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 dihydropyri- dines don’t affect the heart at therapeutic doses, toxic doses can produce dangerous cardiac suppression (just like verapamil
Elimination is primarily by hepatic metabolism. Because the drug is eliminated by the liver, doses must be reduced sub- stantially 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 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 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.
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 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 the 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. Norepi- nephrine 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.
Sites of Action
Indications
Classification Hypertension Angina Dysrhythmias Others
DIHYDROPYRIDINES
Nifedipine [Adalat CC, Nifediac, Nifedical, Procardia] Arterioles ✔ ✔ a
Amlodipine [Norvasc] Arterioles ✔ ✔
Clevidipine [Cleviprex] Arterioles ✔b
Felodipine [Plendil, Renedil ] Arterioles ✔
Isradipine [DynaCirc CR] Arterioles ✔
Nicardipine [Cardene SR] Arterioles ✔ ✔
Nimodipine [Nymalize, Nimotop ] Arterioles c
Nisoldipine [Sular] Arterioles ✔
PHENYLALKYLAMINE
Verapamil [Calan, Covera-HS , Verelan] Arterioles/heart ✔ ✔ ✔
BENZOTHIAZEPINE
Diltiazem [Cardizem, Dilacor XR, Tiazac, others] Arterioles/heart ✔ ✔ ✔
TABLE 45.1 ■ Calcium Channel Blockers: Classification, Sites of Action, and Indications
aSuppression of preterm labor (off-label use).
bOnly for IV treatment of severe hypertension.
cProphylaxis of neurologic injury after rupture of an intracranial aneurysm.
day (using IR tablets), 180 mg of an ER formulation (administered once a day in the morning with food), or 200 mg of Verelan PM (administered once a day at bedtime). Dosages should be reduced for older adult patients and for patients with advanced renal or liver disease. Dosages for dysrhythmias are presented in Chapter 49.
Intravenous. Intravenous verapamil is used for dysrhythmias. Because IV verapamil can cause severe adverse cardiovascular effects, blood pressure and the electrocardiogram (ECG) should be monitored and equipment for resuscitation should be immediately available. Intravenous dosages for dys- rhythmias are presented in Chapter 49.
Diltiazem
Actions and Uses
Like verapamil, diltiazem [Cardizem, Dilacor XR, Tiazac, others] blocks calcium channels in the heart and blood vessels. As a result, the actions and applications of verapamil and diltiazem are very similar. Diltiazem has the same effects on cardiovascular function as verapamil. Both drugs lower blood pressure through arteriolar dilation, and because their direct suppressant actions are balanced by reflex cardiac stimulation, both have little net effect on the heart. Like verapamil, diltiazem is used for angina pectoris, essential hyperten- sion, and cardiac dysrhythmias (atrial flutter, atrial fibrillation, and paroxysmal supraventricular tachycardia).
Pharmacokinetics
Oral diltiazem is well absorbed and then extensively metabolized on its first pass through the liver. As a result, bioavailability is only about 50%. Effects begin rapidly (within a few minutes) and peak within half an hour. The drug undergoes nearly complete metabolism before elimination in the urine and feces.
Adverse Effects
Adverse effects are like those of verapamil, except that diltiazem causes less constipation. The most common effects are dizziness, flushing, headache, and edema of the ankles and feet. Like verapamil, diltiazem can exacerbate cardiac dysfunction in patients with bradycardia, sick sinus syndrome, heart failure, or second-degree or third-degree AV block. Like other CCBs, diltiazem may cause chronic eczematous rash in older adults.
Drug and Food Interactions
Like verapamil, diltiazem can exacerbate digoxin-induced suppression of AV conduction and can intensify the cardiosuppressant effects of beta blockers.
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 it 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.
Drug and Food Interactions
Digoxin. Like verapamil, digoxin suppresses impulse conduction through the AV node. Accordingly, when these drugs are used concurrently, the risk of AV block is increased.
Patients receiving the combination should be monitored closely.
Verapamil increases plasma levels of digoxin by about 60%, thereby increasing the risk of digoxin toxicity. If signs of toxicity appear, digoxin dosage should be reduced.
Beta-Adrenergic Blocking Agents. Beta blockers and verapamil have the same effects on the heart: They decrease heart rate, AV conduction, and contractility. Hence, when a beta blocker and verapamil are used together, there is a risk of excessive cardiosuppression. To minimize risk, beta blockers and IV verapamil should be administered several hours apart.
Grapefruit Juice. Grapefruit juice can inhibit the intestinal and hepatic metabolism of many drugs and thus raise their levels. In a case report on verapamil toxicity, consumption of grapefruit juice and verapamil (360 mg over 24 hours) led to a verapamil blood level of 2772 ng/mL—approximately 8 to 24 times higher than would have been achieved without grapefruit juice.
Toxicity
Clinical Manifestations. Overdose can produce severe hypotension and cardiotoxicity (bradycardia, AV block).
