Bernhard Heintz

Clinical Pharmacokinetics of Vasodilators

Stimulating cardiac β1-adrenoceptors with oxyfedrine causes dilatation of coronary vessels and positive inotropic effects on the myocardium. β1-adrenergic agonists increase coronary blood flow in nonstenotic and stenotic vessels.The main indication for the use of the phosphodiesterase inhibitors pamrinone, mirinone, enoximone and piroximone is acute treatment of severe congestive heart failure. Theophylline is indicated for the treatment of asthma, chronic obstructive pulmonary disease, apnea in preterm infants ans sleep apnea syndrome.Severe arterial occlusive disease associated with atherosclerosis can be beneficially affected by elcosanoids. These drugs must be administered parenterally and have a half-life of only a few minutes.Sublingual or buccal preparations of nitrates are the only prompt method (within 1 or 2 min) of terminating anginal pain, except for biting nifedipine capsules. The short half-life (about 2.5 min) of nitroglycerin (glyceryl trinitrate) makes long term therapy impossible. Tolerance is a problem encountered with longer-acting nitric oxide donors.Knowledge of the pharmacokinetic properties of vasodilating drugs can prevent a too sudden and severe blood pressure decrease in patients with chronic hypertension. In considering the administration of a second dose, or another drug, the time necessary for the initially administered drug to reach maximal efficacy should be taken into account.In hypertensive emergencies urapidil, sodium nitroprusside, nitroglycerin, hydralazine and phentolamine are the drugs of choice, with the addition of β-blockers during catecholamine crisis or dissecting aortic aneurysm.Childhood hypertension is most often treated with angiotensin-converting enzyme (ACE) inhibitors or calcium antagonists, primarily nifedipine. Because of the teratogenic risk involved with ACE inhibitors, extreme caution must be exercised when prescribing for adolescent females.The propagation of health benefits to breast-fed infants, combined with more women delaying pregnancy until their fourth decade, has entailed an increase in the need for hypertension management during lactation. Low dose hydrochlorothiazide, propranolol, nifendipine and enalapril or captopril do not pose enough of a risk to preclude breastfeeding in this group.The most frequently used antihypertensive agents during pregnancy are methyldopa, labetalol and calcium channel antagonists. Methyldopa and β-blockers are the drugs of choice for treating mild to moderate hypertension. Prazosin and hydralazine are used to treat moderate to severe hypertension and hydralazine, urapidil or labetalol are used to treat hypertensive emergencies. The use of overly aggressive antihypertensive therapy during pregnancy should be avoided so that adequate uteroplacental blood flow is maintained. Methyldopa is the only drug accepted for use during the first trimester of pregnancy.

