- Email: [email protected]
Adrenergic responsiveness following abrupt propranolol withdrawal in patients with angina pectoris
ABSTRACTS
ADRENERGIC RESPONSIVENESS FOLLOWING ABRUPT PROPRANOLOL IJITHDQAIHAL IN PATIENTS WITH ANGINA PECTORIS JoAnn Lindenfeld, MD; Michael Crawford, MD, FACC; Robert O'Rourke, MD, FACC; Lawrence Horwitz, MD, FACC, University of Texas Health Science Center and Veterans Administration Hospital, San Antonio, Texas. It has been suggested that propranolol (P) withdrawal phenomena may be due to sympathetic hypersensitivity. We have previously been unable to demonstrate enhanced adrenergic responsiveness following P withdrawal in conscious dogs and normal subjects. Accordingly, we studied 10 patients (pts) with angina pectoris before (C), during P therapy (160 mg/day X 14 days) and at 48, 96 and 144 hrs following abrupt withdrawal of P at rest, during an epinephrine (Epi) infusion (0.1 uq/kq/nin X 5 min) and during treadmill exercise. Below is detailed heart rate(HR), systolic blood pressure (SBP) and plasma Epi levels at peak exercise; free fatty acid(FFA) response to Epi infusion; and resting total serum triiodothyronine (T ) levels: Epi FFa (bea!F/min) ?!Ti!y (pg/mT) (mEg/L) (ng '7 dT) C 22.9f6.6 59t 33 105Oi356 151+27 136t16 P 15.3i4.0* 106'14* 126i129t 530+108* 137+23t 21.3i4.9 58i 27 48 134221 917+155 132?12* 96 136t22 21.626.0 581 28 911i249 137t23+ 22.Ot6.5 56+ 34 926i173 129+20* 144 136?23 4=p<.o5 *=pi.01 Mean i 1SO All measures except T3 differed from control only during P. T was reduced for up to 144 hrs following P. Exercise dura & ion was improved on propranolol therapy (4542128 vs 392t116 set, p<.O5), but returned to control levels during withdrawdl. No patients experienced increased angina or other untoward events after P withdrawal. IJe conclude that enhanced adrenergic responsiveness in the 6 days following abrupt P withdrawal in patients with angina pectorisis unlikely to be the explanation for propranolol withdrawal phenomena.
Ix) BETA BLOCKING AUM’S PREVEN’i- THE M3.E RAPID ONSET OF EFFORT ANGINA DURINGTtIE POSTPRAVDIAL STATE? (;illcs-K. Dagenais, MD, FACC; Francois Delage, KD; Jacques R. Rouleau, MD, FACC, Quebec Heart Institute, Quebec, Canada.
l‘o ~~SWCT the above question,
metoprolol 100 mg 01) was given before an 800 calorie meal to 12 male patients with stable angina and documented coronary artcry disease. ‘Three graded treadmill exercise tests (GET) (Bruce protoAfter an overnight col) were performed daily on 2 days. fast, the first CET on each day was done after a placebo (P) to detect any daily variation. The second GET was
done 90 min after FI or a second f' given orally in a douhle-blind randomized fashion. Immediately after, the patients ate their meal and 30 min later did their third
GET. Angina or fatigue were used as endpoints for each GET. A positive KG (KC+) was defined as a 1 non ST segment depression lasting 0.08 set as compared to the resting tracing. ‘There was no significant day to day difhad anference in the first (M.T. After P, all patients gina, while it occurred in 10 of the 12 patients after M. ‘The results (menn+SBi) of the second (a.~.) and third (p.c.) GET for exercise duration, onset of ECCrt and maximal pressure-rate index (MPRI) were: DlJfUTION (set)
P
3.c. ” k‘ 1
M
9.C.
p.c.
370’28 110+24
40926 386430
ECGF
After I’, angina and ICC+ occurred at similar MPRI (p
438
February 1980
(SK)
280227 228t19 3392.5 317?29
MFRl [Units
10-2)
271+13 268kll 188kll 191t11
sooner p.c. than a.c. i\l, there was no signifiCompared p.c. results. onset of effort angina state (~‘0.01).
