THE EFFECTS OF SALBUTAMOL AND TERBUTALINE ON PHYSIOLOGICAL TREMOR, BRONCHIAL TONE AND HEART RATE

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1 Br. J. clin. Phrmc. (1974), 1, THE EFFECTS OF SALBUTAMOL AND TERBUTALINE ON PHYSIOLOGICAL TREMOR, BRONCHIAL TONE AND HEART RATE JUDITH M. WATSON & A. RICHENS Deprtment of Clinicl Phrmcology, St Brtholomew's Hospitl, London EC1 A 7BE 1 The effects of orl doses of the bronchodiltor drugs, slbutmol (4 nd 8 mg) nd terbutline (5 nd 1 mg), on physiologicl tremor, bronchil tone, hert rte nd blood pressure were studied in six norml subjects. 2 Both drugs produced significnt increse in physiologicl tremor, compred with plcebo. Terbutline, but not slbutmol, produced dose relted response. No significnt differences were observed between drugs. 3 Terbutline (5 nd 1 mg) nd slbutmol (8 mg) produced significnt bronchodilttion compred with plcebo. Dose relted responses were obtined with both drugs, lthough this reched significnce only with terbutline. 4 Both doses of ech drug produced tchycrdi, lthough this ws only sttisticlly significnt with the high doses. 5 No significnt chnge in blood pressure ws observed with either drug. 6 Pek effects of slbutmol occurred between 1 nd 3 h nd terbutline between 1 nd 4 hours. Both drugs were still ctive t 6 hours. Introduction Animl studies hve shown tht 12 -drenoceptor gonists produce n increse in rte of relxtion of slow skeletl muscle, nd decrese in tht of fst skeletl muscle (Bowmn & Zimis, 1958). In mn, skeletl muscle consists of mixture of fst nd slow fibres nd Zimis (1973) hs postulted tht the feeling of wekness nd tremulousness ssocited with cute stress my be ccounted for by the ction of circulting drenline on the slow units. Sympthomimetic bronchodiltor drugs produce n increse in physiologicl tremor s n dverse effect nd it hs been suggested tht this my be cused by their ction on,-drenoceptors in skeletl muscle (Bowmn & Nott, 1969). In mn, Mrsden, Foley, Owen & McAllister (1967) hve shown n increse in physiologicl tremor with isoprenline nd drenline which my be blocked by proprnolol. The selective 2 gonist bronchodiltor drugs, slbutmol nd terbutline, frequently produce n increse in physiologicl tremor when given orlly (Freedmn, 1971; Legge, Gddie & Plmer, 1971) but we know of no ttempts to quntitte this nd to compre the tremor inducing properties of the two drugs. This hs been the object of the present study nd, in ddition, we hve relted chnges in physiologicl tremor to two other,b effects, bronchodilttion (12 ) nd ltertions in hert rte (1). Methods Slbutmol, 4 nd 8 mg (Ventolin, Allen & Hnburys), terbutline, 5 nd 1 mg (Bricnyl, Astr) or plcebo tblets were dministered orlly to six helthy volunteers (one femle nd five mle) in double-blind rndomized tril. The drugs were dministered between 9. nd 1. h, the subjects hving eten light crbohydrte brekfst pproximtely 2 h erlier. Subjects refrined from smoking, strenuous exercise nd cffeinted drinks from midnight until 4 h fter dministrtion of the drugs. A light lunch ws tken fter the 3 h recordings. Physiologicl finger tremor, bronchodilttion, hert rte nd blood pressure were recorded before nd t.5, 1, 1.5, 2, 3, 4 nd 6 h fter dministrtion of the drug. Physiologicl tremor Physiologicl tremor ws recorded from the middle finger by ttching n Ether type BLA 2 ccelerometer to the finger nil with dhesive

