Marcus M. Reidenberg

Adverse nondrug reactions.

Abstract Healthy university students and hospital staff taking no medications were surveyed by questionnaire to obtain data on the occurrence of many symptoms often listed as side effects of drugs....

Relationship between diazepam dose, plasma level, age, and central nervous system depression

Patients undergoing elective cardioversion for treatment of arrhythmias were premedicated with diazepam. The dose was individualized to achieve a degree of central nervous system (CNS) depression characterized by response to painful but not vocal stimulation. Promptly following each cardioversion, blood was drawn and the plasma diazepam concentration was measured by gas chromatography. The plasma levels varied as widely as the diazepam doses so that there was no fixed plasma level of diazepam associated with the degree of CNS depression produced in these patients. However, both the dose of diazepam and the resulting plasma level were inversely correlated to age, indicating that age is a critical factor in the use of diazepam for cardioversion premedication; elderly are more sensitive to the depressant effects of this drug than the young.

Polymorphic acetylation of procainamide in man

N‐Acetylprocainamide (NAPA) and procainamide plasma and urine concentrations were determined by thin‐layer chromatography (TLC) densitometry in people of known acetylator phenotype (dapsone phenotyping) taking procainamide for more than 3 days. The plasma NAPA / procainamide ratio 3 hr after the last dose for fast acetylators (mean ± SD) is 1.8 ± 0.59 (N = 8) and for slow acetylators, 0.61 ± 0.09 (N = 6)(p < 0.001). The renal clearance of NAPA averaged 1.2 times the simultaneously measured endogenous creatinine clearance, whereas procainamide clearance was approximately double the creatinine clearance. There was no difference between slow and rapid acetylators in the renal clearance of either drug or the urine pH, indicating that the difference in plasma NAPA /procainamide ratios between these two groups is due to differences in their rates of acetylation. Therefore, procainamide is probably acetylated by the polymorphic N‐acetyltransferase in man. Reflecting the blood level differences, the NAPA/procainamide ratio in urine (collected 90 to 180 min after last dose) was found to be higher in rapid than in slow acetylators. The plasma protein binding of NAPA and of procainamide are similar. Since NAPA seems to have an antiarrhythmic potency similar to procainamide, NAP A probably contributes to the antiarrhythmic activity of procainamide therapy, especially in genetic rapid acetylators.

INFLUENCE OF DISEASE ON BINDING OF DRUGS TO PLASMA PROTEINS

The idea of a “therapeutic plasma concentration” of a drug is becoming increasingly important in regulating therapy. One problem in interpreting measurements of plasma concentrations of drugs is the evaluation of potential changes in protein binding caused by disease. Although the intensity of a drug’s action is believed to be related to its concentration in plasma water, our present analytical techniques measure this amount plus the drug bound to plasma proteins. Therefore, if drug binding is altered by a disease, the usual value for therapeutic plasma concentration would have to be modified for the usual therapeutic concentration of drug in plasma water to be achieved.

Hydralazine elimination in man

The metabolism of hydralazine has been studied in a series of experiments. The hydralazine plasma half‐life values in volunteers ranged from 2.2 to 7.8 hours in rapid acetylators and from 2.0 to 5.8 hours in slow acetylators. Plasma concentrations following intravenous administration were similar in slow and rapid acetylators, indicating similar volumes of distribution of hydralazine. Plasma concentrations of hydralaZine following oral administration were lower in rapid acetylators than in slow acetylators, indicating a difference in gut wall and liver “first pass” metabolism since it has been shown by Lesser and associates7 that the molecule is well absorbed. Patients with impaired renal function had higher plasma concentrations of hydralaZine at various times after an oral dose than those with normal renal function. The metabolism of hydralaZine includes nonenzymatic degradation to phthalazine at a rate of 0.07 p.g per milliliter per hour in plasma at 37° C. Phthalazine may be subsequently enzymatically metabolized as well as excreted. There is metabolism by the intestinal wall or liver during absorption or “first pass” that is related to genetic acetylator phenotype. There is further biotransformation as well as excretion of the acetylated metabolite. This “first pass” acetylation by the intestinal wall and liver represents a true detoxication mechanism for inactivating orally administered hydralazine. There is also an elimination process that is unrelated to acetylator phenotype.

N-acetylprocainamide: an active metabolite of procainamide.

