STUDIES ON FAZADINIUM BROMIDE (AH 8165): A NEW NON-DEPOLARIZING NEUROMUSCULAR BLOCKING AGENT

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1 STUDIES ON FAZADINIUM BROMIDE (AH 8165): A NEW NON-DEPOLARIZING NEUROMUSCULAR BLOCKING AGENT R. HUCHES, J.P. PAYNE, AND N. SUGAI INTRODUCTION PRELIMINARY REPORTS on the neuromuscular blockng acton of fazadnum (AH 8165) demonstrated that t s a non-depolarzng agent, that ts onset of acton s rapd and that ts duraton s short n cats and dogs but longer n monkeys. 1 In man, ts duraton of acton was longer than expected and resembled that n monkeys; persstence of acton n man was comparable wth that of pancuronum. 2 In cats, Marshall 3 showed that ganglonc blockade was also produced by fazadnum but only wth doses greater than those requred to cause neuromuscular paralyss. Vagal blockade was caused, however, by doses less than those requred for neuromuscular paralyss and t seems lkely that such atropnc effects may lead to undesrable tachycarda n man. 4 Indeed, t has already been reported that heart rate and cardac output ncrease sgnfcantly after fazadnum n man but that arteral blood pressure remans steady. 5 The studes reported here were carred out n anaesthetzed cats, monkeys and man to nvestgate further the neuromuscular, cardovascular and autonomc effects of fazadnum. METHODS Expermental anmals. Four cats weghng between 2.8 and 4.8 kg were studed after anaesthesa was nduced wth 4--8 per cent halothane and mantaned wth chloralose (60 to 80 mg/kg v) after cannulaton of a ugular ven as descrbed prevously. 4,8 The trachea was cannulated to allow artfcal ventlaton and to record the respratory pattern. The carotd artery was cannulated to measure the blood pressure and the cannula nserted n the jugular ven allowed the admnstraton of drugs. Neuromuscular block was assessed by measurng the response of the gastrocnemus muscle to stmulaton of the scatc nerve wth rectangular pulses of supramaxmal voltage and duraton at a frequency of 0.1 Hz. Effects on autonomc mechansms were also nvestgated; parasympathetc actvty was studed by measurng the bradycarda whch ensued when 10-second bursts of perodc stmulaton were appled to the cardac end of the cut rght cervcal vagus nerve and sympathetc actvty by recordng the contractons of the ncttatng membrane when the central end of the cut rght preganglonc cervcal sympathetc nerve was stmulated for 60 seconds at supramaxmal voltage. Atropntc effects were confrmed by nducng bradycarda wth metacholne (100 mg) gven ntravenously. Research Department of Anaesthetcs, Royal College of Surgeons of England, Lncoln's Inn Felds, London WC2A 3PN; St. Peter's Hosptal, London WC2; and Department of Pharmacology, The Wellcome Research Laboratores, Beckenham, Kent. 36 Canad. Anaesth. Soc. J., vol. 23, no. 1, January 1976

