Search

Pharmacodynamics is the study of how drugs have effects on the body. This is typically by interacting with receptors located in cell membranes or in the intracellular fluid, although there are many other types of drug target. The relationship between the drug dose and its effect is described mathematically by the dose–response curve. Drugs acting at the same receptor (or tissue) differ in the size of the response they can achieve (efficacy) and the amount of drug required to achieve it (potency). Drug receptors can be classified on the basis of their selective response to different drugs. Constant exposure of tissues to drugs sometimes leads to a reduced response (desensitization). Pharmacokinetics is the study of the ways drugs are handled in the body. It is usually divided into four phases: absorption of a drug from the site of administration, distribution throughout the body, metabolism and excretion from the body. Differences in these four processes, arising from patient-specific factors (e.g. age, disease, interacting drugs, genetic background), explain much of the interindividual variation in drug response. This article describes the basic principles of pharmacodynamics and pharmacokinetics, and how they support rational prescribing decisions.

Prescribing medicines is the primary tool used by most healthcare systems to cure illness, relieve symptoms and prevent future disease. Prescribing is probably the most complex intellectual task that doctors undertake, requiring the formulation of an appropriate treatment regimen from the many thousands available, taking into account the infinite variation in the patients they encounter. Not surprisingly, suboptimal prescribing is common and represents an obvious target for quality improvement in healthcare. Common prescribing errors include omission of medicines that are indicated, selecting inappropriate drugs, choosing an incorrect dosage or frequency of administration, and failures in the prescription-writing process. Factors involved in poor prescribing include the performance of prescribers themselves, the complexity of the tasks required of them and the systems in which they work. Prescribing can be improved by better education and training of prescribers, focusing on a rational approach. Other improvements should include better supervision and team-working, input from clinical pharmacists, electronic prescribing systems supported by decision support software, standardization of prescribing documentation and governance arrangements that recognize the importance of prescribing as part of good healthcare.

Pharmacodynamics is the study of how drugs have effects on the body. The most common mechanism is by interaction of the drug with tissue receptors located either in cell membranes or in the intracellular fluid. The extent of receptor activation, and the subsequent biological response, is related to the concentration of the activating drug (the agonist). This relationship is described mathematically by the dose–response curve, which plots the drug dose (or concentration) against its effect. This important pharmacodynamic relationship can be influenced by patient factors (e.g. age, disease) and by the presence of other drugs that compete for binding at the same receptor (e.g. receptor antagonists). Some drugs acting at the same receptor (or tissue) differ in the magnitude of the biological responses they can achieve (i.e. their efficacy) and the amount of the drug required to achieve a response (i.e. their potency). Drug receptors can be classified on the basis of their selective response to different drugs. Constant exposure of receptors or body systems to drugs sometimes leads to a reduced response (i.e. desensitization).

Prescribing medicines is the primary tool used by most healthcare systems to cure illness, relieve symptoms and prevent future disease. Prescribing is probably the most complex intellectual task that doctors undertake, requiring the formulation of an appropriate treatment regimen from the many thousands available, taking into account the infinite variation in the patients they encounter. Not surprisingly, suboptimal prescribing is common and represents an obvious target for quality improvement in healthcare. Common prescribing errors include omission of medicines that are indicated, selecting inappropriate drugs, choosing an incorrect dosage or frequency of administration, and failures in the prescription-writing process. Factors involved in poor prescribing include the performance of prescribers themselves, the complexity of the tasks required of them and the systems in which they work. Prescribing can be improved by better education and training of prescribers, focusing on a rational approach. Other improvements should include better supervision and team-working, input from clinical pharmacists, electronic prescribing systems supported by decision support software, standardization of prescribing documentation and governance arrangements that recognize the importance of prescribing as part of good healthcare.

New synthesis shows what a wasted decade means for the climate pact made in Paris.

Pharmacodynamics is the study of how drugs have effects on the body. The most common mechanism is by the interaction of the drug with tissue receptors located either in cell membranes or in the intracellular fluid. The extent of receptor activation, and the subsequent biological response, is related to the concentration of the activating drug (the agonist). This relationship is described by the dose–response curve, which plots the drug dose (or concentration) against its effect. This important pharmacodynamic relationship can be influenced by patient factors (e.g. age, disease) and by the presence of other drugs that compete for binding at the same receptor (e.g. receptor antagonists). Some drugs acting at the same receptor (or tissue) differ in the magnitude of the biological responses that they can achieve (i.e. their efficacy) and the amount of the drug required to achieve a response (i.e. their potency). Drug receptors can be classified on the basis of their selective response to different drugs. Constant exposure of receptors or body systems to drugs sometimes leads to a reduced response (i.e. desensitization).