Summary N-Acetylprocainamide has been detected in the plasma samples of each of four patients receiving procainamide. The metabolite was identified from tlc data and its identity confirmed by gas chomatographic-mass spectroscopic analysis. The metabolite was also detected in the whole blood of Sprague-Dawley rats after administration of PA. NAPA · HCI when injected ip into 42- to 49- day-old ICR male mice prevented coarse ventricular fibrillation caused by deep chloroform anesthesia and resultant hypoxia. NAPA · HCl reduced aconitine-induced arrhythmia to atrial flutter or atrial tachycardia with varying degrees of A-V block in three dogs. Analysis by tlc indicated that the mice, dogs, and rats did not deacetylate NAPA during the period of pharmacologic testing. NAPA was found to cause less ferrihemoglobin in Sprague-Dawley rats than did PA.

Rate of drug metabolism in obese volunteers before and during starvation and in azotemic patients

Abstract The elimination of sulfisoxazole was studied to determine the effects of several clinical states on excretion and metabolism of drugs. Plasma and urine free sulfisoxazole and and urine total sulfisoxazole were measured at intervals after a 2.0-Gm. intravenous dose. Plasma half-life and the rates of metabolism and excretion of free drug were calculated from these values. Six healthy obese volunteers had a range of metabolism rates of 0.052–0.074 hr. −1 and excretion rates of 0.028–0.077 hr. −1 . Five of these were studied during a period of starvation ketoacidosis at which time excretion rates were decreased in all and metabolism rates were unchanged. Three of four patients with azotemia had low excretion rates and all had very low metabolism rates for this drug. We conclude that azotemic patients cannot metabolize some drugs at a normal rate and therefore may require lower than customary doses to avoid excessive cumulation.

The response of bone to metabolic acidosis in man.

Abstract A metabolic acidosis was produced in obese women by a fasting regimen with no caloric intake. The acidosis was then partially corrected by administering NaHCO 3 while continuing caloric starvation. During acidosis the net negative calcium balance was 156 mg. daily and during the alkali administration this calcium loss was reduced to 51 mg. daily. It was calculated that the anions lost from bone accompanying the calcium loss would combine with 4–8 mMoles H + daily and thus act as a buffer for the extracellular fluid during the acidosis.

Chronic morphine administration: Plasma levels and withdrawal syndrome in rats

Morphine, administered to Sprague-Dawley rats over a period of 65 hr either by the simultaneous implantation of two 75 mg pellets, or by a series of twice daily 20 or 30 mg/kg injections, produced dependence as indicated by the precipitation of the abstinence syndrome with the antagonist, naloxone. Plasma morphine levels, analyzed fluorometrically at various times during the treatment procedures, revealed peak concentrations that were 3 or 4 fold higher for injected animals than the maximum steady-state level established in the pellet-implanted animals. The calculated plasma concentration of the drug over time was not statistically different for the groups. It is noted that although the 2 methods of morphine administration produce a qualitatively identical dependent state, the pellet implantation technique causes greater weight loss and a higher incidence of jumping and wet-dog shakes during withdrawal.

Pentobarbital elimination in patients with poor renal function.

Drug oxidation is slowed in experimental uremia in animals but has been reported to be normal or accelerated in uremic patients. Eleven normal subjects and 9 uremic patients were each given 100 mg pentobarbital orally. Several blood samples were drawn over a 36‐hr period starting on the morning after the dose. Plasma pentobarbital concentration was measured by GLC. The log concentration values were graphed against time elapsed after dose for each patient, and the plasma T/2 and extrapolated value of concentration at the time of drug administration (Co) were determined. The T/2 values in normals ranged from 18 to 48 hr; mean, 26.5 ± 9.2 (SD). In uremic patients, T/2 values are 10 to 38 hr, mean, 21.3 ± 8.7. Four of the uremic patients had T/2 values below 18 hr (which was the lowest in the normals). The apparent volumes of distribution of pentobarbital (aVD = dose 7 Co) were 62 ± 25 L in the normal subjects and 58 ± 24 L in the uremic patients. The four uremic patients with the short T /2 values tended to have small apparent volumes of distribution so that the metabolic clearance rates (aVd x 0.693 ÷ half‐life) were normal in 3 of them. We conclude that pentobarbital elimination is normal in renal failure. Some uremic patients have short plasma T/2 values for pentobarbital, and these more likely result from low apparent volumes of distribution with normal metabolic clearance rates than from accelerated metabolism of pentobarbital.