fail to confirm a clinical important role in the management of BPH

AUA 2010 guidelines do not advocate recommending saw palmetto for BPH due to a lack of evidence1

10/9/2015

18

Zinc24High zinc levels found in normal prostate glands

Some men with BPH have low zinc t ticoncentrations

Better conclusions seen in men with prostate cancer

Adverse effects: Nausea, vomiting, abdominal cramps

Surgical InterventionSurgical Intervention11

Indications for surgeryUnresponsive to drug therapy

Refractory urinary retention or other BPH complications

Recurrent UTIs secondary to BPH

Individual preference

Prostatectomy

Transurethral resection of the prostate (TURP)

Transurethral microwave thermotherapy (TUMT)

Quiz Question #Quiz Question #99

Saw palmetto acts similar to tamsulosin to improve the symptoms of BPH.

A. True

B. False

10/9/2015

19

Quiz Question #10Quiz Question #10Mr. Jones has been receiving silodosin 8 mg PO Qdaily and dutasteride 0.5 mg PO Qdaily for 6 months now. His PSA is 3.3 ng/mL. He reports significant improvement in his symptoms and is mostly “symptom free”. Which of the following should occur?should occur?

A. He should continue both medications

B. He should D/C dutasteride and continue

silodosin

C. He should D/C silodosin and continue dutasteride

D. He should D/C both medications

Documents

Urine Luck! A Review of the Managment of BPH - FORPRINT ... file10/9/2015 1 Dana A. Brown, Pharm.D., BCPS Assistant Dean for Academics, Associate Professor of Pharmacy Practice Palm