Antianginal Drugs: Pathophysiological, Haemodynamic, Methodological, Pharmacological, Biochemical and Clinical Basis for Their Use in Human Therapeutics PDF
Preview Antianginal Drugs: Pathophysiological, Haemodynamic, Methodological, Pharmacological, Biochemical and Clinical Basis for Their Use in Human Therapeutics
Handhuch der experimentellen Pharmakologie Handhook of Experimental Pharmacology Heffter Heubner New Series XXXI Herausgeber Editorial Board O. Eichler, Heidelberg . A. Farah, Rensselaer, NY H. Herken, Berlin . A. D. Welch, New Brunswick, NJ Beirat Advisory Board G. Acheson . E. J. Ariens . Z. M. Bacq . P. Calabresi . S. Ebashi E. G. Erdös . V. Erspamer . U. S. von Euler . W. Feldberg R. Furchgott . A. Goldstein' G. B. KoeIle' O. Krayer . H. Raskova M. Rocha e Silva' F. Sakai . P. Waser . W. Wilbrandt Antianginal Drugs Pathophysiological, Haemodynamic, Methodological, Pharmacological, Biochemical and Clinical Basis for Their Use in Human Therapeutics By R. Charlier With 54 Figures Springer-Verlag Berlin· Heidelberg· New York 1971 R~rl Charlier, Director of the Pharmaoological Research Department, LABAZ Research Center. Lecturer, Faculty of Medicine, University of Liege, Belgium ISBN-13: 978-3-642-65167-0 e-ISBN-13:978-3-642-65165-6 001: 10.1007/978-3-642-65165-6 Thla ",orll: la nbleet. to copyrlaht. AU rlaht. an! !'eIerved, II'betller the whole or p&rl of the materiaila concemed apeclllcally tbOIe of wnalatlon, n!prlntlna:, re-uae ofUiuawtlOIll, broad"..tlna:, ",productlon by photocopyina: nach1M or slmU.r moaDll, and ,tora,ge In dst. w.nkl. Under I &It ot the German Copyrlllht Lall' II'he", coplea ""' made for other than prlvate uae, a [ef> la payable to the publlllher, the amount of the fee to ba determlMd by agreement 'With the publlllher. © by 8prln.rer-Veri .. ' Berlin' Heldelbelll 1071. Llbn.ry nt COngrea·(;ataIOll·(;ard Number 711·167000. Softco,'~r "'I,rint of th~ hardco ..~ r IS! <'tIition 1971 The UIIe otsenerai deecrlptlve name., trade name., trade marka, e~. In thl, publlcatlnn, even Ir the former ""' IIOt e.peclaIly JdenUfle<!, le IIOt to Ile taken MaalllU that IUch nam.-," undentood by the Trade Marki and Merohandlae Maru Act, may r.ccordlna!y Ile uaed treely by allYone. Druell:: lnh, Roth sel. W",., MnDchen Contents Introduction. . . . . . • . • . . . . . • . . 1 Coronary Atherosclerosis: General Considerations . 7 Epidemiology of Coronary Atherosclerosis . . . . 7 Clinical Manifestations of Coronary Atheroselerosis 8 General Therapeutie Measures in Angina Peetoris . 8 Physieal Training in Angina Peetoris . . . . . . 8 Treatment of Determining Faetors of Atheroselerosis - of Formed Anatomieal Lesions: Surgery 10 - of Predisposing Factore . . . . . . . . . . . . . 14 a) Hypereholesterolaemia and Hypertriglyeeridaemia 14 b) High Blood Pressure 16 e) Metabolie Diseases . 16 d) Tobacco . . . . . . 16 - of the Anginal Syndrome 17 I. Pathophysiology of .Angina. Peetoris . . . . . . . . . . . . . . . . . . . .. 19 1. Pathophysiology of the Anginal Attack . . . . . . . . . . . . . . . . .. 23 Imbalanee Between Myoeardial Oxygen Consumption and Coronary Blood Flow 23 Laetate Produetion . . . . .. .. 25 Myocardial Eleetrolyte Balanee . . . . . . . . . . . . 26 Robinson's Index . . . . . . . . . . . . . . . . . . 29 2. Cardiae Dynamies during the Anginal Attack . . . . . . . 30 3. Part Played by Hypersympathieotony in the Anginal Attack 35 4. Trends in Pharmaeological Research for the Development of Antianginal Medica- tions . . . . . . . . . . . . . . . 39 4.1. Coronary Vaso-Dilation. . . . . . . . 39 4.2. Reduetion in Cardiae Work . . . . . . 40 4.3. Inhibition of Monoamineoxydase. . . . 41 4.4. Bloekade of Hypersympathicotony. . . 