Allan J. McLean

Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels

BACKGROUND In patients with coronary heart disease and a broad range of cholesterol levels, cholesterol-lowering therapy reduces the risk of coronary events, but the effects on mortality from coronary heart disease and overall mortality have remained uncertain. METHODS In a double-blind, randomized trial, we compared the effects of pravastatin (40 mg daily) with those of a placebo over a mean follow-up period of 6.1 years in 9014 patients who were 31 to 75 years of age. The patients had a history of myocardial infarction or hospitalization for unstable angina and initial plasma total cholesterol levels of 155 to 271 mg per deciliter. Both groups received advice on following a cholesterol-lowering diet. The primary study outcome was mortality from coronary heart disease. RESULTS Death from coronary heart disease occurred in 8.3 percent of the patients in the placebo group and 6.4 percent of those in the pravastatin group, a relative reduction in risk of 24 percent (95 percent confidence interval, 12 to 35 percent; P<0.001). Overall mortality was 14.1 percent in the placebo group and 11.0 percent in the pravastatin group (relative reduction in risk, 22 percent; 95 percent confidence interval, 13 to 31 percent; P<0.001). The incidence of all cardiovascular outcomes was consistently lower among patients assigned to receive pravastatin; these outcomes included myocardial infarction (reduction in risk, 29 percent; P<0.001), death from coronary heart disease or nonfatal myocardial infarction (a 24 percent reduction in risk, P<0.001), stroke (a 19 percent reduction in risk, P=0.048), and coronary revascularization (a 20 percent reduction in risk, P<0.001). The effects of treatment were similar for all predefined subgroups. There were no clinically significant adverse effects of treatment with pravastatin. CONCLUSIONS Pravastatin therapy reduced mortality from coronary heart disease and overall mortality, as compared with the rates in the placebo group, as well as the incidence of all prespecified cardiovascular events in patients with a history of myocardial infarction or unstable angina who had a broad range of initial cholesterol levels.

Aging Biology and Geriatric Clinical Pharmacology

Population aging evokes doomsday economic and sociological prognostication, despite a minority of older people suffering significant dependency and the potential for advances in therapeutics of age-related disease and primary aging. Biological aging processes are linked mechanistically to altered drug handling, altered physiological reserve, and pharmacodynamic responses. Parenteral loading doses need only be adjusted for body weight as volumes of distribution are little changed, whereas oral loading doses in some cases may require reduction to account for age-related increases in bioavailability. Age-related reduction of hepatic blood flow and hepatocyte mass and primary aging changes in hepatic sinusoidal endothelium with effects on drug transfer and oxygen delivery reduce hepatic drug clearance. Primary renal aging is evident, although renal clearance reduction in older people is predominantly disease-related and is poorly estimated by standard methods. The geriatric dosing axiom, “start low and go slow” is based on pharmacokinetic considerations and concern for adverse drug reactions, not from clinical trial data. In the absence of generalizable dosage guidelines, individualization via effect titration is required. Altered pharmacodynamics are well documented in the cardiovascular system, with changes in the autonomic system, autacoid receptors, drug receptors, and endothelial function to modify baseline cardiovascular tone and responses to stimuli such as postural change and feeding. Adverse drug reactions and polypharmacy represent major linkages to avoidable morbidity and mortality. This, combined with a deficient therapeutic evidence base, suggests that extrapolation of risk-benefit ratios from younger adults to geriatric populations is not necessarily valid. Even so, therapeutic advances generally may convert healthy longevity from an asset of fortunate individuals into a general social benefit.

The aging liver. Drug clearance and an oxygen diffusion barrier hypothesis.

