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Marked early attenuation of hemodynamic effects of oral prazosin therapy in chronic congestive heart failure
ABSTRACTS
WEDNESDAY, MARCH !4, 1979 AM VASODILATOR DRUG EFFECTS ON THE NORMAL AND FAILING CIRCULATION 8:30-rl2:00 RADIONUCLIDE ANGIOGRAPHIC AND HEMODYNAMICASSESSMENT OF PRAZOSIN IN PATIENTS WITH MEDICALLY REFRACTORYHEART FAILURE LarryPoliner, MD, FACC; Donald Twieg, PhD; Robert Parkey, ~,-FACC; ~SamueTLewis, MD; Gregory Dehmer, MD; James T. Willerson, MD, FACC; UT Health Science c t r . , Dallas, TX The influence of prazosin (PZN) on ventricular function in patients (pts,)..with severe, medically refractory CHF was evaluated by radionuclide angiography (RNA)using technetium-99m pertechnetate and labeling of RBC's in vivo. Control (C) and treatment (T) measurements of LV ejection fraction (EF), end diastolic and systolic volumes (LVEDV and LVESV) by RNA and phas.ic and mean systemic~arterial (A), pulmonary a r t e r i a l (PAl, and~LV f i I I i ng pressures (LVFP) measured by indwelling catheters were followed over 48 to 72 hrs'during,PZN T. An average~of 4 mg of PZN was given to seven pts that were hemodynamically stable at least 8 hrs prior to the drug evaluation and measurements were followed, sequentially after ~the administration of PZN until' return to baseline levels. PZN was then continued and persistent effect assessed by RNA and hemodynamic pressure measurements. Pre PZN, A was. 86 + 6 (S.E.), PA 41 _+ 5, and LVFP 30 -+ 3. Pressures f e l l significantly at peak PZN effect t o 68 _+ 7 (79% of C) for A at 3 +_ .6 hrs, PA 24 +_ 4 (58% of C) at 3 + ,6 hrs and LVFP 15 _+ 4 (50% of C) at 3 +_ 5 hrs. Duration of PZN effect was 6 _+ .7 hrs. HR was not significantly altered. For,RNA at C,'LVEF was 14 + 4%, LVEDV 212 _+ 33, LVESV 175 + 17, and CO 3.1 L/rain. At 2 hrs. after. PZN, EF increased 93% to 27 + 5% (p<.OOl), LVESV decreased 13% to 152 + 9 (p<.05), LVEDV did not change, and CO increased 93% to 5.8 L/rain. Persistence of drug effect was noted over the duration of the study. The data suggest i n i t i a l PZN T is assoCiatedwith evidence of improved LV function and increased c o n t r a c t i l i t y with decreased LVESV and increased EF and,CO and improving clinical status.
PRAZOSIN KINETICS AND EFFECT IN CONGESTIVE HEART FAILURE Stephen Arnold, MD; Roger Williams, MD; Thomas PortS, MD; Robert Baughman, Pharm D; Leslie Benet, PhD; Kanu Chatterjee, MD, FACC, University of C a l i f o r n i a , San Francisco, CA. r
.,
..
