Pharmacokinetics and pharmacodynamics of propranolol in hypertensive patients after sublingual administration: systemic availability.

The bioavailability of propranolol depends on the degree of liver metabolism. Orally but not intravenously administered propranolol is heavily metabolized. In the present study we assessed the pharmacokinetics and pharmacodynamics of sublingual propranolol. Fourteen severely hypertensive patients (diastolic blood pressure (DBP) > or = 115 mmHg), aged 40 to 66 years, were randomly chosen to receive a single dose of 40 mg propranolol hydrochloride by sublingual or peroral administration. Systolic (SBP) and diastolic (DBP) blood pressures, heart rate (HR) for pharmacodynamics and blood samples for noncompartmental pharmacokinetics were obtained at baseline and at 10, 20, 30, 60 and 120 min after the single dose. Significant reductions in BP and HR were obtained, but differences in these parameters were not observed when sublingual and peroral administrations were compared as follows: SBP (17 vs 18%, P = NS), DBP (14 vs 8%, P = NS) and HR (22 vs 28%, P = NS), respectively. The pharmacokinetic parameters obtained after sublingual or peroral drug administration were: peak plasma concentration (CMAX): 147 +/- 72 vs 41 +/- 12 ng/ml, P < 0.05; time to reach CMAX (TMAX): 34 +/- 18 vs 52 +/- 11 min, P < 0.05; biological half-life (t1/2b): 0.91 +/- 0.54 vs 2.41 +/- 1.16 h, P < 0.05; area under the curve (AUCT): 245 +/- 134 vs 79 +/- 54 ng h-1 ml-1, P < 0.05; total body clearance (CLT/F): 44 +/- 23 vs 26 +/- 12 ml min-1 kg-1, P = NS. Systemic availability measured by the AUCT ratio indicates that extension of bioavailability was increased 3 times by the sublingual route. Mouth paresthesia was the main adverse effect observed after sublingual administration. Sublingual propranolol administration showed a better pharmacokinetic profile and this route of administration may be an alternative for intravenous or oral administration.

Pharmacokinetics and pharmacodynamics of propranolol in hypertensive patients after sublingual administration: systemic availability

The bioavailability of propranolol depends on the degree of liver metabolism. Orally but not intravenously administered propranolol is heavily metabolized. In the present study we assessed the pharmacokinetics and pharmacodynamics of sublingual propranolol. Fourteen severely hypertensive patients (diastolic blood pressure (DBP) =115 mmHg), aged 40 to 66 years, were randomly chosen to receive a single dose of 40 mg propranolol hydrochloride by sublingual or peroral administration. Systolic (SBP) and diastolic (DBP) blood pressures, heart rate (HR) for pharmacodynamics and blood samples for noncompartmental pharmacokinetics were obtained at baseline and at 10,20,30,60 and 120 min after the single dose. Significant reductions in BP and HR were obtained, but differences in these parameters were not observed when sublingual and peroral administrations were compared as follows: SBP (17 vs 18 percent, P=NS), DBP (14 vs 8 percent, P=NS) and HR (22 vs 28 percent, P=NS), respectively. The pharmacokinetic parameters obtained after sublingual or peroral drug administration were: peak plasma concentration (CMAX): 147 + 72 vs 41 + 12 nl/ml, P<0.05; time to reach CMAX (TMAX): 34 + 18 vs 52 + 11 min, P<0.05; biological hall-life (t1/2b): 0.91 + 0.54 vs 2.41 + 1.16 h, P<0.05; area under the curve (AUCT): 245 + 134 vs 79 + 54 ng h(-1) ml(-1), P<0.05; total body clearance (CLT/F):44 + 23 vs 26 + 12 ml min(-1) kg(-1), P=NS. Systemic availability measured by the AUCT ratio indicates that extension of bioavailability was increased 3 times by the sublingual route. Mouth paresthesia was the main adverse effect observed after sublingual administration. Sublingual propranolol administration showed a better pharmacokinetic profile and this route of administration may be an alternative for intravenous or oral administration.

