Biomedical Engineering Reference
In-Depth Information
2.2
Pharmacology and Toxicology
Based on the chemical structure, TA can be subdivided into TTA and QTA depend-
ing on the grade of N-alkylation in the tropane moiety. These structural differences
have major influence on bioavailability and distribution in vivo and should briefly
be outlined below.
2.2.1
Tertiary TA and Quaternary TA
Due to their lipophilicity TTA are rapidly and completely absorbed in the GIT and
cross the blood-brain barrier allowing drug administration as tablets [ 29 ] .
Accordingly, severe intoxication may be caused after ingestion of toxic plants and
berries.
The permanent positive charge of QTA influences distribution in vivo and pre-
vents passage of blood-brain barrier and blood-cerebrospinal fluid barrier [ 30, 31 ] .
Myolitic QTA are muscarinic receptor antagonists but allow a better therapeutic
index as they are insoluble in lipids and thus poorly systemically absorbed (e.g.
bioavailability of N -butyl-scopolamine after oral intake: <1 % [ 30 ] ). Therefore,
spasmolytic activity in the GIT (by, e.g. cimetropium, butropium or N -butyl-
scopolamine, Fig. 1 ), respiratory tract (ipratropium, Fig. 1 ) and overactive bladder
(trospium, Fig. 1 ) appears as the primary local effect whereas systemic side effects
are markedly minimized or absent [ 32- 34 ] .
More common reviews on TA drugs and their synthetic derivatives are given by
Christen [ 9 ] and Grynkiewicz and Gadzikowska [ 1 ] .
2.2.2
Mechanism of Action
In general, diverse TA are known to bind to (a) muscarinic receptors (MR), (b)
5-hydroxytryptamine (serotonin) receptor 3 (5-HT 3 R), (c) a 1-adrenoreceptors
(a1-AR), or (d) a7-nicotinic receptors (a7-nAChR) thus causing different physio-
logical effects. The corresponding mechanisms of action should briefly be addressed
below.
2.2.3
Binding to MR
MR are present in, e.g. the central nervous system (CNS, for respiratory and cardio-
vascular activity, cognition and stress processing), peripheral nervous system (PNS,
for smooth muscle contraction, control of heart rate, vasodilatation), as well as the
sympathetic and parasympathetic ganglion cells [ 1 ] . Five metabotropic cholinergic
MR subtypes (M1-M5) were identified [ 1 ], but selectivity of TA is merely apparent
[ 9 ] except for tiotropium and ipratropium [ 31 ] .
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