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Nine patients on maintenance hemodialysis and transfusion-demanding renal anemia (group A) were treated with rHuEPO 120 IU/kg i.v. three times per week. Hemoglobin-content was raised from 7.2 +/- 0.9 to 10.4 +/- 0.8 g/dl. In all patients blood pressure rose, three patients developed arterial hypertension. Mean diastoloic blood pressure was 66 +/- 12 and 78 +/- 16 mmHg (p less than 0.001) before and after rHuEPO. Rise in blood pressure was accompanied by a significant fall in plasma-noradrenaline-levels (from 498 +/- 100 to 383 +/- 75 pg/ml; p less than 0.05) and alpha 2-adrenoceptor-density (from 574 +/- 76 to 384 +/- 49; p less than 0.05). Compared to nine patients on maintenance hemodialysis and hematocrit over 30% (group B), patients with severe renal anemia (group A before treatment) had higher densities of alpha 2-adrenoceptors (574 +/- 76 vs. 218 +/- 32; p less than 0.001) despite higher plasma-noradrenaline-levels (498 +/- 100 vs. 399 +/- 63; n.s.). We suppose a anemia-related disturbance of alpha 2-receptor-function with the result of abolished receptor down-regulation and impaired vascular reagibility to vasoconstricting stimuli. With the correction of anemia receptor-function improves, receptor down-regulation as well as vascular reagibility is re-established resulting in augmented vascular resistance and higher blood pressure.

Basic research led to the clarification of the mechanisms of action of numerous pharmacotherapeutic agents. Experimental and clinical pharmacology has a key position in the formulation and introduction of effective and safe medications. The investigation of pharmacokinetic and pharmacodynamic effects must use reproducible quantitative methods, such as controlled clinical trials. However, the complexity of medical, ethical and legal problems inherent in controlled clinical trials may explain why few pharmacological studies have been performed in intensive care medicine conditions. A particular problem is undoubtedly the need for a multimodal treatment, as this might well lead to drug interactions in the critically ill. We generally have to distinguish between pharmacokinetic interactions, i.e. resorption, distribution, altered interaction between metabolism and elimination of a drug, and pharmacodynamic interactions due to synergistic or antagonistic affects at the same receptor or target organ. In recent decades clinical pharmacology has developed in a dualistic manner. Whereas the correlation between plasma level and therapeutic effects is considered to be of primary importance, the correlation between dosage and relevant pharmacodynamic effects is thought to be of only secondary relevance. Pharmacokinetics and pharmacodynamics should not be seen as rival approaches, but rather as complementary methods in clinical pharmacology.

A natriuretic factor has long been postulated to play a role in renal mineralocorticoid escape. We therefore investigated changes in plasma levels of atrial natriuretic peptide (ANP) during chronic treatment with 9 alpha-fluorohydrocortisone. Five normal subjects were studied on a constant diet (300 meq Na+ and 72 meq K+ per day) and received 0.8 mg 9 alpha-fluorohydrocortisone for up to 14 days. Sodium balance became positive and body weight increased between 1.0-4.5 kg maximally. Serum aldosterone was suppressed and plasma levels of ANP were stimulated up to 10-fold. Increment in plasma ANP was positively correlated with the gain in body weight (r = 0.666, p less than 0.001). Renormalization of sodium balance was seen in two subjects, however the maximum in plasma ANP did not occur during the time of renal escape. ANP-secretion is stimulated during sodium retention induced by mineralocorticoids, however ANP does not seem to trigger the escape mechanism.