A new classification of β-adrenoceptor blocking drugs

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sponse to isoproterenol in the atria was obtained at a ten-fold lower drug concentration. The maximum response in the ventricles occurred at the same concentration as in control animals but was 40% greater in magnitude.

The authors ask if a similar p h e n o m e n o n occurs in humans. If so, could a near-term w o m a n taking digitalis sensitize her offspring? This could be potentially serious for the offspring years later, in view of the poor therapeutic index of digitalis.

the effects of pollutants on a population is a complex problem, involving numerous uncontrollable variables. Simple test systems that permit a direct measure of relative toxicity are, therefore, important. Bernson 5 has reported one such system for assaying the biological effects of particulate emission from cars driven on different fuels. Cell oxygen consumption is the biological endpoint used. Isolated brown adipocytes contain a hormonal system whereby oxygen consumption is increased tenfold in response to norepinephrine. Any dislocation in this complex hormonal response leads to a fall in the degree of stimulation of oxygen consumption.

had an IC50 of 4 I. Gasoline containing 15% methanol or 23% ethanol was significantly less toxic, with IC50 values in the range of 9-15 l, d e p e n d i n g on the exact composition of the fuel. The experimental procedure is such that only the particulate phase of the exhaust is being tested. It was somewhat surprising, therefore, to discover that the use of a catalytic converter markedly decreased toxicity, implying that catalytic processing removes biologically active c o m p o u n d s from the solid phase.

stability. It would appear that the 'imprinting' phenomenon is modifying the rat digitalis receptor more to the type that exist in other mammals. In addition, 'imprinted' animals showed a change in adrenergic responsiveness. The maximum reDETERMINING

Five automobile fuels were compared. Automobile exhaust was filtered, the filters extracted with acetone, and the acetone taken to dryness. The residue was dissolved in DMSO and added to adipocyte cell suspensions. Toxic-

References 1 Simonds, W. F., Koski, G., Streaty, R.A., Hjelmeland, L.M. and Klee, W. A. (1980) Proc. Natl Acad. Sci. USA 77, 4623-4677 2 Bidlack, J. M., Abood, L.G., OseiGyimah, P. and Archers, S. (1981) Proc. Natl Acad. Sci. USA 78, 636-639 3 Dornay, M. and Simantov, R. (1982) J.

ity was expressed as the liters of exhaust equivalent required to halve the rate of oxygen consumption in norepinephrine-stimulated cells. The most toxic material came from commercially available, olefin-free, leaded gasoline. This Neurochem. 38, 1524-1531 4 0 t t , S., Costa, T., Hietel, B., Schegel, W. and Wistar, M. (1983) Naunyn-Schmied. Arch. Pharmacol. 324, 160-162 5 Bernson, V. (1983) Toxicol. Lett. 19, 119126 6 Melvin, L. S., Johnson, M. R., Harbert, C. A., Milne, G. M. and Weissman, A. (1984) 1. Med. Chem. 27, 67-71 7 Thorup, I., Wurtzen, G., Carstensen, J.

A new classification of blocking drugs The classification of ~-adrenoceptor blocking (B-blocking) drugs, proposed by Fitzgerald in 1969, has been used widely over 15 years. However, development of the new types of ~-blocking drugs has made the classification inadequate. I have tried to reclassify ~blocking drugs, defining the drugs with cardioselectivity and with useful clinical features as the third and fourth generations. The first and second generations corresp o n d to the drugs with and without partial agonist activity, respectively.

