Denise Sorisio

Anticholinergic Activity of 107 Medications Commonly Used by Older Adults

The objective of this study was to measure the anticholinergic activity (AA) of medications commonly used by older adults. A radioreceptor assay was used to investigate the AA of 107 medications. Six clinically relevant concentrations were assessed for each medication. Rodent forebrain and striatum homogenate was used with tritiated quinuclidinyl benzilate. Drug‐free serum was added to medication and atropine standard‐curve samples. For medications that showed detectable AA, average steady‐state peak plasma and serum concentrations (Cmax) in older adults were used to estimate relationships between in vitro dose and AA. All results are reported in pmol/mL of atropine equivalents. At typical doses administered to older adults, amitriptyline, atropine, clozapine, dicyclomine, doxepin, L‐hyoscyamine, thioridazine, and tolterodine demonstrated AA exceeding 15 pmol/mL. Chlorpromazine, diphenhydramine, nortriptyline, olanzapine, oxybutynin, and paroxetine had AA values of 5 to 15 pmol/mL. Citalopram, escitalopram, fluoxetine, lithium, mirtazapine, quetiapine, ranitidine, and temazepam had values less than 5 pmol/mL. Amoxicillin, celecoxib, cephalexin, diazepam, digoxin, diphenoxylate, donepezil, duloxetine, fentanyl, furosemide, hydrocodone, lansoprazole, levofloxacin, metformin, phenytoin, propoxyphene, and topiramate demonstrated AA only at the highest concentrations tested (patients with above‐average Cmax values, who receive higher doses, or are frail may show AA). The remainder of the medications investigated did not demonstrate any AA at the concentrations examined. Psychotropic medications were particularly likely to demonstrate AA. Each of the drug classifications investigated (e.g., antipsychotic, cardiovascular) had at least one medication that demonstrated AA at therapeutic doses. Clinicians can use this information when choosing between equally efficacious medications, as well as in assessing overall anticholinergic burden.

Inhibition of Caffeine Metabolism by Estrogen Replacement Therapy in Postmenopausal Women

This study was conducted to investigate the effect of therapeutic estrogen on cytochrome P450 1A2‐mediated metabolism in postmenopausal women using caffeine as a model substrate. Twelve healthy postmenopausal women underwent estrogen replacement therapy in the form of estradiol (Estrace). Estradiol was initiated at a dose of 0.5 mg a day and titrated to achieve a steady‐state plasma concentration of 50 to 150 pg/ml. Caffeine metabolic ratios (CMR; paraxanthine/ caffeine) were assessed both before and after 8 weeks of estrogen replacement. For the 12 subjects, there was a mean reduction in CMR of −29.2 25.0 (p = 0.0019). Consistent with previous results found in younger women, these results indicate that exogenous estrogen in older women may inhibit CYP1A2‐mediated caffeine metabolism.

Effects of the β2-adrenoceptor agonist clenbuterol on tyrosine and tryptophan in plasma and brain of the rat

The beta 2-adrenoceptor agonist, clenbuterol (initially 5 mg/kg), was found to significantly reduce plasma tyrosine and raise brain tryptophan levels (P less than 0.01). By comparison, decreases in plasma tryptophan and increases in brain tyrosine were small and often nonsignificant. Amino acid levels measured in different brain regions revealed that the elevations were similar among the cerebellum, striatum, and cortex. These effects were partially blocked by propanolol but not by atenolol. The ED50 was estimated from dose-response curves to be about 0.05 mg/kg for both the decrease in plasma tyrosine and the increase in brain tryptophan. The effects of low doses of clenbuterol were prevented completely by propranolol. Peripheral organs displayed strikingly different patterns of change in amino acid concentrations. Only the spleen had any accumulation of tryptophan, but that was much less than in brain. In contrast, tyrosine and tryptophan were decreased in heart and unaltered in liver; tyrosine was decreased in lung. The elevation in brain tryptophan levels was attenuated by the beta 2-antagonist, ICI 118,551, but not by the beta 1-antagonist, betaxolol; but the reduction in plasma tyrosine was unaffected by either drug. The serotonin antagonist, methysergide, failed to block the effects of clenbuterol. We conclude that changes in amino acid concentrations produced by clenbuterol are mediated by beta 2-adrenoceptor stimulation. Although the increases in brain tyrosine and tryptophan were similar to increases in the plasma ratios of these amino acids to the sum of the other large neutral amino acids competing for transport into the brain, the disparity between the effects of ICI 118,551 in brain and plasma suggests that clenbuterol may also have a direct action in brain to regulate levels of aromatic amino acids. Since clenbuterol has been purported to have an antidepressant effect and since other antidepressants also increase brain tryptophan, this may be a common feature of antidepressant drug action.

Quantitative determination of paroxetine in plasma by high-performance liquid chromatography and ultraviolet detection.

