Robert E. Vestal

Drug Use in the Elderly: A Review of Problems and Special Considerations

SummaryWith the recognition that the aged constitute an increasing proportion of our patient population, attention is being directed toward understanding the epidemiology, pharmacology and toxicology of drug use in the elderly. As a group, elderly patients have more illness and inevitably take more medications than younger patients. Although not unique to geriatric medicine, medication errors and lack of comprehension of treatment plans are prevalent. These factors undoubtedly contribute to the increased incidence of adverse drug reactions in the elderly.It is possible that age differences in pharmacokinetics may contribute importantly to the apparent increased ‘sensitivity’ of older persons to both the therapeutic and toxic effects of some drugs. For most drugs studied, such pharmacokinetic differences are generally consistent with age differences in body composition, protein binding, renal function and tissue perfusion. Aging is associated with a decrease in lean body mass and total body water, a decrease in serum albumin concentration, a decline in glomerular and tubular function in the kidney, and diminished cardiac output, liver blood flow and cerebral blood flow. Although some evidence suggests that hepatic metabolism of drugs is impaired with aging, it is increasingly clear that apparent effects of age on antipyrine metabolism may be more related to age differences in other factors, such as diet and smoking, than to age per se. For antipyrine, a model compound for the study of hepatic microsomal drug metabolising enzyme activity in man, biological variation seems to be much more important than any single non-genetic variable presently investigated. The few available studies suggest little effect of age on drug absorption, but more information is needed.In addition to considering the epidemiology of drug use and the altered physiology in the elderly, this review attempts to provide an overview of what is known about the relationship of advanced age and the pharmacokinetics and pharmacodynamics of representative compounds from several groups of drugs. Although the response to isoprenaline (isoproterenol) and propranolol is impaired in the elderly, most studies seem to bear out the long held clinical impression that the elderly are generally more sensitive to drugs than younger individuals.Finally, several general principles of drug use in a patient of any age are restated as guidelines for geriatric pharmacotherapy. Worthy of special consideration are ways of promoting compliance with prescribed therapy.

Comparison of the effects of adenosine and nifedipine in pulmonary hypertension

The hemodynamic effects of intravenously administered adenosine, a potent vasodilator, were examined in 15 patients with pulmonary hypertension. All patients were given adenosine, 50 micrograms/kg per min, increased by 50 micrograms/kg per min at 2 min intervals to a maximum of 500 micrograms/kg per min or until the development of untoward side effects. The patients were then given oral nifedipine, 20 mg every hour, until a greater than or equal to 20% decrease in pulmonary vascular resistance or systemic hypotension occurred. The administration of maximal doses of adenosine, 256 +/- 46 micrograms/kg per min, produced a 2.4% reduction in pulmonary artery pressure (p = NS), a 37% decrease in pulmonary vascular resistance (p less than 0.001) and a 57% increase in cardiac index (p less than 0.001). The administration of maximally effective doses of nifedipine (91 +/- 36 mg) produced a 15% reduction in the mean pulmonary artery pressure (p less than 0.05), a 24% decrease in pulmonary vascular resistance (p less than 0.01) and an 8% increase in cardiac index (p = NS). There was a significant correlation (r = 0.714, p = 0.01) between the reduction in pulmonary vascular resistance that resulted from adenosine administration and that achieved with the administration of nifedipine. Six patients had substantial reductions in pulmonary vascular resistance with adenosine but not with nifedipine. Thus, adenosine is an effective vasodilator in patients with pulmonary hypertension and can be used for safe and rapid assessment of vasodilator reserve in these patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Impaired Bronchodilator Response to Albuterol in Healthy Elderly Men and Women

BACKGROUND Lymphocytes of normal elderly subjects and young asthmatics display dysfunctional beta-adrenoceptors. If beta-adrenoceptor dysfunction were found in senescent airways, it might help explain the pathogenesis of late onset asthma. METHODS The bronchodilatory effects of albuterol after methacholine-provoked bronchoconstriction were compared in 17 healthy young (age 20 to 36 years) and 17 healthy elderly (age 60 to 76 years) volunteer subjects. Albuterol was inhaled via dosimeter (initially 7.8 micrograms, doubling every 7.5 min) with forced expiratory flow at 50% vital capacity (FEF50) measured prior to each dose. Albuterol sensitivity was expressed as the cumulative logarithm of the area under the FEF50 recovery curve (AUC); a greater AUC meant lower sensitivity. On another study day, spontaneous recovery from methacholine was assessed similarly. RESULTS There was no intergroup difference in spontaneous recovery. Despite lower methacholine doses provoking similar (35%) FEF50 falls in elderly subjects, albuterol AUC was greater in elderly subjects (6,552%.min.microgram) than young subjects (3,922%.min microgram; p = 0.03). Multiple regression showed that AUC and age were related (p = 0.02). CONCLUSION Airway beta 2-adrenoceptor responsiveness is diminished in old age, suggesting that airway beta-adrenoceptor dysfunction may be implicated in late-onset asthma.

