Page 124 - Basic _ Clinical Pharmacology ( PDFDrive )

110 SECTION II Autonomic Drugs

Action chiefly muscarinic Action chiefly nicotinic

HO
CH 3
+ N
H C O CH 2 N CH 3 N
3
CH 3 CH 3
Muscarine Nicotine

H C CH 2 O OH
3
CH 2 N CH 3
C CH 2 CH 2 CH
N
O O N C H C H
6 5
6 5
CH 3
Pilocarpine Lobeline

FIGURE 7–3 Structures of some cholinomimetic alkaloids.

Pharmacodynamics binding to M 1 , M , and M receptors activates the inositol trispho-
3
5
sphate (IP ), diacylglycerol (DAG) cascade. Some evidence impli-
3
A. Mechanism of Action cates DAG in the opening of smooth muscle calcium channels; IP
3
Activation of the parasympathetic nervous system modifies organ releases calcium from endoplasmic and sarcoplasmic reticulum.
function by two major mechanisms. First, acetylcholine released Muscarinic agonists also increase cellular cGMP concentrations.
from parasympathetic nerves activates muscarinic receptors on Activation of muscarinic receptors also increases potassium flux
effector cells to alter organ function directly. Second, acetylcho- across cardiac cell membranes (Figure 7–4A) and decreases it in
line released from parasympathetic nerves interacts with musca- ganglion and smooth muscle cells. This effect is mediated by the
rinic receptors on nerve terminals to inhibit the release of their binding of an activated G protein βγ subunit directly to the chan-
neurotransmitter. By this mechanism, acetylcholine release and nel. Finally, activation of M and M muscarinic receptors inhibits
2
4
circulating muscarinic agonists indirectly alter organ function by adenylyl cyclase activity in tissues (eg, heart, intestine). Moreover,
modulating the effects of the parasympathetic and sympathetic muscarinic agonists attenuate the activation of adenylyl cyclase
nervous systems and perhaps nonadrenergic, noncholinergic and modulate the increase in cAMP levels induced by hormones
(NANC) systems. such as catecholamines. These muscarinic effects on cAMP genera-
As indicated in Chapter 6, muscarinic receptor subtypes have tion reduce the physiologic response of the organ to stimulatory
been characterized by binding studies and cloned. Several cellu- hormones.
lar events occur when muscarinic receptors are activated, one or The mechanism of nicotinic receptor activation has been
more of which might serve as second messengers for muscarinic studied in great detail, taking advantage of three factors: (1) the
activation. All muscarinic receptors appear to be of the G protein- receptor is present in extremely high concentration in the mem-
coupled type (see Chapter 2 and Table 7–1). Muscarinic agonist branes of the electric organs of electric fish; (2) α-bungarotoxin, a
component of certain snake venoms, binds tightly to the receptors
and is readily labeled as a marker for isolation procedures; and
TABLE 7–2 Properties of choline esters. (3) receptor activation results in easily measured electrical and
ionic changes in the cells involved. The nicotinic receptor in mus-
Susceptibility to Muscarinic Nicotinic cle tissues (Figure 7–4B) is a pentamer of four types of glycopro-
Choline Ester Cholinesterase Action Action
tein subunits (one monomer occurs twice) with a total molecular
Acetylcholine ++++ +++ +++ weight of about 250,000. The neuronal nicotinic receptor consists
chloride of α and β subunits only (Table 7–1). Each subunit has four
Methacholine + ++++ None transmembrane segments. The nicotinic receptor has two agonist
chloride binding sites at the interfaces formed by the two α subunits and
Carbachol Negligible ++ +++ two adjacent subunits (β, γ, ε). Agonist binding to the recep-
chloride tor sites causes a conformational change in the protein (channel
Bethanechol Negligible ++ None opening) that allows sodium and potassium ions to diffuse rapidly
chloride down their concentration gradients (calcium ions may also carry