Men's health Flashcards
What are the 2 main targets for tackling Benign Prostate Hyperplasia?
- Type II 5a-reductase (converts testosterone to DHT which stimulates prostate growth)
- Alpha-1 adrenergic receptors (once innervated, can stimulate smooth muscle constriction –> narrowing urethral opening)
What are the 2 components responsible for urethral obstruction in BPH?
- Static component (hormonal factors causing enlargement of the prostate)
- Dynamic component (agonism of alpha-1 receptors cause smooth muscle contraction which narrows urethral opening)
Long-term consequences of BPH
- Early phase, bladder muscle compensates the narrow urethral opening by contracting harder
- Over time, bladder muscles undergo hypertrophy
- Once detrusor muscles achieve maximum state of hypertrophy, they will decompensate
- Decompensated muscles are easily irritable to small amounts of stimuli (ie. urine)
What are the 2 types of urinary symptoms associated with BPH?
- Obstructive/ voiding symptoms (Occurs more early on in the disease course)
- Irritative/ storage symptoms (occurs several years later if untreated)
What are the signs of obstructive symptoms?
- hesitancy
- Weak stream
- Sensation of incomplete voiding
- Dribbling
- Straining
- intermittent flow
What are the signs of Irritative symptoms?
- Dysuria
- Frequency
- Nocturia
- Urgency
- Urinary incontinence (UI)
What is the definition of erectile dysfunction?
Persistent (≥6 months) inability to achieve or maintain an erection of sufficient duration and firmness to complete satisfactory intercourse
At what age are men at a higher risk for erectile dysfunction?
≥40 years old
What is the physiology of an erection?
Smooth muscles in the penis relax –> corpora cavernosa fills up with blood –> swelling of the corpora cavernosa causes a compression of the venule against the tunica albuginea –> reduced blood flow causing firmness of the penis
What are the chemical components responsible for an erection?
- Acetylcholine (ACh) –> increases Nitric oxide –> increases activity of guanylate cyclase –> increase cGMP –> smooth muscle relaxation and vasodilation
- Prostaglandins E –> increases adenyl cyclase –> increase cAMP –> smooth muscle relaxation and vasodilation
What is the normal serum concentration of testosterone and when should you check it?
300 – 1000 ng/dL.
Check testosterone levels when patient presents with erectile dysfunction.
What is the subsiding of an erection called?
Detumescence
Physiology of Detumescence
- Deactivating parasympathetic system (cGMP is deactivated by PDE-5 enzyme –> stops vasodilation)
- Activate the sympathetic system (Induce smooth muscle contraction via alpha-2 adrenergic receptors of the arterioles –> reduction of blood input into the corpora cavernosa)
What are the 4 main etiologies of erectile dysfunction?
- Organic ED (compromised vascular, nervous, or hormonal system, or medication-induced)
- Psychogenic ED (Performance anxiety, stress, loss of attraction, malaise, sedation)
- Mixed ED (organic + psychogenic)
- Others (smoking, alcoholism, illicit drug use, obesity)
Complications of Erectile dysfunction?
- Loss of interest of sexual activities
- Depression
- Performance anxiety
- Embarrassment
- Angry
- Low self-esteem
- Disharmony in the r/s
What medications can induce organic erectile dysfunction?
- Drugs that decreases penile blood flow (clonidine, methyldopa, beta-blockers, TZDs)
- Anticholinergics (1st gen antihistamines, phenothiazines)
- Dopamine antagonist (Metoclopramide)
- SSRI
- Drugs that decreases testosterone (finasteride, dutasteride)
- CNS depressants (benzodiazepines, anticonvulsants)
What are the different ways to assess for BPH? (5)
- Digital rectal examination (DRE)
- Ultrasonography
- Maximum urinary flow rate (Qmax)
- Prostate-specific antigen (PSA)
- Postvoidal residual (PVR)
What is the cutoff for prostate-specific antigen to suggest the presence of BPH?
- Positively correlates with prostate volume
- PSA >1.5 ng/mL
What is the cutoff for postvoidal residual to suggest inadequate emptying due to BPH?
