Calcium channel blockers (CCB), calcium channel antagonists or calcium antagonists
are a group of
medications that disrupt the movement of
calcium () through
calcium channel
A calcium channel is an ion channel which shows selective permeability to calcium ions. It is sometimes synonymous with voltage-gated calcium channel, although there are also ligand-gated calcium channels.
Comparison tables
The following tables e ...
s. Calcium channel blockers are used as
antihypertensive drugs, i.e., as medications to decrease
blood pressure
Blood pressure (BP) is the pressure of circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term "blood pressure" r ...
in patients with
hypertension
Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...
. CCBs are particularly effective against large vessel stiffness, one of the common causes of elevated
systolic
Systole ( ) is the part of the cardiac cycle during which some chambers of the heart contract after refilling with blood. The term originates, via New Latin, from Ancient Greek (''sustolē''), from (''sustéllein'' 'to contract'; from ''sun ...
blood pressure in
elderly patients.
Calcium channel blockers are also frequently used to alter
heart rate (especially from atrial fibrillation), to prevent peripheral and
cerebral vasospasm, and to reduce
chest pain
Chest pain is pain or discomfort in the chest, typically the front of the chest. It may be described as sharp, dull, pressure, heaviness or squeezing. Associated symptoms may include pain in the shoulder, arm, upper abdomen, or jaw, along with n ...
caused by
angina pectoris.
N-type,
L-type, and
T-type
The T-Type name was used in a series of Buick automobiles that were popular during the 1980s. This marketing approach for Buick products was a revival of a similar approach used in the 1960s (and later revived in the 1990s) with the Buick GS de ...
voltage-dependent calcium channels are present in the
zona glomerulosa of the
human adrenal gland, and CCBs can directly influence the
biosynthesis
Biosynthesis is a multi-step, enzyme-catalyzed process where substrates are converted into more complex products in living organisms. In biosynthesis, simple compounds are modified, converted into other compounds, or joined to form macromolecules. ...
of
aldosterone
Aldosterone is the main mineralocorticoid steroid hormone produced by the zona glomerulosa of the adrenal cortex in the adrenal gland. It is essential for sodium conservation in the kidney, salivary glands, sweat glands, and colon. It plays a c ...
in
adrenocortical cells
The adrenal cortex is the outer region and also the largest part of an adrenal gland. It is divided into three separate zones: zona glomerulosa, zona fasciculata and zona reticularis. Each zone is responsible for producing specific hormones. It i ...
, with consequent impact on the clinical treatment of
hypertension
Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...
with these
agents.
CCBs have been shown to be slightly more effective than
beta blockers at lowering
cardiovascular mortality
Mortality is the state of being mortal, or susceptible to death; the opposite of immortality.
Mortality may also refer to:
* Fish mortality, a parameter used in fisheries population dynamics to account for the loss of fish in a fish stock throug ...
, but they are associated with more
side effects. Potential major risks however were mainly found to be associated with short-acting CCBs.
Classes
Dihydropyridine
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
Angina, also known as angina pectoris, is chest pain or pressure, usually caused by ischemia, insufficient blood flow to the Cardiac muscle, heart muscle (myocardium). It is most commonly a symptom of coronary artery disease.
Angina is typical ...
, 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.
This CCB class is easily identified by the suffix "-dipine".
*
Amlodipine (Norvasc)
*
Aranidipine
Aranidipine (INN
Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they al ...
(Sapresta)
*
Azelnidipine
Azelnidipine (INN; marketed under the brand name CalBlock — カルブãƒãƒƒã‚¯) is a dihydropyridine calcium channel blocker. Azelnidipine is L and T calcium channel blocker.
It is sold in Japan by Daiichi-Sankyo pharmaceuticals, Inc.
Unlike ...
(Calblock)
*
Barnidipine
Barnidipine (INN
Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they al ...