Clinical pharmacokinetics of vasodilators : Part I

SummaryUnderstanding the mechanism of action and the pharmacokinetic properties of vasodilatory drugs facilitates optimal use in clinical practice. It should be kept in mind that a drug belongs to a class but is a distinct entity, sometimes derived from a prototype to achieve a specific effect. The most common pharmacokinetic drug improvement is the development of a drug with a half-life sufficiently long to allow an adequate once-daily dosage. Developing a controlled release preparation can increase the apparent half-life of a drug. Altering the molecular structure may also increase the half-life of a prototype drug. Another desirable improvement is increasing the specificity of a drug, which may result in fewer adverse effects, or more efficacy at the target site. This is especially important for vasodilatory drugs which may be administered over decades for the treatment of hypertension, which usually does not interfere with subjective well-being. Compliance is greatly increased with once-daily dosing.Vasodilatory agents cause relaxation by either a decrease in cytoplasmic calcium, an increase in nitric oxide (NO) or by inhibiting myosin light chain kinase. They are divided into 9 classes: calcium antagonists, potassium channel openers, ACE inhibitors, angiotensin-II receptor antagonists, α-adrenergic and imidazole receptor antagonists, β1-adrenergic agonists, phosphodiesterase inhibitors, eicosanoids and NO donors.Despite chemical differences, the pharmacokinetic properties of calcium antagonists are similar. Absorption from the gastrointestinal tract is high, with all substances undergoing considerable first-pass metabolism by the liver, resulting in low bioavailability and pronounced individual variation in pharmacokinetics. Renal impairment has little effect on pharmacokinetics since renal elimination of these agents is minimal. Except for the newer drugs of the dihydropyridine type, amlodipine, felodipine, isradipine, nilvadipine, nisoldipine and nitrendipine, the half-life of calcium antagonists is short. Maintaining an effective drug concentration for the remainder of these agents requires multiple daily dosing, in some cases even with controlled release formulations. However, a coat-core preparation of nifedipine has been developed to allow once-daily administration. Adverse effects are directly correlated to the potency of the individual calcium antagonist.Treatment with the potassium channel opener minoxidil is reserved for patients with moderately severe to severe hypertension which is refractory to other treatment. Diazoxide and hydralazine are chiefly used to treat severe hypertensive emergencies, primary pulmonary and malignant hypertension and in severe pre-eclampsia.ACE inhibitors prevent conversion of angiotensin-I to angiotensin-II and are most effective when renin production is increased. Since ACE is identical to kininase-II, which inactivates the potent endogenous vasodilator bradykinin, ACE inhibition causes a reduction in bradykinin degradation. ACE inhibitors exert cardioprotective and cardioreparative effects by preventing and reversing cardiac fibrosis and ventricular hypertrophy in animal models. The predominant elimination pathway of most ACE inhibitors is via renal excretion. Therefore, renal impairment is associated with reduced elimination and a dosage reduction of 25 to 50% is recommended in patients with moderate to severe renal impairment.Separating angiotensin-II inhibition from bradykinin potentiation has been the goal in developing angiotensin-II receptor antagonists. The incidence of adverse effects of such an agent, losartan, is comparable to that encountered with placebo treatment, and the troublesome cough associated with ACE inhibitors is absent.

Tacrolimus- (FK 506) based immunosuppression in severe systemic lupus erythematosus.

In a 30-year-old male patient systemic lupus erythematosus was diagnosed based on the presence of 8 out of 11 ARA criteria. Disease onset was acute and included renal function impairment with biopsy-proven lupus nephritis (WHO class IV) requiring renal replacement therapy. Although conventional immunosuppressive therapy regimens proved effective in controlling disease activity, all of the administered drugs were accompanied by serious side effects: bilateral femur head necrosis with corticosteroids, allergic skin reaction in response to azathioprine, nephrotoxicity with cyclosporine, nausea and abdominal pain with mycophenolate mofetil and life-threatening septicemia with cyclophosphamide treatment. In search for alternative treatment options, tacrolimus (FK506, trough serum levels 3-6 ng/ml) was started. FK506 was well-tolerated and lupus activity completely resolved within 7 months after initiation of therapy. During 36 months of follow-up no arthritic complaints occurred and renal function stabilized at a serum creatinine of 2.1 mg/dl with negative anti-ds-DNA antibodies and ANA titers. In conclusion, FK506 may be considered as alternative immunosuppressive for maintenance treatment in patients with severe lupus erythematosus and side effects to conventional regimens.

VCAM-1, ICAM-1, and E-Selectin in IgA Nephropathy and Schönlein-Henoch Syndrome: Differences between Tissue Expression and Serum Concentration

The tissue expressions of vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1) and endothelial leukocyte adhesion molecule 1 (E-selectin-1) were investigated in biopsy specimens from 28 patients with different stages of IgA nephropathy (IgAN) and 20 patients with acute renal failure (ARF) or chronic renal diseases (amyloidosis, Alport’s glomerulopathy) by immunohistochemistry. The results were compared with the serum levels of the three adhesion molecules. VCAM-1 expression was significantly increased on parietal/tubular epithelial cells in IgAN and ARF. Significantly elevated circulating VCAM-1 levels were measured in IgAN and amyloidosis, but did not correlate with renal function (creatinine clearance). Significantly increased glomerular endothelial/epithelial ICAM-1 expression was found in IgAN and ARF. Intense mesangial ICAM-1 expression was found in mild stages of IgAN and in Schönlein-Henoch syndrome. Circulating ICAM-1 was not significantly elevated in IgAN and different renal diseases. VCAM-1 and ICAM-1 expressions of interstitial infiltrating cells were significantly higher in severe than in mild IgAN and associated with an increased infiltration of inflammatory leukocytes. Patients with IgAN and different renal diseases had decreased mesangial and almost absent interstitial E-selectin expression as compared with controls. The circulating E-selectin levels were significantly elevated in ARF. In conclusion, the tissue expression of adhesion molecules in IgAN reflects a continuous inflammatory renal activity. However, only increased circulating VCAM-1 serum levels correlated significantly with the histological state of renal inflammation and could be used as a disease marker.

