The relationship of plasma guanethidine levels to adrenergic blockade Seventeen hypertensive patients receiving guanethidine for therapy were studied to determine the relationship of guanethidine plasma levels to adrenergic blockade. Plasma levels of guanethidine were measured by gas chromatography-mass spectrometry, and adrenergic blockade was defined by determining the venous reflex response to Valsalva maneuver or deep breath. A significant correlation was found between the change in the venous reflex response and the fall in mean standing pressure when guanethidine is given to patients maintained on a sodium restricted diet. A linear relationship was found between dose and plasma guanethidine concentration (p < 0.0001), but there was a 6jold interindividual variation in the plasma levels resulting from any given dose. Adrenergic blockade occurred when plasma levels were 8 nglml or higher. These results indicate that the large individual variation in dose requirements for the hypotensive effects of guanethidine most likely is not due to requirements for greatly different plasma levels of the drug; that the variation must result from pharmacokinetic determinants of differing plasma levels between individuals or from other factors, such as increased plasma volume, which maintain elevated arterial pressure in the face of adrenergic blockade.

Ingeborg E. Walter, M.D.: Jai Khandelwal, Ph.D., Fred Falkner, Ph.D., and Alan S. Nies, M.D. Nashville, Tenn. Division of Clinical Pharmacology, Department of Medicine and Pharmacology, Vanderbilt University School of Medicine

The relationship between the dose of guanethidine and the hypotensive response in the population of patients with hypertension is not predictable. Possible explanations for this variability include individual differences in sensitivity of the adrenergic nervous system to the drug and individual pharmacokinetic difSupported in part by Public Health Service Grants Nos. }M15431 and 5MOIRR95. Received for publication June 16, 1975. Accepted for publication Aug. 19, 1975. Reprint requests to: Dr. Alan S. Nics, Vanderbilt University :chool of Medicine, Nashville, Tenn. 37232.

* Supported by

the Deutsche Forschungsgemeinschafl.

ferences resulting in variable plasma drug levels for any given dose of drug, Two major difficulties in the proper evaluation of this variable sensitivity to guanethidine have been the lack of a simple method to assess sympathetic blockade and the lack of a plasma level assay for the drug. Blood pressure alone is not always a helpful parameter in deciding when the sympathetic nervous system is blocked. During adrenergic blockade, blood pressure is dependent on the plasma volume, which, if increased, can counteract the hypotensive effect of adrenergic blocking drugs. 2 Therefore, the hemodynamic response to Valsalva's maneuver 571

572

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Walter et al.

Clinical Pharmacology and Therapeutics

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