General Pharmacological Treatment-Urethra

1. Concept

  • The pharmacological treatment for the urethral dysfunction in SCI/D is generally very limited due to a lack of clinical efficacy and tolerability.
  • The need for the functional adjustment of the altered bladder outlet resistance is essential in the SCI/D.
    • Increased bladder outlet resistance caused by DSD, especially in the suprasacral SCI/D, is highly likely predispose to the upper tract deterioration.
    • Decreased outlet resistance is also a problematic in certain situations since it commonly results in urinary incontinence that is a really serious problem in males or females with  SCI/D lesions involving the thoracolumbar outflow.      
  • Various pharmacologic treatments can be applied to urethral dysfunction due to SCI/D. Among the various agents are briefly introduced below.  
  • For more information, please refer to this and this

2. Pharmaceutical Agents

  • Decreasing outlet obstruction
    • α-Adrenergic antagonists
    • Skeletal muscle relaxants
    • Others
  • Increasing outlet obstruction
    • α-Adrenergic agonists
    • Tricyclic antidepressants     
    • Others       

Alpha-adrenergic Antagonists

1. Basic Concept

  • Drugs which influence urethral resistance are an important part of treatment of SCI bladder.
  • Smooth muscle of the bladder base and proximal urethra contains predominantly α-adrenergic receptors.
  • Alpha receptors are present in the entire detrusor, and in structural obstruction, or obstruction associated with neural disease or injury, they become active, contributing to altered compliance, and to a progressive loss of bladder capacity. This means that the effects of alpha blocking agents in neurological conditions are complex and may be more related to detrusor effects than outlet effects.
  • There is also the possibility that certain excitatory aspects of the micturition reflex may involve central α1 -adrenergic receptors [Andersson 2000]

2. Mechanism of actions

  • Affecting the smooth muscle of the bladder neck and proximal urethra
  • Direct inhibitory effect on the striated sphincter: decreasing striated sphincter tone
    • An alpha-adrenergic blocking agent, phentolamine, reduced the external sphincter EMG activity in 3 paraplegic patients [Nanninga 1977]
    • Phenoxybenzamine seems to effect on the central part of the striated urethral sphincter innervation in 5 normal women [Nordling 1981]
    • Alpha-adrenoceptor antagonists and especially prazosin inhibited external sphincter through an action in the central nervous system [Gajewski 1984]
  • Decreasing bladder contractility: contribute storage function

3. Pharmaceutical Agents

1) Older agents

  • Phenoxybenzamine (Dibenzyline)
      • Nonselective alpha-adrenergic blockade [Hoffman 1990]; phenoxybenzamine combines irreversibly with postganglionic alpha-adrenergic receptor sites, preventing or reversing effects of endogenous or exogenous catecholamines
      • Side effects affect approximately 30% of patients: orthostatic hypotension, reflex tachycardia, nasal congestion, diarrhea, miosis, sedation, nausea, and vomiting (secondary to local irritation).
      • mutagenic activity: peritoneal sarcomas, lung tumors [Hoffman 1990] and gastrointestinal tumors in animals but no clinically apparent oncologic associations
    • Prazosin hydrochloride (Minipress)
      • first potent selective α1 antagonist used to lower outlet resistance.
      • The duration of action: 4-6 hours
      • “first-dose phenomenon”: faintness, dizziness, palpitation, and, infrequently, syncope, thought to be caused by acute postural hypotension.

2) Newer agents

    • Commercially available agents
      • Terazosin (Hytrin®) 2mg, 5mg and etc.
      • Doxazosin (Cardura®) 1mg, 2mg, 4mg, 8mg
      • Alfuzosin (Uroxatral®) 10mg
      • Tamsulosin (Flomax®) 0.4mg
    • Common pharmacological features
      • highly selective postsynaptic α1 blockers
      • administered once daily and without titration (tamsulosin)
    • Common side effects:
      • More common side effects: peripheral vasodilatation (postural hypotension), dizziness, drowsiness, fatigue, headache
      • Less common side effects: Abdominal pain, abnormal vision, arthritis, constipation, depression, diarrhea, difficulty sleeping, dry mouth, eye pain, fluid retention, flu-like symptoms, flushing, gas, increased sweating, inability to hold urine or other urination problems, indigestion, inflammation of conjunctiva (pinkeye), itching, flushes, joint pain, lack of muscle coordination, low blood pressure, motion disorders, muscle cramps, muscle pain, muscle weakness, nasal stuffiness, nausea, nervousness, nosebleeds, pain, rash, ringing in ears, shortness of breath, thirst, tingling or pins and needles, weakness