CD40 is functionally expressed on human breast carcinomas: Variable inducibility by cytokines and enhancement of Fas-mediated apoptosis

The CD40 molecule, a member of the TNF receptor gene family, has been intensively studied with respect to regulation of B cell proliferation and survival. Although CD40 is also expressed on carcinoma cell lines, information concerning the biological function of CD40 on cells of epithelial origin is limited. In this study we detected constitutive CD40 on human breast carcinoma cell lines and an increase in CD40 expression following treatment with cytokines IL-1α and IFN-γ. CD40 ligation was also found to increase MHC II expression in cells pretreated with IFN-γ. In contrast to normal B cells, where CD40 signaling provides a potent survival signal, we observed that CD40 ligation in breast carcinoma cells results in growth inhibition and enhanced susceptibility to Fas-mediated apoptosis. Enhanced apoptosis appears to be attributable, at least in part, to an up-regulation of Fas expression caused by CD40 ligation. These results suggest a potentially important role for CD40 in breast tumor biology.

Therapeutic concentrations of theophylline and enprofylline potentiate catecholamine effects and inhibit leukocyte activation

Methylxanthines are primary agents used in treatment of hypersensitivity disease. Because polymorphonuclear leukocyte (PMN) activation is associated with generation of potent inflammatory mediators, xanthine effects on the PMN respiratory burst were studied. Enprofylline, a xanthine with important therapeutic potential, does not antagonize adenosine and was contrasted with theophylline. Although enprofylline was more potent at low concentrations, both drugs exhibited dose-dependent inhibition of PMN activation at concentrations greater than 10 mumol/L (1.8 micrograms/ml). Oxygen metabolite generation was decreased by 30% to 40% at therapeutic drug concentrations and by 85% at 1 mmol/L of theophylline. Inhibition by isoproterenol or prostaglandin E2 but not dibutyryl cAMP was potentiated by either xanthine. Isoproterenol effects were also increased when isoproterenol was evaluated in whole blood specimens obtained from subjects after a loading dose of aminophylline. Although these results were most compatible with cAMP phosphodiesterase inhibition, other commonly proposed mechanisms of methylxanthine activity were also studied. Theophylline but not enprofylline blocked adenosine inhibition of PMN activation. Neither xanthine shifted the calcium dose-response when PMNs were activated with calcium ionophore. Because oxygen metabolites generated by the FMN are mediators of inflammation and hypersensitivity, direct inhibition of PMN activation as well as potentiation of catecholamine activity may be important therapeutic effects of theophylline and enprofylline.

Pharmacokinetic Optimisation of Drug Therapy in Elderly Patients

SummaryWith increasing age, there are a number of physiological changes that affect the handling of drugs in the human body. Increases in body fat percentage as well as decreases in lean body mass, hepatic metabolism and renal elimination capacity are of particular clinical significance. It is important to take these changes into account when choosing drug therapy for older patients in order to minimise adverse effects and maximise potential benefits. This is particularly important when prescribing drugs with a narrow therapeutic index such as digoxin, theophylline, Phenytoin, lidocaine (lignocaine) or warfarin. When available, monitoring of plasma concentrations can assist in the optimisation of drug dosage.

Effects of adenosine in combination with calcium channel blockers in patients with primary pulmonary hypertension

OBJECTIVES The purpose of this study was to evaluate the effects of vasodilator combination therapy in patients with primary pulmonary hypertension. BACKGROUND Calcium channel blockers and adenosine have each been shown to be effective in reducing pulmonary artery pressure and pulmonary vascular resistance in patients with primary pulmonary hypertension. However, the effects of combining these vasodilators have not been studied. METHODS To test the combination, 12 patients were placed on oral nifedipine and 3 on diltiazem therapy, using a dose titrated to maximal effect (mean nifedipine dose 103 +/- 24 mg, mean diltiazem dose 300 +/- 49 mg). Patients were then given maintenance doses of the calcium channel blocker at half the cumulative loading dose at 6-h intervals. One hour after the maintenance dose of calcium blocker, all patients received an infusion of adenosine, starting with 50 micrograms/kg per min and increasing by 50 micrograms/kg per min at 2-min intervals to a maximally tolerated dose (180 +/- 63 micrograms/kg per min). RESULTS Ten patients responded to calcium channel blockers (defined as a > or = 20% decrease in pulmonary vascular resistance), with a 16% decrease in mean pulmonary artery pressure (p = 0.057), a 39% decrease in pulmonary vascular resistance (p = 0.002) and a 24% increase in stroke volume (p = 0.007). Five patients were nonresponders, with no significant changes in pulmonary artery pressure, pulmonary vascular resistance, cardiac index or stroke volume. In the calcium channel blocker responders, the combination of adenosine and calcium blocker reduced pulmonary vascular resistance by 49%, increased stroke volume by 33% and decreased mean pulmonary artery pressure by 14% compared with drug-free baseline values. In nonresponders, combination therapy resulted in nonsignificant changes in pulmonary artery pressure and pulmonary vascular resistance. CONCLUSIONS Adenosine has the ability to further decrease pulmonary artery pressure and pulmonary vascular resistance in patients with primary pulmonary hypertension who respond to calcium channel blockers. Those who fail to respond to these agents have little added effect from adenosine.

