Acute and Chronic Haemodynamic Effects of Doxazosin in Hypertension at Rest and During Exercise

Br. J. c/lin. Pharmac. (1986), 21, 45S-54S

Acute and chronic haemodynamic effects of doxazosin in hypertension at rest and during exercise

P. LUND-JOHANSEN, P. OMVIK & H. HAUGLAND Section of Cardiology, Medical Department, University of Bergen, School of Medicine, Bergen, Norway

1 The acute and chronic haemodynamic effects of doxazosin were studied in 14 patients (10 males, four females) with essential hypertension, at rest supine and sitting and during 100 W bicycling exercise. 2 Blood pressure (BP) was recorded intra-arterially in the brachial artery, cardiac output (CO) was measured by Cardiogreen and heart rate (HR) by ECG. 3 One hour after injection of doxazosin 0.5-1.0 mg i.v., mean arterial pressure (MAP) was reduced by 8% at rest supine, 12% at rest sitting and 10% at 100 W (all changes statistically significant), associated with a reduction in total peripheral resistance index (TPRI) of 5% at rest supine, 9% at rest sitting (P < 0.01) and 14% at 100 W (P < 0.001). HR was slightly increased (5%, NS) and cardiac index (CI) was unchanged during rest and slightly increased during exercise (4%, P < 0.05). 4 Patients were then given doxazosin capsules (2-16 mg once daily), aiming at a casual BP of < 140/90 mmHg without side-effects. Central haemodynamics were restudied after 1 year. 5 After 1 year of doxazosin treatment, MAP was reduced by 13% at rest supine, 16% at rest sitting and 17% at 100 W (all P-values < 0.001). TPRI was reduced by 19% at rest supine, 20% at rest sitting and 18% at 100 W (all changes statistically significant). CI was increased by 8% at rest supine (P < 0.05) but was unchanged sitting and at 100 W. 6 It is concluded that doxazosin lowers BP through a reduction in TPRI acutely as well as chronically, without reductions in CO. BP control was maintained over 1 year without side- effects. Thus, doxazosin normalizes central haemodynamics in patients with mild to moderate essential hypertension, both at rest and during exercise. Keywords cardiac output doxazosin exercise haemodynamics total peripheral resistance

Introduction hypertension, and then to study the changes induced by 8-12 months of chronic treatment with Doxazosin is a new postsynaptic a,-adrenoceptor doxazosin orally. blocker; it is related to prazosin but has a longer half-life (Timmermans et al., 1980; Singleton et al., 1982; Vincent et al., 1983). Its Methods antihypertensive effect has been demonstrated in Patients animals and in man (Beckett & Finch, 1982; Elliott et al., 1982; de Leeuw et al., 1982). So far, no The study protocol was approved by the Norwegian acute and chronic studies on the haemodynamic State Drug Control and informed consent was effects at rest and during exercise in man have been obtained from all patients. The 14 patients (10 reported. males and four females), aged 22-59 (mean 42.4) The purpose of the present study was to investi- years, all had sitting diastolic blood pressure, gate the first-dose effect of doxazosin intravenously between 100 and 120 mmHg on three out-patient at rest and during exercise in patients with essential control visits. Serum creatinine was within normal 45S 46S P. Lund-Johansen et al. limits and in all patients secondary hypertension versation was not allowed in the 10 min before the was excluded by usual routine procedures. All were next haemodynamic recordings. in WHO stage I or II, without other diseases (including obesity), and were actively working. Assessment 2 After 1 h of supine rest, central Twelve patients were previously untreated and two haemodynamics were recorded (assessment 2) and had been on a- or P-adrenoceptor antagonists for immediately thereafter during the next 3 min less than 1 year. In both of these patients the doxazosin 0.5-1.0 mg was injected intravenously washout period without drugs was 2 months. through the catheter in the superior vena cava. The The mean body weight was 72.7 ± 14.9 kg and patients were not aware of the injection. Blood the mean body surface area (BSA) was 1.86 ± 0.22 pressure was recorded continuously for 1 h while mi. the patients rested supine.

