Clinical pharmacokinetic considerations in the treatment of patients with leprosy

On the basis of the efficacy of the available agents, the World Health Organization has recommended only 4 drugs for combined chemotherapy of leprosy: rifampicin, dapsone, clofazimine and ethionamide/prothionamide. Thiacetazone and isoniazid are also used to a lesser extent by some physicians. Pyrazinamide may find a place in treating 'persister' bacilli. Dapsone is absorbed slowly after oral administration. Peak plasma drug concentration is reached at about 4 hours; absorption half-life is 1.1 hours; elimination half-life is about 30 hours. Oral availability is around 90%. Dapsone is approximately 70% protein-bound, while its monoacetylated metabolite is almost entirely bound. Dapsone crosses the placenta and is excreted into breast milk. It is metabolised via acetylation and N-hydroxylation, but acetylation polymorphism has no effect on dapsone handling by leprosy patients. Dapsone penetrates into sciatic nerves of experimental animals but its presence has not been demonstrated in Schwann cells. Oral doses of rifampicin are rapidly and completely absorbed. The bioavailability is greater when the drug is given before meals; peak concentrations occur at 1 to 2 hours. 80 to 90% of rifampicin is bound to plasma proteins, and the drug is found in saliva, cerebrospinal fluid and breast milk. Its main metabolite, desacetyl rifampicin, also exhibits antimycobacterial activity in tuberculosis. Rifampicin induces its own metabolism, as well as that of dapsone and steroids. Absorption of dapsone and rifampicin is reported to be reduced in leprosy patients. Clofazimine has been in use in leprosy treatment since 1960. In higher doses it exerts an anti-inflammatory action which is useful in treating leprosy patients in reaction. Oral absorption of the drug is slow and dose-dependent; faecal excretion also increases with dose. Single- and multiple-dose studies have shown a plasma half-life of around 10 days. Bioavailability of the drug is higher when given with food than when fasting; the peak plasma concentration occurs at 4 to 8 hours when the drug is administered with breakfast. After absorption, the drug is thought to circulate in protein-bound form, accounting for the fact that it is deposited in various tissues. Uneven distribution and prolonged retention in the tissues are special features of clofazimine metabolism. One unconjugated and 2 conjugated metabolites have been detected in urine, and the urinary excretion of both the parent compound and its metabolites is around 1% of the dose.(ABSTRACT TRUNCATED AT 400 WORDS)     

Drug therapy in patients undergoing haemodialysis. Clinical pharmacokinetic considerations

Haemodialysis is utilised therapeutically as supportive treatment for end-stage renal disease (ESRD). In conjunction with haemodialysis therapy, ESRD patients frequently receive a large number of drugs to treat a multitude of intercurrent conditions. Because of the impaired renal function in ESRD patients, dosage reduction is often recommended to avoid adverse drug reactions, particularly for drugs and active metabolites with extensive renal excretion. On the other hand, if the removal of a drug by haemodialysis during concomitant drug therapy is significant, a dosage supplement would be required to ensure adequate therapeutic efficacy. Knowledge of the impact of haemodialysis on the elimination of specific drugs is therefore essential to the rational design of the dosage regimen in patients undergoing haemodialysis. This review addresses the clinical pharmacokinetic aspects of drug therapy in haemodialysis patients and considers: (a) the effects of ESRD on the general pharmacokinetics of drugs; (b) dialysis clearance and its impact on drug and metabolite elimination; (c) the definition of dialysability and the criteria for evaluation of drug dialysability; (d) pharmacokinetic parameters which are useful in the prediction of drug dialysability; and (e) the application of pharmacokinetic principles to the adjustment of dosage regimens in haemodialysis patients. Finally, drugs commonly associated with haemodialysis therapy are tabulated with updated pharmacokinetics and dialysability information.     

