Pharmacokinetic and pharmacodynamic studies with long‐acting propranolol.

Abstract

I The whole blood concentrations of propranolol have been compared, over a 48 h period, in twelve healthy male volunteers dosed with a 160 mg long-acting capsule formulation (LA, United Kingdom patent application No. 23114/77) and three standard tablet regimens; 160 mg once a day (CP 160), 80 mg twice a day (CP80) and 40 mg four times a day (CP40). 2 The mean peak blood level for the long-acting formulation was significantly lower than that obtained with the 160 mg standard tablet. However, from 12 h on the mean levels for the long-acting formulation were higher. 3 The mean peak blood level for the long-acting formulation was significantly lower than that obtained with the 80 mg twice a day regimen and this difference was maintained up to 24 h. Thereafter, however, the situation was reversed. 4 The mean blood levels between 12 and 15 h were lower for the long-acting formulation when compared with the 40 mg four times a day regimen. At all other times, however, the observed levels were very similar. SThe profiles achieved with the long-acting formulation in two separate studies were almost identical over a 48 h period. 6 The percentage reductions in exercise heart rate over the 3-24 h post dosing period were similar for the long-acting formulation and the two standard regimens studied (i.e. CP40 and CP80) when compared with placebo. 7 In the 2 h post dosing period the 80 mg twice a day regimen produced a significant reduction in the post-exercise systolic blood pressure when compared with the long-acting formulation.

Comparison of the efficacy and pharmacokinetics of conventional propranolol and a long acting preparation of propranolol.

“…Similar values were obtained by McAinsh et al (1978). These values probably do not reflect the correct rate of elimination of propranolol but result from a combination of absorption and elimination occurring over a much longer period than with conventional formulation.…”

“…Further support for such a view has recently been described (Harry & Shields, 1978). If propranolol is to be administered on a once daily regime to maintain cardiac fl-adrenoceptor blockade throughout a 24 h period, the conventional formulation (Inderal) would appear to be unsuitable as the present observations confirm that the effect of a single 160 mg dose had largely disappeared at 24 h. Studies with a new formulation of propranolol (Inderal L.A.) have shown that the peak blood level is lower, occurs later than with the same dose of the conventional formulation and that the level at 24 h is greater after L.A. propranolol (McAinsh et al, 1978). The present results confirm these observations and in particular show the marked differences in peak plasma levels produced by the two formulations and that the plasma level changed only by a factor of two between 3 and 24 h after the L.A. propranolol but with propranolol the 3 h value was 14.3 times the 24 h value.…”

“…These values are greater than some of those obtained in previous studies (Table 3) but similar values were described by Chidsey et al (1975) and McAinsh et al (1978). These differences may result from differences in the time interval over which the half-life determination was made.…”

“…Although several studies have shown that the plasma elimination half-life of propranolol is between 2 and 6 h, (Shand et al, 1970;Chidsey et al, 1975;McAinsh et al, 1978) little information is available about the duration of the P-adrenoceptor blocking reduction of an exercise tachycardia Shanks, 1977). Although the plasma elimination halflife of atenolol is shorter, about 6 h, it has a prolonged effect with an 18-25% reduction in an exercise tachycardia occurring 24 h after a 200 mg dose (Brown, Carruthers, Johnston, Kelly, McDevitt & Shanks, 1976).…”

“…A new formulation of propranolol consisting of a hard gelatin capsule filled with a multitude of small spherules of propranolol hydrochloride individually coated with a semi-permeable membrane to allow diffusion release of the drug in a controlled manner has been described (McAinsh, Baber, Smith & Young, 1978). Each capsule contains a total of 160 mg propranolol hydrochloride.…”