2 HUGHES, et al.: FAZADINIUM 37 Four rhesus monkeys of ether sex, weghng between 3.4 and 3.6 kg, were anaesthetzed wth thopentone ( 25 mg/kg v). Anaesthesa was mantaned wth ntrous oxde and oxygen supplemented by ntravenous thopentone (5 to 12 mg) as requred. The methods of study were smlar to those descrbed for cats, but effects on sympathetc mechansms were nvestgated by measurng the vasopressor response to carotd occluson for 30 seconds. Man. Studes were carred out after nformed consent had been obtaned n nne male patents about to undergo urologcal surgery. No premedcaton was gven and anaesthesa was nduced wth halothane, ntrous oxde and oxygen. Endotracheal ntubaton was carred out wthout the use of a neuromuscular blockng agent. The halothane was then dscontnued and anaesthesa mantaned wth ntrous oxde and oxygen supplemented by ntravenous meperdne ( 100 to 200 mg) and dazepam (10 to 20 mg) n dvded doses over two hours. Smultaneous measurements of tetanc and sngle twtch contractons of the adductor pollcs muscles were performed as descrbed prevously. 6 The rght ulnar nerve was stmulated tetancally at 50 Hz for one second every 12 seconds and the left wth sngle square-wave pulses of 200 mcrosecond duraton every 12 seconds. The blood pressure was measured drectly from a polyethylene catheter nserted nto the left radal artery at the wrst and the heart rate was recorded from the electrocardogram. Fazadnum was gven ntravenously n dvded doses of 0.1 or 0.2 mg/kg to three patents to obtan dose-response curves and by a sngle njecton of 0.4 mg/kg to sx patents to measure ts course of acton. The temperature of each hand was montored wth a surface probe; any dfference was wthn one degree centgrade. Arteral blood was sampled from the radal artery for analyss of blood gases whch were mantaned wthn normal lmts by asssted or controlled ventlaton. In sx patents the tetanc-tenson ratos and tetanc transmssons were determned by an Ellott 903 dgtal computer from on-lne real-tme data (See Fgure 1). The tetanc-tenson rato, whch s defned as the percentage magntude of the tetanc contractons at the end of the one-second tetanus compared wth the ntal magntude, reflects the degree of fade produced durng neuromuscular block. Tetanc transmsson was determned as the percentage of the ntal peak tetanc heght compared wth the control peak heght before drug treatment ( Fgure 1). RESULTS Expermental anmals. Intravenous doses of 2 mg/kg fazadnum bromde were requred for complete neuromuscular blockade of the sngle-twtch response of the gastrocnemus muscle n 4 anaesthetzed cats. The onset of acton was about 1 mnute and a mean of 15 mnutes was requred for full recovery. The dose-response relatonshps showed that vagal blockade occurred at doses below those requred for neuromuscular paralyss (Fgure 2). Ths vagal block was atropnc n nature snce the cholnergc receptors n the heart were blocked, as demonstrated by the abolton of metacholne-nduced bradycarda. Slght sympathetc blockade occurred wth supramaxmal doses as wtnessed by some hypotenson and slght bradycarda (Fgure 2). These fndngs are to be publshed n detal elsewhere, s In four rhesus monkeys, fazadnum was found to be about four tmes more

3 38 CANADIAN" ANAESTHETISTS' SOCIETY JOURNAL TETANIC CONTRACTION CONTROL (Sustaned tetanus) PARTIAL BLOCKADE (Tetanc fade) A B TF'TANIC TENSION RATIO-- -x100or-- B D x 100 A C TETANIC TRANSMISSION - C x 100 A FlCum~ 1. Dagram showng control tetanc contracton, tetanc fade and calculaton of tetanc tenson rato and tetane transmsson. potent than n cats, snce a dose of 0.5 mg/kg ntravenously was suffcent for complete paralyss (Fgure 3). Its course of acton was also consderably longer n the prmate, 1.5 to 5 mnutes beng requred for the onset of paralyss and a mean of 36 mnutes for full recovery. Some sympathetc blockade and hypotenson occurred wth supramaxmal doses (Fgure 3); the dose-response curve for vagal blockade was smlar to that seen n the cats ( Fgure 2 ). Man. The dose-response curves obtaned from the results n three patents ( Fgure 4) suggest that the potency of fazadnum n man corresponds more closely to that n cats rather than to that n monkeys. When gven n ncrements of 0.1 or 0.2 mg/kg a total ntravenous dose greater than 0.9 mg/kg was requred for complete paralyss of the sngle-twtch response. As wth other non-depolarzng neuromuscular blockng agents, the tetanc contractons of the muscles were more senstve than the sngle twtches to the effects of fazadnum. Although changes n mean arteral blood pressure were mnmal, the heart rate was progressvely ncreased wth ncreasng dosage and probably reflected the onset of vagal blockade smlar to that observed n cats and monkeys. In those sx patents who receved sngle doses of fazadnum (0.4 mg/kg v), the nset of complete blockade of the tetanc contracton occurred wthn two mnutes but recovery was slow and requred a mean of 48 seconds for completon (Fgure

