The view that digitalis clinically benefits patients with heart failure and sinus rhythm lacks support from a well-controlled study. Using a randomized, double-blind, crossover protocol, we compared the effects of oral digoxin and placebo on the clinical courses of 25 outpatients without atrial fibrillation. According to a clinicoradiographic scoring system, the severity of heart failure was reduced by digoxin in 14 patients; in nine of these 14, improvement was confirmed by repeated trials (five patients) or right-heart catheterization (four patients). The other 11 patients had no detectable improvement from digoxin. Patients who responded to digoxin had more chronic and more severe heart failure, greater left ventricular dilation and ejection-fraction depression, and a third heart sound. Multivariate analysis showed that the third heart sound was the strongest correlate of the response to digoxin (P less than 0.0001). These data suggest that long-term digoxin therapy is clinically beneficial in patients with heart failure unaccompanied by atrial fibrillation whose failure persists despite diuretic treatment and who have a third heart sound.

Heart failure in outpatients: a randomized trial of digoxin versus placebo.

Most drugs are carried from their sites of absorption to their sites of action and elimination by the circulating blood. Some drugs are simply dissolved in serum water, but many others are partly a...

Binding of Drugs to Serum Albumin

Objectives Antipsychotics are widely used in geriatric psychiatric disorders A growing number of atypical antipsychotics are available, expanding clinical options but complicating decision-making Many questions about use of antipsychotics in older patients remain unanswered by available clinical literature We therefore surveyed expert opinion on antipsychotic use in older patients (65 years of age or older) for recommendations concerning indications for antipsychotics, choice of antipsychotics for different conditions (eg, delirium, dementia, schizophrenia, delusional disorder, psychotic mood disorders) and for patients with comorbid conditions or history of side effects, dosing strategies, duration of treatment, and medication combinations Method Based on a literature review, a 47-question survey with 1,411 options was developed Approximately three quarters of the options were scored using a modified version of the RAND 9-point scale for rating appropriateness of medical decisions For other options, experts were asked to write in answers The survey was sent to 52 American experts on treatment of older adults (38 geriatric psychiatrists, 14 geriatric internists/family physicians), 48 (92%) of whom completed it In analyzing responses to items rated on the 9point scale, consensus was defined as a nonrandom distribution of scores by chi-square “goodness-of-fit” test We assigned a categorical rank (first line/preferred, second line/alternate, third line/usually inappropriate) to each option based on the 95% confidence interval around the mean Guidelines indicating preferred treatment strategies were then developed for key clinical situations Results The expert panel reached consensus on 78% of options rated on the 9-point scale The experts did not recommend using antipsychotics in panic disorder, generalized anxiety disorder, nonpsychotic major depression, hypochondriasis, neuropathic pain, severe nausea, motion sickness, or irritability, hostility, and sleep disturbance in the absence of a major psychiatric syndrome However, antipsychotics were favored in several other disorders For agitated dementia with delusions, the experts’ first-line recommendation is an antipsychotic drug alone; they would also consider adding a mood stabilizer Risperidone (05–20 mg/day) was first line followed by quetiapine (50–150 mg/day) and olanzapine (50–75 mg/day) as high second-line options There was no first-line recommendation for agitated dementia without delusions; an antipsychotic alone was high second line (rated first line by 60% of the experts) The experts’ firstline recommendation for late-life schizophrenia was risperidone (125–35 mg/day) Quetiapine (100–300 mg/day), olanzapine (75–15 mg/day), and aripiprazole (15–30 mg/day) were high second line For older patients with delusional disorder, an antipsychotic was the only treatment recommended For agitated nonpsychotic major depression in an older patient, the experts’ first-line recommendation was an antidepressant alone (77% first line); second-line options were an antidepressant plus an antipsychotic, electroconvulsive therapy (ECT), an antidepressant plus a benzodiazepine, and an antidepressant plus a mood stabilizer For nonpsychotic major depression with severe anxiety, the experts recommended an antidepressant alone (79% first line) and would also consider adding a benzodiazepine or mood stabilizer to the antidepressant If an older patient with nonpsychotic major depression fails to respond to antidepressants at adequate dosages for adequate duration, there was limited support for adding an atypical antipsychotic to the antidepressant (36% first line after two failed antidepressant trials) Treatment of choice for geriatric psychotic major depression was an antipsychotic plus an antidepressant (98% first line), with ECT another first-line option (71% first line) For mild geriatric nonpsychotic mania, the first-line recommendation is a mood stabilizer alone; the experts would also consider discontinuing an antidepressant if the patient is receiving one For severe nonpsychotic mania, the experts recommend a mood stabilizer plus an antipsychotic (57% first line) or a mood stabilizer alone (48% first line) and would discontinue any antidepressant the patient is receiving For psychotic mania, treatment of choice is a mood stabilizer plus an antipsychotic (98% first line) Risperidone (125–30 mg/day) and olanzapine (5–15 mg/day) were first-line options in combination with a mood stabilizer for mania with psychosis, with quetiapine (50–250 mg/day) high second line If a patient has responded well, the experts recommended the following duration of treatment before attempting to taper and discontinue the antipsychotic: delirium, 1 week; agitated dementia, taper within 3–6 months to determine the lowest effective maintenance dose; schizophrenia, indefinite treatment at the lowest effective dose; delusional disorder, 6 months–indefinitely at the lowest effective dose; psychotic major depression, 6 months; and mania with psychosis, 3 months For patients with diabetes, dyslipidemia, or obesity, the experts would avoid clozapine, olanzapine, and conventional antipsychotics (especially low- and mid-potency) Quetiapine is first line for a patient with Parkinson’s disease Clozapine, ziprasidone, and conventional antipsychotics (especially low- and mid-potency) should be avoided in patients with QTc prolongation or congestive heart failure For patients with cognitive impairment, constipation, diabetes, diabetic neuropathy, dyslipidemia, xerophthalmia, and xerostomia, the experts prefer risperidone, with quetiapine high second line More than a quarter of the experts considered these combinations contraindicated: clozapine + carbamazepine, ziprasidone + tricyclic antidepressant (TCA), and a low-potency conventional antipsychotic + fluoxetine In combining antidepressants and antipsychotics, the experts would be much more cautious with selective serotonin reuptake inhibitors that are more potent inhibitors of the CYP 450 enzymes (ie, fluoxetine, fluvoxamine, paroxetine) and with nefazodone, TCAs, and monoamine oxidase inhibitors The experts recommended extra monitoring when combining any antipsychotic with lithium, carbamazepine, lamotrigine, or valproate (except aripiprazole, risperidone, or a high-potency conventional plus valproate) or with codeine, phenytoin, or tramadol Conclusions The experts reached a high level of consensus on many of the key treatment questions Within the limits of expert opinion and with the expectation that future research data will take precedence, these guidelines provide direction for common clinical dilemmas in the use of antipsychotics in elderly patients Clinicians should keep in mind that no guidelines can address the complexities of an individual patient and that sound clinical judgment based on clinical experience should be used in applying these recommendations

