Detrusor muscle contracts in response to stimulation of muscarinic receptors by acetylcholine and by electric stimulation of intrinsic cholinergic nerves.
This Ach acts on nicotinic receptors on post-ganglionic parasympathetic neurons on the bladder
In response to this Ach, post-ganglionic parasympathetic neurons release Ach which stimulates muscarinic receptors on the bladder smooth muscle, resulting in bladder contraction
Contractile responses can be completely abolished by atropine
Muscarinic receptors
Coupled to G proteins, but the signal transduction systems may vary.
In general, M1, M3, and M5 receptors are considered to couple preferentially to Gq/11, activating phosphoinositide hydrolysis, in turn leading to mobilization of intracellular calcium.
M2 and M4 receptors couple to pertussis toxin–sensitive Gi/o, resulting in inhibition of adenylate cyclase activity.
5 different subtypes based on molecular cloning and (4 different receptor subtypes based on pharmacology)
M1: thought to be involved in cognition.
M2: primary cholinergic receptor in the heart causing bradycardia when activated and tachycardia when blocked.
M3: primary role in salivation, bowel motility, and visual accommodation.
M4/M5 subtypes are not associated with dry mouth, constipation, tachycardia, drowsiness, blurred vision
M1 to M5 are all found in the bladder
M2 and M3 are the most common type of muscarinic receptors in the bladder, with M2 predominating at least 3:1 over M3 receptors
M3 receptors are the most important for contraction
Stimulation of M3 receptors by ACh induces calcium influx through L-type Ca2+ channels, as well as IP3 hydrolysis as a result of phospholipase C activation, resulting in the release of intracellular calcium, both of which contribute to a smooth muscle contraction
The functional role for M2 receptors is unknown.
M2 receptor stimulation may oppose sympathetically induced smooth muscle relaxation, mediated by β-ARs via inhibition of adenylyl cyclase
Muscarinic receptor subtype-mediated detrusor contractions shift from M3 to M2 receptor subtype in certain pathologic conditions, such as obstructed or neurogenic bladders
Decrease the activity in AFFARENT nerves (both C and Aδ fibers) from the bladder
Primary mechanism; anti-cholinergics act mainly during the storage phase (rather than the voiding phase)
During the storage phase
ACh is released from both neuronal and non-neuronal sources (e.g., the urothelium and suburothelium) anddirectly or indirectly (by increasing detrusor smooth muscle tone) excites afferent nerves in the suburothelium and within the detrusor
Normally no parasympathetic input to the LUT.
Since they act during the storage phase, they can be safely administered in men with bladder outlet obstruction as they do not alter urinary flow rate, voiding pressure, or incidence of urinary retention.
Caution should be used in large PVRs
Blocking the muscarinic receptors on the detrusor muscle, which are otherwise stimulated by ACh released from activated cholinergic (parasympathetic) nerves.
Less significant effect than reducing AFFARENT activity
Reduce the micromotions caused by the release of small packets of Ach
In patients with involuntary bladder contractions (detrusor overactivity) of any cause, anti-cholinergics (5):
Increase the volume to the first detrusor overactivity (affarent)
Increase the total bladder capacity (affarent)
Increase mean voided volume (affarent)
Decrease urgency (affarent)
Decrease the amplitude of the contraction (efferent)
Do not affect detrusor or abdominal leak point pressure
Produce only partial inhibition due to secondary release of a transmitter other than Ach
This is known as atropine resistance and is the most common hypothesis explaining the difficulty of curing detrusor overactivity with anti-cholimergic agents alone, and supports the rationale of combined treatment of detrusor overactivity with agents of different mechanisms of action. The importance or unimportance of an atropine-resistant component to detrusor contraction in the treatment of detrusor overactivity in humans remains to be established.
Anti-cholinergics can be classified as tertiary vs. quaternary amines
Tertiary amines
Oxybutynin, tolterodine, fesoterodine, solifenacin, darifenacin, atropine, imidafenacin, and propiverine
Well absorbed from the GI tract
Theoretically able to pass into the central nervous system (CNS)
Factors that increase the likelihood of an anti-cholinergic passing through the blood-brain barrier (3):
High lipophilicity
Small molecular size
Low electrical charge
Quaternary amines
Trospium and propantheline
Not well absorbed from the GI tract
Pass into the CNS to a limited extent, and have a low incidence of CNS side effects
Metabolism
Many metabolized by the P450 enzyme system to active and/or inactive metabolites.
Most commonly involved P450 enzymes are CYP2D6 and CYP3A4
Metabolic conversion creates a risk for drug-drug interactions; coadministration of a potent inhibitor of this enzyme (e.g., ketoconazole) may lead to an increase in the circulating drug
The clinical usefulness of available antimuscarinic agents is limited by their lack of selectivity
The low persistence with prescribed anti-cholinergic therapy for OAB is due to lack of efficacy and adverse effects.
