VA Class:CV200
Isradipine is a 1,4-dihydropyridine-derivative calcium-channel blocking agent (calcium-channel blocker).1, 2, 3, 4, 7
Isradipine is used alone or in combination with other classes of antihypertensive agents in the management of hypertension.1, 2, 3, 4, 6, 7, 13, 14, 15, 1200
Calcium-channel blockers (e.g., isradipine) are considered one of several preferred antihypertensive drugs for the initial management of hypertension according to current evidence-based hypertension guidelines; other preferred options include angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, and thiazide diuretics.501, 502, 503, 504, 1200 While there may be individual differences with respect to recommendations for initial drug selection and use in specific patient populations, current evidence indicates that these antihypertensive drug classes all generally produce comparable effects on overall mortality and cardiovascular, cerebrovascular, and renal outcomes.501, 502, 504, 1200, 1213 (See Uses: Hypertension, in Amlodipine 24:28.08.)
Calcium-channel blockers may be beneficial in the management of hypertension in patients with certain coexisting conditions such as ischemic heart disease (e.g., angina)523 and in geriatric patients, including those with isolated systolic hypertension.502, 510 (See Uses: Hypertension, in Amlodipine 24:28.08.)
In the Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial (ALLHAT) study, the long-term cardiovascular morbidity and mortality benefit of a long-acting dihydropyridine calcium-channel blocker (amlodipine), a thiazide-like diuretic (chlorthalidone), and an ACE inhibitor (lisinopril) were compared in a broad population of patients with hypertension at risk for coronary heart disease.60, 61, 77, 78, 79, 80 Although these antihypertensive agents were comparably effective in providing important cardiovascular benefit, apparent differences in certain secondary outcomes were observed.60, 61 Patients receiving the ACE inhibitor experienced higher risks of stroke, combined cardiovascular disease, GI bleeding, and angioedema, while those receiving the calcium-channel blocker were at higher risk of developing heart failure.79, 80 The ALLHAT investigators suggested that the favorable cardiovascular outcome may be attributable, at least in part, to the greater antihypertensive effect of the calcium-channel blocker compared with that of the ACE inhibitor, especially in women and black patients.79, 80 (See Clinical Benefits of Thiazides in Hypertension under Hypertension in Adults: Treatment Benefits, in Uses in the Thiazides General Statement 40:28.20.)
Most patients with hypertension, especially black patients, will require at least 2 antihypertensive drugs to achieve adequate blood pressure control.1200 Calcium-channel blockers may be particularly useful in the management of hypertension in black patients;77, 78, 1250, 1251, 1252, 1253, 1254, 1255 these patients tend to have greater blood pressure response to calcium-channel blockers and thiazide diuretics than to other antihypertensive drug classes (e.g., ACE inhibitors, angiotensin II receptor antagonists).501, 504, 1200 However, the combination of an ACE inhibitor or an angiotensin II receptor antagonist with a calcium-channel blocker or thiazide diuretic produces similar blood pressure lowering in black patients as in other racial groups.1200 (See Race under Hypertension: Other Special Considerations for Antihypertensive Therapy, in Uses in Amlodipine 24:28.08.)
For additional information on the role of calcium-channel blockers in the management of hypertension, (See Uses: Hypertension, in Amlodipine 24:28.08.). For information on overall principles and expert recommendations for treatment of hypertension, see Uses: Hypertension in Adults, in the Thiazides General Statement 40:28.20. For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.
Isradipine has a relatively slow (e.g., several hours) onset of hypotensive effect following oral administration,1, 2, 3, 4 and the role, if any, of the currently available conventional dosage form of the drug for use as acute therapy in rapidly reducing blood pressure in patients with hypertensive crises† in whom reduction in blood pressure is considered urgent† (hypertensive urgencies) or an emergency† (hypertensive emergencies) has not been established;4 a sublingual formulation has been investigated for the management of hypertensive urgencies, but currently is not commercially available in the US.22
Isradipine has been used for rapid reduction of blood pressure in children and adolescents†with severe hypertension†.83, 1150
Isradipine is administered orally.1 Administration of isradipine conventional capsules with food decreases the rate (e.g., delaying peak plasma concentrations by about 1 hour) but not the extent of absorption.1, 3 Commercially available conventional capsules of isradipine generally can be given without regard to meals.22
To prepare a 1 mg/mL isradipine suspension, twenty four 5-mg capsules of the drug should be opened and the contents ground to a fine powder with a mortar and pestle.81 The fine powder should be levigated with a small amount of glycerin to form a paste.81 Simple syrup should be added in increasing amounts while mixing thoroughly; the suspension should then be transferred to a graduated cylinder.81 Any remaining drug in the mortar should be added to the graduated cylinder; the final volume of the suspension should be 120 mL.81 Contents of the graduated cylinder should be transferred into an appropriate size amber bottle.81 Isradipine suspension is stable for 35 days when refrigerated.81 The suspension should be shaken well before each use.81
For the management of hypertension, the usual initial adult dosage of isradipine conventional capsules is 1.25-2.5 mg twice daily.1, 2, 3, 4, 7, 14, 15, 16 However, a dosage form suitable for administering 1.25-mg doses currently is not commercially available in the US.1, 22
If blood pressure control is inadequate with initial dosages, isradipine dosage may be increased by increments of 5 mg daily at intervals of 2-4 weeks up to a maximum dosage of 20 mg daily; however, increasing dosage above 10 mg daily usually does not result in further improvement in blood pressure control but may be associated with an increased risk of adverse effects.1, 4 Some experts recommend a usual dosage range of 5-10 mg daily given in 2 divided doses.1200 The full hypotensive effect of isradipine may not be seen for 2-4 weeks.1
The usual initial dosage is recommended when isradipine is added to thiazide diuretic therapy.1, 59
Although isradipine bioavailability may be increased in geriatric patients,1, 3, 4, 7, 20 therapy with the drug can be initiated with the usual initial adult dosage of isradipine (i.e., 1.25-2.5 mg twice daily as conventional capsules) in geriatric patients.1, 3, 4, 7, 16, 20 In general, however, dosage escalation of antihypertensive therapy in geriatric patients should be slower than in younger adults,3, 20 and blood pressure may be adequately controlled with relatively low dosages and once-daily dosing.2, 3, 16
If isradipine is used for the management of hypertension in children†, some experts recommend an initial dosage of 0.05-0.1 mg/kg administered 2-3 times daily as conventional capsules.1150 These experts recommend a maximum dosage of 0.6 mg/kg (up to 10 mg) daily.1150 Experts state that the drug should be initiated at the low end of the dosage range and the dosage may be increased every 2-4 weeks until blood pressure is controlled, the maximum dosage is reached, or adverse effects occur.1150
For rapid reduction of blood pressure in children and adolescents with severe hypertension†, some experts recommend an oral isradipine dosage of 0.05-0.1 mg/kg (up to 5 mg) administered every 6-8 hours.1150
For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.
