Clinical pharmacologists and health care reform: contributing to the debate.
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Delivery of Health Care↗
Biomedical subjects
A M Shepherd
Publications and source records attributed to A M Shepherd.
A combined urodynamic and continence unit--a review of the first 19 years.
We have completed a 19-year audit of all patients referred to the urodynamic/continence unit since its inception in 1972 and their subsequent clinical management; a total of 20,437 patients were referred, increasing from 51 in the first year to 1564 in 1990. Although the annual number of referrals has remained constant for the last 8 years, the need for more complex urodynamic assessment such as video-cystourethrography has increased from 5% (56/1164) in 1981 to 25% (385/1564) in 1990. The number of out-patient attendances to medical, physiotherapy and continence clinics has also increased over that period. We conclude that the number of referrals represents increasing recognition of the value of urodynamic assessment. Accurate diagnosis leads to more effective treatment, whether surgical, medical or conservative. Some methods of diagnosis are complex and suitable only for a tertiary referral centre.
Ambulatory Care↗
Referral patterns and diagnoses in women attending a urodynamic unit.
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Adolescent↗
Comparative bioavailability of a sustained-release ion-exchange hydralazine product with a potassium (cation) challenge.
A sustained-release formulation of hydralazine was manufactured by binding hydralazine to an ion-exchange resin and coating the drug-resin complex with a semipermeable membrane. Because the sustained-release characteristics are due in part to displacement of drug from the drug-resin complex by gastrointestinal ions, the stability of the sustained-release formulation could be compromised if challenged by a high concentration of ions. In this study, 12 healthy male volunteers participated in a two-way crossover trial that was designed to test the bioavailability and release of drug from the sustained-release formulation both with and without concomitant ingestion of a solution of KCl. Blood samples were collected over a 14-h period after administration of either treatment. Analysis of whole blood for hydralazine and comparison of the values of the area under the curve of the concentration of hydralazine versus time, the maximum concentration of hydralazine, and the time to reach the maximum concentration between the two experimental groups showed that KCl had no influence on the bioavailability or release characteristics of hydralazine from the sustained-release formulation.
Adult↗
Resting and maximal forearm skin blood flows are reduced in hypertension.
To find whether the vasodilator capacity of nonacral skin is reduced in hypertension, we measured forearm blood flow by venous occlusion plethysmography in 10 seated normotensive (mean +/- SD mean arterial pressure, 94 +/- 5 mm Hg) and 10 hypertensive (112 +/- 9 mm Hg) men at rest for 39 minutes while the forearm was heated with water at 42 degrees C, a maneuver known to selectively and maximally vasodilate skin. Blood pressure, measured every 5 minutes, did not change with heating. We found that in the normotensive group resting forearm blood flow was higher (3.64 +/- 1.12 versus 2.48 +/- 0.58 ml/100 ml tissue per minute, p less than 0.001; normotensive group versus hypertensive group) and resting forearm vascular resistance lower (30.17 +/- 10.99 versus 48.88 +/- 17.37 mm Hg.min.100 ml tissue per minute, p less than 0.05; normotensive group versus hypertensive group), and maximal forearm blood flow with local heating was higher (29.32 +/- 11.99 versus 18.19 +/- 4.50 ml/100 tissue per minute, p less than 0.018; normotensive group versus hypertensive group and vascular resistance lower (4.07 +/- 1.04 versus 6.54 +/- 1.17 mm Hg.min.100 ml tissue per minute, p less than 0.005; normotensive group versus hypertensive group). To find whether this degree and duration of local warming maximally vasodilated the skin in hypertensive subjects (as it does in normotensive subjects), we measured forearm skin blood flow before and during local heating plus 10 minutes of ischemia using a laser Doppler flowmeter.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Determination of alpha-adrenergic blocking potency.
