Calcium - Channel blockers
The calcium-channel blockers, also called calcium-channel inhibitors or calcium antagonists, are the drugs which inhibit the influx of calcium into the cell through voltage-gated calcium-channels.
By limiting the calcium influx into cells, calcium-channel inhibitors have several effects :
- Cardiac effects
- at the level of the nodal tissue: slowing of slow diastolic depolarization and phase 0 of the action potential.
- at the level of the myocardium: possibility of a negative inotropic effect.
- Vascular effects: vasodilation which is predominantly, peripheral, coronary or cerebral according to the inhibitors.
- Effects on non vascular smooth muscles: relaxation.
- Neurological effects: decrease of excitability.
Each calcium-channel inhibitor has, according to its affinity for certain calcium channels and certain tissues, a predominant effect corresponding to a preferential therapeutic indication.
Calcium-channel inhibitors - with cardiovascular effects
Calcium-channel inhibitors are classified according to their predominant, vascular or cardiac effect.
With a predominant vascular effect
By acting on L type calcium channels, and for some of them on T type, these inhibitors induce vasodilation of arteries, including coronary, reduce peripheral resistance, lower arterial pressure. If this lowering is too fast, it induces a catecholamine release which has a vasoconstrictive action and positive inotropic and chronotropic effects.
- Nifedipine is a calcium-channel inhibitor with predominant vascular effect. Chemically, it is a dihydropyridine which contains a NO 2 group on the benzene nucleus, but is not hovewer a NO donor because, during its metabolism, the NO 2 group is not modified.
The therapeutic uses of nifedipine, Adalate*, Adalat*, in immediate release formulations are limited to the treatment of certain angina pectoris and the phenomena of Raynaud and in sustained-release formulations the treatment of the arterial hypertension for which there are several other drugs acting by different mechanisms.
- Amlodipine (Norvasc*) and felodipine (Plendil*) are also dihydropyridines indicated in the treatment of the common arterial hypertension and for the prevention of angina pectoris attacks.
During clinical studies amlodipine appeared more effective than atenonol, a beta-blocker, to reduce the frequency of cardiovascular and cerebral accidents in hypertensive patients.
- The other inhibitors with dihydropyridine structure used for the treatment of common arterial hypertension are nicardipine (Cardene*), nitrendipine (Baypress*), isradipine (Dynacirc*), felodipine, lacidipine (Motens*), lercanidipine (Zanidip*) and manidipine (Iperten*). The formulations with progressive and sustained effect are the best adapted.
- Buflomedil (Fonzylane*) induces a vasodilation by calcium-antagonist effect not well characterized and an alpha adrenolytic effect. It is used in the treatment of arteriopathies and the phenomenon of Raynaud.
- Mibefradil is a nondihydropyridinic calcium antagonist which preferentially inhibits T type calcium channels and to a lesser degree the L- type channels. It has general arterial and coronary vasodilator effect and was intended for the treatment of the arterial hypertension and the prevention of attacks of angina pectoris. Mibefradil is metabolized by the cytochromes P450 3A4 and 2D6 and was at the origin of pharmacokinetic interactions with other drugs sufficiently important to stop its marketing which had begun in the USA .
With a predominant coronary or sinus effect
The calcium channel blockers with coronary or sinus predominant effects are diltiazem, verapamil, bepridil and perxilline. Their therapeutic uses are angina pectoris and supraventricular tachycardias. Each one has particular characteristics.
- Diltiazem has a benzothiazepine structure. It has coronary dilator and bradycardic effects. Diltiazem, (Tildiem*, Cardizem*), is used for the management of angina pectoris and hypertension .It is available in different formulations, the sustained-release oral formulation being used for arterial hypertension. In injectable form, it is used to treat tachycardias
- Verapamil has a phenylalkylamine structure. By its calcium-channel inhibitor effect it depresses the activity of the sinus node, decreases the rate of conduction at the level of atrioventricular node and depresses myocardial contractibility. It has a vasodilator effect. It is the reference product of class IV antiarrhythmics.
The therapeutic uses of verapamil (Isoptin*), are the preventive and curative treatment of supraventricular paroxystic tachycardias. It is also used for the treatment of angina pectoris and, in sustained-release form, for the treatment of arterial hypertension.
Its most frequent non cardiovascular adverse effect is constipation.
- Bepridil has complex effects: inhibition of calcium and sodium entry into cells and of potassium efflux. It is used for the management of angina pectoris but it has many contraindications because it induces prolongation of the QT interval and torsades de pointes.
- Perxilline is a calcium antagonist effective for prevention of angina pectoris attacks. But it elicited severe adverse effects, peripheral neuropathy with hypoglycemia, loss of weight, cachexia, and hepatitis. Now It is not used as a therapeutic agent. .
With a predominant cerebrovascular effect
- Nimodipine (Nimotop*) is a calcium antagonist with a predominantly cerebrovascular vasodilatator effect used for treatment and prevention of vasospasm of cerebral arteries.
- Flunarizine (Sibelium*), a cinnarizine derivative, is a calcium channel blocker on neurons and vessels, used for the treatment of vertigo and migraine. In addition to its calcium-antagonist effect, flunarizine has an H1 antihistamine effect, which partly explains sedation and drowsiness that it induces, and an antidopamine D2 effect explaining why it can sometimes cause dyskinesia.