The American Journal of CARDIOLOGY
BENEFICIAL HEMODYNAMIC AND ENERGETIC EFFECTS OF AFTERLOAD REWCTION WITH PROSTAGLANDIN E-l IN PATIENTS WITH SEVERE CHRONIC CONGESTIVE HEART FAILURE John Hermanovich, MD; Najam A. Awan, MD, FACC; Mark Evense", BS; Tom Evans, MD, FACC; Dean T. Mason, MD, FACC, University of California, Davis, California. Although nitroprusside (NP) is recognized to be highly beneficial for vasodilator therapy of severe chronic congestive heart failure (CHF), the prostaglandins (PG) represent a more rationale physiological approach. Therefore, the hemodynamic effects of afterload reduction with PGE-1 infusion (0.04 pg/kg/min) were evaluated by cardiac catheterization in nine patients with refractory CHF. PGE-1 did not alter control (C) heart rate (HR) of 71 bpm, while mean blood pressure {BP) decreased mildly from 83 to 75 mmHg (~~0.05) and excessive left ventricular filling pressure (LVFP) fell from 22 to 17 mmHg (p
PtihU4.4c0KIN~TIcs AND Pmmb.coLoG~
EFFECTS AFTER SINGLE DOSES OF ISOSORBIDE DINITRATE Ho-Leung Fun&, PhD; Edward F. McNiff, BS; Donald Ruggirello,BS; Andrew Dsrke, PhD; John 0. Parker, MD, FRCP(C), Udho Thadani, MBBS, MRCP, FRCP(C), State University of New York at Buffalo, Amherst, NY.
AND CHRONIC
The inter-relationships among oral isosorbide dinitrate (ISDN) dose, drug pharmscokinetics and pharmacologic effects were examined in 12 angina patients. Plasma ISDN concentrations were determined by gas chromatography at selected intervals after single oral doses of 15,30,60 and 120 mg and after chronic administration (qid for 1 week) of the same doses. Significant accumulation of intact ISDN in plasma was observed after chronic dosing at 30,60 and 120 mg. The ares under the plasma concentration vs. time curve, from O-6 hr, (AK) was shown to be approximately proportional to dose after single doses, but increased disproportionately with dose after chronic dosing. Apparent elimination of intact drug appeared more prolonged in the latter case, suggesting decreased ISDN plasma clearance after chronic dosing. AUC (O-6 hr) ng-hi-/ml, (mean+S.E.) 30 mg 15 mg 60 mg - 120 mg single dose 15.6+3.4 26.753.8 49.855.9 93.2+x.5 chronic dose 18.6zl.6 43.7+4.8* 133 +18* 304 +34* *Different (p
Volume 45
ADRENERGIC RESPONSIVENESS FOLLOWING ABRUPT PROPRANOLOL IJITHDQAIHAL IN PATIENTS WITH ANGINA PECTORIS JoAnn Lindenfeld, MD; Michael Crawford, MD, FACC; Robert O'Rourke, MD, FACC; Lawrence Horwitz, MD, FACC, University of Texas Health Science Center and Veterans Administration Hospital, San Antonio, Texas. It has been suggested that propranolol (P) withdrawal phenomena may be due to sympathetic hypersensitivity. We have previously been unable to demonstrate enhanced adrenergic responsiveness following P withdrawal in conscious dogs and normal subjects. Accordingly, we studied 10 patients (pts) with angina pectoris before (C), during P therapy (160 mg/day X 14 days) and at 48, 96 and 144 hrs following abrupt withdrawal of P at rest, during an epinephrine (Epi) infusion (0.1 uq/kq/nin X 5 min) and during treadmill exercise. Below is detailed heart rate(HR), systolic blood pressure (SBP) and plasma Epi levels at peak exercise; free fatty acid(FFA) response to Epi infusion; and resting total serum triiodothyronine (T ) levels: Epi FFa (bea!F/min) ?!Ti!y (pg/mT) (mEg/L) (ng '7 dT) C 22.9f6.6 59t 33 105Oi356 151+27 136t16 P 15.3i4.0* 106'14* 126i129t 530+108* 137+23t 21.3i4.9 58i 27 48 134221 917+155 132?12* 96 136t22 21.626.0 581 28 911i249 137t23+ 22.Ot6.5 56+ 34 926i173 129+20* 144 136?23 4=p<.o5 *=pi.01 Mean i 1SO All measures except T3 differed from control only during P. T was reduced for up to 144 hrs following P. Exercise dura & ion was improved on propranolol therapy (4542128 vs 392t116 set, p<.O5), but returned to control levels during withdrawdl. No patients experienced increased angina or other untoward events after P withdrawal. IJe conclude that enhanced adrenergic responsiveness in the 6 days following abrupt P withdrawal in patients with angina pectorisis unlikely to be the explanation for propranolol withdrawal phenomena.