4 Percent Inhbton r~cm~s, et al.: FA.ZADINIUM Mean of 4 Cats AH O 9 Neuromuscular. Vagus -, Sympathetc J jl // j / t J jl /// // '.~01 J I I 0"125 0" Dose I I I 1"0 2"0 4"0 mglkg.v. FlctmE 2. Dose response curves showng blockade of neuromuscular and autonomc mechansms by fazadnum bromde (AH 8165) gven ntravenously to four cats anaesthetzed wth chloralose ( each pont represents the mean of 4 observatons ). 9 Percentage nhbton of the twtch response of the gastrocnemus muscle to ndrect stmulaton at 0.1 Hz. *... * Percentage nhbton of the bradycarda response to vagal stmulaton at Hz for 10 s Percentage nhbton of the response of the ncttatng membrane to sympathetc nerve stmulaton at Hz for 60 s. Vertcal lnes ndcate standard errors. Imparment of the vagally nduced bradycarda occurred at dose-levels below those requred to cause neuromuscular paralyss. The contractons of the ncttatng membrane were slghtly reduced by supramaxmal paralysng doses,

5 40 CANADIAN ANAESTHETISTS SOCIETY JOURNAL Percent Inhbton 100 AH 8165 Mean of 4 Rhesus Monkeys s S /" J 80- s~,~ SfJ ss ss 60 9 Neuromuscular 9r Vagal ~ 9,,- Sympathetc E,,~ o Q jj 40 Isl~ j I / ~ ~ ~ ~ qp 20 o! Do Ip 0 I I I I I I I "125 0'25 0' "0 4.0 Dose mg/kg.v. FICURE 3. Dose response curves showng blockade of neuromuscular and vagal mechansms by fazadnum bromde (AH 8165) gven ntravenously to four rhesus monkeys anaesthetzed wth chloralose. 9 9 Percentage nhbton of the twtch responses of the gastrocnemus muscle to ndrect 9... stmulaton at 0.1 Hz. * Percentage nhbton of the bradycarda responses to vagal stmulaton at Hz for 10 s Percentage nhbton of the vasopressor responses to carotd occulson for 10 s. Vertcal lnes ndcate standard errors. Imparment of the vagally nduced bradycarda occurred at dose levels just below those requred to cause neuromuscu]ar paralyss. The vasopressor response to carotd occ]uson was reduced apprecably by supramaxmal paralysng doses.

6 HUGttES, et (~l. : FAZADINIUM 41 ~t4o.,a- -".a..a-..-.a P~ a,. 'I 9 -~176 c~ t= k-- Z tto U o w~loo / // ~---~ HEART RATE, 9 MEAN BLOOD PRESSURE Z o I-- 6o "1" Z ~ I l' / j ~ ~176 ~..o-e-~.=.~ -r p..o-,/, r / s w W ~-o-~ TETANUS = TWITCH ~ DOSE MClKC f.v. FlcunE 4. Dose-response curves showng percentage nhbton of ndrectly elcted responses of the adductor pollcs muscle to tetanc and sngle twtch stmulaton of the ulnar nerve after ntravenous admnstraton of fazadnum bromde n ncremental doses of 0.1 mg/kg to three anaesthetzed patents. Maxmal changes n heart rate and mean arteral blood pressure were expressed as percentage of ntal and the values averaged. Tetanc contractons of the muscle were more senstve than sngle twtches to the neuromuscular paralysng effects of the drug. Changes n mean arteral blood pressure were small but heart rate ncreased progressvely wth ncreasng dosage. 5, Table I). Neuromuscular paralyss of the twtch response was slower n onset, about fve mnutes, less marked and recovery was slghtly more rapd (mean 40 mn) than the smultaneously recorded tetanc contractons (Fgure 5, Table I). Tachycarda was often apprecable and hypertenson was evdent n at least three

