D. W. G. Harron

Clinical Pharmacokinetics of β-Adrenoceptor Antagonists

SummaryThe β-adrenoceptor antagonists have been widely used clinically for over 20 years and their pharmacokinetics have been more thoroughly investigated than any other group of drugs. Their various lipid solubilities are associated with differences in absorption, distribution and excretion. All are adequately absorbed, and some like atenolol, Sotalol and nadolol which are poorly lipid-soluble are excreted unchanged in the urine, accumulating in renal failure but cleared normally in liver disease. The more lipid-soluble drugs are subject to variable metabolism in the liver, which may be influenced by age, phenotype, environment, disease and other drugs, leading to more variable plasma concentrations. Their clearance is reduced in liver disease but is generally unchanged in renal dysfunction.All the β-adrenoceptor antagonists reduce cardiac output and this may reduce hepatic clearance of highly extracted drugs. In addition, the metabolised drugs compete with other drugs for enzymatic biotransformation and the potential for interaction is great, but because of the high therapeutic index of β-adrenoceptor antagonists, any unexpected clinical effects are more likely to be due to changes in the kinetics of the other drug.Because satisfactory plasma concentration effect relationships have been difficult to establish for most clinical indications, and little dose-related toxicity is seen, plasma β-adrenoceptor antagonist concentration measurement is usually unnecessary.The investigation of the clinical pharmacokinetics of the β-adrenoceptor antagonists has added greatly to our theoretical and practical knowledge of pharmacokinetics and made some contribution to their better clinical use.

Pharmacokinetics of praziquantel in healthy volunteers and patients with schistosomiasis.

The pharmacokinetics of a novel praziquantel preparation (Distocide) were investigated in Sudanese patients with hepatosplenic schistosomiasis and in healthy volunteers, and compared with those of Biltricide. The results of the first study indicated greater (P less than 0.05) plasma concentrations of Biltricide at 1.5, 2, 3 and 5 h after administration than with Distocide; plasma elimination half-lives (t 1/2) were not significantly different. In patients with hepatosplenic schistosomiasis, higher plasma levels of Distocide were noted (P less than 0.05 at 8 h) compared to healthy controls; however, due to wide inter-individual variations, there were no significant differences in maximum plasma concentration, time to maximum plasma concentration, area under the plasma concentration curve (AUC), volume of distribution, or clearance; t 1/2 was greater (P less than 0.05) in patients (11.9 +/- 5.4 h) than controls (2.3 +/- 0.4 h). In the presence of food, higher plasma concentrations of Distocide occurred compared to the fasting state; AUCs were greater (P less than 0.01) in both food groups, although the values of t 1/2 were shorter. The lower plasma levels and longer duration of action of Distocide may be advantageous in reducing side effects and prolonging exposure of the schistosomes to the drug.

Resolution and Electrophysiological Effects of Mexiletine Enantiomers

Abstract— Resolution of mexiletine enantiomers from the racemic mixture has been achieved by fractional crystallization through the formation of diastereoisomeric p‐toluoyl tartrate salts. Following three crystallization steps in methanol, R‐(–)‐ and S‐(+)‐mexiletine were resolved with an optical purity > 98 % (yield ∼ 30%) and their hydrochloride salts formed. Incremental doses of mexiletine enantiomers were administered to dogs with experimentally‐induced arrhythmias to investigate the stereoselective antiarrhythmic and electrophysiological effects of these compounds. Using up to three extrastimuli, programmed electrical stimulation was performed in conscious animals 7–30 days after coronary ligation. R‐(–)‐Mexiletine prevented ventricular tachycardia in 3/6 dogs (2 after 0·5 mg kg−1, 1 after 8 mg kg−1); two animals died after 1 and 8 mg kg−1, respectively; one remained unchanged even at the highest dosage (16 mg kg−1). S‐(+)‐Mexiletine prevented ventricular tachycardia in only one dog (after 1 mg kg−1); two died after 4 and 8 mg kg−1, respectively; 2/5 remained unchanged even after the administration of 16 mg kg−1. No significant changes in any electrocardiographic intervals (PR, QRS, QTc) or refractory periods were induced by mexiletine enantiomers at any doses used (0·5–16·0 mg kg−1). These results suggest that R‐(–)‐mexiletine possesses greater antiarrhythmic properties than the opposite enantiomer.

Propafenone. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in the treatment of arrhythmias.

