DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

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ATROPINE SCOPOLAMINE HOMATROPINE PIRENZEPINE
CHAPTER 9
IPRATROPIUM
TIOTROPIUM
TOLTERODINE
Figure 9–2. Structural formulas of the belladonna alkaloids and semisynthetic and synthetic analogs. The red C identifies an asymmetric
carbon atom.
analogs esterified with synthetic aromatic acids. A similar agent,
oxitropium bromide, an N-ethyl-substituted, quaternary derivative of
scopolamine, is available in Europe.
Structure-Activity Relationships. An intact ester of tropine and
tropic acid is essential for antimuscarinic action, since neither the
free acid nor the basic alcohol exhibits significant antimuscarinic
activity. The presence of a free OH group in the acyl portion of the
ester also is important for activity. When given parenterally, quaternary
ammonium derivatives of atropine and scopolamine are
generally more potent than their parent compounds in both muscarinic
and ganglionic (nicotinic) blocking activities. The quaternary
derivatives, when given orally, are poorly and unreliably
absorbed.
Both tropic and mandelic acids have an enantiomeric center
(boldface red C in the formulas in Figure 9–2). Scopolamine is
l-hyoscine and is much more active than d-hyoscine. Atropine is
racemized during extraction and consists of d,l-hyoscyamine, but
antimuscarinic activity is almost wholly due to the naturally occurring
l isomer. Synthetic derivatives show a wide range of structures
that spatially replicate the aromatic acid and the bridged nitrogen of
the tropine.
Mechanism of Action. Atropine and related compounds compete
with ACh and other muscarinic agonists for a common binding site
on the muscarinic receptor. Since antagonism by atropine is competitive,
it can be overcome if the concentration of ACh at muscarinic
receptors of the effector organ is increased sufficiently. Muscarinic
receptor antagonists inhibit responses to postganglionic cholinergic
nerve stimulation less effectively than they inhibit responses to
injected choline esters. The difference may be explained by the fact
that release of ACh by cholinergic nerve terminals occurs in close
proximity to the receptors, resulting in very high concentrations of
the transmitter at the receptors.
Pharmacological Effects of
Muscarinic Antagonists
The pharmacological effects of atropine, the prototypical
muscarinic antagonist, provide a good background for
understanding the therapeutic uses of the various
muscarinic antagonists. The effects of other muscarinic
antagonists will be mentioned only when they differ significantly
from those of atropine. The major pharmacological
effects of increasing doses of atropine, summarized
in Table 9–2, offer a general guide to the problems associated
with administration of this class of agents.
Cardiovascular System
Heart. The main effect of atropine on the heart is to alter
the rate. Although the dominant response is tachycardia,
the heart rate often decreases transiently with
average clinical doses (0.4-0.6 mg; Table 9–2). The
slowing is modest (4-8 beats per minute) and is usually
absent after rapid intravenous injection. There are no
accompanying changes in blood pressure or cardiac
output. This unexpected effect has been attributed to the
block of presynaptic M 1
muscarinic receptors on
MUSCARINIC RECEPTOR AGONISTS AND ANTAGONISTS