Gillian M. Shenfield

Optimizing the Use of Antithrombotic Therapy for Atrial Fibrillation in Older People: A Pharmacist‐Led Multidisciplinary Intervention

Objectives: To develop, implement, and evaluate a pharmacist‐led multidisciplinary intervention in a hospital setting that would optimize antithrombotic use in elderly atrial fibrillation patients. The hypothesis that there would be an increase in the proportion of patients receiving antithrombotic therapy at discharge was tested.

Influence of thyroid dysfunction on drug pharmacokinetics.

When thyroid function is altered there are a series of physiological changes which are likely to affect drug absorption, metabolism or excretion, and altered pharmacokinetics have been described for a variety of drugs in both hypothyroidism and hyperthyroidism.Absorption of riboflavine is increased in hypothyroidism and decreased in hyperthyroidism due to changes in gut motility. Opposite findings have been described for ethanol in rats, but remain to be confirmed in man. There is definite evidence of induction of hepatic metabolism in hyperthyroidism with reduced metabolism in hypothyroidism. Antipyrine half-lives are therefore decreased in hyperthyroidism and prolonged in hypothyroidism. The same may be true for aminopyrine, but there do not appear to be any significant changes iin phenytoin kinetics. There is need for an increased dose of oral anticoagulants in hypothyroidism and a decreased dose in hyperthyroidism due to altered catabolism of vitamin K-dependent clotting factors in the absence of any alteration in the metabolism of the anticoagulant drugs themselves. At present it is not possible to predict the effect of altered thyroid function on the metabolism of any individual drug.The antithyroid drug methimazole, which is also the active metabolite of carbimazole, has a shorter half-life in hyperthyroid patients than in normal controls. This probably accounts for the need for frequent doses while hyperthyroidism is active and the effectiveness of a once daily dose once the disease is under control. Propylthiouracil has a shorter half-life than methimazole and there is little good evidence of any change in half-life with thyroid dysfunction.Information about the β-adrenoceptor blocking drugs in altered thyroid states is scanty, but there is a trend to a shortened propranolol half-life and reduced area under the serum concentration-time curve in hyperthyroidism and a prolonged half-life in hypothyroidism. The reasons for this will not be known until propranolol metabolites are assayed in states of thyroid dysfunction. There is an increased clearance of practolol in hyperthyroidism, probably due to increased renal excretion.There are lower than normal plasma concentrations of cardiac glycosides in hyperthyroidism and, possibly, higher than normal concentrations in hypothyroidism. There appears to be an altered volume of distribution of digoxin in thyroid dysfunction — being increased in hyperthyroidism and decreased in hypothyroidism. This may be due to altered cardiac and skeletal muscle binding of digoxin in hyperthyroidism. Pharmacokinetic changes alone cannot explain the clinical resistance to digoxin in hyperthyroidism which could be related to the increased number of Na+ K+ -ATPase pumps in that disease state.Altered thyroid function affects the clearance of thyroxine, tri-iodothyronine and cortisol, and for all of these hormones half-lives are shortened in hyperthyroidism and prolonged in hypothyroidism. Plasma concentrations of oestrogen, progesterone and the androgens are raised in hyperthyroidism and lower than normal in hypothyroidism due to parallel changes in sex hormone binding globulin. Insulin half-life is shortened in hyperthyroid rabbits, but this has not been confirmed in man. In spite of reports of altered numbers of β-adrenoceptor binding sites with altered thyroid function, there is no evidence that sympathomimetic drugs behave differently in patients with thyroid dysfunction.It is possible that other drugs are affected by thyroid dysfunction and further studies will be necessary to establish this.

Amelioration of experimental cisplatin and paclitaxel neuropathy with glutamate

A major toxic effect of the chemotherapeutic agents paclitaxel and cisplatin is peripheral neuropathy. We report the use of a rat model of cytotoxic neuropathy to evaluate the role of glutamate as a possible neuroprotectant for these two drugs. Neuropathy was manifest as gait disturbance in 100% of paclitaxel treated animals after 2 weeks and 100% of cisplatin treated animals after 8 weeks. Significant elevations of mean tail-flick threshold, a measure of sensory impairment, were observed in animals treated with both cytotoxics. Impaired rota-rod performance was observed in both light and dark with paclitaxel, indicating motor neuropathy. There was a trend towards impairment in the dark for cisplatin, suggesting proprioceptive loss. In cytotoxic treated animals supplemented with oral sodium glutamate (approx. 500 mg/kg/day in drinking water) from 24 h before chemotherapy, there was a significant delay in time to onset of gait disturbance allowing significantly higher mean doses to be tolerated. Mean tail-flick and rota-rod scores were unchanged from baseline for both drugs. Glutamate therefore protected against both sensory and motor neuropathy. Similar doses of glutamate did not impair the cytotoxic efficacy of paclitaxel or cisplatin against a transplantable rat mammary adenocarcinoma grown subcutaneously in rats. Our findings suggest that glutamate warrants clinical trial as a neuroprotectant in patients receiving paclitaxel or cisplatin.

