Plasma timolol levels and systolic time intervals

Clinical Pharmacology &#38 Therapeutics (Impact Factor: 7.9). 07/1980; 28(2):159-166. DOI: 10.1038/clpt.1980.145

ABSTRACT The -blocking potency of timolol was compared with that of propranolol under steady-state conditions in eight healthy subjects. The effects on systolic time intervals in healthy subjects and patients (n = 6) with coronary artery disease were evaluated in relation to varying timolol dose schedules and plasma concentrations. The -blocking potency was assessed by the inhibition of exercise-induced tachycardia. Timolol was eight times as potent as propranolol. There was wide between-patient variation (2.6 to 13.8) in timolol plasma concentration, and correlation between dose and peak (r = 0.61, p < 0.01) or nadir (r = 0.5, p < 0.01). There was a relatively weak correlation between timolol plasma concentration and degree of -blockade (r = 0.45, p < 0.05) and a linear correlation with dose (r = 0.98, p < 0.001). In healthy subjects timolol and propranolol had variable effects on systolic time intervals but in patients with coronary artery disease equipotent doses prolonged the preejection period, isovolumetric contraction time, and the ratio of the preejection period over the left ventricular ejection time. In patients as well as in normal subjects, the data indicated considerable -blocking effects for both drugs at the end of a 12-hourly dosing schedule, suggesting that twice-daily timolol and propranolol may be clinically practical.

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    ABSTRACT: It is a major goal of clinical pharmacology to understand the dose-effect relationship in therapeutics. Much progress towards this goal has been made in the last 2 decades through the development of pharmacokinetics as a discipline. The study of pharmacokinetics seeks to explain the time course of drug concentration in the body. Recognition of the crucial concepts of clearance and volume of distribution has provided an important link to the physiological determinants of drug disposition. Mathematical models of absorption, distribution, metabolism and elimination have been extensively applied, and generally their predictions agree remarkably well with actual observations. However, the time course of drug concentration cannot in itself predict the time course or magnitude of drug effect. When drug concentrations at the effect site have reached equilibrium and the response is constant, the concentration-effect relationship is known as pharmacodynamics. Mathematical models of pharmacodynamics have been used widely by pharmacologists to describe drug effects on isolated tissues. The crucial concepts of pharmacodynamics are potency — reflecting the sensitivity of the organ or tissue to a drug, and efficacy — describing the maximum response. These concepts have been embodied in a simple mathematical expression, the Emax model, which provides a practical tool for predicting drug response analogous to the compartmental model in pharmacokinetics for predicting drug concentration. The application of pharmacodynamics to the study of drug action in vivo requires the linking of pharmacokinetics and pharmacodynamics to predict firstly the dose-concentration, and then the concentration-effect relationship. This may be done directly by equating the concentration predicted by a pharmacokinetic model to the effect site concentration, but this simplistic approach is often not appropriate for various reasons, including delay in drug equilibrium with the receptor site, use of indirect measures of drug action, the presence of active metabolites, or homeostatic responses, thus often necessitating the use of more complex models. The relative pharmacodynamic bioavailability of different preparations of the same drug may be determined from the time course of a drug effect. Bioavailability determined in this way may differ markedly from bioavailability defined by measurements of drug concentration if active metabolites are formed or if effects are produced in the non-linear region of the concentration-effect relationship. The influence of changes in the extent of plasma protein binding may be important in the interpretation of drug concentration measurements since it is generally held that only the unbound fraction is pharmacologically active. Clear examples of this phenomenon are few, but this reflects the general paucity of adequate observations rather than casting doubt on the usual assumption. The design of rational dosing regimens for clinical therapeutics cannot be performed with a knowledge of pharmacokinelics alone. The time course of drug effect may be essentially independent of concentration when a dose produces near maximal effects throughout the dosing interval. If effects are between 20 and 80% of maximum, the response will decrease linearly even though concentrations are declining exponentially. Finally, at relatively small degrees of effect, the time course of drug effect and concentration will be in parallel. The usual ‘rule of thumb’ of dosing every half-life is a conservative strategy for limiting wide fluctuations in drug effect, but demands more from the patient in terms of dosing frequency than may be necessary to achieve consistent drug action. On the other hand, if therapeutic success is dependent more on cumulative response than moment to moment activity, the use of extended dosing intervals may markedly reduce the effectiveness of the same average dose. Considerations of these factors can be incorporated into a dosing scheme by combined application of the principles of pharmacokinelics and pharmacodynamics.
