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Clinical observations on a new antihypertensive drug,21(2,6-dichlorphenylamine)-24midazolinehydrochloride*Guide Smet, M.D.*S. 14. Hoobler, M.D.Shafeek Sanbar, hI.D.*x*Stcvo Jdizts, M.D.

Ann Arbor, Mich.

E stablishing an effective therapeuticregimen in cases of severe hyper-tension continues to be a highly individ-ualistic process of balancing side effectsagainst blood pressure response. Sym-Ijathetic blocking agents, needed in mostcases of severe hypertension, often disablethe patient by causing an orthostatic hypo-tension as the price he must pay for alxtrt ix1 reduction of recumbent blood pres-sure.During the past several years, a new an-[ihypertensive agent, 2-(2,6-dichlorphenq-l-;tmine)-2-imidazoline hydrochloride (Cata-Ix-es), has been under clinical study. Themode of action of this drug has not yetbeen defined, but it has been shown to beeffeclive and relatively safe, with drowsi-ness as its major side effect. Most impor-tant, the ne\v agent is reported to lowerrecumbent and standing blood pressuresequallv well throughout the day, withoutthe Gide ditlrnal variations that induce

excessive orthostatic hypotension whellthe patient rises in the morning, but itfails to prevent nocturnal recumbent h ,-pertension. Although metabolic side effectsfrom Catapres have not been noted i llclinical reports, a slight diabetogenic ten-dencv has been observed in some speciesof a&als.3

The study reported here was tlesignctltoward three specific objectives: (1) totest the agent aIone in subjects with ln ilt lhypertension in order to examine its rc-ported abil ity to lower recumbent bloodpressure without creating postural hyl)o-tension; (2) to test long-term efficnc~- andacceptabi lity of the agent for severe11hypertensive patients intolerant of COIPventional sympathetic blocking agents;(3) to evaluate the frequency and accept-abi lity of various side effects and to es:m1-ine the drugs effects on liver and henlato-poietic function and 011 carbohydratemetabolism.

1 ix (1liniral Hesearri~ Unit, Ilniversil\ i, T Ivlicl~iga n lI*spiL3l, lias assisted grczrtiy in tliis investigation under

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1 96 962 83 803 92 804 82 785 80 826 88 75--

.Ilecz?r 86 8 81 8

.sign p < 0.05 ss KS

909882ih7880--8.4.0NS

74 90 8095 80 -71 78 7084 82 8185 7580 80 9082 0 80.8 80. .iNis NS NS

0.3750.3000.1500.3750.3000 3000.300

--0 03 -0 19+o. 19-0.02 .-0 11+0.09 SO.31+0.26-0.16 0. 0310.06 0, 00

*Fastin g blood sugar drawn 2 hours after oral administration of drug. T est dose of drug was 0.150 m g.I Ii \~~ lue expresses the slope of disappearance ol the glucose solution (25 m g. per kilogra m) injected at tim e 0. Samples taken at

10. LO . 30, 40, 50. and 60 minu tes. A negative change in 6 value denotes a slower rate of rem twa l of administered glucose. Changesa)bsrrved are within the limits of norma l variation.

7ilblr II I. Repltrcement of convcntiontrl drqs with Lctftrpres in. severely hypertensive pr1tierzt.s

castYO.

Status of blood pressure

Prefreatmetzf:Hospital

admissionBP

recumbent

On USZ~ drug therapy*

G uanethidine7 250/ 1408 250/l 609 260/170

I 0 250/l 40II 230/l 65

Alpha-methyldopo12 240/13813 218/11014 208/150I.5 240/130

Outpatient UP Daily Outpatient BP Duration Dailydose -- ~_..__--__- cn Calapres dose

(mg.) (mu.) (mq.)Recumbent Standixf Recumbent Standing

190/135 lOO/ 70 100 178/030 192/140 7 0.900 A.M. syncope (Lmstipatiun232/123 116/ 68 75 192/128 192/132 7 0.900 A.hf. syncope Constipation190/100 160/100 50 146/ 94 l?O/ 90 10 0.900 Diarrhea 0230/130 160/100 100 232/l 23 198/128 5t 1.200 A.M. syncope 1)217/l 13 208/l 30 100 152/ X6 15oj 120 10 0.400 Kane 0