Haemodynamic methods Assessment 3 After 1 h the haemodynamic study was repeated at rest supine and sitting and then Blood pressure was recorded continuously through during 100 W exercise (assessment 3) (see section a catheter in the brachial artery. Cardiac output was on hypotensive episodes, where the protocol was measured by Cardiogreen injected through a modified). catheter in the superior vena cava. Double determinations were performed in all situations. Chronic study The heart rate was determined from ECG recordings. Cardiac index (CI), stroke index (SI) and total After the acute study had been completed the peripheral resistance index (TPRI) were calculated patients started oral doxazosin treatment. by standard formulae (Lund-Johansen, 1967). Doxazosin was given in capsules once daily in the Studies were performed at rest supine and sitting morning, at a starting dose of 2 mg. and during ergometer bicycling in steady state. The dose of doxazosin was increased gradually Plasma volume (PV) was determined by using every second week, aiming at a casual blood radio-iodinated (125I) human serum albumin (4 ,Ci; pressure of < 140/90 mmHg without side-effects. Radiochemical Centre, Amersham, England) with a The maximal dose was set (by Pfizer Central 10 min equilibration period. Total blood volume Research) at 16 mg. (BV) was calculated from PV and the simul- After 8-12 months the daily doses were 2 mg in taneously determined corrected packed cell three patients, 4 mg in three, 8 mg in four and 12 volume. The extracellular fluid volume (ECF) Was and 16 mg in two. The mean dose ofdoxazosin was measured as the sulphate space: 100 mCi radio- 6.5 mg. sulphate (35SO4) was injected intravenously and During the chronic study there were two drop- plasma samples were collected 30, 45, 60 and 75 outs. One patient had a myocardial infarction after min after injection. The samples were counted in 2 months (male patient, blood pressure 130/90 duplicate in a Nuclear Enterprise beta-gamma mmHg) when taking doxazosin 4 mg. After the counter (NE 8312) and zero time concentration of infarction the patient received timolol as the sole radiosulphate was calculated from the disappear- drug. One female moved to another area (her blood ance curve (Omvik et al., 1979; Omvik & Lund- pressure had fallen from 190/120 to 155/105 mmHg Johansen, 1983). on 8 mg). Statistical methods Acute study The results are presented as mean values + s.d. Assessment I Assessments were performed on Differences between means were statistically tested out-patients in the morning 2 h after a light meal. by Student's t-test for paired samples. Data from all After introduction of the catheters the patients 14 patients in the acute study were analysed and data rested supine for 30 min and central haemo- from the 12 patients fulfilling the whole protocol in dynamics were then measured at rest supine, then the chronic study were analysed. sitting, and thereafter during 6-8 min of exercise on an ergometer bicycle at 100 W (pre-test, assessment 1). After the exercise test the patients rested Results supine for 1 h. During this period the patients were Acute effects ofdoxazosin not allowed to sleep but they were allowed to read. The atmosphere in the laboratory was quiet. Con- The results are shown in Table 1 and Figure 1. Haemodynamic effects ofdoxazosin 47S Table 1 Central haemodynamics at rest supine, sitting and during 100 W at pre-test (1), immediately before doxazosin injection (2) and 1 h after doxazosin i.v.(3) (n = 14).

Supine Sitting 10o W 1 2 3 3-1(%) 1 3 3-1(%) 1 3 3-1(%) SAP (mmHg) mean 164.8 156.5 147.9 -10.3 178.7 150.9 -15.4 214.4 199.5 -6.9 s.d. 17.2 12.4 15.6 21.0 15.1 17.7 20.3 P <0.001 <0.001 <0.001 DAP (mmHg) mean 97.9 96.0 89.5 -8.6 108.9 95.8 -12.0 116.2 105.4 -9.3 s.d. 8.5 8.4 9.8 8.7 10.9 12.5 11.0 P <0.01 <0.001 <0.001 MAP (mmHg) mean 122.9 118.0 112.8 -8.2 133.7 117.5 -12.1 156.4 141.6 -9.5 s.d. 10.7 9.9 12.3 11.2 13.7 15.1 15.1 P <0.01 <0.001 <0.001 TPRI (dyn s cm-5m2) mean 3139 3254 2974 -5.3 3824 3493 -8.6 1734 1500 -13.5 s.d. 546 588 467 702 665 283 233 P NS <0.01 <0.001 HR (beats minm-) mean 69.1 72.2 73.6 +6.5 75.8 79.4 +4.7 139.1 143.4 +3.1 s.d. 7.3 10.5 11.8 9.9 12.5 21.8 20.5 P NS NS NS CI (1 min-lm-2) mean 3.18 3.00 3.09 -2.8 2.92 2.84 -2.7 7.35 7.65 +4.1 s.d. 0.59 0.57 0.49 0.64 0.55 1.09 1.18 P NS NS <0.05 SI (ml stroke 'iM-2) mean 46.4 41.7 42.4 -8.6 38.2 35.8 -6.3 53.6 54.1 +0.9 s.d. 7.6 6.5 6.8 6.8 7.0 9.0 9.3 P <0.05 <0.05 NS

