Appendix: Sympathomimetic Pressors

Appendix: Sympathomimetic Pressors Jeffrey Brent Contents Dopamine Dopamine .......................................... 3009 Action and Structure ................................ 3009 Action and Structure Dosage and Administration . ....................... 3010 Precautions and Contraindications ................. 3010 Dopamine (Fig. 1) exerts its action predominantly Epinephrine ........................................ 3011 through the following three mechanisms: Action and Structure ................................ 3011 Dosage and Administration . ....................... 3011 Precautions and Contraindications ................. 3012 1. Dopamine receptor agonism: Dopamine is an agonist for the dopamine receptor. Dopamine Norepinephrine .................................... 3013 administration causes dopamine1 (D1) Action and Structure ................................ 3013 – Dosage and Administration . ....................... 3013 receptor mediated vasodilation. Precautions and Contraindications ................. 3013 2. β1-receptor agonism: At doses higher than Phenylephrine ..................................... 3014 those required for D1 receptor agonism (see Action ............................................... 3014 subsequently), dopamine may cause stimula- Dosage and Administration . ....................... 3014 tion of β1-receptors. Precautions and Contraindications ................. 3015 3. Generation of norepinephrine: As shown in Fig. 2, dopamine is a precursor in the biosyn- thetic pathway of epinephrine and norepinephrine. Approximately 75% of an administered dose of dopamine is inactivated by either monoamine oxidase (MAO) or catechol O-methyl transferase (COMT), and only about 25% is stoichiometrically converted to norepinephrine. Because of this, norepinephrine-mediated α-receptor agonism is seen only when high doses (see subsequently) of dopamine are administered. Based on animal data, it seems that dopamine J. Brent does not cross the placenta, and it does not cross Department of Medicine, Division of Clinical – Pharmacology and Toxicology, University of Colorado, the blood brain barrier except in preterm infants. School of Medicine, Aurora, CO, USA Its volume of distribution has been reported to # Springer International Publishing AG 2017 3009 J. Brent et al. (eds.), Critical Care Toxicology, DOI 10.1007/978-3-319-17900-1 3010 J. Brent Fig. 1 Chemical structures of dopamine, norepinephrine, epinephrine, and phenylephrine. Where indicated, the (R)-isomer, which possesses the most adrenergic activity, is shown range from 1.81 to 2.45 L/kg, and dopamine’s 2. Intermediate dose: At doses ranging from 3 to primary metabolite by MAO and COMT is homo- 10 μg/kg/min, predominantly β1-receptor vanillic acid. Its half-life is approximately 2 min effects are seen. There is still an increase in in adults, although it can be significantly longer in D1-mediated blood flow in the above- small children. Plasma dopamine concentrations described vascular territories and in the are normally less than 100 pg/mL. β1-receptor effects on the heart, resulting in an increase in heart rate, cardiac contractility, cardiac index, and conduction. At these doses, Dosage and Administration there may be modest increases in blood pressure but generally few effects on systemic vas- Dopamine should be administered intravenously. cular resistance (SVR), although small Solutions may be prepared by mixing decreases in SVR, may be seen. 200–800 mg of dopamine in 250–1000 mL of 3. High dose: At doses greater than 10 μg/kg/min, any standard intravenous solution. the α-adrenergic effects from norepinephrine Because of the various mechanisms by which synthesis tend to predominate and may over- dopamine acts, its effects depend on the dose whelm the D1 receptor–mediated vasodilation administered. There are several possible ranges of the above-described vascular beds. Doses of doses, as follows: greater than 50 μg/kg/min predictably cause severe vasoconstriction and generally should 1. Low dose: Doses ranging from 1 to 3 μg/kg/ not be used. min act primarily to dilate renal, intracerebral, mesenteric, and coronary vascular beds through activation of the D1 receptor. At these Precautions and Contraindications doses, there tends to be little observed effect on most monitored hemodynamic parameters, Because MAO is a major enzyme in the catabo- although in some cases the vasodilation of lism of dopamine, patients taking an inhibitor of these beds may cause a decrease in mean and this enzyme (see ▶ Chap. 50, “Monoamine Oxi- diastolic blood pressure. dase Inhibitors”) are expected to have a Appendix: Sympathomimetic Pressors 3011 Epinephrine Action and Structure Epinephrine (see Fig. 1), a term applicable only to the L-isomer of 1-(3,4-dihydroxy phenyl)-2- methylamino ethanol, exerts its action predominantly through the following two mechanisms: 1. β-Receptor agonism: Epinephrine is an agonist at β-receptors causing an increase in cardiac index, contractility, conduction, and heart rate. At low doses (see subsequently), the vasodilating effects of β-receptor agonism predominate, resulting in a decrease in SVR and widening of the pulse pressure. Epinephrine is not an ideal first-line vasopressor except in cases of anaphylactic shock. 