-adrenoceptor

Many B-blocking drugs have been developed since Powell and Slater first reported dichloroisoproterenol (DCI) in 19581. Fitzgerald's proposal 2,3 (Table I) or its modifications have been widely used in their classification. Prichard's modifications 4 have been the most popular, based on the original criteria of intrinsic sympathomimetic and membrane stabilizing activities, and cardioselectivity. These classifications have n o w become inadequate for the variety of ~-blocking drugs currently available, especially for

B. MAX a n d Olsen, P. (1983) Toxicol. Lett. 19, 207-210 8 T h o r u p , I., W u r t z e n , G., C a r s t e n s e n , J. a n d Olsen, P. (1983) Toxicol. Lett. 19, 211-215 9 C s a b a , G., I n c z e f i - G o n d a , A., D o b o z y , O., Varro, A. a n d Rabloczky, G. (1983) Biochem. Pharmacol. 14, 709-711

those with clinically useful features such as ~¢-adrenoceptor blocking, vasodilating, and calcium-entry blocking activities. I have therefore tried to make a new classification of B-blocking drugs (Table II). I would like to present m y proposed classification of Bblocking drugs, first reported in Japan s where it was well-received.

The first generation B-Adrenoceptor drugs with partial agonist activity (PAA) are defined as the first generation. This includes only drugs without cardioselectivity or clinically useful features. The prototype is DCP and pronethalol 6, the first ~-blocking drugs to be developed. PAA of the ~-blocking drug was originally termed intrinsic sympathomimetic activity 2. (However PAA is current standard pharmacological terminology 7,s.)

1985,ElsevierSciencePublishers B.V.,Amsterdam 0165- 6147/85/$O2.00

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piratory function m u s t be theoretically m i n i m u m . Experimental and clinical data indicate that cardioselective (as well as non-selective) drugs are antihypertensive, while B2-blocking drugs are not effective in lowering blood pressure in h y p e r t e n s i o n 12,13. These results mean that Bl-blockade is essential for the antihypertensive effect of B-blocking drugs. Therefore, it is anticipated that use of cardioselective drugs w o u l d be beneficial in treatment of arrythmia, angina, and h y p e r t e n sion. However, final conclusions m u s t await controlled clinical trials. It was recently reported that atenolol is more effective in antihypertensive action than oxprenolol or pindolol w h e n the three drugs were given at doses causing the same fall in exercise tachycardia (Bl-blockade) 14.

TABLE I. Fitzgerald's classification of the ~adrenoceptor blocking drugs

Group

Drugs

la Ib

dichloroisoproteranol pronethalol, oxprenolol, alprenolol, plndolol, Ro 3-352.8 propranolol, butidrine, bunalol INPEA sotalol practolol

II III IV V

Ariens 9 recently p r o p o s e d that the term 'partial a n t a g o n i s t ' should be u s e d w h e n a d r u g has greater antagonistic than agonistic activity. The first generation is certainly a g r o u p of partial antagonists, according to this proposal. The clinical significance of Bblocking drugs w i t h P A A has b e e n discussed recently 7,8. They m a y b e h a v e differently in m a n comp a r e d w i t h those w i t h o u t PAA. They m a y have less effect on resting heart rate, left ventricular function, p e r i p h e r a l vascular blood flow and resting respiratory function. H o w e v e r , w h e t h e r these differences result in benefits in patients is not proven, b u t largely inferred. The fact that p i n d o l o l has b e e n m o s t w i d e l y u s e d in Japan m a y indicate some clinical benefits of PAA. H o w e v e r , its w i d e use is partly d u e to the fact that pindolol was the first d r u g to be a p p r o v e d for use in essential h y p e r t e n s i o n in Japan in 1976.

Intrinsic sympathomimetic activity

Membrane stabilizing activity

Cardioselectivity

++ +

+ +

-

--

.}.

--

+

-

+

generation. This includes only non-cardioselective and pure Bblocking d r u g s w i t h o u t additional features. The p r o t o t y p e is propranolol 1°. This d r u g is also regarded as the p r o t o t y p e of B-blocking d r u g s as a whole. O n e characteristic of propranolol is m e m b r a n e - s t a b i l i z i n g (local anesthetic or quinidine-like) activity. Fitzgerald has used this as a criterion in his classification m e n t i o n e d above. As this activity is clinically least significant, it is not used in the n e w classification. Clinical significances of noncardioselective drugs have been well established for treatment of arrythmia, angina, a n d h y p e r t e n sion.