42 4.5. Bloekade of the Adrenergie p-Reeeptors . 42 4.6. Overall Inhibition of Hypereympathieotony . . 43 4.7. Dilatationof the Coronary Conduetallee VeeseIs . . . 44 4.8. Improvement of Funetiona! Coronary Mierocireulation 45 4.9. Development of a Collateral Coronary Cireulation . . . . . . . . . .. 45 4.10. Potentiation of the Endogenous Mediatore of the Coronary Autoregulation . 47 4.11. Prophylaxis of Myocardial Neerosis. . • . • . . . . . . . . . . . .. 48 4.12. Inhibition of Platelet Aggregation or Adhesiveness . . . . . . . . . .. 49 n. Haemodynamic Basis for Coronary Pharmacology . 52 General Considerations 52 Blood Pressure . . . . . . . . 55 Myoeardial Oxygen Consumption 55 Cardiae Work . . . . . . . . . 56 Cardiae Output. . . . . . . . . 56 Heart Rate . . . . . . . . . . 56 Regulation of Coronary Cireulation 58 Hypoxaemia 59 Vasomotor Metabolites 59 COa • • • • 59 Lactie Acid 59 VI Contents pH ... 59 Histamine 60 Potassium 60 Adenosine . 60 "Sympathine" 62 Bradykinine . 63 Hyperemine . 64 m. Pharmaeologieal Methodology for Testing Antianginal Drugs 65 Coronary Blood Flow 65 Isolated Heart. . . . . . . . 65 Heart in 8itu . . . . . . . . 68 1. M eaBUrement of Goronary Omfiow . 68 1.1. Morawitz Technique. . 70 1.2. Heart-Lung Preparation . . . . 70 1.3. Rodbard Technique . . . . . . 70 1.4. Busch Technique . . . . . .. .. . . 7l 1.5. Catheterization of the Coronary Sinus without Thoraeotomy 7l 2. Mea8Urement of Goronary Inflow . . . . . . 72 2.1. Techniques with Extra-Arterial Cannulation 72 2.1.1. Melville Technique . . . . . . . . . . 72 2.1.2. Schofield Technique . . . . . . . . . . 72 2.2. Techniques with Intra-Arterial Cannulation. 73 2.2.1. Gregg Technique . . . . . . . . . . 73 2.2.2. Pieper Technique . . . . . . . . . . 74 2.2.3. Beme Technique . . . . . . . . . . 74 2.3. Techniques without Arterial Cannulation 75 2.3.1. Direet Methods . . . . . . . . . . . 75 2.3.1.1. The Thermostromuhr. . . . . . . . 76 2.3.1.2. The Calorimetric Method . . . . . .. ... 76 2.3.1.3. Method Using the Electromagnetic Flow Transdueer . 77 2.3.1.4. Method Using the Ultrasonie Flowmeter . . . . . . 78 2.3.2. Indireet Methods . . . . . . . . . . . . . . . . . 79 2.3.2.1. The Nitrous Oxide Technique . . . . . . . . . . . . . . 79 2.3.2.2. Methods Based on the Employment of Radioaetive Substanees 81 2.3.2.2.1. Non-diffusible Substanees 81 2.3.2.2.2. Diffusible Substanees . . . . . . 81 2.3.2.2.3. Diffusible Inert Gases. . . . . . 83 3. Nutritional Myocardial Micro-Girculation 85 4. Gollateral Goronary Girculation 85 4.1. Aeute Experiment. . . 85 4.1.1. Linder Technique . . 85 4.1.2. Rees Technique . . . 85 4.1.3. MeGregor Technique. 85 4.2. Chronie Experiment. . 86 4.2.1. Meesmann Technique. 86 4.2.2. Schmidt Technique . 86 4.2.3. Sehaper Technique 86 5. Experimental Ghronic Goronary InBUfficiency 87 Measuring Cardiae Output . . . . . . . . 90 Measuring Cardiae Work. . . . . . . . . 92 Measuring Myoeardial Oxygen Consumption 92 IV. Clinieal Methods for Assessment of the Therapeutie Value of Antianginal Medieations 95 Diagnosis of Angina Peetoria . . . . . . 95 Clinieal Assessment of Antianginal Drugs 101 1. Objeetive Methods . 102 1.1. Russek Method . 102 1.2. Levy Method . . 106 Contents VII 1.3. Riseman Method 106 1.4. Solvay Method 108 1.5. Rookmaker Method 109 1.6. Friek Method . . 109 2. Subjeetive Methods . 109 Greiner Method . . . 111 3. Conelusions on Methods of Clinieal Assessment 116 v. Phannacological and Clinical Features of Antianginal Drugs 118 Nitrites . . . . . . . . . . . . . . . 118 1. Nitroglyeerin . . . . . . . . . . . . 120 - Effeet on Coronary Flow in Dogs . . 123 - Effeet on Coronary Flow in Humans 125 - Haemodynamie Effeets in Humans . 