Epinephrine vascular effects

Serious adverse effects of epinephrine potentially occur when it is given in an excessive dose, or too rapidly, for example, as an intravenous bolus or a rapid intravenous infusion. These include ventricular dysrhythmias, angina, myocardial infarction, pulmonary edema, sudden sharp increase in blood pressure, and cerebral hemorrhage. The risk of epinephrine adverse effects is also potentially increased in patients with hypertension or ischemic heart disease, and in those using (3-blockers (due to unopposed epinephrine action on vascular Ui-adrenergic receptors), monoamine oxidase inhibitors, tricyclic antidepressants, or cocaine. Even in these patients, there is no absolute contraindication for the use of epinephrine in the treatment of anaphylaxis [1,5,6]. 

Cardiovascular effects of Infusion of norepinephrine, epinephrine, Isoproterenol, and dopamine in humans. Infusions were made intravenously during the time indicated by the broken lines. Heart rate is given in beats per minute, blood pressure in millimeters of mercury, and peripheral resistance in arterial blood pressure. (Reprinted with permission from Allwood MJ, Cobbald AF, and Ginsburg J. Peripheral vascular effects of noradrenaline, isopropyl-noradrenaline, and dopamine. Br Med Bull 19 132, 1963. Reproduced by permission of the Medical Department, The British Council. 

Presumably, vasoactive substances act upon smooth muscle cells by intimate association with them, and are destroyed in the process of stimulation or depression. Epinephrine, when injected intravenously, can be recovered in much larger amounts from arterial than from venous blood minute doses given intraarterially may affect only the local circulation. If amines formed from the incomplete catabolism of amino acids are active in hypertension, one must postulate their formation by ischemic organs in direct venous connection with the heart (kidneys, brain, liver, adrenals, etc.) or in direct arterial connection with the arteriolar bed (heart and lungs). If the former, they must not be destroyed in large amounts by the lungs. Furthermore, arterial blood could be expected to contain larger quantities than venous. Absorption from or formation in the intestinal tract or spleen of amines would not produce vascular effects, as these substances probably would be metabolized by the liver. 

It is not surprising that intramuscular injection of epinephrine into the vastus lateralis produces a prompt peak plasma epinephrine concentration, because of the large size and excellent vascularization of this muscle. It is also not surprising that subcutaneous injection of epinephrine potentially leads to delayed absorption, because of the potent Ui-adrenergic agonist vasoconstrictor effects in the skin and subcutaneous tissue, as evidenced by skin blanching at the injection site [19, 20]. 

The major circulating hormones that influence vascular smooth muscle tone are the catecholamines epinephrine and norepinephrine. These hormones are released from the adrenal medulla in response to sympathetic nervous stimulation. In humans, 80% of catecholamine secretion is epinephrine and 20% is norepinephrine. Stimulation of cy-adrenergic receptors causes vasoconstriction. The selective a,-adrenergic receptor antagonist, prazosin, is effective in management of hypertension because it causes arterial and venous smooth muscle to relax. 

The answer is d. (Katzung, p 130J Epinephrine has a positive ionotropic and chronotropic effect on the heart because of its pradrenergic activity It also has a-adrenergic activity that causes vasoconstriction in the vascular beds. These actions result in a rise in systolic blood pressure. Epinephrine also has p2-adrenergic activity, which causes vasodilation in skeletal muscle. Because of this latter effect, total peripheral resistance can fall, resulting in a drop in diastolic pressure, particularly at low doses of epinephrine. 

Vasopressin is a potent vasoconstrictor that increases blood pressure and systemic vascular resistance. It may have several advantages over epinephrine. First, the metabolic acidosis that frequently accompanies cardiopulmonary arrest can blunt the vasoconstrictive effect of epinephrine this does not occur with vasopressin. Second, stimulation of P receptors by epinephrine can increase myocardial oxygen demand and complicate the postresuscitative phase of CPR. Vasopressin can also have a beneficial effect on renal blood flow in the kidney, causing vasodilation and increased water reabsorption. 

Altered vascular responses When P2-receptors are blocked, the vasodilating effect of epinephrine is abolished, leaving the a-receptor-mediated vasoconstriction unaffected peripheral blood flow i - cold hands and feet . 

Adrenal medulla. On the one hand, release of epinephrine elicits cardiovascular effects, such as increases in heart rate und peripheral vascular resistance. On the other, it evokes metabolic responses, such as glycogenolysis and li-polysis, that generate energy-rich substrates. The sensation of hunger is suppressed. The metabolic state corresponds to that associated with physical exercise - silent stress . 

On the other hand, )3-adrenoblockers have a minor effect on vascular tonicity. In addition, 8-adrenoblockers prevent the vasodilatory effect of epinephrine. In organs such as the heart, which are regulated mainly by )3-adrenoreceptors, )3-adrenoblockers counteract the excitatory effect of norepinephrine. 

The effect of a given adrenomimetic drug on a particular type of effector cell depends on the receptor selectivity of the drug, the response characteristics of the effector cells, and the predominant type of adrenoceptor found on the cells. For example, the smooth muscle cells of many blood vessels have only or predominantly a-adrenoceptors. The interaction of compounds with these adrenoceptors initiates a chain of events in the vascular smooth muscle cells that leads to activation of the contractile process. Thus, norepinephrine and epinephrine, which have high affinities for a-adrenoceptors, cause the vascular muscle to contract and the blood vessels to constrict. Since bronchial smooth muscle contains p2-adrenoceptors, the response in this tissue elicited by the action of p2-adrenoceptor agonists is relaxation of smooth muscle cells. Epinephrine and isoproterenol, which have high affinities for p2-adrenoceptors, cause relaxation of bronchial smooth muscle. Norepinephrine has a lower affinity for p2-adrenoceptors and has relatively weak bronchiolar relaxing properties. 