Clinical pharmacokinetic considerations in the control of oral anticoagulant therapy

Aspects of the pharmacokinetics of warfarin that are clinically relevant are reviewed here. Since warfarin is normally completely absorbed, resistance to treatment due to impaired absorption is unusual, even in severe short bowel syndrome. Warfarin is highly albumin-bound; thus, hypoalbuminaemic states result in an increased free fraction of the drug and a decreased half-life but, as might be expected, there is no evidence of altered response at steady-state. Warfarin is completely metabolised by the liver to hydroxy-warfarins and warfarin alcohols, and although the latter have some biological activity they do not contribute significantly to the drug effect. No information is available concerning the metabolism of warfarin in chronic liver disease, but there is evidence of increased sensitivity due to impaired vitamin K-dependent clotting factor synthesis. Impaired renal function does not appear to alter the effect of warfarin. Lowered response to the drug may be secondary to poor compliance, kinetic resistance or pharmacodynamic resistance. These factors can be identified using algorithms based on population values for plasma warfarin concentrations and clearances at steady-state. The pharmacokinetics and pharmacodynamics of warfarin indicate that several days' overlap with heparin on initiation of warfarin, and gradual (rather than sudden) discontinuation of warfarin, might theoretically be necessary. However, those studies which have been performed have indicated that a long overlap and gradual discontinuation are not associated with greater safety or efficacy of the drug. Because of the long elimination half-life of warfarin and the short elimination half-life of vitamin K, many days' treatment with phytomenadione may be required after warfarin overdose. The elimination half-life and therefore the duration of therapy may be reduced by regular oral cholestyramine, although the means by which the latter enhances warfarin elimination is still unknown.     

Drug therapy in patients undergoing peritoneal dialysis. Clinical pharmacokinetic considerations

Peritoneal dialysis has become an accepted treatment modality for end-stage renal disease. The introduction of continuous ambulatory peritoneal dialysis (CAPD) has further popularised this technique. The need for adjustment of drug dosage in patients with endstage renal disease and the need for supplemental dosages following haemodialysis are well recognised. Little documentation exists concerning the need for supplemental drug dosage in patients on peritoneal dialysis. Knowledge of the influence of peritoneal dialysis on the elimination of specific drugs is essential to the rational design of dosage regimens in patients undergoing this dialysis technique. This review addresses the clinical pharmacokinetic aspects of drug therapy in patients undergoing peritoneal dialysis and considers: the efficiency of the peritoneal membrane as a dialysing membrane; the effects of peritoneal dialysis on the pharmacokinetics of drugs; the pharmacokinetic models and estimation methods for peritoneal dialysis clearance and the effects of peritoneal dialysis on drug elimination; the influence of the pharmacokinetic parameters of drugs on drug dialysability; and the application of pharmacokinetic principles to the adjustment of drug dosage regimens in peritoneal dialysis patients. Data on drugs which have been studied in peritoneal dialysis are tabulated with inclusion of pharmacokinetic and dialysability information.     

Obstetric analgesia. Clinical pharmacokinetic considerations

All drugs used in obstetric analgesia are more or less lipophilic, their site of action is in the central nervous system, and they have good membrane penetrability in the fetomaternal unit. Thus the dose and method of administration as well as the duration of treatment are important clinical determinants of drug effects in the fetus and newborn. In the past, too much emphasis has been placed on fetomaternal blood concentration ratios of different agents; it is now appreciated that the extent of fetal tissue distribution and the neonatal elimination rate are pharmacokinetically much more important. Extensive fetal tissue distribution is reflected in a low fetomaternal drug concentration ratio, which may be followed by prolonged neonatal elimination of the drug. Currently, the most effective and safest method for obstetric analgesia is regional epidural administration of bupivacaine or lignocaine (lidocaine); only low doses are needed and the newborn is able to handle these agents efficiently. On the basis of pharmacokinetic and neurobehavioural assessments, inhalational anaesthetic agents appear to be more attractive than pethidine (meperidine) or benzodiazepines. Intermittent administration and fast pulmonary elimination of inhalational agents ensure that long-lasting residual effects are unlikely to occur. The kinetics of epidural and intrathecal opiates explain the problems associated with their use in obstetrics. Among the newer drugs used in obstetric analgesia, the properties of meptazinol and isoflurane appear interesting and these agents warrant further study. All drugs used in obstetric analgesia have a potentially detrimental effect on the neonate and, therefore, knowledge of fetal and neonatal pharmacokinetics is of importance to the clinician.     