Determination of the alpha-adrenergic blocking potency of drugs in humans is usually done by measuring the shift in the blood pressure versus logarithm of intravenous phenylephrine dose-response relationship. Change in blood pressure activates homeostatic reflexes that may change this relationship. This study examines the effect of autonomic (beta 1- and beta 2-adrenergic, parasympathetic, and alpha-adrenergic) blockade on the dose versus blood pressure response relationship to sequential doses of phenylephrine in humans. Phenylephrine dose responses were conducted under controlled conditions, during propranolol and atropine infusion, during prazosin-induced alpha 1-adrenergic blockade, and during prazosin, propranolol, and atropine administration. Propranolol-atropine infusion decreased the threshold dose of phenylephrine required to increase mean blood pressure (p less than 0.00001), increased the slope of the phenylephrine dose versus increase in mean blood pressure relationship (p = 0.019), and and decreased the dose of phenylephrine required to increase mean blood pressure by 20 mm Hg (p less than 0.00001). Determination of the alpha-adrenergic blocking potency of prazosin was not affected by autonomic blockade with propranolol and atropine (dose ratio 5.2 before and 5.0 after autonomic blockade; p = 0.465). We conclude that beta 1- and beta 2-adrenergic and muscarinic blockade increase sensitivity to phenylephrine by increasing the slope and decreasing the threshold dose of the phenylephrine dose-response curve, and that alpha-adrenergic-blocking potency of prazosin may be determined with or without blocking homeostatic blood pressure regulatory mechanisms in humans.
Adrenergic beta-Antagonists↗
The determinants of response to diltiazem in hypertension.
We examined factors (blood pressure, plasma renin activity, and age) influencing the antihypertensive response in essential hypertensive patients given 240 mg/day of slow-release diltiazem in an unblinded study after a placebo run-in period. Subjects provided a range of diastolic blood pressures (90 to 115 mm Hg), of age (31 to 70 years), and of plasma renin activity (0.1 to 2.7 ng angiotensin I/ml/hr) on a 70 to 150 mEq sodium diet. Blood pressure, plasma renin activity, and plasma diltiazem concentrations were measured after the first (n = 21) and final dose (n = 19) of 120 mg diltiazem, twice daily for 4 weeks. Multiple linear stepwise regression of change in blood pressure versus age, plasma renin activity, and baseline blood pressure showed baseline blood pressure was the only predictor of response (p = 0.0002). For each increase of 10 mm Hg in baseline pressure there was a 7 mm Hg greater decrease in diastolic blood pressure. We conclude that patient age and plasma renin activity are not clinically significant predictors of antihypertensive response to diltiazem in hypertension.
Adult↗
A randomized controlled trial of the effects of three antihypertensive agents on blood pressure control and quality of life in older women.
We conducted a multicenter, randomized, double-blind, parallel group trial to compare the impact of titrated doses of atenolol (50 to 100 mg once a day), enalapril (5 to 20 mg once a day), and diltiazem (sustained release) (60 to 180 mg twice a day) on blood pressure and quality of life in older hypertensive women. Two hundred forty-two patients were randomized. Dose titration was completed by week 4 after randomization, and the maintenance phase was completed at week 16. Diltiazem (sustained release) demonstrated greater diastolic blood pressure lowering at both weeks 8 and 16 by an intent-to-treat analysis. At week 16, diltiazem changed diastolic blood pressure -13.7 +/- 0.7 mm Hg compared with -10.8 +/- 1.1 mm Hg for atenolol, and -10.5 +/- 0.9 mm Hg for enalapril. Diltiazem also demonstrated greater lowering of systolic blood pressure at week 3, but these differences in systolic blood pressure had decreased by week 16. More patients were classified as treatment failures during the 16 weeks of the trial for atenolol (15%) than for diltiazem (2.5%), while the treatment failure rate was intermediate with enalapril (8%). Total rates of adverse events were equivalent across the three treatment arms. There were few significant differences in the impact of the three treatments on mean scores of quality-of-life measures at week 16. There was a trend for atenolol to have somewhat worse quality-of-life scores, but none of these differences were statistically significant. In conclusion, all three treatment regimens were effective in lowering diastolic blood pressure without significant differences in rates of adverse events or deleterious effects on quality of life.
Aged↗
A perspective on the American Board of Clinical Pharmacology, Inc.
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Certification↗
A perspective on the American Board of Clinical Pharmacology, Inc.
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Certification↗
Effect of food on oral availability of apresoline and controlled release hydralazine in hypertensive patients.