Blood Pressure Monitoring and Treatment Goals
Blood pressure should be monitored regularly (i.e., monthly) during therapy and dosage of the antihypertensive drug adjusted until blood pressure is controlled.1200 If an adequate blood pressure response is not achieved with calcium-channel blocker monotherapy, the dosage may be increased or another antihypertensive agent with demonstrated benefit and preferably with a complementary mechanism of action (e.g., angiotensin-converting enzyme [ACE] inhibitor, angiotensin II receptor antagonist, thiazide diuretic) may be added; if target blood pressure is still not achieved, a third drug may be added.1200, 1216 (See Uses: Hypertension.) In patients who develop unacceptable adverse effects with isradipine, the drug should be discontinued and another antihypertensive agent from a different pharmacologic class should be initiated.1200, 1216
The goal of hypertension management and prevention is to achieve and maintain optimal control of blood pressure.1200 However, the optimum blood pressure threshold for initiating antihypertensive drug therapy and specific treatment goals remain controversial.505, 506, 507, 508, 515, 523, 530, 1201, 1207, 1209, 1222 A 2017 multidisciplinary hypertension guideline from the American College of Cardiology (ACC), American Heart Association (AHA), and a number of other professional organizations generally recommends a blood pressure goal of less than 130/80 mm Hg in all adults regardless of comorbidities or level of atherosclerotic cardiovascular disease (ASCVD) risk.1200, 1207 Many patients will require at least 2 drugs from different pharmacologic classes to achieve this blood pressure goal; the potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs also should be considered when deciding a patient's blood pressure treatment goal.1200, 1220
For additional information on target levels of blood pressure and on monitoring therapy in the management of hypertension, see Blood Pressure Monitoring and Treatment Goals under Dosage: Hypertension, in Dosage and Administration, in the Thiazides General Statement 40:28.20.
Dosage in Renal and Hepatic Impairment
Isradipine bioavailability is increased in patients with hepatic impairment and/or mild renal impairment;1, 2, 3, 4 however, the manufacturer states that therapy with the drug can be initiated with the usual initial adult dosage in such patients.1, 4, 7 Some clinicians caution that dosage modification (i.e., reduced dosage) and careful titration may be necessary during oral isradipine therapy in patients with hepatic dysfunction since clinically important increases in bioavailability secondary to reduced first-pass metabolism may occur in such patients.3, 21
In therapeutic dosage, isradipine usually is well tolerated.1, 2, 3, 4, 11, 13, 14, 15, 16, 17, 18 The adverse effect profile of the drug is similar to that of other 1,4-dihydropyridine-derivative calcium-channel blocking agents.4, 10 Most of the common adverse reactions to isradipine are transient and result from its vasodilating action on vascular smooth muscle. 1, 2, 3, 4, 10, 11, 14 Such effects most frequently include headache, dizziness, and peripheral edema, and less frequently palpitation, tachycardia, and flushing.1, 2, 3, 4, 10, 11, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 51, 52, 53 The frequency of headache appears to decrease with continued therapy,1, 15 while that of other common adverse effects changes little or increases slightly with continued use, particularly at dosages of 15 mg or more daily.1, 2, 3, 10, 11 At lower dosages, the incidence of adverse effects usually diminishes with time.3 Edema, palpitation, fatigue, and flushing appear to be dose related, particularly at dosages of 15-20 mg daily.1, 2, 3, 10, 11 Some evidence also suggests that adverse effects of the drug may be more likely in women than in men.10 Adverse effects required discontinuance of therapy in 5% of patients who received conventional isradipine capsules in clinical trials,1 principally because of vasodilatory effects (e.g., headache, edema, dizziness, palpitation, flushing) and GI disturbances.1, 13, 14, 16, 18 In long-term studies of up to 2 years' duration, adverse effects reported with conventional isradipine capsules generally were mild and transient and similar to those reported in short-term studies, although the frequency of effects increased slightly during long-term use.1 The manufacturer states that the incidences of adverse effects are based principally on experience from controlled studies in patients with hypertension in whom isradipine was given alone or concomitantly with another agent (usually a thiazide diuretic).1
Headache,1, 2, 13, 14, 15, 16, 17 dizziness/vertigo,1, 2, 13, 14, 15, 17 and fatigue1, 14, 15 are the most common adverse nervous system effects of isradipine, occurring in about 14, 7, and 4% of patients overall, respectively, at various dosages employed in clinical studies.1 The frequency of headache or fatigue increases at relatively high dosages, occurring in about 22 or 9%, respectively, of patients receiving dosages of 20 mg daily as conventional isradipine capsules;1 however, the risk of headache appears to diminish with continued therapy.1 Weakness1, 16 occurs in 1.2% of patients receiving conventional isradipine capsules.1 Other adverse nervous system effects generally occur in 0.5-1% or less of patients receiving isradipine, but a causal relationship has not been established.1 Such effects include drowsiness,1 sleep disturbance (e.g., insomnia),1, 14, 15 lethargy,1 nervousness,1 decreased libido/frigidity,1 depression,1 disturbed skin sensation,14 paresthesia (including numbness and tingling),1 and numbness.1
