19 Calcium Channel Blockers Vijay C. Swamy and David J. Triggle DRUG LIST GENERIC NAME PAGE GENERIC NAME PAGE Amlodipine 218 Nifedipine 218 Diltiazem 218 Nimodipine 218 Felodipin 218 Nisoldapine 218 Isradipine 220 Verapamil 218 Nicardipine 218 The agents commonly called the calcium channel ine (Cardene), felodipine (Plendil), nisoldipine (Sular),blockers comprise an increasing number of agents, includ- and amlodipine (Norvasc). These agents differ froming the prototypical verapamil (Calan, Isoptin), nifedipine nifedipine principally in their potency, pharmacokinetic(Adalat, Procardia), and diltiazem (Cardizem). These characteristics, and selectivity of action. Nimodipine hasagents are a chemically and pharmacologically heteroge- selectivity for the cerebral vasculature; amlodipine ex-neous group of synthetic drugs, but they possess the com- hibits very slow kinetics of onset and offset of blockade;mon property of selectively antagonizing Caϩϩ move- and felodipine and nisoldipine are vascular-selectivements that underlie the process of excitation–contraction 1,4-dihydropyridines.coupling in the cardiovascular system. The primary use ofthese agents is in the treatment of angina, selected cardiacarrhythmias, and hypertension. CALCIUM ANTAGONISM Although the Caϩϩ channel blockers are potent va-sodilating drugs, they lack the ﬂuid-accumulating prop- The concept of calcium antagonism as a specific mech-erties of other vasodilators and the persistent activation anism of drug action was pioneered by Albrechtof the sympathetic and renin–angiotensin–aldosterone Fleckenstein and his colleagues, who observed that ve-axes. Furthermore, the broad potential range of activi- rapamil and subsequently other drugs of this classties, both within and without the cardiovascular system, mimicked in reversible fashion the effects of Caϩϩsuggests that they may be clinically useful in disorders withdrawal on cardiac excitability. These drugs inhib-from vertigo to failure of gastrointestinal smooth mus- ited the Caϩϩ component of the ionic currents carriedcle to relax . in the cardiac action potential. Because of this activity, A number of second-generation analogues are these drugs are also referred to as slow channel block-known, particularly in the nifedipine (1,4-dihydropyri- ers, calcium channel antagonists, and calcium entrydine) series, including nimodipine (Nimotop), nicardip- blockers.218
19 Calcium Channel Blockers 219 The actions of these drugs must be viewed from the Site II Site Iperspective of cellular Caϩϩ regulation (Fig. 19.1). Caϩϩ 1,4-DHPis fundamentally important as a messenger, linking cel- Site ϩlular excitation and cellular response. This role is made Diltiazem Activatorpossible by the high inwardly directed Caϩϩ concentra- Antagonisttion and electrochemical gradients, by the existence of Ϫ Ϫspeciﬁc high-afﬁnity Caϩϩ binding proteins (e.g., ϩcalmodulin) that serve as intracellular Caϩϩ receptors,and by the existence of Caϩϩ-speciﬁc inﬂux, efﬂux, and Ca2ϩsequestration processes. Calcium, in excess, serves as a Channelmediator of cell destruction and death during myo- Ϫ Ϫcardial and neuronal ischemia, neuronal degeneration,and cellular toxicity. The control of excess Caϩϩ mobi- Ϫlization is thus an important contributor to cell and tis-sue protection. The available Caϩϩ channel blockers exert their ef-fects primarily at voltage-gated Caϩϩ channels of the Verapamil/D600plasma membrane. There are at least several types ofchannels—L, T, N, P/Q and R—distinguished by theirelectrophysiological and pharmacological characteris-tics. The blockers act at the L-type channel at three dis- Site IIItinct receptor sites (Fig. 19.2). These different receptor FIGURE 19.2interactions underlie, in part, the qualitative and quan- The principal receptors or drug binding sites at the calciumtitative differences exhibited by the three principal channel. These sites are linked to the opening and closingclasses of channel blockers. of the channel and to each other by activating (ϩ) or Cellular stimuli that involve Caϩϩ mobilization by inhibiting (Ϫ) allosteric mechanisms. The 1,4-DHP site is aprocesses other than that at the L-type voltage-gated receptor site for a number of 1,4-dihydropyridinechannels will be either completely or relatively insensi- compounds; D600 is the designation for a close chemicaltive to the channel blockers. This differential sensitivity relative of verapamil.contributes to the variable sensitivity of vascular and nonvascular smooth muscle to the actions of these extracellular drugs, for example, the regional vascular selectivity and intracellular 7 the general lack of activity of these agents in respiratory Ca2؉ MITO ATP Ca2؉ or gastrointestinal smooth muscle disorders. 