Clinical Pharmacokinetics of Contraceptive Steroids An Update

SummaryThe present article should be read in conjunction with the original review published in the Journal in 1983. There is no new information of major significance about the pharmacokinetics of levonorgestrel, norethisterone (norethindrone) or ethinylestradiol, although it has been shown that the concentrations of these hormones secreted in breast milk are small and mothers taking combined oral contaceptive steroids may breast-feed safely. Both levonorgestrel and ethinylestradiol can be successfully administered from appropriate vaginal formulations, but no clear advantages over oral administration have been demonstrated.Several new progestogens have been investigated. Desogestrel is a prodrug for its active metabolite 3-keto-desogestrel, gestodene is itself an active progestogen and norgestimate is a prodrug acting by conversion to norgestrel and its metabolites. All 3 compounds have good bioavailability with wide intersubject variation. The newer progestogens, like norethisterone and levonorgestrel, are bound to sex hormone binding globulin (SHBG). This causes their plasma concentrations to increase with time, since SHBG is induced by ethinylestradiol even in doses of 30μg daily. The binding capacity and affinity of SHBG do not increase in direct proportion to its concentration.Further drug interactions with oral contraceptive steroids have been described. Contraceptive steroids may inhibit hepatic microsomal enzyme metabolism and increase the plasma concentration and effect of some tricyclic antidepressants, the hydroxylated benzodiazepines, some β-blocking drugs, methylxanthines, prednisolone and cyclosporin. There are no significant effects on vitamins. Oral contraceptive steroids induce glucuronidation and hence decrease plasma concentrations of some benzodiazepines, clofibric acid, paracetamol (acetaminophen) and possibly morphine.The plasma concentration of ethinylestradiol may be increased by competitive sulphation with paracetamol. Plasma concentrations of contraceptive steroids are decreased by griseofulvin, which induces their hepatic metabolism. The role of other antibiotics remains controversial but there is probably a group of susceptible women who have lower plasma contraceptive hormone concentrations and experience breakthrough bleeding or pregnancy when given broad spectrum antibiotics. This may relate to interruption of the enterohepatic recirculation of ethinylestradiol. Anticonvulsants, other than valproic acid, all induce contraceptive steroid metabolism and therefore lower plasma hormone concentrations, thus reducing contraceptive effectiveness.

Simultaneous Analysis of Cimetidine and Ranitidine in Human Plasma by HPLC

Abstract A rapid method for the simultaneous quantitation of the H2-receptor antagonist drugs cimetidine and ranitidine in human plasma by isocratic ion-pair reverse-phase HPLC is described. The method involves a simple organic extraction step of the alkalinized plasma containing added internal standard followed by back extraction of the extract with dilute acetic acid and subsequent analysis of the aqueous acidic phase on a reverse-phase (C18) column. The eluting solvent was acetonitrile-water (20:80 v/v) containing 0.005 mole/litre octanesulphonic acid and was monitored at 229 nm. The run time for the assay was 12.5 minutes, with a detection limit for cimetidine of 50 ng/m1/(0.2 μmole/1) and that for ranitidine was 20 ng/ml (0.06 umole/1).

The impact of age on antithrombotic use in elderly patients with non-valvular atrial fibrillation

Aim of study: To investigate the use of antithrombotic therapy in elderly patients with atrial fibrillation (AF). Methods: Data were collected retrospectively from the medical records of 262 AF patients >65 years, who were admitted to a Sydney teaching hospital over a 12‐month period.

Combination Bronchodilator Therapy

SummaryBronchodilators may be classified into 3 groups: anticholinergics, β-adrenoceptor agonists and methylxanthines. These drugs act through related biochemical pathways and there are theoretical reasons for expecting beneficial additive or synergistic interactions between them. While there is in vitro evidence of synergistic interactions producing bronchodilatation, in vivo studies indicate that the interactions are additive rather than synergistic but still of therapeutic value.There have been no clinical studies on methylxanthines combined with anticholinergic drugs, but there is an extensive and growing literature on the other combinations. The majority show clear evidence of an additive bronchodilator effect when anticholinergics are combined with β2-adrenoceptor agonists, although atropine sulphate is less effective in this regard than atropine methylnitrate or ipratropium bromide. This type of combination has only been tested by inhalation and, because of the slower onset of action of the anticholinergic group, it is preferable that the β2-adrenoceptor agonist be inhaled first. There is no evidence for an additive interaction of the side effects of these drugs. In general, bronchitics respond better than asthmatics to anticholinergic drugs.Studies on methylxanthines (usually theophylline) and adrenoceptor agonists may be divided into 2 groups: those using ephedrine and those using more selective β-adrenoceptor agonists. Ephedrine is a relatively ineffective bronchodilator and often fails to add any useful bronchodilatation to theophylline. Also, there does seem to be a synergistic increase in side effects of the two drugs and this combination is therefore undesirable. Ephedrine has now been superseded by the more selective β2- adrenoceptor agonist drugs all of which, whether given orally, intravenously or by inhalation, appear to have an additive effect with the methylxanthines.It is often possible to achieve the same theapeutic effect with half doses of drugs from 2 different groups as with a full dose of 1 drug. This may sometimes, but not always, reduce side effects. There is evidence that giving 2 drugs by different routes is a useful therapeutic procedure: for example, the addition of an inhaled β2-adrenoceptor agonist may improve upon the maximal bronchodilatation achieved with intravenous theophylline. When theophylline is administered plasma levels of the drug should be monitored and it is possible that, when used in combination with a β2-adrenoceptor agonist, a therapeutic range lower than that normally recommended may apply.There is no longer any place for fixed combination bronchodilators and, in spite of recent suggestions, there is no evidence that bronchodilator combinations are responsible for an increase in asthma mortality.Further studies to clarify some aspects of bronchodilator combinations are needed. The therapeutic use of various combinations is briefly discussed.