Drugs in human milk. Clinical pharmacokinetic considerations

Drugs ingested by a lactating mother would be expected to appear in human milk to some extent and be ingested by a breast-feeding infant. Drugs pass from maternal plasma into milk by passive diffusion and are distributed within the aqueous, protein and lipid phases of milk. Distribution into milk will be affected by physiochemical characteristics of the drug: acid-base characteristics, relative protein binding in plasma and milk, and lipid solubility, as well as milk composition. The milk-to-plasma concentration ratio is the most commonly quoted index of drug distribution into human milk. However, calculation of the daily infant dose of drug ingested in milk, and from this the dose in milk relative to the maternal dose on a weight-adjusted basis, is a more relevant indicator of infant exposure to a drug. This is particularly true for drugs with a high volume of distribution, for which only a small proportion of the mother's dose is contained within the plasma and available for distribution into milk. A better indication of infant exposure to a drug is the steady-state plasma drug concentration in a breast-feeding infant, the major determinants of which are the dose rate (via milk) and the oral availability and clearance in the infant. Although in neonates the rate of absorption may be different from adults, there is little evidence that its extent is significantly different. Clearance, however, is impaired in very young infants, particularly if premature. The decreased clearance would result in a proportional increase in steady-state plasma concentrations in the breast-feeding infant. Consideration of the dose ingested in milk and the approximate clearance in infants of different ages allows estimation of likely steady-state plasma concentrations in breast-feeding infants. From these considerations, recommendations regarding the safety of drugs during breast-feeding can be made. Drugs which are very toxic or have dose-independent toxicity should be considered separately. Recommendations regarding 'social' drugs such as nicotine, alcohol, caffeine and theobromine are particularly difficult, as doses are uncontrolled and vary variable.     

Clinical pharmacokinetic considerations in the treatment of increased intracranial pressure

Life-threatening increased intracranial pressure can be reversed by a variety of drugs. These compounds all have some disadvantages, producing rebound effects, severe coma or cardiovascular depression and electrolyte imbalance. However, reduction of intracranial pressure is a prerequisite for recovery and the benefits of treatment outweigh the risks. Dexamethasone is rapidly eliminated, the short half-life (about 3 hours) indicating that dosage intervals should be kept small. As yet, however, its therapeutic efficacy has not been clearly demonstrated. Therefore, an association between pharmacokinetics and pharmacodynamics cannot be established. Osmotic diuretics are the most widely used agents for reduction of intracranial pressure. Pharmacokinetics show a very close relationship to changes in serum osmolality, but there are large variations in the clearance. For the use of osmotics, the blood-brain barrier must be intact. Osmotic diuretics may lead to intracerebral oedema or to acute renal failure as serum osmolality increases. Considering the pharmacokinetics of each drug, and the dynamics of intracerebral pressure and osmolality, an intermittent, individually titrated dosage should be administered, with simultaneous monitoring of intracranial pressure. Frusemide (furosemide) can be used as an adjunct, to enhance the effect of osmotic diuretics. Its pharmacokinetics are limited by renal function, depending on age as well as on the extent of renal impairment. Altered renal elimination of concomitantly administered drugs, and electrolyte imbalances should be anticipated when diuretics are used. Barbiturates are certain to decrease intracranial pressure in humans by an as yet unknown mechanism. Their administration is recommended for patients that do not respond to conventional therapy. As barbiturates can result in deep coma, knowledge of their pharmacokinetics is of great importance for recovery. Following single doses, pentobarbitone has a relatively long elimination half-life (about 22 hours). However, after repeated administration for several days, its elimination may be enhanced due to autoinduction. Thiopentone kinetics are characterised by distribution and redistribution into deep peripheral compartments. Administration of high and frequent doses leads to considerably delayed recovery. This is not true for methohexitone, which shows comparable pharmacokinetics after single and multiple dose administration. Elimination depends on liver blood flow. Thus, recovery from methohexitone-coma is rapid. Rapid elimination is also an important characteristic of etomidate and alphaxalone/alphadolone, two non-barbiturate hypnotics.(ABSTRACT TRUNCATED AT 400 WORDS)     

Safety and tolerability of slow-release oral morphine versus methadone in the treatment of opioid dependence