2 224 JUDITH M. WATSON & A. RICHENS plster. The forerm nd wrist were rested horizontlly in plster splint. Tremor ws recorded with one hnd rised to 45 from the horizontl, s this position ws found to produce the gretest mplitude of tremor. The output of the ccelerometer ws doubly integrted by Rigel TM7 tremor recorder nd the resulting displcement signl recorded on n Elemer- Schonnder Mingogrf-8 1 recorder. The signl ws lso fed into n EEG frequency nlyser (Medicl Electronics Deprtment, St Brtholomew's Hospitl) which ws tuned in 1 Hz bnds from 6-15 Hz. The output of this instrument ws written out s histogrm. The mplitude of the pek frequency bnd nd of the bnd on ech side were summed to give mesure of physiologicl tremor. Bronchodilttion In subjects with norml bronchil tone, the degree of bronchodilttion produced by sympthomimetic mines is too smll to be recorded simply by mesuring the forced expirtory volume in 1 s (FEVy) before nd fter drug dministrtion. We hve, therefore, exmined the bility of these compounds to protect ginst bronchoconstriction induced by histmine chllenge. All subjects showed bronchoconstriction to histmine cid phosphte 34 ;g (Riker) dministered from metered erosol. A Vitlogrph ws used to mesure FEV1 before nd fter histmine dministrtion t hourly intervls up to 6 h fter dministrtion of the sympthomimetic drug. Results hve been expressed s percentge bronchoconstriction to histmine, tking control redings s 1%. Hert rte nd blood pressure Hert rte ws tken from n ECG trcing recorded t the sme time s the tremor. Blood pressure ws mesured with stndrd cuff nd sphygmomnometer. Results Physiologicl tremor Both slbutmol (4 nd 8 mg) nd terbutline (5 nd 1 mg) produced significnt increse in mplitude of physiologicl tremor compred with plcebo (Figures 1 nd 2). Terbutline produced dose relted responses which were significntly different from ech other t 2 hours. Although four of the six subjects produced dose relted tremor response to slbutmol, two produced unexpected responses. One of these two hd complete reversl of the expected dose response effect nd this my ccount for the men results showing similr potency for slbutmol (4 nd 8 mg). Terbutline (5 mg) produced men increse in tremor of 125% nd 1 mg produced n increse of 25% with pek between 1.5 nd 3 hours. Both doses of slbutmol produced men increse of 125% with the pek occurring between 1 nd 2 hours. There ws no sttisticl difference between the increses in tremor produced by slbutmol (4 mg) nd terbutline (5 mg). Terbutline (1 mg) produced greter increse in tremor thn slbutmol (8 mg) but this difference ws not sttisticlly significnt. Five of the six volunteers, however, commented on subjective difference. Bronchodilttion There ws decrese in the bronchoconstriction response to histmine throughout the dy following tretment with plcebo. Terbutline (5 nd 1 mg) nd slbutmol (8 mg) produced significnt bronchodilttion compred with plcebo between 1 nd 3 h, with pek t 2 h (Figures 1 nd 2). The response to terbutline ws dose dependent with significnt difference between doses t 1 h, but there ws no significnt difference between the responses to slbutmol 4 nd 8 mg. Furthermore, there ws no significnt difference between the effects of slbutmol (4 mg) nd terbutline (5 mg) or slbutmol (8 mg) nd terbutline (1 mg). Hert rte In the higher doses only, both drugs produced significnt increse in hert rte. Terbutline (1 mg) produced men increse of 21 bets/min with pek t 3 h nd slbutmol (8 mg) produced n increse of 16 bets/min t 3 hours. Lower doses of slbutmol nd terbutline produced n increse in hert rte of 8 nd 1 bets/min respectively t 4 hours. Significnt differences between the doses were produced t 1 nd 3 h with slbutmol nd t 1.5 h with terbutline. Terbutline (5 mg) nd slbutmol (4 mg) produced similr effects on hert rte s did terbutline (1 mg) nd slbutmol (8 mg). Blood pressure Neither drug produced significnt chnge in blood pressure.