In l i g h t of the reported attenuation of i n i t i a l hemodynamic effects of prazosin, (P), we compared P pharmacokinet.Ics and e f f e c t . Five mg of P were administered o r a l l y to 7 patients with NYHA Class 111 or IV chron,lc Ischemlc congestive heart f a i l u r e , foil, owed 24 hours later by 5 mg of P given o r a l l y every six hours for 5 additional doses. The following measurements were made frequently and a r e reported In relation to the ,first dose (control) at 0 hr, peak plasma drug concentration in hr, 24 hr, and 2 hr a f t e r the second and f i f t h doses: prazosin plasma concentration (Cp, ng/ml) mean a r t e r i a l pressure (MAP, mm Hg), pulmonary capillary wedge (PCW, mm Hg), right atrial pressure (RAP, mm Hg),: cardiac index (el, L/rain/ m2), stroke work index (SWI, g,M/m2) and sys£emlc vascular resistance (SVR, tics-:)). ' '~ CONTROL PEAK 24 HR 2ND+2 HR 5TH+2 HR
,.s÷2
s6,9+2,j
93¥16 79~'I 5~ 90~16 78T1 81~'13 RCW 22+-7 17+'8+ 23~11 22~11 18~'8+ RAP 13+--5 8T3" 11T6 9~6" 8T4" Ci 2 5¥. 5 3.0¥. 8" 2.4¥. 7 Z. 77.8 2.7¥. 9 SWi 37+-17 41¥18 38~'15 31+-11 38¥14 SVR 1450+341 1097~286 * i,493~zt24 1192+--550+ 1319+'534 Mean+SD-- + p < 0.0--5 * p,40~'Ol compar-'ed to contr--ol. We observed significant hemodynamic effects after the f i r s t dose with return towards control as Cp declined. On repeated dosing, we observed attenuation of, effect on CI and SVR despite Cp exceeding those observed wlth initial effect. P effect, after the f i r s t dose, does not appear related to, or predicted by, P Cp.
MARKED EARLY ATTENUATION OF HEMODYNAMIC EFFECTSOF ORAL PRAZOSIN THERAPY IN CHRONIC CONGESTIVE HEART FAILURE Uri Elkayam, MD,JThierry Lejemtel, MD, Mitlesh Mathur, MD, Hillel Ribner, MD, William Frishman, MD, FACC, Joel Strom, MD, Edmund H. Sonnenblick, MD, FACCi, Albert Einstein College of Medicine, Bronx, New York
C O M P A R I S O N OF C A R D I O C I R C U L A T O R Z ACTIONS OF THE ORAL SYSTEMIC V A S O D I L A T O R S TRIMAZOSIN AND PRAZOSIN: DEMONSTRATION OF S I M I L A R USEFUL EFFICACY IN THERAPY OF SEVERE H E A R T FAILURE Dean T. Mason, MD, FACC; N a j a m A. Awan, MD, FACC; John Hermanovich, MD, University of California, Davis, Calif.
Single dose oral prazosin (P)' has been shown to be hemosynamically beneficial in pts with chronic congestive heart failure (CHF). However, the effects of P with sustained use have, been l i t t l e emphasized. To c l a r i f y this, we compared the hemodynamic response to the f i r s t and f i f t h consecutive doses in II pts with CHF treated with 3-'10 mg P every 6 hrs. Heart rate(HR), mean blood pressure (BP) pulmonary capillary wedge pressure (PCW), cardiac index (CI), stroke volume index (SVI) and systemic vascular.resistance (SVR) were determined before and at l , 2, 3, 4 and 6 hrs after the administration of the drug. The peak effects were asfollows" (***P
The b e n e f i c i a l v a s o d i l a t o r actions of p r a z o s i n (PZ) in amb u l a t o r y therapy of heart failure (CHF) have been shown. To evaluate the relative effects of the new oral vasodilator, trimazosin (TZ), the h e m o d y n a m i c actions of oral trimazosin (150 mg) were compared w i t h p r a z o s i n (4 mg) in nine chronic coronary congestive heart failure p a t i e n t s . Measurements: HR = heart rate, bpm; BP = m e a n blood pressure, m m H g ; LVFP = left v e n t r i c u l a r filling pressure, m m H g ; CI = cardiac index, L/min/M2; SWI = s t r o k e w o r k index, gm-m-M2; PTM ( M V O 2 i n d e x ) = p r e s s u r e - t i m e / m i n u t e , m m H g . s e c / m i n ; T S V R = total systemic v a s c u l a r resistance, dsc-5; VT = forearm venous tone, m m Hg/ml; V R = forearm v a s c u l a r resistance, mm Hg/ml/100 g/min. * = p<0.05 and t p<0.01 vs control (C) .
