A survey on the implementation of clinical medication reviews in community pharmacies within a multidisciplinary setting.

BACKGROUND: Polypharmacy is common in chronic medication users, which increases the risk of drug related problems. A suitable intervention is the clinical medication review (CMR) that was introduced in the Netherlands in 2012, but the effectiveness might be hindered by limited implementation in community pharmacies. Therefore our aim was to describe the current implementation of CMRs in Dutch community pharmacies and to identify barriers to the implementation. METHODS: An online questionnaire was developed based on the Consolidated Framework for Implementation Research (CFIR) and consisted of 58 questions with open ended, multiple choice or Likert-scale answering options. It was sent out to all Dutch community pharmacies (n = 1,953) in January 2021. Descriptive statistics were used. RESULTS: A total of 289 (14.8%) community pharmacies filled out the questionnaire. Most of the pharmacists agreed that a CMR has a positive effect on the quality of pharmacotherapy (91.3%) and on medication adherence (64.3%). Pharmacists structured CMRs according to available selection criteria or guidelines (92%). Pharmacists (90%) believed that jointly conducting a CMR with a general practitioner (GP) improved their mutual relationship, whereas 21% believed it improved the relationship with a medical specialist. Lack of time was reported by 43% of pharmacists and 80% (fully) agreed conducting CMRs with a medical specialist was complicated. Most pharmacists indicated that pharmacy technicians can assist in performing CMRs, but they rarely do in practice. CONCLUSIONS: Lack of time and suboptimal collaboration with medical specialists are the most important barriers to the implementation of CMRs.

Medication review and patient counselling at discharge from the hospital by community pharmacists.

AIMS: In 2001, the Association of Amsterdam Community Pharmacists adopted a programme to improve the pharmaceutical care of patients who were discharged from hospital with five or more drug prescriptions. A comprehensive protocol for pharmaceutical care at discharge (IBOM-1) was developed. The aim of the study was to evaluate the initial IBOM protocol and to study the effects of the protocol on drug therapy and patient satisfaction as well as on drug use compliance and mortality. METHOD: A controlled intervention study involving 37 community pharmacies and 715 of their registered patients who were discharged from a hospital and using at least five prescribed drugs in the years 2001-2003. The intervention included an extensive medication review and drug counselling at the patient's home. MAIN OUTCOME MEASURE: Pharmacy intervention activities, changes in medication, discontinuation of drugs prescribed at discharge, mortality, time spent on the intervention activities, and medication cost savings were all evaluated. Patient satisfaction was measured by means of a questionnaire. RESULTS: 379 and 336 patients were enrolled in the intervention and control groups, respectively. The mean number of drugs per patient not dispensed, concomitantly dispensed, or of which the quantity was changed was higher in the intervention group than in the control group (0.70 +/- 1.74 vs. 0.40 +/- 1.43, 0.11 +/- 0.40 vs. 0.038 +/- 0.26, and 0.29 +/- 1.05 vs. 0.097 +/- 0.52, respectively). The mean number of drugs for which the dose or dosage form was changed was similar in both groups. Substitution of brand for generic or vice versa was greater in the intervention group. Changes resulting from a PAIS signal were similar in both groups. The mean number of drugs per patient for which contact was required with the physician or the Pharmacy Hospital Service Desk was higher in the intervention group (0.35 +/- 0.51 vs. 0.16 +/- 0.38). About 40% of home visits resulted in the clearing of redundant drug supplies. The IBOM-1 intervention did not influence discontinuation of drugs prescribed at discharge, nor did it influence mortality. Medication costs were slightly reduced. More patients of intervention pharmacies than of control pharmacies indicated that they were (very) satisfied with the drug counselling by their community pharmacist upon delivery of their discharge medication (87% vs. 50%; chi(2) < 0.001). CONCLUSIONS: Structured pharmaceutical care according to the IBOM-1 protocol led to more changes in drug therapy. Home visits resulted in the clearing of redundant home drug supplies. In addition, patients were highly satisfied with the counselling at discharge from hospital by their community pharmacist. Patient counselling at discharge from hospital by pharmacists, therefore, appears to be a meaningful pharmaceutical care activity.