The third generation

The second generation Drugs w i t h o u t P A A (pure antagonists) are d e f i n e d as the second

Cardioselective B-blocking drugs are defined as the third generation. They are also termed as B1blocking drugs. They m a y or m a y not have PAA. The p r o t o t y p e is practoloPL As the action of these drugs is localized on the heart, their effects on peripheral circulation and res-

TABLE II. A new classification of the ~-adrenoceptor blocking drugs Drugs on Japanese market Generation Definition Prototype

The fourth generation Drugs w i t h clinically useful features such as oc-blocking, vasodilating, a n d calcium-entry blocking activities are defined as the fourth generation. The prototype m a y be labetalo115. The character of these drugs in the fourth generation is complex, because various combinations in blockades of ~1, 0~2, B1 or B2 receptors, of vascular muscle, and of calc i u m - e n t r y could exist. However, controlled clinical trials indicate the usefulness of these drugs 16,z7. Until recently, it was thought that a drug should be chemically pure and have a clear p r i m a r y effect. It is also true that c o m b i n e d

Drugs on market outside Japan

Drugs under development

f st

Drugs with partial agonist dichloroisoactivity (PAA) (partial proterenol antagonists) pronethalol

alprenolol carteolol indenolol oxprenolol pindolol

nifenalol (INPEA) penbutolol (Heo-893d)

bufuralol (Ro-3-4787) pargolol (RU-21824) tiprenolol (Du-21455)

2nd

Drug without PAA (full antagonists)

propranolol

carazolol (BW-51052) nadolol (SQ-t 1725) sotalol (MJ-1999) toliprolol (ICI-45763)

bunolol (W-6412 A) xibenolol (D-32)

3rd

Drugs with cardioselectivity (13~-blocking activity)

practolol

befunolol bucumolol bufetolol bupranolol propranolol timolol acebutolol atenolol metoprolol

betaxolol (SL-75212) celiprolol (ST-1396)

bevantolol (CI-775)

4th

Drugs with clinically useful features (o~-blocking,vasodilating and Ca-entry blocking activities)

labetalol

bunitrolol labetalol

1985

amosulalol (YM-09538) bucinodolol (M J- 13105) medroxalol (RMI-81968) nipradilol (K-351) N-696

TIPS - March 1985 use of several drugs is frequently r e c o m m e n d e d for actual treatment. A l t h o u g h the drugs w h i c h belong to the fourth generation m a y be ' d i r t y ' c o m p o u n d s in their actions, recent clinical data suggest that they have significant potential. I believe that this classification of ~-blocking drugs is more practical than Fitzgerald's or its m o d i fications, with respect to p h a r m a cology, clinical use and development. Each generation was n a m e d in order of appearance of the prototype. All of four generations are still d e v e l o p i n g b y i m p r o v i n g their efficacy, potency, duration of action, adverse reactions, etc. This indicates that none of the four generations has lost value in clinical use.

109

Acknowledgement I thank Dr Y. Hara, S u m i t o m o

7 McDevitt, D. G. (1983) Drugs 25, 331-338 8 Van Zwieten, P. A. (1983) J. Cardiovasc. PharmacoL 5, $1-$67 9 Ariens, E. J. (1983) J. Cardiovasc. Pharmacol. 5, $8-$15 10 Black, J. W., Crowther, A. F., Shanks, R. G., Smith, L. H. and Dornhorst, A. C. (1964) Lancet i, 1080-1081 11 Dunlop, D. and Shanks, R. G. (1968) Br. J. Pharmacol. Chemother. 32, 201-218 12 Imbs, J. L., Miesch, F., Schwarty, J., Velly, J., Leclerc, G., Mann, A. and Wermuth, C. G. (1977) Br. J. Pharmacol. 60, 357-362 13 Fitzgerald, J. D. (1982) Clin. Exp. Hyper., A4, 101-123 14 Costa, F. V. and Ambrosioni, E. (1982) Int. J. Clin. Pharm. Res. 2($1), 75-79 15 Farmer, J. B., Kennedy, I., Levy, G. P. and Marshall, R.J. (1972) Br. J. Pharmacol. 45, 660-675 16 Clinical Research Group on Labetalol (1982) Igakunoayumi 120, 1084-1102 17 Ikeda, M., Arakawa, K., lnagaki, Y., Kaneko, Y., Masuyama, Y., Yamazaki, N. and Tsuchiya, M. (1981) Rinsyohyoka 9, 795~39

Chemical Co., for his help in collecting drug informations used in this letter. HIROFUMI SOKABE

Department of Pharmacology, Jichi Medical School, Tochigi-ken, 329-04 Japan.

