K. O’Malley

Clinical pharmacokinetics of calcium antagonists. An update.

SummaryThe calcium antagonists are valuable and widely used agents in the management of essential hypertension and angina. There is an increasing number of new agents to add to the 3 prototype substances nifedipine, diltiazem and verapamil. These new agents are dihydropyridines structurally related to nifedipine. However, they tend to have longer elimination half-lives (t½β) and may be suitable for twice-daily administration. Amlodipine is an exception with a t½β in excess of 30h. Apart from elimination rates, however, the pharmacokinetic characteristics of the newer agents have a notable tendency to resemble those of the established agents. They are highly cleared drugs, are relatively highly protein bound. As they are subject to significant first-pass metabolism, old age and hepatic impairment will increase their plasma concentrations due to a reduced first-pass effect. Renal impairment does little to their pharmacokinetics since the fraction eliminated unchanged by the kidney is small. For most agents, plasma concentration-response relationships have been described. Interesting areas for further research include chronopharmacokinetics, stereoselective pharmacokinetics and lipid solubility. Drugs affecting hepatic blood flow and drug metabolising capacity have predictable interaction potential. Some of the newer calcium antagonists will, like verapamil, increase plasma digoxin concentrations. Verapamil and diltiazem decrease phenazone (antipyrine) metabolism and therefore tend to decrease the metabolism of other drugs.

Clinical pharmacokinetics of oral anticoagulants.

SummaryWarfarin is clinically the most widely used oral anticoagulant and its properties have been extensively studied. Assay methods for these compounds have until recently been relatively nonspecific. The advent of chromatographically based techniques has enabled a re-evaluation of the pharmacokinetics of oral anticoagulants, but most work continues to involve warfarin. The most important recent work has concerned the different anticoagulant potencies and metabolic pathways of the optical isomers of some of these drugs.The effects of age and some diseases on pharmacokinetics of warfarin have been examined but much remains to be done, especially with oral anticoagulants other than warfarin.There are several well established pharmacokinetic drug interactions with warfarin. There is a wide awareness of the drugs most likely to reduce anticoagulant effects by enzyme induction and alternative drugs can be used. Mechanisms of some interactions have been re-investigated. In vivo drug displacement interactions are complicated by the correlation between hepatic clearance of these drugs and the size of the unbound fraction in plasma. The interactions between phenylbutazone and warfarin and metronidazole and warfarin, resulting in potentiation of anticoagulant effect have been suggested to be due mainly to an inhibition of the metabolism of the more potent S isomer of warfarin.

The Hypertension in the Very Elderly Trial (HYVET). Rationale, methodology and comparison with previous trials

SummaryThe Hypertension in the Very Elderly Trial (HYVET) is a multicentre, open, randomised, controlled trial. The aim of this trial is to investigate the effect of active treatment on stroke incidence in hypertensive patients over the age of 80 years. Secondary end-points include total cardiovascular mortality and morbidity.Entry criteria include a sustained sitting systolic blood pressure of 160 to 219mm Hg plus a sustained sitting diastolic pressure of 95 to 109mm Hg. Also required is a standing systolic blood pressure of at least 140mm Hg. Patients must give their informed consent, and be free of congestive heart failure requiring treatment, gout, renal failure or a recent cerebral haemorrhage. Patients are to be randomised to 3 groups — (i) no treatment; (ii) treatment with a diuretic [bendroflumethiazide (bendrofluazide)]; or (iii) treatment with an angiotensin converting enzyme (ACE) inhibitor (lisinopril).Starting dosage for bendroflumethiazide and lisinopril is 2.5 mg/day. In order to achieve goal sitting systolic and diastolic blood pressures (< 150/80mm Hg), a doubling of the dosage is allowed. Furthermore, slow release diltiazem (120 mg/day increasing to 240 mg/day if required) may be added to the medication of the actively treated groups. These drugs have been chosen as inexpensive and appropriate representatives of their therapeutic classes.700 patients in each group (a total of 2100) will be sufficient to detect a 40% difference in cerebrovascular events between no treatment and active treatment (α = 0.01, 1−β = 0.90). These numbers will also detect a difference in total mortality of 25% and in cardiovascular mortality of 35%.The pilot phase of the trial has been started with support from the British Heart Foundation. Centres which are interested in taking part should contact C. J. Bulpitt or any of the other authors.

Clinical pharmacokinetics of the newer ACE inhibitors. A review.