.
.
HR BP PCW CI, , SVI SVR-dynes/ _ _--~Hg .. mmH----.g L/mi_n/m2 m-~ '~ ' -m2 _s.--~_c/_cm-5 C 88+5 89_+3 ' 23_+i 2.0-+0.l 2 2 + I 2061+I50 I s t dose 88+_-5 8-0-+3*** i4+2 *~* 2,5_+0.2** 29_+I** 1599_+192"* 5th dose E~8_+5 8-3_+3* ~2-4+I 2.2-_+0.I-* 2-5-+I* "18"1'5'_+164, In contPasttoa combined effect of the.l~tdose Of P~.on the preload and afterload associated with a significant improvement of cardiac performance, the administration of the 5th consecutivedose showed no effect on the preload and ra markedly attenuated effect on the afterload. Conclusion- The beneficial hemodynamic effect of P on both preload and afterload suggests its usefulness for acute treatment, of CHF. However, the marked early attenuation of this response indicates a questionable value of P for the chronic management of pts with CHF.
C TZ C PZ
HR 81 78 82 78
BP 96 83% 96 80%
LVFP 31 23# 35 22#
CI 1.8 2.3% 2.0 2.6%
SWI 22 26% 22 27%
PTM 2646 2273* 2930 2359%
TSVR 1882 1444% 1649 ii17%
VT VR 57 131 15" 65* 56 119 18" 59%
Thus trimazosin p r o d u c e d m a r k e d improvement in left ventric u l a r f u n c t i o n and efficiency similar in nature, degree and sustained duration as prazosin. Both agents decreased elevated LV f i l l i n g p r e s s u r e and increased low cardiac index, while enhancing cardiac efficiency (LV work raised with c o n c o m i t a n t MVO 2 fall). Furthermore, as we have observed in instances of p r a z o s i n tolerance, trimazosin substitution without cross-tolerance maintains improved LV function in CHF by b a l a n c e d afterload reduction.
February 1979
The American Journal of CARDIOLOGY
Volume 43
403
WEDNESDAY, MARCH !4, 1979 AM VASODILATOR DRUG EFFECTS ON THE NORMAL AND FAILING CIRCULATION 8:30-rl2:00 RADIONUCLIDE ANGIOGRAPHIC AND HEMODYNAMICASSESSMENT OF PRAZOSIN IN PATIENTS WITH MEDICALLY REFRACTORYHEART FAILURE LarryPoliner, MD, FACC; Donald Twieg, PhD; Robert Parkey, ~,-FACC; ~SamueTLewis, MD; Gregory Dehmer, MD; James T. Willerson, MD, FACC; UT Health Science c t r . , Dallas, TX The influence of prazosin (PZN) on ventricular function in patients (pts,)..with severe, medically refractory CHF was evaluated by radionuclide angiography (RNA)using technetium-99m pertechnetate and labeling of RBC's in vivo. Control (C) and treatment (T) measurements of LV ejection fraction (EF), end diastolic and systolic volumes (LVEDV and LVESV) by RNA and phas.ic and mean systemic~arterial (A), pulmonary a r t e r i a l (PAl, and~LV f i I I i ng pressures (LVFP) measured by indwelling catheters were followed over 48 to 72 hrs'during,PZN T. An average~of 4 mg of PZN was given to seven pts that were hemodynamically stable at least 8 hrs prior to the drug evaluation and measurements were followed, sequentially after ~the administration of PZN until' return to baseline levels. PZN was then continued and persistent effect assessed by RNA and hemodynamic pressure measurements. Pre PZN, A was. 86 + 6 (S.E.), PA 41 _+ 5, and LVFP 30 -+ 3. Pressures f e l l significantly at peak PZN effect t o 68 _+ 7 (79% of C) for A at 3 +_ .6 hrs, PA 24 +_ 4 (58% of C) at 3 + ,6 hrs and LVFP 15 _+ 4 (50% of C) at 3 +_ 5 hrs. Duration of PZN effect was 6 _+ .7 hrs. HR was not significantly altered. For,RNA at C,'LVEF was 14 + 4%, LVEDV 212 _+ 33, LVESV 175 + 17, and CO 3.1 L/rain. At 2 hrs. after. PZN, EF increased 93% to 27 + 5% (p<.OOl), LVESV decreased 13% to 152 + 9 (p<.05), LVEDV did not change, and CO increased 93% to 5.8 L/rain. Persistence of drug effect was noted over the duration of the study. The data suggest i n i t i a l PZN T is assoCiatedwith evidence of improved LV function and increased c o n t r a c t i l i t y with decreased LVESV and increased EF and,CO and improving clinical status.
