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110499 Calcium-Antagonist Drugs

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110499 Calcium-Antagonist Drugs DRUG THERAPY Review Article Drug Therapy smooth muscle (arteriolar and venous), nonvascular smooth muscle (bronchial, gastrointestinal, genitouri- nary, and uterine), and noncontractile tissues (pan- A LASTAIR J.J. WOOD, M.D., Editor creas, pituitary, adrenal glands, salivary glands, gastric mucosa, white cells, platelets, and lacrimal tissue). Blockade of L-type channels in vascular tissues results CALCIUM-ANTAGONIST DRUGS in the relaxation of vascular smooth muscle and in cardiac tisssue results in a negative inotropic effect. DARRELL R. ABERNETHY, M.D., PH.D., The ability of these drugs to decrease smooth-muscle AND JANICE B. SCHWARTZ, M.D. and myocardial contractility results in both clinically desirable antihypertensive and antianginal effects and undesirable myocardial depression. RUGS classified as calcium antagonists or Other calcium channels with electrophysiologic calcium-channel blockers were introduced properties have also been identified. These channels, into clinical medicine in the 1960s and are to which the calcium antagonists do not bind, in- D clude the N-type channels in neuronal tissue, P-type now among the most frequently prescribed drugs for the treatment of cardiovascular diseases.1 Although channels in Purkinje tissues, and T-type (transient potential) channels in cardiac nodal structures and the currently available calcium antagonists are chem- 4,5 ically diverse, they share the common property of vascular smooth muscle. blocking the transmembrane flow of calcium ions Regulation of the L-type channels may differ in through voltage-gated L-type (slowly inactivating) different types of cells. In cardiac myocytes, these channels.2 These drugs have proved effective in pa- channels are activated by catecholamines and other stimuli that activate adenylyl cyclase or cyclic aden- tients with hypertension, angina pectoris, and cardi- 6-8 ac arrhythmias and may be beneficial in patients with osine monophosphate–dependent protein kinase. left ventricular diastolic dysfunction, Raynaud’s phe- In contrast, these stimuli activate, inhibit, or have no nomenon, migraine, preterm labor, esophageal spasm, effect on L-type calcium channels in vascular and vis- and bipolar disorders. ceral smooth-muscle beds, depending on the exper- imental conditions.9,10 L-type channels are also acti- 11 12 L-TYPE CALCIUM CHANNELS vated by the a1-adrenergic system, angiotensin II, and endothelin.13 As an in vivo correlate of these All calcium antagonists bind to the a1c subunit of the L-type calcium channel (Fig. 1), which is the main findings, calcium antagonists block the responses of pore-forming unit of the channel. This subunit is as- vascular smooth muscle to phenylephrine, angioten- sin II, and endothelin-1 in humans.14,15 In addition sociated with a disulfide-linked a2d subunit and an intracellular b subunit. The a d and b subunits modu- to hormonal activation by means of signal-transduc- 2 tion pathways, L-type channels may be directly acti- late the a1c subunit. The phenylalkylamine (verapamil- like) calcium antagonists bind to transmembrane vated at the plasma membrane by guanine nucleo- segment 6 of motif IV (IVS6), the benzothiazepine tide–binding (G) proteins produced in response to (diltiazem-like) calcium antagonists bind to the cyto- hormone binding to its receptors. plasmic bridge between motif III (IIIS) and motif IV CALCIUM CHANNELS AND CELL GROWTH (IVS), and the dihydropyridine (nifedipine-like) calci- L-type (and T-type) calcium channels seem to have um antagonists bind to transmembrane segment 6 of a role in cellular growth and proliferation in addition both motif III (IIIS6) and motif IV (IVS6) (Fig. 1).3 to their role in the acute changes in ion flux associ- The L-type calcium channel was first isolated from ated with changes in membrane potential. Several cardiac muscle and has since been found in vascular calcium antagonists, and possibly all, can inhibit the growth and proliferation of vascular smooth muscle and fibroblasts. All classes of calcium antagonists de- From the Division of Clinical Pharmacology, Georgetown University crease the growth of vascular smooth-muscle cells in Medical Center, Washington, D.C. (D.R.A.); and the Division of Clinical Pharmacology and Geriatrics, Northwestern University Medical Center, vitro and in animals, as measured by decreased up- Chicago (J.B.S.). Address reprint requests to Dr. Abernethy at the National take of uridine (RNA synthesis) and incorporation Institute on Aging, Laboratory of Clinical Investigation, Gerontology Re- of leucine (protein synthesis) at drug concentrations search Center, 5600 Nathan Shock Dr., Baltimore, MD 21224-6825, or at 16,17 [email protected]. associated with clinical effects. Calcium antago- ©1999, Massachusetts Medical Society. nists may also inhibit the synthesis of extracellular- Volume 341 Number 19 · 1447 The New England Journal of Medicine Motif I Motif II Motif III Motif IV 7 Phenylalkylamine Benzothiazepine Glycosylation Dihydropyridine 21 or 22 Extracellular 8 or 8A 27 