5. Indication, Contraindications, Caution, Adverse Effects, Drug Interactions

6. Clinical Outcomes

  • α-Adrenergic blocking agents have also been used to treat both bladder and outlet abnormalities in patients with myelodysplasia, sacral spinal cord or infrasacral neural injury [Norlen 1982].

Author (Year)

Method

Results

Comments

Krane RJ, Olsson CA. [J Urol 1973]

phenoxybenzamine 10-30mg/day

6 patients with neurogenic bladder related to bladder neck dysfunction

Voiding was established in all patients

Orthostatic hypotension managed by elastic stockings

first report on the effect of alpha blocker on the neurogenic bladder 

Chancellor MB, Erhard MJ, Rivas DA. [J Am Paraplegia Soc. 1993]

in 15 SCI patients with DSD treated with external sphincterotomy

9 patients suffered from persistent difficulty voiding after previous sphincterotomy subsequently managed by terazosin

Urodynamic testing

5 patients who improved with terazosin, urodynamic parameters demonstrated obstruction only at the bladder neck

4 patients failed to improve were documented to have an open bladder neck but obstruction at the level of the external sphincter

Terazosin had little or no effect on striated sphincter function in SCI patients

No effect on functional obstruction caused by DSD

Bennett JK, Foote J, El-Leithy TR, Saleem MD, Green B, Archer CL, Gray M. [Mol Urol. 2000]

60 SCI male patients

Terazosin 10 mg/day

prospective study

videourodynamic study

significant decrease in the maximum detrusor pressure (from a mean of 105.3 to 73.9 cm H2O),

significant decrease in MUGP (from a mean of 84.7 to 54.1 cm H2O)

bladder capacity and PVR did not change significantly

Terazosin was well tolerated and effective in reducing bladder outlet obstruction in many SCI patients

Terazosin should be considered a first-line treatment prior to contemplating surgery.

Abrams P, Amarenco G, Bakke A, Buczynski A, Castro-Diaz D, Harrison S, Kramer G, Marsik R, Prajsner A, Stohrer M, Van Kerrebroeck P, Wyndaele JJ; European Tamsulosin Neurogenic Lower Urinary Tract Dysfunction Study Group. [J Urol. 2003]

efficacy and safety of tamsulosin

patients with neurogenic lower urinary tract dysfunction secondary to suprasacral SCI/D

4-week randomized controlled trial and long term open label trial

significant mean decrease in MUP

decreased MUCP

improved several cystometry parameters related to bladder storage and emptying,

increased mean voided volume

significant improvement for the IPSS Quality of Life, symptoms of AD

71% of patients improved

well tolerated

Long-term tamsulosin treatment (0.4 and 0.8 mg once daily) seems to be effective and well tolerated in patients with neurogenic lower urinary tract dysfunction.

it improves bladder storage and emptying, and decreases symptoms of AD.

Perrigot, M., Delauche-Cavallier, M. C., Amarenco, G., Geffriaud, C., Stalla-Bourdillon, A. and Costa, P.[Neurourol Urodyn, 1996]

single intravenous (i.v.) injection of alfuzosin

163 patients with symptomatic neurogenic bladder dysfunction and high urethral tone

a double-blind, placebo-controlled, parallel-group trial

significant decrease in urethral pressure in a dose-related manner

It may be safely used as a pharmacological test as part of an urodynamic investigation.