Edema (e.g., peripheral, pedal),1, 3, 4, 13, 14, 15, 16, 17 palpitation,1, 14, 15, 16, 17 and flushing (hot flushes, facial erythema)1, 3, 13, 14, 15, 16, 17 are the most common cardiovascular effects of isradipine, occurring in about 7, 4, and 3% of patients overall, respectively, at various dosages employed in clinical studies.1 These effects appear to be dose related, occurring in about 9, 5, and 5%, respectively, of patients receiving dosages of 20 mg daily as conventional isradipine capsules.1 Peripheral edema associated with isradipine therapy generally is localized, confined to the lower limbs (e.g., ankles), and not associated with weight gain3, 4, 17, 18 and probably results from an effect on the microvasculature rather than from sodium and/or fluid retention.3, 4, 22 Chest pain1, 14 occurs in 2.4% of patients and tachycardia1, 2, 4, 14, 16 in 1.5%;1 tachycardia generally decreases with continued therapy.4 Other adverse cardiovascular effects generally occur in 1% or less of patients receiving isradipine, but a causal relationship has not been established.1 Such effects include hypotension,1, 16 angina,14 atrial fibrillation,1, 13, 16 ventricular fibrillation,1 myocardial infarction,1, 13, 16, 18 heart failure,1, 16 transient ischemic attack,1 and stroke.1 Despite the lack of establishment of causality, distinct worsening of the patient's condition (e.g., increased frequency of angina with subsequent myocardial infarction) was temporally related to isradipine therapy in several patients with underlying angina; similar effects have been observed with other calcium-channel blocking agents.18
While isradipine occasionally may produce symptomatic hypotension at usual dosages, syncope1, 14 and severe dizziness1 rarely have been reported in hypertensive patients receiving the drug, particularly at initial recommended dosages.1 A small, but clinically relevant, deterioration in renal function, possibly secondary to a marked hypotensive effect of the drug, was observed in at least one patient receiving 10 mg daily but may have been related to a preexisting condition.14 At excessive dosage (e.g., acute overdosage), substantial vasodilation with marked and probably prolonged systemic hypotension may occur.1
Nausea1, 2, 14, 15 and abdominal discomfort1, 14 occur in about 2%1 and vomiting1, 14 and diarrhea1, 15 occur in 1.1% of patients overall at various isradipine dosages employed in clinical studies.1 The frequency of some adverse GI effects (e.g., nausea) may increase with increasing dosage.1 Other adverse GI effects generally occur in 1% or less of patients receiving isradipine, but these effects have not been directly attributed to the drug.1 Such effects include dry mouth1, 15 and constipation.1 In one study, the frequency of dry mouth increased with continued therapy.15
Dyspnea1, 13, 15, 16 occurs in about 2% of patients overall at various isradipine dosages employed in clinical studies.1 Dyspnea may be dose related, occurring in 0.5% of patients receiving conventional isradipine capsules at a dosage of 5 mg daily and in 3.4% at a dosage of 20 mg daily.1 Throat discomfort occurs in 1% or less of patients receiving the drug, but a causal relationship has not been established.1
Dermatologic and Sensitivity Reactions
Rash1, 15 occurs in 1.5% of patients overall at various isradipine dosages employed in clinical studies.1 Pruritus,1, 14, 15 erythema,14 urticaria,1 and allergic skin reactions14 have been reported in 0.5-1% or less of patients receiving the drug but have not been directly attributed to isradipine therapy.1 Gingival hyperplasia has been reported occasionally.22
Pollakiuria occurs in 1.5% of patients overall at various isradipine dosages employed in clinical studies; however, at an isradipine dosage of 20 mg daily as conventional capsules, this effect occurred in 3.4% of patients.1 Minor liver function abnormalities1, 3, 10, 11, 14 were reported in about 6% of patients receiving isradipine conventional capsules in one comparative study and occurred at a frequency greater than that reported with placebo, hydrochlorothiazide, or prazosin.10, 11 Other adverse effects generally occur in 1% or less of patients receiving isradipine, but a causal relationship has not been established.1 Such effects include leg and/or foot cramps,1 pain in the extremities,14 nocturia,1 impotence,1 hyperhidrosis,1 visual disturbances,1 tinnitus,2, 15 and leukopenia.1
Isradipine does not appear to adversely affect serum lipoproteins but actually may produce limited beneficial effects.3, 4, 10, 12 Small increases in the high-density (HDL)/low-density lipoprotein (LDL) ratio and small decreases in serum LDL concentration have been observed.3, 10, 12
Precautions and Contraindications
Some findings concerning possible risks of calcium-channel blocking agents have raised concerns about the safety and efficacy of these agents (mainly conventional [short-acting] preparations of nifedipine).23, 24, 25, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 49 (See Cautions, in Nifedipine 24:28.08.) Findings of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), which compared long-term therapy with a dihydropyridine-derivative calcium-channel blocker, a thiazide-like diuretic, or an angiotensin-converting enzyme (ACE) inhibitor, however, have failed to support these findings.61, 74 (See Clinical Benefits of Thiazides in Hypertension under Hypertension in Adults: Treatment Benefits, in Uses in the Thiazides General Statement 40:28.20.)
