9.1.3 Calcium Channel Blockers. Calcium channel blockers were introduced for use in the management of patients with angina pectoris and have had a major impact in the therapy of patients with cardiac and vascular disease. These agents affect blood vessels by reducing their resistance and preventing vasospasm, which reduces systemic blood pressure. In addition, calcium channel blockers also have a moderate ocular hypotensive effect.27,28

Calcium channel blockers are a heterogeneous group of drugs that may have varying effects on different types of calcium channels. Several voltage-dependent types of calcium channels have been described, including L-, T-, N-, P-, Q-, and R-channels. There are at least four chemically distinct families of calcium antagonists: phenylalkylamines (e.g., verapamil), benzothiazepines (e.g., diltiazem), dihydropyri-dines (e.g., nifedipine), and piperazines (e.g., flunarizine, cinnarizine). Piperazine-type calcium channel blockers are not used for treatment of systemic hypertension.

Because of their varying effects on different calcium channels, dihydropyridine antagonists, such as nifedipine, are more selective for the vasculature compared with phenylalkylamines, such as verapamil. Certain drugs, such as nimodipine, cross the blood-brain barrier and can affect the cerebral vasculature.

Calcium channel blockers available for treatment of systemic hypertension in the United States and their usual systemic dosages are shown in Table 9.3. For

Table 9.3 Systemic Calcium Channel Blockers Available in the United States

Usual Dosage

Range3 Frequency

Drug (total mg/day) (times/day)

Non-Dihydropyridine-Based Antagonists Phenylalkylamine-Based Antagonists

Verapamil immediate releaseb 80-320 2

Calan, Isoptin

Verapamil long-actingb 120-360 1 or 2

Calan SR, Isoptin SR

Verapamil controlled-onset extended release 120-360 1

Covera HS, Verelan PM

Benzothiazepine-Based Antagonists

Diltiazem extended releaseb 180-420 1

Dilacor XR, Tiazac, Cardizem CD

Diltiazem long acting 120-540 1

Cardizem LA

Dihydropyridine-Based Antagonistsc

Amlodipine 2.5-10 1 Norvasc

Felodipine 2.5-20 1 Plendil

Isradipine 2.5-10 2 DynaCirc CR

Nicardipine sustained release 60-120 2 Cardene SR

Nifedipine long-acting 30-60 1 Procardia XL, Adalat CC

Nisoldipine 10-40 1 Sular

^The lower dose indicated is the preferred initial dose, and the higher dose is the maximum daily dose for treatment of systemic hypertension.

bGeneric is available.

cAnother dihydropyridine-based calcium antagonist is nimodipine (Nimotop), which is used for subarachnoid hemorrhage in usual dosage of 60 mg (two 30-mg capsules) every 4 hours for 21 days.

Source: Modified from Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. JAMA. 2003;289:2560-2572.

simplification, antihypertensive calcium channel blockers have been grouped into dihydropyridine-based and non-dihydropyridine-based antagonists.1 The ''non-dihydropyridine'' antagonists include both benzothiazepines and phenylalkyl-amines. The World Health Organization has divided calcium channel blockers into six types based on both their clinical and their pharmacologic effects.29

Systemic administration of these drugs has demonstrated variable effects on IOP, with a trend toward reduction of IOP. Topical administration of verapamil in humans has generally resulted in a mild-to-moderate reduction of IOP. The more consistent reduction of IOP following topical administration compared with systemic administration may be due to different local drug concentrations in the eye following these differing routes of administration. After topical administration of verapamil 0.125%, the peak concentration in the aqueous was in the 10-6 M range, which was 200-fold higher than the concentration observed following high-dose systemic administration.30

In rabbits, intravenous administration of verapamil or nifedipine caused a reduction of IOP.31,32 Oral administration of verapamil in rabbits, however, had no effect on IOP.33 This lack of effect may have been due to lower concentrations in the eye following oral administration compared with intravenous administration.

In patients with systemic hypertension, Monica et al.34 found a significant reduction of IOP after oral nitrendipine. Similarly, Schnell35 reported significant reduction of IOP up to 13% in open-angle glaucoma patients following a single sublingual administration of nifedipine. In contrast, oral verapamil,30 oral or intravenous nifedipine,36 and oral diltiazem37 did not have significant effect on IOP in normal human subjects.

Topical administration of calcium channel blockers has been found to have a moderate ocular hypotensive effect, with a more consistent reduction of IOP than has been observed following systemic administration.27 Topical calcium channel blockers are for investigational use only and are not available for therapeutic use in the United States.

Verapamil causes a dose-related increase in outflow facility in human eyes, which may explain the mechanism of the effect on IOP following topical administration of this calcium channel blocker.38 In addition, episcleral venous pressure is significantly reduced in normal subjects following topical administration of verapamil.39

Topical beta blockers and systemic calcium channel blockers should be used concurrently with caution, especially in patients with impaired cardiovascular function. There have been two reports of severe bradycardia with concomitant use of timolol eye drops and oral verapamil.40,41 Calcium channel blockers appear to have a favorable ocular safety profile. In patients treated with high doses of oral verapamil for hypertrophic cardiomyopathy, there were no adverse ocular effects compared with controls following 1 year of therapy.42

9.1.4 Angiotensin-Converting Enzyme Inhibitors. Angiotensinogen is converted by renin to angiotensin I, which is then converted to angiotensin II by the action of angiotensin-converting enzyme (ACE). Angiotensin II is the principal active component of the renin-angiotensin system, which has potent vasoconstricting and other effects. ACE inhibitors (table 9.4) are effective and well-tolerated medications

Table 9.4 Systemic Angiotensin-Converting Enzyme Inhibitors


Usual Dosage

Rangea (total mg/day)

Frequency (times/day)

Benazepril Lotensin Captoprilb Capoten Enalaprilb Vasotec Fosinopril

Monopril Lisinoprilb

Prinivil, Zestril Moexipril Univasc Perindopril

Aceon Quinapril Accupril Ramipril Altace Trandolapril Mavik

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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