An accurate, reliable procedure was developed for kinetic and therapeutic monitoring of paroxetine in human plasma. Steady-state plasma levels of paroxetine were measured for 18 geriatric patients (mean age 75) in a double-blinded study. Paroxetine doses ranged from 10 to 40 mg/day. The assay was suitable for patients on concurrent medications, and a small sample volume (1 ml) of patient plasma was used with sufficient sensitivity and specificity. After extraction and separation on a Beckman, Ultrasphere 5-microm C18 column (150x2 mm I.D.), the recovery (mean+/-S.D.) for paroxetine was determined to be 86.5+/-5.2%. The limit of quantitation for paroxetine in this assay was 5 ng/ml. Inter-assay reproducibility (C.V.) for the patient samples and quality controls ranged from 3.7 to 7.6%.

Quantitative determination of perphenazine and its metabolites in plasma by high-performance liquid chromatography and coulometric detection.

An accurate, reliable method has been developed for the therapeutic monitoring of perphenazine (PPZ) and its major metabolites in human plasma samples. Steady-state plasma levels of PPZ and its metabolites were quantitated for 30 elderly patients (mean age: 75) undergoing concurrent treatment with nortriptyline (NT) and PPZ, doses ranging from 4 to 32 mg/day for PPZ. The assay was suitable with patients on concurrent medications, and smaller patient plasma volumes (1 ml) were used indicating sufficient sensitivity and specificity. After plasma extraction and separation on a Nucleosil 5-microns C18 column, the recoveries (mean +/- S.D.) of PPZ and its metabolites were determined; perphenazine 92 +/- 7.5%, deshydroxyethylperphenazine 81 +/- 7.2%, perphenazine sulfoxide 68 +/- 6.4%, and 7-hydroxyperphenazine 45 +/- 5.5%. The assay also had limits of quantitative detectability for PPZ and its metabolites as follows: perphenazine 0.5 ng/ml, deshydroxyethylperphenazine 1.0 ng/ml, perphenazine sulfoxide 0.5 ng/ml, and 7-hydroxyperphenazine 5 ng/ml. Inter-assay reproducibility (C.V.) for the quality controls and patient samples ranged from 18.8 to 2.4%. The sensitivity and reproducibility of this method should improve PPZ therapeutic drug monitoring and research on interactions in depressed geriatric patients.

Pharmacologic Profile of Perphenazine's Metabolites

The authors have previously reported that in elderly patients treated with low doses of perphenazine, few extrapyramidal symptoms (EPS) developed in those who were not poor CYP2D6 metabolizers. The authors hypothesized that this atypical side effect profile is due to perphenazines principal metabolite, n-dealkylperphenazine (DAPZ), which is usually present in vivo at concentrations 1.5 to 2 times that of the parent drug. Perphenazine, DAPZ, and 7-hydroxyperphenazine affinities were examined in vitro by competition-binding analysis to isolated human receptors expressed in transfected cell lines. Perphenazine and metabolite effects were examined in vivo in 54 older patients who were treated with perphenazine, at a target dose of 0.1 mg/kg, for 10 to 17 days. Drug concentrations were determined by high-performance liquid chromatography with electrochemical detection. In in vitro binding studies, DAPZ demonstrated a higher affinity for serotonin-2A receptors than for dopamine-2 receptors to an extent comparable to that of some atypical neuroleptic agents. In contrast, perphenazine and 7-hydroxyperphenazine demonstrated a higher affinity for dopamine-2 receptors than for serotonin-2A receptors. The mean +/- SD concentrations in the 54 subjects were the following: perphenazine, 1.5 +/- 1.4 ng/mL; DAPZ, 2.0 +/-1.6 ng/mL; and 7-hydroxyperphenazine, 0.8 +/- 1.9 ng/mL. The mean +/- SD quotient for the DAPZ/perphenazine concentration was 1.7 +/- 1.1 and for the 7-hydroxyperphenazine/perphenazine was 0.54 +/-1.6. EPS onset was not correlated with the perphenazine concentration, the metabolite concentrations, the DAPZ/perphenazine quotient, or the 7-hydroxyperphenazine/perphenazine quotient. Despite a moderately atypical receptor-binding profile, DAPZ does not seem to moderate perphenazine effects in vivo in older patients. This outcome likely reflects the low potency of DAPZ for dopamine-2 and serotonin-2A receptors relative to the potency of perphenazine for these receptors. Further exploration of atypical properties of DAPZ should include de novo administration of this metabolite in animal models.

Effects of imipramine on tyrosine and tryptophan are mediated by β-adrenoceptor stimulation

Imipramine (IMI; 20 mg/kg) in rats decreased the plasma tyrosine concentration by 21% (90 min), whereas norepinephrine (NE; 1.25 mg/kg) raised it by 72% (40 min). Since NE raised plasma tyrosine by stimulating alpha-adrenoceptors, as shown by phenoxybenzamine (PB) completely abolishing this increase, an experiment was done to find out whether IMI lowered plasma tyrosine by blocking alpha-adrenoceptors. In contrast to PB, IMI pretreatment failed to alter the NE-induced elevation in plasma tyrosine, suggesting that at this dose IMI is not an effective alpha-adrenergic antagonist in vivo. Thus, IMI would not appear to reduce plasma tyrosine by blocking alpha-adrenoceptors. In a separate experiment, propranolol blocked the ability of IMI to lower plasma tyrosine. Propranolol also prevented a 17% elevation in brain tryptophan levels induced by IMI but did not alter the 29% decrease in plasma tryptophan. PB by itself decreased plasma tyrosine, but this decrease was not greater by additionally treating with IMI. Salbutamol (10 mg/kg), a beta 2 agonist, lowered plasma tyrosine to 76% and raised brain tryptophan to 143% of control. These results suggest that IMI decreases tyrosine concentrations in plasma and raises tryptophan in brain by stimulating beta-adrenoceptors.

