The relationship of plasma guanethidine levels to adrenergic blockade

Abstract

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.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 dif-

The effect of a single oral dose of prazosin on venous reflex response, blood pressure and pulse rate in normal volunteers.

“…The major determinants of the calibre of cutaneous veins are ambient temperature, emotion and respiratory reflexes (Browse & Hardwick, 1969;Shepherd & Vanhoutte, 1978). Maintenance of a constant environment, with respect to temperature and a constant, relatively low level of external stimulation, has enabled the use of the VRR, which is also activated by resplratory reflexes (Nies, 1978), as a convenient method for assessment of adrenergicneuron blockade by guanethidine (Walter et al, 1975). The similar usefulness of the VRR, as a guide to prazosin dosage and compliance, during maintenance therapy for hypertension and cardiac dysfunction, has yet to be evaluated.…”

“…was estimated by the addition of a third of the pulse pressure to the diastolic pressure, which was determined at the fifth phase of Korotkoff sounds. The pulse rate (PR) expressed as beats/min was determined by doubling the number of beats counted by palpation of the radial pulse for 30 s. The venous reflex response (VRR) was measured by a modification of the occluded limb technique (Browse & Hardwick, 1969;Samueloff, Bevegard & Shepherd, 1966;Walter et al, 1975). The intraluminal pressure of a superficial vein on the dorsum (3).…”

“…Peripheral venoconstriction, measured by the venous reflex response (VRR), has been demonstrated during vasovagal syncope (Epstein, Stampfer & Beiser, 1968). Orthostatic hypotension produced by guanethidine has also been related to sympathetically mediated changes in venous tone, measured by the VRR, when the dietary sodium of hypertensive patients was restricted (Walter et al, 1975).…”

Alfuzosin and the venous reflex response: studies in normal subjects.

“…The venous reflex response (VRR) is considered to be an effective method for assessing noradrenergic systemic venoconstrictor tone (Samueloff et al, 1966;Epstein et al, 1968). Attenuation of the VRR has been shown to parallel the reduction in blood pressure during guanethidine therapy (Walter et al, 1975) and has been associated with postural hypotension and syncope ('first dose' phenomenon) following prazosin (Schapel & Betts, 1981). Alfuzosin, a 1,3 diaminpropane derivative, is a selective post-synaptic aladrenoceptor antagonist with both antihypertensive and peripheral vasodilator properties.…”