P values refer to differences between assessments 1 and 3

Pre-drug results In assessment 1, the intra- rested supine for 1 h and were then restudied in the arterially recorded resting sitting blood pressure supine position immediately before the injection of was 178.4 ± 21.0/108.9 ± 8.7 mmHg, CI was 2.92 doxazosin. Compared with assessment 1 in the + 0.64 1 min-' m-2, HR 75.8 ± 9.9 beats min-, SI supine position, some minor changes were seen in 38.2 ± 6.8 ml stroke-' m-2 and TPRI 3824 ± 702 assessment 2. In most males mean arterial pressure dyn s cm-5m2. (MAP) showed only small changes and the mean These results compare well with results in similar value was 115.1 mmHg (vs 118.6 at assessment 1), groups of patients studied in our laboratory with the a difference of -3 % (NS). In the females the same methods (Lund-Johansen, 1983; Lund- variations were greater. For the whole group MAP Johansen & Omvik, 1983). There is also good was 118.0 versus 122.9 mmHg (a difference of agreement between the intra-arterially recorded -4.9 mmHg). In the males HR was almost back to sitting blood pressure and the casual sitting blood pre-exercise supine values: 68.9 vs 67.9 beats pressure at the last control before the haemo- min', a slight increase of +1 %. In the females the dynamic study (174/107 mmHg vs 178/109 mmHg heart rate was slightly increased compared with pre- intra-arterially). exercise supine values. For the whole group the mean heart rate was 72.2 beats min'-I (vs 69. 1 pre- exercise). The slight fall in MAP was associated Stability of the haemodynamics before drug with an increase in TPRI from 3139 to 3254 dyn s injection After the first recordings the patients cm-5 m2 (+3.7%, NS). 48S P. Lund-Johansen et al.

20 - Rest supine beats min-', and CI showed no changes (2.89 vs

10 2.81 1 min-' m-2). After- these hypotensive I L I reactions, the dose was reduced to 0.5 mg in 0L patients weighing less than 70 kg and 0.7 mg in -10 * patients over 70 kg. No further hypotensive -20- * reactions were seen. The reactions to doxazosin 1 mg i. v. are clearly not the same as those of 20- Rest sitting doxazosin 1 mg orally, due to differences in 10 bioavailability. 0~~~~~~~~ : - 1 0 Haemodynamic changes at rest supine -10 - L* Systolic arterial pressure (SAP) fell in all but one patient. * -20 ** This patient had a low pretreatment SAP ofonly 137 mmHg. One hour after the injection mean SAP was 20 - 100 W exercise 147.9 mmHg vs 164.8 at assessment 1, a difference 10. of -10% (P < 0.001). Diastolic arterial pressure (DAP) fell in all but two patients, both of whom had At F6 Ej 11" n low initial values. After 1 h DAP was 89.5 mmHg vs 97.8 mmHg at assessment 1, a difference of

-20 ** R**** -8.6% (P < 0.01). MAP fell in all but two patients, MAP TPRI Ci HR Si who both had low initial values. After 1 h MAP was 112.8 mmHg vs 122.9 at assessment 1, a difference Figure 1 Acute (D) and chronic (M) changes in mean of -8.2% (P < 0.01). arterial pressure (MAP), total peripheral resistance In spite of these acute reductions in BP, HR index (TPRI), cardiac index (CI), heart rate (HR) and showed only small insignificant changes. After 1 h stroke index (SI) after doxazosin at rest supine, at rest sitting and at 100 W. *P < 0.05, **P < 0.01, ***P < HR was 73.6 beats min-I (vs 69.1 at assessment 1 0.001. and 72.2 immediately before the injection, assessment 2). Thus no reflex tachycardia was seen 1 h after the injection in spite of a 10 mmHg reduction Hypotensive reactions after doxazosin injection In in BP. No clear reflex tachycardia was seen even in the first three patients studied, doxazosin 1 mg was the patients who had the rather severe hypotensive injected over 3 min and hypotensive reactions were reactions with SAP reductions of 56-86 mmHg. seen after 10-15 min. In the first patient, BP fell TPRI fell in all but two patients, who both had from 149/97 to 93/53 mmHg. The patient was pale low initial values. TPRI fell to 2974 dyn s cm-5m2 and sweating but, after the legs had been raised for from 3139 at assessment 1 (a difference of -5.3%, 5-10 min, BP increased to 116/62 mmHg. A NS). However, when compared with TPRI haemodynamic study 30 min after injection showed recorded immediately before the injection, the fall a fall in TPRI from 3288 to 1934 dyn s cm-5 m2, a was greater (-8.6%). Compared with pre-injection decrease of - 40%. CI had increased from 2.77 to levels CI showed only minor changes, an increase 3.43 1 min-' m-2 and SI had increased from 47.8 to from 3.00 to 3.09 1 min-' m-2 3 -1 (+ %, NS). 57.2 ml stroke m-2. HR was practically Compared with assessment I there was a fall of 3 % unchanged, 58 beats min'-I at pre-injection and 60 SI showed minor One hour -I (NS). only changes. beats min during the hypotensive phase. after the injection SI was 40.4 ml stroke-' m 2 vs In the second patient, pre-injection BP was 41.7 immediately before the injection. 163/98 mmHg and after 15 min BP was only 93/57 mmHg. The patient was pale and sweating. After the legs had been elevated the pressure rose to Haemodynamic changes at rest sitting The 143/89 mmHg. HR showed a small increase from reductions in BP were greater at rest sitting than at