A simple and sensitive high-performance liquid chromatographic method to measure antipyrine and its metabolites in human urine

A method which permits the simultaneous HPLC analysis of antipyrine (A), 3-hydroxymethylantipyrine (HMA), 4-hydroxyantipyrine (HOA) and norantiopyrine (NORA) using a single extraction step in a five minute chromatographic run is described. Only 500 micraLitro of urine were necessary for the quantitation of all compounds investigated. An analog derivative, 4-aminoantipyrine, was used as internal standard (IS). Urine samples were hydrolyzed with Limpet acetone powder, 37 graus centigrados, pH 5.0 for 2 h. Sodium chloride was added and urine samples were extracted with diclhormethane-isopropyl alcohol (90:10, v/v) in acidic medium. The residue was dissolved with mobile phase, washed with n-hexane and 20 micralitro of the lower phase were injected into a 4-micron Nova-Pak (R) 'C IND. 18' column. Peaks monitored at 254 nm were eluted with 0.75 M sodium acetate buffer, pH 5.0: methanol, (70:30, v/v) as mobile phase. The method, validated on the basis of the confidence limits for antipyrine and its metabolites, presented good stability, sensitivity, linearity, and intra or interassay precisions lower than 5 percente for all commpounds were investigated. This assay was applied for drug metabolism study carried out in ten healthy volunteers: 23 about 5 yr and 63 about 10 kg(mean about SD) after p.o. single dose of antipyrine, 500 mg/capsule. Diuresis of 24 h up to 72 h of drug administration was preserved with sodium metabisulfite, 4 mg/mL. Biological fluids were stored at -20 centigrade degree until assay. The main hydroxy-metabolites (HMA + HOA) and NORA, minor N-demethylated metabolite of antipyrine, were excreted: 60 percent and 20 percente as percentage of the given dose, respectively. Clearances for production of metabolites expressed as mL/min, were: 8.61 about 4.28 (7.24) for HMA, 13.91 about 6.20(12.67) for HOA, and 8.08 about 4.01(5.93) for NORA, mean about SD (median).

Theophylline-ranitidine interaction in elderly COPD patients.

Most controlled studies in humans indicate that ranitidine does not alter theophylline metabolism, even at high doses. However, there have been several case reports published recently which demonstrate the development of theophylline toxicity mostly in older patients receiving stable oral doses of this drug when ranitidine was administered simultaneously. We studied eleven elderly (mean age, 69.0 +/- 6.2 years) patients with chronic obstructive pulmonary disease (COPD). During one week the patients took slow-release theophylline, 200 mg every 12 h, followed by one week intake of the same dose of theophylline plus ranitidine tablets, 150 mg every 12 h. At the end of each period, blood samples were obtained 0, 1, 2, 3, 4, 5, 6, 7, 8 and 12 h after the morning dose for the determination of serum theophylline levels. The peak theophylline concentration (Tmax) was achieved after 4.1 +/- 0.9 h while the patients were taking theophylline, and after 2.9 +/- 1.4 h with the combined regimen. This difference was statistically significant (P < 0.01). In only 3/11 subjects did Tmax remain unchanged during both phases of the study. The mean theophylline clearance rates while the patients were receiving theophylline alone (39.58 +/- 19.89 ml/min) and when they were receiving both medications (34.42 +/- 10.55 ml/min) were similar. The mean serum levels while the patients were receiving theophylline alone were slightly higher but not statistically different. These results suggest that the reported increases in serum theophylline levels in older patients receiving theophylline and ranitidine cannot be ascribed to slower theophylline metabolism in the geriatric patients with COPD who is also given ranitidine.

Theophylline-ranitidine interaction in elderly COPD patients

Most controlled studies in humans indicate that ranitidine does not alter theophylline metabolism, even at high doses. However, there have been several case reports published recently which demostrate the development of theophylline toxicity mostly in older patients receiving stable oral doses of this drug when ranitidine was administered simultaneously. We studied eleven elderly (mean age, 69,0 + or - 6.2 years) patients with chronic obstructive pulmonary disease (COPD). During one week the patients took slow-release theophylline, 200 mg every 12 h, followed by one week intake of the same dose of theophylline plus ranitidine tables, 150 mg every 12h. At the end of each period, blood samples were obtained 0,1,2,3,4,6,7,8 and 12h after the morning dose for the determination of serum theophylline levels. the peak theophylline concentration was achieved after 4.1 + or - 0.9 h while the patients were taking theophylline, and after 2.9 + or - 1.4 h with the combined regimen. This difference was statistically significant. These results suggest that the reported increases in serum theophylline levels in older patients receiving theophylline and ranitidine cannot be ascribed to slower theophylline metabolism in the geriatric patient with COPD who is also given ranitidine.

Simplified micromethod for the HPLC measurement of diclofenac in plasma.

