Search

We updated the evidence-based recommendations for the diagnosis, assessment, prevention, and treatment of hypertension in adults for 2013. This year's update includes 2 new recommendations. First, among nonhypertensive or stage 1 hypertensive individuals, the use of resistance or weight training exercise does not adversely influence blood pressure (BP) (Grade D). Thus, such patients need not avoid this type of exercise for fear of increasing BP. Second, and separately, for very elderly patients with isolated systolic hypertension (age 80 years or older), the target for systolic BP should be150 mm Hg (Grade C) rather than140 mm Hg as recommended for younger patients. We also discuss 2 additional topics at length (the pharmacological treatment of mild hypertension and the possibility of a diastolic J curve in hypertensive patients with coronary artery disease). In light of several methodological limitations, a recent systematic review of 4 trials in patients with stage 1 uncomplicated hypertension did not lead to changes in management recommendations. In addition, because of a lack of prospective randomized data assessing diastolic BP thresholds in patients with coronary artery disease and hypertension, no recommendation to set a selective diastolic cut point for such patients could be affirmed. However, both of these issues will be examined on an ongoing basis, in particular as new evidence emerges.

We updated the evidence-based recommendations for the diagnosis, assessment, prevention, and treatment of hypertension in adults for 2012. The new recommendations are: (1) use of home blood pressure monitoring to confirm a diagnosis of white coat syndrome; (2) mineralocorticoid receptor antagonists may be used in selected patients with hypertension and systolic heart failure; (3) a history of atrial fibrillation in patients with hypertension should not be a factor in deciding to prescribe an angiotensin-receptor blocker for the treatment of hypertension; and (4) the blood pressure target for patients with nondiabetic chronic kidney disease has now been changed to < 140/90 mm Hg from < 130/80 mm Hg. We also reviewed the recent evidence on blood pressure targets for patients with hypertension and diabetes and continue to recommend a blood pressure target of less than 130/80 mm Hg.

We updated the evidence-based recommendations for the diagnosis, assessment, prevention, and treatment of hypertension in adults for 2011. The major guideline changes this year are: (1) a recommendation was made for using comparative risk analogies when communicating a patient's cardiovascular risk; (2) diagnostic testing issues for renal artery stenosis were discussed; (3) recommendations were added for the management of hypertension during the acute phase of stroke; (4) people with hypertension and diabetes are now considered high risk for cardiovascular events if they have elevated urinary albumin excretion, overt kidney disease, cardiovascular disease, or the presence of other cardiovascular risk factors; (5) the combination of an angiotensin-converting enzyme (ACE) inhibitor and a dihydropyridine calcium channel blocker (CCB) is preferred over the combination of an ACE inhibitor and a thiazide diuretic in persons with diabetes and hypertension; and (6) a recommendation was made to coordinate with pharmacists to improve antihypertensive medication adherence. We also discussed the recent analyses that examined the association between angiotensin II receptor blockers (ARBs) and cancer.

To determine the prevalence of diabetes mellitus (DM) and its complications in the adult population of the United Arab Emirates (UAE) and assess the degree of metabolic control in subjects with diagnosed DM.A random sample of houses of Emirati citizens living in Al Ain, UAE was surveyed. Fasting blood glucose was determined by glucose meter and an oral glucose tolerance test (OGTT) was conducted if blood sugar was7 mmol/l. DM was defined according to the WHO criteria. Pre-diabetes status was based on fasting venous blood glucose concentration of 5.6-6.9 mmol/l or 2h post-OGTT venous blood glucose level of 7.8-11.0 mmol/l.There were 2455 adults (18) living in the 452 surveyed houses of which 10.2% reported having the diagnosis of DM. A total of 373 men and non-pregnant women underwent testing, and after adjustment for factors affecting participation probability the prevalence of diagnosed DM, undiagnosed DM and pre-diabetes was 10.5, 6.6 and 20.2%, respectively. Age-standardized rates for DM (diagnosed and undiagnosed) and pre-diabetes among 30-64 years old were 29.0 and 24.2%, respectively. Logistic regression analysis showed that only age and body mass index (BMI) were significantly independently related to undiagnosed DM. In patients with diagnosed DM, the prevalence rates for retinopathy, neuropathy, nephropathy, peripheral vascular disease and coronary heart disease were 54.2, 34.7, 40.8, 11.1 and 10.5%, respectively. A significant proportion of subjects with undiagnosed DM and pre-diabetes also had micro- and macro-vascular complications. The proportion of subjects with diagnosed DM who achieved internationally recognized targets for HbA1c (7%), LDL-C (2.6 mmol/l) and blood pressure (130/80 mmHg) was 33.3, 30.8 and 42.1%, respectively.This study confirms the previously reported high prevalence of DM in the UAE. Diabetic complications were highly prevalent among subjects with diagnosed and undiagnosed DM. Metabolic control was suboptimal in most subjects with diagnosed DM. Greater efforts are urgently needed to screen early and effectively treat DM in the UAE in order to prevent long-term complications.