65 to 72 beats min ' . rest supine. Thus, 1 h after the doxazosin injection The third patient demonstrated a fall in BP from SAP was 27.5 mmHg lower than at the pre-test 156/98 mmHg to 70/40. After the legs had been assessment 1 (-15.4%, P < 0.001), DAP was 13. 1 raised the pressure rose gradually to 113/63 mmHg. mmHg lower (-12.0%, P < 0.001) and MAP was After 30 min the blood pressure was 120/74. TPRI 16.2 mmHg lower (-12.1 %, P < 0.001). MAP was had fallen from 3241 to 2589 dyn s cm-5 m2 lower in all patients, the differences ranging from (-20%). HR was practically unchanged, 74 vs 72 -1 mmHg to -42 mmHg. Haemodynamic effects ofdoxazosin 49S Compared with assessment 1, HR was slightly (highly significant) between assessment I and 1 h higher, 79.4 beats min-' vs 75.8 (+4.7%, NS). after doxazosin injection were -6.9%, -9.3% and Only in two patients (females) was the increase in -9.5 % for SAP, DAP and MAP, respectively. HR greater than 1-2 beats minm- '. Thus no marked One hour after the injection HR was slightly reflex tachycardia was seen even in the upright higher than at assessment 1, 143.4 beats min- vs position. 139. 1, a difference of + 3. 1 % (NS). TPRI fell in all but three patients and the mean fall TPRI fell in all patients. The fall was more was greater than at rest supine (-8.6%, P < 0.01). pronounced than at rest. The difference between CI showed practically no changes (as at rest assessment 1 and I h after doxazosin infusion was supine). One hour after doxazosin injection, CI was -13.5% (P < 0.001). CI was higher than at 2.84 1 min-m m-2 vs 2.92 at assessment 1 (a assessment I in 10 patients. In the others only small difference of -2.7%, NS). SI tended to be lower changes were seen. The mean value increased from than at assessment 1, 35.8 versus 38.2 ml stroke- 7.35 to 7.65 1 min-Im-2, a difference of 4.1% (P < m-2, a difference of -6.3% (P < 0.05). 0.05). The stroke index showed practically no changes, a difference of 0.9% (NS). Thus the increase in CI was mainly due to the increase in HR. Haemodynamic changes during 100 W exercise The reductions in SAP, DAP and MAP were less than during rest sitting. The differences

Table 2 Central haemodynamics at rest supine, sitting and during 100 W at pre-test (1) and at 1 year (4) following doxazosin orally (n = 12)

