TSH SIH apen Pres, ew Yk Ketanserin in the Acute Management of Severe Hypertension Brendan FE. Murphy, Judith A. Whitworth, and Priscilla Kincaid-Smith Department of Nephrology, The Roval Melbourne Hospital, Methourne, Australia Summary: Ketanserin is 5-H. antagonist with eeadrene receptor blocking activity, This study examines the efficacy and safety of ketanserin in the control of severe primary and Secondary hypertension. including renal hypertension, Patients with uncontrolled hypertension were admitted te hospital and entered the study if the supine diastolic blood pressure phase V (SDBP) way > 110 mm Hy after 2h continuous BP tons toring (Dynamap). Ketanserin way administered sta intr venous (v.15 mg bolus every 6408 until SDBP fell > 15 mm He or maximum dose 130 ing) was reached. then by infusion at 4-20 mesh to maintain SDBP fall = 1S unin over 6 h. Twenty five patients were mionitored and 20 seven men, 13 women, ages HE65 years) Fulfilled the entry criteria Ketanserin Janssen Pharmaceutica, Belgium) is a S- HT, receptor antagonist that also blocks o,-lrenorecep- tors. In patients with mild or moderately severe essential hypertension, ketanserin lowers blood! pressure (BP) both acutely following intravenous (.¥.) administration and with chronic oral therapy (1,2), but whether the drug is effective in secondary. hypertension has not yet been established. While in some animal species its antihyper- tensive action iy clearly due to «-alrenoreceptor block ade (3), there are conflicting data concerning the mechanism of its action in humans, Simikir doses have been reported to cause cither negligible or signiticant qy-adrenoreceptor blockade (4). and the relative im portance of the action of ketanserin on S-HT receptors in the treatment of hypertension in humans is sill to be determined. The present study way undertaken to examine the efficacy and salety of ketanserin in the acute control of severe hypertension, both primary and secondary, and METHODS, Patients with severe uncontrolled hypertension requiring a mission to hospital entered the study #1 supine diastole pres Augress correspondence amd reprint requests Wo Br JA. Whitworth at Deparment of Nephea Melbourne, Aust S168 Seventeen of 20 were on antihypertensive medication, an 1 hhad underlying renal disease, Preinjection mean BP was 188) 123 nim He for the 20 patients falling at $ min to 175/103 rman Hg. Supine diastolic blood! pressure fell 1S mm Hy in 16 of 21 patients. In these patients, BP remained satisfactorily controlled over the 6-h ketanserin infusion. Heart rate: was tunchanged. The four patients who did not respond were re ceiving the «blocker prasesin, bul seven other patients on high-dose pravosin did respond, We conclude that ix, ketam serin is eflective in the aeute management of severe hyperten sion, including hypertension secondary 10 renal divease. Key Words: Ketanscrin—Humanns— Serotonin tor-—Renin--Renal hypertension, a Adrenorcexp: ure phase V (SDBP) was 10 mim Hyg over an observation period of 2 h bedrest with continuous Blood pressure monitor: ing using 4 Dynamap recorder, Prewious drug medication wits withheld for the period of ketanserin administration, Patients ith pregoaney. phasachromees toma, oF a history af myocar lial infarction or eotebrovascule accident in the last 12 mints cluded. Before ketanserin administration, BP and pulse 91, 601, 30, 20. 10, and min, Electr carliogram, creatinine. ure rate were recorded estimations were performed. and sgraptoms were recorded on a questionnaire. Ketanserin was given in noemal saline ay intravenous (.