/pdf/introduction-methods-commentary-and-summary-dicralqd4c.pdf

Introduction: Methods, Commentary, and Summary

Plasma and Tissue Protein Binding of Drugs in Pharmacokinetics

Many mothers are inappropriately advised to discontinue breastfeeding or avoid taking essential medications because of fears of adverse effects on their infants. This cautious approach may be unnecessary in many cases, because only a small proportion of medications are contraindicated in breastfeeding mothers or associated with adverse effects on their infants. Information to inform physicians about the extent of excretion for a particular drug into human milk is needed but may not be available. Previous statements on this topic from the American Academy of Pediatrics provided physicians with data concerning the known excretion of specific medications into breast milk. More current and comprehensive information is now available on the Internet, as well as an application for mobile devices, at LactMed (http://toxnet.nlm.nih.gov). Therefore, with the exception of radioactive compounds requiring temporary cessation of breastfeeding, the reader will be referred to LactMed to obtain the most current data on an individual medication. This report discusses several topics of interest surrounding lactation, such as the use of psychotropic therapies, drugs to treat substance abuse, narcotics, galactagogues, and herbal products, as well as immunization of breastfeeding women. A discussion regarding the global implications of maternal medications and lactation in the developing world is beyond the scope of this report. The World Health Organization offers several programs and resources that address the importance of breastfeeding (see http://www.who.int/topics/breastfeeding/en/).

/pdf/the-transfer-of-drugs-and-therapeutics-into-human-breast-47la9mzf3r.pdf

The Transfer of Drugs and Therapeutics Into Human Breast Milk: An Update on Selected Topics

