Michael Schachter

Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update

Statins are the treatment of choice for the management of hypercholesterolaemia because of their proven efficacy and safety profile. They also have an increasing role in managing cardiovascular risk in patients with relatively normal levels of plasma cholesterol. Although all statins share a common mechanism of action, they differ in terms of their chemical structures, pharmacokinetic profiles, and lipid‐modifying efficacy. The chemical structures of statins govern their water solubility, which in turn influences their absorption, distribution, metabolism and excretion. Lovastatin, pravastatin and simvastatin are derived from fungal metabolites and have elimination half‐lives of 1–3 h. Atorvastatin, cerivastatin (withdrawn from clinical use in 2001), fluvastatin, pitavastatin and rosuvastatin are fully synthetic compounds, with elimination half‐lives ranging from 1 h for fluvastatin to 19 h for rosuvastatin. Atorvastatin, simvastatin, lovastatin, fluvastatin, cerivastatin and pitavastatin are relatively lipophilic compounds. Lipophilic statins are more susceptible to metabolism by the cytochrome P450 system, except for pitavastatin, which undergoes limited metabolism via this pathway. Pravastatin and rosuvastatin are relatively hydrophilic and not significantly metabolized by cytochrome P450 enzymes. All statins are selective for effect in the liver, largely because of efficient first‐pass uptake; passive diffusion through hepatocyte cell membranes is primarily responsible for hepatic uptake of lipophilic statins, while hydrophilic agents are taken up by active carrier‐mediated processes. Pravastatin and rosuvastatin show greater hepatoselectivity than lipophilic agents, as well as a reduced potential for uptake by peripheral cells. The bioavailability of the statins differs greatly, from 5% for lovastatin and simvastatin to 60% or greater for cerivastatin and pitavastatin. Clinical studies have demonstrated rosuvastatin to be the most effective for reducing low‐density lipoprotein cholesterol, followed by atorvastatin, simvastatin and pravastatin. As a class, statins are generally well tolerated and serious adverse events, including muscle toxicity leading to rhabdomyolysis, are rare. Consideration of the differences between the statins helps to provide a rational basis for their use in clinical practice.

Causes of prescribing errors in hospital inpatients: a prospective study

BACKGROUND To prevent errors made during the prescription of drugs, we need to know why they arise. Theories of human error used to understand the causes of mistakes made in high-risk industries are being used in health-care. They have not, however, been applied to prescribing errors, which are a great cause of patient harm. Our aim was to use this approach to investigate the causes of such errors. METHODS Pharmacists at a UK teaching hospital prospectively identified 88 potentially serious prescribing errors. We interviewed the prescribers who made 44 of these, and analysed our findings with human error theory. FINDINGS Our results suggest that most mistakes were made because of slips in attention, or because prescribers did not apply relevant rules. Doctors identified many risk factors-work environment, workload, whether or not they were prescribing for their own patient, communication within their team, physical and mental well-being, and lack of knowledge. Organisational factors were also identified, and included inadequate training, low perceived importance of prescribing, a hierarchical medical team, and an absence of self-awareness of errors. INTERPRETATION To reduce prescribing errors, hospitals should train junior doctors in the principles of drug dosing before they start prescribing, and enforce good practice in documentation. They should also create a culture in which prescription writing is seen as important, and formally review interventions made by pharmacists, locum arrangements, and the workload of junior doctors, and make doctors aware of situations in which they are likely to commit errors.

Prescribing errors in hospital inpatients: their incidence and clinical significance

Background: It has been estimated that 1–2% of US inpatients are harmed by medication errors, the majority of which are errors in prescribing. The UK Department of Health has recommended that serious errors in the use of prescribed drugs should be reduced by 40% by 2005; however, little is known about the current incidence of prescribing errors in the UK. This pilot study sought to investigate their incidence in one UK hospital. Methods: Pharmacists prospectively recorded details of all prescribing errors identified in non-obstetric inpatients during a 4 week period. The number of medication orders written was estimated from a 1 in 5 sample of inpatients. Potential clinical significance was assessed by a pharmacist and a clinical pharmacologist. Results: About 36 200 medication orders were written during the study period, and a prescribing error was identified in 1.5% (95% confidence interval (CI) 1.4 to 1.6). A potentially serious error occurred in 0.4% (95% CI 0.3 to 0.5). Most of the errors (54%) were associated with choice of dose. Error rates were significantly different for different stages of patient stay (p<0.0001) with a higher error rate for medication orders written during the inpatient stay than for those written on admission or discharge. While the majority of all errors (61%) originated in medication order writing, most serious errors (58%) originated in the prescribing decision. Conclusions: There were about 135 prescribing errors identified each week, of which 34 were potentially serious. Knowing where and when errors are most likely to occur will be helpful in designing initiatives to reduce them. The methods developed could be used to evaluate such initiatives.

