Synthetic Catecholamine

Dobutamine is a synthetic catecholamine that is primarily used in heart failure, which could result to cardiogenic shock. This happens usually in cases of massive myocardial infarction or heart attack and usually harbors poor prognosis (Katzung, 2007). Dobutamine is only used in a short-term basis and is indicated in patients with acute decompensations of heart failure associated with poor tissue perfusion or resistant pulmonary edema. Moreover, low doses may also be sufficient to improve renal blood flow and to initiate a diuresis.

By increasing the renal blood flow, dobutamine decreases the risk of renal infarction as well as renal failure, which would further aggravate the situation of the patient (Carruthers, Hoffman, Melmon, & Nierenberg, 2000). Structure of dobutamine is shown in Figure 1. Figure 1. Dobutamine Pharmacodynamics As a positive inotropic agent, dobutamine increases the contractility of the heart resulting to the increase in cardiac output. Generally, dose-dependent increase in the cardiac output is achieved at infusion rates from 0 to 20 µg/kg per minute.

At this infusion rate some reduction in diastolic filling pressures has also been observed. Conventional studies states that dobutamine increases cardiac output but do not cause an increase in heart rate. However, this conclusion is derived from studies in patients with congestive heart failure, a population with ? -adrenergic receptor downregulation and volume overload. In these patients, effects of dobutamine cannot be assessed properly because of the decompensation which have already manifested in the patients.

In other populations that have not undergone decompensation, dobutamine have been shown to increase heart rate even more than epinephrine (Carruthers, Hoffman, Melmon, & Nierenberg, 2000; Zaloga, Prielipp, Butterworth, & Royster, 1993). Furthermore, dobutamine is most useful in the patient with cardiogenic shock because of its pattern of receptor stimulation. It can also be useful in septic shock to increase cardiac output and mean arterial pressure (Carruthers, Hoffman, Melmon, & Nierenberg, 2000; Jardin, Sportiche, & Bazin, 1981).

In a study by Berg, Padbury, Donnerstein, Klewer, & Hutter (1993) among the pediatric adolescents with critical illness or myocardial dysfunction, dobutamine has also been shown to improve systolic fuction in this population even at plasma concentrations attained with low infusions levels of 1 to 2 µg/kg/min. Moreover, in the same study, dobutamine also improved diastolic function and caused reduction in the afterload. Afterload is the force which the heart should overcome as it contract in order to pump blood to the peripheral circulation. Peripheral vascular resistance due to vasoconstriction mainly contributes to the afterload.

By improving the diastolic function, dobutamine allows the heart to be filled with more blood to be pumped. On the other hand, by increasing the force for heart contraction, it also increases the volume of blood pumped and the systolic pressure resulting to improved forward flow. As dobutamine decreases the peripheral vascular resistance by inducing vasodilation thereby decreasing afterload, the drug further reduces the effort required by the heart to pump blood to the peripheral circulation. Mechanisms of action Dobutamine largely acts by stimulating ? 1-adrenergic receptor.

1-adrenergic receptors are primarily present on the heart muscle and stimulation of these receptors results to an increase in both the force and rate of contraction of the heart muscles (Katzung, 2007). Looking at the equation below, we could infer that by increasing both myocardial contractility and heart rate, dobutamine ultimately increases the cardiac output. Dobutamine’s ? 1-adrenergic stimulating activity actually resides on its dextro isomer while its ? -receptor activity resides on the levo isomer (Carruthers, Hoffman, Melmon, & Nierenberg, 2000).

CO = MC x HR where: CO = cardiac output MC = myocardial contractility HR = heart rate Dobutamine’s ? 2-adrenergic effect is weak but its ? 1-adrenergic effect is even weaker, compared with its ? 1-adrenergic effects. ?2-receptors are mainly located in the respiratory, uterine, and vascular smooth muscle; skeletal muscles; and liver. Stimulation of ? 2-receptors by dobutamine promotes moderate smooth muscle relaxation resulting to respiratory muscle and uterine relaxation as well as peripheral vasodilation; promotion of potassium uptake by skeletal muscles; and activation of glycogenolysis by the liver.

Meanwhile, ? 1-adrenergic receptors are located on most vascular smooth muscle, papillary dilator muscle, pilomotor smooth muscle, prostate, and heart. Since dobutamine is only a very weak ? 1-addrenergic stimulator, its effects on these tissues namely vascular constriction; papillary dilation; hair erection; prostatic contraction; and increase in myocardial contraction are not very significant (Katzung, 2007).

