Table Of ContentHandhuch 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
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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];