(HypoCa)
*
Benidipine (Coniel)
*
Cilnidipine (Atelec, Cinalong, Siscard) Not available in US
*
Clevidipine
Clevidipine (INN, trade name Cleviprex) is a dihydropyridine calcium channel blocker indicated for the reduction of blood pressure when oral therapy is not feasible or not desirable. Clevidipine is used IV only and practitioners titrate this dr ...
(Cleviprex)
*
Efonidipine
Efonidipine (INN) is a dihydropyridine calcium channel blocker marketed by Shionogi & Co. of Japan. It was launched in 1995, under the brand name Landel (ランデル). The drug blocks both T-type and L-type calcium channels. Drug Controller ...
(Landel)
*
Felodipine (Plendil)
*
Isradipine (DynaCirc, Prescal)
*
Lacidipine
Lacidipine (tradenames Lacipil or Motens) is a calcium channel blocker. It is available as tablets containing 2 or 4 mg.
It was patented in 1984 and approved for medical use in 1991.
References
External links
Motens 2 mg
Summary ...
(Motens, Lacipil)
*
Lercanidipine
Lercanidipine (trade name Zanidip, among others) is an antihypertensive (blood pressure lowering) drug. It belongs to the dihydropyridine class of calcium channel blockers, which work by relaxing and opening the blood vessels allowing the blood t ...
(Zanidip)
*
Manidipine
Manidipine is a calcium channel blocker (dihydropyridine type) that is used clinically as an antihypertensive
Antihypertensives are a class of drugs that are used to treat hypertension (high blood pressure). Antihypertensive therapy seeks to ...
(Calslot, Madipine)
*
Nicardipine (Cardene, Carden SR)
*
Nifedipine (Procardia, Adalat)
*
Nilvadipine
Nilvadipine is a calcium channel blocker (CCB) used for the treatment of hypertension and chronic major cerebral artery occlusion.
Pathohistochemical studies have revealed that the volume of the infarction in the middle cerebral artery occlusion ...
(Nivadil)
*
Nimodipine (Nimotop) This substance can pass the
blood-brain barrier and is used to prevent
cerebral vasospasm.
*
Nisoldipine
Nisoldipine is a pharmaceutical drug used for the treatment of chronic angina pectoris and hypertension. It is a calcium channel blocker of the dihydropyridine class. It is sold in the United States under the proprietary name Sular. Nisoldipine ...
(Baymycard, Sular, Syscor)
*
Nitrendipine
Nitrendipine is a dihydropyridine calcium channel blocker. It is used in the treatment of primary (essential) hypertension to decrease blood pressure and can reduce the cardiotoxicity of cocaine.
It was patented in 1971 and approved for medica ...
(Cardif, Nitrepin, Baylotensin)
*
Pranidipine
Pranidipine is a calcium channel blocker. It is a long acting calcium channel antagonist of the dihydropyridine group.
References
Calcium channel blockers
Dihydropyridines
Carboxylate esters
Nitrobenzene derivatives
Methyl esters ...
(Acalas)
Non-dihydropyridine
Phenylalkylamine
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.
*
Fendiline
Fendiline is a '' nonselective'' calcium channel blocker.
References
Calcium channel blockers
Amines
{{cardiovascular-drug-stub ...
*
Gallopamil
*
Verapamil (Calan, Isoptin)
Benzothiazepine
Benzothiazepine calcium channel blockers belong to the
benzothiazepine
Thiazepines are substituted thiepins, with a nitrogen replacing a carbon in the seven-membered heterocyclic compound. Depending on the location of the nitrogen, one distinguishes 1,3-thiazepine and 1,4-thiazepine.
Benzothiazepines have a sing ...
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.
*
Diltiazem
Diltiazem, sold under the brand name Cardizem among others, is a calcium channel blocker medication used to treat high blood pressure, angina, and certain heart arrhythmias. It may also be used in hyperthyroidism if beta blockers cannot be used ...
