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.
DIHYDROPYRIDINES: AGENTS THAT
Preparations, Dosage, and Administration
Nifedipine is available in IR capsules (10 mg) as Procardia and in SR tablets (30, 60, and 90 mg) as Adalat CC, Nifedical XL, Nifediac CC, and Procardia XL. Instruct patients to swallow SR tablets whole, without crushing or chewing.
For treatment of angina pectoris, the usual initial dosage is 10 mg 3 times a day. The usual maintenance dosage is 10 to 20 mg 3 times a day. The maximum recommended dosage is 180 mg/day.
For essential hypertension, only the SR tablets are approved. The usual initial dosage is 30 mg once a day.
Other Dihydropyridines
In addition to nifedipine, seven other dihydropyridines are available. All are similar to nifedipine. Like nifedipine, these drugs produce greater blockade of calcium channels in VSM than in the heart.
Nicardipine
At therapeutic doses, nicardipine [Cardene, Cardene SR] produces selective blockade of calcium channels in blood vessels and has minimal direct effects on the heart. The drug has two indications: essential hypertension and effort-induced angina pectoris. The most common adverse effects are flushing, headache, asthenia (weakness), dizziness, palpitations, and edema of the ankles and feet.
As with other CCBs, eczematous rash may develop in older patients. Gingival hyperplasia (overgrowth of gum tissue) has been reported. Like nifedipine, nicardipine can be combined with a beta blocker to promote therapeutic effects and suppress reflex tachycardia. Nicardipine is available in 20- and 30-mg IR capsules (generic only) and in ER capsules (30, 45, and 60 mg) sold as Cardene SR. The usual initial dosage for angina pectoris is 20 mg 3 times a day using the IR capsules. The usual initial dosage for essential hypertension is 20 mg 3 times a day (using IR capsules) or 30 mg twice a day (using ER capsules).
Amlodipine
At therapeutic doses, amlodipine [Norvasc] produces selective blockade of calcium channels in blood vessels, having minimal direct effects on the heart.
Approved indications are essential hypertension and angina pectoris (effort induced and vasospastic). Amlodipine is administered orally and absorbed slowly; peak levels develop in 6 to 12 hours. The drug has a long half-life (30 to 50 hours) and therefore is effective with once-a-day dosing. Principal adverse effects are peripheral and facial edema. Flushing, dizziness, and headache may also occur, as may eczematous rash in older patients. In contrast to other dihydropyridines, amlodipine causes little reflex tachycardia. Amlodipine is available in 2.5-, 5-, and 10-mg tablets. The usual initial dosage for hypertension or angina pectoris is 5 mg once a day. Fixed-dose combinations are also available: amlodipine/benazepril [Lotrel], amlodipine/telmisartan [Twynsta], amlodipine/atorvastatin [Caduet], amlodipine/aliskiren [Tekamlo], amlodipine/
olmesartin [Azor], amlodipine/valsartan [Exforge], aliskiren/amlodipine/
hydrochlorothiazide [Amturnide], amlodipine/valsartan/hydrochlorothiazide [Exforge HCT], and amlodipine/hydrochlorothiazide/olmesartan [Tribenzor].
Isradipine
Like nifedipine, isradipine (generic only) produces relatively selective blockade of calcium channels in blood vessels. In the United States, the drug is approved only for hypertension. Isradipine is rapidly absorbed following oral administra- tion, but undergoes extensive first-pass metabolism. Parent drug and metabolites are excreted in the urine. The most common side effects are facial flushing, headache, dizziness, and ankle edema. Eczematous rash may develop in older patients. In contrast to nifedipine, isradipine causes minimal reflex tachycardia.
The drug is available in capsules (2.5 and 5 mg). The usual antihypertensive dosage is 2.5 to 5 mg twice a day.
Felodipine
Felodipine [Plendil, Renedil ] produces selective blockade of calcium channels in blood vessels. In the United States, the drug is approved only for hypertension. Felodipine is well absorbed following oral administration but undergoes extensive first-pass metabolism. As a result, bioavailability is low—only 20%. Plasma levels peak in 2.5 to 5 hours and then decay with a half-life of 24 hours. Because of its prolonged half-life, felodipine is effective with once-a-day dosing. Characteristic adverse effects are reflex tachycardia, peripheral edema, headache, facial flushing, and dizziness. Eczematous rash may develop in older patients. Gingival hyperplasia has been reported.