Isradipine shares the toxic potentials of other 1,4-dihydropyridine-derivative calcium-channel blocking agents, and the usual precautions of these agents should be observed.1, 4
Because isradipine decreases peripheral vascular resistance and occasionally causes symptomatic hypotension, blood pressure should be monitored carefully, especially during initiation of therapy or upward adjustment of dosage.1 In addition, the frequency, duration, and severity of angina may rarely increase during therapy with isradipine.3, 14, 18
Although isradipine can acutely reduce afterload without impairing myocardial contractility in patients with congestive heart failure, the drug exhibits a negative inotropic effect at high doses in vitro and possibly in some patients.1 In addition, while some evidence suggests that substantial adverse cardiac effects are uncommon with isradipine alone or combined with β-adrenergic blocking agents,2, 3, 14, 17, 18, 19 isradipine should be used with caution in patients with congestive heart failure, especially in those receiving concomitant β-blockers, and the possibility that isradipine might precipitate or worsen heart failure in some of these patients should be considered.1, 16, 18
Isradipine is contraindicated in patients with known hypersensitivity to the drug or any ingredient in the formulation.1
Although safety and efficacy remain to be fully established in children younger than 18 years of age,1, 22 some experts have recommended pediatric dosages for hypertension based on clinical experience.1150 For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.
In geriatric patients, clearance of isradipine is decreased, resulting in increases in peak plasma concentrations and AUC;1, 59 such increased bioavailability also may be associated with reduced first-pass metabolism of the drug.59
Mutagenicity and Carcinogenicity
No evidence of isradipine-induced mutagenicity was seen in a battery of standard in vitro and in vivo test systems,1 including the Ames test, the HGPRT-assay in Chinese hamster cells, the induction of DNA repair synthesis (UDS) in rat hepatocyte primary cultures, and the micronucleus assay in mice.22
No evidence of carcinogenicity was observed in mice receiving isradipine dosages up to 80 mg/kg daily (up to 200 times the maximum recommended human daily dosage) for 2 years.1 However, a dose-dependent increased incidence of benign Leydig cell tumors and testicular hyperplasia was observed in male rats receiving 2.5-62.5 mg/kg of isradipine daily (6-156 times the maximum recommended human daily dosage adjusted for a 50-kg man) for 2 years.1 Such testicular changes may have been related indirectly to isradipine-induced effects on systemic gonadotropin concentrations.1 While such effects on gonadotropins have been observed in rats, a comparable effect has not been observed to date in men during long-term isradipine therapy for hypertension.1
Pregnancy, Fertility, and Lactation
Isradipine has produced maternotoxicity (reduced maternal weight gain) and reductions in birthweight and pup survival during reproductive studies in rats given an oral isradipine dosage of 20 and 60 mg/kg daily (50 and 150 times the maximum recommended human dosage, respectively) during the perinatal and postnatal period.1 In studies in pregnant rats receiving isradipine during organogenesis, dosages of 60 mg/kg daily impaired maternal weight gain but had no lasting effect on dams or offspring.1 Such effects were not observed in these rats at dosages of 6 mg/kg daily.1, 22 The drug has produced maternotoxicity (reduced maternal weight gain) and increased fetal resorption during reproductive studies in rabbits given oral isradipine dosages of 3-10 mg/kg daily (7.5-25 times the maximum recommended human dosage).1, 22 There are no adequate and controlled studies to date with isradipine in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risk to the fetus.1, 22
Reproductive studies in male and female rats using oral isradipine dosages of up to 60 mg/kg daily have not revealed evidence of impaired fertility.1
It is not known whether isradipine is distributed in milk.1 Because of the potential for serious adverse reactions to isradipine in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the women.1
Isradipine is a 1,4-dihydropyridine derivative, and the possibility that the drug may share the drug interaction potential of nifedipine, another 1,4-dihydropyridine derivative, should be considered and the usual precautions observed. (See Drug Interactions in Nifedipine 24:28.08.)