> 200 mL (inadequate)
<100 mL (normal emptying)
What is the severity stratification using the AUA-SI score?
Mild = AUA ≤7 –> usually asymptomatic or mildly symptomatic
Moderate = AUA 8-19 –> obstructive and irritative symptoms
Severe = AUA ≥20 –> obstructive + irritative + complications of BPH
Complications of BPH
- Recurrent UTI
- Bladder stones
- Acute urinary retention
- Urinary incontinence
- Hematuria
When is Transurethral Resection of the Prostate (TURP) considered?
Severe complications of BPH (eg. recurrent UTI, bladder stones, incontinence, acute urinary retention, hematuria)
What drugs can induce BPH?
- Anticholinergics (eg. gen 1 antihistamine, tricyclic antidepressants)
- Alpha-1 adrenergic agonists (eg. Decongestants)
- Opioid analgesics (eg. codeine or tramadol)
- Diuretics
- Testosterone
When do you not need to treat for BPH?
- Mild AUA score ≤7
- Moderate-severe AUA score ≥8 + asymptomatic/ not bothered by symptoms –> watchful wait instead
How often must you monitor a patient’s AUA score?
Annually
What are the non-pharmacological management of BPH?
- Limit fluid intake in the evening
- Minimize caffeine and alcohol intake
- Educate patient to take time to empty their bladder completely and often
- Avoid medications that can exacerbate symptoms (anticholinergics, alpha-1 agonist, opioid analgesics, diuretics, testosterone)
When to start pharmacological management for BPH?
- Bothersome symptoms
- Complications
What are the different alpha-1 antagonists available?
Non-selective (antagonize both peripheral vascular and urinary alpha-1 receptors):
1. Doxazosin
2. Terazosin
3. Prazosin (not recommended for BPH)
Selective (targets urinary alpha-1A adrenergic receptors in urinary tract and prostate):
1. Tamsulosin
2. Alfuzosin
3. Silodosin
What are the advantages of using selective alpha-adrenergic antagonists?
- Lesser risk for hypotension
- Dose titration not needed
MOA of Tamsulosin
- Reversible alpha-1A receptor antagonist
- Decrease vasoconstriction induced by endogenous catecholamines
- Binds to and inhibits alpha-adrenergic receptors on the smooth muscles of the prostate –> reduces muscle tone and reduces urethral obstruction
- Improve the symptoms related to bladder instability and tension of the smooth muscle of the lower urinary tract
Limitations of alpha-1 adrenergic antagonists?
- They do not reduce prostate size (no effect on PSA)
- Does not offer prevention for progression of BPH or the need for surgery (delays the need for TURP/ catheterization)
- Signs and symptoms of BPH may recur if the drug is discontinued
Side effects associated with alpha-1 adrenergic antagonists
General s/es:
1. Ejaculatory disturbance
2. Headache (bedtime administration to decrease orthostatic effects)
3. Muscle weakness
4. Fatigue
5. Back pain
Side effects associated with alpha-1 adrenergic antagonists
General s/es:
1. Ejaculatory disturbance
2. Headache (bedtime administration to decrease orthostatic effects)
3. Muscle weakness
4. Fatigue
5. Back pain
Non-selective specific s/es:
1. Dizziness
2. Syncope and orthostatic hypotension (bedtime dosing)
Alpha-1A selective (uroselective) specific s/es:
1. Ejaculatory disturbances (delayed or retrograde ejaculation) (Sildosin > Tamsulosin > Alfuzosin)
2. Less hypotension or syncope
Complications of alpha-1 antagonists (particularly Tamsulosin)
- Intraoperative Floppy Iris Syndrome (IFIS) –> complication of cataract surgery
- Men with planned cataract surgery should avoid the initiation of alpha-1 inhibitors until surgery has been completed (2-3 weeks hold)
- Hold alpha-1 antagonist 2-3 weeks before surgery
Contraindications of alpha-1 adrenergic antagonists
- Concurrent use of another alpha-1 adrenergic antagonist (eg. prazosin, epinephrine)
- Patients with a history of syncope (non-selective agents)
