Chapter 60: Calcium Channel Blockers

INTRODUCTION

HISTORY AND EPIDEMIOLOGY

In 1964, Albretch Fleckenstein described an inhibitory action of verapamil and prenylamine on excitation–contraction coupling that was similar to calcium depletion.³ By the late 1970s, the clinical use of calcium channel blockers (CCBs) was widely accepted for a variety of cardiovascular indications, including hypertension, dysrhythmias, and angina. Later indications for the use of CCBs include Raynaud phenomenon and disease, migraine and cluster headaches and subarachnoid hemorrhage.¹ There are currently 10 individual CCBs marketed in the United States that are available as immediate- or sustained-release formulations and as combination products with other antihypertensives.³¹

The cardiovascular drug class is one of the leading classes of drugs associated with poisoning fatality. Over the past 5 years of available data, there were more than 12 million poisonings with more than 7,000 poisoning-related deaths reported to the American Association of Poison Control Centers National Poisons Data System (NPDS). Cardiovascular drugs were involved in more than 400,000 of the reported poisonings and accounted for nearly 15% of the overall poisoning fatalities. Within this class, CCBs were the most common cardiovascular drugs involved in poisoning fatalities. Calcium channel blockers accounted for more than 50,000 cases reported over the past 5 years, with more than 300 cases resulting in major effects and more than 100 deaths (Chap. 130).^15,16,77,78 There is a bimodal distribution within the pediatric population that involves unintentional exposures in young infants and toddlers with intentional ingestions in teenagers.⁴⁰

PHARMACOLOGY

Calcium (Ca²⁺) ion channels exist as either voltage-dependent or ligand-gated channels. There are many types of voltage-gated Ca²⁺ channels that include P-, N-, R-, T-, Q-, and L-type channels (Table 60–1). Ligand-gated Ca²⁺ channels include IP₃ and ryanodine receptors, which are found intracellularly and play a critical role in cell signaling. Voltage-gated Ca²⁺ channels are located throughout the body in the heart, nervous system, pancreas, and muscles.¹⁰⁶ Voltage-gated Ca²⁺ channels are composed of several components, including α₂, β, δ, and the ion-conducting α₁-subunit. The α₁-subunit is the most important component of the Ca²⁺ channel because it contains the actual pore through which Ca²⁺ ions pass, and it also serves as the binding site of all CCBs. The other subunits such as β and δ act to modulate the function of the α₁-subunit.^79,122