Part I. Seven healthy male subjects each received on a weekly basis placebo or 10, 20, 40, 80, or 160 mg oral propranolol (P) doses q.i.d. The effect of P on resting heart rate (HR) and the HR response to the Valsalva's maneuver, tilt, isoproterenol (ISO), and exercise were measured. The results indicate that the resting HR and the Tachycardiac response to Valsalva and tilt cannot be used to estimate beta blockade (BB). Although P serum levels correlated well (r² = 0.80) with the ISO dose ratio minus one, ISO challenges appear clinically inappropriate. Reduction in exercise tachycardia correlated best with P serum levels (r² = 0.89). In patients on P therapy, in which exercise would be contraindicated, there appears to be no reliable and safe method of clinically documenting BB. Part II. The parmacokinetics of intravenous P were studied in calves before and after biochemical induction of thyrotoxicosis. The beta adrenergic response to P was measured in both euthyroid and thyrotoxic (T) animals at steady-state serum levels of P by administration of ISO. No pharmacokinetic differences were detected between animal groups; however, T calves displayed a markedly different pharmacologic response to P. On the average, 2-9 times higher serum levels of P were required to facilitate BB in the T calves. These results suggest that in the calf model, thyrotoxicosis induces a decreased sensitivity to P independent of laterations in P's disposition. Part III. The aim of this study was to find a digitalis glycoside (DG) with a t(½) shorter than that of digitoxin (DT), but similar to that of digoxin, and whose disposition characteristics are not influenced by alterations in renal function, as is the case with digoxin. Consequently, the pharmacokinetics of two metabolites of DT, digitoxigenin-bisdigitoxoside (BIS) and digitoxigenin-monodigitoxoside (MONO), were compared to those of DT in a dog model. In normal dogs, appreciable differences were found between the systemic clearance (CL) of DT and the CL of either of the two other DG's. These differences in CL were primarily responsible for the 2.0 and 3.5 fold decrease seen in the t(½)'s of BIS and MONO, respectively. Renal disfunction did not influence the pharmacokinetic parameters of any of the DG's studied. These findings in the dog model suggest that BIS or MONO may provide a pharmacokinetic advantage over DT.
| Identifer | oai:union.ndltd.org:arizona.edu/oai:arizona.openrepository.com:10150/185815 |
| Date | January 1983 |
| Creators | PIENIASZEK, HENRY JOSEPH, JR. |
| Contributors | Carter, Dean E., Schram, Karl, Sipes, I. Glenn |
| Publisher | The University of Arizona. |
| Source Sets | University of Arizona |
| Language | English |
| Detected Language | English |
| Type | text, Dissertation-Reproduction (electronic) |
| Rights | Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. |
Page generated in 0.0024 seconds