Propafenone is a Class I antiarrhythmic agent with weak beta-adrenoceptor antagonist activity which can be given both intravenously and orally. Dosage must be individualised because of dose-dependent pharmacokinetics, a wide range of clinically effective plasma concentrations (64 to 3271 micrograms/L) after comparable doses, the presence of an active metabolite (5-hydroxy-propafenone) and genetically determined metabolic oxidation. In non-comparative studies propafenone 450 and 900 mg/day orally significantly suppressed premature ventricular complexes and couplets in 96% and 75% of patients, respectively, and abolished ventricular tachycardia in 75% of patients. Efficacy was confirmed in placebo-controlled studies in which propafenone 300 to 900mg daily suppressed premature ventricular complexes (greater than 80%) in 77% of patients; 87% of patients had significant reductions in couplets and abolition of ventricular tachycardia. In patients with ventricular arrhythmias refractory to other antiarrhythmic agents, propafenone 450 to 1200 mg/day suppressed arrhythmias in 63% of patients (in long term therapy 66%). Electrically induced arrhythmias were prevented by intravenously administered propafenone in 12 to 23% of patients. However, long term oral therapy was effective in 77% of patients selected using programmed electrical stimulation. Propafenone was also effective in suppressing atrial and AV nodal/junctional re-entrant tachycardias and Wolff-Parkinson-White tachycardias involving accessory pathways. A limited number of comparisons with other antiarrhythmic drugs indicate that the antiarrhythmic efficacy of propafenone is superior or similar to that of quinidine, disopyramide and tocainide, and comparable to that of lignocaine (lidocaine), flecainide and metoprolol against ventricular arrhythmias and a smaller number of atrial arrhythmias. Cardiovascular side effects indicate a proarrhythmic effect similar to that with other Class I drugs, occasional precipitation of congestive heart failure and conduction abnormalities; the latter two occur more often in patients with underlying ventricular dysfunction. Non-cardiovascular side effects (neurological, gastrointestinal) are well tolerated and generally resolve with continued therapy or dosage reduction. Thus, propafenone is an effective antiarrhythmic agent, and is a useful addition to currently available drugs, although further studies will be required to determine clearly its place in therapy compared with more established antiarrhythmic drugs.

Cibenzoline. A review of its pharmacological properties and therapeutic potential in arrhythmias.

Cibenzoline is a class I antiarrhythmic drug with limited class III and IV activity which can be administered orally or intravenously. An elimination half-life of about 8 to 12 hours permits twice daily administration, although age and renal function must be considered when determining dosage. Cibenzoline has some activity in ventricular and supraventricular arrhythmias, including drug-refractory ventricular tachycardia or ventricular arrhythmias following recent acute myocardial infarction, although results in patients with sustained ventricular tachycardia are less promising. In comparative trials, cibenzoline has demonstrated efficacy similar to or better than that of a variety of other class I antiarrhythmic drugs and was at least as well tolerated, with a more convenient dosage schedule. However, further studies to clarify the proarrhythmic effects of cibenzoline and its use in patients with impaired left ventricular function are required, and the use of cibenzoline (and other class I antiarrhythmic agents) in patients with other than potentially lethal ventricular arrhythmias should be avoided following the results of the CAST studies. Thus, cibenzoline is an effective antiarrhythmic agent with a favourable pharmacokinetic profile that may be considered with other class I drugs in patients requiring therapy for high risk arrhythmias.

Effects on exercise tachycardia during forty-eight hours of a series of doses of atenolol, sotalol, and metoprolol.

Beta adrenoceptor blockers differ mainly in their plasma elimination half‐lifes (t½s). It has been assumed that drugs with longer t½s will have a longer duration of effect on exercise tachycardia. Several factors may influence the duration of action of beta blockers; we have investigated the contribution of plasma elimination t½ and dose by comparing the effects on an exercise tachycardia in healthy subjects of placebo, 25, 50, 100, and 200 mg of atenolol and of sotalol, and 50, 100, 200, and 400 mg metoprolol. Subjects exercized before and at 2, 3, 6, 8, 24, 33, and 48 hr after oral doses of each drug. Plasma samples for measurement of drug concentration were drawn before each exercise period. Twenty‐four hours after 50, 100, and 200 mg atenolol and 50, 100, 200, and 400 mg sotalol there were reductions in an exercise tachycardia; at this time reductions were greater after the larger doses. The plasma elimination t½s of atenolol were between 7.2 ± 1.2 and 9.1 ± 1.6 hr and for sotalol were 9.2 ± 0.7 and 10.1 ± 1.0 hr. Although 50, 100, and 200 mg metoprolol induced the same reductions in an exercise tachycardia 2 hr after drug as 25, 50, and 100 mg atenolol and 50, 100, and 200 mg sotalol, these doses were without effect at 24 hr. Metoprolol 400 mg reduced exercise tachycardia at 24 hr but the effect was less than that of the three largest doses of atenolol and sotalol. The plasma elimination t½ for metoprolol was between 3.6 ± 0.6 and 5.0 ± 1.8 hr. These results show that duration of cardiac beta blocking activity of atenolol, sotalol, and metoprolol is determined by the elimination t½ and dose.