126 - Haemodynamie Effeets in the Case of the Angina Patient Suffering an Attack 128 - Meehanisms of the Antianginal Effeet . 129 - Therapeutie Effeet of Nitroglyeerin . 135 - Speeial Galenie Preparations . 137 2. Triethanolamine Trinitrate . 138 3. Erythrityl Tetranitrate. . . 140 4. Pentaerythritol Tetranitrate. 140 5. Mannitol Hexanitrate 143 6. Amyl Nitrite . 143 7. Oetyl Nitrite . . . 144 8. Sodium Nitrite . . 145 9. Isosorbide Dinitrate 146 10. Nilatil . . . . . . 148 11. Etrynit . . . . . 149 12. Propanediol Dinitrates 149 Papaverine 150 Jlanthines . . . . . . . 152 1. Aminophylline 153 2. Choline Theophyllinate . 155 3. Various Theophylline Derivatives 155 }(hellin . . . . . . 157 Carduben. . . . 159 Diaeromone 159 Phenyl-ehromone 160 Reeordil. . . . . . . . . . . . . 160 Monoamineoxydase Inhibitors (Maoi) 160 Irrigor .. 164 Segontin. . 165 m Am~. Isoptin . . 172 Persantine . 181 Intensaine 188 Ustimon. . 192 ndamen. . 196 Clinium .. . ..... 199 p-Adrenergie Blocking Drugs . 205 1. Inderal. . . . . . . . . . 206 - Primary Cardiae Effeet . 207 - Effeet on Coronary Flow . 208 - Effeet on Cardiae Output . 210 - Antianginal Effeet. . . . . . . . 211 - Meehanisms of the Antianginal Effeet 214 - Effeet on the Cardiae Funetion . . . . . . . . 215 - Reeommendations for the Treatment of Angina Peetoris 217 vm Contents - Ineffeetiveness of InderaI in Aeute MyoeardiaI Infaretion 217 - The Use of InderaI in Cardiae Arrhythmia. . . . . . . 218 2. Trasicor. • . . . . . 222 ClinieaI Applleation 227 3. Aptin ....... . 229 4. Eraldin •...... 235 5. ICI 45763 or Kõ 592 (doberoI) 245 6. Visken (LB 46) . 246 7. Ro 3-3528 . . . . 248 8.J]f.PEA ..... 248 9. SotaloI (M.J. 1999) 249 10. Reeetan . 252 11. PhQA 33 253 12. AH 3474 253 13. D 477 A. 254 14. USVC 6524 254 15. S-D/lOOl . 254 16. BunoloI .. 255 Cordarone . . . . . . . . . . . 255 1. PharmacologieaI Properties . 256 1.1. Intrinsie Effeets . . . . . 256 1.2. Antiadrenergie Effeets • . 262 1.2.1. a-antiadrenergie Effeets . 262 1.2.2. p-antiadrenergie Effeets. • . . . . . . . . . 263 1.3. Aetion Meehanisms and Therapeutie Deduetions . 266 1.3.1. Intrinsie Effeets . . . . . . . 266 1.3.2. Antiadrenergie Effeets . . . . . . . . 271 1.4. Anti-Arrhythmie Propertias. . . . . . . 276 2. Therapeutie Properties ......... . 276 2.1. AntianginaI Effeets in Open Teats ............ . 276 2.2. AntianginaI Effeets in Double-Bllnd Tests ......... . 279 2.3. Effects on the Symptomatology of the Cardiae Overload Tests . 280 2.3.1. Hypoxia Teat .................... . 280 2.3.2. Ergometrle Bieyele Test. . . . . . . . . . . . . . . . . 280 2.3.3. Master Type Effort Test ................ . 284 2.4. Effeets on PathologieaI Eleetroeardiogram in Coronary Angina. 285 2.5. Anti-Arrhythmic Effects . . . . . 285 2.6. Clinical Toleranee and Side Effects . 286 Miseellaneous . 288 Section no. 1 288 Adenylocrat . 288 Aminoeetone . 288 Anginin •.. 289 BaraIgin .. . 289 Baxacor .. . 289 Eueilat .. . 291 Griseofulvine . 291 MedereI ... 292 Opticardon . 293 Pexid .... 293 Piridoxilate . . . . 294 Polarlsing Solutions . 295 Sandolanid 296 Surheme . 297 Terodiline . 297 Tromeardin 298 VastareI .. 298 Vialibran . 298 Contants IX Seetion no. 2 299 Morphine . 299 Barbiturates 299 Ethyl AIeohol 300 Valium ... 301 Phenothiazines 302 Chlorpromazine 302 Mepazine 303 Chloraeizine 303 Diphenylhydantoin 303 Cinehona AIealoids 303 Dauearine .... 304 Vitamin E 305 Hexoestrol. . . . .. 305 Adenosine and Related Substanees 305 Thyroxine .......... . 306 Seetion no. 3 . . . . . . . . . 307 Phenoxy-Isopropyl-Norsuprifen 307 Phenyl-Isobutyl-Norsuprifen . 307 Cyelospasmol 308 Vaseulat 308 Reserpine 308 Padutin . 309 Reeosen . 309 Cortunon 310 Heparin . 310 Dieoumarol 311 Ilidar .. 