The longest persistence has been reported for solifenacin
Common side effects include:
Dry mouth (30% medication vs. 8% placebo)
Constipation
Blurred vision
CNS side effects (cognitive dysfunction, memory impairment, dizziness, fatigue, and headache)
Potential serious side effects are cardiac and include:
Increases in heart rate
Arrhythmia (QT prolongation and induction of polymorphic ventricular tachycardia (torsades de pointes)
QT prolongation is not related to muscarinic blockade but rather linked to inhibition of the hERG potassium channel in the heart. Some anti-cholinergic drugs may cause this, but this is not a class effect.
None of the anti-cholinergic drugs in clinical use is ideal as a first-line treatment for all OAB patients. Optimal treatment should be individualized.
Site and speed of anti-cholinergic metabolism has profound effects in terms of clinical efficacy and side effects; therapeutically, it is more important to be tissue selective than subtype selective
Oral immediate-release (IR) oxybutynin has higher risk of dry mouth than tolterodine
IR preparations have higher risk of dry mouth than extended release (ER) preparations of oxybutynin or tolterodine
IR tolterodine has lower efficacy and higher risk of dry mouth than solifenacin
Fesoterodine has higher efficacy but also higher risk of widhdrawal becaue of adverse events in general, in particular a higher risk of dry mouth compared to ER tolterodine
Blocks muscarinic receptors (main effect when given systemically)
Direct muscle relaxant
Local anesthetic effects
The latter 2 may be of importance when the drug is administered intravesically, but probably play no role when it is given orally.
Metabolism: Undergoes extensive upper gastrointestinal and first-pass hepatic metabolism via the cytochrome P450 system (CYP3A4) into multiple metabolites.
The primary metabolite, N-desethyloxybutynin, has been implicated as the major cause of the troublesome side effect of dry mouth associated with oxybutynin.
Selectivity: slightly higher affinity for M1 and M3 receptors than for M2 receptors
Dosing: Immediate release and extended release formulations available, as well as a transdermal patch and gel formulations.
Transdermal delivery also alters oxybutynin metabolism, reducing N-desethyloxybutynin production to an even greater extent than OXY-ER, and is associated with much less dry mouth. Side effects include application site reaction pruritus and erythema
Adverse events:
Immediate release has high incidence of side effects (dry mouth, constipation, drowsiness, blurred vision)
Extended release version was developed to decrease liver metabolite formulation of N-desethyloxybutynin with the presumption that it would result in decreased side effects
A significant dose-response relationship for both urgency incontinence episodes and dry mouth.
Studies show no effect on ECG
May have negative effects on cognitive function, particularly in the elderly population but also in children
Metabolism: extensively metabolized by the liver (cytochrome P450) into its major active metabolite 5-HMT
5-HMT hasa similar pharmacologic profile as the mother compound and significantly contributes to the therapeutic effect of tolterodine.
5-HMT is metabolized in the liver, but a significant part of 5-HMT is excreted renally without additional metabolism
Selectivity: tissue selective (has selectivity for the bladder compared with the salivary gland) but no selectivity for muscarinic receptor subtypes.
Dosing: Available in immediate release and extended release formulations. The extended release form seems to have advantages over the immediate release form in terms of both efficacy and tolerability
Outcomes: significant improvement in frequency and incontinence episodes
Adverse events:
No effect on QT interval
Low incidence of cognitive effects (relatively low lipophilicity of tolterodine and even lesser one of 5-HMT imply limited propensity to penetrate into the CNS)
Metabolism: an orally active prodrug that is converted to the active metabolite 5-hydroxymethyl tolterodine (5-HMT)
All of the effects of fesoterodine are thought to be mediated via 5-HMT.
Selectivity: no selectivity for muscarinic receptor subtypes
Dosing: Recommended doses are 4 and 8 mg/day, with the 8-mg dose having a greater effect at the expense of a higher rate of dry mouth.
The suggested starting dose, 4 mg/day, can be used in patients with moderately impaired renal or hepatic function because of the combination of renal excretion and hepatic metabolism of 5-HMT
Adverse events:
Most common side effects are dry mouth, headache, and constipation
Metabolism: extensively metabolized by the liver (cytochrome P450)
Selectivity: relatively selective muscarinic M3-receptor antagonist; not necessarily tissue selective, because salivary glands and other tissues also contain M3 muscarinic receptors
Dosing: Developed as a controlled-release formulation, which allows once-daily administration; recommended doses are 7.5 and 15 mg/day
Outcomes: improves frequency, urgency, and incontinence episodes, but no improvement in nocturia
Adverse events:
Most common side effects are dry mouth and constipation
No effect on cognition, QT interval, or heart rate
Symptoms improve as early at 6 to 8 days from initiation
Metabolism: mainly eliminated unchanged in the urine; not metabolized by the cytochrome P450 enzyme
Darifenacin, solifenacin, fesoterodine, tolterodine, and oxybutynin, are all actively metabolized in the liver by the cytochrome P450 enzyme system. Trospium chloride is not metabolized to any significant degree in the liver
Selectivity: no selectivity for muscarinic receptor subtypes.