Factors associated with antihypertensive medication non-adherence: a systematic review.

Non-adherence to antihypertensive medication is the most important cause of uncontrolled blood pressure and is influenced by multiple interrelating factors. Understanding the complexity of medication non-adherence and its associated factors is important to determine intervention strategies. Therefore, a systematic review was performed aimed to identify factors associated with antihypertensive medication non-adherence. Different databases were searched for observational studies reporting on factors associated with non-adherence to antihypertensive medication. Titles, abstracts and full texts were reviewed by three researchers. Subsequently, the methodological quality of each study was assessed. Factors that were extracted from the included studies were categorised as factors with consistent or inconsistent evidence to put their potential importance into perspective. Forty-four studies were included. Higher co-payment, side effects and a poor patient-provider relationship were identified as factors with consistent evidence since consistent significant relationships were found for these factors whenever studied. The relationships between non-adherence and multiple other factors were inconsistent among the reviewed studies. However, some of these factors deserve some consideration. Since multiple potentially relevant factors were identified, patient-tailored interventions focussing on identifying and addressing patients' specific barriers to adherence are needed. Further research should clarify the influence of inconsistent factors on adherence and their potential to be addressed in interventions.

Selective regulation of beta 1- and beta 2-adrenoceptors in the human heart by chronic beta-adrenoceptor antagonist treatment.

1. In 44 patients undergoing coronary artery bypass grafting, the effect of chronic administration of the beta-adrenoceptor antagonists sotalol, propranolol, pindolol, metoprolol and atenolol on beta-adrenoceptor density in right atria (containing 70% beta 1- and 30% beta 2-adrenoceptors) and in lymphocytes (having only beta 2-adrenoceptors) was studied. 2. beta-Adrenoceptor density in right atrial membranes and in intact lymphocytes was assessed by (-)-[125I]-iodocyanopindolol (ICYP) binding; the relative amount of right atrial beta 1- and beta 2-adrenoceptors was determined by inhibition of ICYP binding by the selective beta 2-adrenoceptor antagonist ICI 118,551 and analysis of the resulting competition curves by the iterative curve fitting programme LIGAND. 3. With the exception of pindolol, all beta-adrenoceptor antagonists increased right atrial beta-adrenoceptor density compared to that observed in atria from patients not treated with beta-adrenoceptor antagonists. 4. All beta-adrenoceptor antagonists increased right atrial beta 1-adrenoceptor density; on the other hand, only sotalol and propranolol also increased right atrial beta 2-adrenoceptor density, whereas metoprolol and atenolol did not affect it and pindolol decreased it. 5. Similarly, in corresponding lymphocytes, only sotalol or propranolol increased beta 2-adrenoceptor density, while metoprolol and atenolol did not affect it and pindolol decreased it. 6. It is concluded that beta-adrenoceptor antagonists subtype-selectively regulate cardiac and lymphocyte beta-adrenoceptor subtypes. The selective increase in cardiac beta 1-adrenoceptor density evoked by metoprolol and atenolol may be one of the reasons for the beneficial effects observed in patients with end-stage congestive cardiomyopathy following intermittent treatment with low doses of selective beta 1-adrenoceptor antagonists.

Lack of effect of D600 on alpha 1-adrenoceptor-mediated contractions of rat isolated anococcygeus muscle.

The experiments concerned the contractile responses of rat anococcygeus muscle to the selective alpha 1-adrenoceptor agonists cirazoline, phenylephrine, methoxamine, St 587, Sgd 101/75, amidephrine and SK&F 89748-A and the effect of the calcium entry blocker D600 on the responses. The effects of noradrenaline, adrenaline, K+, tyramine and electrical field stimulation were studied as well. The potency series of the various agonists on rat anococcygeus muscle differed from the series for rat and guinea-pig aorta, indicating differences in the structure of the alpha 1-adrenoceptors on these tissues. D600 was ineffective in inhibiting contractions of rat anococcygeus muscle to the various agonists, but effectively attenuated the responses to K+ in anococcygeus muscle from rats pretreated with reserpine or in prazosin-induced preparations. These data indicate that alpha 1-adrenoceptor activation in rat anococcygeus muscle triggers contractions which do not primarily require the influx of extracellular calcium. In this respect, the smooth muscle from the rat anococcygeus muscle differs from vascular smooth muscle from this species.