Opioid substitution treatment (OST) for opioid dependence may be limited by adverse events (AEs). Increasing the range of therapeutic options optimizes outcomes and facilitates patient management. An international, multi-center, two-phase study investigated the efficacy and safety of slow-release oral morphine (SROM) versus methadone in patients receiving methadone therapy for opioid dependence. In phase 1 (two way cross-over, 11 weeks each period) patients were randomized to SROM or methadone oral solution. In phase 2 (25 weeks), patients continued treatment with SROM (group A) or switched from methadone to SROM (group B). In total, 211 out of 276 completed phase 1 and 198 entered phase 2 (n = 95 group A, n = 103 group B). Treatment with both SROM and methadone was well tolerated. However, the mean QTc-interval associated with methadone was significantly longer than that under SROM. Higher treatment satisfaction, fewer cravings for heroin, and lower mental stress were reported with SROM. This study adds a significant further weight of evidence that SROM is an effective and well tolerated long-term maintenance treatment for opioid dependence with a beneficial risk profile compared to methadone regarding cardiac effects and supports its clinical utility.     

盐酸美沙酮口服液在中国美沙酮维持治疗患者体内药动学特征

目的建立盐酸美沙酮（MTD）人体内血药浓度的测定方法 ,并对口服MTD口服液后的美沙酮维持治疗患者（MMTPs）体内的药动学过程进行研究。方法采用Agilent ZORBAX SB-C₁₈（250mm×4.6 mm,5μm）色谱柱,以乙腈-磷酸盐缓冲液（pH 2.5）=32:68（V/V）为流动相,流速1.50 mL·min^-1,检测波长206 nm,盐酸苯海索为内标,对血浆中的MTD浓度进行检测。8名MMTPs口服MTD口服液80 mg,分别于服药前和服药后1、2、3、4、6、8、12、24 h采集血样,测定血浆中MTD的浓度,并采用3P97药动学软件对试验数据进行处理,计算有关药动学参数。结果在0.10～10.00 mg·L^-1内,MTD与内标峰面积的比值与浓度之间呈良好的线性关系（r=0.999 6）。日内及日间精密度（RSD）和回收率均符合要求。MTD药-时曲线经拟合符合二室模型,主要参数:ρ_max（623.13 4-231.06）μg·L^-1;t_max为（2.764±1.13）h;AUC_0→24h为（9 569.56±3 294.88）μg·h·L^-1;AUC_0→∞为（21 522.61±10 825.36）μg·h·L^*（-1）;t_1/2为（23.95±13.61）h。结论本试验建立的检测人血浆中MTD含量的HPLC法,适用性强,重复性好,操作简单,快速准确,成本低廉,可用于MTD药动学的研究;MTD药动学特征和参数在个体间存在较大差异,临床治疗中应实施个体化治疗方案。     

Drug therapy in patients undergoing continuous ambulatory peritoneal dialysis. Clinical pharmacokinetic considerations

Continuous ambulatory peritoneal dialysis (CAPD) is an accepted alternative to haemodialysis in the treatment of end-stage renal failure. The frequently used intraperitoneal administration of antibiotics to treat peritonitis and the possible role of CAPD in the elimination of drugs has stimulated pharmacokinetic research in this field. The 2 principal results derived from these studies are: (1) the elimination capacity of CAPD for drugs given systemically or orally is very low, and (2) drugs administered intraperitoneally rapidly enter the circulation, a significant amount of drug being absorbed from the peritoneal cavity. This pharmacokinetic behavior is easily understood considering some basic and simple pharmacokinetic principles: the higher the volume of distribution of a substance, the lower will be the percentage of drug present in the peritoneal cavity. Thus, a prerequisite for rapid drug elimination by CAPD is a low body volume of distribution of a particular drug. Only in such a case will the drug diffuse into the peritoneal space to a significant extent. For dosing regimens in CAPD patients, the fraction of the dose eliminated by the peritoneal route should be known or estimated. This fraction depends on the relation of the peritoneal clearance to the total body clearance, and on the protein binding of the drug. The low flow rate of the peritoneal effluent (approximately 10 L/day = 7 ml/min) appears to be the most important limiting factor for the low extraction capacity of CAPD. The list of drugs that have been found to be significantly eliminated by CAPD is short: particular mention should be made of the aminoglycosides and some cephalosporins. The data on the peritoneal elimination of vancomycin are inconsistent. Although the intravenous and oral routes have been successfully used for the treatment of peritonitis, the time course of antibiotic concentrations in the peritoneal space appears to favour the peritoneal route of drug administration. During peritonitis, intraperitoneally administered drugs enter the circulation more rapidly and completely, due to the increased permeability of the peritoneal membrane. As long as the dialysate outflow rate and protein binding of the drug are not extensively altered by peritoneal inflammation, however, the extraction capacity of CAPD appears to remain low.     