Supine Sitting 100 W I 4 4-1(%) 1 4 4-1(%) 1 4 4-I(%) SAP (mmHg) mean 163.4 143.2 -12.4 180.2 148.4 -17.6 215.6 187.0 - 13.3 s.d. 18.1 20.5 22.3 19.6 18.8 18.4 p <0.001 <0.001 <0.001 DAP (mmHg) mean 96.3 83.7 -13.1 108.7 91.0 - 16.3 115.4 95.9 -16.9 s.d. 7.9 10.2 9.2 10.7 12.9 10.8 p <0.001 <0.001 <0.001 MAP (mmHg) mean 121.4 105.7 - 12.9 133.8 111.8 - 16.4 156.4 130.1 -16.8 s.d. 11.0 15.1 11.9 13.6 16.2 15.0 p <0.001 <0.O <0.001 TPRI (dyn s cm-5m2) mean 3200 2604 -18.6 3853 3096 -19.7 1735 1418 -18.3 s.d. 527 612 628 578 270 232 p <0.01 <0. 11 <0.00 1 HR (beats min- ) mean 69.7 69.5 -0.3 76.4 75.9 -0.7 140.3 139.1 -0.9 s.d. 7.7 8.8 10.0 11.6 21.9 17.1 p NS NS NS CI (1 min-Im-2) mean 3.09 3.34 +8.1 2.84 2.95 +3.9 7.30 7.45 +2.1 s.d. 0.46 0.56 0.51 0.51 0.89 1.09 p <0.05 NS NS SI (ml stroke-, m -2) mean 44.5 48.3 +8.5 37.3 39.1 +4.8 53.1 54.0 +1.7 s.d. 5.4 7.0 5.7 5.2 9.4 8.4 p NS NS NS

P values refer to differences between assessments 1 and 4 50S P. Lund-Johansen et al. Chronic effects ofdoxazosin after 2 months, 145/88 mmHg after 6 months and 141/87 mmHg after 1 year. The results are shown in Tables 2, 3 and 4. One patient felt 'restless' and had high HR values (84-88 beats min ') at the follow-up controls. He 220 was restudied after 8 months. Thereafter, atenolol 25 mg was added and the patient's complaints 200 a disappeared. His HR dropped to 60 beats min' 0 and he became normotensive. 180 0 0 In the other patients no side-effects were seen. m ob 8 *o (One patient had a non-fatal myocardial infarction E 160U4 9-1^ after 4 months as already stated, but this was E 0 9:0 4~~~ ~~ 0, 0 regarded as a coincidence. The patient was a C- 140 00 0- smoker. His recovery was uneventful, with a BP of cn 120/80 mmHg on timolol monotherapy.) 1201_

10C_ Haemodynamics at rest supine SAP, DAP and MAP were reduced in all but one patient. Mean I . 70 80 90 100 110 120 130 SAP fell from 163.4 to 143.2 mmHg (-12.4%, P < DAP (mmi Ig) 0.001), mean DAP fell from 96.3 to 83.7 mmHg (-13.1%, P < 0.001) and mean MAP fell from Figure 2 Intra-arterially measured bllood pressures at 121.4 to 105.7 mmHg (-12.9%, P < 0.001). The rest sitting before ( H,) and during ((0, D) chronic changes in MAP ranged from +6 to -26 mmHg. therapy (individual results). 0, 0 maale patients, U, O HR showed practically no changes, the mean female patients. values being almost identical at assessment 1 and after 1 year. Thus no tendency to tachycardia was Casual blood pressure and side-ejTects Casual BP seen. The HR ranged from 56 to 82 beats min'-'. at rest sitting fell from 174/107 nnmHg before the TPRI fell in all but one patient the mean reduction haemodynamic study to 156/97 mmHg after 2 being 18.6% (P < 0.01), a greater fall than during weeks, 153/96 mmHg after 4 weekzs, 148/92 mmHg the acute study. CI was increased in eight patients, fell in two and was unchanged in two. The mean 2201- value increased from 3.18 to 3.34 1 min-] m-2 (+8.1%, P < 0.05). Stroke index tended to be 2001- SAP increased (by 5.8%) but the difference was not statistically significant. 180F Rest sitting SAP, DAP and MAP fell in all 1601 patients, the reductions in SAP, DAP and MAP I E being about the same: 17.6, 16.3 and 16.4%, E 140- respectively. Thus the BP fall was more a. pronounced at rest sitting than supine. One patient 1201 had a pressure of only 108/72 mmHg at the re- assessment, but in the others SAP was 177-133 DAP mmHg and DAP 108-81 mmHg (Figure 2). 1001- 6---- **d* HR was practically unchanged in most patients. Only one subject had an increase of more than 8 80J beats min-'. The mean values were practically I11 I 75.8 vs 75.9 beats min-'. O-i lo w unchanged: TPRI was lower than at the pre-study in all Exercise level patients, the mean reduction being -19.7% (P < Figure 3 Systolic (SAP) and diastoli4ic (DAP) blood 0.001). CI was practically unchanged, from 2.84 to pressures before ( ) and during (------) chronic 2.95 1 min-' m-2 (+3.9%, NS). Stroke index was therapy: at rest supine (o0-); at rest siitting(Q,); slightly increased from 37.3 to 39.1 ml stroke-' (1OOW), during 100 W exercise. m-2 (+4.8%, NS). Haemodynamic effects ofdoxazosin 51S