(Cardizem) (also used experimentally to prevent migraine)
Nonselective
While most of the agents listed above are relatively selective, there are additional agents that are considered nonselective. These include
mibefradil
Mibefradil (trade name Posicor) was a pharmaceutical drug used for the treatment of hypertension and chronic angina pectoris. It is a nonselective calcium channel blocker. It was voluntary pulled from the market ten months after FDA approval, cit ...
,
bepridil,
flunarizine (
BBB crossing),
fluspirilene (
BBB crossing),
and
fendiline
Fendiline is a '' nonselective'' calcium channel blocker.
References
Calcium channel blockers
Amines
{{cardiovascular-drug-stub ...
.
Others
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
An analgesic drug, also called simply an analgesic (American English), analgaesic (British English), pain reliever, or painkiller, is any member of the group of drugs used to achieve relief from pain (that is, analgesia or pain management). It ...
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.
Naturally occurring compounds and elements such as
magnesium have also been shown to act as calcium channel blockers when administered orally.
Side effects
Side effects of these drugs may include but are not limited to:
*
Constipation
*
Peripheral edema, which can occur in as much as 70% of people receiving calcium channel blocker, is caused by calcium channel blockers'
preferential arteriolar or precapillary dilation without commensurate dilation in the venous or postcapillary circulation.
Since lymphatic drainage relies on contraction of the
smooth muscle
Smooth muscle is an involuntary non-striated muscle, so-called because it has no sarcomeres and therefore no striations (''bands'' or ''stripes''). It is divided into two subgroups, single-unit and multiunit smooth muscle. Within single-unit mus ...
inside the
lymphatic vessel supported by voltage-gated calcium channels, inhibition of voltage-gated calcium channel poses a threat towards lymphatic removal of interstitial fluid essential for normal lymphatic system functioning.
(See also:
Lymphedema.)
*
Gingival overgrowth
Gingival enlargement is an increase in the size of the gingiva (gums). It is a common feature of gingival disease. Gingival enlargement can be caused by a number of factors, including inflammatory conditions and the side effects of certain medi ...
Toxicity
Mild CCB
toxicity is treated with supportive care. Nondihydropyridine CCBs may produce profound toxicity, and early
decontamination, especially for slow-release agents, is essential. For severe
overdoses
A drug overdose (overdose or OD) is the ingestion or application of a drug or other substance in quantities much greater than are recommended. , treatment usually includes close monitoring of vital signs and the addition of vasopressive agents and intravenous fluids for blood pressure support. Intravenous
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
"Activated" is a song by English singer Cher Lloyd. It was released on 22 July 2016 through Vixen Records. The song was made available to stream exclusively on ''Rolling Stone'' a day before to release (on 21 July 2016).
Background
In an interv ...
,
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 therapy has emerged as a viable form of treatment. Although the mechanism is unclear, increased insulin may mobilize 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
Bradycardia (also sinus bradycardia) is a slow resting heart rate, commonly under 60 beats per minute (BPM) as determined by an electrocardiogram. It is considered to be a normal heart rate during sleep, in young and healthy or elderly adults, a ...
. If unsuccessful, ventricular pacing should be used.
Non-medical calcium channel inhibitors
Ethanol
Research indicates
ethanol is involved in the inhibition of L-type calcium channels. One study showed the nature of ethanol binding to L-type calcium channels is according to first-order kinetics with a
Hill coefficient around 1. This indicates ethanol binds independently to the channel, expressing
noncooperative binding. Early studies showed a link between calcium and the release of
vasopressin by the
secondary messenger system
Second messengers are intracellular signaling molecules released by the cell in response to exposure to extracellular signaling molecules—the first messengers. (Intercellular signals, a non-local form or cell signaling, encompassing both first me ...
.
Vasopressin levels are reduced after the ingestion of alcohol. The lower levels of vasopressin from the consumption of alcohol have been linked to ethanol acting as an antagonist to voltage-gated calcium channels (VGCCs). Studies conducted by Treistman et al. in the
aplysia confirm inhibition of VGCC by ethanol.