Felodipine is available in ER tablets (2.5, 5, and 10 mg). The usual dosage for hypertension is 5 to 10 mg once a day.
Nimodipine
Nimodipine [Nymalize, Nimotop ] produces selective blockade of calcium channels in cerebral blood vessels. The only approved application is prophylaxis
with a beta blocker to prevent reflex stimulation of the heart, which could intensify anginal pain. Long-term use reduces the rates of overt heart failure, coronary angiography, and coronary bypass surgery—but not rates of stroke, myocardial infarction, or death. The role of nifedipine in angina is discussed in Chapter 51.
Hypertension. Nifedipine is used widely to treat essential hypertension. Only the ER formulation should be used. In the past, nifedipine was used for hypertensive emergencies, but it has largely been replaced by drugs that are safer. The use of CCBs in essential hypertension is discussed in Chapter 47.
Investigational Uses. Nifedipine has been used off-label to suppress preterm labor (see Chapter 64).
Adverse Effects
Some adverse effects are like those of verapamil; others are quite different. Like verapamil, nifedipine can cause flushing, dizziness, headache, peripheral edema, and gingival hyperplasia, and may pose a risk of chronic eczematous rash in older patients.
In contrast to verapamil, nifedipine causes very little constipa- tion. Also, since nifedipine causes minimal blockade of calcium channels in the heart, the drug is not likely to exacerbate AV block, heart failure, bradycardia, or sick sinus syndrome.
Accordingly, nifedipine is preferred to verapamil for patients with these disorders.
A response that occurs with nifedipine that does not occur with verapamil is reflex tachycardia. This response is prob- lematic in that it increases cardiac oxygen demand and can thereby increase pain in patients with angina. To prevent reflex tachycardia, nifedipine can be combined with a beta blocker (e.g., metoprolol).
Safety Alert
IMMEDIATE-RELEASE NIFEDIPINE
Immediate-release nifedipine has been associated with increased mortality in patients with myocardial infarction and unstable angina. Other IR CCBs have been associated with an increased risk of myocardial infarction in patients with hypertension.
However, in both cases, a causal relationship has not been established. Nonetheless, the National Heart, Lung, and Blood Institute has recommended that immediate-release nifedipine, especially in higher doses, be used with great caution, if at all. It is important to note that these adverse effects have not been associated with sustained-release nifedipine or with any other long-acting CCB.
Drug Interactions
Beta-Adrenergic Blockers. Beta blockers are combined with nifedipine to prevent reflex tachycardia. It is important to note that, whereas beta blockers can decrease the adverse cardiac effects of nifedipine, they can intensify the adverse cardiac effects of verapamil and diltiazem.
Toxicity
When taken in excessive dosage, nifedipine loses selectivity.
Hence, toxic doses affect the heart in addition to blood vessels.
Consequently, the manifestations and treatment of nifedipine overdose are the same as described previously for verapamil.
Clevidipine
Clevidipine [Cleviprex] is indicated only for intravenous therapy of severe hypertension, defined as systolic blood pressure above 180 mm Hg or diastolic pressure above 110 mm Hg. The drug has an ultrashort half-life (about 1 minute), owing to rapid inactivation by plasma esterases. Effects are not altered by impairment of liver or kidney function. Because of IV dosing and rapid inactivation, blood pressure falls quickly and then rises quickly when the infusion is slowed or stopped. As a result, responses can be easily titrated.
Clevidipine is formulated in a lipid emulsion made from soybean oil and egg yolk phospholipids, and hence is contraindicated for patients allergic to soybeans or eggs. Clevidipine is supplied in single-dose vials (50, 100, or 250 mL) at a concentration of 0.5 mg/mL. For patients with severe hypertension, the infusion rate is 1 to 2 mg/hr initially, and can be doubled every 90 seconds up to a maximum of 32 mg/hr. In clinical trials, the average time to reach the target blood pressure was 10.9 minutes. The most common side effects are headache, nausea, and vomiting. Like other dihydropyridines, clevidipine can cause hypotension and reflex tachycardia.
of neurologic injury following rupture of an intracranial aneurysm. Benefits derive from preventing cerebral arterial spasm that follows subarachnoid hemorrhage (SAH) and can result in ischemic neurologic injury. Dosing (60 mg every 4 hours) should begin within 96 hours of SAH and continue for 21 days.
