Calcium channel blocker

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Calcium channel blockers (CCB), calcium channel antagonists or calcium antagonists[1] are several medications that disrupt the movement of calcium (Ca2+) through calcium channels.[2] Calcium channel blockers are used as antihypertensive drugs, i.e., as medications to decrease blood pressure in patients with hypertension. CCBs are particularly effective against large vessel stiffness, one of the common causes of elevated systolic blood pressure in elderly patients.[3] Calcium channel blockers are also frequently used to alter heart rate, to prevent cerebral vasospasm, and to reduce chest pain caused by angina pectoris. N-type, L-type, and T-type voltage-dependent calcium channels are present in the zona glomerulosa of the human adrenal, and CCBs can directly influence the biosynthesis of aldosterone in adrenocortical cells, with consequent impact on the clinical treatment of hypertension with these agents.[4]

Despite their effectiveness, CCB's often have a high mortality rate over extended periods of use, and have been known to have multiple side effects.[5] Potential major risks however were mainly found to be associated with short-acting CCBs.[6]



Dihydropyridine (DHP) calcium channel blockers are derived from the molecule dihydropyridine and often used to reduce systemic vascular resistance and arterial pressure. Sometimes when they are used to treat angina, the vasodilation and hypotension can lead to reflex tachycardia, which can be detrimental for patients with ischemic symptoms because of the resulting increase in myocardial oxygen demand. Dihydropyridine calcium channel blockers can worsen proteinuria in patients with nephropathy.[7]

This CCB class is easily identified by the suffix "-dipine".

Side effects of these drugs may include but are not limited to:



Phenylalkylamine calcium channel blockers are relatively selective for myocardium, reduce myocardial oxygen demand and reverse coronary vasospasm, and are often used to treat angina. They have minimal vasodilatory effects compared with dihydropyridines and therefore cause less reflex tachycardia, making it appealing for treatment of angina, where tachycardia can be the most significant contributor to the heart's need for oxygen. Therefore, as vasodilation is minimal with the phenylalkylamines, the major mechanism of action is causing negative inotropy. Phenylalkylamines are thought to access calcium channels from the intracellular side, although the evidence is somewhat mixed.[8]


Benzothiazepine calcium channel blockers belong to the benzothiazepine class of compounds and are an intermediate class between phenylalkylamine and dihydropyridines in their selectivity for vascular calcium channels. By having both cardiac depressant and vasodilator actions, benzothiazepines are able to reduce arterial pressure without producing the same degree of reflex cardiac stimulation caused by dihydropyridines.


While most of the agents listed above are relatively selective, there are additional agents that are considered nonselective. These include mibefradil, bepridil, flunarizine (BBB crossing), fluspirilene (BBB crossing),[9] and fendiline.[10]


Gabapentinoids, such as gabapentin and pregabalin, are selective blockers of α2δ subunit-containing voltage-gated calcium channels. They are used primarily to treat epilepsy and neuropathic pain.

Ziconotide, a peptide compound derived from the omega-conotoxin, is a selective N-type calcium channel blocker that has potent analgesic properties that are equivalent to approximate 1,000 times that of morphine. It must be delivered via the intrathecal (directly into the cerebrospinal fluid) route via an intrathecal infusion pump.


Ethanol blocks voltage gated calcium channel

Research indicates that ethanol is involved in the inhibition of L-Type Calcium channels. Earlier studies show a link between calcium and the release of vasopressin by secondary messenger system.[11] Vasopressin levels are reduced after the ingestion of alcohol.[12] The lower levels of vasopressin from the consumption of alcohol has been linked to ethanol acting as an antagonist to voltage-gated calcium channels (VGCC). Studies conducted in the aplysia confirm earlier results. Voltage clamp recordings were done on the aplysia neuron and VGCC were isolated and calcium current was recorded using patch clamp technique having ethanol as a treatment. Recordings were replicated at varying concentrations (0mM, 10mM, 25mM, 50mM, and 100 mM) at a voltage clamp of +30 mV. Results show that calcium current decreases as concentration of ethanol increases.[13] Similar results have shown to be true in single channel recordings form isolated nerve terminal of rats that ethanol does in fact block VGCC.[14]