    Clinical Pharmacokinetics 12/1981; 6(6). DOI:10.2165/00003088-198106060-00002 · 5.05 Impact Factor
  • Article: Acebutolol
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    ABSTRACT: Synopsis: Acebutolol1 is a cardioselective β-adrenoceptor blocking drug possessing both partial agonist (intrinsic sympathomimetic) and membrane stabilising activity. In hypertension, it can be administered once or twice daily with equal effectiveness, and has been as effective at lowering blood pressure as propranolol, diuretics, and other β-blocking drugs (metoprolol, labetalol and atenolol) and more effective than methyldopa. Acebutolol has a significantly smaller effect on resting heart rate than propranolol, metoprolol and atenolol, although direct comparisons with drugs with intrinsic sympathomimetic activity have yet to be undertaken. In both angina and arrhythmia, when administered twice daily it has been as effective as standard therapeutic agents. The side effect profile of acebutolol appears to be comparable to that of other cardioselective β-blockers. Its relative cardioselectivity, partial agonist and membrane stabilising activity, hydrophilicity, and considerable extrarenal excretion may offer advantages over some β-blocking drugs in specific patients. Choosing a β-blocking agent, however, should be made with a knowledge of pharmacodynamic and pharmacokinetic properties of the various agents and careful consideration of how such properties may be of benefit to an individual patient. Pharmacodynamic Studies: In studies using standard animal models, acebutolol has been shown to be a relatively cardioselective β-adrenoceptor blocking drug with partial agonist (intrinsic sympathomimetic) and some membrane stabilising properties. In pharmacodynamic studies in animals and in humans, the relative β-blocking potency of acebutolol was approximately one-fifth to one-tenth that of propranolol, but oral dose ratios used in therapeutic studies using dose titration in individual patients suggest that acebutolol is about one-third as potent as propranolol. As with other β-blocking drugs, acebutolol usually lowers both resting and exercise heart rates. However, significantly greater decreases in resting heart rate are observed after propranolol than after acebutolol in comparative studies, a difference attributable to acebutololβs partial agonist activity. Similarly, acebutolol has a less marked effect on peripheral vascular resistance. A mild myocardial depressant action is seen, but less pronounced than that seen with equipotent doses of propranolol. Electrophysiological effects of acebutolol are similar to those seen with propranolol — a slowing of conduction and increased atrioventricular node refractoriness. Acebutolol does not affect sinus node recovery time, atrial or ventricular effective refractory periods, or HV conduction time. However, these properties have not been directly compared with drugs with intrinsic sympathomimetic activity, such as pindolol or alprenolol. Acebutolol is relatively hydrophilic and penetrates the central nervous system to a lesser degree than propranolol (which is lipophilic) and has no measurable effect on human psychomotor performance. Acebutolol does not exert deleterious metabolic effects in healthy subjects but, as in the case of other β-blockers, acebutolol may increase the hypoglycaemic effect of insulin in diabetics but does not appear to increase the risk of loss of consciousness developing in the wake of hypoglycaemia. The major metabolite of acebutolol, diacetolol, possesses a similar pharmacodynamic profile as the parent compound, but it may be more selective and has a longer duration of action. Pharmacokinetic Studies: Acebutolol is 100% bioavailable, appears to be unaltered by the presence of food in the gut, and is rapidly absorbed, with peak plasma concentrations being reached within 2 to 4 hours. There is evidence of dose proportional increases in plasma acebutolol concentrations over a dose range of 200 to 400mg; non-linearity has been observed at higher doses. It is weakly bound to plasma proteins but erythrocyte binding is somewhat greater. The plasma elimination half-life is about 3 to 4 hours, but terminal elimination half-lives of 8 and 11 hours have been reported. The plasma elimination half-life of diacetolol, acebutolol’s major metabolite, is greater than 12 hours. More than 50% of an oral dose is recovered in the faeces in equal portions of acebutolol and diacetolol, the rest being recovered in the urine predominantly as diacetolol. The elimination of acebutolol is not adversely affected by renal dysfunction, although there is a 2- to 3-fold increase in the half-life of diacetolol. Acebutolol is readily dialysed. Acebutolol is efficiently transported across the placenta with possible uptake by the fetus. Breast milk concentrations are several times higher than that found in plasma. Acebutolol used during pregnancy may be associated with reduced neonatal blood pressure and heart rate; birthweight may be decreased but to a lesser extent than after β-blockers without partial agonist activity. In common with other β-blockers, acebutolol plasma concentrations show wide inter-individual variation, and poor correlation with associated β-blockade and long term clinical effects. Individual dosage must therefore be titrated based on the clinical response of the patient. Therapeutic Trials: In hypertension, several large scale open studies (366 to 1893 patients) have shown once or