Yasuda K, Yamanishi T, Kawabe K, Ohshima H, Morita T. [J Urol. 1996]

prospective double-blind trial

136 neurogenic bladder patients

urapidil (alpha blocker)

Urinary frequencies decreased

The sum of obstructive symptom scores decreased

flow rates, and residual urine improved

pressure at maximum flow rate and minimum urethral resistance decreased

Side effects noted but not severe.

Urapidil improved voiding dysfunction in patients with a neurogenic bladder and decreased urethral resistance in a dose related fashion.

7. Current Significance in SCI

  • α-Adrenergic blocking agents might have effects on varied types of voiding dysfunction—functional outlet obstruction, urinary retention, decreased compliance, and detrusor instability/hyperreflexia.
  • Results with non–BPH-related voiding dysfunction have been less remarkable.

Alpha adrenergic agonist

  • pseudoephedrine is not FDA-approved for treating overactive bladder or stress urinary incontinence.

1. Basic Concept

  • Bladder neck and proximal urethra contain abundant alpha1 receptors. Smooth muscle in these areas contract when the alpha receptors are stimulated.   

2. Mechanism of actions:

3. Pharmaceutical Agents and Adverse Effects

  • Agents
    • Ephedrine:
      • noncatecholamine sympathomimetic agent
      • Directly stimulates both alpha and beta receptors
      •  25-50mg po qid (adult dosage)
    • Pseudoephedrine
      • Stereoisomer of ephedrine
      • 30-60mg po qid
  • Potential side effects:
    • hypertension, palpitation, cardiac arrhythmia, respiratory difficulties.
    • anxiety, insomnia (CNS stimulation), headache, tremor, weakness,
  • Should be used cautiously in patients with hypertension, cardiovascular diseases, hyperthyroidism.

4. Clinical Outcomes

Author (Year)

Method

Results

Comments

Castleden CM, Duffin HM, Briggs RS, Ogden BM. [J Urol. 1982]

24 elderly patients with urinary incontinence associated with unstable detrusor contractions.

After 3 weeks of treatment, repeat cystometry was performed

Mean increases of 21% in bladder capacity and of 23% in urethral pressure.
 
Of 21 patients studied 7 became continent and 12 were improved.

The urodynamic improvement did not reach statistical significance even in the continent group.

The clinical improvement was unlikely to be owing to ephedrine.

Diokno AC, Taub M. [Urology. 1975]

38 patients with sphincteric incontinence treated with ephedrine

Good to excellent results in 71% of patients.

Little benefit in patients with severe stress urinary incontinence

Obrink A, Bunne G. [Scand J Urol Nephrol. 1978]

Norephedrine chloride 100 mg po bid

Measurement of the urethal closure pressure at rest and in a dynamic situation before and after three weeks of treatment

10 severely stress-incontinent women

No improvement

 

Alpha stimulation seems ineffective in severe stress incontinence and is not an alternative to surgical treatment.

5. Current Significance in SCI

  • Efficacy not fully proven
  • Be cautious in using these agents for potential side effects                       

Skeletal Muscle Relaxant

1. Basic Concept

  • A few alpha blockers have been tried on the basis of their potential effectiveness on the striated muscle. However, with no proven clinical success.  
  • Medical therapy for a DSD has not been demonstrated to be significantly effective.

2. Pharmaceutical Agents, Clinical Outcomes and Adverse Effects

  • Diazepam
    • Mechanism: GABA channel activator, centrally acting muscle relaxant   
    • Dosage: 4-40mg/d
    • Effects: ineffective for treating DSD
    • Side Effects: Dizziness, drowsiness, extrapyramidal effects, ataxia, agranulocytosis, sedation
  • Dantrolene
    • Effects: ineffective for treating DSD
    • Side effects: fatal hepatotoxicity
  • Baclofen               
    • Indication: extremity spasticity with DSD
    • Mechanism: GABA-b channel activator (?), exact mechanism unknown; centrally acting muscle relaxant
    • Dosage: 75- 120mg/d
    • Side Effects: CNS depression, cardiovascular collapse, respiratory failure, seizures, dizziness, weakness, hypotonia, constipation, blurred vision
    • Intrathecal administration of baclofen via an implanted pump [Steers 1992; Bushman 1993]
      • adverse effects are primarily limited to the CNS
      • increase in bladder capacity
      • improvement in compliance
      • DSD abolished in 40% of the patients
  • Clonidine
    • Effects: were reported in 4 of 5 patients with external DSD in 1991
    • Limitations: no further followup series