Increased activity of the autonomic nervous system and increased sensitivity to angiotensin II infusion after therapy with recombinant human erythropoietin.

Bernhard Heintz, MD, Department of Internal Medicine II, RWTH Aachen, Pauwelsstreet 30, D-5100 Aachen (FRG) Dear Sir, The pathophysiological role of the autonomic nervous system in the development of arterial hypertension during regular therapy with recombinant human erythropoietin (rh-EPO) is unclear [1]. Recently, Fritschka et al. [2] reported elevated plasma norepinephrine concentrations and a decrease of < 3⁄4-adrenoreceptors in dialysis patients treated with rh-EPO. Blood samples were drawn from 11 haemodialysis patients at rest and at the peak of physical exercise (initially 25 W, increased by 25 W every 2 min) to determine epinephrine (E), norepinephrine (NE), aldosterone (ALD) concentrations and plasma renin activity (PRA) before and after 6 weeks and 3 months of rh-EPO treatment. An initial dose of 40 IU/kg body weight 3 times per week intravenously was administered. If a haematocrit of 35% was not reached after 4 weeks the dose was increased by 40 IU/kg body weight. If the haematocrit exceeded 35% the dose was reduced by 40 IU/kg body weight or the infusion was completely stopped. Before, after 6 weeks and 3 months after rh-EPO administration an angiotensin II infusion test was performed (initial dose 0.5 μg/min with stepwise increase of 0.5 μg/min until the mean arterial pressure showed an increase of 20 mm Hg). Cardiac output (technetium ven-triculography) was measured and total peripheral resistance (TPR) calculated from mean arterial blood pressure as well (table 1). Resting blood pressure values did not change during the course of rh-EPO therapy. Aldosterone and renin activity also remained unchanged, but epinephrine and particularly norepinephrine increased during rh-EPO therapy, with a peak at 6 weeks of treatment. Exercise caused the systolic blood pressure to increase before and

Pressure Oscillation Regulates Human Mesangial Cell Growth and Collagen Synthesis

Experimental renal disease models establish glomerular hypertension as a crucial determinant in glomerulosclerosis progression and demonstrate that glomerular capillary pressure reduction delays sclerosis development. An oscillating pressure (OP) chamber was constructed as an in vitro model to study human mesangial cells. Cell cultures were grown under atmospheric pressure (AP) and a controlled OP corresponding to intraglomerular capillary pressure. We show that OP significantly decreases mesangial cell proliferation within 24 hours and attenuates DNA synthesis throughout a 7-day period. To explore the effects of OP on cell metabolism, cell-associated and medium-secreted extracellular (CA and EC, respectively) collagen synthesis were measured by [3H]proline incorporation. In subconfluent cultures, total CA and EC collagen synthesis was unaffected by OP, while in confluent cultures total EC collagen [3H]proline incorporation was increased. To determine whether OP influenced mesangial cell growth induction, the effects of increasing glucose in the cell culture media were investigated. Our data show that the high glucose growth stimulatory effect on cell number and DNA synthesis was suppressed by OP. Under high glucose conditions, total CA collagen synthesis was increased in confluent cultures, whereas the EC collagen fraction remained unchanged. In these cultures, OP caused an additional increase in CA collagen synthesis. This study shows that mesangial cell growth and collagen synthesis are influenced by hyperbaric OP, supporting the hypothesis that glomerular capillary pressure plays a role in progressive glomerulosclerosis development.