Treatment
General Measures. Verapamil can be removed from the GI tract with gastric lavage followed by activated charcoal. Intravenous calcium gluconate can counteract both vasodilation and negative inotropic effects, but will not reverse AV block.
Hypotension. Hypotension can be treated with IV norepinephrine, which promotes vasoconstriction (by activating alpha1 receptors on blood vessels) and increases cardiac output (by activating beta1 receptors in the heart). Placing the patient in modified Trendelenburg’s position (legs elevated) and administer- ing IV fluids may also help.
Bradycardia and AV Block. Bradycardia and AV block can be treated with atropine (an anticholinergic drug that blocks parasympathetic influences on the heart). If pharmacologic measures are inadequate, electronic pacing may be required. Use of glucagon in animal models has improved heart rate through increasing amounts of intracellular cyclic AMP. It has been used successfully in treating human cases of CCB toxicity.
Preparations, Dosage, and Administration
Oral. Verapamil is available in immediate-release (IR) tablets (40, 80, and 120 mg) as Calan; extended-release (ER) tablets (120, 180, and 240 mg) as Calan SR and Covera-HS ; and ER capsules (120, 180, 240, and 360 mg) as Verelan. In addition, verapamil is available as Verelan PM (100-, 200-, and 300-mg capsules), a timed-release formulation that, when administered at bedtime, produces maximum verapamil levels in the morning. The sustained- and timed-release formulations are approved only for hypertension. Instruct patients to swallow these products intact, without crushing or chewing. A fixed-dose combination with trandolapril (an angiotensin-converting enzyme [ACE]
inhibitor) is available under the brand name Tarka.
The usual initial dosage for angina pectoris is 80 to 120 mg 3 times a day. The usual initial dosage for essential hypertension is 80 mg 3 times a
Calcium Channel Blockers
Life Stage Patient Care Concerns
Infants Verapamil can be used in infants for conversion of certain heart dysrhythmias.
Children/
adolescents Calcium channel blockers are used in children for hypertension, hypertensive emergencies, and hypertrophic cardiomyopathy.
Pregnant
women Calcium channel blockers are classified in U.S.
Food and Drug Administration Pregnancy Risk Category C.a There is a risk of fetal death based on animal data, but inadequate human data exist. Therefore, caution is advised during pregnancy.
Breast-feeding
women Certain drugs such as verapamil may pose harm to the infant. For other drugs such as nifedipine, data are lacking regarding transmission of drug from mother to infant via breast milk.
Older adults In older patients, calcium channel blockers have been associated with chronic eczematous eruptions.
PATIENT-CENTERED CARE ACROSS THE LIFE SPAN
aAs of 2020, the FDA will no longer use Pregnancy Risk Categories.
Please refer to Chapter 9 for more information.
drops quickly and the reflex is turned on. Conversely, with the SR formulation, blood levels of nifedipine rise slowly, so blood pressure falls slowly and the reflex is blunted.
Net Effect. The overall hemodynamic response to nifedipine is simply the sum of its direct effect (vasodilation) and indirect effect (reflex cardiac stimulation). Accordingly, nifedipine (1) lowers blood pressure, (2) increases heart rate, and (3) increases contractile force. Please note, however, that the reflex increases in heart rate and contractile force are transient and occur primar- ily with the IR formulation.
Pharmacokinetics
Nifedipine is well absorbed following oral administration, but undergoes extensive first-pass metabolism. As a result, only about 50% of an oral dose reaches the systemic circulation. With the IR formulation, effects begin rapidly and peak in 30 minutes; with the SR formulation, effects begin in 20 minutes and peak in 6 hours. Nifedipine is fully metabolized before excretion in the urine.
Therapeutic Uses
Angina Pectoris. Nifedipine is indicated for vasospastic angina and angina of effort. The drug is usually combined
Patients receiving diltiazem concurrently with digoxin or a beta blocker should be monitored closely for cardiac status. As with verapamil, grapefruit juice can significantly increase levels of diltiazem.
Preparations, Dosage, and Administration
Oral diltiazem is available in IR tablets (30, 60, 90, and 120 mg) as Cardizem, extended-release (ER) tablets (120, 180, 240, 300, 360, and 420 mg) as Cardizem LA, and SR capsules (120, 180, 240, 300, 360, and 420 mg) as Cardizem CD, Cartia XT, Dilacor XR, Dilt-CD, Dilt-XR, Diltia XT, Taztia XT, and Tiazac.
The drug is also available in solution (5 mg/mL) for IV administration. The usual initial dosage for hypertension is 180 mg once a day with Cardizem CD, 60 to 120 mg twice a day with Cardizem, and 180 to 240 mg once a day with Cardizem LA or Dilacor XR. Angina pectoris can be treated with IR tablets (30 mg 4 times a day initially and 60 mg 4 times a day for maintenance).
Intravenous diltiazem is reserved for dysrhythmias.