The contractions induced in rat and guinea-pig aortic strips by the alpha 2-adrenoceptor selective agonists B-HT 920 and UK 14,304 are mediated by alpha 1-adrenoceptors.

The alpha-adrenergic action of the selective alpha 2-adrenoceptor agonists B-HT 920 and UK 14,304 was investigated on helically cut preparations of rat and guinea-pig isolated aorta. The alpha 1-adrenoceptor selective stimulant (-)-phenylephrine was included for comparison. All agonists induced concentration-dependent contractions in both preparations. Calcium entry blockade by D 600 almost abolished the contractions evoked by B-HT 920 and UK 14,304 in rat aorta while those evoked in guinea-pig aorta were less strongly affected. Contractions elicited by (-)-phenylephrine were moderately impaired by D 600 in rat aorta whereas there was only a limited effect in guinea-pig aorta. Analysis of the prazosin and yohimbine antagonism of B-HT 920- and UK 14,304-evoked contractions showed the involvement of alpha 1-like adrenoceptors in rat and guinea-pig aorta, prazosin being approximately 1000 times more potent that yohimbine. The results show that B-HT 920 and UK 14,304 contract rat and guinea-pig aorta via alpha 1-like adrenoceptors which are not identical. It is submitted that rat and guinea-pig alpha 1-adrenoceptors activate different contractile processes.

The influence of nifedipine and mioflazine on mitochondrial calcium overload in normoxic and ischaemic guinea-pig hearts.

The influence of nifedipine (20 nM) and mioflazine (300 nM), i.e. concentrations inducing a 60-70% recovery of cardiac function during reperfusion of globally ischaemic guinea-pig working hearts, on the mitochondrial calcium content was investigated in normoxic, globally ischaemic and reperfused globally ischaemic guinea-pig working hearts. Mitochondrial calcium was determined electronmicroscopically with oxalate-pyroantimonate method. In normoxic hearts both nifedipine and mioflazine reduced the mitochondrial calcium content. Global ischaemia for 45 min and subsequent reperfusion for 25 min resulted in a pronounced mitochondrial calcium overload and damage to the cellular structure. In ischaemic and in reperfusion hearts the drugs maintained mitochondrial calcium at pre-ischaemic levels and decreased the damage to the cellular structure.

The influence of calcium antagonists on the adenine nucleotide metabolism in the guinea-pig working heart during ischaemia and reperfusion.

With the aim of gaining more insight into the metabolism of adenine nucleotides in working normoxic guinea-pigs and in hearts subjected to 45 min of global ischaemia and subsequent reperfusion for 25 min, we evaluated the effect of nifedipine, verapamil, diltiazem, bepridil, CERM 11956, lidoflazine, mioflazine and dipyridamole on the adenine nucleotide catabolite levels in these hearts. The drugs were applied at the concentrations that reduced the aortic dP/dt of normoxic working hearts by 10% (EC10) and 30% (EC30). In globally ischaemic hearts there was a large accumulation of adenine nucleotide catabolites. Inosine proved to be the major catabolite. The drugs, with the exception of bepridil, CERM 11956 and dipyridamole (3 mumol/l), decreased the accumulation of catabolites. In hearts treated with mioflazine and dipyridamole the amount of adenosine increased. A deficit in the balance between adenine nucleotides and catabolites indicated that in globally ischaemic hearts there was a large accumulation of inosine monophosphate. Indeed, a substantial amount of inosine monophosphate was determined in untreated hearts, and hearts treated with nifedipine (EC30) and mioflazine (EC10). During the first 5 min of reperfusion a large quantity of catabolites, mainly inosine, was washed out. During 20 min of subsequent reperfusion in untreated hearts and in nifedipine and mioflazine-treated hearts the efflux of catabolites returned to normoxic values. Similar to the effect in ischaemic hearts, in early perfusate from lidoflazine, mioflazine and dipyridamole-treated hearts the adenosine/inosine ratio was increased.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of cyclic AMP in the positive inotropic effect mediated by beta 1- and beta 2-adrenoceptors in isolated human right atrium.