1 Na؉ CM Na؉ 8 The Selectivity of Action of Calcium 9 Ca2؉ Channel Blockers ROC Ca2؉ Ca2؉ Although the available Caϩϩ channel blockers exert 2 SR their effects through an interaction at one type of chan- 5 nel, they do so at different sites. Figure 19.2 shows that ATP Ca2؉ VGC the channel blockers act at three discrete receptor sites Ca2؉ 3 6 to mediate channel blockade indirectly rather than by a direct or physical channel block. The existence of the 4 different receptor sites is one basis for the different Ca2؉ Ca2؉ pharmacological proﬁles exhibited by these agents. The activity of the Caϩϩ channel blockers increases with increasing frequency of stimulation or intensityFIGURE 19.1 and duration of membrane depolarization. This use-Cellular calcium regulation. Depicted are several sites that dependent activity is consistent with a preferred interac-control calcium entry, efﬂux, and sequestration. 1. Naϩ,Caϩϩ exchange. 2. Receptor-operated channels. 3. Voltage- tion of the antagonists with the open or inactivated statesgated channels. 4. Leak pathways. 5, 6. Entry and efﬂux of the Caϩϩ channel rather than with the resting state. Thisin sarcoplasmic reticulum. 7. Plasma membrane pump. activity is not shared equally by all Caϩϩ blockers and8, 9. Entry and efﬂux in mitochondria. ATP adenosine , so may provide a further basis for the therapeutic dif-triphosphate; CM, cell membrane. ferences between them. For example, verapamil and
220 III DRUGS AFFECTING THE CARDIOVASCULAR SYSTEMdiltiazem are approximately equipotent in cardiac and tribute to the recently described antiatherogenic actionsvascular smooth muscle, whereas nifedipine and all seen in experimental and clinical states.other agents of the 1,4-dihydropyridine class are signiﬁ-cantly more active in vascular smooth muscle.Furthermore, different members of the 1,4-dihydropyri- PHARMACOLOGICAL EFFECTS ON THEdine class have different degrees of vascular selectivity. CARDIOVASCULAR SYSTEMThese differences are broadly consistent with the obser- The effects of the prototypical calcium channel blockersvation that verapamil and diltiazem act preferentially are seen most prominently in the cardiovascular systemthrough the open channel state, and nifedipine and its (Table 19.1), although calcium channels are widely dis-analogues act through the inactivated state. tributed among excitable cells. The following calcium The clinically available calcium channel antagonists channel–blocking drugs are clinically the most widelyhave also proved to be invaluable as molecular probes used compounds in this very extensive class of pharma-with which to identify, isolate, and characterize calcium cological agents: amlodipine, diltiazem, isradipine,channels of the voltage-gated family. In particular, the nifedipine, nicardipine, nimodipine, and verapamil.1,4-dihydropyridines with their high afﬁnity, agonist–antagonist properties, and selectivity have become de-ﬁned as molecular markers for the L-type channel. Vascular Effects Synthetic drugs of comparable selectivity and afﬁn- Vascular tone and contraction are determined largelyity to the 1,4-dihydropyridines do not yet exist for the by the availability of calcium from extracellular sourcesother channel types, T, N, P/Q, and R; these remain char- (inﬂux via calcium channels) or intracellular stores.acterized by complex polypeptide toxins of the aga- and Drug-induced inhibition of calcium inﬂux via voltage-conotoxin classes. Neuronal pharmacology, including gated channels results in widespread dilation and a de-that of the central nervous system (CNS), is dominated crease in contractile responses to stimulatory agents. Inby the N, P/Q, and R channels. This underscores the general, arteries and arterioles are more sensitive tonormally weak effect of L-channel antagonists on the relaxant actions of these drugs than are the veins,CNS function. Drugs that act at the N, P, and R channels and some arterial beds (e.g., coronary and cerebral ves-with comparable