Background Grapefruit juice can increase the oral bioavailability of a broad range of medications. This interaction has not been assessed in the elderly. Methods Twelve healthy elderly people (70 to 83 years of age) were administered 5 mg felodipine extended release with 250 mL grapefruit juice or water in a single-dose study. Subsequently, 6 of these people received 2.5 mg felodipine for 2 days, followed by 5 mg felodipine for 6 days with 250 mL grapefruit juice or water in a steady-state study. Plasma concentrations of felodipine and dehydrofelodipine metabolite, blood pressure, and heart rate were measured over 24 hours after single and final steady-state dose. Results Mean felodipine area under the curve and maximum concentration were 2.9-fold and 4.0-fold greater, respectively, with grapefruit juice in both studies. Interindividual variability in the extent of the interaction was high. Felodipine apparent elimination half-life was not altered. Dehydrofelodipine area under the curve and maximum concentration were increased and dehydrofelodipine/felodipine area under the curve ratio was reduced. Systolic and diastolic blood pressures were lower with grapefruit juice in the single-dose study, whereas they were not different between treatments in the steady-state study. Curvilinear relationships existed between plasma felodipine concentration and changes in systolic and diastolic blood pressures. Heart rates were higher with grapefruit juice in both studies; however, this effect was greater and more prolonged at steady state. Conclusions A normal dietary amount of grapefruit juice produced a pronounced, unpredictable, and sustained pharmacokinetic interaction with felodipine by reducing its presystemic metabolism in the elderly. The different blood pressure results between the studies can be explained by felodipine concentration-blood pressure response relationships. The elderly should be particularly cautioned about concomitant grapefruit juice and felodipine ingestion. Clinical Pharmacology & Therapeutics (2000) 68, 28–34; doi: 10.1067/mcp.2000.107524

Medical research has helped to clarify the benefits of some therapies for improving the treatment or outcome associated with cardiovascular disease. However, the adoption of these approaches into routine clinical practice is, in many cases, inadequate. Consequently, there are many missed opportunities to reduce the burden of morbidity and mortality from cardiovascular disease. This review summarizes the factors that may prevent modified behavior in medical practice and the effectiveness of interventions that influence change. There are many barriers that may prevent or slow the adoption of new therapeutic advances into routine clinical practice. As a result, the use of well-proven, efficacious therapy can be suboptimal. Because of this underuse, the realized benefits of treatment are below the potential benefits. Adoption of new therapies is highly dependent on the use of interventions to promote clinical change. However, the effectiveness of different types of interventions varies greatly. Nevertheless, there is a wide range of strategies available that can be used to induce real changes in practice performance and potentially improve patient outcomes. It is essential that future intervention strategies focus on improving adoption of new therapies into clinical practice. The physician must be encouraged to prescribe proven treatments to those patients who stand to benefit most. In addition, better systems of care should be developed that improve the identification of patients as suitable candidates for proven treatments and sustain their long-term commitment to therapy.

Angiotensin (Ang) II antagonists are a novel class of drugs developed to block Ang II receptors. This approach is deemed more direct and more likely to be effective than the earlier pharmacological approach of inhibiting the enzyme (ACE inhibitor) responsible for converting Ang I to Ang II. Furthermore, it is expected that the approach will avoid problems associated with pathways that bypass ACE, e.g., tissue chymase.

