Chapter 4

Clinical pharmacology associated with cardiac surgery is an important part of patient management. Patients in the perioperative period receive multiple agents that affect cardiovascular and pulmonary function. This chapter summarizes the pharmacology of the agents commonly used for treating the primary physiologic disturbances associated with cardiac surgery, hemodynamic instability, respiratory insufficiency, and alterations of hemostasis. For cardiovascular drugs, the common theme is that pharmacologic effects are produced by intracellular ion fluxes.

Several basic subcellular/molecular pathways are important in cardiovascular pharmacology, as shown in Fig. 4-1. The action potential in myocardial cells is a reflection of ion fluxes across the cell membrane, especially Na+, K+, and Ca2+.1,2 Numerous drugs used to control heart rate and rhythm act by altering Na+ (eg, lidocaine and procainamide), K+ (eg, amiodarone, ibutilide, and sotalol), or Ca2+ (eg, diltiazem) currents. Calcium also has a dominant effect on the inotropic state.3,4

###### Figure 4-1

Cardiac ion fluxes and the action potential. The resting membrane potential is largely a reflection of the intercellular/intracellular potassium gradient. Depolarization of the membrane during phase 4 triggers an initial fast sodium channel with overshoot (phase 0) followed by recovery (phase 1) to a plateau (phase 2) maintained by an inward calcium flux and then repolarization owing to an outward potassium flux (phase 3).

Myocardial contractility is a manifestation of the interaction of actin and myosin, with conversion of chemical energy from ATP hydrolysis into mechanical energy. The interaction of actin and myosin in myocytes is inhibited by the associated protein tropomyosin. This inhibition is "disinhibited" by intracellular calcium. A similar situation occurs in vascular smooth muscle, where the interaction of actin and myosin (leading to vasoconstriction) is modulated by the protein calmodulin, which requires calcium as a cofactor. Thus intracellular calcium has a "tonic" effect in both the myocardium and vascular smooth muscle.

Numerous drugs used perioperatively alter intracellular calcium.3,4

Catecholamines (eg, norepinephrine, epinephrine, and dobutamine) with beta agonist activity regulate intramyocyte calcium levels via the nucleotide cyclic adenosine monophosphate (cyclic AMP) (Fig. 4-2). Beta agonists bind to receptors on the cell surface that are coupled to the intracellular enzyme adenylate cyclase via the stimulatory transmembrane GTP-binding protein. This leads to increased cyclic AMP synthesis, and cyclic AMP, in turn, acts as a second messenger for a series of intracellular reactions resulting in higher levels of intracellular calcium during systole. Less well known is that drugs with only alpha-adrenergic agonist activity also may increase intracellular Ca2+ levels, although by a different mechanism.5,6 Although under investigation, the probable basis for the inotropic effect of alpha-adrenergic drugs is the stimulation of phospholipase C, which catalyzes hydrolysis of phosphatidyl inositol to diacylglycerol and inositol triphosphate (see Fig. 4-2). Both ...

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