Dosing: Extended release formulation available
Outcomes: reduces nocturia
Adverse events:
Most common side effects are dry mouth, constipation, and headache
No negative cognitive effects (quaternary amines are expected to cross the blood-brain barrier to a limited extent)
Metabolized in the liver via multiple pathways, mainly by cytochrome P450
Subject to clinically relevant drug-drug interactions; should be used with caution in patients who are taking ketoconazole or other potent CYP3A4 inhibitors.
The mean increase (compared with placebo) in systolic and diastolic blood pressure after therapeutic doses of mirabegron once daily was ≈0.5-1 mm Hg and was reversible on discontinuation of treatment.
In the clinical efficacy and safety studies, the change from baseline in mean pulse rate for mirabegron 50 mg was ≈1 beat/min and reversible on discontinuation of treatment.
Tachycardia
Nasopharyngitis
Urinary tract infection
Headache
Constipation
Does not cause increase QT interval
Effects on HR and blood pressure need to be monitored when the drug is prescribed, even if the cardiovascular effects of mirabegron observed in clinical studies have been minimal and clinically not relevant
A neurotoxin produced bygram-positive Clostridium botulinum
7 subtypes; subtype A has the longest duration of action, making it the most relevant clinically.
Subtype A is available in different forms:
OnabotulinumtoxinA (onabotA) - Botox
AbobotulinumtoxinA (abobotA) - Dysport
IncobotulinumtoxinA (incobotA) - Xeomin
Although the toxin is the same, it is wrapped by different proteins that modify the relative potency of each brand.
Most of the information available about intravesical application of BoNTA derives from the use of onabotA (Botox).
Dysport associated with higher rates of need for clean intermittent self-catheterization
Clinical dose conversion studies for the LUT do not exist.
Mechanisms of action (4):
Inhibits release of acetylcholine from pre-synaptic cholinergic motor nerve endings by cleaving SNAP 25 and rendering the SNARE complex inactive, resulting in muscle paralysis
Acts on both striated muscle and smooth muscle
Striated muscle paralysis recovers within 2-4 months
Terminal axonal degeneration due to accumulation of neurotransmitter-containing synaptic vesicles
Inhibits the release of other neurotransmitters including ATP and neuropeptides such as substance P
Reduces afferent activity from bladder
Efficacy
RCTs have documented the clinical effects of onabotulinumtoxinA both in neurogenic detrusor overactivity and idiopathic detrusor overactivity, wherein the drug decreases incontinence episodes, frequency, and urgency and improves QoL.
Shown to be effective in patients with OAB.
Successful OAB treatment with BoNTA does not appear to be related to the existence of DO. No differences in outcomes were found between those with and those without baseline DO
Dosing: FDA-approved dose of 200U for neurogenic OAB§§
Not FDA-approved in non-neurogenic OAB patients, 100U typically used
Contraindications (4):
Active urinary tract infection
Acute urinary retention
Unwillingness or inability to self-catheterize
Hypersensitivity
Adverse events:
Most common (3):
Bladder pain
Gross hematuria (usually mild)
Urinary tract infection
Most serious (2):
Urinary retention and a transient necessity to perform CIC (≈5%)
Patient must be able and willing to return for frequent post-void residual evaluation and able and willing to perform self-catheterization if necessary
The proportion of patients who initiate CIC at any time during treatment cycle 1 was 6.1% versus none in the placebo group; for over half the patients who initiated CIC, the duration of CIC was 6 weeks or less.
Paralysis of the striated musculature caused by circulatory leakage of the toxin
Has never been reported.
Caution should be used in treating high-risk patients, including:
Children
Patients with low pulmonary reserve
Patients with myasthenia gravis
Transient muscle weakness was reported with abobotA application
Other:
Dry mouth
Dysphagia
Impaired vision
Eyelid weakness
Arm weakness
Leg weakness
Torso weakness
Aminoglycosides should be avoided during BoNTA treatment because they might block motor plates and therefore enhance BoNTA effect
Many factors seem to be involved in the pathogenesis of SUI: urethral support, vesical neck function, and function of the nerves and musculature of the bladder, urethra, and pelvic floor. Anatomic factors cannot be treated pharmacologically. However, women with SUI have lower resting urethral pressures than age-matched continent women
The pharmacologic treatment of SUI aims at increasing intraurethral closure forces by increasing the tone in the urethral smooth and striated muscles but relative lack of efficacy and/or side effects have limited their clinical use.