Author (Year)

Method

Results

Comments

Bushman W, Steers WD, Meythaler JM. [Neurourol Urodyn. 1993]

three men with hereditary spastic paraplegia (HSP) showing urgency or urge incontinence, involuntary detrusor contractions, DSD
 and diminished bladder compliance

urodynamic evaluation and response to continuous intrathecal baclofen

All patients reported marked symptomatic improvement.

 

4. Current Significance in SCI

  • There is no selective pharmacological agent that is specific for the rhabdosphincter and pelvic floor musculature. 

Tricyclic Antidepressants

1. Mechanism of actions: increasing bladder outlet resistance

  • Pharmacologic actions on the outlet at a local level:
    • Sympathomimetic
    • Enhanced α-adrenergic effect in the smooth muscle of the bladder base and proximal urethra
  • Pharmacologic actions on the outlet at a central level:
    • Centrally mediates increase in bladder capacity

2. Name of agents

  • Imipramine (Tofranil)
  • Duloxetine
    • Combined serotonin and norepinephrine reuptake inhibitor
    • Duloxetine facilitates sphincter contraction during bladder filling but not during bladder contraction in micturition [Thor 2003]

3. Dosage, Contraindications, Caution, Adverse Effects, Drug Interactions and Comments

4. Clinical Outcomes

Author (Year)

Method

Results

Comments

Lin HH, Sheu BC, Lo MC, Huang SC. [Br J Obstet Gynaecol. 1999]

A prospective study involving 40 women with genuine stress incontinence

imipramine 25 mg po tid for 3 months.

pad test and urodynamic study

Successful treatment in 60% of patients
 
Functional urethral length and urethral closure pressure significantly improved in the treatment success group

The pre-treatment high urethral closure pressure may serve as a predictor for treatment success.

Millard RJ, Moore K, Rencken R, Yalcin I, Bump RC; Duloxetine UI Study Group. [BJU Int. 2004]

a double-blind, placebo-controlled phase 3 multinational study

227 women aged 27-79 years with stress urinary incontinence

duloxetine 40 mg po bid for 12 weeks

incontinence episode frequency and the Incontinence Quality of Life questionnaire

Discontinuation rates for adverse events 17.2%

Nausea being the most common reason for discontinuation (3.1%)

 

improvements in incontinence and quality of life

5. Current Significance in SCI

  • Clinical data solely regarding the effect on the urethral sphincteric function in the nuerogenic bladder are not available. Most data have been from non-neurogenic stress urinary incontinence.
  • Many clinicians use tricyclic antidepressants for primary purpose on the effects for the bladder in patients with bladder overactivity with some component of sphincteric incontinence.

Key Points of This Medication

  • Alpha blocking agents are useful in SCI/D to improve bladder capacity and compliance. . This effect does not seem to be an outlet effect as clinically significant decreases in outlet resistance have not been achieved with these agents in patients with DSD
  • Alpha blocking agents are also useful to treat autonomic dysreflexia.
  • Sympathomimetic agents are not very useful in patients with SCI/D.

