Pharmacists' role in the post-discharge management of patients with heart failure: a literature review.

BACKGROUND AND OBJECTIVE: The incidence of heart failure is increasing in developed countries. In the aged population, heart failure is a common cause of hospitalization and hospital readmission, which in conjunction with post-discharge care, impose a significant cost burden. Inappropriate medication management and drug-related problems have been identified as major contributors to hospital readmissions. In order to enhance the care and clinical outcomes, and reduce treatment costs, heart failure disease management programmes (DMPs) have been developed. It is recommended that these programmes adopt a multi-disciplinary approach, and pharmacists, with their understanding and knowledge of medication management, can play a vital role in the post-discharge care of heart failure patients. The aim of this literature review was to assess the role of pharmacists in the provision of post-charge services for heart failure patients. METHOD: An extensive literature search was undertaken to identify published studies and review articles evaluating the benefits of an enhanced medication management service for patients with heart failure post-discharge. RESULTS: Seven studies were identified evaluating 'outpatient' or 'post-discharge' pharmacy services for patients with heart failure. In three studies, services were delivered prior to discharge with either subsequent telephone or home visit follow-up. Three studies involved the role of a pharmacist in a specialist heart failure outpatient clinic. One study focused on a home-based intervention. In six of these studies, positive outcomes, such as decreases in unplanned hospital readmissions, death rates and greater compliance and medication knowledge were demonstrated. One study did not show any difference in the number of hospitalizations between intervention and control groups. The quality of evidence of the randomized controlled trials was assessed using the Jadad scoring method. None of the studies achieved a score of more than 2, out of a maximum of 5, indicating the potential for bias. DISCUSSION: The DMPs carried out by pharmacists have contributed to positive patient outcomes, which has highlighted the value of extending the traditional roles of pharmacists from the provision of professional guidance to the delivery of continuity of care through a more holistic and direct approach. CONCLUSION: This review has demonstrated the effectiveness of pharmacists' interventions to reduce the morbidity and mortality associated with heart failure. However, there is an on-going need for the development and evaluation of pharmacy services for these patients.

A double-blind randomized controlled trial of ginger for the prevention of postoperative nausea and vomiting.

The efficacy of ginger for the prevention of postoperative nausea and vomiting was studied in a double-blind, randomized, controlled trial in 108 ASA 1 or 2 patients undergoing gynaecological laparoscopic surgery under general anaesthesia. Patients received oral placebo, ginger BP 0.5g or ginger BP 1.0g, all with oral diazepam premedication, one hour prior to surgery. Patients were assessed at three hours postoperatively. The incidence of nausea and vomiting increased slightly but nonsignificantly with increasing dose of ginger. The incidence of moderate or severe nausea was 22, 33 and 36%, while the incidence of vomiting was 17, 14 and 31% in groups receiving 0, 0.5 and 1.0g ginger, respectively (odds ratio per 0.5g ginger 1.39 for nausea and 1.55 for vomiting). These results were essentially unchanged when adjustment was made for concomitant risk factors. We conclude that ginger BP in doses of 0.5 or 1.0 gram is ineffective in reducing the incidence of postoperative nausea and vomiting.

Site-directed mutation studies of human liver cytochrome P-450 isoenzymes in the CYP2C subfamily.

Evidence from human studies in vivo and in vitro strongly suggests that the methylhydroxylation of tolbutamide and the 4-hydroxylation of phenytoin, the major pathways in the elimination of these two drugs, are catalysed by the same cytochrome P-450 isoenzyme(s). In the present study we used site-directed mutagenesis and cDNA expression in COS cells to characterize in detail the kinetics of tolbutamide and phenytoin hydroxylations by seven CYP2C proteins (2C8, 2C9 and variants, and 2C10) in order to define the effects of small changes in amino acid sequences and the likely proteins responsible in the metabolism of these two drugs in man. Tolbutamide was hydroxylated to varying extents by all expressed cytochrome P-450 isoenzymes, although activity was much lower for the expressed 2C8 protein. While the apparent Km values for the 2C9/10 isoenzymes (71.6-131.7 microM) were comparable with the range of apparent Km values previously observed in human liver microsomes, the apparent Km for 2C8 (650.5 microM) was appreciably higher. The 2C8 enzyme also showed quite different sulphaphenazole inhibition characteristics. The 4-hydroxylation of phenytoin was also more efficiently catalysed by the 2C9/10 enzymes. These enzymes showed similarities in kinetics of phenytoin hydroxylation and sulphaphenazole inhibition compared with human liver phenytoin hydroxylase. Also of interest was the observation that, among the 2C9 variants, small differences in amino acid composition could appreciably affect both tolbutamide and phenytoin hydroxylations. The amino acid substitution Cys-144-->Arg increased both the rates of tolbutamide and phenytoin hydroxylations, while the Leu-359-->Ile change had a greater effect on phenytoin hydroxylation. We conclude that: (1) although 2C8 and 2C9/10 proteins metabolize tolbutamide. only 2C9/10 proteins play a major role in human liver; (2) 2C9/10 proteins also appear to be chiefly responsible for phenytoin hydroxylation; and (3) subtle differences in the amino acid composition of these 2C9/10 proteins can affect the functional specificities towards both tolbutamide and phenytoin.

Co-regulation of phenytoin and tolbutamide metabolism in humans.