160 3800F 150 -- N - 140 E E 8 I 3000h E c E 130F_ ,0 6 co 0- I? ** < 120 /,** C a I-_ 4 _ 1 101- 20001 2 1 0 1600 I ) -jI I 0*** o 2- 1 OOW o---i % 1 OOW 0_-- 1 OOw

60 140h

E 50 c

2 40 E 10oo- C- 0) * 30 - Fn I 60T

o-- 1 OOW o~ 21 s 1 10OOW Exercise level

Figure 4 Haemodynamic profile of doxazosin after 1 year of treatment. Mean values s.e. mean. MAP, mean arterial pressure; TPRI, total peripheral resistance index; CI, cardiac index; HR, heart rate; SI, stroke index; ( ), before therapy; (------), during therapy; (o-j), at rest; (Q), at rest sitting; (100 W), during 100 W exercise.

Exercise 100 W Blood pressure control was (8.2%). Changes in ECF ranged from +2.6 to -3.1 maintained during exercise, the reductions in DAP 1 and changes in body weight from +6 to -8 kg. and MAP being about the same as during rest sitting The mean increase in body weight of0.7 kg was not (Figure 3). The relative fall in SAP was slightly statistically significant. Similarly the ECF remained less. SAP, DAP and MAP were lower in all virtually unchanged. The PV/IF ratio showed a patients. The reductions in MAP ranged from -11 significant increase from 0.31 to 0.36. to -33 mmHg, the mean reduction being 26.3 mmHg or -16.8%. Relation between acute and chronic changes Very small changes appeared in HR. The mean values were about the same, 140.3 vs 139.1 beats The haemodynamic alterations seen 1 h after the min'-'. injection of0.5-1.0 mg doxazosin resemble largely As at rest sitting, TPRI fell in all patients. The those seen after 1 year. The fall in TPRI was the mean reduction was -18.3 %, thus about the same most dominant haemodynamic change. However, as during rest. Also as at rest sitting, CI was the changes were more pronounced after 1 year than practically unchanged (7.30 vs 7.45 1 min-' m-2). after 1 h. Since the doses are not the same, it is SI also showed only a negligible change, +1.7% impossible to make a direct comparison between the (NS). acute and chronic responses, but there seemed to be no clear relationship between the fall in MAP in the acute study compared with the change after 1 year. Bodyfluid volumes The results are shown in Table 3. During doxazosin treatment there was a consistent rise in PV and in BV. On average PV increased by 305 ml (9.8%) and BV by 408 ml 52S P. Lund-Johansen et al.

Table 3 Body weight and volumes of extracellular fluid (ECF), interstitial fluid (IF), plasma (PV) and blood (BV) and the ratio before (B) and after (A) chronic doxazosin treatment (n = 12)

Bodv weight ECF PV BV PV/IF (kg) (1) (ml) (ml) ratio B A B A B A B A B A Mean 72.7 73.4 13.4 13.4 3126 3431 4994 5402 0.31 0.36 s.d. 14.9 11.9 2.9 2.4 485 584 897 1033 0.09 0.08 A-B(%) 1.0 0 9.8 8.2 0.05a P NS NS <0.01 <0.01 <0.05