2uo/ 130 170/l u4 1.500 134/ 88 l42j 94 11 0.500 A.M. qncope Drowiness24U/llO 180/124 1.500 184/102 167/108 1u 0.500 Dizziness Drowsiness186/l/109 174/120 1.500 180/100 192/108 11 1.200 None Kane198/113 160/l 14 2 ( 000 164/104 146/104 7 0.525 Fatigue Kane

Usual drzzg Catapres

Depression Iione

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476 Smet et nl. .4m . Heurt 3..4pril, 1969

1.V TOLBUTAMIDE TES TSN = 6 patients

x, \. BEFORE CATAPRES

6O-

50-I , I I I I I0 IO 20 30 40 50 60

MINUTESFig. 1. Respon se to tolbutamide before md afterCatapres. Vertica l bars indicate standard error ofthe mean for each observation. See text for deta ils.

the hospital was adjusted to bring abouta maximal blood pressure reduction withinthe patients tolerance to side ef fec ts. Thepatients were then followed in the out-patient clinic at monthly intervals. Theycontinued to take their diuretic drugswithout change, but their dosage of Cata-pres was readjusted in accordance withthe blood pressure as recorded at home andin the clinic.

ResultsThe first oral test dose of 0.150 mg. of

Catapres regularly lowered the bloodpressure of patients in Group 1, the aver-age decline being -4O/-228 mm. Hg re-cumbent and -35/-16 mm. Hg standing(Table I). The maximum decline occurredbetween the second and third hour, withoffset of action at four to six hours. At theend of one month, the drug in the originaldose appeared to lose some of its anti-hypertensive effectiveness.

These patients were studied primarilylo evaluate the short-term effect of thedrug 011glucose tolerance. The metabolic

tests were applied at the time intervalwhen a slight hyperglycemic influencehad been noted in the dog studies. Tahlc11 shows that the drug had no effect onthe fast-ing blood sugar or on the intra-venous glucose tolerance test. The irl-f-luence of the drug on insulin release wasstudied using the tolbutamide test. There\\ras HO il~dicat ion of an\. consistent clin-betogenic trend which inight be attribute(lto the drug (Fig. 1).

I>ong-lt:rm c;ffP i-ts. i\fter 5 to 11 llloiltllsof therap). with Catapres aittl a diuretic.,most Ijatients achieved :L blood pressurelevel coluparable to or better than thatrecorded w:ith prior conventional ar~t i-hypertensive treatment. Dosage of thellern drug was gradually increased as sitlceffe cts wore of f. A dose of 0.5 to 1.2 iiig.dail>r served to replace such other agents;LS al~~ha-inethyldoI~a (1.5 to 2.0 Grn.daily) CJr guaiie~hk~iile (50 to 100 111~.daily), with respect to maintaining similarblood pressure levels (Table III) . Dis-abling postural hypotension, occurring withthe previous regimens iit Patients 7 and S,were nluch less apparent 011 Cataprcs at.approxilnatel>~ the same levels of recunl-bent blood pressure. Blood pressure con-trol was sonlewhat erratic; home bloodI,ressurcs were generally lower than tht:clinic readiligs, taken two hours after in-gestioll of the morning dose of drug.Jatients 9, 11, l.?, and 16 derived clearbenefit from the conversion to Catapres.The other patients had generally lowerhome blood pressures, but they were plotnecessarilv better controlled on the newregimen. lhese cases were chosen becausetheir blood pressure was refractory toprior sympathetic blocking agents, orthey were disabled by orthostatic hype-tension. 1 t is therefore not surprising thatthe new drug did not benefit all the IX-tients.