Prescribing medicines is the primary tool used by most healthcare systems to cure illness, relieve symptoms and prevent future disease. Prescribing is probably the most complex intellectual task required of doctors, requiring the formulation of an appropriate treatment regimen from the many thousands available, taking into account the infinite variation in the patients they encounter. Not surprisingly, suboptimal prescribing is common and represents an obvious target for quality improvement in healthcare. Common prescribing errors include omission of medicines that are indicated, selecting inappropriate drugs, choosing an incorrect dosage or frequency of administration and failures in the prescription-writing process. Factors involved in poor prescribing include the performance of prescribers themselves, the complexity of the tasks required of them and the systems in which they work. Prescribing can be improved by better education and training of prescribers, focusing on a rational approach. Other improvements should include better supervision and team-working, input from clinical pharmacists, electronic prescribing systems supported by decision support software, standardization of prescribing documentation and governance arrangements that recognize the importance of prescribing as part of good healthcare.

Medical textbooks are an important teaching supplement. Few have junior doctors or medical students (‘juniors’) as primary contributors. However, the strengths of junior-led face-to-face teaching are now well-established, and we hypothesized that similar advantages would be transferrable to a textbook setting. Juniors were approached to contribute to an independently published medical textbook, with senior clinicians recruited in parallel to ensure factual accuracy. Juniors directed every aspect of textbook writing and the production process. The published book stressed that it was an open collaboration with readers, inviting them to get in touch to evaluate the text and suggest ideas for new titles. Of 75 respondents, 93 % awarded the first textbook in the series 4 or 5 out of 5 for overall quality. Five other titles have been released, with seven more in development. Over 100 juniors are currently involved, with two students progressing from reviewers to editors after less than a year of mentorship. Juniors can be a motivated, dynamic, innovative group, capable of significant contributions to the medical textbook literature. This initiative has generated a sustainable infrastructure to facilitate junior-led publishing, and has the capacity for expansion to accommodate new initiatives and ideas.

Pharmacodynamics is the study of how drugs have effects on the body. The most common mechanism is by the interaction of the drug with tissue receptors located either in cell membranes or in the intracellular fluid. The extent of receptor activation, and the subsequent biological response, is related to the concentration of the activating drug (the ‘agonist’). This relationship is described by the dose–response curve, which plots the drug dose (or concentration) against its effect. This important pharmacodynamic relationship can be influenced by patient factors (e.g. age, disease) and by the presence of other drugs that compete for binding at the same receptor (e.g. receptor ‘antagonists’). Some drugs acting at the same receptor (or tissue) differ in the magnitude of the biological responses that they can achieve (i.e. their ‘efficacy’) and the amount of the drug required to achieve a response (i.e. their ‘potency’). Drug receptors can be classified on the basis of their selective response to different drugs. Constant exposure of receptors or body systems to drugs sometimes leads to a reduced response (i.e. ‘desensitization’).

Prescribers should have some understanding of receptor mechanisms because many drugs commonly used in modern practice act on receptors, safe drug usage requires an understanding of receptor pharmacology and future advances in pharmacology and therapeutics are likely to develop from the discovery of further receptors and molecular modelling of drugs to interact with them. This article covers basic concepts such as receptors and ligands, agonists and antagonists, dose–response curves, efficacy, potency, selectivity and affinity. It illustrates the different ways that ligand–receptor interactions can be coupled to responses (e.g. channel-linked receptors, G-protein-coupled receptors, kinase-linked receptors and receptors regulating gene transcription). The potential for agonists, partial agonists and antagonists to interact with each other is examined. The importance of understanding the dose–response curve, and its influence on the likelihood of achieving clinical efficacy without causing adverse effects, is emphasized.