DDI associated with Tamsulosin
- Grapefruit juice/ grapefruit
- CYP3A4 and CYP2C9 inhibitors/ inducers
Other advantages of using non-selective alpha-1 adrenergic antagonists
- Beneficial for hypertensive patients that need additional BP lowering effect
- Not to be used as monotherapy for patients with HTN and BPH concurrently
List some examples of 5Alpha Reductase Inhibitors
- Finasteride
- Dutasteride
What is the MOA of finasteride (5ARI)
- Competitively inhibit Type II 5alpha reductase –> decrease the conversion of testosterone to DHT –> reduce the size of the prostate (decrease PSA too)
- Slow down the progression of disease –> decrease the need for surgery
When is 5ARI indicated
- Moderate or severe LUTS (AUA ≥8) + large prostate (>40g)
- Patients who want to avoid surgery or cannot tolerate the side effects of alpha-1 antagonist
- Considered if initial PSA >1.5 ng/mL
Counseling point for 5ARI
- Onset of action is slow, may take up to 6-12 months to decrease the prostate size and experience BPH clinical effect
Side effects of 5ARI
- Ejaculatory disorders (5ARI > alpha1-antagonist)
- Decreased libido and sexual potency
- Erectile dysfunction
- Gynecomastia
- Breast tenderness
Contraindication of 5ARI
- Pregnant/ Child-bearing age females (women may use it for hirsutism)
- Children
What should be done before initiating 5ARI
Obtain PSA levels (ensure it is >1.5 ng/mL) –> not easily interpretable after initiation
Which Phosphodiesterase 5 inhibitor is approved for BPH
Tadalafil
Limitations of PDE5 in BPH
- Does not affect prostate size
- Usually only used as add-on therapy, especially if patient has concomitant erectile dysfunction
Can Tadalafil be used as monotherapy for BPH?
Controversial but yes due to likely smooth muscle relaxation.
Administer Tadalafil 5mg daily
Which patient group is more likely to benefit from initial combination therapy?
Moderate symptoms (AUASI score 8-19) + prostate size >25g
(must fulfill these 2 criteria)
Types of initial combination therapy available
- alpha1 antagonist + 5ARI
- 5ARI + PDE5 inhibitor
- Alpha1-antagonist + PDE5 inhibitor (rarely used)
Benefits of alpha1 antagonist + 5ARI combination therapy
- Alpha1 antagonist provides quick onset of action (reduce vasoconstriction) while 5ARI have time for onset to be felt (6-12 months)
- Reserved for symptomatic patients with an enlarged prostate
- After 6 months of combination therapy, can consider dropping alpha-1 antagonist in moderate BPH
Benefits of 5ARI + PDE5 inhibitors initial combination therapy
- Mitigate the sexual adverse effects that may arise from 5ARIs
- Useful for concomitant erectile dysfunction that may arise from 5ARIs use
Contraindication of 5ARI + PDE5 initial combination therapy
- Cardiac comorbidities (unstable angina)
Limitations of alpha1 antagonist + 5PDE inhibitors initial combination therapy
- Can cause severe life-threatening hypotension (esp if alpha1 antagonist is non-selective)
- Optimization and stabilization of alpha1 antagonist dose is required first before adding PDE5 inhibitors (use lowest PDE5 inhibitor dose possible)
- Would not address prostate enlargement issue
Pharmacological treatment for irritative symptoms of BPH
- Anti-muscarinic
Examples of anti-muscarinic agents for irritative symptoms of BPH
- Oxybutynin
- Tolterodine
- Solifenacin
MOA of anti-muscarinic agents
Block muscarinic receptors in detrusor (bladder) muscle –> decreasing involuntary contraction of the bladder
Conditions to be met before starting anti-muscarinic agents for BPH
PVR must be <250mL (or <150mL for more conservative guidelines)
Severity stratification by Sexual Health Inventory for Men (SHIM) ranges
Mild-no ED: 17 – 21 points
Moderate-severe ED: <11 points
When should cardiovascular disease evaluation be conducted for patients with ED?