3 SALBUTAMOL AND TERBUTALINE ON TREMOR 225 C._ E L 15. -s ~~~~~ -A I - I --- I I ---A c i, ) i1 -,, E o,1-5 - CO L m o tc m Cc -4-2,- b (D-c b b b 1.-co ~ ) -c co Time (h) Fig. 1 Effects of orl dministrtion of slbutmol 4 mg (-), 8 mg (s) or plcebo (A) on physiologicl tremor, bronchil tone nd hert rte. The results re the mens of mesurements in six subjects. Significnt difference between drug nd plcebo: () P <.5; (b) P <.2. Significnt difference between 4 nd 8 mg slbutmol: (c) P <.5. A probbility level of 5% or less using Student's t test ws ccepted s significnt. "c- 2 co -- E 1,.C 1 Cl' C: CZ ) -1 -c or- CO :~~~~~~8 - A Time (h) Fig. 2 Effects of orl dministrtion of terbutline 5 mg (-), 1 mg () or plcebo (A) on physiologicl tremor, bronchil tone nd hert rte. The results re the mens of mesurements in six subjects. Significnt difference between drug nd plcebo: () P <.5; (b) P <.1. Significnt difference between 5 nd 1 mg terbutline: (c) P <.2; (d) P <.5. A probbility level of 5% or less using Student's t test ws ccepted s significnt. Discussion The mplitude of control tremor vried widely between individuls nd therefore we chose to express the results s percentge of the control response for ech subject. There ws no correltion between the mplitude of the control tremor nd the increse produced by the bronchodiltor drugs. Previous studies with orlly dministered terbutline nd slbutmol hve shown n increse in physiologicl tremor s n dverse effect (Dind, Bernstein & Chtterjee, 1971; Freedmn, 1971; Legge et L, 1971; Dulfno & Glss, 1973). In these trils tremor ws recorded subjectively nd no physiologicl mesurements were mde. The increse in tremor observed with these orl bronchodiltor drugs vried between trils. Dind et l. (1971) reported tremor in eight out of twelve sthmtic subjects with n orl dose of terbutline (5 mg) wheres Dulfno & Glss (1973) noted tremor in only two out of twenty-six subjects with the sme dose. In our tril n increse in physiologicl tremor ws recorded on most occsions yet subjectively t the lower doses the effects were not lwys noticed. There ws n individul vrition not only in the ctul increse of tremor produced by the bronchodiltors but lso in the subjective threshold. Some subjects complined of tremor t reltively low level wheres others were not distressed by mrked tremor. The wreness of tremor lso depended on

4 226 JUDITH M. WATSON & A. RICHENS the degree of ctivity of the subjects nd the dexterity required for their work. Clinicl trils of bronchodiltor drugs should monitor tremor s it my be severely disbling side effect (Prime, 1971). The time course of the bronchodilttion produced by slbutmol nd terbutline ws similr to tht obtined by Legge et l. (1971). The difference between the bronchodilttion produced by terbutline (5 mg) nd tht produced by 1 mg ws significnt only t 1 h, confirming results of Freedmn (1971) showing no therpeutic dvntge in the higher dose. Dulfno & Glss (1973) showed tht terbutline (5 mg) produced significntly greter bronchodilttion thn 2.5 mg, suggesting tht 5 mg is the optimum therpeutic dose. Both drugs produced dose relted tchycrdi lthough this ws significnt only t the higher doses. Other workers hve shown smller effect on hert rte with these bronchodiltor drugs (Mttil & Muittri, 1969; Dind et l., 1971; Formgren, 1971; Simpson, 1971; Minette, 1971). Increses in hert rte were seen which vried between nd 6 bets/min with terbutline (5 mg) nd 5 nd 1 bets/min with 1 mg compred with increses of 1 nd 2 bets/min