nifedipine therapy prinzmetal's -...

Nifedipine Therapy for Prinzmetal's AnginaJAMES E. MULLER, M.D., AND STEPHEN J. GUNTHER, M.D.

SUMMARY A case is described in which nifedipine, a new cor-onary vasodilator, was effective in relieving attacks of Prinzmetal'sangina unresponsive to conventional therapy. The extreme frequencyof the anginal attacks provided evidence that lower doses of nifedipine

SINCE its description in 1959,1 Prinzmetal's angina hasfascinated clinicians with its dramatic pathophysiologicevents. The unprovoked attacks of chest pain and ST-segment elevation have been clearly shown to result fromspasm of a major coronary artery.2 But despite this un-derstanding of the mechanism of the disorder, therapy ofPrinzmetal's angina with conventional agents is often un-successful. Evidence from Germany' and Japan4 indicatesthat nifedipine [4-(2'-nitrophenyl)-2,6-dimethyl-3,5-di-carbomethoxy- 1 ,4-dihydropyridine], a potent coronaryvasodilator, may be remarkably effective in the treatment ofthis disorder. We have recently had the opportunity to ad-minister nifedipine to a patient with extremely frequent at-tacks of coronary spasm unresponsive to nitrates, beta oralpha adrenergic blockade. The elimination of these attacksby the combination of nifedipine and nitroglycerin therapy,and the occurrence of a myocardial infarction (presumablydue to coronary spasm) during withdrawal of nitroglycerintherapy, form the basis for this report.

Case Report

A 43-year-old white male was transferred to the PeterBent Brigham Hospital for control of frequent attacks ofPrinzmetal's angina. He had been in relatively good healthuntil two months prior to transfer when he noted the onset ofepisodes of substernal chest tightness, lasting one to threeminutes, occurring usually at rest and only rarely with exer-tion. These episodes were occasionally accompanied bylightheadedness. On one occasion he experienced a brief lossof consciousness and presented to a nearby emergencyroom. An ECG recorded during an attack of chest tightnessand dizziness revealed marked ST-segment elevation inleads I, aV,, V2- Vff followed by a run of ventriculartachycardia at a rate of 280 beats/min. The ECG returnedto normal within minutes and enzymatic studies for myocar-dial necrosis were later found to be negative. He washospitalized and treated with sublingual isosorbide dinitrate5 mg q 3h, oral propanolol 80 mg t.i.d. and oral quinidine300 mg q 6h. However, the frequent attacks persisted and hewas transferred for further management.On admission to the Peter Bent Brigham Hospital, he was

noted to be a well-developed male in no acute distress. Thevital signs were within normal limits as was the examinationof the cardiovascular system. The admission ECG showedonly minor nonspecific T wave changes. Cardiac catheteriza-

From the department of Medicine, Peter Bent Brigham Hospital and Har-vard Medical School, Boston, Massachusetts.

Dr. Muller is the recipient of an NIH Research Fellowship #5F32 HL05110-02 CBV.

Address for reprints: Dr. James E. Muller, Harvard Medical School,180 Longwood Avenue, Boston, Massachusetts 02115.

Received June 20, 1977; revision accepted August 4, 1977.

lost their effectiveness approximately 4 hours after administration. Amonth after initiation of nifedipine, nitrates were withdrawn sincethey had been ineffective in controlling the attacks. A myocardial in-farction occurred immediately, presumably due to coronary spasm.

tion revealed a normally-contracting left ventricle andangiographically normal coronary arteries. During the ensu-ing week he was noted to have more than 18 distinct episodeswhich were attributed to coronary artery spasm. A typicalepisode began with the appearance of ST-segment elevationin the monitor leads, followed within minutes by ventricularectopic activity followed within several minutes by chesttightness (figs. 1, 2). All episodes terminated spontaneouslyor within 5 minutes of the administration of 0.3 to 0.6 mgnitroglycerin sublingually. Since propranolol had been in-effective in preventing the attacks and theoretically mayhave potentiated the coronary spasm by allowing unopposedalpha adrenergic-mediated vasoconstriction, it was discon-tinued. He was begun on a regimen of oral isosorbidedinitrate 5 mg q 2h and nitroglycerin ointment 1 in q 4h.Alpha blockade was initiated with phenoxybenzamine in adosage of 10 mg q.d. which was increased over six days to 40mg q.d. Despite this intensive therapy the attacks continued.On the tenth hospital day phenoxybenzamine was discon-tinued and nifedipine* in a sublingual dosage of 10 mg q 6hwas begun. Prior to the administration of nifedipine, thepotential risks, benefits and experimental nature of the agentwere fully explained to the patient, who indicated his consentin writing. There was an immediate decrease in the frequen-cy of the attacks. Furthermore, the attacks always occurredwhen the pharmacologic action of nifedipine was expected tobe at its nadir, i.e., 4-6 hours after the preceding dose.Gradual increases in the nifedipine dosage to 20 mg q 4hresulted in a complete elimination of the attacks for the lastfour days of his hospitalization (fig. 3). He was dischargedon a regimen of isosorbide dinitrate 5 mg q 2h, nitroglycerinointment 1 in q 4h, nitroglycerin 0.3 mg p.r.n. and nifedipine20 mg q 4h. During the month following discharge heremained totally free of his typical episodes of chesttightness or syncope. He noted four episodes of slight chestdiscomfort occurring immediately before a nifedipine dose.A 24 hour Holter monitor recording showed several episodesof possible ST elevation but no ventricular ectopic activity.He remained disabled by the frequency and number of hismedications.One month following discharge he was readmitted for

evaluation of his recurrent chest discomfort and possiblesimplification of his medical regimen. Observation in thehospital for 48 hours failed to reveal evidence of coronaryartery spasm. Since long-acting nitrates had been ineffectivein preventing his attacks, it was decided to discontinue themwhile maintaining nifedipine. For 24 hours after withdrawalof isosorbide dinitrate he remained free of symptoms andnitroglycerin ointment was then discontinued. Twelve hoursafter the last administration of nitroglycerin he began to ex-

*Supplied by Delbay Pharmaceuticals under IND #9863.137

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VOL 57, No 1, JANUARY 1978

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FIGURE 1. The patient's ECG prior to an episode of coronary spasm. Only nonspecific T wave changes are present.

perience prolonged substernal pressure unrelieved by five(0.3 mg) sublingual tablets of nitroglycerin. An anteroseptalmyocardial infarction occurred, complicated by ventricularfibrillation, from which he was successfully resuscitated. Theelectrocardiographic changes that characterized the infarc-tion occurred in the same leads which showed ischemia dur-ing the attacks of Prinzmetal's angina. He tolerated his in-farction well with no persistent ventricular ectopic activityor congestive heart failure. At the time of discharge he wasfree of angina pectoris, congestive heart failure or ven-tricular arrhythmias, off nifedipine, nitroglycerin and allother cardiac medication.

Discussion

This case of a patient with extremely frequent and severeattacks of Prinzmetal's angina provides information aboutthe use of a promising new therapy. The agent, nifedipine,was synthesized by the West German firm, Bayer, in 1971.'It is a dihydropyridine derivative (fig. 4) which producesmarked coronary vasodilatation9 by blocking the slowcalcium currents that are responsible for the action potentialand contraction of smooth muscle cells.5 There have beenextensive studies of the pharmacokinetics and safety ofnifedipine in humans.6 In the doses used in this patient it has

been shown to produce a slight fall in blood pressure leadingto a slight reflex increase in heart rate, and variable butsmall (< 12%) changes in contractility as measured bydp/dtmaxj7, 8The use of nifedipine for Prinzmetal's anginawas first reported by Hosada et al.4 The same group laterreported the effectiveness of nifedipine in 19 patients withPrinzmetal's angina and normal coronaries.'0The unusual frequency of the attacks in this patient allows

an extension of these observations by indicating the ap-parent duration of nifedipine effect. In this patient the lowerdoses of nifedipine prevented attacks for four hours only, atwhich time "breakthrough" occurred. This interval coin-cides with observations in dogs that a single dose ofnifedipine produces coronary vasodilatation for a four tofive hour period.9The occurrence of an infarction during nitroglycerin

withdrawal in a patient with angiographically normal cor-onary arteries adds support to the argument that in certaininstances myocardial infarction can result from coronaryspasm." Although postinfarction angiograms were not ob-tained, it is likely that in this patient the infarction resultedfrom intense and prolonged coronary vasoconstriction.

In addition, this case demonstrates an importantrelationship between nifedipine and nitroglycerin, an agentwith which nifedipine will frequently be used. The reason for

3 MINUTES LATER TNG GIVEN

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FIGURE 2. The patient's ECG during an episode of coronary spasm. A bigeminal rhythm has appeared. The STsegments are now markedly elevated in I, aV, V, - V6 and reciprocally depressed in III and aVF. Five minutes after thenitroglycerin was administered the ECG returned to its baseline appearance (fig. 1).

138 CIRCULATION

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NIFEDIPINE FOR PRINZMETAL'S/Muller, Gunther

4

3

2 No Episodes

1 2 3 4 5 6

Hours After Nifedipine

FIGURE 3. The e,ffiect of nifedipine on episodes of c,spasm. An episode was defined as the appearanceXelevation, and/or signi,ficant ventricular ectopyhigeminy or ventricular tachycardia) and/or typicali(total number of episodes and their distribution dunrisix hour periods pre-nifedipine (six days) are showniIn the middle and bottom rows the total number otime of their occurrence relative to the administratio;(10 mg q 6h or q 4h, 20 mg q 6h) and higher dosenifedipine are shown. Pre-nifedipine the episodesdomly throulghout the 24 hour period. With lowerstthere was a marked decrease in the frequwency of at,and most occurred four to six hours after nifedipine.tack ducring the first hour occurred 10 minutes after ttion of nifedipine -before the expected onset of ac;dose.

the occurrence of an infarction during wnitroglycerin ointment is uncertain. It seemsnitrate withdrawal caused a rebound phenomeduration of exposure was far shorter than thatin whom infarction has been reportedswithdrawal from industrial exposure to nitrog]