Every patient requires CV evaluation (ED might be early symptom of unidentified comorbid CVD)
Non-pharmacological management of ED
- Address modifiable risk factors (smoking cessation, control weight, control glucose/ BP/ lipids, exercise, decrease alcohol)
- Psychotherapy
- Vacuum erection devices
- Surgery (penile implant)
MOA of phosphodiesterase 5 inhibitors
- Inhibit PDE5 enzyme degradation of cGMP –> enhance cGMP activity –> induce smooth muscle relaxation –> erection (increase blood flow to corpora cavernosa)
- Enhances erection only after sexual stimulation (release of Nitric oxide)
General counseling for PDE5 agents
- Take before intercourse (1 hour before for Sildenafil and Vardenafil; 30 mins before for Avanafil; 36 hours before for Tadalafil)
- Take on an empty stomach (Except Tadalafil and Avanafil –> regardless of food)
What are the PDE5 inhibitors agents available?
- Sildenafil
- Vardenafil
- Tadalafil
- Avanafil
When to consider lower initial dose of PDE5 inhibitors for erectile dysfunction?
- Patients ≥65 yo
- Patients taking alpha blockers (risk for hypotension)
- Patients with renal failure
- Patients taking with CYP3A4 inhibitors (eg. erythromycin, cimetidine, ketoconazole, itraconazole, clarithromycin, grapefruit, ritonavir, saquinavir, etc)
Side effects associated with PDE5 inhibitors
- Headache
- Rhinitis
- Flushing
- Muscle and back pain
- Dizziness
- Hypotension
- Priapisms (seek emergency department if >4hours)
- Sudden hearing loss (very rare)
- QTc prolongation (Vardenafil)
- Muscle pain (Tadalafil – PDE11 affinity)
- Ocular problems (Sildenafil and vardenafil) –> blur vision or blue-green tinting of vision
How does ocular problems arise with PDE5 use for ED?
- Mostly occurs with sildenafil and vardenafil
- Affinity to PDE6 in the retina
- Reversible ocular problem with color discrimination (difficulty discriminating blue from green)
- Sensitivity to light
Counseling points for ocular problems associated with PDE5 inhibitors
- If patient experience sudden decreased vision or vision loss, STOP the use and look for immediate medical attention
Risk factor for nonarteritic anterior ischemic optic neuropathy (NAION)
- Blood flow to optic nerve is blocked
- DM
- Smoking
- HTN
- CVD
- Dyslipidemia
- Age >50 yo
Contraindications of PDE5 inhibitors
- Nitrates (GTNs/ nitroglycerin) + PDE5 inhibitors = potentially fatal hypotension
Avoid nitrates for 12hrs after Avanafil, 24hrs after Sildenafil or Vardenafil, and 48hrs after Tadalafil
DDI with PDE5 inhibitors and their effects
- Nitrates (fatal hypotension)
- Multiple antihypertensive (increase risk for hypotension)
- Alcohol (hypotension)
- CYP3A4 inhibitors (increase concentration of PDE5 inhibitors)
When is testosterone replacement indicated for erectile dysfunction?
Symptomatic hypogonadism confirmed by:
1. Decreased libido, and
2. Low serum testosterone concentrations (<300-1100 ng/dL)
Side effects associated with testosterone repalcement
- Irritability
- Aggressive behaviour
- Undesirable hair growth
- Increase BP
- Hepatotoxicity
- Dyslipidemia
- Polycythemia
- Prostatic hyperplasia (c/i for prostate cancer)
Monitoring for testosterone replacement therapy
- Monitor serum testosterone within 1-3 months and at 6-12 months interval
- Stop if no improvement after 3 months
MOA of Alprostadil for ED
Prostaglandin E1 analog that stimulates adenyl cyclase and increase cAMP –> inducing smooth muscle relaxation –> erection
Benefits of alprostadil over PDE5i for ED
- Does not need sexual stimulation to work
- Fast onset (5-10 mins)
Route of administration for Alprostadil
- Intraurethral (pain, warmth or burning sensation in urethral, voiding difficulties, bleeding/ spotting, priapism)
- Intracavernosa (preferred over intraurethral; but higher risk for priapism, bleeding, hematoma, fibrosis)
What are the pharmacological agents used for treatment of ED?
- Phosphodiesterase 5 inhibitors
- Testosterone replacement
- Alprostadil