PRAZOSIN KINETICS AND EFFECT IN CONGESTIVE HEART FAILURE Stephen Arnold, MD; Roger Williams, MD; Thomas PortS, MD; Robert Baughman, Pharm D; Leslie Benet, PhD; Kanu Chatterjee, MD, FACC, University of C a l i f o r n i a , San Francisco, CA. r
.,
..
In l i g h t of the reported attenuation of i n i t i a l hemodynamic effects of prazosin, (P), we compared P pharmacokinet.Ics and e f f e c t . Five mg of P were administered o r a l l y to 7 patients with NYHA Class 111 or IV chron,lc Ischemlc congestive heart f a i l u r e , foil, owed 24 hours later by 5 mg of P given o r a l l y every six hours for 5 additional doses. The following measurements were made frequently and a r e reported In relation to the ,first dose (control) at 0 hr, peak plasma drug concentration in hr, 24 hr, and 2 hr a f t e r the second and f i f t h doses: prazosin plasma concentration (Cp, ng/ml) mean a r t e r i a l pressure (MAP, mm Hg), pulmonary capillary wedge (PCW, mm Hg), right atrial pressure (RAP, mm Hg),: cardiac index (el, L/rain/ m2), stroke work index (SWI, g,M/m2) and sys£emlc vascular resistance (SVR, tics-:)). ' '~ CONTROL PEAK 24 HR 2ND+2 HR 5TH+2 HR
,.s÷2
s6,9+2,j
93¥16 79~'I 5~ 90~16 78T1 81~'13 RCW 22+-7 17+'8+ 23~11 22~11 18~'8+ RAP 13+--5 8T3" 11T6 9~6" 8T4" Ci 2 5¥. 5 3.0¥. 8" 2.4¥. 7 Z. 77.8 2.7¥. 9 SWi 37+-17 41¥18 38~'15 31+-11 38¥14 SVR 1450+341 1097~286 * i,493~zt24 1192+--550+ 1319+'534 Mean+SD-- + p < 0.0--5 * p,40~'Ol compar-'ed to contr--ol. We observed significant hemodynamic effects after the f i r s t dose with return towards control as Cp declined. On repeated dosing, we observed attenuation of, effect on CI and SVR despite Cp exceeding those observed wlth initial effect. P effect, after the f i r s t dose, does not appear related to, or predicted by, P Cp.
MARKED EARLY ATTENUATION OF HEMODYNAMIC EFFECTSOF ORAL PRAZOSIN THERAPY IN CHRONIC CONGESTIVE HEART FAILURE Uri Elkayam, MD,JThierry Lejemtel, MD, Mitlesh Mathur, MD, Hillel Ribner, MD, William Frishman, MD, FACC, Joel Strom, MD, Edmund H. Sonnenblick, MD, FACCi, Albert Einstein College of Medicine, Bronx, New York
C O M P A R I S O N OF C A R D I O C I R C U L A T O R Z ACTIONS OF THE ORAL SYSTEMIC V A S O D I L A T O R S TRIMAZOSIN AND PRAZOSIN: DEMONSTRATION OF S I M I L A R USEFUL EFFICACY IN THERAPY OF SEVERE H E A R T FAILURE Dean T. Mason, MD, FACC; N a j a m A. Awan, MD, FACC; John Hermanovich, MD, University of California, Davis, Calif.
