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Pharmacological tolerance to alpha 1-adrenergic receptor antagonism mediated by terazosin in humans
J Vincent1, W Dachman, T F Blaschke
1Stanford University, California 94305.
Abstract:
Chronic administration of alpha 1-receptor antagonists is associated with loss of clinical efficacy, especially in congestive heart failure, although the mechanism is uncertain. To evaluate changes in venous alpha 1-adrenoceptor responsiveness during chronic alpha 1-adrenoceptor blockade, dose-response curves to phenylephrine and angiotensin II were constructed in 10 healthy subjects before, during, and after administration of terazosin 1 mg orally for 28 d. Terazosin initially shifted the dose-response curve of phenylephrine to the right, with a significant increase in ED50 for phenylephrine from a control value of 102 to 759 ng/min on day 1 of terazosin (P < 0.001). However, by day 28, the dose-response curve had shifted back towards baseline with an ED50 of 112 ng/min. After discontinuing terazosin, the ED50 for phenylephrine remained near the baseline value, indicating no evidence of supersensitivity to phenylephrine. There was no change in responsiveness to angiotensin II during the course of treatment with terazosin. Plasma terazosin concentrations were stable throughout the period of drug administration. The mean Kd of terazosin was estimated as 11 +/- 15 nM in the first few days of treatment. This study demonstrates that pharmacological tolerance to the alpha 1-adrenoceptor blocking action of terazosin occurs in man and may be responsible for loss in efficacy with chronic therapy.
Insights
Tolerance develops to alpha 1-receptor antagonists like terazosin during chronic use. This pharmacological tolerance in humans may explain the reduced clinical efficacy observed with long-term therapy.
Area of Science:
- Pharmacology
- Cardiovascular Medicine
Background:
- Chronic administration of alpha 1-receptor antagonists can lead to reduced clinical efficacy.
- The underlying mechanisms for this loss of efficacy, particularly in conditions like congestive heart failure, remain unclear.
Purpose of the Study:
- To investigate the changes in venous alpha 1-adrenoceptor responsiveness during prolonged blockade with terazosin.
- To determine if pharmacological tolerance develops to the alpha 1-adrenoceptor blocking effects of terazosin in humans.
Main Methods:
- Dose-response curves to phenylephrine and angiotensin II were measured in 10 healthy subjects.
- Measurements were taken before, during (day 1 and day 28), and after 28 days of oral terazosin administration (1 mg/day).
- Plasma concentrations of terazosin were monitored throughout the study.
Main Results:
- Terazosin initially caused a significant rightward shift in the phenylephrine dose-response curve (increased ED50 from 102 to 759 ng/min on day 1).
- By day 28, the ED50 for phenylephrine returned towards baseline (112 ng/min), indicating tolerance.
- No changes in responsiveness to angiotensin II or evidence of supersensitivity to phenylephrine were observed after discontinuation.
Conclusions:
- Pharmacological tolerance to the alpha 1-adrenoceptor blocking action of terazosin develops in humans with chronic administration.
- This tolerance may be the mechanism responsible for the loss of clinical efficacy associated with long-term use of alpha 1-receptor antagonists.
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