Nimotop is available in 30-mg liquid-filled capsules for oral administration and as a 60 mg/20 mL oral solution [Nymalize]. Nimodipine must never be given intravenously, owing to a risk of potentially fatal cardiovascular events.
Nisoldipine
Like nifedipine, nisoldipine [Sular] produces selective blockade of calcium channels in blood vessels; the drug has minimal direct effects on the heart.
The only approved indication is hypertension. Nisoldipine is well absorbed following oral administration, but the first-pass effect limits bioavailability to 5%. Plasma levels peak 6 hours after administration. The most common side effects are dizziness, headache, and peripheral edema. Reflex tachycardia may also occur. As with other CCBs, eczematous rash may develop in older patients. Nisoldipine is available in ER tablets (8.5, 17, 20, 25.5, 30, 34, and 40 mg). The dosage for hypertension is 17 to 60 mg once a day.
KEY POINTS
■ Calcium channels are gated pores in the cytoplasmic membrane that regulate calcium entry into cells.
■ In blood vessels, calcium entry causes vasoconstriction, and hence calcium channel blockade causes vasodilation.
■ In the heart, calcium entry increases heart rate, AV conduc- tion, and myocardial contractility, so calcium channel blockade has the opposite effects.
■ In the heart, calcium channels are coupled to beta1 receptors, activation of which enhances calcium entry. As a result, calcium channel blockade and beta blockade have identical effects on cardiac function.
■ At therapeutic doses, nifedipine and the other dihydro- pyridines act primarily on VSM; in contrast, verapamil and diltiazem act on VSM and on the heart.
■ All CCBs promote vasodilation, and hence are useful in hypertension and angina pectoris.
■ Because they suppress AV conduction, verapamil and diltiazem are useful for treating cardiac dysrhythmias (in addition to hypertension and angina pectoris).
■ Because of their cardiosuppressant effects, verapamil and diltiazem can cause bradycardia, partial or complete AV block, and exacerbation of heart failure.
■ Beta blockers intensify cardiosuppression caused by verapamil and diltiazem.
■ Nifedipine and other dihydropyridines can cause reflex tachycardia. Tachycardia is most intense with immediate- release formulations, and much less intense with sustained- release formulations.
■ Beta blockers can be used to suppress reflex tachycardia caused by nifedipine and other dihydropyridines.
■ Because they cause vasodilation, all CCBs can cause dizziness, headache, and peripheral edema.
■ In toxic doses, nifedipine and other dihydropyridines can cause cardiosuppression, just like verapamil and diltiazem.
■ Immediate-release nifedipine has been associated with increased mortality in patients with myocardial infarction and unstable angina, although a causal relationship has not been established. The National Heart, Lung, and Blood Institute recommends that immediate-release nifedipine, especially in higher doses, be used with great caution, if at all.
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Summary of Major Nursing Implications
aVERAPAMIL AND DILTIAZEM Preadministration Assessment Therapeutic Goal
Verapamil and diltiazem are indicated for hypertension, angina pectoris, and cardiac dysrhythmias (atrial fibrillation, atrial flutter, and paroxysmal supraventricular tachycardia).
Baseline Data
For all patients, determine blood pressure and pulse rate, and obtain laboratory evaluations of liver and kidney function.
For patients with angina pectoris, obtain baseline data on the frequency and severity of anginal attacks. For baseline data relevant to hypertension, see Chapter 47.
Identifying High-Risk Patients
Verapamil and diltiazem are contraindicated for patients with severe hypotension, sick sinus syndrome (in the absence of electronic pacing), and second-degree or third-degree AV block. Use with caution in patients with heart failure or liver impairment and in patients taking digoxin or beta blockers.
Implementation: Administration Routes
Oral, IV.
Administration
Oral. Verapamil and diltiazem may be used for angina pectoris and essential hypertension. Verapamil may be used
Continued
Continued
with digoxin to control ventricular rate in patients with atrial fibrillation and atrial flutter.
Extended-release formulations are reserved for essential hypertension. Instruct patients to swallow extended-release formulations whole, without crushing or chewing.
Before dosing, measure blood pressure and pulse rate. If hypotension or bradycardia is detected, withhold medication and notify the prescriber.