The time course of the effects of isoprenaline (3 X 10(-7) mol/l) on contractile force and on the cyclic AMP level was studied in the electrically driven isolated muscle strip of the human right atrium. Isoprenaline produced a rise in cyclic AMP content (maximum increase after 60 s) preceding the increase in contractile force. The effects of isoprenaline on contractile force and on the intracellular level of cyclic AMP were enhanced in the presence of the phosphodiesterase inhibitor papaverine (10(-5) mol/l). On the other hand, the beta-adrenoceptor antagonist propranolol (10(-7) mol/l) suppressed isoprenaline-induced cyclic AMP increases, but reduced the increase in force of contraction by only 35%. In addition, both the beta 1-selective antagonist bisoprolol (3 X 10(-9)-3 X 10(-8) mol/l) and the beta 2-selective antagonist ICI 118,551 (3 X 10(-9)-3 X 10(-8) mol/l) inhibited the isoprenaline-induced cyclic AMP increase concentration-dependently; ICI 118,551 produced more pronounced inhibition than bisoprolol. It is concluded that cyclic AMP is involved in the positive inotropic action of isoprenaline evoked by beta 1- and beta 2-adrenoceptor stimulation in isolated human right atrium; however, an additional cyclic AMP independent mechanism cannot be ruled out.

Differences between negative inotropic and vasodilator effects of calcium antagonists acting on extra- and intracellular calcium movements in rat and guinea-pig cardiac preparations.

In order to get more insight into the utilization of calcium in the mammalian heart and the influence of calcium antagonists on this process we have evaluated the negative inotropic and vasodilator effect of nifedipine, diltiazem, verapamil, bepridil and lidoflazine as well as of the intracellularly acting calcium antagonists ryanodine and TMB-8 in the presence of 0.9 and 1.8 mmol/l calcium in rat Langendorff hearts. The effect of ryanodine was also studied in guinea-pig Langendorff hearts. In addition, in rat and guinea-pig papillary muscles the effect of these drugs on the force of contraction was examined. With the exception of ryanodine and TMB-8 all calcium antagonists induced a pronounced coronary vasodilator effect. The rank order of potency for this effect was: nifedipine greater than verapamil = diltiazem = bepridil = lidoflazine in the presence of 0.9 mmol/l calcium. At a calcium concentration of 1.8 mmol/l nifedipine and verapamil proved more potent, whereas diltiazem was less active. All calcium antagonists completely suppressed the development of the left ventricular pressure. At a calcium concentration of 0.9 mmol/l the potency order for this effect was: ryanodine greater than nifedipine = verapamil greater than diltiazem = bepridil = lidoflazine greater than TMB-8. In the presence of 1.8 mmol/l calcium the concentration-response curves for reduction of the left ventricular pressure by nifedipine, verapamil and diltiazem slightly shifted to the right. In contrast to all calcium antagonists investigated, in guinea-pig Langendorff hearts ryanodine only partially decreased the left ventricular pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

The differential effect of calcium antagonists on the positive inotropic effects induced by calcium and monensin in cardiac preparations of rats and guinea-pigs.