Conflicting findings suggest that serum quinidine concentrations may be decreased or increased by nifedipine. We performed a double-blind, placebo-controlled trial of Latin-square design. Twelve healthy men received 3 days of pretreatment with nifedipine prolonged action (20 mg twice a day) or felodipine extended release (10 mg every day), another dihydropyridine calcium antagonist, followed by coadministration of quinidine (400 mg). Quinidine pharmacokinetics were not changed by either dihydropyridine. However, 3-hydroxyquinidine area under the concentration-time curve (AUC) and 3-hydroxyquinidine/quinidine AUC ratio were decreased by felodipine, consistent with reduced metabolite formation. Heart rates and adverse events were higher with felodipine, demonstrating lack of bioequivalence with nifedipine. The QTcinterval did not deviate from that expected for the observed quinidine concentration, suggesting the pharmacokinetics of active quinidine metabolites were not markedly altered among treatments. Quinidine disposition did not appear to be changed sufficiently to be clinically important by sustained-release nifedipine and felodipine. Clinical Pharmacology and Therapeutics (1993) 53, 354–359; doi:10.1038/clpt.1993.32

Although beta-blockers and diuretics are presently the only medications shown to reduce morbidity and mortality in hypertensives in large clinical trials, these drugs have not exerted optimal expected benefits in reducing cardiac events. Alpha-1 selective blockers exhibit a favorable impact on lipids, particularly on HDL-cholesterol. Unlike beta-blockers, they do not increase triglycerides and they do not produce the increase in LDL-cholesterol observed with traditional doses of diuretics. Alpha-blockers should be considered in the treatment of hypertensives with lipid disorders or diabetes and in those who have contraindications, failure to respond or toxicity associated with diuretics and/or beta-blockade.

Venoconstriction of the dorsal hand vein by local norepinephrine infusion was measured by the linear variable differential transformer method in 15 healthy unrelated subjects and eight pairs of monozygotic and six pairs of dizygotic twins. Incremental norepinephrine infusion produced dose-related venoconstriction. In unrelated subjects the doses of norepinephrine constricting basal vein diameter by 50% (ED50) ranged from 3.9 to 120.5 ng/min. There was a positive linear relationship between doses of norepinephrine infused and local steady-state plasma concentrations of norepinephrine achieved in each subject. The reciprocals of the slopes of these dose-concentration relationships, which reflect local norepinephrine clearance (disposition) in the vein, ranged from 0.47 to 1.86 ml/min. Plasma concentrations of norepinephrine associated with reduction of basal vein diameter by 50% (EC50) ranged from 1.4 to 110.2 ng/ml, with variability similar to that of ED50. There was a very high level of concordance in ED50, EC50, and clearance of norepinephrine within pairs of monozygotic twins but not within dizygotic twins. Differences in pharmacokinetics of infused norepinephrine exert a minor impact on overall intersubject variability. Genetic aspects of “tissue responsiveness” (i.e., vascular a-adrenoceptor response, smooth muscle contractility, and endothelial function) appear to be largely responsible for the wide intersubject variability in venoconstrictor responsiveness to norepinephrine. Clinical Pharmacology and Therapeutics (1991) 49, 355–361; doi:10.1038/clpt.1991.41

Hepatic enzymes, pulmonary function, serum amiodarone and desethylamiodarone (DEA) concentrations and erythrocyte superoxide dismutase (SOD) activity were monitored at regular intervals for 1 year in 30 patients receiving amiodarone. Subclinical hepatotoxicity developed in 5 patients. These patients had higher baseline alanine transaminase values (42.6 +/- 6.8 vs 22.9 +/- 1.8 U/liter) and had an increase in serum aspartate transaminase from 27 +/- 4.1 at baseline to 147 +/- 77.3 U/liter at 12 months. The other patients had little variation in aspartate transaminase. Six patients with normal baseline carbon monoxide diffusing capacity had subclinical pulmonary toxicity develop with a mean decrease in diffusing capacity to 0.7 +/- 0.05 of the baseline value, which correlated with decreasing erythrocyte SOD activity. Mean carbon monoxide diffusing capacity and SOD activity remained unchanged in the other patients. The mechanisms of hepatic and pulmonary injury remain unknown, but appear to be associated with exposure to higher total serum concentrations of amiodarone plus DEA. Patients who had hepatic and/or pulmonary abnormalities develop received higher doses of amiodarone (440 +/- 27 vs 340 +/- 18 mg/day), but also had a higher amiodarone:DEA ratio suggesting that dose-dependent kinetics contributed to the higher concentrations. Elevated baseline alanine transaminase may indicate increased risk for hepatotoxicity while a progressive decrease in erythrocyte SOD may be an early indication of pulmonary toxicity. The latter finding indicates a need to investigate the role of free radicals in the pathogenesis of amiodarone pulmonary toxicity.