Urine drug screens in overdose patients do not contribute to immediate clinical management

A prospective study assessed whether routine urine drug screens might alter the management of overdose patients. Urine was collected from 107 patients with a diagnosis of deliberate self-poisoning seen in the emergency department (ED) of a teaching hospital. The mean age of patients was 36 years (range 13–86 years) and 64% were female. All patients recovered after standard investigations and management, which did not include knowledge of urinary drug screen results. Two hundred ninety-seven compounds were detected in the 107 urine samples. Twenty percent were drugs administered in the ED. Sixty-five percent of patients were found to have taken more than one drug. Benzodiazepines were detected in 18% of samples, paracetamol in 10%, and alcohol in 8%. Sixty-one drugs, in 35 people, were identified that the patients did not report taking. Of these, paracetamol (10), benzodiazepines (9), and tetrahydrocannabinol (8) were the most common. All patients in whom paracetamol was found had already had paracetamol detected in blood and appropriate management instituted. If the results of urine screening had been immediately available this would not have affected the management or outcome of any patient.

Modified high-performance liquid chromatographic method to measure both dextromethorphan and proguanil for oxidative phenotyping

The activities of the polymorphic enzymes cytochromes P450 2D6 and 2C19 can be assessed by administering the probe drugs, dextromethorphan and proguanil, respectively. An existing high-performance liquid chromatographic technique, which measures dextromethorphan and its metabolites, has been modified to also measure proguanil and its polymorphic metabolite, cycloguanil in urine. Proguanil and cycloguanil are assayed in separate aliquots of urine to that used for dextromethorphan/dextrorphan as pretreatment with beta-glucuronidase is required for the analysis of dextrorphan. To assay all four compounds a common extraction procedure is used and a single reversed-phase column and isocratic mobile phase with UV and fluorescence detectors connected in series are required. This technique is specific and sensitive for each analyte (limits of detection, dextrorphan/dextromethorphan/proguanil: 0.1 microgram/ml, cycloguanil: 0.2 microgram/ml). All assays are linear over the concentration ranges investigated (dextromethorphan/dextrorphan: 0.5-10 micrograms/ml, proguanil/cycloguanil: 1-20 micrograms/ml). The method described therefore uses laboratory resources very efficiently for all the assays required for hydroxylation phenotyping using proguanil and dextromethorphan.

Gliclazide hydroxylation by rat liver microsomes

1. The metabolism of gliclazide to hydroxygliclazide has been investigated in Sprague-Dawley rat liver microsomes. 2. The kinetics of hydroxygliclazide formation are consistent with Michaelis-Menten kinetics (mean (+/- SD, n = 3) apparent K(m) and Vmax = 256 +/- 27 microM and 1.85 +/- 0.10 nmol/ min/mg respectively). 3. Tolbutamide competitively inhibited hydroxygliclazide formation (Ki = 840 microM) and gliclazide competitively inhibited hydroxytolbutamide formation (Ki = 240 microM) with Ki similar to K(m). Therefore gliclazide and tolbutamide may be metabolized by the same enzyme in the rat. In nine livers the formation of hydroxygliclazide correlated with the formation of hydroxytolbutamide (rs = 0.82, p < 0.01). 4. Diclofenac (Ki = 64 microM), phenytoin (Ki = 38 microM), mephenytoin (Ki = 66 microM), glibenclamide (Ki = 14 microM) and glipizide (Ki = 189 microM) were fully competitive inhibitors of gliclazide hydroxylation. The rank order of Ki constants differed for gliclazide and tolbutamide suggesting that gliclazide and tolbutamide hydroxylases are not identical enzymes. 5. Quinine (Ki = 0.3 microM) and quinidine (Ki = 4.3 microM) were partially competitive inhibitors of hydroxygliclazide formation. Hydroxylation of gliclazide was related to the activity of CYP2D1 as assessed by dextrorphan production from dextromethorphan (rs = 0.83, p = 0.01). 6. In the rat gliclazide is metabolized to hydroxygliclazide by at least two cytochrome P450 isoforms, including tolbutamide hydroxylase and 2D1, which have similar affinities for gliclazide.