Adverse effects of calcium-channel blockers
Since calcium channel inhibitors have often several important effects, their prescription should take into account the existence in patients of concomitant disorders, arterial hypertension, angina pectoris, tachycardia so that the drug chosen could improve them while reducing the risk of adverse effects.
Calcium-channel blockers with cardiovascular indications have common side effects.
- Excessive vasodilation inducing hypotension, flushing, headache, dizziness, lower limb edema, reactional tachycardia by release of catecholamines.
- An increase in the frequency of myocardial infarctions in patients treated with some calcium-channel inhibitors was observed. The prescription of preparations with non progressive effect is generally disadvised, that of preparations with progressive release appears more suitable. Calcium antagonists are in competition with other drugs acting by different mechanisms. In addition all the calcium antagonists have not the same characteristics.
- Bradycardia with decrease of atrioventricular conduction and negative inotropic effect.
- Gingival hyperplasia, adverse effect observed with calcium antagonists but especially with nifedipine. Other drugs, such as phenytoin and cyclosporine, can also give gingival hyperplasia.
- The combination of calcium antagonists with other drugs with vasodilatator or cardiac negative chronotropic and inotropic action could induce excessive effects.
Extracellular calcium has a membrane stabilizing effect and an increase of calcium intake tends to reduce arterial pressure. In patients treated by calcium-channel inhibitors, there is no reason to reduce the calcium intake nor to disadvise a calcium supplementation.
Calcium-channel blockers acting on nonvascular smooth muscle
Several compounds used as antispasmodics act, at least partly by inhibiting the penetration of calcium into cells. The products having this property at different degrees are pinaverium, fenoverine , mebeverine, phloroglucinol and perhaps partly trimebutine.
These drugs are or have been used for several years in different countries according to their therapeutic habits.
Calcium-channel inhibitors can also have a tocolytic effect. The drug most often used for this purpose is nifidipine.
Calcium-channel inhibitors as antiepileptics
Ethosuximide is an antiepileptic known for a long time, active in the treatment of absence seizures (petit mal)
Its mechanism of action was not known but now we know that it inhibits T-type calcium channels in particular those of the neurons of the thalamus and thus reduces their excitability.
The plasma half-life of ethosuximide is approximately 60 hours in adults and 30 hours in children. It is not an enzyme inducer.
Ethosuximide (Zarontin*) can induce digestive disorders, anorexia, nausea, vomiting, blood disorders, leukopenia, agranulocytosis, aplastic anemia, and nervous disorders, drowsiness, dizziness…
Pregabalin (Lyrica*), isobutyl GABA and gabapentin, Neurontin *, used in the treatment of partial epilepsies and post-herpetic pains, act at least partially by inhibiting L-type calcium channels present in neurons.
Calcium-channel inhibitors with analgesic effect
Ziconotide is a peptide which inhibits N-type calcium channels present in neurons. Injected by intraspinal route, it has an analgesic effect and is used for the treatment of intense chronic pains.
Ziconotide, constituted of 25 amino acids, is a synthetic equivalent of an omega-conotoxine isolated from a marine mollusc, Conus magus. The conotoxins are thus called because they are toxic venoms, found in cones which are marine gastropodes.
There is a very great number of conotoxins which interacts with receptor-channels and voltage-dependant channels; the omega-conotoxins, peptides from 24 to 27 amino acids, inhibit N-type calcium channels and thus prevent calcium penetration into the nervous terminations which cease to release their transmitters.
Ziconotide, when it is given by intraspinal route in perfusion by catheter, has an analgesic action and reduces intense chronic pains by acting at the level of the posterior horn of the spinal cord where it inhibits the release of transmitters like substance P.
Ziconotide is inactivated by hydrolysis by endopeptidases and exopeptidases.
Ziconotide, (Prialt*) is used for the management of intense chronic pains which requires treatment by intraspinal route.
Ziconotide has several adverse effects:
- neuropsychiatric: confusional state, hallucinations, memory impairment, suicidal anxiety, delusion ideas, dysarthria, disorders of equilibrium
- other effects: nauseas, vomiting, abdominal pains, myalgia .....
Taking into account its complicated mode of administration, the risk of infections which it induces as well as its adverse effects, ziconotide should remain a drug of limited prescription.
See information of the EMEA on Prialt .
Calcium-channel inhibitors acting on skeletal muscles
Dantrolene is a direct skeletal muscle relaxant. It reduces the force of contraction of the striated muscles by inhibiting the calcium release from the sarcoplasmic reticulum, probably by inhibiting the ryanodine receptors.
At therapeutic doses, it does not have effect on the myocardium nor on the smooth muscles, because the inhibition of calcium intracellular exchanges is masked by the predominant influx of extracellular calcium.
Dantrolene (Dantrium*) is used by oral route for the treatment of the spastic contractures of neurological origin and by intravenous route for the treatment of malignant hyperthermia to reduce the muscular contractures.
The principal adverse effect of dantrolene chronic use is hepatitis. It can give an orange color to urine. A muscular hypotonia is possible in case of overdose.
Magnesium has a calcium-antagonist effect by reducing the transfer of calcium through various types of channels (See “Magnesium”.).