Source Citation The IONA Study Group. Effect of nicorandil on coronary events in patients with stable angina: the Impact of Nicorandil in Angina (IONA) randomised trial. Lancet. 2002 Apr 13;359:126...

Source Citation Moher M, Yudkin P, Wright L, et al., for the Assessment of Implementation Strategies (ASSIST) Trial Collaborative Group. Cluster randomised controlled trial to compare three methods...

Source Citation Schmieder RE, Martus P, Klingbeil A. Reversal of left ventricular hypertrophy in essential hypertension. A meta-analysis of randomized double-blind studies. JAMA. 1996 May 15; 275:1...

Source Citation Newman AB, Sutton-Tyrrell K, Vogt MT, Kuller LH. Morbidity and mortality in hypertensive adults with a low ankle/arm blood pressure index. JAMA. 1993 Jul 28;270:487-9.

The effects on standing heart rate and respiratory function of two relatively selective beta 1-adrenoceptor antagonists, metoprolol and bevantolol, were compared in a double-blind, randomized, crossover study of 16 patients with asthma. After control observations on 2 separate days, the patients received approximately equivalent cardiac beta-adrenoceptor antagonist doses of metoprolol, 12.5, 25, 50, and 100 mg, and bevantolol, 18.75, 37.5, 75 and 150 mg, at intervals of 2 hours. Dosing was stopped if symptoms warranted or if there was a fall of greater than or equal to 20% in the forced expiratory volume in 1 second. In general, the cumulative dosing regimen proved a safe and effective means of assessing bronchial responsiveness to these beta-blockers in asthma, but one patient had to be dropped from the study because of severe bronchoconstriction after the first dose. Of the 15 patients studied who were taking both drugs, seven patients were withdrawn prematurely. In these seven patients, the average maximum tolerated cumulative doses were 45.5 mg bevantolol and 26.8 mg metoprolol, doses that are much lower than those usually required for therapeutic activity. The respiratory response to either drug could not be predicted.

Over the last decade there has been increasing awareness that some cardiovascular medications may adversely affect serum cholesterol concentrations. It has been suggested previously that amiodarone may alter serum cholesterol, triglyceride and glucose concentrations, but no substantive data support this observation. During the course of a 1-year study of adverse effects in patients taking amiodarone, 21 patients with normal total serum cholesterol before entry in the study were prospectively investigated for changes in lipid metabolism. A statistically significant sustained rise of 17% in total serum cholesterol occurred from a baseline of 178 +/- 7 mg/dl (4.6 +/- 0.2 mmol/liter) to 208 +/- 9 mg/dl (5.4 +/- 0.2 mmol/liter). Ten of the patients developed elevations of cholesterol above the 75th percentile for their age and sex. This group experienced a sustained rise of 20% in mean cholesterol concentration from baseline, had statistically significant elevations of triglyceride concentrations and had higher glucose and desethylamiodarone concentrations than patients who did not develop elevations in cholesterol greater than the 75th percentile. It may be possible to predict these differences in response as early as 4 to 8 weeks after starting therapy. Because amiodarone is increasingly used in patients without ischemic heart disease or life-threatening arrhythmias, the potential atherogenic risk of these metabolic abnormalities merits further investigation.