Isradipine is a 1,4-dihydropyridine-derivative calcium-channel blocking agent that is structurally related to felodipine, nifedipine, and nimodipine.1, 2, 3, 4, 7
Additional Information
SumMon® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the labeling be consulted for detailed information on the usual cautions, precautions, and contraindications concerning potential drug interactions and/or laboratory test interferences and for information on acute toxicity.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules | 2.5 mg* | Isradipine Capsules | |
5 mg* | Isradipine Capsules |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
1. Reliant Pharmaceuticals. DynaCirc® (isradipine) capsules prescribing information. Liberty Corner, NJ; 2003 Oct.
2. Lopez LM, Santiago TM. Isradipine—another calcium-channel blocker for the treatment of hypertension and angina. Ann Pharmacother . 1992; 26:789-99. [PubMed 1535246]
3. Fitton A, Benfield P. Isradipine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in cardiovascular disease. Drugs . 1990; 40:31-74. [PubMed 2143980]
4. Walton T, Symes LR. Felodipine and isradipine: new calcium-channel blocking agents for the treatment of hypertension. Clin Pharm . 1993; 12:261-75. [PubMed 8458178]
6. Prisant LM, Carr AA, Nelson EB et al. Isradipine vs propranolol in hydrochlorothiazide-treated hypertensives: a multicenter evaluation. Arch Intern Med . 1989; 149:2453-7. [PubMed 2530945]
7. Anon. Isradipine for hypertension. Med Lett Drugs Ther . 1991; 33:51-4. [PubMed 1827655]
8. Alderman MH. Which antihypertensive drugs first—and why! JAMA . 1992; 267:2786-7. Editorial.
9. Weber MA, Laragh JH. Hypertension: steps forward and steps backward: the Joint National Committee fifth report. Arch Intern Med . 1993; 153:149-52. [PubMed 8422205]
10. Dahlof B. Hemodynamic response, safety, and efficacy of isradipine in the treatment of essential hypertension. Am J Med . 1988; 86(Suppl 4A):19-26.
11. Kirkendall WM. Comparative assessment of first-line agents for treatment of hypertension. Am J Med . 1988; 84(Suppl 3B):32-41. [PubMed 3260071]
12. Rauramaa R, Taskinen E, Seppanen K et al. Effects of calcium antagonist treatment on blood pressure, lipoproteins and prostaglandins. Am J Med . 1988; 84(Suppl 3B):93-6.
13. Cocco G, Alfiero R, Boxho G et al. Multicenter evaluation of the safety and efficacy of isradipine in hypertension. The Italian-Belgian Isradipine Study Group. Am J Med . 1989; 86(Suppl 4A):94-7.
14. Sundstedt CD, Ruegg PC, Keller A et al. A multicenter evaluation of safety, tolerability, and efficacy of isradipine in the treatment of essential hypertension. Am J Med . 1989; 86(Suppl 4A):98-102. [PubMed 2523665]
15. De Keyser P, Bouve J, Clement D et al. Isradipine in essential hypertension: the Belgian general practitioners' study. Am J Med . 1989; 86(Suppl 4A):103-9. [PubMed 2565687]
16. Anderton JL, Adams RM, Chowdary KVG et al. Evaluation of the safety and efficacy of isradipine in elderly patients with essential hypertension. The British Isradipine Hypertension Group. Am J Med . 1989; 86(Suppl 4A):110-14.
17. O'Rourke MF, Balasubramaniam A, Anavekar S et al. A multicenter evaluation of the safety and efficacy of isradipine and atenolol in the treatment of hypertension. Isradipine in Hypertension Study Group. Am J Med . 1989; 86(Suppl 4A):119-23.
18. Ruegg PC, Nelson DJ. Safety and efficacy of isradipine, alone and in combination, in the treatment of angina pectoris. Am J Med . 1989; 86(Suppl 4A):70-4. [PubMed 2565689]
19. McGrath BP, Newman R, Older P. Hemodynamic study of short- and long-term isradipine treatment in patients with chronic ischemic congestive heart failure. Am J Med . 1989; 86(Suppl 4A):75-80. [PubMed 2523660]
20. Chellingsworth MC, Willis JV, Jack DB et al. Pharmacokinetics and pharmacodynamics of isradipine (PN 200-110) in young and elderly patients. Am J Med . 1988; 84(Suppl 3B):72-9.
21. Cotting J, Reichen J, Kutz K et al. Pharmacokinetics of isradipine in patients with chronic liver disease. Eur J Clin Pharmacol . 1990; 38:599-603. [PubMed 2142648]
22. Sandoz Pharmaceuticals Corp, East Hanover, NJ: Personal communication.
23. Glasser SP, Clark PI, Lipicky RJ et al. Exposing patients with chronic, stable, exertional angina to placebo periods in drug trials. JAMA . 1991; 265:1550-4. [PubMed 1671885]
24. National Heart, Lung, and Blood Institute. NHLBI panel reviews safety of calcium channel blockers. Rockville, MD; 1995 Aug 31. Press release.
25. National Heart, Lung, and Blood Institute. New analysis regarding the safety of calcium-channel blockers: a statement for health professionals from the National Heart, Lung, and Blood Institute. Rockville, MD; 1995 Sep 1.
26. Anon. NHLBI panel stands by JNC V in response to Circulation CCB article; AIM report supports use of beta blockers for prevention of sudden cardiac death. F-D-C Rep . 1995; 57(Sep 4):3- 4.
27. American Heart Association. Public advisory statement on calcium channel blocker drugs. Dallas, TX; 1995 Aug 28.
28. Psaty BM, Heckbert SR, Koepsell TD et al. The risk of myocardial infarction associated with antihypertensive drug therapies. JAMA . 1995; 274:620-5. [PubMed 7637142]
29. Psaty BM, Heckbert SR, Koepsell TD et al. The risk of incident myocardial infarction associated with anti-hypertensive drug therapies. Circulation . 1995; 91:925.