Established hypertension is characterized by increased peripheral vascular resistance and endothelial dysfunction, features that may underlie the reduced exercise-induced vasodilatation seen in hypertensive patients. Sildenafil citrate is a phosphodiesterase type 5 (PDE5) inhibitor used clinically for the treatment of male erectile dysfunction. Its vasodilating properties are due to the inhibition of cyclic guanosine monophosphate (cGMP) breakdown and prolongation of the signalling actions of the nitric oxide (NO)–cGMP pathway in vascular smooth muscle cells. Sildenafil has beneficial effects on endothelial function and exercise tolerance in congestive heart failure and pulmonary hypertension, and we hypothesized that it would improve exercise-induced vasodilatation in hypertensive patients.

Peripheral exercise blood pressure and resting central blood pressure are considered more relevant to cardiovascular health than resting peripheral blood pressure. Central exercise blood pressure may well be an even more useful measure, but there is no simple non-invasive means of determining it. The aim of the present study was to establish whether the estimation of central blood pressure from peripheral blood pressure using a transfer function derived at rest, would hold after aerobic exercise.

Our series on serious ADRs focusses on rare but important drug reactions and how to recognise and avoid them. Here, Dr Maxwell describes the signs and symptoms of rhabdomyolysis and the importance of early diagnosis in its effective management. Copyright © 2006 Wiley Interface Ltd

Blood flow and plasma fibrinolytic factors were measured on five occasions in both forearms of eight otherwise healthy male smokers during unilateral brachial artery infusion of the endothelium-dependent vasodilator, substance P (2 to 8 pmol/min), and the endothelium-independent vasodilator, sodium nitroprusside (2 to 8 μg/min). On the first occasion, intra-arterial vitamin C was co-infused at 25 mg/min. On subsequent occasions, subjects attended after 28 and 35 days treatment with oral vitamin C (1 g daily) or placebo in a double-blind randomized crossover design still smoking but with and without acute smoke inhalation (3 cigarettes over 30 minutes). Basal plasma ascorbate concentrations increased from 37 ± 6 μmol/L to 105 ± 11 μmol/L following oral vitamin C supplementation (P0.002). Substance P caused dose-dependent increases in forearm blood flow (P< 0.001, ANOVA) and t-PA release (P< 0.05, ANOVA) that was unaffected by acute recent smoke inhalation, intra-arterial vitamin C, or oral vitamin C administration (p ns). Likewise there were no effects on sodium nitroprusside-induced vasodilatation (p ns). Neither acute local intra-arterial nor prolonged oral vitamin C supplementation reverses smoking-related endothelial dysfunction and impaired endogenous t-PA release. We conclude that the adverse vascular actions of smoking are not principally mediated through oxidative stress.

Arterial stiffness is an emerging major risk factor for cardiovascular morbidity and mortality. The aim of the present study was to assess if coronary artery plaque load correlates with non-invasive measures of arterial stiffness.

Supplementary oxygen is commonly administered in current medical practice. However, attention has recently been drawn to the potentially disadvantageous hemodynamic consequences in certain patients. Possible mechanisms underlying the cardiovascular responses to acute hyperoxia are unclear. The effects of acute oxygen administration on heart rate, blood pressure, cardiac output, systemic vascular resistance, and baroreflex sensitivity were studied in a series of randomised, placebo-controlled studies in healthy individuals, using validated, non-invasive techniques. The effects of oxygen administration on forearm blood flow responses to locally administered acetylcholine, an endothelium-dependent vasodilator, sodium nitroprusside, an endothelium-independent vasodilator, and l-NG-monomethylarginine, a nitric oxide synthase inhibitor, were studied using venous occlusion plethysmography. Oxygen administration for 1 hour caused a reduction in heart rate (P< 0.01) and cardiac index (P< 0.05), and an increase in mean arterial pressure (P< 0.01), systemic vascular resistance (P< 0.05), large artery stiffness (P< 0.05), and baroreflex sensitivity (P< 0.05). There were no effects on vascular responses in the isolated forearm bed. These findings indicate that oxygen administration causes acute effects on cardiovascular function, which might be important in the context of acute illness.