SummaryThe orally active angiotensin-converting inhibitors (ACE inhibitors) such as captopril and enalapril represent a significant therapeutic advance in the treatment of hypertension and congestive heart failure. Enalapril differs from captopril in several respects. It is a prodrug converted by hepatic esterolysis to the active (but more poorly absorbed) diacid, enalaprilat. Enalaprilat is more potent than captopril, more slowly eliminated and does not possess a sulfhydryl (SH) group.Enalapril was rapidly followed by a number of newer ACE inhibitors, the majority of which are similar to enalapril in that they are prodrugs, converted by hepatic esterolysis to a major active but poorly absorbed diacid metabolite. In one case (delapril) there are 2 active metabolites; in another (alacepril) the prodrug is converted in vivo to captopril. Lisinopril is an exception in that it is an enalaprilat-like diacid but with acceptable oral bioavailability, so that the prodrug route is not employed. The newer ACE inhibitors are at widely different stages of development, and it is not yet clear how many will reach regular clinical use. Of these newer drugs, lisinopril is the longest established and is the subject of the widest published literature. For a number there is as yet little published pharmacokinetic information.A variety of assay methods have been employed to characterise the pharmacokinetics of the ACE inhibitors, including enzymatic techniques, radioimmunoassay and chromatography. The peak plasma concentrations of the prodrugs are generally observed at around 1 hour and those of the diacid metabolites at about 2 to 4 hours. However, there is considerable variation within and between drugs, with benazepril and benazeprilat reaching peak concentrations early and enalapril and enalaprilat typical of later times to peak. Absorption of the active diacids is generally poor, and moderate (typically 30 to 70%) for the prodrugs. The bioavailability of lisinopril is about 25%.It is difficult to talk meaningfully about half-lives of the active drugs. The declines in their plasma concentrations are polyphasic and, if analytical sensitivity allows, active drug may be found at 48 hours or more following administration. This may reflect binding to ACE in plasma. Half-lives of accumulation are of the order of 12 hours; protein binding varies from little (lisinopril) to 90% (benazeprilat). Elimination is mostly renal but there may be biliary elimination for some, such as benazeprilat and fosinopril. The half-lives of the prodrugs are short.Impaired renal function decreases the elimination rate of the diacids. The largest effects on plasma concentrations are associated with severe renal impairment (glomerular filtration rate; < 30 ml/min). Increasing renal impairment is associated with longer times to peak of the diacids. Lisinopril and enalaprilat have been shown to be dialysable. Increasing age has variable effects, but is often accompanied by a decreased rate of elimination related to renal function, best demonstrated in population pharmacokinetic studies. Congestive heart failure may be associated with higher plasma concentrations but the pharmacokinetics of these agents in uncomplicated essential hypertension appear to be normal. The effects of hepatic impairment have been little studied, but severe hepatic impairment would be expected to result in impaired esterolysis of the prodrugs.

Twenty-four hour blood pressure monitoring in the Syst-Eur trial

This article describes the objectives and protocol of a study on ambulatory blood pressure in elderly patients with isolated systolic hypertension. This study constitutes an optional side-project to the Syst-Eur trial.The multicentre Syst-Eur trial investigates whether antihypertensive treatment of elderly patients with isolated systolic hypertension will influence the incidence of stroke. Secondary endpoints include cardiovascular events, such as myocardial infarction.The main objective of the side-project is to investigate whether ambulatory blood pressure monitoring will improve the prediction of cardiovascular complications based on blood pressure measurement in the clinic. The side-project also provides the opportunity to evaluate the diurnal profile of blood pressure in elderly patients with isolated systolic hypertension randomized to placebo or active antihypertensive treatment.

Adverse Effects of Antidepressants in the Elderly

SummaryDepression is a common problem in old age and the use of antidepressant drugs is particularly prevalent among elderly patients. Limited data suggest that dose requirements may be lower in the elderly because of age-related changes in pharmacokinetics and perhaps also in sensitivity. The side effect profiles of the various antidepressants are reviewed with regard to their potential to cause specific problems in the older patients. Anticholinergic actions, orthostatic hypotension and sedative effects warrant particular care in the elderly.

Interscalene brachial plexus blockade with lidocaine in chronic renal failure - a pharmacokinetic study

Plasma lidocaine concentrations, latency of onset, and duration of anaesthesia, were determined after interscalene brachial plexus block in 16 patients presenting for elective upper limb surgery. Eight patients had normal renal function and eight had chronic renal failure, as determined by creatinine clearance. Significantly higher plasma lidocaine levels were recorded ten minutes after infiltration in patients with chronic renal failure (p < 0.05). Cmax plasma levels for normal patients (5.6 ±1.1 μg · ml-1) and for patients with chronic renal failure (6.6 ± 1 .6 μg · ml-1) were not significantly different. The latency of onset and duration of anaesthesia were similar in both groups. One per cent lidocaine solution may be administered to patients with normal and impaired renal function to provide effective brachial plexus blockade for short surgical procedures.

