Calcium Channel Blockers

Figure 37.1 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 (e.g., 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 guanosine diphosphate [GDP] is bound to the alpha subunit) to an active state (in which guanosine triphosphate [GTP] is bound to the alpha subunit). (G protein is so named because it binds guanine nucleotides: GDP and GTP.) After activation, the alpha subunit dissociates from the rest of G protein and activates adenylyl cyclase, an enzyme that converts adenosine triphosphate (ATP) to cyclic adenosine monophosphate (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 [i.e., 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 37.1). The largest family is the dihydropyridines, for which nifedipine is the prototype. This family name is encountered frequently and hence 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.

Protoytpe Drugs

Calcium Channel Blockers

Agent that Affects the Heart and Blood Vessels

Verapamil

Dihydropyridine: Agent that Acts Mainly on Blood Vessels

Nifedipine

TABLE 37.1

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

Classification	Sites of Action	Indications
Classification	Sites of Action	Hypertension	Angina	Dysrhythmias	Migraine*	Others
DIHYDROPYRIDINES
Nifedipine [Adalat CC, Nifediac, Nifedical, Procardia]	Arterioles	✔	✔		✔	^†
Amlodipine [Norvasc]	Arterioles	✔	✔
Felodipine [Plendil, Renedil]	Arterioles	✔
Isradipine [DynaCirc CR]	Arterioles	✔
Nicardipine [Cardene SR]	Arterioles	✔	✔
Nimodipine [Nymalize, Nimotop]	Arterioles				✔	^§
Nisoldipine [Sular]	Arterioles	✔
PHENYLALKYLAMINES
Verapamil [Calan, Covera-HS , Verelan]	Arterioles/heart	✔	✔	✔	✔
BENZOTHIAZEPINES
Diltiazem [Cardizem, Dilacor XR, Tiazac, others]	Arterioles/heart	✔	✔	✔	✔

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 37.1). 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, Verelan, Covera-HS ] 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, because 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 intravenously. The drug is well absorbed after 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 43.

Essential Hypertension

Verapamil is a second-line agent for chronic hypertension, used after thiazide diuretics. The drug lowers blood pressure by dilating arterioles. The role of verapamil and other CCBs in hypertension is discussed in Chapter 39.

Cardiac Dysrhythmias

Verapamil, administered intravenously, 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 41.

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 older adults, 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.

Other Effects

In older patients, CCBs have been associated with chronic eczematous eruptions, typically starting 3 to 6 months after treatment onset. If the reaction is mild, switching to a different CCB may help. If the condition is severe, use of verapamil and other CCBs should stop.

Gingival hyperplasia (overgrowth of gum tissue) has been reported.

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Tags: Lehne's Pharmacotherapeutics for Advanced Practice Providers

Apr 8, 2017 | Posted by admin in PHARMACY | Comments Off

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Calcium Channel Blockers