To investigate the role of intrinsic sympathomimetic activity on left ventricular (LV) function during antianginal therapy with beta-adrenoreceptor antagonists, 23 patients with chronic, exercise-induced angina pectoris and normal or near normal LV function underwent radionuclide ventriculography at rest and during exercise, during 3 randomly allocated periods: (1) treatment with oral propranolol, a drug without intrinsic sympathomimetic activity, 40 to 80 mg 4 times a day; (2) treatment with pindolol, a drug with marked intrinsic sympathomimetic activity, 5 to 10 mg 2 times a day; and (3) a control period. During the control period, the LV ejection fraction decreased from rest (58.9 ± 8.2%) to exercise (54.3 ± 10.7%), and the wall motion score decreased from 0.57 ± 1.08 at rest to 2.39 ± 2.10 during exercise, p

Dose-response curves for propranolol and oxprenolol were studied in healthy volunteers, with a standardized excercise test and percentage reduction in excercise heart rate (EHR) as the index of drug effect. The dose-response curves obtained were compared with similar curves previously reported for sotalol, practolol, and atenolol with identical experimental methods. Two distinct types of response were identified: in the first, shown by propranolol and sotalol, increasing doses of the beta adrenoceptor-blocking drug continued to produce increasing effects to the limits of the dose levels examined; with the second (oxprenolol and practolol), increasing the dose initially resulted in substantial increase in effect but subsequently larger doses produced almost no increase in effect. Consideration of the additional properties of these beta adrenoceptor-blocking drugs revealed that both practolol and oxprenolol have intrinsic sympathomimetric activity (ISA), whereas propranolol and sotalol do not. In addition, practolol is cardioselective. Further investigation of the possible influence of ISA or cardioselectivity on beta adrenoceptor-blocking activity was undertaken by studying the effects of combinations of drugs on EHR. Sotalol produced greater effect when given 2 hr after sotalol, oxprenolol, practolol, or atenolol. When oxprenolol was given after sotalol or oxprenolol, or practolol was given after sotalol or practolol, there was no further increase in percentage reduction in EHR. When atenolol was given, the combinations of sotalol and atenolol together with two doses either of sotalol or atenolol all induced increases and similar final percentage reductions in EHR. Thus atenolol induces effects like those of sotalol, which are quite different from those of oxprenolol or practolol. The presence or absence of ISA would appear to be the important difference between these two groups of drugs: ISA would, therefore, appear to be demonstrated in man by flattening of the dose-response curves with exercise.

A Phase I evaluation of a new adrenoceptor blocker, pamatolol, was performed in 10 healthy male volunteers. Minor reductions in standing and exercise and isoproterenol-induced increases in heart rate were observed with the 10-mg oral dose and appeared maximal with the 400-600 mg dose. The rate of decline of effect averaged 1.5% of the exercise heart rate/hr. Neither resting systolic time intervals nor post-exercise pulmonary function was affected by this dose range of pamatolol. Based on the latter responses and the isoproterenol dose response curve, we tentatively conclude that pamatolol is relatively cardioselective in man.

Diurnal, day-to-day, intrasubject, and intersubject variability of responsiveness of dorsal hand veins to norepinephrine has been investigated in healthy young subjects through the use of a novel technique in which a linear variable differential transformer (LVDT) is placed directly over the vein. Under constant operating conditions, control vein diameter remained consistent. There is a log dose responsiveness to norepinephrine infused directly into the hand vein. There was little diurnal, day-to-day, or intrasubject variability in the dose of norepinephrine required to induce 50% constriction of hand vein diameter. The responsiveness to norepinephrine of different veins in either hand was also consistent. However, there was wide intersubject variability, apparently unrelated to age, gender, or other subject characteristics. We conclude that the LVDT method is reproducible and reliable and offers a relatively noninvasive means of assessing the effects of disease and drugs on the human dorsal hand vein in vivo. The LVDT technique has been applied to study the rate of onset, magnitude of effect, dose responsiveness, and duration of action of intravenous dihydroergotamine, 0.1, 0.2, and 0.4 mg, on human dorsal hand veins. Despite systemic intravenous administration, there was an average delay in maximum response of 30 minutes to 1 hour. Venoconstriction was incomplete, with a maximum reduction of approximately 50% of vein diameter after each of the larger doses. There was no significant difference between the effects produced by 0.2 or 0.4 mg, which persisted for 6 hours after dosing.

