Use of inotropes and vasopressor agents in critically ill patients

Abstract

Inotropes and vasopressors are biologically and clinically important compounds that originate from different pharmacological groups and act at some of the most fundamental receptor and signal transduction systems in the body. More than 20 such agents are in common clinical use, yet few reviews of their pharmacology exist outside of physiology and pharmacology textbooks. Despite widespread use in critically ill patients, understanding of the clinical effects of these drugs in pathological states is poor. The purpose of this article is to describe the pharmacology and clinical applications of inotropic and vasopressor agents in critically ill patients.

Figure 1

Intracellular mechanisms of catecholamine and PDE inhibitor (PDEI) modulation of chronotropy, dromotropy, lusitropy and inotropy. β adrenoreceptors coupled positively to adenylate cyclase via Gs increase cAMP levels and PKA activity. PDEIs inhibit cAMP breakdown, increasing levels and PKA activity. cAMP increases the open state of if(Na+) channels to increase pacemaker rate. PKA co-ordinates by activating i(K+) channels involved in repolarization. This is the cellular mechanism of chronotropy and dromotropy. PKA also increases L-type Ca2+ channel activity and enhances sarcoplasmic reticulum (SR) Ca2+ uptake and lusitropy. Increased SR Ca2+ content and L-type Ca2+ channel activation increases myocardial Ca2+ transients, resulting in greater contractile strength and inotropy. α1 adrenoceptors may also increase Ca2+ levels in a manner similar to that in vascular smooth cells, but the increase is only 10–15% of that achievable by β adrenoceptor mechanisms. α₂ adrenoceptors have not been found on cardiomyocytes. 5′AMP, 5′ adenosine monophosphate; Gs/q, G-protein signalling α subunit to which receptor is coupled; if(Na+), channel related to inward ‘funny’ sodium current involved in pacemaker rate; ifK+, channel related to delayed rectifier potassium current involved in repolarisation; iLCa2+-_, channel related to inward calcium current; IP₃, inositol 1,4,5 trisphosphate; PIP₂, phosphatidylinositol 4,5 bisphosphate.

Figure 2

Intracellular mechanisms of catecholamine and PDEI modulation of vascular tone. Catecholamines and PDEIs modulate [Ca2+]i and, therefore, vascular smooth muscle cell tone as Ca2+ activates myosin light chain kinase (MLCK) and downstream contractile events. Vasoconstriction follows cAMP decreases or PLC stimulation. Vasodilatation follows cAMP increases. cAMP is broken down by PDE and generated by adenylate cyclase (AC). β adrenoceptors positively couple to AC by Gs whereas α2 adrenoceptors negatively couple via Gi. cAMP activates PKA, which is responsible for enhancing calcium pumping into sarcoplasmic reticulum (SR) and extracellular spaces, for MLCK inhibition and cellular hyperpolarization consequently inhibiting voltage-sensitive calcium channel (VSCC). α1 adrenoceptors positively couple to PLC via Gq resulting in the generation of inositol 1,4,5 trisphosphate (IP3) and DAG from phosphatidylinositol 4,5 bisphosphate (PIP2). IP3 activates SR calcium channels, increasing [Ca2+]i while DAG and calcium both stimulate PKC. PKC enhances contractile element sensitivity. Receptor-operated calcium channels (ROCC) are positively coupled to α1 adrenoceptors via non Gq subunits. NO is generated by NOS 3 in endothelium following α2 and β adrenoceptor ligation. NO diffuses to vascular smooth muscle resulting in protein kinase G mediated decreases in calcium, PDE inhibition and vasodilatation. The endothelium is thus a powerful modulator of vascular tone. 5′AMP, 5′ adenosine monophosphate; Gs/i/q, relevant G-protein α subunit.