A change in drug clearance with age is considered an important factor in determining the high prevalence of adverse drug reactions associated with prescribing medications for the elderly. Despite this, no general principles have been available to guide drug administration in the elderly, although a substantial body of clearance and metabolism data has been generated in humans and experimental animals. A review of age-related change in drug clearances established that patterns of change are not simply explained in terms of hepatic blood flow, hepatic mass and protein binding changes. In particular, the maintained clearance of drugs subject to conjugation processes while oxygen-dependent metabolism declines, and all in vitro tests of enzyme function have been normal, requires new explanations.Reduction in hepatic oxygen diffusion as part of a general change in hepatocyte surface membrane permeability and conformation does provide one explanation for the paradoxical patterns of drug metabolism, and increased hepatocyte volume would also modify oxygen diffusion path lengths (the ‘oxygen diffusion barrier’ hypothesis). The reduction in clearances of high extraction drugs does correlate with observed reduction in hepatic perfusion.Dosage guidelines emerge from these considerations. The dosage of high clearance drugs should be reduced by approximately 40% in the elderly while the dosage of low clearance drugs should be reduced by approximately 30%, unless the compound is principally subject to conjugation mechanisms. If the hepatocyte diffusion barrier hypothesis is substantiated, this concept may lead to therapeutic (preventative and/or restorative) approaches to increased hepatocyte oxygenation in the elderly. This may lead to approaches for modification of the aging process in the liver.

Pesticides and Parkinson’s Disease

Epidemiological studies and case reports provide evidence for an association between Parkinsons disease and past exposure to pesticides. Susceptibility to the effects of pesticides and other putative neurotoxins depends on variability in xenobiotic metabolism possibly generated by genetic polymorphisms, aging and variation in exposure to environmental agents including pesticides. The simplest mechanistic hypothesis for the association of pesticides with Parkinsons disease is that pesticides or their metabolites are directly toxic to mitochondria, although modulation of xenobiotic metabolism by pesticides provides an adjunct or alternative hypothesis.

Clinical Pharmacokinetic and Pharmacodynamic Considerations in Patients with Liver Disease: An Update

SummaryThe effects of liver disease on pharmacokinetics and pharmacodynamic s are highly variable, and difficult to predict as the mechanisms of these effects are not well understood. Since the majority of the published literature is concerned with cirrhotic liver disease, this review also focuses mainly on this area.Four different theories have been proposed to account for the effects of chronic liver disease with cirrhosis on hepatic drug elimination: the sick cell theory; the intact hepatocyte theory; the impaired drug uptake theory; and the oxygen limitation theory. While some data in support of each of the first 2 theories have been published recently, a large amount of clinical data would appear to refute both of these theories. These clinical data are substantially consistent with the latter 2 theories, which regard the decreased permeability of the capillarised sinusoid as the critical feature in cirrhosis. Further work is required to determine the applicability of each of these theories.In cirrhosis, drug glucuronidation is spared relative to oxidative drug metabolism; however, in advanced cirrhosis this pathway may also be impaired substantially. There is evidence that in cirrhosis other conjugation pathways may also be impaired to variable degrees. Growing evidence suggests that biliary drug excretion is impaired in cirrhosis. Recent studies with several racemic drugs indicate that the disease can have different effects on the hepatic elimination of individual enantiomers, which may lead to a change in the concentration-response relationships of racemic drugs in cirrhosis.A major finding which has emerged in recent years is that, even with moderate degrees of hepatic impairment, there is a decrease in clearance of drugs or active metabolites normally cleared by the kidney. The effect on renal clearance of unbound drug may be masked if there is a concomitant decrease in plasma protein binding of the drug. Neither serum creatinine levels nor creatinine clearance are useful markers of the renal dysfunction associated with cirrhosis. Both may greatly overestimate renal function in patients with cirrhosis due to increased fractional renal tubular secretion of creatinine.Altered receptor sensitivity has been observed with some drugs in cirrhosis, while for other drugs there is no change in pharmacodynamics. Precise determination of drug dosage in cirrhosis requires information on changes in pharmacodynamics and plasma protein binding in addition to changes in drug elimination.Pharmacokinetic investigations in a variety of chronic liver diseases without cirrhosis (e.g. carcinoma, schistosomiasis and viral hepatitis) suggest that in the absence of cirrhosis, impairment of drug elimination is not sufficient to warrant reduction of drug dosage. However, if cirrhosis is present, ‘safe’ drug use requires an awareness of the possibility of multiple interactions between changes in hepatic and renal disposition and pharmacodynamics.In chronic liver disease with cirrhosis, dosage reduction is the general rule regardless of the route of elimination of drug or metabolite.

