Calcium channel blocker/ja

ジヒドロビリジン系

一般名	先発名	日本	開発	備考
Amlodipine/ja	ノルバスク(Norvasc) (PI) (IF)	販売	Pfizer
Aranidipine/ja	サプレスタ(Sapresta) (PI IF)	終了	マルコ製薬 大鵬薬品

医薬品 > 降圧薬 > Calcium channel blocker/ja

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CA拮抗剤
Drug class
Class identifiers
Use	hypertension/ja, 不整脈, cluster headache/ja
ATC code	C08
External links
MeSH	D002121
Legal status

カルシウム拮抗剤(Calcium channel blockers, CCB)、カルシウムチャネル拮抗薬(calcium channel antagonists)、カルシウム拮抗薬(calcium antagonists)は、カルシウムチャネルを介したカルシウム(Ca²⁺
)の移動を阻害する医薬品群である。 カルシウム拮抗薬は降圧薬、すなわち高血圧患者の血圧を低下させる医薬品として使用される。CCBは、高齢者における収縮期血圧上昇の一般的な原因の一つである大血管硬化に対して特に有効である。カルシウム拮抗薬はまた、心拍数の変化（特に心房細動）、末梢および脳血管攣縮の予防、狭心症による胸痛の軽減にも頻繁に使用される。

N型、L型、T型の電位依存性カルシウムチャネルは、ヒトの副腎糸球体座に存在し、CCBは副腎皮質細胞におけるアルドステロンの生合成に直接影響を与えることができ、その結果、これらの薬剤による高血圧の臨床治療に影響を与える。

CCBは、脳卒中に伴う心血管系死亡率を低下させるという点ではβ遮断薬よりもわずかに有効であるが、より多くの副作用を伴うことが示されている。しかし，潜在的な重大リスクは主に短時間作用型のCCBに関連することがわかった。

クラス

ジヒドロピリジン(Dihydrophyridine)系

ジヒドロピリジン系カルシウム拮抗薬（ジピン系）の一般的な化学構造

ジヒドロピリジン（DHP）系カルシウム拮抗薬は、ジヒドロピリジン分子から誘導され、しばしば全身血管抵抗と動脈圧を低下させるために使用される。狭心症の治療に使用される場合、血管拡張と低血圧が反射性頻脈を引き起こすことがあり、その結果、心筋の酸素要求量が増加するため、虚血症状を有する患者にとって有害となることがある。ジヒドロピリジン系カルシウム拮抗薬は腎症患者の蛋白尿を悪化させることがある。

このCCBクラスは"-dipine"という接尾辞で容易に識別できる。

• Amlodipine/ja (ノルバスク:Norvasc)
• Aranidipine/ja (サプレスタ:Sapresta)
• Azelnidipine/ja (カルブロック:Calblock)
• Barnidipine/ja (ヒポカ:HypoCa)
• Benidipine/ja (コニール:Coniel)
• Cilnidipine/ja (アテレック:Atelec, Cinalong, Siscard) 米国では入手不可
• Clevidipine/ja (クレビジピン:Cleviprex)
• Efonidipine/ja (ランデル:Landel)
• Felodipine/ja (プレンディル:Plendil)
• Isradipine/ja (ダイナサーク:DynaCirc, Prescal)
• Lacidipine/ja (モーテンス:Motens, Lacipil)
• Lercanidipine/ja (ザニディップ:Zanidip)
• Manidipine/ja (カルスロット:Calslot, Madipine)
• Nicardipine/ja (カルデン:Cardene, Carden SR)
• ニフェジピン (プロカーディア:Procardia, Adalat)
• Nilvadipine/ja (ニヴァディル:Nivadil)
• Nimodipine/ja (ニモトップ:Nimotop) この物質は血液脳関門を通過することができ、脳血管攣縮の予防に用いられる。
• Nisoldipine/ja (ベイミーカード:Baymycard, Sular, Syscor)
• Nitrendipine/ja (カルディフ:Cardif, Nitrepin, Baylotensin)
• Pranidipine/ja (アカラス:Acalas)

Non-dihydropyridine

Phenylalkylamine

Skeletal formula of verapamil

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
• Gallopamil
• Verapamil (Calan, Isoptin)

Benzothiazepine

Structural formula of diltiazem

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 (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, bepridil, flunarizine (BBB crossing), fluspirilene (BBB crossing), 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 (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 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

Toxicity

Main article: Calcium channel blocker toxicity

Lipid emulsion as used in CCB 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, 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, 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. If unsuccessful, ventricular pacing should be used.

Non-medical calcium channel inhibitors

Ethanol

Ethanol blocks voltage-gated calcium channel

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. 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 Ca²⁺
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, 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

A calcium channel embedded in a cell membrane.

In the body's tissues, the concentration of calcium ions (Ca²⁺
) outside cells is normally about 10,000-fold higher than the concentration inside 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.

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 coupling of skeletal, smooth, and cardiac muscle and for regulating aldosterone and cortisol secretion in endocrine cells of the adrenal cortex. In the heart, they are also involved in the conduction of the pacemaker 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), 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 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.

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.

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 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.

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 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, 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 came into wide use in the 1960s, having been first identified in the lab of German pharmacologist Albrecht Fleckenstein in 1964.

External links

• Calcium+Channel+Blockers at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• "Official Adalat (Nifedipine) site". Bayer. Archived from the original on 2008-04-08. Retrieved 2021-06-18.
• Video – Calcium Channel Blockers