It was the aim of the present study to gain more insight into the role of extracellular calcium and of calcium from intracellular sources in the development of contractile force in the mammalian heart. In rat Langendorff hearts the effect of nifedipine, verapamil, diltiazem, bepridil and lidoflazine as well as of the intracellularly acting calcium antagonists ryanodine and TMB-8 on the increase of the left ventricular pressure induced by calcium and the sodium ionophore monensin, respectively, was studied. In rat and guinea-pig papillary muscles the influence of nifedipine, ryanodine and lidoflazine on the effect of monensin on the force of contraction was evaluated. Calcium and monensin concentration-dependently increased the left ventricular pressure in rat Langendorff hearts. The calcium-induced effect was characterized by a sharp initial rise of the left ventricular pressure which stabilized at a lower level while monensin elicited a gradual rise of the left ventricular pressure. Nifedipine, verapamil and diltiazem, applied at the EC50 and the EC80 for the reduction of the left ventricular pressure under control conditions, shifted the concentration-response curves for calcium and monensin into the right. Ryanodine, TMB-8, lidoflazine and bepridil, applied at the EC50, displaced the concentration-response curves for calcium and monensin to the right but reduced the maximal increase of the left ventricular pressure. At the EC80, these drugs almost completely abolished the positive inotropic effects elicited by calcium and monensin, respectively. In rat papillary muscles monensin did not influence the basal force of contraction. A clear positive inotropic effect was only observed in the presence of nifedipine.(ABSTRACT TRUNCATED AT 250 WORDS)

A comparison of the cardioprotective effects of calcium antagonists from different classes upon ischaemic damage in the guinea-pig working heart.

The cardioprotective effects of nifedipine, verapamil, diltiazem, bepridil, CERM 11956, lidoflazine, mioflazine and the coronary vasodilator dipyridamole were evaluated in the guinea-pig working heart with respect to cardiac function and high energy phosphate content after 45 min of global ischaemia and 25 min of reperfusion. All drugs, with the exception of dipyridamole, induced a negative inotropic effect, which resulted in a decrease of the aortic pressure (AoP), of its first derivative dAoP/dt and the cardiac output. To compare the anti-ischaemic effect of the calcium antagonists, concentrations were selected that reduced the dAoP/dt by 10% (EC10) and 30% (EC30), respectively. With the exception of nifedipine at the EC10 and bepridil and CERM 11956 at the EC30, perfusion with the calcium antagonists and dipyridamole (3 mumol/l) improved the recovery of contractile function after global ischaemia and reperfusion to a value between 60 and 80% of the controls in normoxic hearts. Pretreatment with nifedipine, verapamil, diltiazem, lidoflazine and mioflazine, but not with bepridil, CERM 11956 and dipyridamole led to slightly increased ATP levels in ischaemic hearts as compared to the control value in ischaemic hearts. After subsequent reperfusion for 25 min, for all drugs, ATP levels were further enhanced to 50% of the level in normoxic hearts; phosphocreatine levels reached normoxic values. In particular at the EC30, the effects of calcium antagonists on cardiac function varied in accordance with their known pharmacological and physiological profile. However, there appeared to exist no direct relationship between their beneficial effects on contractile activity and those on the levels of high energy phosphates after ischaemia and reperfusion.

Alpha 1-adrenoceptors: the ability of various agonists and antagonists to discriminate between two distinct [3H]prazosin binding sites.

Recently, it has been demonstrated that two distinct alpha 1-adrenoceptor binding sites showing high and low affinity for WB-4101 (2-(2,6-dimethoxyphenoxy)ethyl-aminomethyl-1,4-benzodioxane) and 5-methyl-urapidil can be distinguished. In the present study we examined the ability of several agonists and antagonists to discriminate between these alpha 1-adrenoceptor binding sites. [3H]Prazosin binding to membranes of rat liver, heart, cerebral cortex and hippocampus was inhibited monophasically by butanserine, I-BE 2254 (2-(3-(4-hydroxy-3-iodophenyl)ethylaminomethyl)tetralone-hydrochloride), prazosin, rauwolscine and verapamil. In contrast, competition curves of adrenaline, oxymetazoline, amidephrine and YM-12617 (5-[2-[[2-(o-ethoxy-phenoxy)ethyl]-amino]propyl]-2- methoxybenzenesulfonamide HCl) were best described by a model of two binding sites. Chloroethylclonidine (CEC), a compound shown to irreversibly eliminate binding sites with low affinity for WB-4101, increased the proportion of high affinity binding sites for oxymetazoline and amidephrine, whereas the binding data for prazosin and adrenaline remained unchanged. These results indicate that amidephrine, oxymetazoline and YM-12617, but not the other drugs tested discriminate between different alpha 1-adrenoceptor recognition sites labelled by [3H]prazosin.

