R. Kirsten

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.

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

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.

Clinical pharmacokinetics of urapidil.

SummaryUrapidil is a selective α1adrenoceptor antagonist with central antihypertensive action which is increasingly used in the treatment of hypertension. Urapidil is readily absorbed, is subject to moderate first-pass metabolism and is eliminated primarily as metabolites of much lower antihypertensive activity than the parent drug.The influences of age, renal and hepatic disease on the disposition of urapidil are reviewed. Studies on the relationship between pharmacodynamics and pharmacokinetics show that the optimum use of urapidil in clinical practice depends on an understanding of the pharmacokinetic properties of the drug.

Response of Vasoactive Substances to Intermittent Ultrafiltration in Normotensive Hemodialysis Patients

The changes in blood volume (BV), atrial natriuretic peptide (ANP), plasma renin activity (PRA), aldosterone (Aldo), norepinephrine (NE), epinephrine (Epi), parathyroid hormone (PTH), arginine vasopressin (AVP) and the cyclic nucleotides cAMP and cGMP were measured during a fluctuating BV cycle in 15 patients with end-stage renal failure maintained on chronic hemodialysis (HD). HD consisted of 4 periods of about 60 min each. The first half of each HD period consisted of ultrafiltration (UF) greater than 1,000 ml/h, and the second half consisted of no UF. Changes in relative BV were measured using continuous hemoglobinometry. Total BV at the end of treatment was 74.3 +/- 6.9% of the pretreatment volume. A significant positive correlation between BV and the levels of ANP, PTH, Epi and cGMP and an inverse correlation between BV and PRA, Aldo, AVP and NE were demonstrated. While mean values of NE and AVP levels were directly related to actual changes in BV, individual values did not homogeneously reflect this relationship. The cyclic nucleotides cGMP and cAMP did not follow immediate BV changes, but showed a significant decrease correlated with diminished BV. Based on a pre-postdialysis analysis, significant changes in PRA and Aldo were missing. It seems possible that vascular stability in dialysis patients may be maintained by the response of NE and AVP, and not by the renin-aldosterone system. The changes in ANP and cGMP values correlated most significantly (r = 0.38 and r = 0.51, p < 0.005) with the changes in BV, but no single variable could explain the blood pressure regulation during HD with intermittent rapid UF.

Pharmacodynamics and pharmacokinetics of urapidil in hypertensive patients: a crossover study comparing infusion with an infusion-capsule combination

SummaryThe pharmacokinetics and haemodynamic effects of infused urapidil and an infusion-capsule combination were followed to study the correlation between the serum urapidil level and the blood pressure. Prior to urapidil administration, basal blood pressure and heart rate were measured for 16 h in 12 male hypertensive patients. Six patients received infusions lasting for 4 h of urapidil 10, 2.5 and 5 mg/h. Six patients were infused with urapidil 10 mg/h for 4 h and 2 h after the end of the infusion each took a 60-mg capsule. After a 5 day washout period the procedures were crossed over. A maximum serum urapidil level of 625±232 ng/ml was achieved at the end of the 10 mg/h infusion, when the fall in blood pressure was 37/21 mmHg. During the 2.5 and 5 mg/h infusions the serum urapidil level was 330 and 420 ng/ml, respectively, and the corresponding decreases in blood pressure were 28/16 mmHg and 31/8 mmHg. Although the urapidil concentration 1 hour after beginning the infusion was only 184±89 ng/ml a near maximal blood pressure decrease had already occurred 33±9/20±8 mmHg, whereas, 1 h after the end of the infusion the reduction in blood pressure was only 10±12/3±8 mm, with a urapidil concentration of 358±120 ng/ml. During the plateau phases of both the infusion and infusion-capsule treatments the falls in blood pressure followed the serum urapidil levels. Only in the initial rising and final falling phases of the treatments were the pharmacodynamics and pharmacokinetics of urapidil not correlated.