The extent and nature of furosemide (F) binding to human albumin (HA) and to the plasma of 6 children with nephrotic syndrome were studied by equilibrium dialysis at 37 degrees C and pH 7.4 with 14C-F. At a total concentration of 3.4 mug/ml (therapeutic range), the unbound fraction of F to 4 gm per 100 ml HA was 2.79 plus or minus 0.35. The degree of binding was relatively constant from 1.8 to 36 mug/ml of F concentration. The percentage of unbound F doubled when total concentration of the drug was increased more than 130 times (1.8 to 245 mug/ml). F has two classes of binding sites (n1 = 1.42, k1 = 5.07 times 10-4 M-minus 1; n2 = 3.4, k2 = 1.58 times 10-4 M-minus 1); interaction with HA involves hydrophobic, ionic, and hydrogen forces. Acetylsalicylic acid (ASA), acetazolamide, diazoxide, phenylbutazone, sulfisoxazole (S), and tolbutamide (T) decreased F binding. Combinations of ASA, S, and T exerted a strong additive displacing effect. The binding of the F metabolite (4-chloro-5-sulfamoylanthranilic acid, CSA) was studied at 1.3 and 2.6 mug/ml. The unbound fraction was 5 times that of F. CSA did not influence F binding. Studies with plasma of 7 healthy adults showed that albumin is the only plasma protein responsible for F binding. The plasma albumin concentration range of the children with nephrotic syndrome was 0.6 to 2.1 gm per 100 ml. There was some correlation between albumin concentration and binding of F (2.8 to 9.6% unbound); this corresponded with findings with HA. Albumin concentrations lower than 2 gm per 100 ml seemed to influence the extent of the unbound fraction of F considerably.

Furosemide binding to human albumin and plasma of nephrotic children.

Systolic time intervals (STI) and serum digoxin concentrations (SDC) were measured in eight patients with compensated atherosclerotic and/or hypertensive heart disease who received oral digoxin 0.25 mg/day or 0.5 mg/day for alternate two-week periods without a loading dose. Control data were obtained both before and after the four weeks of treatment. After 13 days treatment with digoxin, 0.5 mg/day, there was a significant decrease in total electromechanical systole corrected for heart rate (QS2i), pre-ejection period (PEP), pre-ejection period corrected for heart rate (PEP1) and PEP/left ventricular ejection time (LVET). After the thirteenth dose of 0.25 mg/day there was significant shortening of PEP1 and PEP/LVET. Shortening of QS2i correlated significantly with SDC 24 hours after the thirteenth dose of 0.5 mg. These data suggest that after 13 days of treatment with 0.25 and 0.5 mg/day of digoxin, a positive inotropic effect occurs as reflected by STI shortening. A greater effect was recorded with the 0...

Effects of Maintenance Digoxin Therapy on Systolic Time Intervals and Serum Digoxin Concentrations

Pulmonary effects of furosemide in preterm infants with lung disease.

Accurate prediction of fetal/neonatal risks following maternal psychotropic drug consumption by the human will require much additional study. Based upon our present understanding of fetal exposure to psychotropic drugs, there would appear to be an increased risk for spontaneous malformations in the case of lithium. There have been inconsistent reports of structural abnormalities following exposure to phenothiazines and benzodiazepines. In animal models that demonstrate structural changes due to neuroleptic exposure, in general, extremely large dosages of medication had been given. Thus, their correlative value is limited. Behavioral alterations in animals following drug exposure during pregnancy tend to support increased concerns about the safety of psychotropic drugs for the fetus but cannot be used alone in making a final decision. Behavioral studies evaluating drugs in breast milk have been restricted to experimental animals; hence, the associated risks from this form of drug dosing in man remain unknown. At present, neither gross anatomic nor motor side effects have been apparent in the infant. The question of the development of subtle behavioral changes as a long-term consequence will remain undetermined until careful assessments have been completed.

https://pediatrics.aappublications.org/content/pediatrics/69/2/241.full.pdf

Psychotropic Drugs in Pregnancy and Lactation

The renal clearance of furosemide and tetraethylammonium (TEA) were compared in 10 patients with hypertensive nephropathy. BUN and creatinine ranges were 10 to 88 mg/dl and 0.9 to 3.8 mg/dl, respectively. Diuretics were discontinued 48 hr prior to the study, and 2 consecutive clearances (ml/min/1.73 m2BSA) of creatinine were performed. The patient then received a bolus followed by a constant infusion of furosemide-14C and tetraethylammonium-14C (analyzed by specific methodology for plasma and urine), both in subpharmacologic doses. After 40-min equilibration sequential 20-min clearance periods were obtained. Both the clearance of furosemide (range 17 to 133) and TEA (range 99 to 443) correlated negatively with BUN and serum creatinine and positively with creatinine and urea clearances. Thus, by using a constant-infusion technique we demonstrated that the renal clearance of furosemide is depressed by azotemia in man and that there was greater depression with furosemide than with TEA.

Albert W. Pruitt

Papers

Furosemide binding to human albumin and plasma of nephrotic children.

Effects of Maintenance Digoxin Therapy on Systolic Time Intervals and Serum Digoxin Concentrations

Pulmonary effects of furosemide in preterm infants with lung disease.

Psychotropic Drugs in Pregnancy and Lactation

Depression of renal clearance of furosemide in man by azotemia