Statin-fibrate combination therapy for hyperlipidaemia: a review

SUMMARY Statins and fibrates are well-established treatments for hyperlipidaemias and the prevention of vascular events. However, fibrate + statin therapy has been restricted following early reports of rhabdomyolysis that mainly involved gemfibrozil, originally with lovastatin, and recently, with cerivastatin. Despite this limitation, several reports describing combination therapy have been published. This review considers these studies and the relevant indications and contraindications. Statin + fibrate therapy should be considered if monotherapy or adding other drugs (e.g. cholesterol absorption inhibitors, omega-3 fatty acids or nicotinic acid) did not achieve lipid targets or is impractical. Combination therapy should be hospital-based and reserved for high-risk patients with a mixed hyperlipidaemia characterised by low density lipoprotein cholesterol (LDL) > 2.6 mmol/l (100 mg/dl), high density lipoprotein cholesterol (HDL) < 1.0 mmol/l (40 mg/dl) and/or triglycerides > 5.6 mmol/l (500 mg/dl). These three ‘goals’ are individually mentioned in guidelines. Patients should have normal renal, liver and thyroid function tests and should not be receiving therapy with cyclosporine, protease inhibitors or drugs metabolised through cytochrome P450 (especially 3A4). Combination therapy is probably best conducted using drugs with short plasma half-lives; fibrates should be prescribed in the morning and statins at night to minimise peak dose interactions. Both drug classes should be progressively titrated from low doses. Regular (3-monthly) monitoring of liver function and creatine kinase is required. In conclusion, fibrate + statin therapy remains an option in high-risk patients. However, long-term studies involving safety monitoring and vascular endpoints are required to demonstrate the efficacy of this regimen.

Tyrosine kinase inhibitors block calcium channel currents in vascular smooth muscle cells.

Selective inhibitors of tyrosine kinases, tyrphostin 23 and genistein, produced concentration-dependent inhibition of voltage-operated calcium channel currents in vascular smooth muscle cells isolated from rabbit ear artery. The potency of these two structurally dissimilar inhibitors was similar to that reported for their action as inhibitors of tyrosine kinases. Daidzein, an inactive analogue of genistein, had little inhibitory effect on calcium channel currents at concentrations below 300 microM consistent with an action of these agents at a tyrosine kinase. However, tyrphostin 1, a reportedly less active tyrphostin derivative, also inhibited calcium channel currents with a potency similar to tyrphostin 23. These findings suggest that voltage-operated calcium channels in vascular smooth muscle may be modulated by endogenous tyrosine kinase(s) which display different sensitivities to inhibitors compared with the epidermal growth factor (EGF) receptor. Alternatively the possibility of direct blocking actions of these inhibitors at voltage-operated calcium channels cannot be excluded.

The incidence of prescribing errors in hospital inpatients: an overview of the research methods.

Many different methods have been used to study the incidence of prescribing errors in hospital inpatients. The objectives of this review were to outline the methods used, highlight their strengths and limitations, and summarise the incidence of prescribing errors reported.Methods used may be retrospective or prospective and based on process or on outcome. Reported prescribing error rates vary widely, ranging from 0.3% to 39.1% of medication orders written and from 1% to 100% of hospital admissions. Unfortunately, there is no standard denominator for use when expressing prescribing error rates. It could be argued that the most meaningful is the number of medication orders written; however, it is also helpful to consider the number of medication orders written per patient stay in order to understand the risk that a given prescribing error rate poses to an individual patient. Because of wide variation in the definitions and methods used, it is difficult to make comparisons between different studies.Each method for identifying prescribing errors has advantages and disadvantages. Process-based studies potentially allow all errors to be identified, giving more scope for the identification of trends and learning opportunities, and it may be easier to collect sufficient data to show statistically significant changes in prescribing error rates following interventions to reduce them. However, studies based on process may be criticised for focusing on many minor errors that are very unlikely to have resulted in patient harm. Focusing instead on harm, as in outcome-based studies, allows efforts to reduce errors to be targeted on those areas that are likely to result in the highest impact. Therefore, the most appropriate method depends on the study’s aims. However, using a combination of methods is likely to be the most useful approach if comprehensive data are required.

Characterisation of [3H]lysergic acid diethylamide binding to a 5-hydroxytryptamine receptor on human platelet membranes.

