and diltiazem do not bind to a channel in the resting state, only after the channel has been opened. They are ionized, water-soluble Ca2+-entry blockers that reach their binding sites by the hydrophilic pathway when the channel is open. Verapamil and diltiazem are use dependent (i.e., their Ca2+-blocking activity is a function of the frequency of contractions). An increase in contraction frequency causes a reduction, rather than an augmentation, of contractions. Nifedipine is a neutral molecule at physiological pH and can cause interference with the Ca2+ in the open or closed state. In the closed state, nifedipine can traverse the phospholipid bilayer to reach its binding site because of its lipid solubility.
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