¥:) § mug bolks every 64s until SDP fell = 15 mm He or the maximum dose (30 nym Heb sas reached. I the desired BP fall wats achieved, iv. infusion of ketanserin sway ven at 4.20 mph, to maintain SDBP fall = 15 mm He over a (+h period, No infusion wis aministered to patients who falled to aehieve the required fall in SDP. Folkwing ketanserin injection, BP snd pulse rate were recorded wach hnvnute until the fast bolus injection. anal then at, 1, 20, 3 4 90,120. and E80 min and 4, 6, 10, 14, 16, 20 and 24h Blood samples for binchemistry, plasma renin concentration, wi. i the first O80 eases, phism ketanserin concentrations 1 and 4h. Symptoms and side effects. were assesced hy the questionnaire immediately after imyection, af band again if side effects developed. Statistical analysis was performed with Student's «text for paired! observations The Regal Methsrne Hospital ISOKETANSERIN IN SEVERE HYPERTENSION S169 TABLE 1. Patient details am creatinine Dose of ketanserin for Plasma renin concentration owl Li supine Uiestlie Bo pressure culUienly Seviage Diagnosis eos Drug therapy tails) fall 15 am He 7X5) MAX Essential on Methy lop, 2 Wo me hypertension Iydevchlonothiavide, ing M4 Essontial on Methyl, 780 me, 1s me hypertension Prazosin, 2 me: Fatt, 1.2000 mg F62 Analgesic 00 Cappel. iS mg: 10m Pre nephropathy Trasemide, 8m vy th M65 Refluy nephropathy was Pind, 10 me 10 me Pre Vh 4h F 1S Polycystic kidneys, oun 1S me Pre vh 4h FAS Previous 07 Prazosin, 1 mg Wome Pre posta “dine, 900 Uh Iictoangiopathy Trusemide. 49 me ah MMe Mesangiowuillary a Prazosin. 1 mg “Treatment failure Pre tlomceulonephti xonlol, 1 mg 1h FAT eA nepheopathy aso Verapamil, 240m, 30 me Pre Piro, 1S mgs 1h Chlorothiaride, Tg MAK Conn’s synome ay Metopra 400 nig Treatment fare Subsequent Trusemide, 4 mg diagnosed prsvosin, 1S me hypertension MAT IgA nepheopathy Low Captopril, 100 mg: Treatment fale Pravosin, 20 me. fruscmide. S00 mg M50 Malignant essential 27 Nil WW me hypertension FY Esemial ons Propane. 160 mg Sime Inypertension diazoxide, 30 Fd Renal ams loud 0.70 Prazosin, 20 mg: Treatment faire metoprolol, 200 mg: frusemide, 120 F560 BA nephropathy or Nil 30 me FAS Membranous 0.09 Captopril, 40) mg 10 me nepheop. rethshlopa, 750 mg: prazsin, 20 tg, chlorotic se FSI pA nepheoputhy 07 Propranolol, 120 mg 10 mg Pravin, Mm Chlorthiarides | g E48 Analgesic v.66 Pravosin, 1S mg, wimg ‘nephropathy nsthyilop 1g netopmole 0) mg PSs oad Pind. 20 me 1S me ‘nephropathy pravesin, 4 me rasemide, 40) me F 37 Refluy nephropathy 6.10 Propranslo, 480 mgs Wo me Ihydralavine, 180 nig. prazosin, 20 2 chlorothiaide, F 14 Reflux nephropathy oan sme. chloroihiaride, Ug J Ganda, Phar ol 7 Sa Phsi70 ‘Twenty-six patients were monitored and 20 fultiled the entry criteria, Patient details are shown in Table 1 ‘A fall in SDBP > 15 mm Hg way achieved in 16 of 20 patients, Figure 1 shows mean BPS for all patients before ketanserin administration and Sand 10 min after the initial injection. Monitoring was only continued in the 16 patients who had an initial fall in SDBP = 15 mm Hg. Their BPS and heart rates at 60 min. at the conclu: sion of the 6-h infusion, and at 24 h are also shown in Fig. 1. There was a significant fall in mean systolic and diastolic BP for all subjects at Smin, which was main: tained during the 6-h infusion, but no signiticant change in heart rate One patient reported severe dizziness and nausea fol lowing a bolus of 30 my i.¥. and vomited. Blood pressure fell trom 170/112 to 115/76 mm Hg. Other symptoms, reported were mild dizziness (three) and dryness in the mouth (one). The four treatment failures received max- imum bolus dose without symptoms Plasma renin concentrations (PRC) were available for eight patients and are shown in Table 1. Mean PRC preketanserin was 26 (+ [SEM) qlUiml, at Lh it was 24.0 11) lim, and at 4 hours it was 27.