'For PV/IF A-B is expressed as a ratio not a percentage

Discussion reduction was greater than in the acute study in all situations (supine, sitting and 100 W). In all these This study has shown that doxazosin, both situations the fall in TPRI was greater than during intravenously and orally, reduces BP in the majority the acute study. At rest supine, CI increased by 8% of patients with mild and moderately severe (P < 0.05). At rest sitting and during exercise there essential hypertension and that the effect is was a slight insignificant trend toward an increase in maintained over 1 year of chronic therapy. CI. At rest supine there was an increase in SI of In the acute study, doxazosin 0.5-0.7 mg approximately 8%, but the change was not statist- injected intravenously over 3 min did not induce ically significant. At rest sitting and during exercise hypotensive reactions, although 1.0 mg induced there was a slight trend toward an increase. severe hypotension while the patients rested in the These chronic effects resemble those seen in a 1 supine position. year study on prazosin. However, compared with The acute fall in BP was associated with a the pretreatment level, in the prazosin study both SI reduction in TPRI. In the patients with a severe and CI were significantly increased after 1 year blood pressure reduction of -56 to -86 mmHg, (Lund-Johansen, 1975). TPRI was greatly reduced, by approximately 40%. In spite of the vasodilating effect, no significant CI did not show any significant changes at rest fluid retention was noticed and in no patient was supine. In spite of the sudden fall in BP, HR was oedema seen. There was, however; a significant practically unchanged. In other words, no marked increase in plasma volume of 10% and in blood reflex tachycardia was seen. volume of 8%, and an increase in the PV/IF ratio. These acute haemodynamic changes resembled These changes in body fluid volumes are similar to those seen with other postsynaptic a,-adreno- those seen during chronic prazosin treatment receptor antagonists such as prazosin and (Stanaszek et al., 1983) and are consistent with trimazosin (Chrysant et al., 1981; Constantine et vasodilation and peripheral fluid retention. al., 1973; Falch etal., 1979; de Leeuw etal., 1980; However, in contrast to prazosin, doxazosin Pool et al., 1983; Stanaszek et al., 1983). maintained good control of BP in spite of significant The observations in the sitting position showed intravascular fluid expansion. that the falls in blood pressure and TPRI were more The acute and chronic haemodynamic effects of marked than at rest supine. In the sitting position doxazosin (and other al-adrenoceptor antagonists) there was a slight increase in HR. This has also been in hypertension are basically similar. The blood reported for prazosin (Stanaszek et al., 1983). pressure is reduced exclusively through a fall in The exercise recordings show that doxazosin TPRI. This is in contrast to the blood pressure maintained blood pressure control during work. reduction by P-adrenoceptor blockade, where the The relative fall in TPRI was greater than at rest and immediate effect is a reduction in HR and CI and a CI was actually increased by 4%, owing to marked increase in TPRI. After a certain time-lag increased HR and no change in SI. the increased TPRI falls and this brings down the During the chronic study it was shown that a blood pressure. During chronic P-adrenoceptor suitable maintenance dose ranged between 2 and 16 blocker therapy CI remains reduced, usually in the mg with a mean of 6.5 mg daily. At the haemo- order of 15 to 25% (Tarazi & Dustan, 1972; Lund- dynamic re-assessment the blood pressure Johansen, 1983). Haernodlvnanic effects ofdoxazosinl 53S The haemodynamic changes induced by chronic Birkenhager, W.H. (1982). Within patient doxazosin treatment are comparable with those seen comparison of prazosin and UK-33274. A new alpha- after other vasodilator drugs such as converting adrenoceptor-antagonist. Eur. J. cliii. Pharmac., 23, 397-401. enzyme inhibitors and calcium channel blockers de Leeuw, P.W., Wester, A., Willemse, P.J. & (Lund-Johansen & Omvik, 1983, 1984). Birkenhager, W.H. (1980). Effects of prazosin on The spontaneously occurring haemodynamic plasma noradrenaline and plasma renin concentrations changes in essential hypertension are characterized in hypertensive subjects. J. cardiovasc. Pharmac., 2 by a gradual increase in TPRI and a fall in CI (Lund- (Suppi. 