Antidepressants
Imipramine
Tricyclic antidepressant (TCA)
Mechanism of action: complex pharmacologic effects, including strong systemic anti-cholinergic activity and blockade of the reuptake of serotonin and noradrenaline, but its mode of action in DO has not been established; theoretically facilitates urine storage, both by decreasing bladder contractility and by increasing outlet resistance
Contraindications:
Concomitant use of monoamine oxidase inhibitors
Severe CNS toxicity can be precipitated, including hyperpyrexia, seizures, and coma
If any of the TCAs are prescribed for the treatment of voiding dysfunction, the patient should be thoroughly informed of the fact that this is not the usual indication for this drug and that potential side effects exist.
Imipramine is the only drug that has been widely used clinically to treat storage symptoms without good-quality RCTs that support is effectiveness
Has been known for a long time that imipramine can have favorable effects in the treatment of nocturnal enuresis in children.
Adverse events:
Most frequent side effects of TCAs are those attributable to their systemic anti-cholinergic activity
Therapeutic doses of TCAs may cause serious toxic effects on the cardiovascular system (orthostatic hypotension, ventricular arrhythmias).
Imipramine prolongs QTc.
Children seem particularly sensitive to the cardiotoxic action of TCAs.
It should be noted that data in the literature refer to therapeutic doses of these medications for depression and not the smaller (in comparison) doses of imipramine used for the treatment of voiding dysfunction.
Other adverse events include weakness, fatigue, hepatic dysfunction, allergic phenomena (including rash), obstructive jaundice, and agranulocytosis
Reports of significant side effects (severe abdominal distress, nausea, vomiting, headache, lethargy, and irritability) after abrupt cessation of high doses of imipramine in children would suggest that the drug should be discontinued gradually, especially in patients receiving high doses.
In a cat model, significantly increases sphincteric muscle activity during the filling and storage phase of micturition, and increased bladder capacity.
Lipophilic, well absorbed, and extensively metabolized by the liver
Has been shown to improve storage symptoms, but trials are lacking; may result in subjective more than objective improvements
Currently, duloxetine is licensed in the European Union for women with moderate to severe SUI. It is approved in the United States for treatment of a variety of disorders, but was withdrawn from the approval process for the treatment of SUI.
α-adrenergic agonists (e.g. ephedrine)
Hypogastric nerve stimulation and α-adrenergic agonists raise intraurethral pressure. These findings provide the rationale for use of α-adrenergic agonists to promote urine storage by increasing urethral resistance.
The use of peripheral α-adrenergic agonists has largely been abandoned because of the adverse effects associated with these agents and the weak evidence of efficacy compared with placebo
Phenylpropanolamine is associated with significantly increased risk of stroke in women
β-AR agonists and antagonists
Paradoxically, there are theoretic rationales for using both β-AR agonists and antagonists for treatment of SUI
β-AR stimulation is generally conceded to decrease urethral pressure, but β2-AR agonists have been reported to increase the contractility of striated muscle fibers.
Conversely, the blockade of urethral β-ARs by β-AR antagonists may enhance the effects of NA on urethral α-ARs.
There are few data suggesting significant efficacy.
There is currently no effective drug for male SUI.
Duloxetine has been evaluated in this context but usage of duloxetine for SUI in men is universally off-label.
Plus progesterone worsened urinary incontinence in older postmenopausal women with incontinence.
Plus progesterone increases the risk of de novo SUI and UUI in those continent at baseline
And progesterone increases the frequency of incontinence in those incontinent at baseline
Alone or with progestin increases the risk of de novo UI in postmenopausal women
Local (vaginal) estrogen
May improve OAB symptoms in postmenopausal women by treating urogenital atrophy
The vaginal route improves dryness, pruritus, and dyspareunia and provides a greater improvement in physical findings than oral administration.
Estrogen when given alone does not appear to be an effective treatment for SUI in the woman
Although many clinicians prescribe transvaginal estrogen or estrogen plus progestin cream for symptoms of OAB or/and SUI, there is no real evidence that vaginal estrogen, with or without progesterone, is useful in the treatment of urinary incontinence.
Progesterone and progestogens are thought to increase the risk of UI.
LUTS, especially SUI, have been reported to increase in the progestogenic phase of the menstrual cycle
Pharmacologic therapy to facilitate bladder emptyingedit
Decreasing Outlet Resistance at the Level of the Smooth Sphincteredit
Capable of reducing smooth muscle tone in the bladder outlet in both men and women and in the prostatic muscle.
Facilitate urine release in conditions of functionally increased urethral resistance, such as with BOO secondary to prostatic enlargement and bladder neck dysfunction
Urethral tone and intraurethral pressure are influenced by α-adrenergic receptors
Hypogastric nerve stimulation and α-adrenergic agonists raise intraurethral pressure, which is blocked by α1-adrenergic antagonists.
