Benign Prostatic Hyperplasia (BPH)

• Benign Prostatic Hyperplasia (BPH) involves the enlargement of the prostate gland and may or may not present symptoms, risk increases with age.
• Static BPH is characterized by increased prostate size, leading to blockage of flow and is androgen derived.
• Dynamic BPH involves increased smooth muscle contraction due to excessive alpha-adrenergic tone.
• The progression of BPH is staged as BPH → BPE → BPO.
• Treatment includes controlling symptoms, preventing disease progression and complications, and delaying surgery.

Treatment Options

• Alpha-1 antagonists like Tamsulosin.
• 5 alpha-reductase inhibitors helps reduce complications such as Finasteride.
• PDE5 inhibitors.
• Anticholinergics like Oxybutynin.
• B3 agonists.
• Surgery is considered for moderate to severe BPO.

Key Factors in BPH Development

• Age ≥ 40 years.
• From birth pea size 1g increases by puberty to (15-20g by age 25-30) until age increases leading to BPE.
• Androgens stimulates: testosterone is converted to DHT by 5 alpha reductase.
• DHT promotes prostate growth and stability and is key for most.
• Increased alpha-adrenergic tone in the prostate and urethra.
• Alpha 1A adrenergic receptors are stimulated by NE.
• The chronic inflammation potential triggers include Dyslipidemia, Low serum testosterone and Hypoestrogenism.
• Goals of treatment include symptom control, prevent disease progression and complications, and delay surgery along with increased peak urinary flow rate and normalization of PVR to <50mL.

Non-Pharmacological Therapy

• Lifestyle modifications are recommended for all patients.
• Healthy diet, regular exercise, smoking cessation, weight loss and control of comorbidities
• Reduced caffeine and alcohol intake. Void before bedtime/long trips.
• Herbal products are not recommended due to lack of evidence. Includes SAW palmetto, stinging nettle, south African star grass, pumpkin seed, and African plum.

Medications for BPH

• To relax prostatic smooth muscle (↓dynamic factors) use Alpha1 adrenergic antagonists like Tadalafil.
• To relax prostate size (target static factors) use 5 alpha reductase inhibitor.
• To relax the bladder detrusor muscle (↓dynamic factors) use Anticholinergics as well as Beta 3- adrenergic agonists.

Combo pharmacotherapy

• BPH with ED use Alpha adrenergic antagonist + PDE5i.
• BPH with a small prostate and low PSA use Alpha adrenergic AA
• BPH with a large prostate and high PSA use 5A-reducatse inhibitor and Alpha adrenergic AA. It is most studied & effective
• For predominant irritative symptoms use Alpha adrenergic AA + Anticholinergic or beta 3 A.

Evaluation

• Symptoms improvement of > 3 point AUA reduction.
• Regular follow-up is within 6-12 weeks for most (> 6 months for 5 alpha reductase inhibitors).
• Complete annual PSA & DRE screening for cancer as well as evaluating Renal function by BUN/SCr.

Alpha 1 Adrenergic Antagonists

• These are Alpha 1 adrenergic antagonists like Phenoxybenzamine (Prazosin, terazosin, doxazosin, alfuzosin), (tamsulosin, silodosin) are the 1st line treatment for mod-severe BPH.
• Indications BPH & lower urinary tract symptoms (LUTS) related to BPH
• Alpha 1 Adrenergic Antagonists are the 1st line monotherapy for BPH & HTN & WON'T: reduce prostate size.
• The MOA antagonizes alpha-1 rec, taking 1-6 weeks for onset of action that relax smooth muscle in the prostate & bladder neck.
• These improve urinary flow and reduce LUTS in BPH that AUA symptom score by 30-40%, Jurinart flow rate 2-3mL/s & ↓post void residual volume

Alpha 1 Adrenergic Antagonists: Dosing

• 2nd gen: terazosin, doxazosin: start low, titrate slowly to reduce hypotension
• Alfuzosin ER: 10mg daily, no titration needed
• 3rd gen: tamsulosin after meals(once daily same meal)
• This medication rise slowly from sitting/lying position to avoid dizzniness as well as reporting ant vision changes before eye surgery