Clinical pharmacokinetic considerations in the elderly. An update

There are numerous studies of drug handling in the elderly, but it is difficult to assess the significance of changes seen in vitro, or after single-dose administration, because they are often compensated by other mechanisms at steady-state. However, a knowledge of these studies is important as the results alert the investigator to possible treatment problems. The high incidence of adverse drug reaction in the elderly population leaves no doubt that improvements in therapy are needed. Research has been directed at seeking patterns of abnormality in the elderly on which to base recommendations for alterations in dosage regimens. The major shortcoming of this approach has been the failure to distinguish between the effect of chronological age on drug pharmacokinetics, and drug kinetics in elderly people with multiple pathology. The latter concern appreciates the variety of factors involved and the importance of treating each patient as an individual: presentation of mean data is confusing and misleading. The objective of drug treatment in any age group, but particularly in the elderly, is to administer the smallest possible dose which gives adequate therapeutic benefit throughout the entire dosage interval with the minimum of side effects. For most drugs the safe starting dose in the elderly is one-third to half that recommended in the young. Vigilance for potential side effects with plasma concentration monitoring, if available, should help keep toxicity to a minimum. When other medications are added or changed, the possibility of interaction should be anticipated. Methods for individualisation of dosage regimens and the use of sustained-release formulations in the elderly are discussed. Dosage alteration in the elderly in terms of reduced dose frequency, rather than dose size, may help improve compliance. A knowledge of the pharmacokinetics of a drug helps determine which approach will be most beneficial.     

Comparative pharmacodynamics and pharmacokinetics of methadone and slow-release oral morphine for maintenance treatment of opioid dependence

BACKGROUND: Slow-release oral morphine (SROM) has been proposed as an alternative maintenance pharmacotherapy to methadone for treatment of opioid dependence. However, the pharmacodynamics and pharmacokinetics of SROM have not been previously assessed in a methadone maintenance population. METHODS: In 14 methadone maintenance patients reporting adequate (holders, n=7) or inadequate (non-holders, n=7) withdrawal suppression between doses, plasma drug concentrations and indices of opioid effect (withdrawal severity, pupil diameter, and respiratory rate) were determined across a 24 h inter-dosing interval on one occasion at steady-state for methadone and SROM (once-daily Kapanol) using an open-label, crossover design. RESULTS: Opioid effects were of a similar overall magnitude following dosing for each drug and showed an inverse association with plasma drug concentrations, which peaked later for morphine compared to (R)-methadone (6.5 +/- 2.3 h vs. 2.5 +/- 1.4 h, P<0.001). For methadone non-holders, the number of self-reported opioid withdrawal symptoms prior to dosing was less for SROM compared to methadone (3.4 +/- 2.6 vs. 9.0 +/- 3.2, P<0.01); for holders it was approximately equal (4.4 +/- 3.0 vs. 4.0 +/- 3.7, P<0.76). Maintenance doses were more strongly related to plasma drug concentrations for SROM compared to methadone and may thus be more predictive of therapeutic response for the former medication. Twelve of the 14 subjects preferred SROM to methadone (P=0.01). CONCLUSIONS: The pharmacodynamics and pharmacokinetics of SROM support its use as an alternative once-daily agonist option in the treatment of opioid dependence, particularly for patients responding poorly to methadone maintenance treatment.     

Drug treatment of patients with insomnia and excessive daytime sleepiness: pharmacokinetic considerations.