Ix) BETA BLOCKING AUM’S PREVEN’i- THE M3.E RAPID ONSET OF EFFORT ANGINA DURINGTtIE POSTPRAVDIAL STATE? (;illcs-K. Dagenais, MD, FACC; Francois Delage, KD; Jacques R. Rouleau, MD, FACC, Quebec Heart Institute, Quebec, Canada.
l‘o ~~SWCT the above question,
metoprolol 100 mg 01) was given before an 800 calorie meal to 12 male patients with stable angina and documented coronary artcry disease. ‘Three graded treadmill exercise tests (GET) (Bruce protoAfter an overnight col) were performed daily on 2 days. fast, the first CET on each day was done after a placebo (P) to detect any daily variation. The second GET was
done 90 min after FI or a second f' given orally in a douhle-blind randomized fashion. Immediately after, the patients ate their meal and 30 min later did their third
GET. Angina or fatigue were used as endpoints for each GET. A positive KG (KC+) was defined as a 1 non ST segment depression lasting 0.08 set as compared to the resting tracing. ‘There was no significant day to day difhad anference in the first (M.T. After P, all patients gina, while it occurred in 10 of the 12 patients after M. ‘The results (menn+SBi) of the second (a.~.) and third (p.c.) GET for exercise duration, onset of ECCrt and maximal pressure-rate index (MPRI) were: DlJfUTION (set)
P
3.c. ” k‘ 1
M
9.C.
p.c.
370’28 110+24
40926 386430
ECGF
After I’, angina and ICC+ occurred at similar MPRI (p
438
February 1980
(SK)
280227 228t19 3392.5 317?29
MFRl [Units
10-2)
271+13 268kll 188kll 191t11
sooner p.c. than a.c. i\l, there was no signifiCompared p.c. results. onset of effort angina state (~‘0.01).
The American Journal of CARDIOLOGY
BENEFICIAL HEMODYNAMIC AND ENERGETIC EFFECTS OF AFTERLOAD REWCTION WITH PROSTAGLANDIN E-l IN PATIENTS WITH SEVERE CHRONIC CONGESTIVE HEART FAILURE John Hermanovich, MD; Najam A. Awan, MD, FACC; Mark Evense", BS; Tom Evans, MD, FACC; Dean T. Mason, MD, FACC, University of California, Davis, California. Although nitroprusside (NP) is recognized to be highly beneficial for vasodilator therapy of severe chronic congestive heart failure (CHF), the prostaglandins (PG) represent a more rationale physiological approach. Therefore, the hemodynamic effects of afterload reduction with PGE-1 infusion (0.04 pg/kg/min) were evaluated by cardiac catheterization in nine patients with refractory CHF. PGE-1 did not alter control (C) heart rate (HR) of 71 bpm, while mean blood pressure {BP) decreased mildly from 83 to 75 mmHg (~~0.05) and excessive left ventricular filling pressure (LVFP) fell from 22 to 17 mmHg (p
PtihU4.4c0KIN~TIcs AND Pmmb.coLoG~
EFFECTS AFTER SINGLE DOSES OF ISOSORBIDE DINITRATE Ho-Leung Fun&, PhD; Edward F. McNiff, BS; Donald Ruggirello,BS; Andrew Dsrke, PhD; John 0. Parker, MD, FRCP(C), Udho Thadani, MBBS, MRCP, FRCP(C), State University of New York at Buffalo, Amherst, NY.
AND CHRONIC
The inter-relationships among oral isosorbide dinitrate (ISDN) dose, drug pharmscokinetics and pharmacologic effects were examined in 12 angina patients. Plasma ISDN concentrations were determined by gas chromatography at selected intervals after single oral doses of 15,30,60 and 120 mg and after chronic administration (qid for 1 week) of the same doses. Significant accumulation of intact ISDN in plasma was observed after chronic dosing at 30,60 and 120 mg. The ares under the plasma concentration vs. time curve, from O-6 hr, (AK) was shown to be approximately proportional to dose after single doses, but increased disproportionately with dose after chronic dosing. Apparent elimination of intact drug appeared more prolonged in the latter case, suggesting decreased ISDN plasma clearance after chronic dosing. AUC (O-6 hr) ng-hi-/ml, (mean+S.E.) 30 mg 15 mg 60 mg - 120 mg single dose 15.6+3.4 26.753.8 49.855.9 93.2+x.5 chronic dose 18.6zl.6 43.7+4.8* 133 +18* 304 +34* *Different (p
Volume 45