Clinical Pharmacokinetics in Patients with Liver Disease

SummaryFrom considerations of hepatic physiology and pathology coupled with pharmacokinetic principles, it appears that altered drug elimination in liver disease may result from the following mechanisms: reduction in absolute cell mass, in cellular enzyme content and/or activity, in portal vein perfusion due to extrahepatic/intrahepatic shunting, or of portal perfusion of hepatocyte mass due to decreased portal flow or sinusoidal perfusion; increase in arterial perfusion relative to portal perfusion; preferential perfusion of the sinusoidal midzone and terminal zones by arterioles; potential for direct mixing of arterial blood within the space of Disse; reduced exchange across the endothelial lining; and impaired diffusion within the space of Disse.In general, oxidative drug metabolism is impaired in liver disease and the degree of impairment of oxidisation differs between drugs but correlates best with the degree of sinusoidal capillarisation, i.e. the degree of access of the drug from the sinusoid to the hepatocyte. Drug conjugation appears to be relatively unaffected by liver disease, whereas elimination by biliary excretion correlates best with the degree of intrahepatic shunting and not with sinusoidal capillarisation. As the latter should impair hepatocyte access of all compounds similarly, a potentially important mechanism could be impaired access of oxygen to hepatocytes as oxidative metabolism is much more sensitive to oxygen supply than are conjugation or biliary excretion. This suggests a potentially important therapeutic role for agents which increase the hepatic oxygen supply.Useful adjunctive strategies may also derive from the oxygen limitation hypothesis. Anaemia should be targeted as a critically important variable, as should oxygen-carrying capacity, i.e. modification of the smoking habit. Additionally, enzyme inducers such as barbiturates may be used if overriding hypoxic constraints are removed by oxygen supplementation. Agents likely to seriously compromise arterial perfusion of the hepatic vascular bed should be avoided, e.g. those causing postural hypotension or vasospasm. Vasodilators can be used to actively promote arterial perfusion.While the effect of liver disease on drug handling is highly variable and difficult to predict, there are well recognised principles for modifying dosage. These include halving the dose of drugs given systemically (or of low clearance drugs given orally) and a 50 to 90% reduction in the dose of drugs with a high hepatic clearance given orally. Changes in the pharmacodynamic effects of drugs (either alone or in addition to pharmacokinetic changes) can also be profound, and awareness of this possibility should be increased.

Cimetidine-procainamide pharmacokinetic interaction in man: Evidence of competition for tubular secretion of basic drugs

SummaryThe hypothesis that basic drugs can compete for active tubular secretion by the kidney was tested in six healthy volunteers by comparing the single dose pharmacokinetics of oral procainamide before and during a daily dose of cimetidine. The area under the procainamide plasma concentration-time curve was increased by cimetidine by an average of 35% from 27.0±0.3 µg/ml·h to 36.5±3.4 µg/ml·h. The elimination half-life increased from an harmonic mean of 2.92 to 3.68 h. The renal clearance of procainamide was reduced by cimetidine from 347±46 ml/min to 196±11 ml/min. All these results were statistically significant (p<0.016). The area under the plasma concentration-time curve for n-acetylprocainamide was increased by a mean of 25% by cimetidine due to a significant (p<0.016) reduction in renal clearance from 258±60 ml/min to 197±59 ml/min. The data suggests that cimetidine inhibits the tubular secretion of both procainamide and n-acetylprocainamide, and, if so, represents the first documented evidence for this type of drug interaction in man. The clinical implications from this study necessitate dosage adjustments of procainamide in patients being concomitantly treated with cimetidine. The interaction is pertinent not only for basic drugs that are cleared by the kidney, but also for metabolites of basic drugs and endogenous substances which require active transport into the lumen of the proximal tubule of the kidney for their elimination.