The cardiovascular effects of norepinephrine, epinephrine, and isoproterenol are shown in Table 10.1. Differences in the action of these three catecholamines on various vascular beds are due both to the different... 

Although several factors can influence the flow of blood through the coronary vessels, the most important of these is the local production of vasodilator metabolites that results from stimulation-induced increased work by the heart. a-Adrenoreceptors and -adrenoceptors in the coronary vascular beds do not play a major role in determining the vasodilator effects of the administration of epinephrine or norepinephrine. 

A small dose of epinephrine causes a fall in mean and diastolic pressure with little or no effect on systolic pressure. This is due to the net decrease in total peripheral resistance that results from the predominance of vasodilation in the skeletal muscle vascular bed. The intravenous infusion or subcutaneous administration of epinephrine in the range of doses used in humans generally increases the systolic pressure, but the diastolic pressure is decreased. Therefore, the mean pressure may decrease, remain unchanged, or increase slightly, depending on the balance between the rise in systolic and fall in diastolic blood pressures (Rg. 10.4). 

In any blood vessel, the final integrated response to either neuronally released norepinephrine or to circulating epinephrine probably depends on the relative participation of at least four populations of a-adreno-ceptors postjunctional i- and az-adrenoceptors mediate constriction of vascular smooth muscle, while prejunctional and endothelial az-adrenoceptors mediate vasodilation. An understanding of the vessel vascular response to adrenomimetic drugs also must include the effects of drugs on adventitial innervation, smooth muscle, and other vascular factors that may be present. 

Halothane administration can result in a marked reduction in arterial blood pressure that is due primarily to direct myocardial depression, which reduces cardiac output. The fall in pressure is not opposed by reflex sympathetic activation, however, since halothane also blunts baroreceptor and carotid reflexes. Systemic vascular resistance is unchanged, although blood flow to various tissues is redistributed. Halothane also sensitizes the heart to the arrhythmogenic effect of catecholamines. Thus, maintenance of the patient s blood pressure with epinephrine must be done cautiously. 

The a receptors are generally excitatory, as shown in table 4.2, and mediate a constricting effect on vascular, uterine, and intestinal muscle when stimulated by an agonist. They respond to different adrenergic agonists in the following order epinephrine >... 

Enflurane produces a dose-related decrease in systemic arterial blood pressure secondary to reductions in cardiac output and systemic vascular resistance. There is evidence that cardiac output is partially maintained by a compensatory increase in heart rate. This effect seems dependent on a degree of hypercardia and does not occur during controlled ventilation. Enflurane and halothane depress myocardial contractility to a similar extent and less than isoflurane. Enflurane does not sensitise the heart to the effects of catecholamines to any significant extent and adrenaline (epinephrine) may be given subcutaneously for control of bleeding. 

The effects of sympathomimetic drugs on blood pressure can be explained on the basis of their effects on heart rate, myocardial function, peripheral vascular resistance, and venous return (see Figure 6-7 and Table 9-4). The endogenous catecholamines, norepinephrine and epinephrine have complex cardiovascular effects because they activate both and 13 receptors. It is easier to understand these actions by first describing the cardiovascular effect of sympathomimetics that are selective for a given adrenoreceptor. 

Intravenous administration of dopamine promotes vasodilation of renal, splanchnic, coronary, cerebral, and perhaps other resistance vessels, via activation of Di receptors. Activation of the Di receptors in the renal vasculature may also induce natriuresis. The renal effects of dopamine have been used clinically to improve perfusion to the kidney in situations of oliguria (abnormally low urinary output). The activation of presynaptic D2 receptors suppresses norepinephrine release, but it is unclear if this contributes to cardiovascular effects of dopamine. In addition, dopamine activates Bj receptors in the heart. At low doses, peripheral resistance may decrease. At higher rates of infusion, dopamine activates vascular a. receptors, leading to vasoconstriction, including in the renal vascular bed. Consequently, high rates of infusion of dopamine may mimic the actions of epinephrine. 

By constricting the vascular bed, such coadministered vasoactive excipients as epinephrine can reduce the rate of uptake from the SC sites (4a). By contrast, the excipient hyaluronidase breaks down the interstitial barrier by lysing hyaluronic acid, a polysaccharide that helps form the intercellular ground substance of connective tissue (4b). This in effect spreads the injected drug solution over a larger area of connective tissue, increasing the absorption surface, and thereby increasing both the volume that can normally be injected SC (Table 1) and the rate of uptake (6). 

Adrenal medulla Epinephrine, Norepinephrine Vascular and metabolic effects that facilitate increased physical activity... 

Vascular smooth muscle tone is regulated by adrenoceptors consequently, catecholamines are important in controlling peripheral vascular resistance and venous capacitance. Alpha receptors increase arterial resistance, whereas 2 receptors promote smooth muscle relaxation. There are major differences in receptor types in the various vascular beds (Table 9-4). The skin vessels have predominantly receptors and constrict in the presence of epinephrine and norepinephrine, as do the splanchnic vessels. Vessels in skeletal muscle may constrict or dilate depending on whether ffor 13 receptors are activated. Consequently, the overall effects of a sympathomimetic drug on blood vessels depend on the relative activities of that drug at and 8receptors and the anatomic sites of the vessels affected. In addition, Di receptors promote vasodilation of renal, splanchnic, coronary, cerebral, and perhaps other resistance vessels. Activation of the Di receptors in the renal vasculature may play a major role in the natriuresis induced by pharmacologic administration of dopamine. 

---