312 Priseol 312 Hydergine . 312 Ronicol .. . ... 313 Poly-Methoxyphenol Derivatives 313 Triparanol ........ . 314 Varia ........... . 314 Carotid Sinus N erve Stimulation 315 Prospeets of future research. 316 Table of Side Effects in Man . 320 References. . 323 Author Index 372 Subject Index 431 1 Hdb. exp. Pharmacology, Vol. XXXI Introduction If the numerous therapeutic acquisitions of the past few years have enriched very different fields of human pathology, it does seem that coronary pathology has been given very special attention, as witness the wide variety of antianginal medications placed at the disposal of the medical profession. There are various explanations for this state of affairs, one of them probably being that the medica tions successively proposed do not fully satisfy the practitioner and another that the total number of individuals suffering from the clinicaI manifestations of coronary heart disease offers, by its size, a vast profit potential for the pharma ceuticaI industry. This field of applications opens up such prospects that it has encouraged a prolific amount of competition between various research laborato ries, and it is no exaggeration to say that every major firm has its individuaI anti anginaI drug in its therapeutic cataIogue. A further factor has aIso contributed enormously to this proliferation of medi cinal preparations intended for the treatment of angina pectoris: this is the rapid advance in our knowIedge of the physiopathoIogy of angina, which in turn has produced originaI concepts of pharmacological and biochemical research. As a result, there have emerged new substances whose action mechanisms have claimed to be best suited to the cardiovascular disorders responsible for cardiac pain. These constantly changing trends in biologicaI research have of necessity called for ever more diversilled methodoIogical deveIopment which has made it possibIe to investigate and measure biological parameters hitherto unobtainable, especially in humans. Even more specialised and poIyvalent equipment has thus been perfected, making it possibIe to combine in a single exploration a whole mass of data which, up to now, could only be gathered separately. Whereas only a short time ago, the various haemodynamic parameters were registered, so to speak, in dividually and often under diverse experimental conditions and then compared in an attempt to arrive at a synthesis, necessarily handicapped by variations in sensitivity of the preparations used and by the lack of homogeneousness in experi mentaI conditions, the technieal equipment currently available makes it possible to gather in a single test the desired information which, because of its diverse character, gives an overall picture of the variations in the parameters investigated under identical experimental conditions for each of those parameters. We thus get more effective comparison of information gathered at the same time as in creased knowIedge. A striking example of this development is the study of the action mechanisms of nitroglycerin on the angina subject. Long tackled from the angle of fragmentaI exploration of the multiple haemodynamic disturbanees which this medication entails, it has recently been possible to do this on an all-in basis with the resuit that a coherent synthesis of the cardiovascular changes occurring could be arrived at, and certain action mechanisms put forward (see p. 129). StiIl in the field of apparatus, many animal and human exploration methods have been perfected. Regarding the problem of angina, methodological advances have been especially marked in the measurement of myocardium blood irrigation 2 Introduction and its metabolism. We have