24 33 space 5 14 26 30 15 36 3 20 28 37 Cell membrane Intracellular 35 12 C 38 space 4 6 16 C 13 23 25 34 11 1 19 29 31 or 32 N C 39 9 2 10 C 17 40 18 C 48 49 50 47 C A CCC A/C 41 C A C C 42 46 44 43 45 Protein kinase A Protein kinase C Figure 1. Proposed Arrangement of the Polypeptide Chain of the Channel-Forming a1C Subunit of the L-Type Calcium Channel in Humans. The four repetitive motifs (I, II, III, and IV) each consist of six putative transmembrane segments. Both the N terminal and the C terminal point to the cytoplasm. Gold rings separate the segments encoded by numbered exons. The transmembrane segments encoded by alternative exons 8 or 8A, 21 or 22, and 31 or 32 are shown. Sequences encoded by invariant exons 7, 33, and 45, which are subject to constitutive splicing, are blue. Exons 40, 41, and 42 are subject to alternative splicing. Putative sites of glycosylation and of phosphorylation involving protein kinase C (C) and protein kinase A (A) are shown, as are the discrete binding areas of the three types of calcium antagonists — phenylalkylamine (verapamil-like), benzothiazepine (diltiazem-like), and dihydropyridine (nifedipine-like). matrix collagen proteins,18 and they prevent athero- the intestinal wall and liver.22 All are metabolized to sclerosis in animals with hyperlipidemia.19 However, less active metabolites in the liver by oxidative path- in most clinical studies calcium antagonists did not re- ways, predominantly by cytochrome P-450 CYP3A, verse or slow the progression of atherosclerosis.20,21 a subgroup of the cytochrome P-450 enzyme family, and to a lesser extent by other members of this en- CLINICAL PHARMACOLOGY zyme family.23-25 All calcium antagonists, with the ex- Nine calcium antagonists are currently marketed in ception of diltiazem and nifedipine, are administered the United States for the treatment of hypertension, as racemic mixtures, with one active and one inactive angina, and supraventricular arrhythmias, and one — stereoisomer with respect to blockade of L-type cal- nimodipine — is approved for short-term use in pa- cium channels.26 The cytochrome P-450 CYP3A en- tients with subarachnoid hemorrhage (Table 1). Only zymes metabolize each isomer at a different rate, re- diltiazem, nicardipine, and verapamil are available in sulting in stereoselective drug clearance.27 Hepatic intravenous formulations, and long-term treatment biotransformation of calcium antagonists such as ver- with calcium antagonists is usually by the oral route. apamil may be greater in women than men.28 Pharmacokinetics Pharmacodynamics After oral administration, the bioavailability of these All currently available calcium antagonists cause vas- drugs varies depending on first-pass metabolism in odilation, with lowering of blood pressure. Their rel- 1448 · November 4, 1999 DRUG THERAPY TABLE 1. CLINICAL DOSING INFORMATION FOR THE CALCIUM ANTAGONISTS APPROVED FOR USE IN THE UNITED STATES. TIME TO ELIMINATION DRUG APPROVED INDICATIONS FORM AND DOSE PEAK EFFECT HALF-LIFE hours Amlodipine Angina, hypertension Tablet; 2.5–10 mg once daily 6–12 30–50 Bepridil* Refractory angina Tablet; 200–400 mg once daily 2–3 26–64 Diltiazem† Angina, hypertension Immediate-release tablet; dose 0.5–1.5 2–5 varies depending on indication Atrial fibrillation or flutter, Sustained-release tablet; 180– 6–11 2–5 paroxysmal supraventric- 480 mg once daily ular tachycardia Felodipine Hypertension Sustained-release tablet; 2.5–10 2.5–5 11–16 mg once daily Isradipine Hypertension Tablet; 2.5–10 mg twice daily 1.5 8–12 Nicardipine† Angina, hypertension Immediate-release tablet; 20–40 0.5–2.0 8 mg three times daily Angina, hypertension Sustained-release tablet; 60–120 ?8 mg once daily Nifedipine Angina, hypertension Immediate-release capsule; dose 0.5 2 varies depending on indication Angina, hypertension Sustained-release capsule; 30– 62 120 mg once daily Nimodipine Subarachnoid hemorrhage Capsule; 60 mg every 4 hr for 1 1–2 21 days Nisoldipine Hypertension Sustained-release tablet; 20–40 6–12 7–12 mg once daily Verapamil† Angina, hypertension Immediate-release tablet; dose 0.5–1.0 4.5–12 varies depending on indication Atrial fibrillation or flutter, Sustained-release tablet; 120– 4–6 4.5–12 paroxysmal supraventric- 480 mg once daily ular tachycardia *Bepridil is indicated only for patients with angina that is refractory to treatment with other drugs. †This drug is also available in an intravenous formulation, with a time to peak effect ranging from 5 to 15 minutes after administration. THERAPEUTIC USES AND ative potency as vasodilators varies, with nifedipine CONTROVERSIES typically considered the most potent of the dihydro- pyridines, and verapamil, diltiazem, and bepridil hav- Hypertension ing less potency. In vitro, several calcium antagonists In the United States, amlodipine, diltiazem, felo- (e.g., nifedipine, nisoldipine, and isradipine) bind with dipine, isradipine, nicardipine, nifedipine, nisoldipine, some selectivity to the L-type calcium channel in and verapamil are currently approved for the treat- blood vessels, whereas verapamil binds equally well to ment of patients with hypertension (Table 1).
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