Hydralazine is a vasodilator antihypertensive drug that has been in use for many years. Efficacy after oral administration correlates well with the levels of the drug in blood. Factors such as food ingestion that affect blood levels of hydralazine may therefore be of importance. There is dispute regarding the effect of food intake on blood levels of hydralazine and on the antihypertensive response. This randomized cross-over study examined the effect of food (642 K calories, 25 g protein, 43 g fat, 40 g carbohydrates, 32 mEq sodium, 17 mEq potassium) ingested immediately before hydralazine (taken as Apresoline, Ciba Geigy, or as slow-release hydralazine, SRH, Pennwalt Corporation) on the blood levels of hydralazine in 16 essential hypertensive patients who were slow acetylators currently taking at least 100 mg Apresoline daily. Peak blood hydralazine levels were reduced by food after both Apresoline and SRH, by 69 and 66%, respectively. Time to peak blood hydralazine concentration was delayed significantly with SRH. We could detect a statistically significant food-related reduction of area under blood hydralazine concentration versus time curves (AUC) only with Apresoline (by 44%). The AUC for SRH was decreased only 29% by food. Hydralazine should be taken at a consistent time with respect to meals.
Administration, Oral↗
Drug interactions in hypertensive patients. Pharmacokinetic, pharmacodynamic and genetic considerations.
Antihypertensive treatment has proven benefits, and the number of patients being treated with these drugs is significant. Hypertensive patients may have other medical illnesses for which they receive medications, and interactions between antihypertensive agents and other drugs is likely. Some of these interactions may lead to undesirable effects or even loss of blood pressure control. However, drug interactions can also be beneficial when 2 antihypertensive drugs with different pharmacological actions are prescribed in combination and with a clear therapeutic objective in mind. Clinicians should be aware of the mechanisms and the consequences of the different types of interaction in hypertensive patients, so that a desired pharmacological response can be achieved with the fewest side effects in the patients.
Antihypertensive Agents↗
Forearm and finger hemodynamics, blood pressure control, and lipid changes in diabetic hypertensive patients treated with atenolol and prazosin. A brief report.
Hypertension and diabetes mellitus frequently coexist and are independent risk factors for reduced peripheral perfusion. Antihypertensive medications that reduce blood pressure and improve peripheral perfusion would have advantages in diabetic hypertensive patients. In a randomized, two-placebo-period, single-blind, two-way, crossover study, finger and forearm blood flow, lipid levels, and blood pressure control were determined in 19 diabetic hypertensive patients given prazosin and atenolol, with each drug and placebo period lasting four weeks. Both drugs reduced blood pressure (sitting, 157/95 to 142/84 mm Hg for atenolol and 155/95 to 138/82 mm Hg for prazosin; standing, 154/94 to 144/84 mm Hg for atenolol and 154/94 to 133/81 mm Hg for prazosin). Lipid levels did not change, except that low-density lipoprotein levels decreased from 148 to 127 mg/dl with prazosin. Atenolol did not change forearm or finger blood flow or vascular resistance. Prazosin increased blood flow and reduced vascular resistance in both finger and forearm. In conclusion, prazosin demonstrated a potentially more appropriate hemodynamic profile than atenolol in diabetic hypertensive patients in this study.
Adult↗
Efficacy and safety of isradipine in hypertension.
Of the calcium channel blocking drugs, only verapamil is approved in the United States for treatment of hypertension. Isradipine is a 1,4-dihydropyridine calcium blocker that may be given on a twice-daily basis. It causes peripheral vasodilation with minimal cardiodepressant activity. We undertook a double-blind, parallel group randomized, multicenter study of 203 hypertensive subjects to examine the efficacy and safety of isradipine in treatment of hypertension. Subjects were given 0, 2.5, 5, 7.5, or 10 mg isradipine twice daily for up to 5 weeks. There was a significant dose-response relationship between isradipine dose and decrease in systolic blood pressure (SBP) and diastolic blood pressure (DBP). Isradipine 15 mg/day reduced supine pressure by 16/15 mm Hg in patients with starting DBP less than 105 mm Hg and by 38/22 mm Hg in those with starting DBP greater than or equal to 105 mm Hg. There was no significant orthostatic fall in blood pressure at any dose. Heart rate (HR) increased on an average by only a maximum of four beats/min. The drug was slightly more effective in the elderly in the standing position than in the young in the standing position. Adverse effects were mild, and only six patients were discontinued from the study because of adverse effects. Isradipine appears to be a safe, effective drug in monotherapy of hypertension at a wide range of patient ages.
Adolescent↗
Determinants of antihypertensive response to calcium antagonists in systemic hypertension.
