Diltiazem mechanism of action
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Diltiazem Mechanism of Action: Calcium Channel Blockade
Diltiazem is primarily known as a calcium channel blocker, specifically targeting voltage-gated L-type calcium channels in cardiac and vascular smooth muscle cells. It binds within the central cavity of these channels, physically blocking the passage of calcium ions and thereby reducing calcium influx into the cells 79. This blockade is both voltage- and use-dependent, meaning diltiazem is more effective when the channels are frequently activated or in a particular electrical state, such as inactivation 159.
Cardiac Effects: Negative Inotropy and Excitation-Contraction Uncoupling
In the heart, diltiazem reduces the force of contraction (negative inotropic effect) by limiting the amount of calcium available for muscle contraction. This effect is achieved without significantly altering the resting membrane potential or the basic electrical properties of the cardiac cells at lower concentrations 110. At higher concentrations, diltiazem can further reduce the rate of rise of the action potential, but the main action remains the reduction of intracellular free calcium . Diltiazem’s suppression of tension in human myocardium is due to its voltage-dependent block of the calcium channel and inhibition of calcium release from internal stores, not by affecting sodium-calcium exchange or the sensitivity of contractile proteins to calcium .
Vascular Smooth Muscle: Inhibition of Contraction
In vascular smooth muscle, diltiazem inhibits contraction by blocking calcium influx through the same L-type channels. This effect is dose-dependent and is closely related to its ability to inhibit calcium entry during muscle excitation, rather than by directly competing with calcium ions for entry . Diltiazem is effective in reducing contractions induced by both depolarization (high potassium) and adrenergic stimulation (norepinephrine), although higher concentrations of norepinephrine can make the muscle more resistant to diltiazem’s effects .
Molecular and Structural Insights
At the molecular level, diltiazem binds to specific amino acid residues within the channel’s transmembrane segments, particularly in the IIIS6 and IVS6 regions of the channel’s alpha1 subunit . Structural studies show that diltiazem’s binding site overlaps with that of other calcium channel blockers like verapamil, and its binding can be modulated by other drugs such as dihydropyridines . The drug can block the channel in different conformational states, with higher affinity for the inactivated state 59.
Additional Mechanisms and Effects
Beyond its primary action on calcium channels, diltiazem has been shown to have other effects, such as anti-inflammatory and anti-apoptotic actions in certain disease models, though these are not directly related to its main cardiovascular mechanism . Diltiazem can also alter the metabolism of other drugs, such as cyclosporine, but does not have significant direct immunosuppressive activity at therapeutic concentrations .
Conclusion
Diltiazem acts mainly by blocking L-type voltage-gated calcium channels in the heart and blood vessels, reducing calcium influx, and thereby decreasing muscle contraction and oxygen demand. Its effects are state-dependent, with a preference for inactivated channels, and it binds to specific sites within the channel pore. These actions underlie its clinical use in treating hypertension, angina, and certain cardiac arrhythmias 1357910.
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