Magnesium pyridoxal 5-phosphate glutamate reduces hyperlipidaemia in patients with chronic renal insufficiency

SummaryChronic renal insufficiency is often accompanied by hyperlipidaemia and subsequent coronary heart disease.Two groups of 15 patients with serum creatinine >2 mg/100 ml and serum cholesterol >250 mg/100 ml were given 3×50 mg magnesium pyridoxal 5-phosphate glutamate (MPPG) or placebo for 12 weeks in a double-blind, randomised study.Total cholesterol in the MPPG group (282.4 mg·100 ml−1) was lower than in the placebo group (354.3 mg·100 ml−1) after 12 weeks of treatment. Triglycerides in the MPPG group were 265.1 mg·100 ml−1 compared to 361.9 mg·100 ml−1. After 12 weeks on MPPG the LDL/HDL ratio of 3.56 was lower than in the placebo group — 6.83. Side effects in the MPPG group were similar to those in the placebo group. Thus, MPPG was an effective antihyperlipidaemic agent in patients with renal insufficiency.

Decreased glomerular basement membrane heparan sulfate proteoglycan in essential hypertension

Abstract Heparan sulfate proteoglycans are major components of the glomerular basement membrane and play a key role in the molecular organization and function of the basement membrane. Moreover, their presence is essential for maintenance of the selective permeability of the glomerular basement membrane. Recently, we isolated and characterized a novel small basement membrane–associated heparan sulfate proteoglycan from human aorta and kidney. Partial amino acid sequence data clearly show that this heparan sulfate proteoglycan is distinct from the large basement membrane–associated heparan sulfate proteoglycan (perlecan). Using specific monoclonal antibodies, we have shown that the novel heparan sulfate proteoglycan is located predominantly in the glomerular basement membrane and, to a lesser extent, in the basement membrane of tubuli. Turnover or, in the course of kidney diseases, degradation of heparan sulfate proteoglycan from glomerular basement membranes may lead to urinary excretion of heparan sulfate proteoglycan, which can be measured by a sensitive enzyme immunoassay. The aim of the present study was to analyze whether changes in the structure and function of glomerular basement membranes can be directly detected by measurement of the excretion of a component of this basement membrane, eg, heparan sulfate proteoglycan into urine. The excretion of this small heparan sulfate proteoglycan was compared after physical exercise in normotensive and hypertensive subjects. Normotensive subjects and treated, essential hypertensive patients underwent a standardized workload on a bicycle ergometer. Biochemical characterization of the urinary proteins and heparan sulfate proteoglycan was performed before and 15 and 45 minutes after exercise. In both groups, physical exercise induced a significant increase in the excretion of urinary α1 microglobulin and albumin. However, a 10-fold increase in the urinary excretion rate of heparan sulfate proteoglycan was seen in normotensive subjects under exercise. In hypertensive patients, the relative increase in heparan sulfate proteoglycan excretion was significantly diminished ( P <.05). These data, supported by immunohistochemistry, indicate changes in the glomerular basement membrane of the kidney in hypertension. Therefore, determination of urinary excretion of this novel small heparan sulfate proteoglycan after exercise may be a sensitive marker for the detection of basement membrane alterations in hypertension.

Hemodialysis Procedure Does Not Affect the Levels of sICAM-1 and sVCAM-1 in Patients with End Stage Renal Disease