There has been additional studies on mouse cerebral cortical neurons and the effects of prolonged ethanol exposure. Neurons were exposed to sustained ethanol concentrations of 50mM for 3 days in vitro. Western blot and protein analysis were conducted to determine the relative amounts of VGCC subunit expression. α1C, α1D, and α2/δ1 subunits show an increase of expression after sustained ethanol exposure. However, the β4 subunit showed a decrease. Furthermore, α1A, α1B, and α1F subunits did not alter in their relative expression. Thus sustained ethanol exposure may participate in the development of ethanol dependence in neurons.[15]

Other experiments have looked into ethanol effects on voltage-gated calcium channels on detrusor smooth muscle (DSM) cells in guinea pigs. Perforated patch clamp technique was used having intracellular fluid inside the pipette and extracellular fluid in the bath with added 0.3% vol/vol (~ 50mM) ethanol. Results show that ethanol decreased the Ca2+ current in DSM cells and induced muscle relaxation. Ethanol inhibits VGCC and is involved in alcohol-induced relaxation of the urinary bladder.[16]

Studies have shown that the nature of ethanol binding to L-type calcium channels is according to first order kinetics with a Hill coefficient of approximately 1. Thus, indicating completely independent binding of ethanol to the channel and expressing non-cooperative binding[17]


Mild CCB toxicity is treated with supportive care. Non-dihydropyridine CCB may produce profound toxicity and early decontamination, especially for slow release agents, is essential. For severe overdoses, treatment usually includes close monitoring of vital signs and the addition of vasopressive agents and intravenous fluids for blood pressure support. IV calcium gluconate (or calcium chloride if a central line is available) and atropine are first-line therapies. If the time of the overdose is known and presentation is within two hours of ingestion, activated charcoal, gastric lavage, and polyethylene glycol may be used to decontaminate the gut. Efforts for gut decontamination may be extended to within 8 hours of ingestion with extended release preparations.

Hyperinsulinemia-euglycemia (HIE) therapy has emerged as a viable form of treatment. Although the mechanism is unclear, it has been hypothesized that increased insulin mobilizes glucose from peripheral tissues to serve as an alternative fuel source for the heart (the heart mainly relies on oxidation of fatty acids). Theoretical treatment with lipid emulsion therapy has been considered in severe cases, but is not yet standard of care.

Caution should be taken when using verapamil with a Beta blocker due to the risk of severe bradycardia. If unsuccessful, ventricular pacing should be used.[18]

Mechanism of action[edit]

A calcium channel embedded in a cell membrane.

In the body's tissues, the concentration of calcium ions (Ca2+) outside of cells is normally about ten-thousand-fold higher than the concentration inside of cells. Embedded in the membrane of some cells are calcium channels. When these cells receive a certain signal, the channels open, letting calcium rush into the cell. The resulting increase in intracellular calcium has different effects in different types of cells. Calcium channel blockers prevent or reduce the opening of these channels and thereby reduce these effects.

There are several types of calcium channels, and a number of classes of calcium channel blockers, but almost all of them preferentially or exclusively block the L-type voltage-gated calcium channel.[19]

Voltage-dependent calcium channels are responsible for excitation-contraction coupling of skeletal, smooth, and cardiac muscle and for regulating aldosterone and cortisol secretion in endocrine cells of the adrenal cortex.[4] In the heart they are also involved in the conduction of the pacemaker signals. CCBs used as medications primarily have four effects:

Since blood pressure is in intimate feedback with cardiac output and peripheral resistance, with relatively low blood pressure, the afterload on the heart decreases; this decreases how hard the heart must work to eject blood into the aorta, and so the amount of oxygen required by the heart decreases accordingly. This can help ameliorate symptoms of ischaemic heart disease such as angina pectoris.