Cardiac effects of single doses of conventional oral pindolol, sustained-released oral pindolol, and intravenous pindolol were studied in healthy male volunteers, aged 21 to 27 years, weighing 70.8 to 92.1 kg. The studies were designed to evaluate the oral dose-response curve of pindolol, to assess the partial agonist activity of pindolol, to determine the systemic bioavailability of oral pindolol, and to compare the systemic bioavailability, potency, and duration of action of comparable beta-adrenergic-blocking doses of pindolol and propranolol. In study A, eight subjects randomly received at weekly intervals oral pindolol, 5, 10, 15, and 20 mg (2 × 10 mg), and sustained-release pindolol, 20 and 30 mg. Supine resting (RHR), standing (SHR), and exercise heart rates (EHR) were recorded at 0 hours (before dose) and at 2, 8, and 24 hours after dose. Control RHR averaged 57.0, SHR 98.2, and EHR 162.8 bpm. None of the doses produced any significant reduction in RHR or SHR. Average EHR at 2 hours was 122.3 bpm, with no significant difference between the six doses. At 8 and 24 hours, the larger doses produced greater reductions in EHR. At 24 hours, the 5 mg dose had no residual effect, whereas other doses had intermediate residual blockade with the maximum of 50% recorded after the sustained-release 30 mg dose. The effects of the 20 mg doses were not significantly different. In study B, eight subjects randomly received at weekly intervals oral pindolol, 5 mg; intravenous pindolol, 0.045 mg/kg; oral propranolol, 80 mg; and intravenous propranolol, 0.3 mg/kg. Intravenous pindolol (0.2 mg/ml) and intravenous propranolol (1 mg/ml) were administered by Harvard pump at 1 mg/min. RHR, SHR, and EHR were measured at 0 hours (before dose) and 0.5, 1, 2, 4, 6, 8, and 24 hours after dose. No dose had any significant effect on RHR. Pindolol doses had no effect on SHR but propranolol orally and intravenously reduced SHR to about 82 bpm; the difference between the drugs was significant ( p

The effects of oral cholestyramine 4 gm 8 times daily and spironolactone 300 mg daily, given independently and in combination, on the elimination rate of digitoxin were studied in 6 healthy subjects pretreated with 0.1 or 0.15 mg oral digitoxin daily for 30 days before each intervention. The mean pretreatment digitoxin concentrations for the group ranged from 21 ± 2.9 (SD) ng/ml to 28.5 ± 6.9 ng/ml. The mean control digitoxin half-life (½) was reduced from 141.6 to 84.4 by treatment with cholestyramine alone. Treatment with spironolactone alone prolonged the mean digitoxin ½ to 192.2 hr. The mean digitoxin ½ after both active drugs was intermediate at 102.9 hr. Spironolactone did not fulfill the expectation from animal studies that it would enhance the clearance of digitoxin by cholestyramine. The prolongation of digitoxin elimination after spironolactone may contraindicate this drug in digitoxin intoxication. Clinical Pharmacology and Therapeutics (1980) 27, 184–187; doi:10.1038/clpt.1980.28

The influence of age on the responsiveness of dorsal hand vein α-receptors to local infusions of norepinephrine was investigated by the use of a novel technique, the linear variable differential transformer. Studies were conducted in two groups of healthy subjects, 26 elderly individuals (14 men and 12 women) 60 to 78 years old and 32 young individuals (24 men and eight women) 16 to 29 years old. There was wide interindividual variation in responsiveness to norepinephrine within both groups of subjects. The dose of norepinephrine required to produce 50% venoconstriction in the elderly ranged from 1.5 to 300 ng/min (geometric mean 24.0 ng/min). The dose required to produce 50% venoconstriction in younger individuals ranged from 1.6 to 360 ng/min (geometric mean 23.8 ng/min). These results suggest that there is no systematic influence of age on dorsal hand vein α-receptor responsiveness. A power calculation demonstrates a very small likelihood of a type II error. Clinical Pharmacology and Therapeutics (1986) 40, 257–260; doi:10.1038/clpt.1986.172