1. The disposition of phenytoin and tolbutamide was compared in eighteen healthy young adults separately administered single therapeutic doses (sodium phenytoin 300 mg, tolbutamide 500 mg) of the two drugs. 2. Within the group, ratios of ranges of total and unbound areas under the plasma concentration-time curves were similar for both drugs. 3. There were significant (P < 0.001) correlations between total (r = 0.88) and unbound (r = 0.86) areas under the plasma phenytoin and tolbutamide concentration-time curves. 4. The results are consistent with the involvement of the same cytochrome P-450 isoenzyme(s) in the metabolism of tolbutamide and phenytoin.

Standardised initial warfarin treatment: evaluation of initial treatment response and maintenance dose prediction by randomised trial, and risk factors for an excessive warfarin response.

We report a comparison of warfarin treatment outcomes in 172 inpatients in two general hospitals randomly assigned to commence warfarin therapy by one of two methods; the first where warfarin dosage was determined using a flexible dose induction protocol, and the other where dosage was prescribed empirically by resident medical staff. The mean INR for each treatment day, the mean time to reach a therapeutic level of INR, the mean maintenance dose and the mean time to reach maintenance dose were not significantly different between the protocol and empirical treatment groups. Although the mean observations of warfarin effect were similar between the two groups, there were more patients with excessive warfarin effect (INR greater than 4.0) during empirical treatment. In addition, age and identified complicating factors such as interfering drugs, heart failure or alcohol abuse were significant predictors of excessive warfarin effect, regardless of treatment group. The protocol dose administered on day 4 of treatment, which has been used as a determinant of maintenance dose, predicted maintenance dose to within 1 mg in 57/83 patients (69%, 95% confidence interval: 59-79%). We conclude that as a method for safely and effectively initiating warfarin therapy, this protocol at least matches the empirical prescribing skills of medical staff in a teaching hospital.

Tolbutamide and phenytoin hydroxylations by cDNA-expressed human liver cytochrome P4502C9.

A human cytochrome P4502C9 cDNA clone has been isolated from a human liver bacteriophage Lambda gt11 library using oligonucleotide probes. Expression of the 1762 base pair cDNA in COS cells demonstrated that the encoded enzyme has a molecular mass of 55 kDa as determined by sodium dodecyl sulphate-polyacrylamide gel electrophoresis. The expressed enzyme catalysed the methylhydroxylation of tolbutamide with an apparent Km of 131.7 microM, similar to that observed in human liver microsomes. P4502C9 also catalysed the 4-hydroylation of phenytoin, and inhibition experiments demonstrated that phenytoin was a competitive inhibitor of tolbutamide hydroxylation with an apparent Ki of 19.1 microM. Sulphaphenazole was a potent inhibitor of the expressed enzyme with respect to both tolbutamide and phenytoin hydroxylations. These data demonstrate that a single isozyme can catalyse the hydroxylations of both tolbutamide and phenytoin, and suggest that both reactions are mediated by the same isozyme(s) of cytochrome P450 in human liver.

Relationship between phenytoin and tolbutamide hydroxylations in human liver microsomes.

1. The metabolic interaction of phenytoin and tolbutamide in human liver microsomes was investigated. 2. Phenytoin 4-hydroxylation (mean Km 29.6 microM, n = 3) was competitively inhibited by tolbutamide (mean Ki 106.2 microM, n = 3) and tolbutamide methylhydroxylation (mean Km 85.6 microM, n = 3) was competitively inhibited by phenytoin (mean Ki 22.6 microM, n = 3). 3. A significant correlation was obtained between phenytoin and tolbutamide hydroxylations in microsomes from 18 human livers (rs = 0.82, P less than 0.001). 4. Sulphaphenazole was a potent inhibitor of both phenytoin and tolbutamide hydroxylations with IC50 values of 0.4 microM and 0.6 microM, respectively. 5. Mephenytoin was a poor inhibitor of both phenytoin and tolbutamide hydroxylations with IC50 values greater than 400 microM for both reactions. 6. Anti-rabbit P450IIC3 IgG inhibited both phenytoin and tolbutamide hydroxylations in human liver microsomes by 62 and 68%, respectively. 7. These in vitro studies are consistent with phenytoin 4-hydroxylation and tolbutamide methylhydroxylation being catalysed by the same cytochrome P450 isozyme(s) in human liver microsomes.

Phenytoin 4-hydroxylation by rabbit liver P450IIC3 and identification of orthologs in human liver microsomes.

The ability of rabbit liver microsomes to 4-hydroxylate phenytoin to 5-(4-hydroxyphenyl)-5-phenylhydantoin was studied. No significant difference was observed between the capacity of control and rifampicin, phenobarbital, acetone, 2,3,7,8-tetrachlorodibenzo-p-dioxin and phenytoin induced rabbit liver microsomes to 4-hydroxylate phenytoin. In reconstitution experiments using six purified rabbit cytochromes P450 isozymes, only P450IIC3 was capable of 4-hydroxylating phenytoin whereas P450IA1, P450IA2, P450IIB4, P450IIIA6, and P450IVB1 were inactive. Further, anti-P450IIC3 IgG completely inhibited phenytoin 4-hydroxylase activity in rabbit liver microsomes. The above data suggest a major role for the constitutive isozyme P450IIC3 in phenytoin 4-hydroxylase activity in rabbit liver. In human liver microsomes P450IIC3 IgG inhibited phenytoin 4-hydroxylase activity by 66%, suggesting that an ortholog to rabbit P450IIC3 is in part responsible for this activity in man.