Insomnia and excessive daytime sleepiness (EDS) are frequently observed conditions in the general public. A national survey in the USA in 1979 indicated that 35% of American adults experience insomnia in the course of a year. The prevalence of EDS varies depending on the survey (0.3 to 13.3%), but a recent study stated that 2.4% of individuals reported that they continually fell asleep at work. These problems are often long term and negatively affect the individuals' quality of life. People with these sleep problems often have difficulties maintaining high levels of productivity at work or pursuing their daily activities; individuals with insomnia lack the feeling of being rested or refreshed in the morning and EDS is unavoidable in most cases. Behavioural therapy has been shown to be effective for many people affected with insomnia and EDS. However, pharmacological treatments using hypnosedatives and central nervous system (CNS) stimulants are usually necessary, and effective, for those with more severe cases. These compounds have thus been widely prescribed in clinical practice (e.g., 2.6% of all adults surveyed used medically prescribed hypnosedatives and 4.5% used over-the-counter drugs to promote sleep). The onset and duration of action of these hypnosedatives and CNS stimulant drugs are important factors to be considered when prescribing these compounds. These factors primarily depend on physicochemical properties (lipid solubility and protein binding), as well as the pharmacokinetic profile (absorption, distribution, elimination and clearance) of the compounds. Significant differences in profile exist amongst hypnosedatives and CNS stimulants, and these differences may account for the observed variations in clinical action and adverse effects during and after treatment. In this review, we will introduce recently obtained knowledge of the pharmacokinetics of hypnosedatives and CNS stimulants and their applications for patients affected with insomnia and EDS.     

Opioid addicts at admission vs. slow-release oral morphine, methadone, and sublingual buprenorphine maintenance treatment participants

With use of a randomized study design, quality of life (QOL) and physical symptoms of opioid addicts at admission were compared with slow-release oral morphine, methadone, and sublingual buprenorphine maintenance program participants after 6 months of treatment. The study was conducted from February to July 2004 in the outpatient drug user treatment center at University Department of Psychiatry at Innsbruck, providing maintenance treatment programs and detoxification in Tyrol, Austria. One hundred twenty opioid users seeking treatment were compared with 120 opioid-dependent patients retained for 6 months on a slow-release oral morphine, methadone, or sublingual buprenorphine maintenance program. The German version ("Berlin Quality of Life Profile") of the Lancashire Quality of Life Profile was used, and illicit opioid use was determined by urinalysis. Physical symptoms were measured by using the Opioid Withdrawal Scale. Urinalyses revealed a significantly lower consumption of cocaine and opioids in all three substitution groups than in patients at admission (p < 0.001 and p < or = 0.004, respectively). Both the buprenorphine and the methadone maintenance group showed significantly more favorable values than opioid clients at admission for stomach cramps (p < or = 0.002), muscular tension (p < or = 0.027), general pain (p < or = 0.001), feelings of coldness (p < or = 0.000), heart pounding (p < or = 0.008), runny eyes (p < or = 0.047), and aggressions (p < or = 0.009). Patients who received slow-release oral morphine treatment generally showed the least favorable QOL scores compared with patients at admission or sublingual buprenorphine and methadone clients. Patients in the sublingual buprenorphine or methadone program showed nearly the same QOL scores. The buprenorphine and the methadone maintenance group showed significantly more favorable values than opioid clients at admission regarding leisure time (p < or = 0.019), finances (p < or = 0.014), mental health (p < or = 0.010), and overall satisfaction (p < or = 0.010). Slow-release oral morphine is a well-established treatment for pain, but more research is required to evaluate it as a treatment for heroin dependence. The present data indicate that slow-release oral morphine could have some disadvantages compared with sublingual buprenorphine and methadone in QOL, physical symptoms, and additional consumption. The results further suggest that buprenorphine treatment is as effective as methadone in effects on quality of life and physical symptoms.     

Effects of parenteral morphine and oral methadone on self-stimulation in the rat

Facilitation of self-stimulation has been reported following the administration of various opiates. Methadone, a synthetic narcotic used in the treatment of narcotic addiction, has recently been demonstrated to facilitate self-stimulation when administered parenterally. The present study examined the effects of orally administered methadone (20 and 30 mg/kg), the route of administration used clinically, on MFB-LH self-stimulation at 2.5, 5, 8, 12, 17, and 24 hours post-administration. reliable facilitation was observed at 2.5 hours post-administration. However, the effect of methadone was less pronounced than that observed with a dose of parenteral morphine which was approximately equivalent in terms of analgesic potency.     

Antihypertensive therapy in the aged patient. Clinical pharmacokinetic considerations.