Specific binding of [3H]lysergic acid diethylamide (LSD) to human platelet membranes, as defined by 300 nM spiperone, was saturable over the concentration range of 0.25-2.5 nM [3H]LSD. At 0.5 nM [3H]LSD the half-time for association at 37 degrees C was 56 min, half-time for dissociation was 173 min, and the kinetically derived affinity was 0.24 nM. In 19 control subjects equilibrium binding studies gave an affinity of 0.53 +/- 0.02 nM (mean +/- S.E.M.) and capacity of 57.1 +/- 5.6 fmol/mg protein (mean +/- S.E.M.). The inhibition profile was consistent with that of a 5-hydroxytryptamine (5-HT) receptor. There was a significant correlation between the inhibition of [3H]LSD binding and the inhibition of 5-HT-induced shape change, but not inhibition of active platelet uptake of 5-HT. There was also a significant correlation between the inhibition of [3H]LSD binding to human platelet membranes and human frontal cortex. Platelet [3H]LSD binding may therefore be a useful model for study of peripheral and central 5-HT receptors in man.

Inhibition of human vascular smooth muscle cell proliferation by lovastatin: the role of isoprenoid intermediates of cholesterol synthesis

Abstract Restenosis remains the largest single obstacle to the long‐term success of invasive vascular interventions. Lovastatin, an HMG‐CoA reductase inhibitor, has been shown to reduce myointimal hyperplasia in animal models of restenosis and in one clinical coronary restenosis trial. We have assessed the effect of lovastatin on the growth of cultured human vascular smooth muscle cells derived from saphenous vein and vascular graft stenoses. Lovastatin (2 μM) inhibited proliferation over 14 days in saphenous vein (and graft stenoses) derived vascular smooth muscle cells by 42% and 32%, respectively: this was not significantly different. Lovastatin (10 μM) reduced [methyl 3H]‐thymidine uptake by 51% in saphenous vein‐derived cells. These concentrations were significantly higher than those achieved in plasma during therapeutic dosage. Lovastatin‐induced inhibition of vascular smooth muscle cell proliferation and [methyl 3H]‐thymidine uptake was completely reversed by adding mevalonate (100 μM) but cholesterol (10–40 μl‐1) had no effect. Isopentenyl adenine (25–50 μM) did not affect the inhibition of [methyl 3H]‐thymidine uptake by lovastatin (10 μM), but farnesol (20 μM), another isoprenoid precursor of cholesterol synthesis, reversed the antiproliferative effect.

Vitamins and cardiovascular disease

CVD is a major cause of mortality and morbidity in the Western world. In recent years its importance has expanded internationally and it is believed that by 2020 it will be the biggest cause of mortality in the world, emphasising the importance to prevent or minimise this increase. A beneficial role for vitamins in CVD has long been explored but the data are still inconsistent. While being supported by observational studies, randomised controlled trials have not yet supported a role for vitamins in primary or secondary prevention of CVD and have in some cases even indicated increased mortality in those with pre-existing late-stage atherosclerosis. The superiority of combination therapy over single supplementation has been suggested but this has not been confirmed in trials. Studies have indicated that beta-carotene mediates pro-oxidant effects and it has been suggested that its negative effects may diminish the beneficial effects mediated by the other vitamins in the supplementation cocktail. The trials that used a combination of vitamins that include beta-carotene have been disappointing. However, vitamin E and vitamin C have in combination shown long-term anti-atherogenic effects but their combined effect on clinical endpoints has been inconsistent. Studies also suggest that vitamins would be beneficial to individuals who are antioxidant-deficient or exposed to increased levels of oxidative stress, for example, smokers, diabetics and elderly patients, emphasising the importance of subgroup targeting. Through defining the right population group and the optimal vitamin combination we could potentially find a future role for vitamins in CVD.

The use of ezetimibe in achieving low density lipoprotein lowering goals in clinical practice: position statement of a United Kingdom consensus panel

ABSTRACT There is no doubt that lowering serum cholesterol levels reduces the risk of major coronary events. This evidence has led treatment guidelines to set progressively lower targets for low density lipoprotein cholesterol (LDL-C). However, despite widespread use of statins, substantial numbers of patients do not achieve the LDL-C goals. Using higher doses of statins in an attempt to achieve these targets may increase the risk of serious adverse effects. Furthermore, the use of combination therapy with agents such as bile acid sequestrants, niacin and fibrates has been limited by increased potential for side effects, drug interactions and poor compliance. Ezetimibe, a selective cholesterol transport inhibitor, reduces the intestinal uptake of cholesterol without affecting absorption of triglycerides or fatsoluble vitamins. In clinical studies, ezetimibe 10 mg, in combination with statins or as monotherapy, was well tolerated and reduced LDL-C by 34–53% and 17–18%, respectively. The available evidence for ezetimibe is reviewed. The role of ezetimibe in increasing the proportion of patients attaining LDL-C treatment goals is discussed.