Angiotensin-converting enzyme inhibitors: a comparative review.

The chemistry, pharmacology, pharmacokinetics, adverse effects, and dosages of the three currently available angiotensin-converting enzyme (ACE) inhibitors are reviewed. This class of agents effectively inhibits the conversion of angiotensin I to the active vasoconstrictor angiotensin II, a hormone that also promotes, via aldosterone stimulation, increased sodium and water retention. The ACE inhibitors, therefore, are capable of lowering blood pressure primarily by promoting vasodilatation and reducing intravascular fluid volume. Captopril, the first orally active, commercially available ACE inhibitor, is a sulfhydryl-containing compound. Captopril was followed by the introduction of enalapril and lisinopril, two non-sulfhydryl ACE inhibitors. The pharmacokinetic profiles of these three ACE inhibitors differ. Captopril has rapid onset with relatively short duration of action, whereas enalapril and lisinopril have slower onset and relatively long duration of action. Captopril is an active ACE inhibitor in its orally absorbable parent form. In contrast, enalapril must be deesterified in the liver to the metabolite enalaprilat in order to inhibit the converting enzyme; this accounts for its delayed onset of action. Lisinopril does not require metabolic activation to be effective; however, a slow and incomplete absorption pattern explains the delay in onset of activity. Captopril and its disulfide metabolites are primarily excreted in the urine with minor elimination in the feces. Approximately two-thirds of an administered enalapril dose is excreted in the urine as both the parent drug and the metabolite enalaprilat; the remainder of these two substances are excreted in the feces. Lisinopril does not undergo measurable metabolism and approximately one-third is excreted unchanged in the urine with the remaining parent drug being excreted in the feces. The ACE inhibitors lower systemic vascular resistance with a resultant decrease in blood pressure. Their efficacy is comparable to diuretics and beta-blockers in treating patients with mild, moderate, or severe essential and renovascular hypertension. In those patients with severe congestive heart failure (CHF) the ACE inhibitors produce a reduction in systemic vascular resistance, blood pressure, pulmonary capillary wedge pressure, and pulmonary artery pressure. These drugs may produce improvement in cardiac output and stroke volume and, with chronic administration, may promote regression of left ventricular hypertrophy. The antihypertensive effects of the ACE inhibitors are enhanced when these agents are combined with a diuretic. Captopril and enalapril have been shown to be of particular benefits as adjunctive therapy in patients with congestive heart failure, both in terms of subjective improvement of patient symptoms, and in improving overall hemodynamic status.(ABSTRACT TRUNCATED AT 400 WORDS)

Evaluation of the effects of multiple-dose activated charcoal on the absorption of orally administered salicylate in a simulated toxic ingestion model.

The effects of multiple-dose activated charcoal administration on the absorption of orally administered salicylate were evaluated in a simulated overdose model. Thirteen adult volunteers were each given 24 81-mg aspirin tablets during a control phase, and during three randomized treatment periods the volunteers received 50 g activated charcoal for one, two, or three doses (separated by four hours). The control phase and treatment periods were separated by a one-week interval. Urine was collected for 48 hours to determine percent total salicylate excretion. Ten subjects completed all four phases of the study. Mean +/- SD percent recovery of salicylate from urine was: control, 91.0 +/- 6.12; one-dose charcoal, 68.3 +/- 12.46; two-dose charcoal, 65.9 +/- 13.48; and three-dose charcoal, 49.2 +/- 12.48. Each charcoal treatment significantly lowered the absorption of aspirin as compared with the control (P less than .01). There was no significant difference between one-dose and two-dose charcoal regimens. There was a statistically significant decrease in salicylate absorption with the three-dose charcoal regimen as compared to one-dose and two-dose regimens (P less than .01). We conclude that activated charcoal is effective in inhibiting absorption of orally administered salicylate, in a small-dose aspirin ingestion model, with a three-dose multiple charcoal regimen being superior to either single-dose or two-dose regimens.

DPI 201-106 for severe congestive heart failure.

DPI 201-106 is a new oral inotropic agent that exerts its effects through a novel mechanism of action, namely, by enhancing sensitivity of myofilaments to calcium and prolonging inward sodium current. In a double-blind, randomized, placebo-controlled fashion, single oral doses (80 and 100 mg) of DPI 201-106 were administered to 15 patients with severe congestive heart failure. Dose-dependent increases in cardiac index (25%, p = 0.016), left ventricular stroke work index (24%, p = 0.018), left ventricular stroke volume index (32%,p = 0.005) and QTc interval (7%, p = 0.009) were observed. Significant effects on heart rate and systemic arterial pressure were not observed. Positive correlations of QTc interval with DPI plasma level (r = 0.64, p = 0.0001), stroke work index (r = 0.47, p = 0.0001) and ventricular ectopic activity on ambulatory electrocardiography (r = 0.49, p = 0.0001) were observed. Maximum changes occurred approximately 3 to 4 hours after ingestion and lasted more than 8 hours. Plasma drug levels were consistent with a 2-compartment model exhibiting first-order absorption and elimination kinetics. DPI 201-106 produced hemodynamic improvement in patients with severe congestive heart failure.

Pharmacist participation in the management of incidents involving hazardous materials.

The role of the pharmacist as a hazardous materials consultant is described. Pharmacists in a university-affiliated teaching hospital are contacted by either emergency medical services or the emergency department to assist in the management of incidents involving toxic hazardous materials. These incidents can range from major chemical spills or leaks to long-term exposures involving generalized, nonspecific symptoms. An advanced pharmacy resident in emergency medicine is the primary pharmacy contact for hazardous materials consults. The services provided by the clinical pharmacist include identification of the hazardous materials involved, initiation of special precautions for rescue-squad and hospital-based personnel, clinical assessment of the toxicologic problem, and formulation of therapeutic recommendations. Teaching programs have been developed for pharmacy, nursing, and medical students, hospital employees, and emergency-response agencies. Pharmacy participation in the management of hazardous materials incidents has been well received by emergency department physicians and nurses, as well as by rescue personnel. During the period between January 1 and July 1, 1986, the pharmacy was consulted on 66 hazardous materials incidents. Since pharmacists have traditionally been used as information resources for clinical toxicology questions, it follows that their participation can extend into the field of environmental toxicology, specifically involving hazardous materials. The pharmacist's input as a hazardous materials consultant in our institution has been well received, and we believe that pharmacy departments can play an important role in the management of incidents involving hazardous materials.

Combination dihydroergotamine mesylate and heparin sodium with lidocaine HCl. Pharmacokinetics, mechanism of action, clinical efficacy, and adverse effects.

Dihydroergotamine(DHE)-heparin combination offers a unique treatment modality for the prevention of deep vein thrombosis. The combination appears to affect all 3 limbs of Virchow's triad: hypercoagulability, venous stasis, and endothelial damage. In most efficacy studies, data indicated that the combination of DHE 0.5 mg and heparin 5000 IU was superior to low-dose heparin alone. Even when the efficacy of DHE-heparin was the same as that of heparin alone, the use of the combination allowed for a decrease in the heparin dose required.