α1 and α2 adrenoceptors have been shown in the urethra
α2 receptors
More common than α1
α1 receptors
More important for adrenergically induced lower urinary tract smooth muscle contraction and prostate smooth muscle contraction.
Subtypes (3): α1A, α1B, and α1D
Structurally and pharmacologically distinct and have different tissue distributions
All mediate blood vessel dilation
A 4th subtype, α1L, also found in human prostate is derived from the same gene as the α1A subtype, but α1L and α1A receptors have different pharmacologic properties.
α1A adrenoceptor is the major subtype expressed in urethral smooth muscle and prostate and mediates their contraction
Although the α1A adrenoceptor is the major subtype in the prostate and urethra, highly selective α1A-adrenoceptor antagonists (e.g., RS-17053) do not alter LUTS scores in men with BPH, but are effective at relaxing prostate smooth muscle and increasing urine flow
In contrast, α1-adrenoceptor antagonists that contain α1D-adrenoceptor blocking activity improve bladder-based symptoms, suggesting the important role of the α1D-adrenoceptors for storage symptoms associated with BOO, and receptors potentially located at the bladder or the spinal cord
The contribution of α1D receptors to DO observed in a variety of pathologic conditions, including obstructive uropathy and incontinence, still needs to be established
An individual’s response to the different α1-AR antagonists may vary based on the expression level of α1-AR subtype mRNA in their prostate
The α1-blockers vary in their selectivity for the different subtypes
Selectivity for α1B-AR has been considered disadvantageous from a cardiovascular point of view
Considered effective for treatment of both storage and voiding symptoms in men with LUTS associated with bladder outlet obstruction secondary to benign prostatic enlargement.
However, in a study in which tamsulosin was given alone or together with tolterodine to patients with male LUTS and OAB symptoms, monotherapy with the drug was not effective.
In females, treatment of OAB symptoms with α1-blockers seems to be ineffective and may produce stress incontinence
Comparing different alpha-blockers:
In a trial comparing silodosin 8-mg to tamsulosin 0.4-mg to placebo, silodosin overall efficacy was not inferior to tamsulosin.
Only silodosin showed a significant effect on nocturia over placebo.
Terazosin and doxazosin require dose titration and blood pressure monitoring
Orthostatic hypotension
Headache
Nasal congestion
Retrograde ejaculation
Most often reported with silodosin and tamsulosin.
Silodosin is associated with higher rates of ejaculatory dysfunction (14%) compared to tamsulosin (2%). However, only 1.3% of silodosin-treated patients discontinued treatment because of this adverse event.
Can complicate cataract surgery by inducing sudden iris prolapse and pupil constriction during the surgery, known as "intraoperative floppy iris syndrome§
Tamsulosin has the highest risk for IFIS (40x that of alfusozin), but all alpha blockers increase the risk of IFIS to some degree.§
For every 255 men receiving tamsulosin in the immediate preoperative cataract surgical period, one serious complication (e.g., retinal detachment, lost lens or lens fragment, endophthalmitis) would result.§
When initiating alpha blocker therapy, patients with planned cataract surgery should be informed of the associated risk of intraoperative floppy iris syndrome risk and be advised to discuss these risks with their ophthalmologists, ideally with delay of medication initiation until after planned procedures.★
Discontinuation of tamsulosin 4 to 7 days prior to cataract surgery is routine practice, but it does not completely eliminate intraoperative floppy iris syndrome risk.★
Patients on several antihypertensives, or with orthostatic hypotension★
When treating patients on several antihypertensives, or with orthostatic hypotension, it is best to select an alpha blocker that exhibits minimal impact on blood pressure (eg, the highly selective alpha 1a blocker silodosin)§
The hypotensive effects of terazosin and doxazosin can be potentiated by concomitant use of a PDE5, such as sildenafil or vardenafil.★
Tamsulosin at a dose of 0.4 mg/day, however, does not appear to significantly potentiate the hypotensive effects of sildenafil.§
Regardless, patients utilizing both these medications should be counselled appropriately regarding the risk for drops in blood pressure and symptoms associated with this.§
With tamsulosin, caution may be required in patients with serious sulfonamide allergy§
Decreasing Outlet Resistance at a Site of Anatomic Obstructionedit
Type 1 5α-reductase is expressed primarily in the non-genital skin and liver, and to a lesser extent in the prostate, testis, and brain
Type 2 5α-reductase is expressed predominantly in the prostate epithelium and other genital tissues such as the epididymis, genitalia, seminal vesicle, testis, but also in liver, uterus, breast, hair follicles, and placenta
Finasteride inhibits type 2, dutasteride inhibits both type 1 and 2
895 men with some symptoms of urinary obstruction, an enlarged prostate gland on digital rectal examination, and maximal urinary-flow rates of less than 15 ml per second (with a voided volume of 150 ml or more).
