Drugs with a negative impact on cognitive function (Part 1): chronic kidney disease as a risk factor.

People living with chronic kidney disease (CKD) frequently suffer from mild cognitive impairment and/or other neurocognitive disorders. This review in two parts will focus on adverse drug reactions resulting in cognitive impairment as a potentially modifiable risk factor in CKD patients. Many patients with CKD have a substantial burden of comorbidities leading to polypharmacy. A recent study found that patients seen by nephrologists were the most complex to treat because of their high number of comorbidities and medications. Due to polypharmacy, these patients may experience a wide range of adverse drug reactions. Along with CKD progression, the accumulation of uremic toxins may lead to blood-brain barrier (BBB) disruption and pharmacokinetic alterations, increasing the risk of adverse reactions affecting the central nervous system (CNS). In patients on dialysis, the excretion of drugs that depend on kidney function is severely reduced such that adverse and toxic levels of a drug or its metabolites may be reached at relatively low doses, unless dosing is adjusted. This first review will discuss how CKD represents a risk factor for adverse drug reactions affecting the CNS via (i) BBB disruption associated with CKD and (ii) the impact of reduced kidney function and dialysis itself on drug pharmacokinetics.

The effect of diabetes mellitus on α1-adrenergic receptor subtypes in the bladder of rats.

OBJECTIVE: To detect the possible alterations on density or sensitivity of α1-adrenergic subtypes in diabetic bladder by reverse transcriptase-polymerase chain reaction technology and in vitro studies. METHODS: Experimental diabetes was induced by administration of streptozotocin with a single injection through the tail vein. Rats were divided into control and diabetic groups. Contractile responses of bladder strips from each group were obtained for postassium chloride, adenosine triphosphate, and electrical field stimulation (0.5-32 Hz) in organ bath. Electrical field stimulation responses of strips were evaluated in the presence of PPADS (nonselective P2 antagonist), atropine (cholinergic antagonist), 5 MU (α-1a-adrenergic antagonist), BMY-7378 (α-1d-adrenergic antagonist), and finally CED (α-1b-adrenergic antagonist). mRNA expression of α1-adrenergic subtypes was determined for each group. RESULTS: The difference between contractile responses related to electrical field stimulation with incubation with PPADS, atropine, 5 MU, BMY-7378, and CED, respectively, was not significant in the control and diabetic groups (P > .05). The electrical field stimulation responses of strips at 0.5-2 Hz without incubation were significantly different between the control and diabetic groups (P < .05). The contractile responses of strips with PPADS + atropine + 5 MU and BMY-7378 incubations in the diabetic group were significantly lower than in the control group in all doses (P < .05), The mRNA expression of α-1a-adrenergic in the diabetic group was significantly lower than in the control group (P < .05). No change was found in the expression of mRNA of α-1b-adrenergic. CONCLUSION: These results support the probability of changes in presynaptic and autonomic receptor sensitivity. We believe that α-1a-adrenergic and α-1d-adrenergic subtypes should be kept in mind in the treatment of diabetic cystopathy.

Alteration in contractile responses in human detrusor smooth muscle from obstructed bladders with overactivity.

INTRODUCTION: In this study, we aimed to evaluate changes in contractile responses under in vitro conditions in detrusor overactivity (DO) in patients with bladder outflow obstruction (BOO). MATERIALS AND METHODS: Detrusor strips obtained during open prostatectomy procedure from 16 patients with BOO related to benign prostate hyperplasia were evaluated under in vitro conditions. Patients were assigned to two groups as patients with (DO) and without (no DO) DO. Four detrusor strips were prepared from each bladder in dimensions of 2 x 10 mm, and were suspended in organ bath. Responses to carbachol (10(-8) to 10(-3)M), electrical field stimulation (EFS) (0.5-32 Hz), single-dose adenosine 5'-triphosphate (ATP) (10(-3)M) and KCl (120 mM) were recorded to evaluate the contractile responses. EFS responses were repeated in the presence of NG-nitro-L-arginine methyl ester (L-NAME; 10 muM) and L-NAME + indomethacin. All responses were expressed as mg tension developed per mg of bladder tissue. Data obtained were compared using independent t test and one-way ANOVA test. Values of p < 0.05 were accepted as statistically significant. RESULTS: Of the 16 patients on whom open prostatectomy was performed because of BOO, 8 of the patients were determined as no DO and 8 as DO. There were no differences between groups regarding age and residual urine. We found statistically significant differences between groups regarding dimensions of prostate, maximum bladder capacity and maximum bladder pressure. In the comparison of cumulative dose of carbachol, it was seen that responses were higher in the DO group, but the differences were not statistically significant. In EFS application, contractile responses were found to increase significantly in the DO group. No changes were observed between groups for ATP and KCl. EFS responses were found to be significantly higher in presence of L-NAME + indomethacin in the no DO group; however, no difference was seen in the DO group. CONCLUSIONS: Detrusor contractile responses to EFS increased in patients with BOO in presence of overactivity. These changes in contractile responses are observed possibly as a result of deterioration in neuromodulation, rather than as a result of changes in purinergic or cholinergic receptor sensation or level. We suggest that a noncholinergic-nonpurinergic mechanism can have some effect on these changes.

Short-term effects of arsenic sulfur in deficits of contractile and relaxant responses on urinary bladder: pharmacological and structural changes.

INTRODUCTION: Our goal was to investigate the effects of arsenic sulfur (AsS) on the detrusor smooth muscle reactivity. MATERIAL AND METHODS: AsS (100 ppm microg/g) in drinking water was administered for 2 weeks to two groups of female Wistar rats. The contractile responses of urinary bladders to electrical field stimulation, carbachol, ATP and KCl, and the relaxant responses to ATP, adenosine and isoproterenol were examined. Urinary bladder strips were collected for light microscopic examination. RESULTS: Our results demonstrate that oral inorganic AsS exposure induced enhanced contractile and reduced relaxant responses in rats. We hypothesize that AsS is involved in deficiencies of isolated urinary bladder in rats. CONCLUSION: These functional and morphological changes may be important as an intermediate link in urinary bladder oncogenesis induced by AsS.