Nitrates in the Elderly

SummaryAlthough a significant proportion of patients receiving nitrates are elderly, surprisingly little published work is available describing the pharmacokinetics and pharmacodynamics of these agents in elderly patients. The lack of pharmacokinetic data is related to the difficulty in assaying nitrates and there are at present no definitive data describing the effect of aging on their bioavailability or elimination.A common finding in old age is of decreased hepatic first-pass metabolism. This would affect isosorbide-2-mononitrate and isosorbide-5-mononitrate less than isosorbide dinitrate and nitroglycerin (glyceryl trinitrate). Venous responsiveness to nitrates does not appear to alter with age, so that pharmacodynamic properties would not be expected to alter. However, decreased baroreflex function causes an increased tendency for posturally related side effects to occur. Mechanisms of tolerance are likely to be unaltered but any possible alteration in quantitative aspects of tolerance has not been studied.Nitrate therapy in the elderly would benefit from systematic investigation. At the moment, therapy needs to be titrated to the individual patient, with care taken to avoid age-related side effects by careful initiation of therapy and appropriate reviews of each patient.

Calcium Antagonists in the Elderly

SummaryThe calcium antagonists are associated with a number of advantages over other antihypertensive agents, such as a lack of metabolic, vascular and respiratory adverse events, yet are effective in reducing blood pressure.The currently available calcium antagonists are widely used, and new members, particularly of the dihydropyridine group, continue to emerge. These agents may well be considered for use in the management of hypertension and angina in elderly people.They undergo significant first-pass metabolism and tend to have high values of hepatic clearance with minimal amounts of unchanged drug in the urine. Plasma concentrations tend to be higher in elderly people and for that reason it may be prudent to initiate therapy with lower dosages.With this caveat, adverse effect profiles seem to be qualitatively and quantitatively similar in younger and older people. At equivalent plasma concentrations, the antihypertensive effect appears similar in young and elderly patients, and clinical studies point to comparable efficacy with other drug classes.Calcium antagonists do not have adverse renal, respiratory, cardiovascular, metabolic or peripheral vascular effects and therefore may be useful in patients with relevant concomitant disease.

The effect of local anaesthetics on epine-phrine absorption following rectal mucosal infiltration

This study was undertaken to investigate the effects of lidocaine and bupivacaine on epinephrine absorption following rectal mucosal infiltration, to assess the cardiovascular and metabolic effects of the absorbed epinephrine and to compare the systemic absorption of the local anaesthetics employed. Three groups of five greyhounds received 1.5 μg · kg−1 of epinephrine 1:200,000 in lidocaine 0.5 per cent, bupivacaine 0.5 per cent or 0.9 per cent saline. Plasma epinephrine, lidocaine, bupivacaine, lactate, glucose and potassium concentrations were measured at 1, 2, 5, 10, 15 and 30 minutes following infiltration. Plasma epinephrine concentrations were significantly higher in the lidocaine group at one and two minutes following infiltration. Plasma bupivacaine concentrations were significantly higher than plasma lidocaine concentrations throughout the study period. There were no significant differences in metabolic or biochemical indices within or between the three groups. A local vasodilatory action of lidocaine may enhance epinephrine absorption. Differences in hepatic uptake and rate of metabolism may explain the increased plasma bupivacaine measured. Lidocaine may be the local anaesthetic of choice for ano-rectal procedures, especially when large volumes of local anaesthetic are being infiltrated.RésuméCe travail avait pour but de comparer la lidocaine et la bupivacaïne injectées dans la muqueuse rectale quant à leur absorption et à leur effet sur l’absorption de l’adrénaline. On voulait aussi mesurer l’impact cardiovasculaire et métabolique de l’adrénaline. Nous avons injecté 1.5 μg · kg−1 d’adrénaline 1:200,000 avec soit de la lidocaine 0.5 pour cent, soit de la bupivacaïne 0.5 pour cent ou du NaCl 0.9 pour cent chez trois groupes de cinq lévriers. Les mesures sériées des concentrations sériques d’adrénaline, de lidocaïne, de bupivacaïne, de lactate, de glucose et de potassium étaient faites 1, 2, 5, 10, 15 et 30 minutes après l’infltraiton de la muqueuse. Nous avons mesuré des concentrations sériques d’ adrénaline plus élevées dans le groupe lidocaïne à une et deux minutes et trouvé que les niveaux plasmatiques de bupivacaine étaient systématiquement supérieurs à ceux de lidocaïne. Les variables métaboliques et biochimiques étaient semblables d’un groupe à l’autre. En vasodilatant, la lidocaïne peut faciliter l’absorption de l’adrénaline alors qu’une captation hépatique et un métabolisme plus faibles pourraient expliquer les niveaux plasmatiques élevés de bupivacaïne. La lidocaïne est probablement le meilleur choix pour les infiltrations locales de grands volumes d’anesthésique lors de chirurgies ano-rectales.