SURGICAL PHARMACOLOGY Advances in Calcium Blocker Therapy Davkl R. Larach, MD, PhD, Hershey, Pennsylvania Robed Zelis, MD, Hershey, Pennsylvania The universal necessity of calcium in living systems was first demonstrated by the physiologist Sidney Ringer [I], who induced cardiac arrest in frog hearts by perfusing them with calcium-free saline solution. Today, calcium ions are added to most clinical re- placement fluids such as Ringer’s lactate. How, then, can calcium blocking drugs, which reduce the entry of calcium ions into cells, possibly have a therapeutic use? The answer lies in two observa- tions. First, excessive entry of calcium ions into cells is implicated in a number of pathologic states, such as ischemia-induced cell death, hypertension, and angina pectoris. Second, the clinically useful calci- um blocker drugs possess selective actions, and they neither totally block entry of calcium ions nor do they affect all tissues and organs equally. The first calcium blocker was described in 1964 [2]. New calcium blockers, which hold the promise of more precise and selective actions, continue to be developed and tested. The therapeutic indications for calcium blockers are rapidly expanding, and the use of these drugs will probably continue to grow dramatically. The surgeon may currently find him- self prescribing calcium blockers because of his pa- tients’ associated medical conditions, but increas- ingly, he will also utilize them to help treat the primary surgical problem. The basic physiologic characteristics of calcium ions and the pharmacologic actions of the calcium blockers have been the subjects of excellent recent reviews [3-71. Herein, we will review current aspects of the clinical pharmacologic actions and use of calcium blockers, important new drugs in the sur- geon’s armamentarium. From the Departments of Anesthesia and Medicine, College of Medicine, The Pennsylvania State University, Hershey, Pennsylvania. Requests for reprints should be addressed to David R. Larach, MD. Department of Anesthesia, The Milton S. Hershey Medical Center, PO Box 650. Hershey, Pennsylvania 17033. Definitii and Mechanism of Action The calcium blocking drugs are a diverse group of compounds that impede the entry of extracellular calcium ions into cells. No unifying structure and activity relationship has yet been identified. These drugs are known by a variety of names, including calcium blockers, slow-channel blockers, calcium- entry blockers, and calcium antagonists. In many tissues, an increase in the concentration of free intracellular calcium ions is needed to pro- duce a contractile or secretory response. These cal- cium ions may come from two main sources: the extracellular space and intracellular storage depots. External calcium usually enters cells by traveling through protein pores within the cell membrane. These pores are quite selective for calcium ions, and are commonly called slow or calcium channels. Calcium blockers impede the passage of calcium ions through these channels, generally by altering the molecular conformation of the channel protein. Calcium blockers do not totally block the calcium ion channels, since it would be incompatible with life. Instead, a reduction in channel activity occurs. The pharmacologic actions of calcium blockers are determined by a combination of many factors. Tissue responsiveness to calcium channel blockade: Tissues that have small intracellular cal- cium ion storage depots, such as vascular smooth muscle, are highly dependent on entry of external calcium ions for contraction, and therefore may be very sensitive to calcium blockers. On the other hand, tissues such as skeletal muscle contain vast stores of calcium ions within their cells; inhibiting entry of external calcium ions with a drug causes minimal change in function for such tissues. Selective drug actions on calcium channels in different tissues: Each calcium blocking drug has its own individual profile of tissue selectivity, inhib- Volume 151, April 1686 527