Atherosclerosis is by far the leading cause of mortality and morbidity in patients with end stage renal disease undergoing chronic hemodialysis (HD). Vascular endothelial cell adhesion molecules like the intercellular adhesion molecule-1 (ICAM-1) and the vascular cell adhesion molecule-1 (VCAM-1) are involved in the pathogenesis of atherosclerosis. Their soluble forms (sICAM-1, sVCAM-1) are considered potential serum markers of endothelial activation and atherosclerosis. The aim of this study was to clarify the influence of the HD procedure on the levels of sICAM-1 and sVCAM-1 in patients with end stage renal disease. We evaluated 35 clinically stable patients (18 males, 17 females, mean age 61 ± 12) on chronic HD treatment. Diabetes mellitus coexisted in eight patients and arterial hypertension in 23 patients. Blood was drawn before, every hour during, and after a single HD session in each patient. Low-flux cuprophane dialyzers (GFS 12®, Gambro, Lund, Sweden) were used in 22 and high-flux polysulfone dialyzers (Hemoflow F 60S®, Fresenius, Oberursel, Germany) in 13 cases. At 30 min into the HD session (n = 31, 20 low-flux HD, 11 high-flux HD) blood was drawn simultaneously from the entrance and the exit line of the dialyzer. From all these samples, serum concentrations of sICAM-1 and sVCAM-1 were determined by commercially available enzyme immunoassays (ELISA, R&D Systems, Minneapolis, USA). Results were corrected according to hemoconcentration, where appropriate. Plasma levels of sVCAM-1 were elevated in patients with end stage renal disease before the beginning of the dialysis session when compared to healthy controls (1449 ± 497 ng/mL vs. 691 ± 118 ng/mL). On the contrary, such an elevation was not found in the case of sICAM-1 (231 ± 58.5 ng/mL vs. 236.4 ± 96.8 ng/mL in healthy controls). These levels remained stable in all measurements throughout the dialysis procedure. Furthermore, serum sICAM-1 and sVCAM-1 levels remained unaltered after the passage of the dialyzer. The levels of sICAM-1 and sVCAM-1 were not influenced by the existence of diabetes mellitus, hypertension, or by the utilization of biocompatible, high flux dialyzers. Our study confirms that in chronic HD patients serum levels for sVCAM-1 are elevated. The levels of adhesion molecules are not affected by the HD procedure. These findings probably can be attributed to a decreased renal clearance or catabolism of sICAM-1 and sVCAM-1 and to the different sources of the two molecules. Neither coexisting diabetes mellitus nor arterial hypertension influences the circulating levels of these adhesion molecules. The functional role of sVCAM-1 and sICAM-1, the exact renal contribution to their metabolism, and their role as markers of atherosclerosis in chronic renal disease need further evaluation.

Plasma endothelin-1 in hemodialysis treatment - the influence of hypertension.

In patients on chronic hemodialysis hypotensive episodes are frequently encountered during the course of treatment and the prevalence of atherosclerosis is increased. Endothelin-1 (ET-1), an endothelium-derived peptide with vasoconstrictive and mitogenic effects on smooth muscles, is involved in vascular tone regulation and in the pathogenesis of atherosclerosis. The aim of the present study was to investigate plasma ET-1 during hemodialysis treatment and to explore the probable influence of pre-existing hypertension. Forty-seven hemodialysis patients (21 females, mean age 62 ± 12 years) were evaluated and hypertensive patients (n = 33) were compared to normotensive patients (n = 14). Relative blood volume changes (hemoglobinometry) and blood pressure were measured. Samples were taken before, every hour during and after hemodialysis. Plasma ET-1 was measured by enzyme-linked immunosorbent assay and results were corrected according to hemoconcentration. Hemodialysis with an ultrafiltration rate of 2224 ± 933 mL was performed. Total blood volume at the end of hemodialysis was 89.4 ± 8.2% of the pretreatment volume. The fall in blood pressure (137/74 ± 22/11 mmHg vs 127/73 ± 30/14 mmHg) correlated with the decrease in blood volume (mean blood pressure: r = 0.33). Plasma ET-1 increased from 1.29 ± 0.47 pg/mL before to 1.46 ± 0.56 pg/mL (reference range 0.3-0.9) at the end of hemodialysis (P < 0.05). This rise was more pronounced in patients with hypertension than in normotensive individuals (P < 0.05). The change in blood volume (r = 0.41) and blood pressure (mean blood pressure: r = 0.34) correlated with plasma ET-1 at the end of hemodialysis (P < 0.05). Plasma ET-1 was enhanced in hemodialysis patients compared to normal subjects. During the hemodialysis session an increase in ET-1 was encountered, which was more pronounced in hypertensive than in normotensive patients and paralleled the hemodynamic changes. Apart from pre-existing hypertension, further factors potentially influencing ET-1 include local endothelial injury (arteriovenous fistula) and generalized bioincompatibility reactions (e.g. foreign surface contact) occurring during hemodialysis.