Established risk factors for cardiovascular disease (CVD), such as hypertension, smoking and diabetes mellitus, explain only some of the observed variation in clinical events. This has maintained interest in other nutritional and biochemical factors that might contribute to the underlying pathophysiology of CVD. All of these risk factors are associated with increased oxidative stress in the vessel wall, which may contribute to CVD by several mechanisms. Studies in animal models of CVD have suggested that natural and synthetic anti-oxidants can prevent the development of clinical end points. These observations have generated the hypothesis that anti-oxidant therapy might also prevent CVD in human populations. This has been supported by epidemiological studies showing a negative correlation between circulating concentrations or dietary intake of natural anti-oxidant vitamins and CVD event rate. Many studies have also demonstrated a beneficial effect of anti-oxidants on surrogate markers of CVD such as endothelial function and lipoprotein oxidation. However, the results of large prospective randomised controlled intervention trials, mostly involving vitamin E in patients at increased risk of CVD, have been disappointing and have failed to demonstrate the anticipated benefits. This paper will critically examine the evidence and try to offer some explanation for the apparent failure of animal and epidemiological data to translate into meaningful clinical benefits.

Oxidative stress plays an important role in the development of atherosclerosis and contributes to tissue damage that occurs as a consequence, particularly in myocardial infarction and acute stroke. Antioxidant properties of uric acid have long been recognized and, as a result of its comparatively high serum concentrations, it is the most abundant scavenger of free radicals in humans. Elevation of serum uric acid concentration occurs as a physiologic response to increased oxidative stress—for example, during acute exercise—thus providing a counterregulatory increase in antioxidant defenses. In view of its antioxidant properties, uric acid may have potentially important and beneficial effects within the cardiovascular system. We wished to investigate whether administration of uric acid was feasible and if it could have an impact on antioxidant function in vivo. We have, therefore, performed a randomized, placebocontrolled doubleblind study of the effects of systemic administration of uric acid, 1,000 mg, in healthy volunteers, compared with vitamin C, 1,000 mg. We observed a significant increase in serum freeradical scavenging capacity from baseline during uric acid and vitamin C infusion, using two methodologically distinct antioxidant assays. The effect of uric acid was substantially greater than that of vitamin C.

We present the results of subcutaneous microdialysis, a new minimally invasive biochemical monitoring technique, in mitochondrial cytopathy. We studied 6 ambulatory patients with mitochondrial cytopathy and 6 controls without mitochondrial disease using a subcutaneous probe for continuous microdialysis, and obtained measurements of lactate, pyruvate, and glucose from samples gathered at 30–60 min intervals during the day and at 3‐h intervals at night. The lactate:pyruvate ratio (LPR) was calculated and related to disease severity and metabolic stress. Microdialysis was well tolerated. Controls had stable lactate and pyruvate values in the normal range and a low LPR (average values between 0.0114 and 0.0145). Patients had widely fluctuating lactate and pyruvate values, a higher average LPR between 0.0187 and 0.0724, and marked diurnal variation, especially in the severely affected patients. Increases in the LPR coincided with metabolic stress in individual cases. We conclude that subcutaneous microdialysis is well tolerated and enables continuous metabolic monitoring of patients with mitochondrial cytopathy. It has particular potential for use in the identification of metabolic risk factors and may help to assess the impact of therapeutic regimens. © 2001 John Wiley & Sons, Inc. Muscle Nerve 24: 648–653, 2001

International development targets adopted by UN Conferences provide political impetus, focus expenditure and help in monitoring progress. However, simple targets can misrepresent complex realities and distort policy. Monitoring targets can have a high opportunity cost. Political impetus can be lost if targets are over-ambitious. Food security illustrates the uses of targets and the risks involved. Simple hunger or nutrition targets have been attractive to policymakers but have been problematic conceptually, and routinely overambitious in practice. Greater subsidiarity may be the answer, with simple international targets being used as a platform for local action. Subsidiarity means more than developing national action plans to implement international targets: it is potentially more open, participatory subversive and deviant.

Several lines of evidence suggest that free radical‐mediated oxidative damage to lipoproteins may be an important factor predisposing them to uptake into the vascular wall. This has led to interest in the factors that determine the susceptibility of lipoproteins to oxidation and their relationship to the development of coronary heart disease. Of these factors, the lipoprotein content of natural antioxidant vitamins such as vitamin E, and beta‐carotene have aroused particular interest. Studies in animal models of atherosclerosis suggest that natural and synthetic antioxidants can retard the development of atheroma. Epidemiological comparisons between populations and studies within populations also support the contention that high plasma levels or dietary intake of natural antioxidant vitamins may protect against the development of coronary disease in man. Prospective randomized controlled trials of antioxidants in high risk groups are underway to test whether the theoretical promise of a beneficial role for antioxidants in coronary heart disease prevention will be fufilled.

