61: Calcium Channel Blockers

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 variety of cardiovascular indications, including hypertension, dysrhythmias, and angina. Later indications, including Raynaud phenomenon, migraine headaches, and subarachnoid hemorrhage, have been adopted. 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.

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 7000 poisoning-related deaths reported to the American Association of Poison Control Centers Toxic Exposure Surveillance System. Cardiovascular drugs were involved in more than 474,000 of the reported poisonings and accounted for nearly 18% of the overall poisoning fatalities. Within this class, CCBs were the most common cardiovascular drugs involved in poisoning fatalities. CCBs accounted for more than 50,000 cases reported over the past 5 years, with 289 cases resulting in major effects and more than 100 deaths (Chap. 136).

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 61–1). 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.⁹⁰ The structure of voltage-dependent Ca²⁺ channels is composed of several components that include α₂, β, δ, and the ion-conducting α₁-subunit. The α₁-subunit is the most important component of the Ca²⁺ channel as it contains the actual pore through which Ca²⁺ ions pass and 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.^65,104

The primary action of all CCBs available in the United States is antagonism of the L-type or “long-acting” voltage-gated Ca²⁺ channels. CCBs are often classified into three groups based on ...