twice daily acebutolol (400 to 1200 mg/day) to be an effective and well tolerated antihypertensive agent. In well-designed studies, individually titrated doses of acebutolol were clearly superior to placebo and equally as effective as titrated doses of propranolol and diuretics in reducing blood pressure. Acebutolol 400 to 800 mg/day was more effective than usual doses of methyldopa (0.5 to 1 g/day), and was better tolerated. Acebutolol was as effective as atenolol and metoprolol and less effective, but not significantly so, than labetalol. Age, race or renal dysfunction did not alter the antihypertensive response of acebutolol. With long term use (1 year or longer), antihypertensive efficacy is well maintained without a progressive reduction in heart rate. Combining acebutolol with small doses of diuretic results in greater reduction in blood pressure than with either therapy alone. Combination of low dose acebutolol (200mg) and hydrochlorothiazide (12.5 to 25mg) as a once daily regimen also effectively reduced blood pressure and the adverse metabolic consequences of higher dose thiazide monotherapy. In controlled studies of patients with tangina pectoris, individually titrated doses (up to 400mg thrice daily) were clearly superior to a placebo and at least as effective as propranolol using such parameters as frequency of anginal attacks, glyceryl trinitrate (nitroglycerin) consumption, exercise performance, and ECG changes with exercise as end-points of efficacy. Acebutolol improved work capacity, as did nifedipine, with a significant additive effect when the two were combined. Over the long term, antianginal efficacy has been maintained for up to 5 years. In patients with arrhythmias, controlled studies have shown individually titrated doses up to 400mg three times daily to be superior to placebo and at least as effective as propranolol and quinidine in reducing the frequency and grade of premature ventricular contractions and ventricular ectopic beats on ambulatory recordings and during exercise. Antiarrhythmic efficacy has been well maintained for up to 1 year. Side Effects: Acebutolol has been generally well tolerated with those side effects reported being typical of β-blockers. However, as a result of its partial agonist activity, reductions in heart rate are less marked than seen with non-cardioselective propranolol and other cardioselective agents (metoprolol and atenolol); bradycardia (< 48 beats/min) is rarely seen. Most frequently reported side effects are fatigue, headache, gastrointestinal upset and dizziness. Acebutolol does not produce any consistent changes in laboratory parameters. Although some patients have developed antinuclear antibody titres, the incidence of associated clinical symptoms is rare, and when present, clear promptly upon discontinuing therapy. Dosage: The dosage of acebutolol is titrated to an optimum level in the individual patient according to clinical response. In hypertension, the initial starting dose is 400mg once daily which may be increased to 400mg three times daily. Most patients are controlled on 400 to 800 mg/day although higher doses or the addition of a second drug, i.e. a thiazide diuretic, may be necessary. In angina pectoris and ventricular arrhythmia, the usual initial dose is 400 mg/day in 2 divided doses increased gradually to optimum effect. Most patients respond to doses of 800 mg/day or less. In the presence of renal dysfunction, the daily dose should be halved if creatinine clearance is < 3 L/h and reduced by 75% when < 0.6 L/h.
    Drugs 06/1985; 29(6):531-569. DOI:10.2165/00003495-198529060-00003 · 4.34 Impact Factor
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    ABSTRACT: The degree of intrinsic sympathomimetic activity (ISA) is reported to influence the effects of beta blockade at rest, but the effects during exercise are not well documented. Heart rate, blood pressure and left ventricular (LV) function (as assessed by systolic time intervals) were measured at rest and during upright bicycle exercise as well as with flow-volume spirometry at rest in 13 healthy volunteers. The measurements were performed before and 4 and 24 hours after a single oral dose of pindolol (10 mg), nadolol (80 mg) and acebutolol (400 mg) in a double-blind, randomized, crossover manner. All drugs reduced heart rate, but nadolol had the most pronounced and longest bradycardic effect at rest. Diastolic blood pressure was only slightly influenced by the drugs, whereas systolic pressure was significantly lower compared with control values, especially during exercise (p less than 0.001). Neither preejection period (PEP) nor LV ejection time (LVETc) was changed at rest after pindolol, but PEP increased and LVETc decreased significantly after nadolol (p less than 0.05 for PEP and p less than 0.01 for LVETc) and acebutolol (p less than 0.05 for both). During exercise, PEP and LVET were significantly longer after all 3 drugs compared with control values. Only nadolol, which lacks ISA, significantly decreased expiratory flow values (p less than 0.05). Thus, unlike the other beta blockers, pindolol (with strong ISA) did not depress LV function at rest, while during exercise all 3 beta blockers had equal adverse effects. The degree of ISA appears to be important in determining the hemodynamic effects of beta-blocking drugs.
    The American Journal of Cardiology 07/1986; 57(15):1394-9. DOI:10.1016/0002-9149(86)90225-0 · 3.28 Impact Factor
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