Lymphocyte beta 2-adrenoceptors mirror precisely beta 2-adrenoceptor, but poorly beta 1-adrenoceptor changes in the human heart.

To study the relationship of changes in human lymphocyte beta-adrenoceptors to changes potentially occurring in solid tissues we studied 16 patients undergoing elective coronary artery bypass grafting and determined the density of lymphocyte beta 2-adrenoceptors [by (-)125I-iodocyanopindolol (ICYP) binding] in comparison to beta-adrenoceptor density and responsiveness (contractile responses to isoprenaline) in the corresponding right atria. Lymphocyte beta 2-adrenoceptor density (with a range of 278-2442 ICYP binding sites/cell) was significantly correlated with beta-adrenoceptor density in the corresponding atria (54.8-171.6 fmol ICYP bound/mg protein, r = 0.784, P less than 0.001). In these atria the levels of beta 1- and beta 2-adrenoceptors (assessed by non-linear regression analysis of competition curves of the selective beta 2-adrenoceptor antagonist ICI 188,551 with ICYP binding) were approximately .70 and 30%, respectively. Lymphocyte beta 2-adrenoceptor density, however, correlated significantly better with atrial beta 2-adrenoceptor (r = 0.8441; P less than 0.001) than beta 1-adrenoceptor (r = 0.6226, P less than 0.05) density. On 12 of the 16 atria (electrically driven with 1 Hz at 37 degrees C) isoprenaline (10(-9) to 3 X 10(-6) mol/l) caused positive inotropic effects. The maximum increase in contractile force evoked by saturating concentrations of isoprenaline (mean: 3.52 +/- 0.62 mN), however, correlated equally well with beta 1- and beta 2-adrenoceptor density in the corresponding atria (r = 0.6834 and 0.6567, respectively). These results indicate that changes in lymphocyte beta 2-adrenoceptors can be taken as a precise index of changes of beta 2-adrenoceptors in other (solid) tissues; beta 1-adrenoceptor alterations, however, are only poorly reflected in the lymphocytes.

Sensitivity of alpha-1 adrenoceptor-mediated pressor responses to inhibition by Ca++ entry blockers in the pithed rat: arguments against the role of receptor reserve.

In pithed rats, nifedipine (i.a., -15 min) maximally shifted the alpha-1 adrenoceptor-mediated log dose-pressor response curve to i.v. (-)-phenylephrine 5-fold to the right, doses of 1 and 3 mg/kg being equieffective. Phenoxybenzamine (3-1000 micrograms/kg i.v., -60 min) enhanced the potency of nifedipine, expressed as -log ID50, to inhibit the vasopressor response to (-)-phenylephrine. After treatment with 0.1, 0.3 or 1 mg/kg of phenoxybenzamine a dose of 1 mg/kg of nifedipine was sufficient to virtually eliminate the pressor responses. The potentiating effect of phenoxybenzamine was already present at a low dose of 3 micrograms/kg, which by itself had no influence on the log dose-pressor response curve to (-)-phenylephrine. It was also clearly limited, inasmuch as the -log ID50 values of nifedipine determined after treatment with 0.1, 0.3 and 1 mg/kg of phenoxybenzamine were identical and similar to the value reported for nifedipine against alpha-2 adrenoceptor-mediated vasoconstriction in pithed rats. Infusion of vasopressin to counteract the vasodilatory action of nifedipine did not affect its inhibitory potency compared to the effectiveness quantified under the conditions of reduced baseline diastolic pressure. The data support the conclusions that the resistance of the pressor response to (-)-phenylephrine (and other full alpha-1 adrenoceptor agonists) to inhibition by nifedipine (or other Ca++ channel blockers) is due to the dual nature of the Ca++ utilization in the vasoconstriction to these stimulants, i.e., transmembranous influx of extracellular Ca++ (sensitive to Ca++ channel blockers) and a mobilization of intracellular Ca++ (insensitive to Ca++ channel blockers).(ABSTRACT TRUNCATED AT 250 WORDS)

Beta-2 adrenoceptor-mediated relaxation of the isolated human saphenous vein.