¢© 13) pl tl, Playma ketanserin concentrations were determined for two patients who received 10 mg bolus and 4-8 m: bh infusion of ketanserin and were 55 and 57 ng/ml at 1 hand 77 and 84 ng/ml at 4 h. There was no significant change in blood glucose, plasma creatinine, urea, or electrolytes following ketanserin administration, nor wats there any change in 12-lead electrocardiogram, 200] 100) Blood ressure mmig ad 129] a a i a 100) BLK MURPHY ET AL. DISCUSSION In these patients, ketanserin appeared to be effective in the acute mana re hypertension. All four patients with essential hypertension responded, as il 12 of the 15 with renal hypertension, which indicates that the drug is effective in both these conditions. The patient with malignant hypertension, shown subsequently to be due to Conn’s syndrome, failed, however, to re spond. These results compare favourably with other agents used intravenously in severe hypertension. Ina very similar group of patients, fixed doves of clonidine. dia- voxide. and labetalol achieved satisfactory blood pres sure control in 6 of 10, 8 of 10, and 2 of 10 patients (5). Parenteral therapy is. however, rarely indicated even in severe hypertension, and. in clinical practice. it should be reserved for hypertensive emergencies, One patient developed symptoms in relation to a some whut precipitate BP fll, but otherwise ketanserin was generally well olerated, and there were no abnormalities Uctected on electrocardiographic or biochemical moni- toring, Heart rate did not change, but most of these patients were receiving other medications, ineluding B- aurenoreceptor blocking drugs, Although data were available on only eight patients, there way no appreciable change in phism renin concentration during the period ‘oF ketanserin infusion, This study: was not designed 40 investigate the mech= anism of action of ketanserin in humans, However. the hypotensive response in these patients in relation to their previous therapy with the j-receptor blocking agent prazosin provides some indirect data on the importance of the ay-blocking action of ketanserin, IF y-blockade ment of Sei FIG. 1. Mean blood pressures and heart rates for all patients (Solid bars) (n~ 20) and successiuly treated pa- ents (hatched bars) (n= 16). Sight: cant fallin systolic and diastolic blood Dressutes at 5,10, and 60 min, and 6 lle. ae me EOP ta 4 a a ae aKETAM ‘was the major hypotensive mechanism of ketanserin in cour study, patients treated with high-dose prazosin would be expected to have already maximal a,-receptor bloc! ade, and hence not respond to ketanserin, The four pi tients in whom ketanserin therapy was unsuccessful were all receiving prazoxin, three in high dose. Seven of the 16 patients in whom the ketanserin injection was suc cessful. however, were also receiving prazosin, Two of these seven patients were receiving 20 mgiday of pra zoxin and one 30 mg/day. The rapid hypotensive response to Ketanserin in these patients suggests that a,-receptor blockade is not responsible for the acute hypotensive effect of ketanserin in humans, Acknowledgment: The Dynamap revorder used in these studies was generously donated by Jannsen Pharmaceutica Pty ISERIN IN SEVERE HYPERTENSION si7t Lid. Syuney. Dr. Ross Bury measured the plasma ketanserin levels und Sister Dianne Saifes helped with the patient studies REFERENCES 1. Wenting GJ, Man nt Veld AJ, Woithe AJ, Boomsma F, Schale amp ADH, Hemodynumiceifets of ketarcrin, lective 5 hydroxyteyptamine (serotonin receptor antagonist, in event hypertension, Clin Sev IADRAA58-48, 2. Andren L, Swenson A, Dahlot B. Eggsrigen R. Hanon L Ketannern in fypertension, Avra Med Sean IOKS 214 125-90, 3. Fuvand JR. Mecham of the hypotensive elfet of Ketannert Gardisuse Pharmacol 1982482938 4 Reimann TW, Frosh JC. Mecham of antichypertenive action tof tannin in an. Br Med J 19KX2N7 381-2 5. Young CK. Thomas GW, Whitworth JA. Kincaid-Smith PS CGonspusison of label, uinidine and daroxide intravesns administered in severe bypertemsiom. Meu J Aww 1979.2-499