Alpha 1 Adrenergic Antagonists: ADEs

• Caution using with history of Severe hepatic insufficiency or Sulfa allergy.
• Precautions include caution for Orthostatic hypotension (IR>) & inform ophthalmologist before cataract surgery as well as stopping preoperatively if there is no benefit stopping med.
• 2nd gen: Dizziness, Orthostatic hypotension & First does syncope.
• 3rd gen: Ejaculatory disorders and Nasal congestion.
• ADME says: 3rd gen are uroselective alpha1 antagonists with Renal & hepatic excretion along with Sexual side effects and Sulfa-sensitivity allergy w/ tamsulosin. Er versions will reduce CV Side effects
• Alpha 1 antagonists medchem: 2nd gen are More selective NOT UROSELECTIVE with SAR comparable to norepinephrine & Lack hydroxyls with Bearing bulky groups on the amine via Structure pattern: Quinazoline +piperazine + acyl substituent
• Third gen: are uroselective: less CV SEs, More sexual SEs due to Lack hydroxyls with Monoalkylated amines & 2-Phenylethylamine derivatives

5-Alpha Reductase Inhibitors

• Finasteride, Dutasteride treat moderate-to-severe BPH with prostate > 40g or PSA > 1.4ng/mL that are Preferred for enlarged prostates (> 40g)
• Reduce the risk of disease progression and complications that can be used as combo w/ a1 blockers for faster symptoms relief.
• The MOA inhibits conversion of testosterone to DHT → ↓prostate growth that Reduce intraprostic DHT by 80-90%.
• ↓prostate size & risk of acute urinary retention, ſurinary flow rate, which DHT suppression results in; finasteride: targets type II enzyme (prostate predominant)
• Prevents finasteride and dutasteride chemo.
• ADEs is Rare: gynecomastia, depression, dizziness & rash but can also cause persistent sexual dysfunction.
• Decreases libido as well as causing erectile dysfunction and ejaculatory disorders.

5-Alpha Reductase Inhibitors: Cautions

• Contraindications in Pregnancy stating it is teratogenic effect on male fetus.
• Precaution should be executed such as, avoid having pregnant patients handling and PSA monitoring for prostate cancer risk
• ADME results in onset of action and symptom improvement in 6-12months seeing Max effects seen @ 12months after long term use of approximately 4-6 years when needed for sustained benefit.
• Monitoring with levels by ↓PSA by 50% after 6-12monthhs including Adjustment; double PSA for accurate prostate cancer screening as well as getting baseline PSA & DRE before starting and repeating at 6 months and annually.
• 5 alpha reductase inhibitors Medchem TC is anti-BPH agent that STOPS DHT conversion CC 4-azasteroids

Anticholinergics/ Antimuscarinics

• Darifenacin, festoterodine, oxybutynin, solifenacin, tolterodine, trospium treat Overactive bladder (OAB) w/urgency, frequency, urge incontinence involving Urge urinary incontinence (z) & Neurogenic detrusor overactivity.
• The MOA blocks muscarinic receptors(M2,3) which also is associated with effects of increasing Bladder capacity leading to a decreases of urgency and incontinence
• This reduces bladder contractions but M2 affects heart rate making for a small roll in the bladder.
• Narrow-angle glaucoma, Urinary retention, Gastric retention and Severe Gl motility issues are major contraindication when using this treatment
• Can cause Dry mouth, Constipation, Blurred vision and/or Dizziness are expected with patients prescribed this.
• Serious ADEs include Cognitive decline in elderly and/or QT prolongation as well as acute urinary retention.

Anticholinergics/ Antimuscarinics: Dose

• Adults: titrate prn
• Older adults: use w/caution, that slowly titrate to avoid CNS effects
• Renal/hepatic impairment: will need needed
• The ADME offers of the transdermal Extended release/ DR to minimize Side effects where (Oxybutynin crosses BBB) and Trospium (doesn't cross BBB)
• These are Receptors interactions that are competitive Antagonist of muscarinic receptors which provides a dose response relationship in order to assist with dependent reduction in bladder contractions & ADEs as peak effect will take weeks to occur

Anticholinergic Medchem

• SAR will mimic acetylcholine where 2nd gen are more uroselective or also SLUDGE

Beta 3-adrenergic agonists

• Mirabegron (Myrbetriq) & Vibegron (Gemtesa) treatments are used with other indications in order to aid with enhanced efficacy in relation to Overactive Bladder (OAB) and/or urgency, frequency and urge incontinence who can also be offered and/or alternative to Anticholinergics
• agonism of beta3 receptors in bladder increasescAMP→relax→enhance blaster storage in order to reduce irritating voiding symptoms while also attempting to increase bladder capacity & interval between needing to void for 4-8 weeks for efficacy.
• Mirabegron (myrbetriq): plasma concentration:3.5hrs while Half-life is approximately 50hrs with a maintainer dose of around 25mg → 50mg However sever uncontrolled HTN is a cause for caution to avoid in severe hepatic impairment ESRD which leads to ades like QT-prolongation (rare), Hypotension (monitor BP @ home), Headache, UTI

Vibegron (Gemtesa)

• This medications has a plasa concentration of about 1 to 3.5hrs a half life around 30hrs, in dosage 75mg once daily and can be crushed if needed. Has fewer CV precautions and ADEs with a milder range hen compared against Mirabegron.