The cause of pruritus of cholestasis is unknown. We have hypothesized that pruritus may be caused by an indirect effect of high hepatic concentrations of toxic bile acids. To test this hypothesis, we have conducted a double-blind, controlled, crossover clinical trial of rifampin, an agent that inhibits hepatic bile acid uptake and may detoxify hepatic bile acids by stimulation of mixed-function oxidases. Nine patients with primary biliary cirrhosis received 300-450 mg/day of rifampin and placebo sequentially, in random order. Each treatment was administered for 14 days, with a 14-day washout between treatments. Endpoints included patient preference, changes in a daily visual analogue scale pruritus score, and amount of cholestyramine ingested. Antipyrine elimination rates and serum bile acids were tested at the end of each treatment period. All 9 patients completed the trial and 8 of them preferred rifampin to placebo (p = 0.03). There were no adverse reactions. Visual analogue scale pruritus scores showed no significant placebo response or any effect from the order of treatment, but did show a highly significant reduction in pruritus in response to rifampin (p less than 0.002). This effect was evident within the first week of rifampin treatment. Rifampin produced a 33% reduction in antipyrine plasma half-life, but no change in fasting total serum bile acids. Cholestyramine usage did not change significantly. We conclude that rifampin is useful for short-term relief of pruritus in primary biliary cirrhosis; however, the mechanism of this effect is unknown. Longer trials are needed, as are trials in other cholestatic disorders.

Herein, updated evidence-based recommendations for the diagnosis, assessment, prevention, and treatment of hypertension in Canadian adults are detailed. For 2014, 3 existing recommendations were modified and 2 new recommendations were added. The following recommendations were modified: (1) the recommended sodium intake threshold was changed from ≤ 1500 mg (3.75 g of salt) to approximately 2000 mg (5 g of salt) per day; (2) a pharmacotherapy treatment initiation systolic blood pressure threshold of ≥ 160 mm Hg was added in very elderly (age ≥ 80 years) patients who do not have diabetes or target organ damage (systolic blood pressure target in this population remains at < 150 mm Hg); and (3) the target population recommended to receive low-dose acetylsalicylic acid therapy for primary prevention was narrowed from all patients with controlled hypertension to only those ≥ 50 years of age. The 2 new recommendations are: (1) advice to be cautious when lowering systolic blood pressure to target levels in patients with established coronary artery disease if diastolic blood pressure is ≤ 60 mm Hg because of concerns that myocardial ischemia might be exacerbated; and (2) the addition of glycated hemoglobin (A1c) in the diagnostic work-up of patients with newly diagnosed hypertension. The rationale for these recommendation changes is discussed. In addition, emerging data on blood pressure targets in stroke patients are discussed; these data did not lead to recommendation changes at this time. The Canadian Hypertension Education Program recommendations will continue to be updated annually.

The partial agonist activity of pindolol was assessed by examining the action of cumulative doses on the heart rate of resting, standing, and exercising healthy men and by studying the interaction of pindolol with metoprolol, a beta blocker devoid of partial agonist activity. Pindolol did not affect resting or standing heart rates (RHR, SHR) but reduced the heart rate after vigorous exercise by approximately 25%. The flatter dose-response curve of pindolol for exercise heart rate (EHR) has been reported from practolol and oxprenolol, which also exert partial agonist activity. After extremely large doses of pindolol there was no evidence of enhancement of agonist activity on RHR, nor was there any evidence of dominance of agonist activity over antagonist activity on EHR. Metoprolol did not alter RHR but reduced SHR by approximately 20% and EHR by approximately 31%. The effects of pindolol on SHRs and EHRs were not enhanced by metoprolol, even though the drug itself induced greater reductions of both. The reduction of SHR by metoprolol was reversed by pindolol. Pindolol appears to have greater affinity than metoprolol for atrial beta adrenoceptors in man.

The effects of the beta-adrenoceptor blockers atenolol, metoprolol, pindolol, and propranolol on the ventilatory response to carbon dioxide rebreathing have been determined in a double-blind randomized manner. Eight healthy, male, nonsmoking subjects received cumulative doses of each drug over a 10-hr period. The effects of each drug on heart rate and carbon dioxide sensitivity were determined at intervals of 2 hr and were related to plasma concentrations of each drug. Maximum reduction of exercise heart rate was achieved with all four beta blockers and plasma concentrations were in the usual therapeutic range for these drugs. There was considerable intersubject and within-subject variability in ventilatory responsiveness to inhaled carbon dioxide, but we were not able to discern any alteration in central sensitivity to increasing carbon dioxide concentrations. Clinical Pharmacology and Therapeutics (1982) 32, 289–294; doi:10.1038/clpt.1982.162