2. α-Receptor agonism: At higher doses (see subsequently), epinephrine has significant α-receptor agonism resulting in an increase in SVR and mean arterial blood pressure. These effects may result in a reflex decrease in heart rate. Plasma epinephrine concentrations normally are 15–55 pg/mL. It is metabolized by MAO and COMT (Fig. 3). Its half-life is 2–3 min. Dosage and Administration Epinephrine is compatible with most standard intravenous fluid solutions. Autooxidation may Fig. 2 Biosynthesis of catecholamines occur in bicarbonate-containing solutions, how- ever. It is generally constituted as a 1:1000 (1 mg/mL) or 1:10,000 (100 μg/mL) solution; 10 mL of 1:100,000 is equivalent to 1 mg. When substantially exaggerated effect. It is generally given as a constant infusion, typically 1–2mgis recommended that doses of dopamine approxi- diluted into 250 mL (i.e., 4–8 μg/mL) of 5% mating one tenth of standard doses be adminis- dextrose in water or normal saline. tered in patients taking these agents. If these doses Epinephrine is best administered intrave- are ineffective, the dose can be titrated to the nously. If access is not immediately available, desired clinical effect. Because many dopamine other routes are possible. It can be given subcuta- preparations contain sodium metabisulfite, neously, typically as a 1:1000 solution, but the patients with sulfite allergies may develop allergic effects are delayed and variable, particularly reactions to dopamine administration. because of the local vasoconstriction it causes. 3012 J. Brent Fig. 3 Metabolism of norepinephrine and epinephrine by glycol, DHMA 3,4-dihydroxymandelic acid, MHPG monoamine oxidase (MAO) and catechol O-methyl- 3-methoxy-4-hydroxyphenylethylene glycol, VMA transferase (COMT). DHPGAL 3,4-dihydroxyphenyl- 3-methoxy-4-hydroxymandelic acid, MHPGAL 3-methoxy- glycolaldehyde, DHPEG 3,4-dihydro-xyphenyl ethylene 4-hydroxyphenylglycol aldehyde Epinephrine also can be administered via an endo- α-adrenergic effects become evident and eventu- tracheal tube in an emergent situation, whereby its ally predominate. The exact doses at which these pharmacologic effect is approximately half of that effects occur in the individual patient are variable which would be achieved by intravenous and should be determined based on the assess- administration. ment of the clinical response. In almost all circumstances in a critically ill patient, epinephrine should be infused intravenously, typically at doses ranging from 1 to Precautions and Contraindications 10 μg/min (0.02–0.2 μg/kg/min) and subsequently titrated to the desired effect. At the lower Patients on β-receptor antagonist therapy may end of this dose spectrum, β-adrenergic effects have an exaggerated hypertensive effect after the predominate. As the dose is increased, administration of epinephrine due to unopposed Appendix: Sympathomimetic Pressors 3013 α-receptor agonism. In patients taking these Norepinephrine generally is used primarily for agents, epinephrine should be used at the lowest its α-receptor–mediated vasoconstrictive proper- possible doses, which can be titrated as necessary. ties. As described earlier, it is preferable to epi- This effect potentially is seen even with patients nephrine in this regard despite norepinephrine’s using β-receptor antagonist eye drops. Because lower potency at the α-receptor because of epi- patients taking tricyclic antidepressants or nephrine’s vasodilating effect secondary to its venlafaxine have reduced reuptake of sympatho- agonist properties at the β2-receptor. The net result mimetic amines, their response to epinephrine of the administration of norepinephrine is an may be exaggerated. Here too doses should start increase in SVR and mean arterial blood pressure. low and be titrated gradually to the desired clinical Norepinephrine is metabolized by COMT and effect. MAO. The product of COMT metabolism is Because of a possible “catecholamine-sensitiz- normetanephrine, which is inactive. MAO action ing” effect of halogenated hydrocarbons on the forms norepinephrine aldehyde, which is subse- heart, epinephrine and other β-receptor agonists quently methylated by COMT to the inactive should be used cautiously in patients poisoned by vanillylmandelic acid. these agents. If it is necessary

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