30. Buring JE, Glynn RJ, Hennekens CH. Calcium channel blockers and myocardial infarction: a hypothesis formulated but not yet tested. JAMA . 1995; 274:654- 5. [PubMed 7637148]
31. Furberg CD, Psaty BM, Meyer JV. Nifedipine: dose-related increase in mortality in patients with coronary heart disease. Circulation . 1995; 92:1326-31. [PubMed 7648682]
32. Opie LH, Messerli FH. Nifedipine and mortality: grave defects in the dossier. Circulation . 1995; 92:1068-73. [PubMed 7648646]
33. Kloner RA. Nifedipine in ischemic heart disease. Circulation . 1995; 92:1074-8. [PubMed 7648647]
34. Yusuf S. Calcium antagonists in coronary artery disease and hypertension: time for reevaluation? Circulation . 1995; 92:1079-82. Editorial.
35. Lenfant C. The calcium channel blocker scare: lessons for the future. Circulation . 1995; 91:2855-6. [PubMed 7796490]
36. Habib GB. Are calcium antagonists harmful in hypertensive patients? Distinguishing hype from reality. Chest . 1995; 108:3-5. [PubMed 7606987]
37. Horton R. Spinning the risks and benefits of calcium antagonists. Lancet . 1995; 346:586- 7. [PubMed 7650997]
38. Yusuf S, Held P, Furberg C. Update of effects of calcium antagonists in myocardial infarction or angina in light of the Second Danish Verapamil Infarction Trial (DAVIT-II) and other recent studies. Am J Cardiol . 1991; 67:1295-7. [PubMed 2035457]
39. Egstrup K, Andersen PE Jr. Transient myocardial ischemia during nifedipine therapy in stable angina pectoris, and its relation to coronary collateral flow and comparison with metoprolol. Am J Cardiol . 1993; 71:177- 83. [PubMed 8421980]
40. Wagenknecht LE, Furberg CD, Hammon JW et al. Surgical bleeding: unexpected effect of a calcium antagonist. BMJ . 1995; 310:776-7. [PubMedCentral][PubMed 7711582]
41. Miles Inc. American Heart Association, Dr. Psalty and Miles Inc. release statements qualifying possible risks of calcium channel blockers. West Haven, CT; 1995 Mar 15. Press release.
42. Dear healthcare professional letter regarding calcium-channel blockers and increased risk of heart attack. Chicago:Searle. 1995 Mar 17.
43. McClellan K. Unexpected results from MIDAS in atherosclerosis. Inpharma Wkly . 1994; Apr 9:4.
44. Anon. Groups act to dispel concerns about calcium-channel blockers. Am J Health-Syst Pharm . 1995; 52:1154, 1158. [PubMed 7656105]
45. Waters D. Proischemic complications of dihydropyridine calcium channel blockers. Circulation . 1991; 84:2598-600. [PubMed 1959210]
46. Messerli FH. Case-control study, meta-analysis, and bouillabaisse: putting the calcium antagonist scare into context. Ann Intern Med . 1995; 123:888-9. [PubMed 7486476]
47. Reviewers' comments (personal observations).
48. Pratt Pharmacueticals. Procardia® (nifedipine) capsules prescribing information (dated 1993 Feb). In: Physicians' desk reference. 49th ed. Montvale, NJ: Medical Economics Company Inc; 1995:1906-7.
49. Held PH, Yusuf S, Furberg CD. Calcium channel blockers in acute myocardial infarction and unstable angina: an overview. BMJ . 1989; 299:1187-92. [PubMedCentral][PubMed 2513047]
51. Kaplan NM. Choice of initial therapy for hypertension. JAMA . 1996; 275:1577-80. [PubMed 8622249]
52. Psaty BM, Smith NL, Siscovich DS et al. Health outcomes associated with antihypertensive therapies used as first-line agents: a systematic review and meta-analysis. JAMA . 1997; 277:739-45. [PubMed 9042847]
53. American College of Cardiology and American Heart Association. ACC/AHA guidelines for the management of patients with acute myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). J Am Coll Cardiol . 1996; 28:1328-428. [PubMed 8890834]
55. Izzo JL, Levy D, Black HR. Importance of systolic blood pressure in older Americans. Hypertension . 2000; 35:1021-4. [PubMed 10818056]
56. Frohlich ED. Recognition of systolic hypertension for hypertension. Hypertension . 2000; 35:1019-20. [PubMed 10818055]
57. Bakris GL, Williams M, Dworkin L et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach. Am J Kidney Dis . 2000; 36:646-61. [PubMed 10977801]
58. Associated Press (American Diabetes Association). Diabetics urged: drop blood pressure. Chicago, IL; 2000 Aug 29. Press Release from web site. [Web]
59. Reliant Pharmaceuticals, LLC. DynaCirc CR® (isradipine) controlled release tablets prescribing information. Liberty Corner, NJ; 2005 Aug.
