Central nervous system Anorectic
*Numbers bearing an asterisk refer to the substituents numbered in the bottom rows of the table; substituent 3 replaces the N atom, substituent 5 replaces the phenyl ring, and 6, 7, and 8 are attached directly to the phenyl ring, replacing the ethylamine side chain.
^The a and b in the prototypical formula refer to positions of the C atoms in the ethylamine side chain.
SPrenalterol has —OCH2— between the aromatic ring and the carbon atom designated as b in the prototypical formula.
BLOOD PRESSURE Epi is a potent vasopressor. A pharmacological dose of Epi, given rapidly by an intravenous route, rapidly increases blood pressure to a peak that is proportional to the dose. The increase in systolic pressure is greater than the increase in diastolic pressure, so that the pulse pressure increases. As the response wanes, the mean pressure may fall below normal before returning to control levels. The mechanism of the rise in blood pressure due to Epi is threefold: (1) a direct myocardial stimulation that increases the strength of ventricular contraction (positive inotropic action, via b1 receptors); (2) an increased heart rate (positive chronotropic action, via b1 receptors); and (3) vasoconstriction in many vascular beds (especially in the precapillary resistance vessels of skin, mucosa, and kidney) along with marked constriction of the veins (via a receptors). The pulse rate, at first accelerated by the direct positive chrontropic effect of Epi, may slow down markedly as blood pressure rises, due to the compensatory baroreceptor reflex (bradycardia due to vagal discharge). Small doses of Epi (0.1 mg/kg) may cause the blood pressure to fall; the depressor effect of small doses and the biphasic response to larger doses are due to greater sensitivity to Epi of vasodilator b2 receptors than of constrictor a receptors.
The effects are somewhat different when the drug is given by slow intravenous infusion or by subcutaneous injection. Absorption of Epi after subcutaneous injection is slow due to local vasoconstrictor action. There is a moderate increase in systolic pressure due to increased cardiac contractile force and a rise in cardiac output (Figure 10-2). Peripheral resistance decreases, owing to a dominant action on b2 receptors of vessels in skeletal muscle, where blood flow is enhanced; as a consequence, diastolic pressure usually falls. Since the mean blood pressure usually is not greatly elevated, compensatory baroreceptor reflexes do not appreciably antagonize the direct cardiac actions. Heart rate, cardiac output, stroke volume, and left ventricular stroke work increase as a result of direct cardiac stimulation and increased venous returns to the heart, which is reflected by an increase in right atrial pressure. At slightly higher rates of infusion, there may be no change or a slight rise in peripheral resistance and diastolic pressure, depending on the dose and the resultant ratio of a to b responses in the various vascular beds; compensatory reflexes also may come into play. The effects of intravenous infusion of Epi, NE, and isoproterenol are compared in Table 10-2 and Figure 10-2.
VASCULAR EFFECTS The chief vascular action of Epi is on the smaller arterioles and precapillary sphincters, although veins and large arteries also respond. Various vascular beds react differently, resulting in substantial redistribution of blood flow. Injected Epi markedly decreases cutaneous blood flow, constricting precapillary vessels and small venules. Cutaneous vasoconstriction accounts for a marked decrease in blood flow in the hands and feet. The "after congestion" of mucosa following the vasoconstriction from locally applied Epi probably is due to changes in
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