Calcium channel blockers

Calcium channel blockers

Calcium channel blockers (CCBs) are drugs that prevent calcium ions from entering cells. These agents have their greatest effects on the heart and blood vessels. CCBs are used widely to treat hypertension, angina pectoris, and cardiac dysrhythmias. Since 1995, there has been controversy about the safety of CCBs, especially in patients with hypertension and diabetes. Alternative names for CCBs are calcium antagonists and slow channel blockers.

Calcium channels: physiologic functions and consequences of blockade

Calcium channels are gated pores in the cytoplasmic membrane that regulate entry of calcium ions into cells. Calcium entry plays a critical role in the function of vascular smooth muscle (VSM) and the heart.

Vascular smooth muscle

In VSM, calcium channels regulate contraction. When an action potential travels down the surface of a smooth muscle cell, calcium channels open and calcium ions flow inward, thereby initiating the contractile process. If calcium channels are blocked, contraction will be prevented and vasodilation will result.

At therapeutic doses, CCBs act selectively on peripheral arterioles and arteries and arterioles of the heart. CCBs have no significant effect on veins.

Heart

In the heart, calcium channels help regulate the myocardium, the sinoatrial (SA) node, and the atrioventricular (AV) node. Calcium channels at all three sites are coupled to beta₁-adrenergic receptors.

Myocardium.

In cardiac muscle, calcium entry has a positive inotropic effect. That is, calcium increases force of contraction. If calcium channels in atrial and ventricular muscle are blocked, contractile force will diminish.

SA node.

Pacemaker activity of the SA node is regulated by calcium influx. When calcium channels are open, spontaneous discharge of the SA node increases. Conversely, when calcium channels close, pacemaker activity declines. Hence, the effect of calcium channel blockade is to reduce heart rate.

AV node.

Impulses that originate in the SA node must pass through the AV node on their way to the ventricles. Because of this arrangement, regulation of AV conduction plays a critical role in coordinating contraction of the ventricles with contraction of the atria.

The excitability of AV nodal cells is regulated by calcium entry. When calcium channels are open, calcium entry increases, and cells of the AV node discharge more readily. Conversely, when calcium channels are closed, discharge of AV nodal cells is suppressed. Hence, the effect of calcium channel blockade is to decrease velocity of conduction through the AV node.

Coupling of cardiac calcium channels to beta₁-adrenergic receptors.

In the heart, calcium channels are coupled to beta₁-adrenergic receptors (Fig. 45–1). As a result, when cardiac beta₁ receptors are activated, calcium influx is enhanced. Conversely, when beta₁ receptors are blocked, calcium influx is suppressed. Because of this relationship, CCBs and beta blockers have identical effects on the heart. That is, they both reduce force of contraction, slow heart rate, and suppress conduction through the AV node.

Figure 45–1 Coupling of cardiac calcium channels with beta₁-adrenergic receptors.
In the heart, beta₁ receptors are coupled to calcium channels. As a result, when cardiac beta₁ receptors are activated, calcium influx is enhanced. The process works as follows. Binding of an agonist (eg, norepinephrine) causes a conformational change in the beta receptor, which in turn causes a change in G protein, converting it from an inactive state (in which GDP is bound to the alpha subunit) to an active state (in which GTP is bound to the alpha subunit). (G protein is so named because it binds guanine nucleotides: GDP and GTP.) Following activation, the alpha subunit dissociates from the rest of G protein and activates adenylyl cyclase, an enzyme that converts ATP to cyclic AMP (cAMP). cAMP then activates protein kinase, an enzyme that phosphorylates proteins—in this case, the calcium channel. Phosphorylation changes the channel such that calcium entry is enhanced when the channel opens. (Opening of the channel is triggered by a change in membrane voltage [ie, by passage of an action potential].)
The effect of calcium entry on cardiac function is determined by the type of cell involved. If the cell is in the SA node, heart rate increases; if the cell is in the AV node, impulse conduction through the node accelerates; and if the cell is part of the myocardium, force of contraction is increased.
Because binding of a single agonist molecule to a single beta receptor stimulates the synthesis of many cAMP molecules, with the subsequent activation of many protein kinase molecules, causing the phosphorylation of many calcium channels, this system can greatly amplify the signal initiated by the agonist.