selectivity and afﬁnity to the 1,4- sels) show greater sensitivity than others. Peripheraldihydropyridines may be expected to offer major po- vasodilation and the consequent fall in blood pressuretential for a variety of CNS disorders, including neu- are commonly accompanied by reﬂex tachycardiaronal damage and death from ischemic insults. when nifedipine and its analogues are used; this is in The Caϩϩ channel blockers also differ in the extent of contrast to verapamil and diltiazem, whose effects ontheir additional pharmacological properties. Verapamil peripheral vessels are accompanied by cardiodepres-and to a lesser extent diltiazem possess a number of re- sant effects.ceptor-blocking properties, together with Naϩ and Kϩchannel–blocking activities, that may contribute to their Cardiac Effectspharmacological proﬁle. Nifedipine and other 1,4-dihy-dropyridines are more selective for the voltage-gated Calcium currents in cardiac tissues serve the functionsCaϩϩ channel, but they may also affect other pharmaco- of inotropy, pacemaker activity (sinoatrial (SA) node),logical properties because their nonpolar properties and conduction at the atrioventricular (A-V) node. Inmay lead to cellular accumulation. Together with their principle, the blockade of calcium currents should resultchannel-blocking properties, these properties may con- in decreased function at these sites. In clinical use, how- TA B L E 1 9 . 1 Cardiovascular Effects of Calcium Channel Blockers* Nifedipine Diltiazem Verapamil Blood pressure Ϫ Ϫ Ϫ Vasodilation ϩϩϩ ϩϩ ϩϩ Heart rate ϩϩ Ϫ Ϯ Contractility 0/ϩ 0 0/Ϫ Coronary vascular resistance Ϫ Ϫ Ϫ Blood ﬂow ϩϩϩ ϩϩϩ ϩϩ Key: ϩ ϭ increase; Ϫ ϭ decrease; 0 ϭ no signiﬁcant effect. *Changes are those seen commonly following oral doses used in therapy of hypertension or angina. The magnitude of response is indicated by number of symbols.
19 Calcium Channel Blockers 221ever, dose-dependent depression is seen only with vera- Their antihypertensive efﬁcacy is comparable to thatpamil and diltiazem and not with nifedipine, reﬂecting of ␤-adrenergic blockers and angiotensin-convertingmainly differences in the kinetics of their interaction at enzyme (ACE) inhibitors. The choice of a calcium chan-calcium channels (see section on calcium antagonism). nel blocker, especially for combination therapy, isCharacteristic cardiac effects include a variable slowing largely inﬂuenced by the effect of the drug on cardiacof the heart rate, strong depression of conduction at the pacemakers and contractility and coexisting diseases,A-V node, and inhibition of contractility, especially in the such as angina, asthma, and peripheral vascular disease.presence of preexisting heart failure. Ischemic Heart Disease The effectiveness and use of calcium channel blockersTHERAPEUTIC APPLICATIONS in the management of angina are well established (seeThe calcium channel–blocking drugs have been investi- Chapter 17); their beneﬁt in postinfarction stages is lessgated for an unusually wide number of clinical applica- certain. Efﬁcacy in angina is largely derived from theirtions. Verapamil-induced improvement of diastolic func- hemodynamic effects, which inﬂuence the supply andtion has proved to be beneﬁcial in the treatment of demand components of the ischemic balance (1) by in-hypertrophic cardiomyopathy. Vasodilatory properties of creasing blood ﬂow directly or by increasing collateralthese drugs are used in the treatment of peripheral vaso- blood ﬂow and (2) by decreasing afterload and reducingconstrictive disorders (Raynaud’s disease) and in reliev- oxygen demand. All three agents are useful in the man-ing vasospasm following subarachnoid hemorrhage. agement of stable exertional angina, with their vasodila-There is ongoing interest in investigating protective ef- tory and cardiac effects making beneﬁcial contributions.fects on renal function and in the ability to reduce dele- Given the differences in their relative effects (Tableterious vascular changes in diabetes mellitus. Similarly, 19.1), the response of the patient can vary with thethe potential beneﬁt afforded by their selective vasodila- agent used and the preexisting cardiac status.tory action (especially the second-generation agents) in All agents are also effective in the control of variantthe management of heart failure is an area of interest. (Prinzmetal’s) angina, in which