Intravenous. Intravenous therapy with verapamil or diltiazem is reserved for cardiac dysrhythmias. Perform injections slowly (over 2 to 3 minutes). Monitor the ECG for AV block, sudden reduction in heart rate, and prolongation of the PR or QT interval. Have facilities for cardioversion and cardiac pacing immediately available.
Ongoing Evaluation and Interventions Evaluating Therapeutic Effects
Angina Pectoris. Keep an ongoing record of anginal attacks, noting the time and intensity of each attack and the likely precipitating event. Teach outpatients to chart the time, intensity, and circumstances of their attacks, and to notify the prescriber if attacks increase.
Essential Hypertension. Monitor blood pressure periodically.
For most patients, the goal is to reduce systolic/diastolic pressure to a value below 140/90 mm Hg. Teach patients to self-monitor their blood pressure and to maintain a blood pressure record.
Minimizing Adverse Effects
Cardiosuppression. Verapamil and diltiazem can cause bradycardia, AV block, and heart failure. Inform patients about manifestations of cardiac effects (e.g., slow heartbeat, shortness of breath, weight gain) and instruct them to notify the prescriber if these occur. If cardiac impairment is severe, drug use should stop.
Peripheral Edema. Inform patients about signs of edema (swelling in ankles or feet), and instruct them to notify the prescriber if these occur. If necessary, edema can be reduced with a diuretic.
Constipation. Constipation occurs primarily with vera- pamil. Advise patients that constipation can be minimized by increasing dietary fluid and fiber.
Minimizing Adverse Interactions
Digoxin. The combination of digoxin with verapamil or diltiazem increases the risk of partial or complete AV block.
Monitor for indications of impaired AV conduction (missed beats, slowed ventricular rate).
Verapamil (and possibly diltiazem) can increase plasma levels of digoxin. Digoxin dosage should be reduced.
Beta Blockers. Concurrent use of a beta blocker with vera- pamil or diltiazem can cause bradycardia, AV block, or heart failure. Monitor closely for cardiac suppression. Administer intravenous verapamil and beta blockers several hours apart.
Grapefruit Juice. Grapefruit juice can raise levels of vera- pamil and diltiazem. Toxicity may result. Advise patients that it may be prudent to minimize grapefruit juice consumption.
Managing Acute Toxicity
Remove unabsorbed drug with gastric lavage followed by activated charcoal. Give IV calcium to help counteract exces- sive vasodilation and reduced myocardial contractility.
To raise blood pressure, give IV norepinephrine. Intrave- nous fluids and placing the patient in modified Trendelenburg’s position can also help.
Bradycardia and AV block can be reversed with atropine and glucagon. If these are inadequate, electronic pacing may be required.
DIHYDROPYRIDINES Amlodipine
Clevidipine Felodipine Isradipine Nicardipine Nifedipine Nimodipine Nisoldipine
Preadministration Assessment Therapeutic Goal
Amlodipine, nifedipine, and nicardipine are approved for essential hypertension and angina pectoris.
Isradipine, felodipine, and nisoldipine are approved for hypertension only.
Nimodipine is used only for subarachnoid hemorrhage.
Clevidipine is used only for IV therapy of severe hypertension.
Baseline Data
See nursing implications for Verapamil and Diltiazem.
Identifying High-Risk Patients
Use dihydropyridines with caution in patients with hypoten- sion, sick sinus syndrome (in the absence of electronic pacing), angina pectoris (because of reflex tachycardia), heart failure, and second-degree or third-degree AV block.
Implementation: Administration Route
Oral. All dihydropyridines except clevidipine.
Intravenous. Nicardipine, clevidipine.
Administration
Instruct patients to swallow sustained-release formulations whole, without crushing or chewing.
Ongoing Evaluation and Interventions Evaluating Therapeutic Effects
See nursing implications for Verapamil and Diltiazem.
Minimizing Adverse Effects
Reflex Tachycardia. Reflex tachycardia can be suppressed with a beta blocker.
Peripheral Edema. Inform patients about signs of edema and instruct them to notify the prescriber if these occur. If necessary, edema can be reduced with a diuretic.
Managing Acute Toxicity
See nursing implications for Verapamil and Diltiazem.
aPatient education information is highlighted as blue text.
46 Vasodilators
Basic Concepts in Vasodilator Pharmacology, p. 505 Selectivity of Vasodilatory Effects, p. 505