Pharmacokinetics Dobutamine is solely available in parenteral preparation at 12. 5 mg/mL for intravenous infusion and so the drug is directly applied in the circulation circumventing absorption in the intestines. Pharmacokinetic data have revealed a wide range of plasma clearance rate in patients with critical illnesses or myocardial dysfunction. In order to more clearly elucidate the underlying pharmacologic processes, Berg et. al. (1993) sequentially administered graded intravenous dobutamine infusions of 0. 5, 2. 5 and 5. 0 micrograms/kg/min to healthy children and adolescents.

In their study, it has been found that mean plasma dobutamine clearance was 115 +/- 63 ml/kg/min, with an intersubject variability greater than 5-fold. The variability demonstrated in this study suggests that previously published wide variability in dobutamine clearance is not due simply to underlying disease states. This variability is also in parallel with the result of the study by Martinez, Padbury, & Thio (1992) among neonates showing dobutamine’s clearance in this population to be 90±38 mL/min per kilogram.

Furthermore, both of the above studies demonstrated that dobutamine clearance is linear and is most consistent with first-order kinetics over the dosage range evaluated, which has also been exhibited among healthy adult volunteers (Ahonen, Aranko, Iivanainen, Maunuksela, Paloheimo, & Olkkola, 2008). The mean calculated threshold value, or the minimum plasma concentration necessary for a change in cardiac output, was 39±8 ng/mL. Plasma catecholamine levels were unchanged during the dobutamine infusions (Martinez, Padbury, & Thio, 1992).

Dobutamine onset of action is rapid such that the effect could already be seen within 1 to 2 minutes. Nevertheless, it may require as much as 10 minutes for the peak effect to be obtained. Adverse effects Dobutamine’s adverse effects are mainly extensions of its therapeutic effects. The drug was reported to cause marked tachycardia or increase in heart rate and systolic blood pressure (Carruthers, Hoffman, Melmon, & Nierenberg, 2000).

In a study by Mertes, et al. (1993) among 1,118 patients, 19. 3% experienced angina pectoris while 3% experienced non-cardiac effects including nausea, anxiety, headache, tremor, and urgency. In the same study, 736 or 65% of the patients had stable sinus rhythm throughout the test while the most common arrhythmias experienced were premature ventricular complexes and premature atrial complexes, which occurred in 172 (15%) and 86 (8%) of the patients, respectively. There were also 40 patients who experienced non-sustained ventricular tachycardia. ?

Bibliography

  • Ahonen, J. , Aranko, K. , Iivanainen, A. , Maunuksela, E. , Paloheimo, M. , & Olkkola, K. (2008). Pharmacokinetic-pharmacodynamic relationship of dobutamine and heart rate, stroke volume and cardiac output in healthy volunteers. Clin Drug Investig , 28 (2), 121-127.
  • Berg, R. A. , Padbury, J. F. , Donnerstein, R. L. , Klewer, S. E. , & Hutter, J. J. (1993). Dobutamine pharmacokinetics and pharmacodynamics in normal children and adolescents. J Pharmacol Exp Ther June 1993 265:1232-1238 , 265 (3), 1232-1238.
  • Berg, R. A. , Padbury, J. F. , Donnerstein, R. L. , Klewer, S. E. , & Hutter, J. J. (1993). Dobutamine pharmacokinetics and pharmacodynamics in normal children and adolescents. J Pharmacol Exp Ther , 265, 1232-1238.
  • Carruthers, S. G. , Hoffman, B. B. , Melmon, K. L. , & Nierenberg, D. W. (2000). Melmon and Morrelli’s Clinical Pharmacology (4th ed. ). USA: McGraw-Hill.
  • Jardin, F. , Sportiche, M. , ; Bazin, M. (1981). Dobutamine: A hemodynamic evaluation in human septic shock. Crit Care Med , 9, 329-331.
  • Katzung, B. G. (2007). Basic and Clinical Pharmacology (10th ed. ). USA: McGraw-Hill Companies, Inc.
  • Martinez, A. , Padbury, J. F. , ; Thio, S. (1992). Dobutamine pharmacokinetics and cardiovascular responses in critically ill neonates. Pediatrics , 89 (1), 47-51.
  • Mertes, H. , Sawada, S. , Ryan, T. , Segar, D. , Kovacs, R. , Foltz, J. , et al. (1993). Symptoms, adverse effects, and complications associated with dobutamine stress echocardiography. Circulation , 88, 15-19.
  • Zaloga, G. P. , Prielipp, R. C. , Butterworth, J. F. , ; Royster, R. L. (1993). Pharmacologic cardiovascular support. Crit Care Clin , 9 (2), 335-362.
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