Randomized to 3 arms: 1mg finasteride vs. 5mg finasteride vs. placebo once daily for 12 months
Results
The mean serum dihydrotestosterone concentrations decreased significantly in the two finasteride-treated groups (P<0.001) during the first two weeks of treatment and did not change thereafter
The decrease in serum dihydrotestosterone concentrations among the men who received 5 mg of finasteride daily was significantly greater than that among the men who received 1 mg of finasteride daily
In both finasteride-treated groups, serum testosterone concentrations increased approximately 8 to 10 percent after two weeks of treatment, and they remained increased thereafter.
Despite the increases, all values were within the normal range at all times.
Serum luteinizing hormone concentrations increased in all three groups during the first two months. However, the increases in both finasteride-treated groups were significantly higher than those in the placebo group
the men in both finasteride-treated groups had significant reductions in serum prostate-specific antigen for the comparison with the placebo group) at all times from month 3 through month 12 of treatment
The median decrease was 50 percent among the men who received 5 mg of finasteride and 48 percent among those who received 1 mg of finasteride.
Men treated with 5 mg of finasteride had a significant decrease in total symptom scores. The men treated with 1 mg of finasteride had no significant changes in the symptom scores.
During the 12 months of treatment, the maximal urinary-flow rates increased progressively in both finasteride-treated groups, but not in the group given placebo
During the first six months, the median size of the prostate decreased progressively in both finasteride-treated groups, after which it did not change significantly, and it was significantly smaller in both finasteride-treated groups than in the placebo group at all times. After 12 months of treatment, the prostate had shrunk by 19 percent from base line in the group given 5 mg of finasteride, by 18 percent in the group given 1 mg of finasteride, and by 3 percent in the group given placebo
Improves sensitivity of PSA and DRE for prostate cancer detection
Reduced risk of prostatitis
Reduced risk of acute urinary retention
Reduced risk of BPH-related surgical intervention
Decreasing Outlet Resistance at the Level of the Striated Sphincteredit
No class of pharmacologic agents that will selectively relax the striated musculature of the pelvic floor.
Injection of botulinum toxin into the striated sphincter has been used with some clinical success, especially in patients with neurologic striated sphincter dyssynergia.
The potential for spread to nearby structures is greater than with intravesical therapy, and distant effects can also occur, but these are rare
Increasing Intravesical Pressure and Bladder Contractilityedit
Currently no effective drug for the treatment of detrusor underactivity or underactive bladder
Parasympathomimetic agents
ACh, which stimulates bladder contraction, cannot be used for therapeutic purposes because of its action at both muscarinic and nicotinic receptors and it is rapidly hydrolyzed by cholinesterases.
Many ACh-like drugs exist, but only bethanechol chloride exhibits a relatively selective in vitro action on the urinary bladder and gut with little or no nicotinic action.
Bethanechol
Cholinesterase resistant
Causes an in vitro contraction of smooth muscle from all areas of the bladder.
Little evidence of its efficacy
At least in a "denervated" bladder, an oral dose of 200 mg is required to produce the same urodynamic effects as a subcutaneous dose of 5 mg.
Prostaglandins
Synthesized both locally in bladder muscle and mucosa
Synthesis initiated by various physiologic stimuli such as detrusor muscle stretch, mucosal injury, and neural stimulation; directly by adenosine triphosphate; and by mediators of inflammation.
Have been variably reported to be useful in facilitating bladder emptying with intravesical administration. Possible roles include:
Neuromodulators of efferent and afferent transmission
Sensitization
Activation of certain sensory nerves
Potentiation of acetylcholine (but not ATP) release from cholinergic nerve terminals through prejunctional prostanoid receptors.
Initial reports of the use of intravesical prostanoids producing lasting favorable clinical effects have not been confirmed.
Mechanism: drugs acting through the nitric oxide (NO)/cGMP system, such as PDE5 inhibitors, can relax the smooth muscle of the bladder outflow region and may improve urinary bladder blood perfusion
As monotherapy, PDE5 inhibitors significantly improve IPSS and International Index of Erectile Function (IIEF) scores, but not Qmax, when compared with placebo.
PDE inhibitors seem to improve subjective measurements but not objective ones, eg. Qmax
The mechanism behind the beneficial effect of the PDE inhibitors on LUTS and OAB and their site(s) of action largely remain to be elucidated.
Combination of PDE5 inhibitors and α-blockers led to significant improvements of the IPSS and IIEF scores as well as Qmax when compared with the use of α-blockers alone.
As of the time of Campbell’s writing, only tadalafil has been approved for the treatment of LUTS caused by benign prostatic obstruction (BPO)
There is insufficient information is available on the combination of PDE5 inhibitors with other LUTS medications such as 5α-reductase inhibitors.
225 men age >49 with moderate-to-severe symptoms of benign prostatic hyperplasia
Randomized to to one year of treatment with saw palmetto extract (160 mg twice a day) or placebo.
