Fig. 6.1
Direct (bethanechol) and indirect (distigmine) agonist treatment of underactive bladder
Current approaches toward medical treatment of UAB aim at providing additional stimulation of bladder muscarinic receptors. This can be done by a direct stimulation of muscarinic receptors by agonists such as bethanechol or carbachol. Alternatively, it can be done by inhibiting acetylcholinesterase, the enzyme inactivating the endogenous agonist acetylcholine. Common cholinesterase inhibitors include distigmine, pyridostigmine, and neostigmine (Tyagi et al. 2014). The latter approach depends on the presence of at least some endogenous acetylcholine, the effects of which can be amplified by inhibiting its breakdown by the cholinesterase inhibitor.
The most attractive feature of the use of direct muscarinic receptor agonists is that it does not require the presence of endogenous acetylcholine to be effective. One should remember that in order for muscarinic stimulation or cholinesterase inhibition to have a chance to work, it depends on some degree of preserved responsiveness to acetylcholine in the bladder wall.
Muscarinic Mechanisms
There are five bladder muscarinic receptor subtypes based on molecular cloning and four different receptor subtypes based on pharmacology (M1 to M5) (Yoshimura and Chancellor 2011; Yamaguchi et al. 1996). Ligand receptor binding studies revealed that M2 receptors predominate but it is mostly M3 receptors that mediate cholinergic contractions in the urinary bladder. Muscarinic receptors are also located on the bladder on cholinergic nerve terminals prejunctionally (Yoshimura and Chancellor 2011; Somogyi and de Groat 1992).
M1 prejunctional receptor activation will facilitate acetylcholine release. whereas activation of M2 receptors inhibits the release (Somogyi and de Groat 1992; Braverman, Kohn et al. 1998). It has been proposed that inhibitory M2–M4 receptors are preferentially activated by auto-feedback mechanisms during short periods of low-frequency nerve activity and thereby suppress cholinergic transmission during urine storage (Somogyi and de Groat 1992). M1 receptors are activated during more prolonged high-frequency nerve firing that would occur during voiding. M1 receptors participate in an amplification mechanism to promote complete bladder emptying (Somogyi et al. 1996; Tyagi et al. 2014). The ability to modulate neurotransmission in the bladder through the selective activation and inhibition of specific presynaptic receptors may lead to novel forms of pharmacologic therapy for UAB.
Clinical Results of Muscarinic Agents for UAB
Available data show little beneficial effect of parasympathomimetic agents in treating or preventing UAB (Barendrecht et al. 2007; Krishnamoorthy and Kekre 2009). The main reason why these agents are approved by regulatory agencies in many countries for treating UAB is that such registration was typically obtained many years ago prior to requirement of randomized clinical trials.
Table 6.1 lists the randomized clinical trials on the use of muscarinic agents to treat UAB. The table is a modification and update of the excellent work by Barendrecht et al. (2007) who published a systematic review of randomized clinical trials on muscarinic agents to treat UAB. The study was independently evaluated by two investigators and scored for its technical quality and evidence level, according to the Oxford Centre for Evidence-Based Medicine (2001).
Table 6.1
Current drug treatment of underactive bladder
Treatment | Indication | Patients # | Endpoint | Did drug help | Results | Evidence level | Reference |
|---|---|---|---|---|---|---|---|
Bethanechol 50 mg × 3 oral from 3 days after surgery, vs. no treatment | Prophylaxis of detrusor hypotonia after radical hysterectomy | 40 | Hospital stay, catheter treatment, rate of cystitis, and residual urine | Yes | Hospital stay 18.6 vs. 15.5 days; catheter treatment 13.3 vs. 9.6 days; rate of cystitis 25.0 vs. 18.8 %; residual urine <50 mL after 13 vs. 8 days for no treatment vs. bethanechol; all differences p < 0.01 | 2b | Kemp et al. (1997) |
Bethanechol 25, 50 or 100 mg × 1 oral vs. placebo 60 min before urodynamic investigation | Women with persistent high residual urine but no sign of neurological disease or outlet obstruction | 48 | Urodynamic parameters | No | No significant difference between groups for voided volume, residual volume, % residual volume, mean flow rate, and intravesical pressure | 2b | Barrett (1981) |
Bethanechol 15 mg every 4 h (6 doses) vs. no treatment | Prevention of acute urinary retention postpartum | 1,796 | Catheterization and residual volume | No | No significant difference between both groups | 2b | Fleming (1957) |
Bethanechol 25 mg × 1 oral vs. placebo for 2 weeks in cross-over design | Treatment of underactive bladder | 16 | Urodynamic parameters | Yes | Significant reduction of residual urine and increase in max urinary flow vs. placebo (p < 0.02 and <0.03), detrusor pressure tended to increase | 1b | Riedl et al. (2002) |
Bethanechol 4 × 50 mg daily oral + intravesical PGE2 × 1/week vs. placebo for 6 weeks | Treatment of underactive bladder | 19 | Residual urine volume | Inconclusive | Relative to baseline statistically significant reduction with active treatment but not with placebo, but effect size judges as ”limited therapeutic effect” by investigator | 1b | Hindley et al. (2004) |
Bethanechol 20 mg tid vs. placebo | Prevention of underactive bladder after radical hysterectomy | 62 | Rate of urethral catheter removal at 1 week post surgery | Yes | 67.7 % in treatment group vs. 38.7 % in placebo group had catheter removal at 1 week postoperatively (p = 0.04). Residual urine volume and infection at 1 month were similar between groups | 2b | Manchana and Prasartsakulchi (2011) |
Cholinesterase inhibitor | |||||||
Distigmine 0.5 mg i.m. × 1 for 4 days vs. placebo | Treatment of acute urinary retention after prostatectomy | 93 | Flow rates and re-catheterization rate | No | No significant difference between groups | 2b | Shah et al. (1983) |
Combination therapy | |||||||
Carbachol/diazepam 2 mg each vs. alfuzosin 2.5 mg vs. placebo, all 1 × oral | Treatment of acute urinary retention after general surgery | 249 | Voiding within 2 h after medication | No | No significant difference between groups | 2b | Burger et al. (1997) |
Bethanechol 10 mg × 1 s.c. vs. midazolam vs. combination vs. placebo | Treatment of acute urinary retention after anorectal surgery | 132 | Incidence of catheterization | Yes | 0 vs. 69 % responders for placebo and bethanechol (p = 0.05) irrespective of other treatments | 2b | Gottesman et al. (1989) |
Bethanechol 20 mg × 3 or distigmine 5 mg × 3 oral vs. urapidil 30 mg × 2 vs. combined for 4 weeks | Treatment of underactive bladder | 119 | Urinary flow rate, post-void residual volume, and symptom scores | No | No significant effect of cholinergic agonists vs. baseline
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