Voltage clamp recordings have been done on the aplysia neuron. VGCCs were isolated and calcium current was recorded using
patch clamp technique having ethanol as a treatment. Recordings were replicated at varying concentrations (0, 10, 25, 50, and 100 mM) at a voltage clamp of +30 mV. Results showed calcium current decreased as concentration of ethanol increased. Similar results have shown to be true in single-channel recordings from isolated nerve terminal of rats that ethanol does in fact block VGCCs.
Studies done by Katsura et al. in 2006 on mouse cerebral cortical neurons, show the effects of prolonged ethanol exposure. Neurons were exposed to sustained ethanol concentrations of 50 mM 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 showed 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.
Other experiments done by Malysz et al. have looked into ethanol effects on voltage-gated calcium channels on
detrusor smooth muscle 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 (about 50-mM) ethanol. Ethanol decreased the current in DSM cells and induced muscle relaxation. Ethanol inhibits VGCCs and is involved in alcohol-induced relaxation of the urinary bladder.
Agatoxin in spider venom
Research on the desert grass spider, ''
Agelenopsis aperta
''Agelenopsis aperta'', also known as the desert grass spider or funnel-web spider, is a species of spider belonging to the family Agelenidae and the genus ''Agelenopsis''. It is found in dry and arid regions across the southern United States a ...
,'' has shown that agatoxins IVA and IVB found in their venom selectively block calcium channels. These agatoxins are found in other spider species as well. Desert grass spider bites to insects result in rapid paralysis, but bites to humans are not considered medically significant.
Mechanism of action
In the body's tissues, the concentration of calcium ions () outside cells is normally about 10,000-fold higher than the concentration inside cells. Embedded in the
membrane of some cells are
calcium channel
A calcium channel is an ion channel which shows selective permeability to calcium ions. It is sometimes synonymous with voltage-gated calcium channel, although there are also ligand-gated calcium channels.
Comparison tables
The following tables e ...
s. 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.
Several types of calcium channels occur, with a number of classes of blockers, but almost all of them preferentially or exclusively block the
L-type voltage-gated calcium channel.
Voltage-dependent calcium channels are responsible for excitation-
contraction
Contraction may refer to:
Linguistics
* Contraction (grammar), a shortened word
* Poetic contraction, omission of letters for poetic reasons
* Elision, omission of sounds
** Syncope (phonology), omission of sounds in a word
* Synalepha, merged ...
coupling of
skeletal
A skeleton is the structural frame that supports the body of an animal. There are several types of skeletons, including the exoskeleton, which is the stable outer shell of an organism, the endoskeleton, which forms the support structure inside ...
,
smooth, and
cardiac muscle and for regulating
aldosterone
Aldosterone is the main mineralocorticoid steroid hormone produced by the zona glomerulosa of the adrenal cortex in the adrenal gland. It is essential for sodium conservation in the kidney, salivary glands, sweat glands, and colon. It plays a c ...
and
cortisol
Cortisol is a steroid hormone, in the glucocorticoid class of hormones. When used as a medication, it is known as hydrocortisone.
It is produced in many animals, mainly by the ''zona fasciculata'' of the adrenal cortex in the adrenal gland ...
secretion in
endocrine cells
The endocrine system is a messenger system comprising feedback loops of the hormones released by internal glands of an organism directly into the circulatory system, regulating distant target organs. In vertebrates, the hypothalamus is the neu ...
of the
adrenal cortex
The adrenal cortex is the outer region and also the largest part of an adrenal gland. It is divided into three separate zones: zona glomerulosa, zona fasciculata and zona reticularis. Each zone is responsible for producing specific hormones. It is ...
.
In the heart, they are also involved in the conduction of the
pacemaker
An artificial cardiac pacemaker (or artificial pacemaker, so as not to be confused with the natural cardiac pacemaker) or pacemaker is a medical device that generates electrical impulses delivered by electrodes to the chambers of the heart eith ...
signals. CCBs used as medications primarily have four effects:
* By acting on
vascular smooth muscle, they reduce contraction of the arteries and cause an increase in
arterial diameter, a phenomenon called
vasodilation (CCBs do not work on
venous smooth muscle).