The interaction between oral verapamil and propranolol may involve negative chronotropic, inotropic or dromotropic effects. The immediate effects of orally administered verapamil (120 mg) and propranolol (80 mg), alone and combined, on submaximal exercise hemodynamics and on pharmacokinetics were studied in eight healthy male volunteers in a randomized, double-blind, crossover manner. Maximum effects on heart rate, systolic blood pressure, PR interval and rate-adjusted PR prolongation were greatest with the combined administration of verapamil and propranolol. The combination caused a high frequency of adverse drug events, predominantly exercise fatigue. Verapamil increased the AUC and Cmax and shortened the tmax of propranolol. Propranolol decreased the AUC and Cmax of verapamil. The greater reduction of heart rate with the combination of verapamil and propranolol was only partially explained by higher plasma concentrations of propranolol. The combination of propranolol and verapamil produced clinically important synergistic adverse effects during exercise. Negative dromotropic effects occurred primarily by direct AV node inhibition and were more important than previously recognized.

Pharmacokinetic-dynamic relations for amiodarone have been difficult to define. Few studies have successfully correlated serum amiodarone concentration with either dose or pharmacodynamic effects. Reduction in heart rate, prolongation of corrected QT interval and accumulation of corneal microdeposits are 3 clinical effects well suited for making kinetic-dynamic comparisons because they occur in virtually all patients receiving amiodarone. Data on heart rate, corrected QT interval, corneal microdeposits, cumulative dose and serum concentrations of amiodarone and desethylamiodarone (DEA) were collected over the course of 1 year after initiation of therapy in 27 patients (mean age 55.4 +/- 2.35 years). Mean elimination half-lives in this study population were 56 days for amiodarone and 129 days for DEA, as estimated from cumulation kinetics without drug withdrawal. The extremely long half-lives of amiodarone and DEA make demonstration of steady-state concentration-response relations difficult. A new approach using analysis of sequential data before steady-state reveals general relations between dose, DEA concentration and 3 clinically observable effects of amiodarone. A linear relation was evident between DEA concentration and log mean cumulative amiodarone dose (mg/kg) for the population. The steep segments of the concentration-response curves for heart rate, microdeposits and corrected QT interval occurred at low, medium and high serum amiodarone and DEA concentrations, respectively. Patients not developing a decrease in heart rate or corneal microdeposits likely have very low serum drug concentrations and may not be adequately treated. The monitoring of heart rate, corrected QT interval and corneal microdeposits as an aid to assessing adequacy of amiodarone therapy requires further study.

The systemic bioavailability, elimination half-life (t1/2), and plasma concentration--response relationships of pamatolol, a relatively cardioselective beta adrenoceptor blocker, have been measured in healthy subjects. Pamatolol is rapidly and completely absorbed after oral dosing. Elimination t1/2 ranged from 2.9 to 4.6 hr after oral doses and from 2.2 to 5.6 hr after intravenous doses. There was a clear relationship between log plasma pamatolol concentration and sympathetic blockade assessed by reduction of exercise heart rate. Concentration-response curves were essentially identical after oral and intravenous doses. There is no evidence of a first-pass effect, nor is there any evidence of metabolite activity.

The sedative and antihistamine effects of diphenhydramine were assessed in relation to plasma concentration after placebo, diphenhydramine 50 mg intravenously, and diphenhydramine 50 mg orally to each of 6 healthy volunteers on three separate occasions. Diphenhydramine plasma elimination t1/2 was 3.0 to 4.3 hr, volume of distribution was 188 to 336 L, and clearance was 637 to 1,014 ml/min. Systemic bioavailability of the oral preparation ranged from 0.26 to 0.60. The sedative effect of intravenous diphenhydramine differed from that of placebo only during the first 3 hr. Antihistamine effect, as measured by reduction of histamine provoked skin wheal diameter, was significantly different from that of placebo for at least 8 hr. There was a positive correlation between plasma diphenhydramine level and sedative and antihistamine effects, but wide variation in the extent and rate of change of these effects were observed between the subject. There appears to be a concentration range of 25 to 50 ng/ml, within which there is significant antihistamine effect without significant sedation.