Effect of nortriptyline and paroxetine on CYP2D6 activity in depressed elderly patients.

This study was performed in elderly patients (1) to assess in vivo the degree to which CYP2D6mediated metabolism of debrisoquine at baseline determines plasma concentration to dose quotients for nortriptyline or paroxetine after 4 weeks of treatment, and (2) to compare the effects of nortriptyline and paroxetine on debrisoquine metabolism after 6 weeks of treatment. CYP2D6 activity was estimated in 66 subjects (71.4 ± 7.2 years) before initiating treatment and again after 6 weeks of treatment with either nortriptyline or paroxetine under randomized, double-blind conditions according to a standard protocol. CYP2D6 activity was estimated by the debrisoquine recovery ratio in a 6- to 8-hour urine sample collected after oral administration of 10 mg debrisoquine sulfate. Nortriptyline and paroxetine plasma concentrations were obtained weekly. Baseline debrisoquine recovery ratio values were significantly correlated with the plasma concentration to dose quotient at 4 weeks for both nortriptyline (r = −0.75, p = 0.0001, N = 29) and paroxetine (r = −0.50, p = 0.003, N = 33). Treatment with either nortriptyline or paroxetine was associated with a significant decrease in the median debrisoquine recovery ratio, reflecting inhibition of CYP2D6 metabolism. The percent decrease associated with nortriptyline was significantly smaller than that with paroxetine (p < 0.0001). None of the patients treated with nortriptyline but 19 of the 32 extensive metabolizers treated with paroxetine were converted to phenotypic poor metabolic status. Our observations of CYP2D6 inhibition are consistent with in vitro data and results obtained in younger healthy volunteers. The significant correlations between baseline debrisoquine recovery ratio and the plasma concentrations to dose quotients at 4 weeks for both nortriptyline and paroxetine are consistent with CYP2D6 playing a major role in the metabolism of both drugs. CYP2D6 inhibition by paroxetine, which effectively converted 59% of patients to phenotypic PMs, may be especially relevant for elderly patients given their generally higher concentration of paroxetine.

Determination of imipramine, desipramine and their hydroxy metabolites by reversed-phase chromatography with ultraviolet and coulometric detection

A reversed-phase high-performance liquid chromatographic method is described which analyzes imipramine, desipramine and their corresponding 2-hydroxy metabolites with sequential ultraviolet and coulometric detection from a single common extraction step, so that a wider dynamic range of plasma concentrations can be measured requiring smaller sample volumes. Applicability is broader including single-dose pharmacokinetic studies as well as steady-state concentrations. The extraction procedure gives excellent recoveries for imipramine, desipramine and their metabolites (mean +/- S.D.): ultraviolet detection, imipramine 99.5 +/- 0.68%, desipramine 100 +/- 0.0%, 2-hydroxyimipramine 97.8 +/- 3.5% and 2-hydroxydesipramine 93.1 +/- 4.22%; coulometric detection, imipramine 97.5 +/- 1.9%, desipramine 98.3 +/- 1.2%, 2-hydroxyimipramine 90.3 +/- 4.0% and 2-hydroxydesipramine 86.6 +/- 7.5%.

Decreases in tyrosine and p-hydroxyphenylglycol caused by various antidepressants

The effects of eleven different antidepressant drugs on brain p-hydroxyphenylglycol (pHPG) and on brain and plasma tyrosine concentrations were investigated in rats. Imipramine, amitriptyline, amoxapine, desmethylimipramine and iprindole (20 mg/kg each) and bupropion (50 mg/kg) decreased brain pHPG levels 4.5 or 6 hr after injection. Each of these drugs also significantly reduced plasma tyrosine levels 1.5 hr after injection. In contrast, zimelidine, amitriptylinoxide, trimipramine and trazodone had no significant effect on either brain pHPG or plasma tyrosine. Mianserin significantly lowered plasma tyrosine but produced a nonsignificant decrease in brain pHPG. The decreases in brain pHPG caused by the various drugs were significantly correlated with 3,4-dihydroxyphenylethyleneglycol. Moreover, decreases in brain pHPG and brain and plasma tyrosine concentrations were correlated with the potencies of these drugs to inhibit in vitro norepinephrine uptake. These results suggest the possibility that noradrenergic (or similar) mechanisms regulate both pHPG and tyrosine levels. However, the decreases in pHPG cannot be explained entirely by a deficiency in tyrosine, since the depletions in pHPG were much larger and longer lasting than those of tyrosine.