Immunohistochemical analysis of L-type calcium channel Cav1.3 (CACNA1D) in human adrenal cortex. Marked immunoreactivity was detected in the zona glomerulosa. In the figure: ZG = zona glomerulosa, ZF = zona fasciculata, AC = adrenal capsule. Immunohistochemistry was performed according to published methods.[4]

Reducing the force of contraction of the myocardium is known as the negative inotropic effect of calcium channel blockers. Slowing down the conduction of electrical activity within the heart, by blocking the calcium channel during the plateau phase of the action potential of the heart (see: cardiac action potential), results in a negative chronotropic effect, or a lowering of heart rate. This can increase the potential for heart block. The negative chronotropic effects of calcium channel blockers make them a commonly used class of agents in individuals with atrial fibrillation or flutter in whom control of the heart rate is generally a goal. Negative chronotropy can be beneficial when treating a variety of disease processes because lower heart rates represent lower cardiac oxygen requirements. Elevated heart rate can result in significantly higher "cardiac work," which can result in symptoms of angina.

The class of CCBs known as dihydropyridines mainly affect arterial vascular smooth muscle and lower blood pressure by causing vasodilation. The phenylalkylamine class of CCBs mainly affect the cells of the heart and have negative inotropic and negative chronotropic effects. The benzothiazepine class of CCBs combine effects of the other two classes.

It is because of the negative inotropic effects that the nondihydropyridine calcium channel blockers should be avoided (or used with caution) in individuals with cardiomyopathy.[20]

Unlike beta blockers, calcium channel blockers do not decrease the responsiveness of the heart to input from the sympathetic nervous system. Since moment-to-moment blood pressure regulation is carried out by the sympathetic nervous system (via the baroreceptor reflex), calcium channel blockers allow blood pressure to be maintained more effectively than do beta blockers. However, because dihydropyridine calcium channel blockers result in a decrease in blood pressure, the baroreceptor reflex often initiates a reflexive increase in sympathetic activity leading to increased heart rate and contractility.

Ionic calcium is antagonized by magnesium ions in the nervous system. Because of this, bioavailable supplements of magnesium, possibly including magnesium chloride, magnesium lactate, and magnesium aspartate, may increase or enhance the effects of calcium channel blockade.[21]

N-type calcium channels are found in neurons and are involved in the release of neurotransmitter at synapses. Ziconotide is a selective blocker of these calcium channels and acts as an analgesic.


Calcium channel blockers were first identified in the lab of German pharmacologist Albrecht Fleckenstein beginning in 1964.[22]

See also[edit]


