Single-dose and steady-state pharmacokinetics and pharmacodynamics of perindopril in hypertensive subjects.

In a double-blind, placebo-controlled, parallel group study, 24 essential hypertensive subjects were randomised to receive either placebo or 2, 4, or 8 mg perindopril. Perindopril, its deesterified metabolite, perindoprilat, and perindoprilat glucuronide were separated with an ion-exchange resin and determined by a radioimmunoassay (RIA). Pharmacokinetic and pharmacodynamic parameters were estimated for 96 h after the first dose and after 4-week once-daily treatment. Perindopril peak levels were achieved in less than or equal to 2 h after dosing with an elimination t1/2 of 1-2 h. Peak levels of perindoprilat were achieved more slowly, reaching a maximum level 5-8 h after dosing, and had an elimination t1/2 of 40 h. Levels of the perindopril glucuronide peaked approximately 0.5 h later than perindopril, with an elimination t1/2 of approximately 2 h. Perindopril, perindoprilat, and its glucuronide conjugate followed linear kinetics in the dose range of 2-8 mg, and there was no evidence of accumulation with chronic dosing. Perindopril 4 and 8 mg produced significant decreases in predose blood pressure (BP) with chronic dosing, with maximal decreases occurring 5-7 h after dosing. Perindopril also produced a prolonged dose-dependent inhibition of plasma angiotensin-converting enzyme (ACE) activity that was maximum after 4 h and had not fully recovered by 48 h after a single dose.

Pain management for the elderly.

Pain management for the elderly is based on the same principles as for all other age groups. There is no evidence that the elderly patient and the young patient perceive pain differently. Pain management should aim at achieving a specific diagnosis and a specific treatment with the appropriate choice of analgesic used in the optimal regimen and should give attention to all other factors contributing to the patient's suffering. Geriatric medicine uses an essentially multidisciplinary approach to treatment of medical problems, and this doctrine should apply to treatment of pain.

Effect of age on pharmacokinetics of and blood pressure responses to prazosin and terazosin.

Prazosin and terazosin are two alpha 1-adrenoceptor blocking agents, their principal difference being the longer half-life of terazosin. The present study was carried out to determine if elderly subjects are different from the young in their pharmacokinetic handling of these two drugs and if age influences the blood pressure response to each drug. Ten young healthy subjects (aged 19-30 years) and five older healthy subjects (aged 54-62 years) received 1 or 2 mg terazosin, 1 or 2 mg prazosin, or placebo 1 week apart according to a 5 X 5 Latin square design. Concentrations of prazosin and terazosin were measured using a high-performance liquid chromatographic procedure with a detection limit of approximately 0.25 ng/ml. Pharmacokinetic parameters of prazosin were virtually the same in both groups, whereas mean terazosin plasma concentrations were higher in the older group and pharmacokinetic analysis revealed higher peak plasma concentrations and a longer terminal elimination half-life. There was no evidence of increased sensitivity to the hypotensive action of the drug, as peak upright blood pressure falls were similar in the two groups. Symptoms of dizziness in the upright position were also less common. In view of their lack of sedative effects and minimal metabolic disturbances, further studies should be conducted to assess the suitability of these drugs as monotherapy for hypertension in elderly patients.

A pharmacokinetic study of carvedilol (BM 14.190) in elderly subjects: preliminary report.

This study in eight elderly male volunteers examined the pharmacokinetics of carvedilol following intravenous and oral administration of the drug. Blood pressure and pulse rate responses were also determined and compared with those to labetalol. Carvedilol was absorbed rapidly after oral administration with a bioavailability of approximately 45% and obeyed linear pharmacokinetics over the dose range 25-50 mg. The terminal elimination half-life varied between 5 and 14 h. Administration of the drug with food did not alter the bioavailability or kinetic handling of carvedilol. The hemodynamic responses to carvedilol followed the same pattern as those to labetalol. There was a rapid dose-related fall in blood pressure maximal after 4-5 h and disappearing by 12 hours. Tachycardia that was evident on placebo was inhibited by both drugs. Postural hypotension and dizziness were also apparent with both drugs.

The pharmacokinetics of captopril and captopril disulfide conjugates in uraemic patients on maintenance dialysis: comparison with patients with normal renal function.

We have measured the plasma concentrations of captopril and total disulfide conjugates of captopril after a 50 mg oral dose in 6 uraemic patients on maintenance dialysis and in 8 hypertensive subjects with normal renal function. The mean peak plasma concentration of captopril was 2.5 times higher (0.447 micrograms X ml-1 vs 0.181 micrograms X ml-1) and the concentrations of the disulfides 4 times higher (3.62 micrograms X ml-1 vs 0.924 micrograms X ml-1) in the uraemic patients. Moreover captopril disulfide conjugates in the uraemic subjects reached peak concentrations at 8 h after the dose and subsequently felt. The apparent plasma half-time was 46 +/- 19 h. Only 15% of these conjugates were removed by dialysis. This marked accumulation of captopril conjugates was associated with a sustained fall in both systolic and diastolic blood pressures. In uraemic patients the mean maximum reduction in systolic and diastolic blood pressures were 37 +/- 7 mmHg and 24 +/- 9 mmHg respectively, occurring 6 h after the dose, compared with 8 +/- 7 and 8 +/- 1 mmHg respectively at 30 min in normal renal function patients. These results are consistent with the results of animal experiments, which show that captopril disulfides can be converted back to free captopril and can contribute to the antihypertensive effect of the drug. They provide a reationale for reducing the dose and frequency of administration of captopril in patients with significant renal impairment.