Doxorubicin cardiac dysfunction

Utilizing a model of chronic doxorubicin cardiomyopathy, this study examines the relationship between changes in expression and function of calcium handling proteins and contractile dysfunction. Apossible mechanism to account for this relationship is suggested. New Zealand white rabbits were injected with either doxorubicin (1 mg/kg, twice weekly for 8 wk) or 0.9% NaCl. Gene transcript, protein levels, and the function of several proteins from the left ventricle were assessed. Protein levels of sarcoplasmic reticulum (SR) Ca2+ transporting ATPase (SERCA2a and b), Ca2+ release channel (RYR2), calsequestrin, Na/Ca exchanger, mRNA levels of RYR2, and [3H]-ryanodine binding (Bmax) to RYR2 were significantly decreased in doxorubicin-treated rabbits; protein levels of phospholamban, dihydropyridine receptor α2 subunit, and SR Ca2+ loading rates were not decreased. However, only protein levels of SERCA2 and RYR2, mRNA levels of RYR2, and Bmax of RYR2 significantly regressed with left-ventricular fractional shortening. Analysis of contractile function of atrial preparations isolated from doxorubicin-treated rabbits revealed that doxorubicin diminished contractility (dF/dt) of rest-potentiated contractions consistent with SR dysfunction. Serum concentrations of free triiodothyronine (T3) decreased in doxorubicin-treated rabbits. Our results suggest that chronic doxorubicin administration in the rabbit causes a SR-dependent contractile dysfunction that may result, in part from decreased T3.

Effects of adenosine on polymorphonuclear leucocyte function, cyclic 3': 5'-adenosine monophosphate, and intracellular calcium.

1 Inhibition of human polymorphonuclear leucocyte (PMN) function by adenosine was studied with respect to effects of adenosine on intracellular cyclic AMP and calcium during the PMN respiratory burst. 2 The adenosine analogue 5′‐N‐ethylcarboxamide‐adenosine (NECA) and L‐N6‐phenyl‐isopropyladenosine (L‐PIA) inhibited PMN oxygen metabolite generation with relative potencies (NECA > adenosine > L‐PIA) characteristic of an A2 receptor. 3 The respiratory burst was inhibited by adenosine when PMN were activated by calcium ionophore or chemotactic peptide but not when cells where activated by oleoyl‐acetyl‐glycerol (OAG). 4 Adenosine increased intracellular cyclic AMP during the PMN respiratory burst regardless of whether cells were stimulated by ionophore, chemotactic peptide or OAG. 5 To determine whether the differences in cell inhibition by adenosine were related to differences in intracellular calcium mobilization by each activating agent, calcium was evaluated with the fluorescent probe, indo‐1. Adenosine suppressed the increase in intracellular calcium following PMN activation by calcium ionophore or chemotactic peptide. In contrast, calcium did not increase in PMN activated by OAG and adenosine did not affect intracellular calcium changes following this stimulus. 6 These results demonstrate that physiological concentrations of adenosine inhibit the PMN respiratory burst in association with an increase in intracellular cyclic AMP and reduction of intracellular calcium.

Cigarette smoking and theophylline metabolism: Effects of cimetidine

The inhibition of theophylline metabolism by cimetidine was investigated in young male cigarette smokers (>20 cigarettes/day) and nonsmokers by stable isotope methodology. Subjects received oral theophylline (510 mg/day) for 14 days and cimetidine (1200 mg/day) over days 1 to 7 or 8 to 14. On days 7 and 14, a tracer dose (10 mg) of stable isotope‐labeled theophylline was injected intravenously with the oral dose of theophylline. Serial plasma samples were then obtained for 24 hours and both molecular forms of theophylline were assayed by mass spectrometry after purification by HPLC. Theophylline bioavailability, volume of distribution, and protein binding were of the same order in both groups and were not affected by cimetidine. Although the basal theophylline elimination rate constant was 46% greater and clearance was 54% greater in smokers than in nonsmokers, the proportionate changes in steady‐state plasma concentrations, t½, and clearance due to cimetidine were much the same in both groups. Plasma thiocyanate concentrations were higher in smokers than in nonsmokers and were related to theophylline clearance. Our findings indicate that cimetidine inhibits theophylline metabolism to a similar extent in both smokers and nonsmokers. Determination of plasma thiocyanate levels may be valuable in the prediction of theophylline clearance.