7 42 CANADIAN ANAESTHETISTS' SOCIETY JOURNAL FmURE 5. Tracng from two anaesthetzed patents (K.H. and G.H. ) showng responses of the adductor pollcs muscle to tetanc and sngle twtch stmulaton of the ulnar nerve. Upper porton: Progressve ncrease n neuromuscular blockade of both tetanc and twtch responses after eght ncremental doses of 0.1 mg/kg.v. fazadnum. Lower porton: Rapd complete block of tetanc contractons by sngle dose of 0.4 mg/kg fazadnum - slow recovery ensued wth tetanc fade. Blockade of the sngle twtches was slower n onset, less marked and the subsequent recovery was more rapd than the tetanc responses. of the patents studed (Table I). In contrast wth the pattern of potency, the course of acton of fazadnum n man was consderably longer than n cats and comparable wth that n rhesus monkeys. The tetanc-tenson rato was plotted aganst tetanc transmsson both durng the onset of neuromuscular blockade by fazadnum and tubocurarne and durng the subsequent recovery as shown n Fgure 6. Tetanc-tenson ratos at 30 and 50 per cent recovery of tetanc transmsson were compared wth those obtaned wth tubocurarne. The tetanc-tenson ratos wth fazadnum were consstently lower than those observed wth tubocurarne durng both the onset and the recovery phase. Thus, tetanc fade was greater and more persstent after fazadnum than after tubocurarne. DISCUSSION Although fazadnum was ntroduced as a short actng non-depolarzng neuromuscular blockng agent, n our experence ts course of acton n cats was longer

8 Neuromuscular blockade Heart rate Mean blood pressure beats per ran mm Hg Twtch Tetanus Patent Intal %Increase Intal %Increase %Block Onset Dur. Rec. ~ Onset Dur. Rec. SH GH PP JMW FC BH TABLE I EFFECTS OF INTRAVENOUS DOSES OF 0.4 M(/K( FAZADINIUM BROMIDE ON THE INDIRECTLY ELICITED RESPONSES OF THE ADDUCTOR POLLICIS MUSCLE TO SINGLE TWITCH AND TETANIC STIM ULATION OF THE ULNAR NERVE IN SIX ANAESTHETIZED PATIENTS. MAXIMAL EFFECTS ON HEART RATE AND MEAN ARTERIAL BLOOD PRESSURE ARE SHOWN AS PERCENTAGE INCREASE

9 44 CANADIAN ANAESTHETISTS' SOCIETY JOURNAL to0 - o g 80- / u 20- o I I I O bo TETANIC TRAN~ISSION Ill too g 60- u 40 o,- I I t I I ~0 80 to0 TETANIC TRANSM]SSION 17,1 FmURE 6. Tetauc-tenson ratos plotted aganst tetanc transmsson durng the onset and recovery phases from two patents, one (top) gven fazadnum (0.4 mg/kg v) and the other ( bottom ) tubocurarne ( 0.'2 mg/kg v). In both patents the control recordngs are ndcated at the top rght of each tracng thereafter the fazadnum tracng falls steeply dnrng onset whereas n the ease of tuboeurarne the tetanetenson ratos are well mantanect untl tetanc transmsson has been reduced to below 20 per cent. The same pattern s seen durng the recovery perod from the bottom left of each tracng when the ratos at the same level of tetane transmsson are lower wth fazadnum than wth tubocurarne. than predcted from earler work. 1 It was not apprecably shorter actng than gallamne and, lke gallamne, vagal blockade occurred at doses below those requred for neuromuscular paralyss, s Unlke gallamne, supramaxmal paralysng doses caused sympathetc blockade whch was slght n comparson wth that produced by tubocurarne. When the nvestgaton was extended to rhesus monkeys

