Importance of pharmacological and physicochemical properties for tolerance of antimuscarinic drugs in the treatment of detrusor instability and detrusor hyperreflexia--chances for improvement of therapy.
BACKGROUND
Antimuscarinic side-effects are relatively frequent problems in oral pharmacotherapy of detrusor instability and neurogenic dysfunction of the urinary bladder. Results of recent clinical trials demonstrate differences in tolerance between antimuscarinic drugs. It is the purpose of this paper to relate the available clinical data to the pharmacological and physicochemical properties of the different antimuscarinic drugs, in order to discuss the reasons for this enhanced tolerance and to make possible modes for improvement of antimuscarinic therapy plainly visible.


METHODS
Therefore, we reviewed the available literature using among others the computerized library systems Medline (National Library of Medicine, Bethesda, Maryland, USA) and Embase (Excerpta Medica, Amsterdam, the Netherlands). Differences in tolerance of oral antimuscarinic drugs may result from muscarine-receptor selectivity, organ selectivity, and pharmacokinetic as well as physicochemical properties. While the roles of m-receptor and organ selectivity need more detailed clarification, influences of differences in bioavailability and physicochemical properties on the tolerance of antimuscarinic drugs are more sufficiently investigated.


RESULTS
Generally, tolerance as well as efficacy of antimuscarinic drugs seem to be a complex result of a combination of various pharmacological properties distinguishing the individual substances. The enhancement of tolerance of propiverine hydrochloride, tolterodine tartrate and trospium chloride compared to oxybutynin chloride seems to be reached by different modes, from which the molecular structure -- propiverine and tolterodine are tertiary amines, trospium chloride possesses a quarternary ammonium structure -- may be of great importance. First investigations with alternative transdermal and intravesical application routes show interesting possibilities for further improvement of antimuscarinic therapy in urological indications.


CONCLUSIONS
In conclusion, from pharmacological and clinical data it becomes obvious that there are significant differences between antimuscarinic drugs, which are of clinical relevance and include possible starting points for the development of new drugs and application forms.
Schwantes
U
U
Department of Medical Science and Clinical Research, Dr. R. Pfleger GmbH, Bamberg, Germany.
Topfmeier
P
P
D000279:Administration, Cutaneous; D000283:Administration, Intravesical; D000284:Administration, Oral; D001682:Biological Availability; D006801:Humans; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology; D011976:Receptors, Muscarinic / Q000187:drug effects; D012021:Reflex, Abnormal / Q000187:drug effects*; D014570:Urologic Diseases / Q000188:drug therapy*
D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic