Mechanism of Action of Antiarrhythmic Drugs

  • Luc M. Hondeghem
  • Bertram G. Katzung
Part of the Developments in Cardiovascular Medicine book series (DICM, volume 34)


In this chapter we describe the modulated receptor hypothesis for the action of certain antiarrhythmic drugs. We briefly review the work that led to this hypothesis, present a detailed description of the mechanism, and apply it to a group of antiarrhythmic agents and the arrhythmias in which they are used.


Antiarrhythmic Drug Action Potential Duration Sodium Current Purkinje Fiber Voltage Shift 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Weidmann S: Effects of calcium ions and local anaesthetics on electrical properties of Purkinje fibres. J Physiol (Lond) 129:568–582Google Scholar
  2. 2.
    Hondeghem L, Grant AO, Jensen RA: Antiar-rhythmic drug action: selective depression of hypoxic cardiac cells. Am Heart J 87: 602–605, 1974.PubMedCrossRefGoogle Scholar
  3. 3.
    Grant AO, Katzung BG: The effects of quinidine and verapamil on electrically-induced automaticity in the ventricular myocardium of guinea pig. J Pharmacol Exp Ther 196: 407–419, 1976.PubMedGoogle Scholar
  4. 4.
    Fleckenstein A: Specific inhibitors and promotors of calcium action in the excitation-contraction coupling of heart muscle and their role in the prevention or production of myocardial lesions. In: Harris P, Opie LH (eds) Calcium and the heart. New York: Academic, 1971, pp 135–188.Google Scholar
  5. 5.
    Grant AO, Katzung BG: Ability of epinephrine, but not increased extracellular calcium, to reverse the effects of verapamil on ventricular automaticity in vitro. Proc West Pharmacol Soc 18: 34–36, 1975.PubMedGoogle Scholar
  6. 6.
    Hondeghem LM, Ayad MJ: K Nifedipine blocks the voltage dependent potentiation of norepinephrine in vascular smooth muscle. Proc West Pharmacol Soc, 26: 231–233, 1983.PubMedGoogle Scholar
  7. 7.
    Hille B: Local anesthetics: hydrophilic and hydrophobic pathways for the drug-receptor reaction. J Gen Physiol 69: 497–515, 1977.PubMedCrossRefGoogle Scholar
  8. 8.
    Hondeghem LM, Katzung BG: Time-and voltage-dependent interaction of antiarrhythmic drugs with cardiac sodium channels. Biochim Biophys Acta 472: 373–398, 1977.PubMedCrossRefGoogle Scholar
  9. 9.
    Attwell D, Cohen I: The voltage clamp of multicellular preparations. Prog Biophys Mol Biol 31: 201–245, 1977.PubMedCrossRefGoogle Scholar
  10. 10.
    Beeler GW, McGuigan JA: Voltage clamping of multicellular myocardial preparations: capabilities and limitations of existing methods. Prog Biophys Mol Biol 34: 219–254, 1978.PubMedCrossRefGoogle Scholar
  11. 11.
    Hondeghem LM: Validity of Vmax as a measure of the sodium current in cardiac and nervous tissues. BiophysJ 23: 147–152, 1978.CrossRefGoogle Scholar
  12. 12.
    Walton M, Fozzard HA: The relation of Vm to ‘Na, GNc and h, in a model of the cardiac Purkinje fiber. BiophysJ 25: 407–420, 1979.CrossRefGoogle Scholar
  13. 13.
    Ebihara L, Shigeto N, Lieberman M, Johnson EA: The initial inward current in spherical clusters of chick embryonic heart cells. J Gen Physiol 75: 437–456, 1980.PubMedCrossRefGoogle Scholar
  14. 14.
    Colatsky TJ: Voltage clamp measurements of sodium channel properties in rabbit cardiac Purkinje fibres. J Physiol (Lond) 305: 215–234, 1980.Google Scholar
  15. 15.
    Brown AM, Lee KS, Powell T: Sodium current in single rat heart muscle cells. J Physiol (Lond) 318: 479–500, 1981.Google Scholar
  16. 16.
    Spach MS, Miller WT III, Geselowitz DB, Barr RC, Kootsey JM, Johnson EA: The discontinuous nature of propagation in normal canine cardiac muscle: evidence for recurrent discontinuities of intracellular resistance that affect the membrane currents. Circ Res 48: 39–54, 1981.PubMedCrossRefGoogle Scholar
  17. 17.
    Jensen RA, Katzung BG: Electrophysiological action of diphenylhydantoin on rabbit atria: dependence on stimulation frequency, potassium, and sodium. Circ Res 26: 17–27, 1970.PubMedCrossRefGoogle Scholar
  18. 18.
    Singh BN, Vaughan Williams EM: Effect of altering potassium concentration on the action of lidocaine and diphenylhydantoin on rabbit atrial and ventricular muscle. Circ Res 29: 286–295, 1971.PubMedCrossRefGoogle Scholar
  19. 19.
    Hope RR, Williams DO, EI-Sherif N, Lazzara R, Scherlag BJ: The efficacy of antiarrhythmic agents during acute myocardial ischemia and the role of heart rate. Circulation 50: 507–514, 1974.Google Scholar
  20. 20.
    Kupersmith J, Antman EM, Hoffman BF: In vivo electrophysiologic effects of lidocaine in canine acute myocardial infarction. Circ Res 36: 84–91, 1975.PubMedCrossRefGoogle Scholar
  21. 21.
    Michelson EL, Spear JF, Moore EN: Effects of procainmide on strength-interval relations in normal and chronically infarcted canine myocardium. Am J Cardiol 47: 1223–1232, 1981.PubMedCrossRefGoogle Scholar
  22. 22.
    Lamanna V, Antzelevitch C, Moe GK: Effects of lidocaine on conduction through depolarized canine false tendons and on a model of reflected reentry. J Pharmacol Exp Ther 221: 353–361, 1982.PubMedGoogle Scholar
  23. 23.
    Wong SS, Myerburg RJ, Ezrin AM, Gelband H, Bassett AL: Electrophysiologic effects of encainide on acutely ischemic rabbit myocardial cells. Eur J Pharmacol 80: 323–329, 1982.PubMedCrossRefGoogle Scholar
  24. 24.
    Okumura K, Horio Y, Tokuomi H: Effects of lidocaine on conduction in normal and acutely ischemic ventricular myocardium of dogs. Arch Int Pharmacodyn 256: 269–282, 1982.PubMedGoogle Scholar
  25. 25.
    Johnson EA, McKinnon MG: Differential effect of quinidine and pyridamine on the myocardial action potential at various rates of stimulation. J Pharmacol Exp Ther 120: 460–465, 1957.PubMedGoogle Scholar
  26. 26.
    Heistracher P: Mechanism of action of antifibrillatory drugs. Naunyn Schmiedebergs Arch Pharmacol 269: 199–212, 1971.PubMedCrossRefGoogle Scholar
  27. 27.
    Strichartz G: The inhibition of sodium currents in myelinated nerve by quaternary derivatives of lidocaine. J Gen Physiol (Lond) 62: 37–57, 1973.CrossRefGoogle Scholar
  28. 28.
    Courtney KR: Mechanism of frequency-dependent inhibition of sodium currents in frog myelinated nerve by the lidocaine derivative GEA 968. J Pharmacol Exp Ther 195: 225–236, 1975.PubMedGoogle Scholar
  29. 29.
    Chen C-M, Gettes LS, Katzung BG: Effect of lidocaine and quinidine on steady-state characteristics and recovery kinetics of (dV/dt)mxx in guinea pig ventricular myocardium Circ Res 37: 20–29, 1975.Google Scholar
  30. 30.
    Hondeghem LM, Katzung BG: Effect of quinidine and lidocaine on myocardial conduction. Circulation 61: 1217–1224, 1980.PubMedCrossRefGoogle Scholar
  31. 31.
    Hodgkin AL, Huxley AF: The dual effect of membrane potential on sodium conductance in the giant axon of Loligo. J Physiol (Lond) 116: 497–506, 1952.Google Scholar
  32. 32.
    Bean BP, Cohen CJ, Tsien RW: Lidocaine block of cardiac sodium channels. J Gen Physiol, 81: 613–642, 1983.PubMedCrossRefGoogle Scholar
  33. 33.
    Sada H: Effect of phentolamine, alprenolol, and prenylamine on maximum rate of rise of action potential in guinea-pig papillary muscles. Naunyn Schmiedebergs Arch Pharmacol 304: 191–201, 1978.PubMedCrossRefGoogle Scholar
  34. 34.
    Sada H, Kojima M, Ban T: Effect of procainamide on transmembrane action potentials in guinea-pig papillary muscles as affected by external potassium concentration. Naunyn Schmiedebergs Arch Pharmacol 309: 179–190, 1979.PubMedCrossRefGoogle Scholar
  35. 35.
    Courtney KR: Interval-dependent effects of small antiarrhythmic drugs on excitability of guinea pig myocardium. J Mol Cell Cardiol 12: 1273–1286, 1980.PubMedCrossRefGoogle Scholar
  36. 36.
    Courtney KR: Antiarrhythmic drug design: frequency-dependent block in myocardium. In: Fink RB (ed) Molecular mechanisms of anesthesia. Progress in anesthesiology, vol 2. New York: Raven, 1980, pp 111–118.Google Scholar
  37. 37.
    Kohlhardt M, Seifert C: Inhibition of V,,,a, of the action potential by propafenone and its voltage-, time-, and pH-dependence in mammalian ventricular myocardium. Naunyn Schmiedebergs Arch Pharmacol 315: 55–62, 1980.PubMedCrossRefGoogle Scholar
  38. 38.
    McDonald T, Pelzer D, Trautwein W: On the mechanisms of slow calcium channel block in heart. Pflugers Arch 385: 175–179, 1980.PubMedCrossRefGoogle Scholar
  39. 39.
    Oshita S, Sada H, Kojima M, Ban T: Effects of tocainide and lidocaine on the transmembrane action potentials as related to external potassium concentrations in guinea-pig papillary muscles. Naunyn Schmiedebergs Arch Pharmacol 314: 67–82, 1980.PubMedCrossRefGoogle Scholar
  40. 40.
    Sada H, Ban T: Effects of acebutolol and other structurally related beta adrenergic blockers on transmembrane action potential in guinea-pig papillary muscles. J Pharmacol Exp Ther 215: 507–514, 1980.PubMedGoogle Scholar
  41. 41.
    Arlock P: Actions of lofepramine, a new tricyclic antidepressant, and desipramine on electrophysiological and mechanical parameters of guinea pig atrial and papillary muscles. Acta Pharmacol Toxicol 49: 248–258, 1981.CrossRefGoogle Scholar
  42. 42.
    Catterall WA: Inhibition of voltage-sensitive sodium channels in neuroblastoma cells by antiarrhythmic drugs. Mol Pharmacol 20: 356–362, 1981.PubMedGoogle Scholar
  43. 43.
    Cardinal R, Janse MJ, Van Eeden I, Werner G, Naumann d’Alnoncourt C, Durrer D: The effects of lidocaine on intracellular and extracellular potentials, activation and ventricular arrhythmias during acute regional ischemia in the isolated procine heart. Circ Res 49: 792–806, 1981.Google Scholar
  44. 44.
    Carson DL, Dresel PE: Effects of lidocaine on conduction of extrasystoles in the normal canine heart. J Cardiol Pharmacol 3: 924–935, 1981.CrossRefGoogle Scholar
  45. 45.
    Cordova MA, Bagwell EE, Lindenmayer GE: Studies on the interaction of propranolol and tetrodotoxin on dV/dtmax of canine Purkinje fiber action potentials. J Pharmacol Exp Ther 219: 187–191, 1981.PubMedGoogle Scholar
  46. 46.
    Courtney KR: Comparative actions of mexiletine on sodium channels in nerve, skeletal and cardiac muscle. Eur J Pharmacol 74: 9–18, 1981.PubMedCrossRefGoogle Scholar
  47. 47.
    Courtney KR: Significance of bicarbonate for antiarrhythmic drug action. J Mol Cell Cardiol 13: 1031–1034, 1981.PubMedCrossRefGoogle Scholar
  48. 48.
    Gilmour RF, Ruffy R, Lovelace DE, Mueller TM, Zipes DP: Effect of ethanol on electrogram changes and regional myocardial blood flow during acute myocardial ischemia. Cardiovasc Res 15: 47–58, 1981.PubMedCrossRefGoogle Scholar
  49. 49.
    Gilmour RF, Chikharev VN, Jurevichus JA, Zacharow S, Zipes DP: Effect of aprindine on trans-membrane currents and contractile force in frog atria. J Pharmacol Exp Ther 217: 390–396, 1981.PubMedGoogle Scholar
  50. 50.
    Kolhardt M, Haap K: The blockade of Vmax of the atrioventricular action potential produced by the slow channel inhibitors verapamil and nifedipine. Naunyn Schmiedebergs Arch Pharmacol 316: 178–185, 1981.CrossRefGoogle Scholar
  51. 51.
    Nattel S, Elharrar V, Zipes DP, Bailey JC: pH-dependent electrophysiological effects of quinidine and lidocaine on canine cardiac Purkinje fibers. Circ Res 48: 55–61, 1981.PubMedCrossRefGoogle Scholar
  52. 52.
    Rudiger HJ, Homburger H, Antoni H: Effects of a new antiarrhythmic compound [2-benzol-1-(2’ diisopropyl-amino-ethoxy-imino)-cycloheptome hydrogen fumarate] on the electrophysiological properties of mammalian cardiac cells. Naunyn Schmiedebergs Arch Pharmacol 317: 238, 1981.PubMedCrossRefGoogle Scholar
  53. 53.
    Sada H, Ban T: Time independent effects on cardiac action potential upstroke velocity (resting block) and lipid solubility of beta adrenergic blockers. Experientia 37: 171–172, 1981.PubMedCrossRefGoogle Scholar
  54. 54.
    Sada N, Ban T: Effects of various structurally related beta-adrenocepter blocking agents on maximum upstroke velocity of action potential in guinea-pig papillary muscles. Naunyn Schmiedebergs Arch Pharmacol 317: 245–251, 1981.PubMedCrossRefGoogle Scholar
  55. 55.
    Campbell TJ, Vaughan Williams EM: Electrophysiological and other effects on rabbit hearts of CCl22277, a new steroidal antiarrhythmic drug. Br J Pharmacol 76: 337–345, 1982.PubMedCrossRefGoogle Scholar
  56. 56.
    Carmeliet E, Saikawa T: Shortening of the action potential and reduction of pacemaker activity by lidocaine, quinidine, and procainamide in sheep cardiac Purkinje fibers: an effect on Na or K currents? Circ Res 50: 257–272, 1982.PubMedCrossRefGoogle Scholar
  57. 57.
    Colatsky TJ: Mechanisms of action of lidocaine and quinidine on action potential duration in rabbit cardiac Purkinje fibers. Circ Res 50: 17–27, 1982.PubMedCrossRefGoogle Scholar
  58. 58.
    Connors BW, Prince DA: Effects of local anesthetic OX314 on the membrane properties of hippocampal pyramidal neurons. J Pharmacol Exp Ther 220: 476–481, 1982.PubMedGoogle Scholar
  59. 59.
    Grant AO, Trantham JL, Brown KK, Strauss HC: pH-dependent effects of quinidine on the kinetics of dV/dtmax in guinea pig ventricular myocardium. Circ Res 50: 210–217, 1982.PubMedCrossRefGoogle Scholar
  60. 60.
    Kojima M, Ban T, Sada H: Effects of disopyramide on the maximum rate of rise of the potential (V,) in guinea-pig papillary muscles. Jpn J Pharmacol 32: 91–102, 1982.PubMedCrossRefGoogle Scholar
  61. 61.
    Hohnloser S, Weirich J, Antoni H: Effects of mexiletine on steady-state characteristics and recovery kinetics of Vmax and conduction velocity in guinea pig myocardium. J Cardiovasc Pharmacol 4: 232–239, 1982.PubMedCrossRefGoogle Scholar
  62. 62.
    Weld FM, Coromilas J, Rothman JN, Bigger JT Jr: Mechanisms of quinidine-induced depression of maximum upstroke velocity in ovine cardiac Purkinje fibers. Circ Res 50: 369–376, 1982.PubMedCrossRefGoogle Scholar
  63. 63.
    Payet MD: Effect of lidocaine on fast and slow inactivation of sodium current in rat ventricular cells. J Pharmacol Exp Ther 223: 235–240, 1982.PubMedGoogle Scholar
  64. 64.
    Rosen MR, Hoffman BF, Wit AL: Electrophysiology and pharmacology of cardiac arrhythmias. V. Cardiac antiarrhythmic effects of lidocaine. Am Heart J 89: 526–536, 1975.PubMedCrossRefGoogle Scholar
  65. 65.
    Ehring GR, Moyer JW, Hondeghem LM: Implications from electrophysiological differences resulting from small structural changes in antiarrhythmic drugs. Proc West Pharmacol Soc 25: 65–67, 1982.PubMedGoogle Scholar
  66. 66.
    Mason JW, Hondeghem LM, Katzung BG: Amiodarone blocks inactivated cardiac sodium channels. Pflugers Arch 396: 79–81, 1983.PubMedCrossRefGoogle Scholar
  67. 67.
    Ehara T, Kaufmann R: The voltage-and time-dependent effects of (—)-verapamil on the slow inward current in isolated cat ventricular myocardium. J Pharmacol Exp Ther 207: 49–55, 1978.PubMedGoogle Scholar
  68. 68.
    Kanaya S, Arlock P, Katzung BG, Hondeghem LM: Diltiazem and verapamil preferentially block inactivated calcium channels. J Mol Cell Cardiol 15: 145–148, 1983.PubMedCrossRefGoogle Scholar
  69. 69.
    Morad M, Tung L, Greenspan AM: Effect of diltiazem on calcium transport and development of tension in heart muscle. Am J Cardiol 49: 595–601, 1982.PubMedGoogle Scholar
  70. 70.
    Kolhardt M, Fleckenstein A: Inhibition of the slow inward current by nifedipine in mammalian ventricular myocardium. Naunyn Schmiedebergs Arch Pharmacol 298: 267–272, 1977.CrossRefGoogle Scholar
  71. 71.
    Bayer R, Ehara T: Comparative studies with calcium antagonists. In: Van Zwieten PA, Schonbaum E (eds) The action of drugs on calcium metabolism. Stuttgart: Fischer Verlag, 1978, pp 31–37.Google Scholar
  72. 72.
    Moyer J, Hondeghem LM: Characterization of activation and inactivation block in a series of aprindine derivatives using voltage clamp technique. Fed Proc 42: 634, 1983.Google Scholar
  73. 73.
    Kawai C, Konishi T, Matsuyama E, Okazaki H: Comparative effects of three calcium antagonists, diltiazem, verapamil, and nifedipine, on the sinoatrial and atrioventricular nodes: experimental and clinical studies. Circulation 63: 1035–1042, 1981.PubMedCrossRefGoogle Scholar
  74. 74.
    Bayer R, Hennekes R, Kaufmann R, Mannhold R: Inotropic and electrophysiological actions of verapamil and D600 in mammalian myocardium. I. Patterns of inotropic effects of racemic compounds. Naunyn Schmiedebergs Arch Pharmacol 290: 49–68, 1975.PubMedCrossRefGoogle Scholar
  75. 75.
    Linden J, Brooker G: The influence of resting membrane potential on the effect of verapamil on atria. J Mol Cell Cardiol 12: 325–331, 1980.PubMedCrossRefGoogle Scholar
  76. 76.
    Bayer R, Rodenkirchen R, Kaufmann R, Tec JH, Hennekes R: The effect of nifedipine on contraction and monophasic action potential of isolated cat myocardium. Naunyn Schmiedebergs Arch Pharmacol 301: 29–37, 1977.PubMedCrossRefGoogle Scholar
  77. 77.
    Rowland E, Krikler DM: Electrophysiological assessment of amiodarone in treatment of resistant supra-ventricular arrhythmias. Br Heart J 44: 82–90, 1980.PubMedCrossRefGoogle Scholar
  78. 78.
    Kokubun S, Nishimura M, Noma A, Irasawa H: Membrane currents in the rabbit atrioventricular node cell. Pflugers Arch 393: 15–22, 1982.PubMedCrossRefGoogle Scholar
  79. 79.
    Sami M, Harrison DC, Kraemer H, Houston N, Shimasaki C, De Busk RF: Antiarrhythmic efficacy of encainide and quinidine: validation of a model of drug assessment. Am J Cardiol 48: 147–156, 1981.PubMedCrossRefGoogle Scholar
  80. 80.
    Mason JW, Winkle RA: Electrode-catheter arrhythmia induction in the selection and assessment of antiarrhythmic drug therapy for recurrent ventricular tachycardia. Circulation 58: 971–985, 1978.PubMedCrossRefGoogle Scholar
  81. 81.
    Breithardt G, Seipel L, Abendroth RR: Comparison of antiarrhythmic efficacy of disopyramide and mexiletine against stimulus-induced ventricular tachycardia. J Cardiovasc Pharmacol 3: 1026–1037, 1981.PubMedCrossRefGoogle Scholar
  82. 82.
    Singh BN, Vaughan Williams EM: The effect of amiodarone, a new anti-anginal drug, on cardiac muscle. Br J Pharmacol 39: 657–667, 1970.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 1984

Authors and Affiliations

  • Luc M. Hondeghem
  • Bertram G. Katzung

There are no affiliations available

Personalised recommendations