A simple and sensitive micromethod based on HPLC is described for the measurement of diclofenac in 200 microliters plasma. A single extraction with dichloromethane in acidic medium was an essential clean-up step. Diclofenac and its internal standard (cyclohexendiphenyl propionic acid) was eluted at 3.3 and 6.5 min from a 4-micron C18 reverse-phase column using a mobile phase consisting of 0.75 M sodium acetate buffer, pH 5.0, and acetonitrile (55:45, v/v) at a flow rate of 0.9 ml/min with detection at 282 nm. The method, validated on the basis of parameters evaluated for the confidence limits of diclofenac measurements in spiked plasma, presented 1 ng/ml sensitivity, 10-10,000 ng/ml linearity, and 3.5% and 5.7% intra- and interassay precision, respectively. Peak plasma diclofenac levels ranging from 177 to 841 ng/ml and from 276 to 1008 ng/ml were obtained for two slow-release formulations. A wide range (1 ng/ml-3 micrograms/ml) was observed for plasma diclofenac levels of volunteers during a 24-h study period.

Ranitidine increases the bioavailability of nitrendipine in patients with arterial hypertension.

1. In a randomized placebo-controlled study, 12 hypertensive patients were treated po for one week with 20 mg nitrendipine once daily plus placebo, twice daily and later with the same dose of nitrendipine plus 300 mg ranitidine (150 mg twice a day). 2. When ranitidine was coadministered, plasma nitrendipine levels (0-24 h) were significantly increased (P < 0.001), although no significant increase in peak plasma nitrendipine level (Cmax) was observed due to the wide range of variation of this parameter (Cmax) in hypertensive patients. 3. Ranitidine coadministration increased the area under the curve for 24-h (AUC0-24) plasma concentration vs time, from 49.07 +/- 6.28 micrograms.h/l to 82.35 +/- 2.57 micrograms.h/l (P < 0.01). This significant increase caused a reduction in total body clearance from 2008.33 +/- 246.33 to 1284.00 +/- 182.16 ml/min (P < 0.002). 4. Nitrendipine bioavailability was increased by 89% when ranitidine was coadministered but the kinetic effect of this drug interaction is unlikely to be of clinical relevance since no adverse effects were observed in patients evaluated after ranitidine association.

Simplified micromethod for the HPLC measurement of diclofenac in plasma

A simple and senmsitive micromethod based on HPLC is described for the measurement of diclofenac in 200 ul plasma. A single extraction with dichlormethane in acidic medium was an essential clean-up step. Diclofenac and its internal standard (cyclohexendiphenyl propionic acid) were eluted at 3.3 and 6.5 min from a 4-micron C18 reverse-phase column using a mobile phase consisting of 0.75 M sodium acetate buffer, pH 5.0, and acetonitrile (55:45, v/v) at a flow rate of 0.9 ml/min with detection at 282 nm. The method, validated on the basis of parameters evaluated nfor the confidence limits of diclofenac measurements in spiked plasma, presented 1 ng/ml sensitivity, 10-10,000 ng/ml linearity, and 3.5% and 5.7% intra-and interassay precision, respectively. Peak plasma diclofenac levels ranging from 177 to 841 ng/ml and from 276 to 1008 ng/ml were obtained for two slow-release formulations. A wide range (1 ng/ml-3 ug/ml) was observed for plasma diclofenac levels of volunteers during a 24-h study period

Ranitidine increases the bioavailability of nitrendipine in patients with arterial hypertension

In a randomized placebo-controlled study, 12 hypertensive patients were treated po for one week with 20 mg nitrendipine once daily plus placebo, twice daily and later with the same dose of nitrendipine plus 300 mg ranitidine (150 mg twice a day). When ranitidine was coadministered, plasma nitrendipine levels (0-24 h) were significantly increased (P<0.001),although no significant increase in peak plasma nitrendipine level (C max) was observed due to the wide range of variation of this parameter (C max) in hypertensive patients. Ranitidine coadministration increased the area under the curve for 24-h (AUC 0-24) plasma concentration vs time, from 49.07 ñ 6.28 ug h/l to 82.35 ñ 2.57 ug h/l (P<0.01). This significant increase caused a reduction in total body clearance from 20008.33 ñ 246.33 to 1284.00 ñ 182.16 ml/min (P<0.002). Nitrendipine bioavailability weas increased by 89% when ranitidine was coadministered but the kinetic effect of this drug interaction is unikely to be of clinical relevance since no adverse effects were observed in patients evaluated after ranitidine association