Primary outcome: changes in the scores on the American Urological Association Symptom Index (AUASI) and the maximal urinary flow rate.
Secondary outcome measures included changes in prostate size, residual urinary volume after voiding, quality of life, laboratory values, and the rate of reported adverse effects.
Results
No significant difference between the saw palmetto and placebo groups in the change in AUASI scores, maximal urinary flow rate, prostate size, residual volume after voiding, quality of life, or serum prostate-specific antigen
Analogue of the endogenous hormonevasopressin (also known as antidiuretic hormone).
Vasopressin
Functions (2):
Causes contraction of vascular smooth muscle
Stimulates water reabsorption from the collecting ducts
Release stimulated by:
Hyperosmolality
Hypovolemia
Stress
Nausea
Pregnancy
Hypoglycemia
Nicotine
Morphine
Other drugs
Release inhibited by:
Hypoosmolality
Hypervolemia
Ethanol
Phenytoin
Pharmacology
More powerful and longer-lasting antidiuretic action than vasopressin/anti-diuretic hormone due to selectivity for antidiuretic over vasopressor effects.
Fast onset of action, with urine production decreasing within 30 minutes of oral administration
Available in formulations for oral, parenteral, and nasal administration.
Because symptomatic hyponatremia with water intoxication, which is the only serious adverse event reported in children, occurred after intranasal or intravenous administration of desmopressin, the FDA and the European Medicines Agency (EMA) removed the indication for the treatment of primary nocturnal enuresis from all intranasal preparations of desmopressin.An oral lyophilisate formulation (MELT) requiring no concomitant fluid intake is currently available
Efficacy
Nocturia
Desmopressin is the most common vasopressin analogue used to treat nocturia in children and adults.
Decreased vasopressin levels are believed to be important in the pathophysiology of some forms of polyuria, specifically nocturnal polyuria.
Results in significant improvements in reducing nocturnal voids and increasing the hours of undisturbed sleep.
Generally well tolerated in all the studies on nocturia.
Enuresis
In children, effective in reducing bedwetting. However, there was no effect after discontinuation of treatment, indicating that desmopressin suppresses the symptom of enuresis but does not cure the underlying cause.
In addition, not all children responded sufficiently to desmopressin monotherapy.
The combination of desmopressin and an enuresis alarm resulted in a greatly improved short-term success rate and decreased relapse rates
Contraindications (drug monograph):
Patients with type IIB or platelet-type (pseudo) Willerbrand disease, because of the risk of platelet aggregation and thrombocytopenia
Any condition associated with impaired water excretion, such as:
Hyponatremia
Severe liver disease
[Hydro]nephrosis
Cardiac insufficiency
Chronic renal insufficiency
Congestive heart failure
Habitual or psychogenic polydypsia
Any medical conditions which lead to sodium losing states such as:
Vomiting
Diarrhea
Bulimia
Anorexia nervosa
Adrenocortical insufficiency
Salt losing nephropathies
Lactose intolerance/allergies
Adverse events
Hyponatremia
Can lead to a variety of adverse events ranging from mild headache, anorexia, nausea, and vomiting to loss of consciousness, seizures, and death
Usually occurs soon after treatment is initiated
Risk factors:
Increasing age
Female gender
Cardiac disease
Increasing 24-hour urine volume
Dosing
Females demonstrate increased sensitivity to demopression; recommended efficacious doses are 25 μg MELT for females and 50 to 100 μg MELT for males
Prior to initiation, a serum sodium should be obtained at baseline, then again after initiation. Serum sodium should be assessed regularly, at least every 6 months with long-term desmopressin administration
Initiation of desmopressin is currently not indicated for patients age ≥ 65 (different than CUA guidelines, see below)
2018 CUA MLUTS Guidelines
While the risk of hyponatremia is low in men with normal baseline serum sodium, sodium must be checked at baseline and 4–8 days as well as 30 days after initiation of treatment in (2):
All men taking desmopressin melts
Men ≥65 years taking 50 μg oral disintegrating tablet
Note that these guidelines are for male LUTS and therefore recommendations for females are not provided.
A yellowish tinge of the skin or sclera may indicate accumulation due to impaired renal excretion and the need to discontinue therapy
Urine discoloration
Patients should be informed that phenazopyridine produces a reddish-orange discoloration of the urine and may stain fabric.
GI disturbance
Rare but serious: methylglobinemia, hemolytic anemia, thrombocytopenia, neutropenia, nephrotoxicity, and hepatotoxicity, usually at overdosage levels
Dosing
200 mg three times daily after meals
Duration of treatment
When used concomitantly with an antibacterial agent for the treatment of a urinary tract infection, the administration of Phenazopyridine HCl should not exceed 2 days.[11]
American Hospital Formulary Service states that therapy may be extended for up to 15 days in non-infectious scenarios[12]
Another study found no difference in adverse drug reactions among patients receiving phenazopyridine for >14 days compared to a matched comparator group[13]
Mechanism of action: depresses monosynaptic and polysynaptic excitation of motor neurons and interneurons in the spinal cord by activating GABAB receptors.