Calcium antagonists are an important group of drugs in the treatment of systemic hypertension. Examination of the factors that determine the magnitude of antihypertensive response to calcium antagonists is of interest for clinical and basic pathophysiologic reasons. Possible factors influencing response include drug dose, plasma drug concentration, plasma renin activity, baseline blood pressure, nonionized calcium in blood and inside vascular smooth muscle cells, patient age and patient race. Published studies have examined the determinants of antihypertensive response. The striking fact about many of these studies is that they fail to control for other possible factors that might influence response. This article reviews the methods used and the results of 23 different studies that examined the determinants of response to calcium antagonists. Possible relationships between plasma renin activity, intra- and extracellular calcium levels, and the antihypertensive response, are of interest from a pathophysiologic point of view. From a clinician's standpoint, the only determinants that matter are the dose of the drug and the degree of elevation of the blood pressure. In this regard, calcium channel blocking drugs are no different from other drugs that act by peripheral vasodilation.
Age Factors↗
Relative bioavailability of immediate- and sustained-release hydralazine formulations.
The in vivo performance of hydralazine sustained-release dosage forms prepared using an ethylcellulose-coated drug:resin complex was studied in healthy males who were determined to be slow acetylators. Two studies were performed. The first study (I) compared four different coating levels (6.8, 8.7, 10, and 12%) with an immediate-release tablet and a solution. The second study (II) compared three additional coating levels (4, 5, and 7.8%) to the 6.8% formulation from the first study. Both hydralazine peak blood concentration (Cmax) and area under the blood concentration-time curves (AUC) decreased as the coating level increased [coating level (Cmax, ng/mL; AUC, ng.h/mL): 4% (37; 58), 5% (31; 55), 6.8% (13; 42 and 14; 39); 7.8% (16; 38), 8.7% (11; 34), 10% (7.8; 21), 12% (8.9; 17)]. In Study I both the solution and the immediate-release tablet were administered in two divided doses at 8 a.m. (fasting) and 2 p.m. (post-prandial). There was evidence for decreased bioavailability of unchanged hydralazine after the 2 p.m. doses as compared with the 8 a.m. doses. On the other hand, an assay that measures primarily the pyruvic acid conjugate of hydralazine yielded much higher concentrations after the afternoon dose. The results of these studies indicate that a sustained-release dosage form of hydralazine can be prepared using an ethyl-cellulose coated drug:resin complex and its in vivo characteristics are related to the coating level. Hydralazine bioavailability is influenced by food or recent prior exposure to hydralazine.
Adult↗
Forearm and finger hemodynamics, blood pressure control, and lipid changes in patients with diabetic hypertension treated with atenolol and prazosin.
Hypertension and diabetes mellitus frequently coexist and are independent risk factors for reduced peripheral perfusion. Antihypertensive medications that reduce blood pressure and improve peripheral perfusion would have advantages in diabetic patients with hypertension. In a randomized, two-placebo period, single-blind, two-way crossover study, we determined finger and forearm blood flow, lipid levels, and blood pressure control in 19 diabetic patients with hypertension, with each atenolol or prazosin and placebo period of 4 weeks' duration. Both drugs reduced blood pressure (sitting: 157/95 to 142/84 mm Hg, atenolol; 155/95 to 138/82 mm Hg, prazosin; standing: 154/94 to 144/84 mm Hg, atenolol; 154/94 to 133/81 mm Hg, prazosin). Lipid levels did not change except that low-density lipoprotein levels fell from 148 to 127 mg/dl with prazosin. Atenolol did not change forearm or finger blood flow or vascular resistance. Prazosin increased blood flow and reduced vascular resistance in both finger and forearm. In conclusion, prazosin has a potentially more appropriate hemodynamic profile than has atenolol in diabetic patients with hypertension.
Adult↗
Human pharmacology of urapidil.
Urapidil is a phenylpiperazine-substituted uracil derivative used in hypertension. It is rapidly absorbed when given by mouth. Peak blood concentrations of the slow release capsule occur 4 to 6 hours after administration. Oral bioavailability is 78% (range 72 to 84%) and distribution half-life and terminal half-life are about 35 minutes and 3 hours, respectively. Plasma clearance is 12 L/h and renal clearance 1.8 L/h. Seventeen percent appears in urine as the parent compound within 24 hours of dosing. There is extensive hepatic metabolism to the parahydroxylated (34% in urine). N-demethylated (4% in urine) and O-demethylated (3% in urine) products. Elimination is not saturable at usual clinical doses. The major action of urapidil is post-synaptic alpha 1-adrenergic blockade, with a minor degree of beta 1-adrenergic blockade and a centrally mediated reduction in sympathetic outflow which has an as yet unidentified basis.
Antihypertensive Agents↗