Side efl~ts. The 11~0s~ commo11 reactionwas drowsiness which was usually transien Iand did not cancel the patients abilitv IOmobilize his attention to sudden crjses.1)rowsiiiess became less eviclent with (OII-tinued use of the drug, but initially it \\-a~the chief limiting factor to the size of dosewhich the patient would ;tccept. At Ilight,ho\\-ever, this side effect I)ecnnle ;t(lv;tI \-

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Clin ical observations OH (1 new cuztihypertensive drug 477

tageous, sirlce a larger dose at bedtimeresulted in good sedative ef fec ts and ap-peared to exert some influence on themorning blood pressure reading. Dry mouthwas a minor complaint in most cases; const ipntion was easily controlled by laxn-t ives.

n larked bradycardia was noted 0111~.occ;~sionally in our series and seemed quite\r;u-inble. One patient, Ko. 13, taking 0.6111x. ;L da>., telephoned to report that hislmlse had falle11 to 42 beats per minutebut was regular. An electrocardiogramtaken one-half hour later showed a sinusrhythm with a rate of 66.

III the majorit?. of patients, after 6111o11ths or Illore of treatment, the sideeffec ts were greatly diminished and rarelydisabling, although the eff ect s on bloodpressure reu1ainet1, as evidenced by apro1npt rise ill blood pressure during abrief substitution of a placebo for theactive drug. None of the patients OII long-term treatnrent, 111ost of whom had beenro11\:erted fro111 conventional n1edicationbecause of side ef fec ts, elected to discon-ti11ue (atapres when given this option.No evidenc*e of progression of the cardiacor renal complications of their disease wasnoted. The fasting blood sug-nr at the endof the observation period was unchangedfrolll the pretreatn1ent values.

Real, hepatic, and hematopoietic func-tion R~S unchanged for periods of treat-111ent up to 11 months, as judged by serialdetcrminatio11 of blood ureanitrogen (BUN),seru111 glutamic pyruvic transaminase(SGIT), alkaline phosphatase, hemato-c.ri(, he1noglobin, and leukocyte and dif-ferential cc,11 counts.

DiscussionTo achieve general usage among current

;tr1tihppertensive agents, a drug must beshown to be safe and continuously effec-tive iu reducing blood pressure. Catapresfulfills the criteria of long-term effec tive-ness .znd no long-term toxicity developedin 10 patients observed for a median periodof 9 months. While the short-term low-dosage study detailed in Table 1 suggeststhat alone the drug loses some of its initialeffectiveness, our later experience giving(atapres in c-ombination with diuretics

indicates that as side ef fec ts become lessprominent dosage may have to be in-creased, but that eventually one reachesa stable dosage level which maintnins anti-hypertensive effectiveness. ~1 potential nd-vantage of this agent over sympatheticblockers is that it does not interfere withpostural reflexes. The chief disadvantageis that it is not as potent or as continuouslyeffective as guanethidine, for esample.

For these reasons we believe Catapreswill be useful in the management of se-lected cases of moderately severe hyper-tension, particularly where sl-mpatheticblockers are needed, but cause severepostural hypote11sion.

SummaryThe drug 2-(2,6-dichlorphenylamine)-2-

imidazoline hydrochloride, available asCatnpres, was given to 16 patients withestablished hypertension. Six patients werestudied for one mouth to detect abnor-malities in carbohydrate metabolism. Xorlewere found. Ten severely hypertensive pa-tients were maintained for front 5 to 11months on Catapres and diuretics.III a single dose, Catapres invariablylowered the blood pressure significantly- ,but without producing orthostatic hype-tension. The maximum effect occurred be-tween 2 aml 3 hours after ingestion of thedrug. The duration of drug action was 4to 6 hours.

In long-term treatment of ten patients,Catapres, combined with a diuretic, provedto be as effective as a diuretic plus guane-thidine or Aldomet, which the patients hadpreviously been taking. A dose of 0.400 to1.200 mg. of Catapres was equivalent to I .5to 2.0 C;rn. of Aldomet or 50 to 100 mg.of guanethidine.

The chief side ef fect of the drug wasdrowsiness, but this was not incapacitating,it did not require cessation of treatment,and it becatne less prominent with thepassage of time. In patients who had es-perienced severe orthostatic hypotensiouon other drug regimens, the condition wasconsiderably relieved by Catapres. NOsigns of toxicity were noted, as judged bycarbohydrate tolerance, BUN, SGPT, al-kaline phosphatase, and hematologic de-terminations.

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