only to compare the technieal conditions of the isolated heart methods with the highly physiological methods formulated, for example, byGREGGin 1965 in the case of the unanaesthetised dogwith its coronary circulation restricted at will by controllable pneumatic occlusive cuff (see p. 90), to appreciate the progress made within a few decades. It goes without saying that a technological evolution of this nature has made for accuracy of experimental ob. servations. Concurrently, methods have been developed for measuring the coronary How in humans which in 1966 cuIminated in the development of bloodless tech. niques applicable to angina pectoris subjects and allowing accurate and reproduc· ible results to be rapidly obtained (see p. 82). A newand comparatively reeent branch of activity has similarly contributed to the development of new treatments: clinical pharmacology, which by an ob· jective functional assessment of the reaetions of the human subject provides the necessary link betwoon animal pharmacology and subjective symptomatology in man. The discovery of antianginal drugs of ever.increasing diversity as regards chemical structure and action mechanisms has also been stimulated by the change in fundamental clinical notions as to the angina syndrome. Over the past ten years, our knowledge of the physiology of angina pectoris has been much enriched, and consequently that of the way in which various medications used for this syn· drome exert their action. There is no doubt whatsoever that it is the development of more and more sophisticated and ingenious techniques for exploring the cardiovascular system that has contributed to the achievement of such progress. Of these techniques, first place undoubtedly goes to cardiac catheterisation since from this derive directly all the techniques of intravascular investigation. The originaI Forssman and Cournand method, catheterisation 01 the right cavities, has already for a long time made it pos· sible to measure the cardiac output from the Fick principle by enabling the sampl. ing of mixed venous blood in the pulmonary artery, and alao the pulmonary arterial "wedge" pressure. Its first variant was the catheterisation 01 the coronary sinus which makes it poss· ible to colleet the myocardium venous drainage and thereby measure the coronary Howand myocardial oxygen consumption, and at the same time to study the metabolism of the various energy.producing substrates of the cardiac muscle. Leit catheterisation then supplied a reading of the left systolic and end·diastolic ventrio cular pressures, followed by that of its first derivative (dpjdt) which expresses the maximum rate at which the ventricular pressure rises [671, 15U], this maximum being directly proportionate to the maximum tension potential of the ventricle at the start of contraction [15U], and then, quite recently [UU], its second deri· vative (d2pfdt2) which expresses the acceleration of ventricular pressure, a func· tion whose maximum changes occur at the initial phase of the isometric ventricular contraction. It also makes it possible to measure, from the inner heart surface, the degree and velocity of shortening of the myocardial fibres with the aid of a new type catheter [1206]. Cardiac catheterisation has also to its credit the following further attain· ments: - the production of experimental myocardial infarction in a dog with its thorax elosed by blockade of the anterior interventricular artery [1507], a method which avoids any handling of the heart and its innervation, and enables the sub· sequent measurement as required of the anastomotic coronary blood How during the recovery period [1505];
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