Figure 45–1 Coupling of cardiac calcium channels with beta₁-adrenergic receptors.
In the heart, beta₁ receptors are coupled to calcium channels. As a result, when cardiac beta₁ receptors are activated, calcium influx is enhanced. The process works as follows. Binding of an agonist (eg, norepinephrine) causes a conformational change in the beta receptor, which in turn causes a change in G protein, converting it from an inactive state (in which GDP is bound to the alpha subunit) to an active state (in which GTP is bound to the alpha subunit). (G protein is so named because it binds guanine nucleotides: GDP and GTP.) Following activation, the alpha subunit dissociates from the rest of G protein and activates adenylyl cyclase, an enzyme that converts ATP to cyclic AMP (cAMP). cAMP then activates protein kinase, an enzyme that phosphorylates proteins—in this case, the calcium channel. Phosphorylation changes the channel such that calcium entry is enhanced when the channel opens. (Opening of the channel is triggered by a change in membrane voltage [ie, by passage of an action potential].)
The effect of calcium entry on cardiac function is determined by the type of cell involved. If the cell is in the SA node, heart rate increases; if the cell is in the AV node, impulse conduction through the node accelerates; and if the cell is part of the myocardium, force of contraction is increased.
Because binding of a single agonist molecule to a single beta receptor stimulates the synthesis of many cAMP molecules, with the subsequent activation of many protein kinase molecules, causing the phosphorylation of many calcium channels, this system can greatly amplify the signal initiated by the agonist.

Calcium channel blockers: classification and sites of action

Classification

The CCBs used in the United States belong to three chemical families (Table 45–1). The largest family is the dihydropyridines, for which nifedipine is the prototype. This family name is encountered frequently and hence the name is worth remembering. The other two families consist of orphans: verapamil is the only phenylalkylamine, and diltiazem is the only benzothiazepine. The drug names are important; the family names are not.

TABLE 45–1

Calcium Channel Blockers: Classification, Sites of Action, and Indications

		Indications
Classification	Sites of Action	Hypertension	Angina	Dysrhythmias	Migraine*	Others
Dihydropyridines
Nifedipine [Adalat CC, Nifediac, Nifedical, Procardia]	Arterioles					^†
Amlodipine [Norvasc]	Arterioles
Clevidipine [Cleviprex]	Arterioles	^‡
Felodipine [Plendil, Renedil]	Arterioles
Isradipine [DynaCirc CR]	Arterioles
Nicardipine [Cardene SR, Cardene I.V.]	Arterioles
Nimodipine [Nimotop]	Arterioles					^§
Nisoldipine [Sular]	Arterioles
Phenylalkylamines
Verapamil [Calan, Covera-HS, Isoptin SR, Verelan]	Arterioles/heart
Benzothiazepines
Diltiazem [Cardizem, Dilacor XR, Tiazac, others]	Arterioles/heart

^*Investigational use.

^†Suppression of preterm labor (investigational use).

^‡Only for IV treatment of severe hypertension.

^§Prophylaxis of neurologic injury after rupture of an intracranial aneurysm.

Sites of action

At therapeutic doses, the dihydropyridines act primarily on arterioles; in contrast, verapamil and diltiazem act on arterioles and the heart (see Table 45–1). However, although dihydropyridines don’t affect the heart at therapeutic doses, toxic doses can produce dangerous cardiac suppression (just like verapamil and diltiazem can). The differences in selectivity among CCBs are based on structural differences among the drugs themselves and structural differences among calcium channels.