Single dose oral prazosin (P)' has been shown to be hemosynamically beneficial in pts with chronic congestive heart failure (CHF). However, the effects of P with sustained use have, been l i t t l e emphasized. To c l a r i f y this, we compared the hemodynamic response to the f i r s t and f i f t h consecutive doses in II pts with CHF treated with 3-'10 mg P every 6 hrs. Heart rate(HR), mean blood pressure (BP) pulmonary capillary wedge pressure (PCW), cardiac index (CI), stroke volume index (SVI) and systemic vascular.resistance (SVR) were determined before and at l , 2, 3, 4 and 6 hrs after the administration of the drug. The peak effects were asfollows" (***P
The b e n e f i c i a l v a s o d i l a t o r actions of p r a z o s i n (PZ) in amb u l a t o r y therapy of heart failure (CHF) have been shown. To evaluate the relative effects of the new oral vasodilator, trimazosin (TZ), the h e m o d y n a m i c actions of oral trimazosin (150 mg) were compared w i t h p r a z o s i n (4 mg) in nine chronic coronary congestive heart failure p a t i e n t s . Measurements: HR = heart rate, bpm; BP = m e a n blood pressure, m m H g ; LVFP = left v e n t r i c u l a r filling pressure, m m H g ; CI = cardiac index, L/min/M2; SWI = s t r o k e w o r k index, gm-m-M2; PTM ( M V O 2 i n d e x ) = p r e s s u r e - t i m e / m i n u t e , m m H g . s e c / m i n ; T S V R = total systemic v a s c u l a r resistance, dsc-5; VT = forearm venous tone, m m Hg/ml; V R = forearm v a s c u l a r resistance, mm Hg/ml/100 g/min. * = p<0.05 and t p<0.01 vs control (C) .
.
.
HR BP PCW CI, , SVI SVR-dynes/ _ _--~Hg .. mmH----.g L/mi_n/m2 m-~ '~ ' -m2 _s.--~_c/_cm-5 C 88+5 89_+3 ' 23_+i 2.0-+0.l 2 2 + I 2061+I50 I s t dose 88+_-5 8-0-+3*** i4+2 *~* 2,5_+0.2** 29_+I** 1599_+192"* 5th dose E~8_+5 8-3_+3* ~2-4+I 2.2-_+0.I-* 2-5-+I* "18"1'5'_+164, In contPasttoa combined effect of the.l~tdose Of P~.on the preload and afterload associated with a significant improvement of cardiac performance, the administration of the 5th consecutivedose showed no effect on the preload and ra markedly attenuated effect on the afterload. Conclusion- The beneficial hemodynamic effect of P on both preload and afterload suggests its usefulness for acute treatment, of CHF. However, the marked early attenuation of this response indicates a questionable value of P for the chronic management of pts with CHF.
C TZ C PZ
HR 81 78 82 78
BP 96 83% 96 80%
LVFP 31 23# 35 22#
CI 1.8 2.3% 2.0 2.6%
SWI 22 26% 22 27%
PTM 2646 2273* 2930 2359%
TSVR 1882 1444% 1649 ii17%
VT VR 57 131 15" 65* 56 119 18" 59%
Thus trimazosin p r o d u c e d m a r k e d improvement in left ventric u l a r f u n c t i o n and efficiency similar in nature, degree and sustained duration as prazosin. Both agents decreased elevated LV f i l l i n g p r e s s u r e and increased low cardiac index, while enhancing cardiac efficiency (LV work raised with c o n c o m i t a n t MVO 2 fall). Furthermore, as we have observed in instances of p r a z o s i n tolerance, trimazosin substitution without cross-tolerance maintains improved LV function in CHF by b a l a n c e d afterload reduction.
February 1979
The American Journal of CARDIOLOGY
Volume 43
403