Calcium channel blockers, calcium channel antagonists or calcium antagonists are a number
of medications that disrupts the movement of calcium through calcium channels.
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.
Calcium channel blockers are also frequently used to alter heart rate, to prevent cerebral
vasospasm, and to reduce chest pain caused by angina pectoris.
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.
Potential major risks however were mainly found to be associated with short-acting CCBs.
Classes Dihydropyridine
Dihydropyridine 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.
This CCB class is easily identified by the suffix "-dipine".
Amlodipine Aranidipine
Azelnidipine Barnidipine
Benidipine Cilnidipine Not available in US
Clevidipine Isradipine
Efonidipine Felodipine
Lacidipine Lercanidipine
Manidipine Nicardipine
Nifedipine Nilvadipine
Nimodipine This substance can pass the blood-brain barrier and is used to prevent cerebral vasospasm.
Nisoldipine Nitrendipine
Pranidipine Side effects of these drugs may include but
are not limited to: Dizziness, headache, redness in the face
Fluid buildup in the legs and ankle edema Rapid heart rate
Slow heart rate Constipation
Gingival overgrowth 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.
Verapamil Gallopamil
Fendiline Benzothiazepine
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.
Diltiazem Nonselective
While most of the agents listed above are relatively selective, there are additional
agents that are considered nonselective.
These include mibefradil, bepridil, flunarizine, fluspirilene, and fendiline.
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 properties that are equivalent to approximate
1,000 times that of morphine.
It must be delivered via the intrathecal route via an intrathecal infusion pump.
Toxicity
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 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 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.
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.
Mechanism of action
In the body's tissues, the concentration of calcium ions 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.
L-type calcium channels are responsible for excitation-contraction coupling of skeletal,
smooth, and cardiac muscle and for hormone secretion in endocrine cells.
In the heart they are also involved in the conduction of the pacemaker signals.
CCBs used as medications primarily have three effects:
by acting on vascular smooth muscle they reduce contraction of the arteries and cause an increase
in arterial diameter, a phenomenon called vasodilation
by acting on cardiac muscles, 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.
Since blood pressure is determined by cardiac output and peripheral resistance, CCBs reduce
blood pressure.
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.
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, 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 in individuals with cardiomyopathy.
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, 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.
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.
History Calcium channel blockers were first identified
in the lab of German pharmacologist Albrecht Fleckenstein beginning in 1964.
See also ACE inhibitor
Nitrate References
External links Calcium Channel Blockers at the US National
Library of Medicine Medical Subject Headings Official Adalat site, Bayer
Video - Calcium Channel Blockers