* By acting on cardiac muscles (
myocardium
Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that ...
), they reduce the force of contraction of the heart.
* By slowing down the conduction of electrical activity within the heart, they slow down the heart beat.
* By blocking the calcium signal on adrenal cortex cells, they directly reduce aldosterone production, which correlates to lower blood pressure.
Since blood pressure is in intimate feedback with cardiac output and peripheral resistance, with relatively low blood pressure, the
afterload
Afterload is the pressure that the heart must work against to eject blood during systole (ventricular contraction). Afterload is proportional to the average arterial pressure. As aortic and pulmonary pressures increase, the afterload increases on ...
on the heart decreases; this decreases how hard the heart must work to eject blood into the aorta, so the amount of oxygen required by the heart decreases accordingly. This can help ameliorate symptoms of
ischaemic heart disease such as
angina pectoris.
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 CCBs make them a commonly used class of agents in individuals with
atrial fibrillation or
flutter
Flutter may refer to:
Technology
* Aeroelastic flutter, a rapid self-feeding motion, potentially destructive, that is excited by aerodynamic forces in aircraft and bridges
* Flutter (American company), a gesture recognition technology company acqu ...
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.
Because of the negative inotropic effects, the nondihydropyridine calcium channel blockers should be avoided (or used with caution) in individuals with
cardiomyopathy
Cardiomyopathy is a group of diseases that affect the heart muscle. Early on there may be few or no symptoms. As the disease worsens, shortness of breath, feeling tired, and swelling of the legs may occur, due to the onset of heart failure. A ...
.
Unlike
beta blockers, calcium channel blockers do not decrease the responsiveness of the heart to input from the
sympathetic nervous system
The sympathetic nervous system (SNS) is one of the three divisions of the autonomic nervous system, the others being the parasympathetic nervous system and the enteric nervous system. The enteric nervous system is sometimes considered part of th ...
. Since moment-to-moment blood pressure regulation is carried out by the sympathetic nervous system (via the
baroreceptor reflex
The baroreflex or
baroreceptor reflex is one of the body's homeostatic mechanisms that helps to maintain blood pressure at nearly constant levels. The baroreflex provides a rapid negative feedback loop in which an elevated blood pressure causes the ...
), calcium channel blockers allow blood pressure to be maintained more effectively than do beta blockers. However, because dihydropyridine CCBs 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
Magnesium aspartate, the chelated magnesium salt of aspartic acid, it is a mineral supplement.
Chemical action
This form of magnesium supplementation has increased bioavailability compared to magnesium oxide and magnesium citrate. There were som ...
, may increase or enhance the effects of calcium channel blockade.
N-type calcium channels are found in
neurons and are involved in the release of
neurotransmitter
A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell.
Neuro ...
at
synapse
In the nervous system, a synapse is a structure that permits a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or to the target effector cell.
Synapses are essential to the transmission of nervous impulses from ...
s.
Ziconotide is a selective blocker of these calcium channels and acts as an
analgesic
An analgesic drug, also called simply an analgesic (American English), analgaesic (British English), pain reliever, or painkiller, is any member of the group of drugs used to achieve relief from pain (that is, analgesia or pain management). It ...
.
History
Calcium channel blockers came into wide use in the 1960s, having been first identified in the lab of German pharmacologist
Albrecht Fleckenstein
Albrecht Fleckenstein (3 March 1917 – 4 April 1992) was a German pharmacologist and physiologist best known for his discovery of calcium channel blockers.
Life and career
Albrecht Fleckenstein was born on 3 March 1917 in Aschaffenburg, Ge ...
in 1964.
References
External links
*
*
* Video â€
Calcium Channel Blockers
{{DEFAULTSORT:Calcium Channel Blocker