On isolated strips of human saphenous vein, pretreated with 5 microM phenoxybenzamine and contracted with 10 mM KCl, the beta adrenoceptor mediating the relaxant effects of isoproterenol, procaterol and norepinephrine was characterized using the selective beta-1 adrenoceptor antagonist, bisoprolol, and the selective beta-2 adrenoceptor antagonist, ICI 118,551. All three agonists produced concentration-dependent relaxations of the isolated saphenous vein with an order of potency: procaterol (pD2 value, 7.69) greater than isoproterenol (pD2 value, 7.41) much greater than norepinephrine (pD2 value, 5.30). ICI 118,551 (3 X 10(-10) to 3 X 10(-9) M) was nearly 100 times more potent than bisoprolol (10(-7) to 10(-6) M) in antagonizing the relaxant effects of isoproterenol and procaterol. The slopes of the Schild plots for the antagonistic effects of ICI 118,551 and bisoprolol against isoproterenol- and procaterol-induced relaxations were not significantly different from unity indicating interaction with a homogeneous population of beta adrenoceptors. The pA2 value for ICI 118,551 amounted to 9.11 to 9.20 and for bisoprolol to 6.50 to 6.63. In addition, the concentration-response curve for the relaxant effect of norepinephrine was significantly shifted to the right by 10(-9) M ICI 118,551, but not affected by 10(-7) M bisoprolol. These results indicate that on the isolated strips of the human saphenous vein the beta adrenoceptor mediating relaxation is of the beta-2 subtype.

Communicating with patients the second time they present their prescription at the pharmacy. Discovering patients' drug-related problems.

OBJECTIVE: To assess the effect of a short inquiry the second time that the prescription was presented at the pharmacy (SP) counter on the detection of drug related-problems as perceived by patients in a community pharmacy. The implementation of the SP procedure is also described. METHOD: At SP patients were asked to give a short description of their experience with their newly prescribed drug. Patients' drug-related problems were recorded on a SP form and were categorised into three groups: side effects, inefficacy, and problems with use or instruction. Data were also matched with drug categories. The ATC classification was used. A comparison with a control pharmacy was made. MAIN OUTCOME MEASURES: Drug experience, patients' drug-related problems, side effects, inefficacy, problems with the use or instruction. RESULTS: Data from 700 SP forms showed that in 78% of cases patients did not have problems with the use of their new drugs. In the remainder of cases (22%), drug-related problems mainly concerned side effects (49%; 76 out of 156) and complaints about the drugs not being as effective as expected (inefficacy: 49%; 77 out of 156). In the control pharmacy no drug-related problems were detected in 30 SP contacts. Patients using gastrointestinal drugs reported fewer side effects than patients using cardiovascular drugs. Patients using respiratory drugs reported more often that the drug was not effective than patients using cardiovascular drugs. CONCLUSION: It was concluded that the SP procedure encourages patients to report their drug problems at the counter in the pharmacy.

Alpha and beta-adrenoceptors in hypertension. I. Cardiac and renal alpha 1-, beta 1-, and beta 2-adrenoceptors in rat models of acquired hypertension.