3), S361-S372. Johansen, 1978; Messerli et al., 1981). Doxazosin Lund-Johansen, P. (1967). Hemodynamics in early essential hypertension. Acta meld. Scand., 181 (Suppl. treatment opposed these changes and tended to 482), 1-101. normalize total peripheral resistance at rest as well Lund-Johansen, P. (1975). Hemodynamic changes at rest as during exercise. At rest supine there was an and during exercise in long-term prazosin therapy for increase in cardiac index due to the increase in essential hypertension. Postgrad. med. J., 58 stroke volume. It is possible that this normalization (Suppl.), 45-52. of the heart pump function and of the arteriolar Lund-Johansen, P. (1978). Spontaneous changes in central hemodynamics in essential hypertension - a resistance could partly be due to regression of the 10 year follow-up study. In HIpertenlsion1: structural changes in the heart and in the resistance determinants, complications and inters'ention, eds vessels seen in established hypertension. Doxazosin Onesti, G. & Klimt, C.R., pp 201-209. New York: was well tolerated, could be given in one daily dose, Grune & Stratton. and appears to be an interesting and useful Lund-Johansen, P. (1983). Central haemodynamic effects alternative to the antihypertensive agents available of beta-blockers in hypertension: a comparison between atenolol, metoprolol, timolol, penbutolol, at present. alprenolol, pindolol and bunitrolol. Eur. Heart J., (Suppl. D) 4, 1-12. Lund-Johansen, P. & Omvik, P. (1983). Hemodynamic We thank Inger Elizabeth Urheim Johannessen and Helen effects of nifedipine in essential hypertension at rest Wergeland for excellent secretarial aid. Liv Digranes and during exercise. J. Hypertension, 1, 159-163. (RN), Aud Sissel Eriksen, Randi J0sok and Ellen Lund-Johansen, P. & Omvik, P. (1984). Long-term Pedersen are gratefully acknowledged for their excellent haemodynamic effects of enalapril at rest and during technical assistance. exercise in essential hypertension. Scand. J. Urolog. Nephrol., (Suppl. 79), 87-91. Messerli, F.H., Frohlich, E.D., Suarez, D.H., Reisin, E., Dreslinski, G.R., Dunn, F.G. & Cole, F.E. (1981). Borderline hypertension: relationship between References age, hemodynamics and circulating catecholamines. Circulation, 64, 760-764. Beckett, P.J. & Finch, L. (1982). The al- and Omvik, P., Tarazi, R.C. & Bravo, E.L. (1979). a2-adrenoceptor involvement in the central Determination of extracellular fluid volume in uremic cardiovascular action of clonidine in the conscious patients by oral administration of radiosulphate. renal hypertensive cat. Eur. J. Pharmac., 82, Kidne Int., 15, 71-79. 155-160. Omvik, P. & Lund-Johansen, P. (1983). Long-term Chrysant, S.G., Miller, R.F., Brown, J.L. & Danisa, K. effects on central hemodynamics and body fluid (1981). Long-term hemodynamic and metabolic volumes of ketanserin in essential hypertension studies effects of trimazosin in essential hypertension. Clini. at rest and during dynamic exercise. J. Hypertension, Pharinac. Ther., 30, 600-604. 1, 405-412. Constantine, J.W., McShane, W.K., Scriabine, A. & Pool, P.E., Seagren, S.C. & Salel, A.F. (1983). Clinical Hess, H.-J. (1973). Analysis of the hypotensive action hemodynamic profile of trimazosin in hypertension. of prazosin. In Hypertension: Mechanisms and Am. Heart J., 106, 1237-1242. Management, eds Onesti, G., Kim, K.E. & Moyer, Singleton, W., Saxton, C.A.P.D., Hernandes, J. & J.H., pp. 429-444. New York: Grune and Stratton. Prichard, B.N.C. (1982). Postjunctional selectivity of Elliott, H.L., Meredith, P.A., Sumner, D.J., McLean, K. a-blockade with prazosin, trimazosin and UK-33274 & Reid, J.L. (1982). A pharmacodynamic and in man. J. cardiovasc. Pharmac., 4, S145-S151. pharmacokinetic assessment of a new a-adrenoceptor Stanaszek, W.F., Kellerman, D., Brogden, R.N. & antagonist, doxazosin (UK33274) in normotensive Romankiewicz, J.A. (1983). Prazosin update: A subjects. Br. J. clin. Pharmac., 13, 699-703. review of its pharmacological properties and Falch, D.K., Paulsen,, A.Q., Odegaard, A.E. & therapeutic use in hypertension and congestive heart Norman, N. (1979). Central and renal circulation, failure. Drugs, 25, 339-384. renin and aldosterone in plasma during prazosin Tarazi, R.C. & Dustan, H.P. (1972). Beta adrenergic treatment in essential hypertension. Acta med. Scand., blockade in hypertension: Practical and theoretical 206, 489-494. implications of long-term hemodynamic variations. de Leeuw, P.W., Ligthart, J.J., Smout, A.J.P.M. & Am. J. Cardiol., 29, 633-640. 54S P. Lund-Johansen et al.

Timmermans, P.B.M.W.M., Kwa, H.Y., Karamat Ali, Vincent, J., Elliott, H.L., Meredith, P.A. & Reid, J.L. F. & van Zwieten, P.A. (1980). Prazosin and its (1983). Doxazosin, an a1-adrenoceptor antagonist: analogues UK-18596 and UK-33274: A comparative Pharmacokinetics and concentration-effect study on cardiovascular effects and a-adrenoceptor relationships in man. Br. J. clin. Pharmac., 15, blocking activities. Arch. int. Pharmacodyn., 245, 719-725. 218-235.