Additional Notes

• Surgery: TURP
• Vascular system & erection begins wit Ach→ NO release➔ cGMP production→ ↓intracellular Ca2+➔ smooth muscle relax.
• The neurotransmitter/vasodilator of cAMP works with Ach/ prostaglandin E → cAMP production→ ↓intracellular Ca²+→ smooth muscle relax under Nervous system psychogenic stimuli.

Neural pathways

• Reflexogenic erections: mediated by sacral reflex arc
• Psychogenic erections: initiated via CNS that aids with processing of sensory stimuli.
• Regarding Hypothalamic role Dopamine plays in erection while stimulation via Alpha2-adrenergic Maintains flaccidity
• Under Neural: Sympathetic plays a role in the Inhibitory response while Parasympathetic aids at Pro-erectogenic and Somatic is considered Pro-erectogenic.

ED:

• ED: persistent/ recurrent failure to achieve or maintain erection that lasts approximately > 3 months for satidifactory intercourse.
• Medical conditions: HTN, arteriosclerosis, metabolic syndrome, psychiatric disorders and DLD or DM autonomic neuropathy.
• Other Psyshogenic factors like Dental health factors and age can factor as well in addiction to medications: diuretics, other chronic diseases as well as Anticholinergic, Dopamine, estrogen, CNS depressants & 5-ARi

Types of ED

• Organic ED: vascular, neurologic or hormonal
• Psychogenic ED: poor response to sexual stimuli

Diagnostics evaluations for ED

• Severity of ED
• Medical, psychological, surgical history
• Review of current meds
• Cardiac reserve assessment
• Select lab test

Outcomes of ED

• Identify and treat underlying causes
• Address modified risk factors
• Lifestyle modifications

phosphodiesterase type 5 inhibitors

• Sildenafil, Vardenafil, tadalafil, avanafil are used to target erectile dysfunction
• Can also treat BPH and Pulmonary arterial HTN

MOA

• inhibits PDE5→ cGMP→ smooth muscle relaxation.
• Comparable LUTS improvements across all PDE5
• relaxes prostate, urethra, bladder neck pelvic blood vessels that interrupts Rho-kinase pathway improving pelvic perfusion & reduces inflammation

Side Effects

• headaches, flushing, nasal congestion, dyspepsia, back pain
• Visual disturbances as well as in serious vision loss
• Tadalafil specific: back pain, mild hypotension w/ a1 blockers

contraindications

• Caution: use of a1 blockers; use with nitrates
• concurrent nitrate therapy
• unstable CV conditions & History of NAION
• The use of Sildenafil, Vardenafil, tadalafil, avanafil have side effects of headache, which has a better result when used with Tadalafil
• Dosing considerations: before declaring failure 7-8 doses need patients need for an ADME with varied half lives in order to (patients still need sexual stimulation to be effective)

Doses

• Sildenafil:30-60 min before intercourse
• Vardenafil: 30-60 min before intercourse
• Tadalafil: 5 mg daily for BPH & 2.5-20mg prn for BPH
• Avanafil: approximately 15-30 mins before intercourse

Action and Durations

• Action Sildenafil/ Vardenafil at 30-60mins
• Tadalafil at approximately 2 hours
• Longest Duration of up to 36 hours (Tadalafil)
• Followed by 4-6 (general)

Prostaglandin E1 analog

• Alprostadil is recommended as a Monotherapy for ED: preferred agent when PDE5i are ineffective or contraindicated when patients aren't seeking help

Route and Counseling

• intracavernosal: no more than 3 times per week
• intraurethral: no more than 2 doses per day
• The intracavernosal: No More than 3 times per week

Benign Prostatic Hyperplasia (BPH) involves prostate enlargement, increasing with age. Static BPH is due to increased prostate size, while dynamic BPH involves smooth muscle contraction. Treatment options include alpha-1 antagonists, 5 alpha-reductase inhibitors and surgery if needed.