To determine whether adrenoceptor changes in genetic hypertension occur primary or secondary to blood pressure elevation, we measured cardiac and renal alpha 1- (by [125I]Be 2254 binding) and beta 1- and beta 2-adrenoceptors (by (-)-[125I]iodocyanopindolol binding) densities in various rat models of acquired hypertension (Dahl S rats on a high-sodium diet, 1-clip-1-kidney (1C-1K) renal hypertensive and DOCA-salt hypertensive rats) in comparison with genetically identical age-matched untreated rats. In addition, alpha 1-adrenoceptors were assessed in spontaneously hypertensive rats (SHR) and in SHR treated with the immunosuppressant cyclosporin A. In heart, no clear pattern of changes in alpha 1- or beta 1- and beta 2-adrenoceptors was obtained. In kidney, however, beta 1- and beta 2-adrenoceptors were increased in all models of hypertension, and a good correlation between renal beta-adrenoceptors and systolic blood pressure was found. In contrast, renal alpha 1-adrenoceptors were only increased in SHR but not in any form of acquired hypertension. Thus, renal beta-adrenoceptor increases probably occur secondary to blood pressure elevation, whereas alpha 1-adrenoceptor increases appear to be associated with genetic hypertension. Because renal alpha-adrenoceptors are linked to tubular sodium reabsorption, we suggest that an increase in renal alpha 1- (and alpha 2)-adrenoceptors may be a very early step in the development of genetic hypertension.

Increased beta 2-adrenoreceptor density in heart, kidney and lung of spontaneously hypertensive rats.

The development of beta-adrenoreceptor density and beta 1- and beta 2-adrenoreceptor distribution has been investigated in heart, kidney and lung of spontaneously hypertensive (SHR) and normotensive (WKY) rats by (-)125I-iodocyanopinolol binding at the age of 5-6, 9-10 and 19-21 weeks. At all ages beta-adrenoreceptor density was similar in hearts of both strains, while it was increased in kidney and lung of SHR compared to WKY. The beta 2-adrenoreceptor density was higher in all three tissues of SHR at all ages investigated. On the other hand, beta 1-adrenoreceptor density was decreased in heart, unchanged in lung and increased in kidney of SHR compared to WKY. Destruction of presynaptic nerve terminals by treatment of WKY with 6-hydroxydopamine produced a 24% loss of cardiac beta 2-adrenoreceptors, whereas the beta 1-adrenoreceptor density remained unchanged, suggesting that at least part of the cardiac beta 2-adrenoreceptor population is localized prejunctionally. It is suggested that beta 2-adrenoreceptors are involved in the development or maintenance of high blood pressure in SHR, possibly by facilitating noradrenaline release.

Differentiation of beta 1- and beta 2-adrenoceptor-mediated effects in humans.

To differentiate beta 1- and beta 2-adrenoceptor-mediated effects in humans, we studied the effects of a 2-wk treatment of 12 male volunteers with the selective beta 1-adrenoceptor antagonist bisoprolol (1 x 10 mg/day) and the beta 2-selective antagonist ICI 118,551 (3 x 25 mg/day) on lymphocyte beta 2-adrenoceptor density and responsiveness [10 microM l-isoproterenol (IPN) evoked adenosine 3',5'-cyclic monophosphate (cAMP) increase] as well as on exercise- and IPN-induced changes in lymphocyte beta 2-adrenoceptor density, blood pressure, heart rate, and plasma norepinephrine levels. ICI 118,551 administration increased lymphocyte beta 2-adrenoceptor density and responsiveness by approximately 50%, whereas bisoprolol had no effect. Dynamic exercise on a bicycle and infusion of graded doses of IPN led to an approximately 100% increase in lymphocyte beta 2-adrenoceptor density; this was abolished by ICI 118,551 but not affected by bisoprolol. ICI 118,551 markedly attenuated IPN-induced decrease in diastolic blood pressure but did not affect increase in systolic blood pressure, whereas bisoprolol had opposite effects. The IPN-induced increase in heart rate, however, was antagonized by both bisoprolol and (to a greater extent) ICI 118,551. Finally, ICI 118,551 completely abolished the IPN-induced increase in plasma norepinephrine levels, whereas bisoprolol had no effect. These results indicate that bisoprolol and ICI 118,551 are suitable tools to differentiate in humans beta 1- and beta 2-adrenoceptor-mediated effects.