Has been tried in idiopathic detrusor overactivity but with poor efficacy
Although there are theoretic mechanisms by which prostaglandin synthesis inhibitors could affect filling and storage symptoms, clinical evidence for this is scarce. The interest in the use of selective COX-2 inhibitors was tempered by concerns about long-term cardiovascular toxicity with these drugs.
Activation of detrusor muscle seems to require influx of extracellular Ca2+ through Ca2+ channels as well as via mobilization of intracellular Ca2+. The influx of extracellular calcium can be blocked by calcium antagonists, blocking L-type Ca2+ channels, and theoretically this would be an attractive way of inhibiting DO and regulating detrusor smooth muscle tone. Although these in vitro data suggest a possible role for calcium channel inhibitors, in the treatment of DO and incontinence, only limited clinical studies are available
Potassium channels contribute to the membrane potential of smooth muscle cells and hence to the regulation of smooth muscle tone. Despite promising preclinical efficacy data, potassium channel openers at present are not a therapeutic option and may never become one owing to a lack of selectivity for bladder over cardiovascular tissues
Population: 3047 men age ≥ 50 with IPSS 8-30, PSA ≤ 10 ng/mL, Qmax ≥4 but ≤15 ml/s with minimum voided volume ≥125 ml
Mean prostate volume: 36mL
Mean PSA: 2.4ng/mL
Randomized to placebo, doxazosin, finasteride, or combination therapy
Primary outcome: overall clinical progression, defined as the first occurrence of:
≥ 4 points increase from baseline AUA symptom score
Acute urinary retention
Renal insufficiency
Recurrent UTI
Urinary incontinence
Secondary outcomes: changes over time in the AUA symptom score and the maximal urinary flow rate
Results:
Mean follow-up: 4.5 years
Rate of overall clinical progression:
Placebo 4.5 per 100 person-years
Doxazosin: 2.7 per 100 person-years (P<0.001)
Finasteride: 2.9 per 100 person-years (P=0.002)
No difference between doxazosin alone vs. finasteride alone
Combination therapy: 1.5 per 100 person-years (P<0.001), a significantly greater reduction than doxazosin alone (P<0.001) or finasteride alone (P<0.001)
CombAT§
Population: 4844 men age ≥ 50 with a clinical diagnosis of BPH, IPSS ≥ 12,prostate volume ≥ 30g, PSA 1.5-10 ng/ml, Qmax >5 but ≤15 ml/s with minimum voided volume ≥125 ml
Mean prostate volume: 55mL (larger than MTOPS)
Mean PSA: 4.0ng/mL (higher than MTOPS)
Randomized to daily tamsulosin, dutasteride, or a combination of both (no placebo)
Primary end point: time to first AUR or BPH-related surgery
Secondary end points included BPH clinical progression, symptoms, Q(max), prostate volume, safety, and tolerability
BPH clinical progression defined as one of the following: symptom deterioration by International Prostate Symptom Score ≥4 points on two consecutive visits; BPH-related AUR; BPH-related urinary incontinence; recurrent BPH-related urinary tract infection or urosepsis; BPH-related renal insufficiency
Results:
Combination therapy was significantly better than tamsulosin monotherapy but not dutasteride monotherapy at reducing the relative risk of AUR or BPH-related surgery
Combination therapy was significantly superior to both monotherapies at reducing the relative risk of BPH clinical progression
Combination therapy provided significantly greater symptom benefit than either monotherapy at 4 yr.
Summary of evidence for combination alpha-blockers and 5-ARIs from these trials:
Combination better reduces risk of clinical progression and symptoms benefit at 4 years
Monotherapy with 5-ARI and alpha-blockers are equally effective in risk of overall clinical progression
5-ARI reduces risk of AUR or BPH-related surgery, addition of tamsulosin does not increase benefit
Several RCTs have demonstrated that the combination treatment of anti-cholinergics and α1-blockers was more effective at reducing male LUTSthan α1-blockers alone in men with OAB and coexisting bladder outlet obstruction
α1-blockers and anti-cholinergics may have an additional synergistic effect on the bladder in the neurogenic population. This suggests that targeting multiple receptors may maximize the effectiveness of pharmacologic treatment of neurogenic bladder and should be considered in patients in whom treatment with antimuscarinics alone fails
Mirabegron combination therapy with solifenacindemonstrated greater efficacy than solifenacin alone on voided volume and micturition frequency.
The enhanced efficacy with the combination was of a magnitude that is probably similar to the enhanced efficacy one might expect from uptitrating the dose of the anti-cholinergic. However, the combination was not associated with the adverse effects one would expect to encounter with higher doses of antimuscarinics.