10 rrvcaes, et al.: FAZADINIUM 45 the neuromuscular paralysng actvty was found to be about four tmes greater than n cats and ts course of acton was apprecably longer. Effects on autonomc mechansms were not substantally dfferent from those n cats. A feature of the dose-response curves n man was the progressve ncrease n heart rate wth ncreasng dosage. Ths was perhaps to be expected from the vagal blockade observed n cats and monkeys. A sgnfcant ncrease n heart rate after fazadnum n man has also been reported by earler workers ~ and the tachycarda whch we observed was of smlar magntude. However, whereas prevous reports 2,5 have ndcated that arteral blood pressure was unchanged, we have presented evdence that the drug may cause hypertenson n some patents. The fact that n the earler studes the patents were gven halothane 2 or suxamethonum 5 may explan the dscrepancy. In relaton to the neuromuscular-blockng actons of fazadnum the doseresponse curves obtaned from the clncal studes ( Fgure 4) show that the potency of fazadnum n man corresponds more closely to that n cats than to that n rhesus monkeys. As wth other non-depolarsng agents, the tetanc contractons were more senstve than the sngle twtches to the effects of the drug. Furthermore, the shape of the dose-response curves obtaned from nhbton of the sngle-twtches dffered from that derved from the tetanc-contractons ( Fgure 4). Ths mples that there are both quanttatve and qualtatve dfferences nvolved n these responses. After sngle doses of fazadnum (0.4 mg/kg v), the onset of complete neuromuscular blockade of the tetanc contractons occurred wthn two mnutes of njecton but recovery was relatvely slow, beng of the order of 50 mnutes ( Fgure 5). As opposed to the relatve potences, the duraton of acton of fazadnum n man was consderably longer than n cats and comparable wth that n rhesus monkeys, and n man the drug was only slghtly shorter actng than tubocurarne. Depresson of the smultaneously recorded sngle twtches by fazadnum was less marked, slower n onset and recovery was slghtly more rapd than the tetanc responses. For complete paralyss of the sngle-twtch responses at least 0.9 mg/kg v was requred when gven n dvded doses. In our studes the paralysng potency of fazadnum n man was less than that reported prevously. ~ Ths can possbly be explaned by the fact that n the earler studes anaesthesa was mantaned wth halothane and we have observed that ths anaesthetc enhances the neuromuscular blockng acton of fazadnum as t does wth other non-depolarzng neuromuscular blockng agents. 4 In our experence the potency of fazadnum s approxmately half that of tubocurarne as shown by the fact that a dose of 0.4 mg/kg fazadnum s needed to obtan the same degree of block produced by 0.2 mg/kg tubocurarne. Agan compared wth tubocurarne, the tetanc-tenson rato was substantally smaller after fazadnum and ths low rato perssted longer. The concluson s that tetanc-tenson fade s more pronounced after fazadnum than after a correspondng dose of tubocurarne. Overall, the fndngs suggest that fazadnum reaches ts actve stes at the neuromuscular juncton more rapdly than does tubocurarne, but snce t s slghtly shorter-actng t may be released more quckly. Fazadnum also appears to depress the sustaned supply of acetylcholne more readly than does tubocurarne, demonstrated perhaps by the greater fade of tetanc tenson when equpotent doses are

11 46 CANADIAN ANAESTHETISTS' SOCIETY JOURNAL compared. Ths could mean that f a large or a repeated dose of fazadnum s used a profound neuromuscular block mght ensue and clncal experence suggests that ths can happen. SUMMARY Intravenous dose-response relatonshps were used to correlate neuromuscular paralyss wth the effects of fazadnum (AH 8165) on autonomc mechansms n anaesthetzed cats and rhesus monkeys and wth cardovascular effects n man. In cats and monkeys neuromuscular paralyss of the twtch responses of the gastroenemus muscle by fazadnum was accompaned by mparment of the vagally nduced bradyearda, but cardovascular dsturbances were small. Blockade of sympathetc mechansms and hypotenson were only evdent wth supra-maxmal doses. In man tachycarda was a common occurrence and n some patents hypertenson occurred wth doses of the drug needed for complete neuromuscular paralyss. Fazadnum was three to four tmes more potent n rhesus monkeys than n cats and ts course of acton was consderably longer. The potency of the drug n man corresponded more closely to that n cats than n rhesus monkeys but ts course of acton n patents was smlar to that n monkeys. In man, dose-response curves were constructed for the contractons of the adductor polles muscles elcted by tetane and sngle twteh stmul appled to the correspondng ulnar nerves. The onset of paralyss of the tetanc contractons after the ntravenous njecton of fazadnum (0.4 mg/kg) occurred wthn two mnutes, but recovery was slow and about 50 mnutes were needed for ts completon. Depresson of the smultaneously recorded twtch responses was less marked, slower n onset and recovery was slghtly more rapd. These effects were smlar to those obtaned wth tubocurarne (0.2 mg/kg) but the acton of fazadnum was slghtly shorter. Tetanc-tenson ratos were computed after 30 and 50 per cent recovery from neuromuscular blockade n man. These ratos were lower wth fazadnum than wth tubocurarne and ndcated that tetanc fade was greater and more persstent after fazadnum than after tubocurarne. r r RESUME On a admnstr6 par voe IV du Fazadnum (AH 8165) au chat et au snge de type Rh&us afn d'&uder les relatons de doses ~ effet sur les m6cansmes autonomes. Cette &ude a auss &6 fate chez rhomme pour les effets cardovasculares du produt. Chez le chat et le snge, la paralyse du muscle gastrocnemen de la jambe a ~t6 accompagn6e par une dmnuton de la bradycarde vaguale. De m~me on n'a observ6 que des effets sympathques mnmes alors que chez certans patents les doses n6cessares ~t robtenton d'une paralyse neuromusculare ont entraln6 une hypertenson art&dle. On a not6 chez le snge une pussance d'acton 3 ~ 4 los plus grande que chez le chat ans qu'une plus longue dur6e d'acton.