Pharmacodynamics and pharmacokinetics of three different doses of urapidil infused in hypertensive patients

SummaryThe study was designed to follow the haemodynamic effects and pharmacokinetics under steady-state conditions of three different doses of urapidil infused continuously. Nine male hypertensive patients received three randomly assigned intravenous infusions of 32.5, 65 and 130 mg urapidil, over 14 h during 6 consecutive days, in a change-over fashion. Blood pressure and heart rate were measured over a period of 28 h after the infusion began and were compared with a reference profile obtained prior to the treatment periods. Urapidil and its main metabolite, parahydroxylated urapidil, were also determined for 28 h after the infusion began using HPLC. The 32.5 mg dose of urapidil caused a maximum decrease in systolic blood pressure of 33±8 mmHg, the 65 mg dose a maximum decrease of 39±12 mmHg and the 130 mg dose a maximum decrease of 50±12 mmHg. The 32.5 and 65 mg doses resulted in similar serum urapidil concentrations, with maximum levels in the 100 to 200 ng/ml range, and the 130 mg dose caused a maximum level approximately four times that achieved with the 32.5 mg dose. The serum concentration of parahydroxy urapidil was proportional to the corresponding dose of urapidil. Four patients reported mild headache, fatigue, weakness, pressure in the head, perspiration and orthostatic dysregulation. The side-effects were probably drug related but required no specific therapy. In summary, the 32.5 mg dose of urapidil resulted in a pronounced decrease in blood pressure. The average pressure reduction over the 14-h infusion period showed further dose-dependent increases after the 65 and 130 mg doses. In severe hypertension, the 130 mg dose can be employed, since it does result in a further, significantly larger decrease in blood pressure.

Endothelin-1 Potentiates ADP-Induced Platelet Aggregation in Chronic Renal Failure

The effect of preincubation of heparinized whole blood with endothelin-1 (ET-1) on the ADP (adenosine diphosphate) and epinephrine-induced platelet aggregation was examined in 20 healthy donors compared with 20 patients with chronic renal failure (CRF). ET-1 significantly stimulated ADP-induced aggregation in CRF: EC (effective concentration)25 = 2.3 +/- 0.20 with ET-1 vs. 2.7 +/- 0.22 mumol/L without ET-1; EC50: 3.8 +/- 0.18 with ET-1 vs. 4.4 +/- 0.24 mumol/L without ET-1; and EC75: 5.7 +/- 0.22 with ET-1 vs. 6.4 +/- 0.21 mumol/L without ET-1). In healthy donors only the EC25 was significantly increased: EC25 = 2.5 +/- 0.13 with ET-1 vs. 2.8 +/- 0.20 mumol/L without ET-1. No significant influence of ET-1 in epinephrine-induced aggregation was observed in CRF or in healthy donors. The basal values of determined ET-1 were significantly elevated in CRF: 6.99 +/- 0.29 pmol/mL vs. 5.65 +/- 0.33 pmol/mL in healthy donors. The high endogenous level of ET-1 in CRF patients together with an observed higher endogenous plasma level of cAMP (58 +/- 5.2 nmol/L compared to 29 +/- 2.0 nmol/L in healthy donors) may explain the enhanced pharmacological interaction of ET-1 and ADP in CRF patients. The data suggest that positive agonist interaction between ET-1 and ADP may result from effects on the concentrations of cAMP within the platelet rather than from direct interaction on the membrane receptors or the transmembrane coupling mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)

Naftopidil inhibits 5-hydroxytryptamine-induced platelet aggregation and 5-hydroxytryptamine uptake in platelets of healthy volunteers

Naftopidil exerts its antihypertensive action via α1-adrenoceptor blockage and Ca2+ antagonism in vascular smooth muscle. Since the chemically similar 1-(1-naphthyl) piperazine is known to be a 5-hydroxytryptamine2 receptor antagonist, the 5-hydroxytryptamine (5-HT) antagonistic properties of naftopidil were tested by examining 5-HT-induced aggregation and 5-HT uptake in platelets from 12 healthy volunteers after oral administration of 60 mg naftopidil or placebo.Platelet aggregation in vitro was inhibited by naftopidil with a Ki value of 1.1 μM, the pIC50 was 5.09 with induction of aggregation by 1 μM 5-HT. After oral administration of naftopidil, 5-HT-induced aggregation was significantly inhibited by 36%. 4 h after naftopidil administration, 5-HT uptake velocity was reduced by 33%. Naftopidil not only cancelled the circadian increase in 5-HT-induced aggregation velocity observed during placebo application, but also caused a decrease in aggregation velocity directly after peak plasma naftopidil levels. 5-HT uptake in platelets was also reduced following peak naftopidil plasma concentrations. The 5-HT inhibitory action of naftopidil adds a third possible antihypertensive property to naftopidils α1-adrenoceptor blocking and Ca2+ antagonistic properties.