References 1 Powel, C. E. and Slater, I. H. (1958) J. Pharmacol. Exp. Ther. 122, 48(3--488 2 Fitzgerald, J. D. (1969) Clin. Pharmacol. Ther. 10, 292-306 3 Fitzgerald, J. D. (1972) Acta Cardiol. 15 (Suppl.), 199-216 4 Pritchard, B. N. C. (1978) Br. J. Clin. Pharmacol. 5, 379-399 5 Sokabe, H. (1984) Igakunoayumi 128, 349-355 6 Black, J. W. and Stephenson, J. S. (1962) Lancet ii, 1080-1081

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ecular sites of action, structure-activity relationships and hence with different pharmacological and clinical profiles. There have been previous attempts to differentiate calcium antagonists into s u b g r o u p s (Table I), but with differing results. I propose that three functional classes of calcium antagonist exist, with appropriate b i n d i n g sites.

i

Calcium antagonist subgroups Michael Spedding The disparate structures, pharmacological effects and clinical profiles of calcium antagonists indicate that, within the overall classification, different subgroups exist with separate molecular sites of action and, consequently, diverse effects. Michael S p e d d i n g discusses the proposal that at least three, and possibly four, different subclasses exist on the basis of structure-activity relationships and differential effects in binding and in functional tests. The subclasses have distinct therapeutic profiles. The clinical success of calcium antagonists has evoked w i d e spread interest in their mechanism(s) of action. These comp o u n d s are thought to act b y i n h i b i t i n g Ca 2+ entry t h r o u g h distinct ion channels which can be activated b y cellular depolarization (voltage operated channel: VOC) (Ref. 1, 2). O n e would, therefore, expect calcium antagonists to be active in situations where cellular activation is conseq u e n t to Ca 2+ entry via VOCs and also, as a group, to b e h a v e similarly. However, there are m a n y differences b e t w e e n calcium antagonists both at the experimental Michael Spedding is project leader for cardiovascular drugs in the MerreU Dow Research Institute, Strasbourg Center, 16 rue d'Ankara, Strasbourg 67084, France.

Historical perspective The foresight of two groups led b y Fleckenstein and Godfraind initiated the present ideas on h o w calcium antagonists act. The effects of verapamil and the dih y d r o p y r i d i n e , nifedipine, on the heart and coronary vessels were explored by Fleckenstein whereas Godfraind and co-workers characterized the effects of the d i p h e n y l alkylamines, cinnarizine and flunarizine, in peripheral blood vessels. However, the failure of diphenylalkylamines at reasonable concentrations to affect cardiac parameters meant that there was little overlap between the work of the two groups at the time when the concepts were being devel-

level and also in clinical practice. Indeed, it has been claimed that no other single class of drugs comprises so m a n y chemically diverse structures 3 and it is difficult to envisage h o w such disparate c o m p o u n d s can interact with a single site. The aim of this article is to rationalize the situation b y r e v i e w i n g the evidence for different s u b g r o u p s of calcium antagonists, each with different mol-

TABLE I. Literature classifications

of calcium antagonists

Dihydropyridines Fleckenstein I Glossrnann e t aL 7 Rodenkirchen e t aL to Murphy e t al. 9 Spedding 4

I IA II I I

Verapamil I II I II II

afendiline classed with verapamil, prenylamine

Diltiazem I III I II II

Diphenylalkylamines II IB III a II III

with dihydropyridines.

1985,ElsevierSciencePublishersB.V.,Amsterdam 0165 6147/85/$02.00