The incidence of both systolic and diastolic hypertension is increased in elderly patients, therefore antihypertensive drugs are commonly used in this population. In addition to changes in blood pressure, the aging process also causes numerous changes in other physiological parameters, resulting in altered pharmacokinetic and pharmacodynamic responses to the drugs. The dosage regimens for thiazide diuretics and amiloride must be individually titrated in the elderly patient, since the elimination of these agents decreases concurrently with decreased renal function, as indicated by compromised creatinine clearance. The initial doses of the calcium antagonists should be decreased in elderly patients, since representative compounds from all 3 chemically heterogeneous classes have been shown to have decreased clearance in these patients which appears to be primarily due to the status of hepatic function in the patient. However, with verapamil, the dosage should be further decreased in association with compromised renal function. The dosage of the angiotensin converting enzyme (ACE) inhibitors should be adjusted according to renal function rather than age. Lisinopril, which is primarily eliminated unchanged, is usually given in lower doses in the elderly, and doses of both captopril and enalapril may need to be reduced, depending on renal function. While there is no need to adjust the dosage regimen for the alpha-adrenoceptor blocking drugs (prazosin, terazosin), caution should be used with the beta-adrenergic blockers, particularly the hydrophilic agents, since they are renally eliminated. Labetalol may be a suitable alternative beta-blocker for the elderly patient, since its pharmacodynamic properties of decreased systemic vascular resistance without changes in heart rate or stroke volume are preferential for the elderly patient, and its pharmacokinetics are relatively unchanged in this population. Drugs that act primarily through the central nervous system, such as clonidine, methyldopa and guanfacine, require smaller doses in the presence of renal dysfunction. In contrast, guanabenz is metabolised primarily by the liver, so it would appear to be useful in elderly patients with renal dysfunction despite the lack of studies in this population. Guanadrel, an adrenergic neuron blocking drug, also requires a dosage reduction in patients with impaired renal function. In addition to the pharmacokinetic changes that occur in the elderly patient, pharmacodynamic changes may also be anticipated due to receptor modifications. Older patients have a decrease in beta-receptor sensitivity, while alpha-receptor sensitivity does not change. When designing the dosage regimen for a senior patient with hypertension, the combination of all these variables must be considered.     

Steady-state kinetics and analgesic effect of oral morphine in cancer patients

The steady-state kinetics of morphine given as tablets and solution were compared in 7 cancer patients with chronic pain. There was no accumulation of morphine (20-40 mg) when repeatedly administered every 4 to 6 h. The mean steady-state concentration of morphine during the dose interval varied between 5.9 and 68.4 ng/ml (20.7-240 nmol/l), and was linearly related to the daily dose of morphine. There were no significant differences between the tablets and the solution of morphine with regard to relative oral bioavailability or peak concentration. The time-to-maximum plasma concentrations was significantly longer for the tablets. The pain score profile, assessed by a visual analogue scale during a dose interval, showed a similar pattern after the two oral formulations of morphine. No significant linear relationship between the scores and the plasma concentrations of morphine was observed.     

The polymorphic oxidation of beta-adrenoceptor antagonists. Clinical pharmacokinetic considerations

Wide variability in response to some drugs such as debrisoquine can be attributed largely to genetic polymorphism of their oxidative metabolism. Most beta-blockers undergo extensive oxidation. Anecdotal reports of high plasma concentrations of certain beta-blockers in poor metabolisers (PMs) of debrisoquine have claimed that the oxidation of these drugs is under polymorphic control. Subsequently, controlled studies have shown that debrisoquine oxidation phenotype is a major determinant of the metabolism, pharmacokinetics and some of the pharmacological actions of metoprolol, bufuralol, timolol and bopindolol. The poor metaboliser phenotype is associated with increased plasma drug concentrations, a prolongation of elimination half-life and more intense and sustained beta-blockade. Phenotypic differences have also been observed in the pharmacokinetics of the enantiomers of metoprolol and bufuralol. In vivo and in vitro studies have identified some of the metabolic pathways which are subject to the defect, viz. alpha-hydroxylation and O-demethylation of metoprolol and 1'- and possibly 4- and 6-hydroxylation of bufuralol. In contrast, the overall pharmacokinetics and pharmacodynamics of propranolol, which is also extensively oxidised, are not related to debrisoquine polymorphism, although 4'-hydroxypropranolol formation is lower in poor metabolisers. As anticipated, the disposition of atenolol which is eliminated predominantly unchanged by the kidney and in the faeces, is unrelated to debrisoquine phenotype. The clinical significance of impaired elimination of beta-blockers is not clear. If standard doses of beta-blockers are used in poor metabolisers, these subjects may be susceptible to concentration-related adverse reactions and they may also require less frequent dosing for control of angina pectoris.