Verapamil and diltiazem: agents that act on vascular smooth muscle and the heart

Verapamil

Verapamil [Calan, Covera-HS, Isoptin SR, Verelan] blocks calcium channels in blood vessels and in the heart. Major indications are angina pectoris, essential hypertension, and cardiac dysrhythmias. Verapamil was the first CCB available and will serve as our prototype for the group.

Hemodynamic effects

The overall hemodynamic response to verapamil is the net result of (1) direct effects on the heart and blood vessels and (2) reflex responses.

Direct effects.

By blocking calcium channels in the heart and blood vessels, verapamil has five direct effects:

• Blockade at peripheral arterioles causes dilation, and thereby reduces arterial pressure.

• Blockade at arteries and arterioles of the heart increases coronary perfusion.

• Blockade at the SA node reduces heart rate.

• Blockade at the AV node decreases AV nodal conduction.

• Blockade in the myocardium decreases force of contraction.

Of the direct effects on the heart, reduced AV conduction is the most important.

Indirect (reflex) effects.

Verapamil-induced lowering of blood pressure activates the baroreceptor reflex, causing increased firing of sympathetic nerves to the heart. Norepinephrine released from these nerves acts to increase heart rate, AV conduction, and force of contraction. However, since these same three parameters are suppressed by the direct actions of verapamil, the direct and indirect effects tend to neutralize each other.

Net effect.

Because the direct effects of verapamil on the heart are counterbalanced by indirect effects, the drug has little or no net effect on cardiac performance: For most patients, heart rate, AV conduction, and contractility are not noticeably altered. Consequently, the overall cardiovascular effect of verapamil is simply vasodilation accompanied by reduced arterial pressure and increased coronary perfusion.

Pharmacokinetics

Verapamil may be administered orally or IV. The drug is well absorbed following oral administration, but undergoes extensive metabolism on its first pass through the liver. Consequently, only about 20% of an oral dose reaches the systemic circulation. Effects begin 30 minutes after dosing and peak within 5 hours. Elimination is primarily by hepatic metabolism. Because the drug is eliminated by the liver, doses must be reduced substantially in patients with hepatic impairment.

Therapeutic uses

Angina pectoris.

Verapamil is used widely to treat angina pectoris. The drug is approved for vasospastic angina and angina of effort. Benefits in both disorders derive from vasodilation. The role of verapamil in angina is discussed in Chapter 51.

Essential hypertension.

Verapamil is a first-line agent for chronic hypertension. The drug lowers blood pressure by dilating arterioles. The role of verapamil and other CCBs in hypertension is discussed in Chapter 47.

Cardiac dysrhythmias.

Verapamil, administered IV, is used to slow ventricular rate in patients with atrial flutter, atrial fibrillation, and paroxysmal supraventricular tachycardia. Benefits derive from suppressing impulse conduction through the AV node, thereby preventing the atria from driving the ventricles at an excessive rate. Antidysrhythmic applications are discussed in Chapter 49.

Verapamil can help prevent migraine headache. This investigational use is discussed in Chapter 30.

Adverse effects

Common effects.

Verapamil is generally well tolerated. Constipation occurs frequently and is the most common complaint. This problem, which can be especially severe in the elderly, can be minimized by increasing dietary fluids and fiber. Constipation results from blockade of calcium channels in smooth muscle of the intestine. Other common effects—dizziness, facial flushing, headache, and edema of the ankles and feet—occur secondary to vasodilation.

Cardiac effects.

Blockade of calcium channels in the heart can compromise cardiac function. In the SA node, calcium channel blockade can cause bradycardia; in the AV node, blockade can cause partial or complete AV block; and in the myocardium, blockade can decrease contractility. When the heart is healthy, these effects rarely have clinical significance. However, in patients with certain cardiac diseases, verapamil can seriously exacerbate dysfunction. Accordingly, the drug must be used with special caution in patients with cardiac failure, and must not be used at all in patients with sick sinus syndrome or second-degree or third-degree AV block.

Tags: Pharmacology for Nursing Care

Jul 24, 2016 | Posted by admin in NURSING | Comments Off

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