spasm of the coronaryThese drugs are of some beneﬁt in a variety of noncar- arteries is the main factor. Their usefulness in the morediovascular conditions characterized by hyperactivity of complex unstable (preinfarction) angina is less deﬁnite,smooth muscle (e.g., achalasia). However, their main ap- depending on the hemodynamic status and the suscep-plications are as follows. tibility of the patient to infarction.Hypertension Cardiac ArrhythmiasThe calcium channel–blocking drugs are effective anti- The prominent depressant action of verapamil and dil-hypertensive agents and enjoy widespread use as single tiazem at the SA and A-V nodes ﬁnds use in speciﬁc ar-medication or in combination. Their effectiveness is re- rhythmias. They are of proven efﬁcacy in acute controllated to a decrease in peripheral resistance accompanied and long-term management of paroxysmal supraventric-by increases in cardiac index. The magnitude of their ef- ular tachycardia (see Chapter 16). Their ability to inhibitfects is determined partly by pretreatment blood pres- conduction at the A-V node is employed in protectingsure levels; maximum blood pressure lowering gener- ventricles from atrial tachyarrhythmias, often in combi-ally is seen 3 to 4 weeks after the start of treatment. nation with digitalis or propranolol.These drugs possess some distinct advantages relativeto other vasodilators, including the following: PHARMACOKINETICS 1. Their relaxant effect on large arteries results in A comparison of the pharmacokinetic properties of greater compliance, which is beneﬁcial in older these agents is listed in Table 19.2. All three drugs are persons. well absorbed following oral administration. Verapamil 2. Tolerance associated with renal retention of ﬂuid and diltiazem undergo greater ﬁrst-pass metabolism rel- does not occur; an initial natriuretic effect is often ative to nifedipine, resulting in lower bioavailability of observed, especially with the nifedipine group of the former two drugs. Hepatic metabolism of nifedipine blockers. is complete, yielding inactive metabolites; this is unlike 3. They do not have signiﬁcant effects on the re- verapamil and diltiazem, whose metabolites have phar- lease of renin or cause long-term changes in lipid macological activity. Verapamil is metabolized stereose- or glucose metabolism. lectively in favor of the more active (Ϫ) enantiomer, 4. Postural hypotension, ﬁrst-dose effect, and re- thus requiring higher plasma concentrations after oral bound phenomenon are not commonly seen. administration.
222 III DRUGS AFFECTING THE CARDIOVASCULAR SYSTEM TA B L E 1 9 . 2 Pharmacokinetics of Calcium Channel Blockers Verapamil Nifedipine Diltiazem Absorption, oral (%) Ͼ90 Ͼ90 Ͼ90 Bioavailability (%) 20 60–80 ~40 Onset of action: oral (min) 90–120 Ͻ20 Ͻ30 Peak effect 5 hr 1–2 hr 3–5 hr Protein binding (%) 90 90 90 Plasma half-life 4–8 hr 5 hr* 5 hr Metabolism 80% 1st-pass active metabolites Inactive metabolites 60% of 1st dose: 10% steady state Excretion Renal (%) 70 90 30 Fecal (%) 15 10 70 *Six to 11 hours after oral tablets: above value for capsules.TOXICITYThe common side effects seen in chronic therapy (Table enhancement of the action of other cardiodepressant19.3) are mostly related to vasodilation—headaches, drugs. Their use is generally contraindicated in obstruc-dizziness, facial ﬂushing, hypotension, and so forth. High tive conditions (e.g., aortic stenosis). No consistent ordoses of verapamil in elderly patients are known to signiﬁcant changes in lipid and glucose levels have beencause constipation. Serious side effects, especially fol- reported with chronic therapy. Non–sustained releaselowing the intravenous use of verapamil, include formulations of nifedipine are contraindicated in hyper-marked negative inotropic effects and depression of tension because of sympathetic rebound that may ag-preexisting sick sinus syndrome, A-V nodal disease, and gravate existing left ventricular dysfunction. TA B L E 1 9 . 3 Adverse Effects of Calcium Channel Blockers Verapamil Diltiazem Nifedipine Tachycardia 0 0 ϩ Decreased heart rate* ϩ ϩ 0 Depressed A-V nodal conduction* ϩϩϩ ϩϩ 0 Negative inotropy ϩϩ ϩ 0 Vasodilation (ﬂushing, edema, hypotension, headaches) ϩ ϩ/0 ϩϩϩ Constipation, nausea ϩϩ ϩ ϩ/0 Key: ϩ ϭ increase; 0 ϭ no change. *Marked effect in presence of sick sinus syndrome and A-V nodal disease.