References

  • Abrams P, Amarenco G, Bakke A, Buczynski A, Castro-Diaz D, Harrison S, Kramer G, Marsik R, Prajsner A, Stohrer M, Van Kerrebroeck P, Wyndaele JJ; European Tamsulosin Neurogenic Lower Urinary Tract Dysfunction Study Group. Tamsulosin: efficacy and safety in patients with neurogenic lower urinary tract dysfunction due to suprasacral spinal cord injury. J Urol. 2003 Oct;170(4 Pt 1):1242- 51.   
  • Andersson KE. Mode of action of alpha1-adrenoreceptor antagonists in the treatment of lower urinary tract symptoms. BJU Int. 2000 Apr;85 Suppl 2:12-8.
  • Bennett JK, Foote J, El-Leithy TR, Saleem MD, Green B, Archer CL, Gray M. Terazosin for vesicosphincter dyssynergia in spinal cord-injured male patients. Mol Urol. 2000;4(4):415-20.
  • Bushman W, Steers WD, Meythaler JM. Voiding dysfunction in patients with spastic paraplegia: urodynamic evaluation and response to continuous intrathecal baclofen. Neurourol Urodyn. 1993;12(2):163-70.
  • Castleden CM, Duffin HM, Briggs RS, Ogden BM. Clinical and urodynamic effects of ephedrine in elderly incontinent patients. J Urol. 1982 Dec;128(6):1250-2.                                          
  • Chancellor MB, Erhard MJ, Rivas DA. Clinical effect of alpha-1 antagonism by terazosin on external and internal urinary sphincter function. J Am Paraplegia Soc. 1993 Oct;16(4):207-14.
  • Diokno AC, Taub M. Ephedrine in treatment of urinary incontinence. Urology. 1975 May;5(5):624-5.                                             
  • Gajewski J, Downie JW, Awad SA. Experimental evidence for a central nervous system site of action in the effect of alpha-adrenergic blockers on the external urinary sphincter. J Urol. 1984 Aug;132(2):403-9.
  • Hoffman BB, Lefkowitz RJ. Adrenergic receptor antagonists. In: Gilman AG, Rall TW, Nies AS, Taylor P, eds. The pharmacological basis of therapeutics. New York: Pergamon Press, 1990; 221-5.
  • Krane RJ, Olsson CA. Phenoxybenzamine in neurogenic bladder dysfunction. II. Clinical considerations. J Urol. 1973 Dec;110(6):653-6.                                               
  • Lin HH, Sheu BC, Lo MC, Huang SC. Comparison of treatment outcomes for imipramine for female genuine stress incontinence. Br J Obstet Gynaecol. 1999 Oct;106(10):1089-92.              
  • Millard RJ, Moore K, Rencken R, Yalcin I, Bump RC; Duloxetine UI Study Group. Duloxetine vs placebo in the treatment of stress urinary incontinence: a four-continent randomized clinical trial. BJU Int. 2004 Feb;93(3):311-8.
  • Nanninga JB, Kaplan P, Lal S. Effect of phentolamine on perineal muscle EMG activity in paraplegia. Br J Urol. 1977 Nov;49(6):537-9.
  • Nordling J, Meyhoff HH, Hald T. Sympatholytic effect on striated urethral sphincter. A peripheral or central nervous system effect? Scand J Urol Nephrol. 1981;15(3):173-80.
  • Norlen L. Influence of the sympathetic nervous system on the lower urinary tract and its clinical implications. Neurourol Urodyn 1982;1:129-33.
  • Obrink A, Bunne G. The effect of alpha-adrenergic stimulation in stress incontinence. Scand J Urol Nephrol. 1978;12(3):205-8.                               
  • Perrigot M, Delauche-Cavallier MC, Amarenco G, Geffriaud C, Stalla-Bourdillon A, Costa P. Effect of intravenous alfuzosin on urethral pressure in patients with neurogenic bladder dysfunction. DORALI Study Group. Neurourol Urodyn. 1996;15(2):119-31.                              
  • Steers WD, Meythaler JM, Haworth C, Herrell D, Park TS. Effects of acute bolus and chronic continuous intrathecal baclofen on genitourinary dysfunction due to spinal cord pathology. J Urol. 1992 Dec;148(6):1849-55.
  • Thor KB. Serotonin and norepinephrine involvement in efferent pathways to the urethral rhabdosphincter: implications for treating stress urinary incontinence. Urology. 2003 Oct;62(4 Suppl 1):3-9.
  • Yasuda K, Yamanishi T, Kawabe K, Ohshima H, Morita T. The effect of urapidil on neurogenic bladder: a placebo controlled double-blind study. J Urol. 1996 Sep;156(3):1125-30.

 

 

©2018 University of Michigan - Tx

Home Link to UMHS