Free radical oxidative stress has been implicated in the pathogenesis of a variety of human diseases. Natural antioxidant defences have been found to be defective in many of the same diseases. This has led to suggestions that oxidative damage and therefore disease progression may be retarded by supplementing natural antioxidant defences. Potential antioxidant therapy includes natural antioxidant enzymes and vitamins or synthetic agents with antioxidant activity. Diseases where antioxidant therapy may be beneficial include diabetes mellitus, reperfusion injury, inflammatory diseases and the prevention of chronic processes such as atherosclerosis and carcinogenesis. Further well controlled prospective clinical trials of antioxidants are required to establish the efficacy and tolerability of antioxidant therapy in the treatment of human diseases.

SummariesCounterpart funds generated by programme aid do not provide real resources over and above the commodities or foreign exchange transferred as aid: they represent the tail not the tiger. However, donor policy has evolved to recognise this fact and now focuses less on specific ear‐marking of counterpart funds, more on the overall quality of the budget process. This development opens up new and more interesting possibilities for evaluating the effectiveness and efficiency of counterpart fund management. The paper proposes performance criteria, especially for bilateral donors supporting the budget through counterpart fund generation. Existing evaluations do not generally provide information about whether these standards have been satisfied. This is a task for the future.

Increasing poverty and social exclusion (PSE) open up the possibility of fertile dialogue between North and South on three issues of successively greater depth: first, new comparisons or lessons to be drawn across geographical boundaries about the characteristics, causes and remedies of PSE. Second, the implications of a new convergence between North and South. And third, the possibility of a new theory to expose connections between PSE in North and South. New alliances of disciplinary and sectoral specialists suggest themselves.

To determine whether soluble E-selectin levels were raised in hypertension and whether such levels correlated with those of von Willebrand factor.

Antioxidants are important species which possess the ability to protect the body from damage caused by free radical-induced oxidative stress. A variety of free radical-scavenging antioxidants exist within the body many of which are derived from dietary sources. There is currently much interest in the antioxidant role of flavonoids and other polyphenols found in tea, wine, fruit and vegetables. Enhanced chemiluminescence is a simple technique which can be used as a rapid and sensitive assay for measuring the antioxidant activity of beverages such as green and black tea. This article examines the impact of water temperature, stewing time, leaf concentration and the addition of milk upon the antioxidant activity of black tea solutions. The antioxidant activity of a range of commercially available black and green teas has also been measured.

Free radical oxidative stress has been implicated in the pathogenesis of a variety of human diseases. Natural anti-oxidant defences have also been found to be defective in many of the same diseases. Many researchers have concluded that, if the imbalance between the oxidative stresses and anti-oxidant defence can be corrected by supplementing natural anti-oxidant defences, it may be possible to prevent or retard disease progression. Potential anti-oxidant therapies include natural anti-oxidant enzymes and vitamins or synthetic agents with anti-oxidant activity. Diseases where anti-oxidant therapy may be beneficial can be divided into those involving acute intervention, such as reperfusion injury or inflammation, and those involving chronic preventative therapy, such as atherosclerosis, carcinogenesis and diabetic vascular disease. The pharmaceutical considerations are different in each case. The principles guiding the development, use and assessment of anti-oxidant therapies are discussed in this review.

Several lines of evidence suggest that free radical-mediated oxidative damage to lipoproteins may be an important factor predisposing them to uptake into the vascular wall. This has led to interest in the factors that determine the susceptibility of lipoproteins to oxidation and their relationship to the development of coronary heart disease. Of these factors, the lipoprotein content of natural antioxidant vitamins such as vitamin E, and beta-carotene have aroused particular interest. Studies in animal models of atherosclerosis suggest that natural and synthetic antioxidants can retard the development of atheroma. Epidemiological comparisons between populations and studies within populations also support the contention that high plasma levels or dietary intake of natural antioxidant vitamins may protect against the development of coronary disease in man. Prospective randomized controlled trials of antioxidants in high risk groups are underway to test whether the theoretical promise of a beneficial role for antioxidants in coronary heart disease prevention will be fufilled.