Page 126 - Basic _ Clinical Pharmacology ( PDFDrive )

112 SECTION II Autonomic Drugs

charge through the nicotinic receptor ion channel). Binding of TABLE 7–3 Effects of direct-acting cholinoceptor
an agonist molecule by one of the two receptor sites only mod- stimulants. 1
estly increases the probability of channel opening; simultaneous
binding of agonist by both of the receptor sites greatly enhances Organ Response
opening probability. Nicotinic receptor activation causes depolar- Eye
ization of the nerve cell or neuromuscular end plate membrane. Sphincter muscle of iris Contraction (miosis)
In skeletal muscle, the depolarization initiates an action potential
that propagates across the muscle membrane and causes contrac- Ciliary muscle Contraction for near vision
(accommodation)
tion (Figure 7–4B).
Prolonged agonist occupancy of the nicotinic receptor abol- Heart
ishes the effector response; that is, the postganglionic neuron Sinoatrial node Decrease in rate (negative
chronotropy)
stops firing (ganglionic effect), and the skeletal muscle cell relaxes
(neuromuscular end plate effect). Furthermore, the continued Atria Decrease in contractile strength
(negative inotropy). Decrease in
presence of the nicotinic agonist prevents electrical recovery of the refractory period
postjunctional membrane. Thus, a state of “depolarizing block- Atrioventricular node Decrease in conduction velocity
ade” occurs initially during persistent agonist occupancy of the (negative dromotropy). Increase in
receptor. Continued agonist occupancy is associated with return refractory period
of membrane voltage to the resting level. The receptor becomes Ventricles Small decrease in contractile strength
desensitized to agonist, and this state is refractory to reversal by Blood vessels
other agonists. As described in Chapter 27, this effect can be Arteries, veins Dilation (via EDRF). Constriction
exploited to produce muscle paralysis. (high-dose direct effect)
Lung
B. Organ System Effects
Most of the direct organ system effects of muscarinic cholino- Bronchial muscle Contraction (bronchoconstriction)
ceptor stimulants are readily predicted from knowledge of the Bronchial glands Secretion
effects of parasympathetic nerve stimulation (see Table 6–3) Gastrointestinal tract
and the distribution of muscarinic receptors. Effects of a typical Motility Increase
agent such as acetylcholine are listed in Table 7–3. The effects Sphincters Relaxation
of nicotinic agonists are similarly predictable from knowledge Secretion Stimulation
of the physiology of the autonomic ganglia and skeletal muscle Urinary bladder
motor end plate.
Detrusor Contraction
1. Eye—Muscarinic agonists instilled into the conjunctival sac Trigone and sphincter Relaxation
cause contraction of the smooth muscle of the iris sphincter Glands
(resulting in miosis) and of the ciliary muscle (resulting in accom- Sweat, salivary, lacrimal, Secretion
modation). As a result, the iris is pulled away from the angle of nasopharyngeal
the anterior chamber, and the trabecular meshwork at the base of 1 Only the direct effects are indicated; homeostatic responses to these direct actions
the ciliary muscle is opened. Both effects facilitate aqueous humor may be important (see text).
outflow into the canal of Schlemm, which drains the anterior EDRF, endothelium-derived relaxing factor.
chamber.

2. Cardiovascular system—The primary cardiovascular effects and also in atrial and ventricular muscle cells; (2) a decrease in the
of muscarinic agonists are reduction in peripheral vascular slow inward calcium current (I Ca ) in heart cells; and (3) a reduc-
resistance and changes in heart rate. The direct effects listed in tion in the hyperpolarization-activated current (I ) that underlies
f
Table 7–3 are modified by important homeostatic reflexes, as diastolic depolarization (Figure 7–4A). All these actions are medi-
described in Chapter 6 and depicted in Figure 6–7. Intravenous ated by M receptors and contribute to slowing the pacemaker
2
infusions of minimally effective doses of acetylcholine in humans rate. Effects (1) and (2) cause hyperpolarization, reduce action
(eg, 20–50 mcg/min) cause vasodilation, resulting in a reduc- potential duration, and decrease the contractility of atrial and
tion in blood pressure, often accompanied by a reflex increase in ventricular cells. Predictably, knockout of M 2 receptors eliminates
heart rate. Larger doses of acetylcholine produce bradycardia and the bradycardic effect of vagal stimulation and the negative chro-
decrease atrioventricular node conduction velocity in addition to notropic effect of carbachol on sinoatrial rate.
causing hypotension. The direct slowing of sinoatrial rate and atrioventricu-
The direct cardiac actions of muscarinic stimulants include the lar conduction that is produced by muscarinic agonists is
following: (1) an increase in a potassium current (I K(ACh) ) in the often opposed by reflex sympathetic discharge, elicited by
cells of the sinoatrial and atrioventricular nodes, in Purkinje cells, the decrease in blood pressure (see Figure 6–7). The resultant