for the two doses respectively in our tril. Freedmn (1971) nd Arner, Bertler, Krlefors & Westling (197) hve shown greter effects on hert rte with terbutline (n increse of 18 bets/min with 5 mg nd 35 bets/min with 1 mg) but these results my be ccounted for by more rpid bsorption. Freedmn (1971) dministered the tblets crushed in wter nd Arner et l. (197) dministered the drugs to fsting subjects. The pek tremor effect of slbutmol ppered to be erlier thn tht of terbutline. The pek effects on bronchil tone, tremor nd hert rte occurred between 1 nd 3 h with slbutmol, which confirms the results of Mrtin, Hobson, Pge & Hrrison (1971) nd Wlker, Evns, Richrds & Pterson (1972). In this nd other trils (Dind et l., 1971 nd Freedmn, 1971) terbutline produced pek effects between 1 nd 4 hours. Both drugs were still ctive t 6 hours. Previous workers hve shown the durtion of ction of slbutmol to be 6 h (Simpson, 1971) nd terbutline 12 h (Nillson, Persson & Tegner, 1972). This difference in length of ction my be ccounted for by differences in the metbolism of the two drugs. The metbolite of terbutline is ctive wheres tht of slbutmol hs, s yet, not been shown to hve gonist ction (Wlker et L, 1972). Mrsden et l. (1967) hve shown n increse in physiologicl tremor with isoprenline nd hve demonstrted blockde of this induced tremor by proprnolol, suggesting tht 3 receptor my be involved. Animl studies hve shown tht bronchil nd skeletl muscle receptors hve similr pttern of response to,-sympthomimetic mines (Bowmn & Nott, 197; Rodger, 1971; Apperley & Dly, 1972; Bowmn & Rodger, 1972; Gwee, Nott, Rper & Rodger, 1972). It seems likely, therefore, tht the tremorogenic properties of 3-gonist bronchodiltor drugs my be inseprble from their bronchil relxing properties. We would like to thnk the Bord of Governors of St Brtholomew's Hospitl for finncil ssistnce. Requests for reprints should be sent to A.R. References APPERLEY, G.H. & DALY, M.J. (1972). Simultneous mesurement of skeletl muscle, pulmonry mechnicl nd vsculr responses to bronchodiltors in the ct. J. Phrm. Phrmc., 24, ARNER, B., BERTLER, A., KARLEFORS, T. & WESTLING, 14. (197). Circultory effects of orciprenline, drenline nd new sympthomimetic,-receptor-stimulting gent, terbutline, in norml humn subjects. Act med. Scnd. suppl., 512, BOWMAN, W.C. & NOTT, M.W. (1969). Actions of sympthomimetic mines nd their ntgonists on skeletl muscle. Phrmc. Rev., 21, BOWMAN, W.C. & NOTT, M.W. (197). Actions of some sympthomimetic bronchodiltor nd,-drenoceptor blocking drugs on contrctions of ct soleus muscle. Br. J. Phrmc., 38, BOWMAN, W.C. & RODGER, I.W. (1972). Actions of the sympthomimetic bronchodiltor, rimiterol (R798) on the crdiovsculr, respirtory nd skeletl muscle systems of the nesthetized ct. Br. J. Phrmc., 45, BOWMAN, W.C. & ZAIMIS, E. (1958). The effects of drenline, nordrenline nd isoprenline on skeletl muscle contrction in ct. J. PhysioL, Lond., 144, DINDA, P., BERNSTEIN, A. & CHATTERJEE, S.S. (1971). A new bronchodiltor: Terbutline. Br. J. Clin. Prct., 25, DULFANO, M.J. & GLASS, P. (1973). Evlution of new,2 -drenergic receptor stimulnt, terbutline, in bronchil sthm. II. Orl comprison with ephedrine. Reserch, 15, FORMGREN, H. (1971). Clinicl comprison of inhled terbutline nd orciprenline in sthmtic ptients. Scnd. J. Resp. Dis, 51, FREEDMAN, B.J. (1971). Tril of new bronchodiltor, terbutline, in sthm. Br. med J., 1, GWEE, M.C.E., NOTT, M.W., RAPER, C. & RODGER,

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