Farmer's Lung

_~~~~EIA JORAL 10 standing position.It is interesting that the hypotension in the sitting postion is not greater, and, in fact, that the blood pressure rises promptly on sitting down.A great deal of attention has been paid in these experi- ments to recording blood pressure in the erect posture, using a fixed time limit as described.Standing systolic readings have proved to be a convenient measure of the total effect of the drug on the blood pressure, since the changes in these readings are bigger in proportion to the errors of tech- nique than in the sitting or recumbent positions, and, moreover, they provide an important measure of the maximum effect of the drug.The distribution of hexamethonium in the body and its excretion at a rate comparable to that of inulin correspond to its quaternary nature.Bases in general penetrate the cell membrane only in the un-ionized form (Hober, 1945).Salts of quaternary nitrogen when in solution are completely ionized, and hence can only traverse the cell membranes very slowly.Accordingly they must lead an extracellular exist- ence in the body, and should be unable to be either secreted or reabsorbed by the kidney tubules.The indication from clinical data (Fig. 4) that normal subjects vary considerably in their response to hexa- methonium was borne out and further elucidated by the plasma-concentration curves.Part of this variation is obviously due to the differences in absorption, distribution, and excretion already described; but the main variation, and one that cannot be eliminated by changing the route of administration, lies in the actual response of different sub- jects to the same concentration of the drug in the plasma (Fig. 6).The immediate practical application is that it is not safe to give initial doses of more than about 30-40 mg.subcutaneouLsly to ambulant patients, even though this dose may produce little response in many individuals.The somewhat unexpected finding of a linear rather than a logarithmic relationship between the plasma concentration and the effect on the blood pressure has some practical im- portance in addition to its theoretical interest ; when treat- ing patients for hypertension the dose should not be increased too rapidly.Increments of not more than 25-50 mg.should be used according to the individual patient's sensitivity.The manner in which these findings in normal subjects may be applied to hypertensive patients under treatment is being studied and will be reported later. SummaryA detailed study of the clinical effects of a sub- cutaneous test dose of hexamethonium in 16 normal individuals is reported, and plasma-concentration curves are described in eight of these.No effects have been observed which could not be attributed to ganglionic block, with the possible excep- tion of drowsiness.Calculations from the concentration-time curves of hexamethonium in the plasma indicate that the drug is evenly distributed through the extracellular fluid, and they are compatible with its excretion by glomerular filtration.Considerable variation in the response of different individuals to hexamethonium has been shown to occur, in relation both to the dose given per kilogram of body weight and to plasma levels.The thresholds for reduc- tion of blood pressure, for elevation of pulse rate, and for interference with three separate pupillary functions varied from subject to subject, independently of each other.For a given individual there was a close linear relationship between the plasma concentration and the degree of blood-pressure reduction.We should like to thank Professor J. McMichael for his advice and helpful criticism in the carrying out of this work.