Adrenaline, noradrenaline, dopamine and dobutamine infusions are given to patients who need longlas

Fråga: Adrenaline, noradrenaline, dopamine and dobutamine infusions are given to patients who need longlasting and intensive inotropic support. If the patients also have liver diseases or a liver transplantation, could there be a change in elimination of these drugs? Should the dosage policy be changed?

Sammanfattning: After an extensive literature search, no reports could be found concerning a change in elimination of adrenaline, noradrenaline, dopamine or dobutamine in clinical doses, when liver diseases are involved. The plasma half-life of these drugs is known to be very short, due to rapid distribution and metabolism by several enzyme systems. Since dobutamine is mainly metabolized in the liver, this process could be disturbed in case of liver diseases, though no specific reports could be found on this matter. Concerning the endogenous compounds adrenaline, noradrenaline and dopamine, the liver is not the only organ system responsible for elimination. In these complex clinical situations of cardiac failure, shock and liver disease, interindividual variability in pharmacodynamic effects is probably of higher importance than changes in pharmacokinetic parameters. Accordingly, the use of these drugs should be accompanied by close hemodynamic monitoring.

Svar: Catecholamines produce a variety of cardiac and vascular effects that may be useful in the treatment of shock (1).

Adrenaline exerts positive inotropic and chronotropic actions on the heart (beta-1) and vasoconstriction in many vascular beds (alpha), but increases blood flow to the skeletal muscles (beta-2). The usual initial dose is 5-20 ug/min.

Noradrenaline is used primarily as a vasoconstrictor, since it produces only a modest increase in heart rate and cardiac contractility. The primary indication for noradrenaline is low systemic vascular resistance. The initial dose is 4-8 ug/min.

Dopamine is used for all types of shock. At low doses, 1-5 ug/kg/min, it increases cardiac contractility (beta-1) and renal and mesenteric blood flow (D1). At higher doses, 5-15 ug/kg/min, activation of vascular alpha-receptors leads to vasoconstriction.

Dobutamine exerts a relatively selective inotropic action (beta-1) and can be used for additional inotropic support. The initial dose is 2.5 ug/kg/min up to 15 ug/kg/min.

The plasma half-life of these catecholamines is very short, 1-3 min, due to rapid redistribution and metabolism (2). In one study (3) elimination of dopamine from plasma after infusion of 2 and 5 ug/kg/min for 30 min showed a biphasic course with t1/2-alpha around one minute and t1/2-beta of 9 minutes. Most of the adrenaline and noradrenaline that enters the circulation after intravenous administration is first methylated by catechol-O-methyltransferase (COMT) to metanephrine or normetanephrine respectively, or deaminated by MAO to 3-4-dihydroxy-mandelic acid. The main endproduct is "vanillylmandelic acid", VMA, which is the major inactive metabolite excreted in the urine. Conjugated forms of normetanephrine or metanephrine or unmetabolized catecholamines, excreted by the kidney are of minor importance (4). The corresponding product of dopamine is homovanillic acid (HVA). Both MAO and COMT are widely distributed throughout the body, including the intestine and the plasma (5). The highest concentrations are in the liver and the kidneys. The major metabolites of dobutamine are dobutamine glucuronide and 3-0-methyldobutamine. Both are pharmacologically inactive (6).

Hepatic arterial and portal resistance can be increased by adrenaline and noradrenaline (7). Total hepatic blood flow is increased by adrenaline, due to intestinal vasodilatation. Portal blood flow is increased by dopamine (8), but not by dobutamine (6). After an extensive literature search, including Medline, no data could be found concerning the use of these drugs for cardiac support in combination with liver diseases and the possible need for dose adjustment.

One study investigated the relative contribution of hepatic, renal and portal circulation to the clearance of exogenous catecholamines in dogs (9). The hepatic circulation cleared 16 per cent of noradrenaline, 24 per cent of adrenaline and 9 per cent of dopamine after infusion of clinical doses. The corresponding figures for portal circulation were 12, 22 and 10 per cent and for renal circulation 9, 22 and 9 per cent. Plasma noradrenaline and adrenaline concentrations were determined in nine controls and 32 patients with different stages of cirrhosis, during liver, heart and renal vein catherisation (10). In the cirrhotic patients, hepatic extraction ratios of noradrenaline and adrenaline were on the average 25 per cent and 20 per cent less than those in the controls. Renal extraction of adrenaline was not changed and renal extraction of noradrenaline was increased compared to the controls. The conclusion was that the increased plasma noradrenaline levels, found in some cirrhotic patients were only slightly due to a reduced splanchnic elimination, and merely the result of increased sympathic nervous activity. The effects of exogenous dopamine (2,4 and 6 ug/kg/min intravenously) on the portal circulation were studied in six patients following therapeutic hepatic artery ligation (9). Portal blood flow was dose-dependently increased by dopamine, to an increase of 53 per cent using a dose of 6 ug/kg/min. The portal venous pressure was not significantly affected. The pharmacokinetics of dopamine did not differ from data obtained from patients with an intact arterial supply.