60. Appel LJ. The verdict from ALLHAT—thiazide diuretics are the preferred initial therapy for hypertension. JAMA . 2002; 288:3039-60. [PubMed 12479770]
61. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-riskhypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA . 2002; 288:2981-97. [PubMed 12479763]
62. Velussi M, Brocco E, Frigato F et al. Effects of cilazapril and amlodipine on kidney function in hypertensive NIDDM patients. Diabetes . 1996; 45:216-22. [PubMed 8549868]
63. Estacio RO, Jeffers BW, Hiatt WR et al. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension. N Engl J Med . 1998; 338:645-52. [PubMed 9486993]
64. Pahor M, Psaty BM, Furberg CD. Treatment of hypertensive patients with diabetes. Lancet . 1998; 351:689-90. [PubMed 9504510]
65. Tatti P, Pahor M, Byington RP et al. Outcome results of the Fosinopril versus Amlodipine Cardiovascular Events randomized Trial (FACET) in patients
66. Byington RP, Craven TE, Furberg CD et al. Isradipine, raised glycosylated haemoglobin, and risk of cardiovascular events. Lancet . 1997; 350:1075-6. [PubMed 10213554]
67. Alderman M, Madhavan S, Cohen H. Calcium antagonists and cardiovascular events in patients with hypertension and diabetes. Lancet . 1998; 351:216-7. [PubMed 9449897]
68. Josefson D. Infarction risk found with calcium channel blocker. BMJ . 1998; 316:797.
69. Cutler JA. Calcium-channel blockers for hypertension—uncertainty continues. N Engl J Med . 1998; 338:679-81. [PubMed 9486999]
70. Bayer, West Haven, CT: Personal communication on amlodipine.
71. Bakris GL, Copley JB, Vicknair N et al. Calcium channel blockers versus other antihypertensive therapies on progression of NIDDM associated nephropathy. Kidney Int . 1996; 50:1641-50. [PubMed 8914031]
72. National Heart, Lung, and Blood Institute National High Blood Pressure Education Program. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VII) Express. Bethesda, MD: May 14 2003. From NIH website. (Also published in JAMA . 2003; 289. [Web]
73. American Diabetes Association. Position statements: treatment of hypertension in adults with diabetes. Diabetes Care . 2003; 26(Suppl 1):S80-S82.
74. Kaplan NM. The meaning of ALLHAT. J Hypertens . 2003; 21:233-4. [PubMed 12569243]
77. Wright JT, Dunn JK, Cutler JA et al. Outcomes in hypertensive black and nonblack patients treated with chlorthalidone, amlodipine, and lisinopril. JAMA . 2005; 293:1595-607. [PubMed 15811979]
78. Neaton JD, Kuller LH. Diuretics are color blind. JAMA . 2005; 293:1663-6. [PubMed 15811986]
79. Leenen FHH, Nwachuku CE, Black HR et al. Clinical events in high-risk hypertensive patients randomly assigned to calcium-channel blocker versus angiotensin-converting enzyme inhibitor in the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial. Hypertension . 2006; 48:374-84. [PubMed 16864749]
80. Messerli FH, Staessen JA. Amlodipine better than lisinopril: how one randomized clinical trial ended fallacies from observational studies? Hypertension . 2006; 48:359-61. Editorial.
81. (Isradipine Suspension 1 mg/mL) In: Jew RK, Mullen RJ, Soo-Hoo W. Extemporaneous formulations. Bethesda, MD; American Society of Health-System Pharmacists, Inc: 2003:(page 32).
82. Cobalt Laboratories. Isradipine capsules prescribing information. Bonita Springs, FL; 2008 May.
83. Miyashita Y, Peterson D, Rees JM et al. Isradipine for treatment of acute hypertension in hospitalized children and adolescents. J Clin Hypertens (Greenwich) . 2010; 12:850-5. [PubMedCentral][PubMed 21054771]
501. James PA, Oparil S, Carter BL et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA . 2014; 311:507-20. [PubMed 24352797]
502. Mancia G, Fagard R, Narkiewicz K et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens . 2013; 31:1281-357. [PubMed 23817082]
503. Go AS, Bauman MA, Coleman King SM et al. An effective approach to high blood pressure control: a science advisory from the American Heart Association, the American College of Cardiology, and the Centers for Disease Control and Prevention. Hypertension . 2014; 63:878-85. [PubMed 24243703]
504. Weber MA, Schiffrin EL, White WB et al. Clinical practice guidelines for the management of hypertension in the community: a statement by the American Society of Hypertension and the International Society of Hypertension. J Clin Hypertens (Greenwich) . 2014; 16:14-26. [PubMed 24341872]
505. Wright JT, Fine LJ, Lackland DT et al. Evidence supporting a systolic blood pressure goal of less than 150 mm Hg in patients aged 60 years or older: the minority view. Ann Intern Med . 2014; 160:499-503. [PubMed 24424788]
506. Mitka M. Groups spar over new hypertension guidelines. JAMA . 2014; 311:663-4. [PubMed 24549531]
507. Peterson ED, Gaziano JM, Greenland P. Recommendations for treating hypertension: what are the right goals and purposes?. JAMA . 2014; 311:474-6. [PubMed 24352710]
508. Bauchner H, Fontanarosa PB, Golub RM. Updated guidelines for management of high blood pressure: recommendations, review, and responsibility. JAMA . 2014; 311:477-8. [PubMed 24352759]
510. Staessen JA, Fagard R, Thijs L et al. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet . 1997; 350:757-64. [PubMed 9297994]
511. JATOS Study Group. Principal results of the Japanese trial to assess optimal systolic blood pressure in elderly hypertensive patients (JATOS). Hypertens Res . 2008; 31:2115-27. [PubMed 19139601]
515. Thomas G, Shishehbor M, Brill D et al. New hypertension guidelines: one size fits most?. Cleve Clin J Med . 2014; 81:178-88. [PubMed 24591473]
516. Wright JT, Bakris G, Greene T et al. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. JAMA . 2002; 288:2421-31. [PubMed 12435255]
522. Patel A, ADVANCE Collaborative Group, MacMahon S et al. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet . 2007; 370:829-40. [PubMed 17765963]
523. Fihn SD, Gardin JM, Abrams J et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation . 2012; 126:e354-471.
524. WRITING COMMITTEE MEMBERS, Yancy CW, Jessup M et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation . 2013; 128:e240-327.
