Page 159 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 9 Adrenoceptor Agonists & Sympathomimetic Drugs 145

TABLE 9–3 Distribution of adrenoceptor subtypes. Patients who have an impairment of autonomic function (due
to pure autonomic failure as in the case study or to more common
Type Tissue Actions conditions such as diabetic autonomic neuropathy) exhibit this
Most vascular smooth muscle Contraction extreme hypersensitivity to most pressor and depressor stimuli,
α 1
(innervated) including medications. This is to a large extent due to failure of
Pupillary dilator muscle Contraction (dilates baroreflex buffering. Such patients may have exaggerated increases
pupil) in heart rate or blood pressure when taking sympathomimetics
Pilomotor smooth muscle Erects hair with β- and α-adrenergic activity, respectively. This, however, can
be used as an advantage in their treatment. The α agonist mido-
Prostate Contraction
drine is commonly used to ameliorate orthostatic hypotension in
Heart Increases force of these patients.
contraction
There are major differences in receptor types predomi-
Postsynaptic CNS neurons Probably multiple
α 2
nantly expressed in the various vascular beds (Table 9–4).
Platelets Aggregation The skin vessels have predominantly α receptors and constrict
Adrenergic and cholinergic Inhibits transmitter in response to epinephrine and norepinephrine, as do the
nerve terminals release
splanchnic vessels. Vessels in skeletal muscle may constrict or
Some vascular smooth muscle Contraction dilate depending on whether α or β receptors are activated.
Fat cells Inhibits lipolysis The blood vessels of the nasal mucosa express α receptors, and
Heart, juxtaglomerular cells Increases force and rate local vasoconstriction induced by sympathomimetics explains
β 1
of contraction; increases their decongestant action (see Therapeutic Uses of Sympatho-
renin release mimetic Drugs).
Respiratory, uterine, and vas- Promotes smooth muscle
β 2
cular smooth muscle relaxation B. Effects of Alpha -Receptor Activation
2
Skeletal muscle Promotes potassium Alpha adrenoceptors are present in the vasculature, and their acti-
2
uptake
vation leads to vasoconstriction. This effect, however, is observed
Human liver Activates glycogenolysis only when α agonists are given locally, by rapid intravenous
2
Bladder Relaxes detrusor muscle injection or in very high oral doses. When given systemically, these
β 3
Fat cells Activates lipolysis vascular effects are obscured by the central effects of α receptors,
2
which lead to inhibition of sympathetic tone and reduced blood
Smooth muscle Dilates renal blood
D 1
vessels pressure. Hence, α agonists can be used as sympatholytics in the
2
Nerve endings Modulates transmitter treatment of hypertension (see Chapter 11). In patients with
D 2
release pure autonomic failure, characterized by neural degeneration
of postganglionic noradrenergic fibers, clonidine may increase
blood pressure because the central sympatholytic effects of cloni-
effect on cardiac function is of relatively less importance. A rela- dine become irrelevant, whereas the peripheral vasoconstriction
tively pure α agonist such as phenylephrine increases peripheral remains intact.
arterial resistance and decreases venous capacitance. The enhanced
arterial resistance usually leads to a dose-dependent rise in blood C. Effects of Beta-Receptor Activation
pressure (Figure 9–6). In the presence of normal cardiovascular The cardiovascular effects of β-adrenoceptor activation are exempli-
reflexes, the rise in blood pressure elicits a baroreceptor-mediated fied by the response to the nonselective β agonist isoproterenol,
increase in vagal tone with slowing of the heart rate, which may which activates both β and β receptors. Stimulation of β receptors
2
1
be quite marked (Figure 9–7). However, cardiac output may not in the heart increases cardiac output by increasing contractility and
diminish in proportion to this reduction in rate, since increased by direct activation of the sinus node to increase heart rate. Beta
venous return may increase stroke volume. Furthermore, direct agonists also decrease peripheral resistance by activating β 2 recep-
α-adrenoceptor stimulation of the heart may have a modest posi- tors, leading to vasodilation in certain vascular beds (Table 9–4).
tive inotropic action. It is important to note that any effect these The net effect is to maintain or slightly increase systolic pressure
agents have on blood pressure is counteracted by compensatory and to lower diastolic pressure, so that mean blood pressure is
autonomic baroreflex mechanisms aimed at restoring homeosta- decreased (Figure 9–6).
sis. The magnitude of the restraining effect is quite dramatic. If The cardiac effects of β agonists are determined largely by
baroreflex function is removed by pretreatment with the gangli- β 1 receptors (although β and α receptors may also be involved,
2
onic blocker trimethaphan, the pressor effect of phenylephrine especially in heart failure). Beta-receptor activation results in
is increased approximately 10-fold, and bradycardia is no longer increased calcium influx in cardiac cells. This has both electrical
observed (Figure 9–7), confirming that the decrease in heart and mechanical consequences. Beta-activation in the sinoatrial
rate associated with the increase in blood pressure induced by node increases pacemaker activity and heart rate (positive
phenylephrine was reflex in nature rather than a direct effect of chronotropic effect). Excessive stimulation of ventricular muscle
-receptor activation. and Purkinje cells can result in ventricular arrhythmias. Beta
α 1