12 I-II.IGI-IES~ et al. : FAZADINIUM 47 Chez l'homme, la pussance a ~t6 comparable tt celle du Fazadnum chez le chat et la dur~e d'acton plus longue. On a pu 6tablr chez l'homme des courbes repr6sentant les relatons dose/effet en observant la contracton de l'addueteur du pouce apr~s applcaton de stmul t&anques ou sol6s aux nerfs correspondants. On a observ~ une contracton soutenue avec une dose de 0.5 mg/kg apr~s 40 sec. Le retour ~ la normale s'est fat apr~s mnutes. De msme on a enregstr6 smultan~ment la r6ponse aux fascculatons. Le temps d'apparton a ~t~ plus long, la r~ponse mons marqu6e et la duroc d'acton plus courte. Ces effets sont smlares ~t ceux obtenus avec 0.2 mg/kg de DTC. Le rapport t6tanos/tenson &ud8 apr~s pour cent de r~cup~raton chez rhomme, s'est r6v~l~ nf~reur avec le Fazadnum compar~ tt la DTC et l'affablssement t~tanque (Tetane fade) plus persstant. ACKNOWLEDGMENTS We are grateful to Mr. D.J. Chapple for help wth the anmal experments, to Mss Susan Galloway, S.R.N., and Mr. R. Worsley for techncal assstance and to Mr. R. Bartholomew and Mr. A. Sandman for the llustratons. We are also ndebted to our nursng and surgcal colleagues for ther tolerance and patence and to the volunteers for ther co-operaton. REFERENCES 1. BRITTAIN, R.T. & TYERS, M.B. The pharmacology of AH 8165: a rapd-actng, short-lastng, compettve neuromuscular blockng drug. Brt. J. Anaesth. 45:837 (1973). 2. SrMPsoN, B.R., STnUNIN, L., SAV~CE, T.M., WALTON, B., BLOCC, B., FAT v.y, E.I., MAXWrLL, M.P., Ross, L.A., & HARRXS, D.M. An azobs-anylmdazopyrdnum dervatve: a rapdly actng non-depolarzng muscle relaxant. Lancet 1 : 516 ( 1972 ). 3. MAnSHALI,, I.G. The ganglon blockng and vago]ytc actons of three short-actng neuromuscular blockng drugs n cats. J. Pharm. Pharmacol. 25:530 (1973). 4. HtrGnES, R. Evaluaton of the neuromuscular blockng propertes and sde effects of two new soqunolnum-bs-quaternary compounds (BW 252C64 and BW 403C65). Brt. J. Anaesth. 44:27 (1972). 5. SAVEGE, T.M.. BLOGG, C.E., Ross, L., LANG, M., & SXMPSON, B.R. The cardovascular effects of AH A new non-depolarzng muscle relaxant. Anaesthesa 28:253 (1973). 6. SUCAI, N., HUGHES, R., & PAYNE, J.P. The effect of suxamethonum alone and ts nteracton wth gallamne on ndrectly elcted tetane and sngle twtch contractons of skeletal muscle n man durng anaesthesa. Br. J. Cln. Pharmac. 2: In press (1975). 7. SucAI, N., HUCHES, R., & PAYNE, J.P. Sequental changes n the fade of tetanc tenson after the admnstraton of tubocurarne n man. In Preparaton ( 1975 ). 8. HUGHES, R. & CHAPPLE, D.J. Effects of non-depolarzng neuromuscular blockng agents on perpheral autonomc mechansms n cats. Brt. J. Anaesth. In Press (1975).