525. Smith SC, Benjamin EJ, Bonow RO et al. AHA/ACCF Secondary Prevention and Risk Reduction Therapy for Patients with Coronary and other Atherosclerotic Vascular Disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation. Circulation . 2011; 124:2458-73. [PubMed 22052934]
526. Kernan WN, Ovbiagele B, Black HR et al. Guidelines for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke . 2014; :. [PubMed 24788967]
527. O'Gara PT, Kushner FG, Ascheim DD et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation . 2013; 127:e362-425. [PubMedCentral]
530. Myers MG, Tobe SW. A Canadian perspective on the Eighth Joint National Committee (JNC 8) hypertension guidelines. J Clin Hypertens (Greenwich) . 2014; 16:246-8. [PubMed 24641124]
535. Taler SJ, Agarwal R, Bakris GL et al. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for management of blood pressure in CKD. Am J Kidney Dis . 2013; 62:201-13. [PubMedCentral][PubMed 23684145]
536. Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group. KDIGO clinical practice guideline for the management of blood pressure in chronic kidney disease. Kidney Int Suppl . 2012: 2: 337-414.
541. Perk J, De Backer G, Gohlke H et al. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Eur Heart J . 2012; 33:1635-701. [PubMed 22555213]
1150. Flynn JT, Kaelber DC, Baker-Smith CM et al. Clinical practice guideline for screening and management of high blood pressure in children and adolescents. Pediatrics . 2017; 140 [PubMed 28827377]
1200. Whelton PK, Carey RM, Aronow WS et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension . 2018; 71:el13-e115. [PubMed 29133356]
1201. Bakris G, Sorrentino M. Redefining hypertension - assessing the new blood-pressure guidelines. N Engl J Med . 2018; 378:497-499. [PubMed 29341841]
1202. Carey RM, Whelton PK, 2017 ACC/AHA Hypertension Guideline Writing Committee. Prevention, detection, evaluation, and management of high blood pressure in adults: synopsis of the 2017 American College of Cardiology/American Heart Association hypertension guideline. Ann Intern Med . 2018; 168:351-358. [PubMed 29357392]
1207. Burnier M, Oparil S, Narkiewicz K et al. New 2017 American Heart Association and American College of Cardiology guideline for hypertension in the adults: major paradigm shifts, but will they help to fight against the hypertension disease burden?. Blood Press . 2018; 27:62-65. [PubMed 29447001]
1209. Qaseem A, Wilt TJ, Rich R et al. Pharmacologic treatment of hypertension in adults aged 60 years or older to higher versus lower blood pressure targets: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med . 2017; 166:430-437. [PubMed 28135725]
1210. SPRINT Research Group, Wright JT, Williamson JD et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med . 2015; 373:2103-16. [PubMed 26551272]
1213. Reboussin DM, Allen NB, Griswold ME et al. Systematic review for the 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol . 2017; [PubMed 29146534]
1216. Taler SJ. Initial treatment of hypertension. N Engl J Med . 2018; 378:636-644. [PubMed 29443671]
1220. Cifu AS, Davis AM. Prevention, detection, evaluation, and management of high blood pressure in adults. JAMA . 2017; 318:2132-2134. [PubMed 29159416]
1222. Bell KJL, Doust J, Glasziou P. Incremental benefits and harms of the 2017 American College of Cardiology/American Heart Association high blood pressure guideline. JAMA Intern Med . 2018; 178:755-7. [PubMed 29710197]
1223. LeFevre M. ACC/AHA hypertension guideline: what is new? what do we do?. Am Fam Physician . 2018; 97(6):372-3. [PubMed 29671534]
1224. Brett AS. New hypertension guideline is released. From NEJM Journal Watch website. Accessed 2018 Jun 18. [Web]
1229. Ioannidis JPA. Diagnosis and treatment of hypertension in the 2017 ACC/AHA guidelines and in the real world. JAMA . 2018; 319(2):115-6. [PubMed 29242891]
1250. Weir MR, Josselson J, Giard MJ et al. Sustained-release diltiazem compared with atenolol monotherapy for mild to moderate systemic hypertension. Am J Cardiol . 1987; 60:36-41I. [PubMed 3604943]
1251. Muller FB, Bolli P, Erne P et al. Use of calcium antagonists as monotherapy in the management of hypertension. Am J Med . 1984; 77(Suppl 2B):11-5. [PubMed 6385691]
1252. Kiowski W, Bühler FR, Fadayomi MO et al. Age, race, blood pressure and renin: predictors for antihypertensive treatment with calcium antagonists. Am J Cardiol . 1985; 56:81-5H.
1253. Frishman WH, Charlap S, Michelson EL. Calcium channel blockers in systemic hypertension. Am J Cardiol . 1986; 58:157-60. [PubMed 3524178]
1254. Halperin AK, Cubeddu LX. The role of calcium channel blockers in the treatment of hypertension. Am Heart J . 1986; 111:363-82. [PubMed 3511651]
1255. Laragh JH. Issues, goals, and guidelines in selecting first-line drug therapy for hypertension. In: The National Heart, Lung, and Blood Institute workshop on antihypertensive drug treatment. Bethesda, MD; June 11-12, 1987. Hypertension . 1989; 13(Suppl I):I-103-12. [PubMed 2490815]