The hepatic sinusoid in aging and cirrhosis: effects on hepatic substrate disposition and drug clearance.

The fenestrated sinusoidal endothelium (‘liver sieve’) and space of Disse in the healthy liver do not impede the transfer of most substrates, including drugs and oxygen, from the sinusoidal lumen to the hepatocyte. Plasma components transfer freely in both directions through the endothelial fenestrations and into the space of Disse. The endothelium is attenuated, there is no basement membrane and there is minimum collagen in the space of Disse, thus minimising any barriers to substrate diffusion.Both cirrhosis and aging are associated with marked structural changes in the sinusoidal endothelium and space of Disse that are likely to influence bulk plasma transfer into the space of Disse, and diffusion through the endothelium and space of Disse. These changes, termed capillarisation and pseudocapillarisation in cirrhosis and aging, respectively, impede the transfer of various substrates. Capillarisation is associated with exclusion of albumin, protein-bound drugs and macromolecules from the space of Disse, and the progressive transformation of flow-limited to barrier-limited distribution of some substrates.There is evidence that the sinusoidal changes in cirrhosis and aging contribute to hepatocyte hypoxia, thus providing a mechanism for the apparent differential reduction of oxygen-dependent phase I metabolic pathways in these conditions. Structural change and subsequent dysfunction of the liver sieve warrant consideration as a significant factor in the impairment of overall substrate handling and hepatic drug metabolism in cirrhosis and aging.

Age-related pseudocapillarization of the human liver.

Age‐related changes in liver function are important because they may promote susceptibility to adverse drug reactions, neurotoxicity, atherosclerosis, and other important diseases in older people. Age‐related changes in the rat hepatic sinusoidal endothelium, termed pseudocapillarization, have been described recently and these may contribute to hepatic impairment. The present study has examined surgical and post‐mortem specimens with immunohistochemistry and transmission electron microscopy to determine whether pseudocapillarization also occurs in older humans. The age of the subject, independent of systemic disease or hepatic pathology in surgical and post‐mortem samples of human liver, was associated with increased peri‐sinusoidal expression of von Willebrands factor, collagen I, collagen IV, and staining with Massons trichrome. Electron microscopy revealed significant age‐related thickening of the sinusoidal endothelium (young 165 ± 17 nm, middle age 222 ± 11 nm, older 289 ± 9 nm, p < 0.001) with loss of fenestrations (young 7.7 ± 0.7 per 10 µm, middle age 3.6 ± 0.5 per 10 µm, older 1.5 ± 0.4 per 10 µm, p < 0.001), and age‐related deposition of basal lamina and collagen. In conclusion, ageing in humans is associated with morphological changes in the sinusoidal endothelium and space of Disse which are presumptively related to the ageing process and potentially represent an important link between the ageing process and disease susceptibility. Copyright

Hepatic pseudocapillarisation and atherosclerosis in ageing.

Cardiovascular disease secondary to atherosclerosis is the main cause of death and disability in industrialised countries, and ageing is the foremost risk factor for atherosclerosis. We present a hypothesis linking age-specific structural change in the liver with accepted pathogenic mechanisms leading to atherosclerosis. Ageing in the liver is associated with pseudocapillarisation of the sinusoidal endothelium, which is characterised by thickening of endothelium, basement membrane formation, and defenestration (loss of pores). Fenestrations (pores) normally form a liver sieve that allows passage of chylomicron remnants for subsequent uptake and metabolism by hepatocytes. Ageing is associated with impaired clearance of chylomicron remnants, postprandial hypertriglyceridaemia, and hence, atherosclerosis, which we propose is linked directly to loss of permeability of the liver sieve because of defenestration associated with pseudocapillarisation. Development of methods to maintain fenestrations of sinusoidal endothelium or to facilitate refenestration might be a new therapeutic strategy for management of cardiovascular disease in old people.