19 Calcium Channel Blockers 223 Study Questions1. Which of the following statements most accurately ANSWERS characterize the cellular action of the calcium chan- 1. C. The available blockers act primarily at voltage- nel blockers? gated calcium channels of the L type. The three pro- (A) Their interaction with membrane phospho- totypes, verapamil, nifedipine, and diltiazem, act at lipids results in a nonselective decrease of ion trans- three discrete sites at this channel. port. 2. B. The other three drugs (dihydropyridines) are (B) They inhibit the Naϩ–Caϩϩ exchanger in car- characterized by relatively selective vasodilator ef- diac and smooth muscle. fects with little if any cardiac effects at doses em- (C) They interact at three distinct sites at the L- ployed clinically for hypertension or angina. type voltage-gated calcium channels. 3. D. The vasodilatory effects of nifedipine are largely (D) Their interaction with the sodium pump results restricted to arteries (and consequently the after- in an inhibition of calcium transport. load). It does not alter venous tone (and thus pre-2. Which of the following calcium channel blockers load) signiﬁcantly. would be most likely to suppress atrial tach- 4. C. Since they are metabolized in the liver, hepatic yarrhythmias involving the A-V node? cirrhosis can be expected to alter their half-life. (A) Nifedipine 5. A. Skeletal muscles depend on the mobilization of (B) Verapamil intracellular stores of calcium for their contractile (C) Nicardipine responses rather than transmembrane ﬂux of cal- (D) Amlodipine cium through the calcium channels. Therefore,3. All of the following statements are applicable with skeletal muscle weakness is not likely to occur. regard to the systemic effects caused by nifedipine EXCEPT: SUPPLEMENTAL READING (A) It typically causes peripheral vasodilation. Abernathy DR and Schwartz JB. Calcium-antagonist (B) It often elicits reﬂex tachycardia. drugs. N Engl J Med 1999;34:1447–1457. (C) It causes coronary vasodilatation and an in- Epstein M (Ed.). Calcium Antagonists in Clinical crease in coronary blood ﬂow. Medicine (3rd Ed.). Philadelphia: Hanley & Belfus, (D) Its beneﬁt in the management of angina is re- 2002. lated to the reduction in preload that it induces. Kizer JR and Kimmel SE. Epidemiologic review of the4. All of the following statements regarding the phar- calcium channel blocker drugs: An up-to-date per- macokinetics of calcium channel blockers are cor- spective on the proposed hazards. Arch Intern Med rect EXCEPT 2001;161:1145–1158. (A) They are characterized by signiﬁcant amount Taira N. Differences in cardiovascular proﬁle among (~ 90%) of protein binding. calcium antagonists. Am J Cardiol 1987;59:24B–29B. (B) They undergo signiﬁcant ﬁrst-pass metabolism. Triggle DJ. Mechanisms of action of calcium channel (C) Their half-life is not altered by hepatic cirrho- antagonists. In Epstein EM (Ed.). Calcium sis. Antagonists in Clinical Medicine (3rd Ed.). (D) They can be administered orally. Philadelphia: Hanley & Belfus, 2002.5. All of the following adverse effects are likely to oc- Tulenko TN et al. The smooth muscle membrane dur- cur with long-term use of calcium channel blockers ing atherogenesis: A potential target in atheropro- EXCEPT tection. Am Heart J 2001;141(2Suppl): S1–S11. (A) Skeletal muscle weakness (B) Flushing (C) Dizziness (D) Headache
224 III DRUGS AFFECTING THE CARDIOVASCULAR SYSTEM Case Study Nifedipine-Induced Vasodilatation A 65-year-old recently retired man is being evaluated for elevated blood pressure. He occasionally has angina precipitated by physical ANSWER: Nifedipine, unless formulated for slow, sustained release, is characterized by relatively rapid onset of vasodilatory effects. This man’s side exertion and rapidly controlled by sublingual use of effects reﬂect the rapid and intense fall in blood nitroglycerin. His blood pressure is 160/100 mm Hg. pressure and consequent reﬂex increases in He is advised to take nifedipine 80 mg/day, which sympathetic tone. The increase in anginal episodes he does, in divided doses of 20 mg (capsules). He also is a result of drug-induced periodic increases in develops ﬂushing, dizziness, and nervousness shortly heart rate. (Ͻ30 minutes) after taking the drug, and these symptoms persist for approximately 1 hour. The number of anginal episodes have increased during this period. QUESTION: How do the properties of nifedipine relate to the above development?