  1. ^ Olson, Kent (2011). "Calcium Channel Antagonists". Poisoning & drug overdose (6th ed. ed.). New York: McGraw-Hill Medical. pp. Chapter 40. ISBN 0071668330. 
  2. ^ "calcium channel blocker" at Dorland's Medical Dictionary
  3. ^ Nelson M (2010). "Drug treatment of elevated blood pressure" (pdf). Australian Prescriber 33 (4): 108–112. 
  4. ^ a b c Felizola SJA, Maekawa T, Nakamura Y, Satoh F, Ono Y, Kikuchi K, Aritomi S, Ikeda K, Yoshimura M, Tojo K, Sasano H. (2014). "Voltage-gated calcium channels in the human adrenal and primary aldosteronism.". J Steroid Biochem Mol Biol. 144 (part B): 410–416. doi:10.1016/j.jsbmb.2014.08.012. PMID 25151951. 
  5. ^ "Calcium Channel Blockers". MedicineNet. p. 2. 
  6. ^ Norman M Kaplan, MD; Burton D Rose, MD (Apr 3, 2000). "Major side effects and safety of calcium channel blockers". Chinese Medical & Biological Information. 
  7. ^ Remuzzi G, Scheppati A, Ruggenenti P (2002). "Clinical Practice. Nephropathy in Patients with Type 2 Diabetes". New England Journal of Medicine 346 (15): 1145–1151. doi:10.1056/NEJMcp011773. PMID 11948275. 
  8. ^ Hockerman, G.H.; Peterson, B.Z.; Johnson, B.D.; Catterall, W.A. (1997). "Molecular Determinants of Drug Binding and Action on L-Type Calcium Channels". Annual Review of Pharmacology and Toxicology 37: 361–396. doi:10.1146/annurev.pharmtox.37.1.361. PMID 9131258. 
  9. ^ Bezprozvanny I, Tsien RW (1995). "Voltage-Dependent Blockade of Diverse Types of Voltage-Gated Ca2+ Channels Expressed in Xenopus Oocytes by the Ca2+ Channel Antagonist Mibefradil (Ro 40-5967)". Molecular Pharmacology 48 (3): 540–549. PMID 7565636. 
  10. ^ Scultéty S, Tamáskovits E (1991). "Effect of Ca2+ Antagonists on Isolated Rabbit Detrusor Muscle". Acta Physiologica Hungarica 77 (3–4): 269–278. PMID 1755331. 
  11. ^ Tobn, Vicky; Leng, Gareth; Ludwig, Mke (12 July 2010). "The involvement of actin, calcium channels and exocytosis proteins in somato-dendritic oxytocin and vasopressin release". Frontiers in Physiology: 1–7. Retrieved 7 November 2014. 
  12. ^ Chiodera, Coiro (1990). "Inhibitory effect of ethanol on the arginine vasopressin response to insulin-induced hypoglycemia and the role of endogenous opioids.". Neuroendocrinology 51 (5): 501–504. 
  13. ^ Treistman, Steven; Bayley, Hagan; Lemos, Jose; Wang, Xiaoming; Nordman, Jean; Grant, Alan (June 1991). "Effects of Ethanol on Calcium Channels, Potassium Channels, and Vasopressin Release". Annals of the New York Academy of Sciences 625 (1): 249–263. 
  14. ^ Walter, Helen; Essing, Robert (August 1999). "Regulation of neuronal voltage-gated calcium channels by ethanol". Neurochemistry International 35 (2): 95–101. 
  15. ^ Katsura, Masashi; Shibasaki, Masahiro; Hayashida, Shinsuke; Torigoe, Fumiko; Tsuhi, Atsushi; Ohkuma, Seitaro (2006). "Increase in Expression of α1 and α2/δ1 Subunits of L-Type High Voltage-Gated Calcium Channels After Sustained Ethanol Exposure in Cerebral Cortical Neurons". Journal of Pharmacological Sciences 102: 221–230. 
  16. ^ Malysz, John; Afeli, Serge; Provence, Aaron; Petkov, Georgi (2014). "Ethanol-mediated relaxation of guinea pig urinary bladder smooth muscle: involvement of BK and L-type Ca2+ channels". American Journal of Physiology 306 (1): 45–58. 
  17. ^ Wang, Xiaoming; Wang, Gang; Lemos, Jose; Treistman, Steven (1994). "Ethanol Directly Modulates Gating of a Dihydropyridine-Sensitive Ca*+ Channel in Neurohypophysial Terminals". The Journal of Neuroscience 14 (9): 5453–5460. 
  18. ^ Buckley N, Dawson A, Whyte I (2007). "Calcium Channel Blockers". Medicine 35 (11): 599–602. doi:10.1016/j.mpmed.2007.08.025. 
  19. ^ Yousef et al. (2005). "The mechanism of action of calcium channel blockers in the treatment of diabetic nephropathy". Int J Diabetes & Metabolism 13: 76–82. 
  20. ^ Lehne R (2010). Pharmacology for Nursing Care (7th ed.). St. Louis, Missouri: Saunders Elsevier. p. 505. ISBN 978-1-4160-6249-3. 
  21. ^ Iseri LT, French JH (1984). "Magnesium: Nature's Physiologic Calcium Blocker". American Heart Journal 108 (1): 188–193. doi:10.1016/0002-8703(84)90572-6. PMID 6375330. 
  22. ^ Fleckenstein, A. (1983). "History of calcium antagonists". Circulation research 52 (2 Pt 2): I3–16. PMID 6339106.  edit

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