Nifedipine(Adalat, BAY a1040)

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FIGURE 4. The chemical structure of nifedipinphenyl)-2,6-dimethyl-3,5-dicarbomethoxy-1,4-dihyd;

more likely that the stimulus for spasm was sufficientlystrong that both nitrates and nifedipine were necessary to

Pre Nifedipine prevent it. It might be expected that the vasodilatory actionsof these two agents would be additive, because the nitratescan produce relaxation of smooth muscle in calcium-poorpreparations,'3 while nifedipine causes relaxation by block-

Post Nifedipine ing slow calcium currents.6 Further observations are neededLower Dose but it is possible that nitrates plus nifedipine may be the

therapy of choice for this disorder.Finally, this experience with nifedipine adds to the

Post Nifedipine evidence indicating the need for the randomized, double-Higher Dose blind study to assess its role in the therapy of Prinzmetal's

angina which is now in the planning stages. With such a trialthe current optimism regarding the use of nifedipine for the

oronary artery treatment of Prinzmetal's angina can be critically tested.of ST-segment(i.e., couplets, Acknowledgmentchest pain. Theng consecutive We are grateful to Dr. J. Olatunde Kuye for supplying the nifedipine and toin the top row. Miss Patricia Kalick for assistance in the preparation of the manuscript.f episodes and Referencesn oflower dose'(20 mg q 4h) 1. Prinzmetal M, Kennamer R, Merliss R, Wada T, Bor N: Angina pec-occurred ran- toris. I. A variant form of angina pectoris. Am J Med 27: 375, 1959lose nifedipine 2. Oliva R, Potts D, Pluss R: Coronary arterial spasm in Prinzmetal angina:

documentation by coronary arteriography. N Engl J Med 288: 745, 1973tacks (19 to 7) 3. Bossert F, Vater W: Dihydropyridine, eine neue Gruppe stark wirksamerThe single at- Coronartherapeutika. Naturwissen 58: 578, 1971

'he administra- 4. Hosada S, Kimura E: In Proceedings, First International Nifedipinetion of the new (Adalat) Symposium, Tokyo 1973. Editors: K Haschimoto, E Kimura, T

Kobayashi. Tokyo, University of Tokyo Press, 1974, p 1755. Grun G, Fleckenstein A: Die elektromechanische Entkoppelung det

glatten Gefassmuskulatur als Grundprinzip det Coronardilatation durch4-(2'-nitrophenyl)-2,6-dimethyl-1 ,4-dihydropyridine-3,5-dicarbosaure-di-

ithdrawal of methylester (BAY a 1040, Nifedipine*). Arzniem Forsch 22: 334, 19726. Third International Adalat Symposium: New Therapy of Ischemic Heartunlikely that Disease, edited by Jatene AD, Lichten PR. Amsterdam-Oxford, Excerp-non since the ta Medica, 1976,nonsincethe

7. Lohmoller R, Lydtin H: Untersuchen uber das hamodynamischeof individuals Wirkungsprofil von Nifedipine (BAY a 1040) vor und nach kardialerecondary to Sympathikusblockade durch Practalol (ICI 50 172). Int J Clin Phar-

lycerin.12 It is macol 8: 118, 19738. Ebner F, Dunschunde HB: In the Third International Adalate Sym-

posium. New Therapy of Ischemic Heart Disease. Jatene AD, LichtlenPR eds. Amsterstam-Oxford, Excerpta Medica, 1976, p 283

9. Vater W, Kroneberg G, Hoffmeister F, Kaller H, Meng K, Oberdorf A,Puls W, Schlossmann K, Stoepel K: Zur Pharmakologie von 4-(2'-nitro-phenyl)-2,6-dimethyl- 1 ,4-dihydropyridine-3,5-dicarbonsaure-dimethyles-

S-N02 ter (Nifedipine,* BAY a 1040). Arzniem Forsch 22: 1, 197210. Endo M, Kanda I, Hosada S, Hayashi H, Hirosawa K, Konno S:

H Prinzmetal's variant form of angina pectoris: Reevaluation ofmechanisms. Circulation 52: 33, 1975

I f''-" 3 11. Cheng TO, Bashour T, Singh BK, Kelser G: Myocardial infarction in the-CH3 absence of coronary arteriosclerosis. Result of coronary spasm? Am J

Cardiol 30: 680, 197212. Lange RL, Reid MS, Tresch DD, Keelan M, Bernhard V, Coolidge G:

Nonatheromatous ischemic heart disease following withdrawal fromchronic industrial nitroglycerin exposure. Circulation 46: 666, 1972

13. Anderson R: Cyclic AMP as a mediator of the relaxing action ofie [4-(2'-nitro- papoverine, nitroglycerin, diazoxide and hydralazine in intestinal andropyridine]. vascular smooth muscle. Acta Pharmacol Toxicol (kbh) 32: 321, 1973

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J E Muller and S J GuntherNifedipine therapy for Prinzmetal's angina.

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 1978 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation doi: 10.1161/01.CIR.57.1.137

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