The effects of rilmenidine on tests of autonomic function in humans

The effects of rilmenidine, a new centrally acting antihypertensive agent, on a number of tests of autonomic function were investigated in six healthy male volunteers. Baroreflex function (ΔRR interval [in milliseconds] with each millimeter of mercury change in systolic blood pressure) was determined in response to changes in pressure after injections of phenylephrine and nitroglycerin. Reflex cardiovascular responses to handgrip and standing, as well as during deep breathing and the Valsalva maneuver, were also investigated. Rilmenidine produced a dose‐dependent decrease in blood pressure that was not accompanied by an increase in heart rate. Under conditions of low basal sympathetic activity, rilmenidine enhanced parasympathetic tone during the early reflex heart rate changes that occur immediately after standing and during deep breathing, as well as baroreflex heart rate responses to phenylephrine. During a test of sympathetic function, standing blood pressure, and heart rate after 3 minutes, rilmenidine reduced sympathetic tone.

Haemodynamic and pharmacokinetic evaluation of alfuzosin in man. A dose ranging study and comparison with prazosin.

SummaryIn an open dose ranging study with random inclusion of placebo, alfuzosin (α1-adrenoceptor antagonist) 1, 2.5 and 5 mg was administered to 6 healthy volunteers, 3 of the volunteers received 10 mg alfuzosin.Supine systolic blood (SBP) pressure was not reduced by alfuzosin although significant increases occurred in supine heart rate (HR) after 2.5 and 5 mg. In the standing position, SBP was reduced at 2 and 4 h with 5 mg alfuzosin; significant increases in HR occurred following 1, 2.5 and 5 mg at 2, 4, 6 and 8 h after administration. Exercise SBP was not reduced; diastolic blood pressure was significantly reduced at 4 and 6 h with 5 mg alfuzosin. More marked effects were seen in the 3 subjects who received 10 mg alfuzosin. After 1 and 5 mg, tmax ranged from 1–2 h; Cmax (4.1 to 20.8 ng · ml−1; AUC (0–24) 20 to 132 ng · ml−1 · h (1 and 5 mg respectively) increased progressively with dose indicating dose dependent kinetics; no significant changes occurred in the visual analogue scale for sedation.A comparison of alfuzosin 5 mg, prazosin 1 mg and placebo each administered for 4 days, indicated that alfuzosin did not significantly reduce standing SBP on either Day 1 or Day 4; prazosin reduced SBP at 2 and 4 h on Day 1 and 6 h on Day 4 compared to placebo. Standing HR was increased by alfuzosin at 2 h on Day 1 and Day 4; increases occurred with prazosin at 2, 4, 6 and 8 h on Day 1 and 6 h on Day 4.Supine plasma noradrenaline increased with alfuzosin and prazosin at 2 and 4 h on Days 1 and 4; the increases were not significantly different. The plasma elimination half-life (t1/2) for alfuzosin was 3.4 h and 3.1 h after acute and chronic administration; (t1/2) for prazosin was 2.6 and 2.9 h.In conclusion alfuzosin causes small reductions in systolic blood pressure, accompanied by a dose dependent increase in heart rate in the supine and standing position and following exercise.

Alinidine reduces heart-rate without blockade of beta-adrenoceptors.

Alinidine is a new drug which reduces heart-rate in animals by an unknown mechanism. Oral administration of 40 and 80 mg significantly reduced an exercise tachycardia in healthy people, with small reductions in heart-rate in the standing and supine positions. Alinidine 80 mg reduced arterial pressure in the standing and supine positions. The reduction in exercise tachycardia produced by 80 mg alinidine was similar to that after 40 mg propranolol, but alinidine had no effect on an isoprenaline tachycardia. These observations indicate that alinidine reduces heart-rate without blocking beta-adrenoceptors and may be useful in patients with angina and in patients with tachyarrhythmias.

Effects of the myocardial‐selective α1‐adrenoceptor antagonist UK‐52046 and atenolol, alone and in combination, on experimental cardiac arrhythmias in dogs

1 Adrenaline‐induced arrhythmias in anaesthetized dogs respired with halothane were attenuated in 3 groups of 6 dogs by either UK‐52046, 3.8 ± 1.4μgkg−1 (mean ± s.e.mean), atenolol 14.6 ± 2.1 μgkg−1, or a combination containing equal amounts of the two drugs of 0.36 ± 0.1 μgkg−1. The pressor response to adrenaline was reduced (P < 0.01) by UK‐52046 but not by atenolol or the combination of both drugs. 2 In a group of 6 dogs with multiventricular ectopic beats 24 h after coronary artery ligation (CAL), UK‐52046, 32μgkg−1, increased the number of sinus beats in each 5min period from 137 ± 47 to 662 ± 99 (P < 0.01); this was associated with a significant (P < 0.01) fall in blood pressure. Atenolol in doses of up to 800μg kg−1 had no effect. 3 UK‐52046, 3.7 ± 1.4μgkg−1, prevented adrenaline‐induced arrhythmias 3–4 days after CAL in 6/6 conscious dogs; atenolol in doses of up to 100μgkg−1 produced an 84.4 ± 7.4% reduction in the number of ventricular ectopic beats. A combination containing 3.7 ± 1.1 μgkg−1 of each drug prevented the arrhythmia in 6/6 dogs. The pressor response to adrenaline was attenuated (P < 0.05) by UK‐52046, but resting blood pressure was unaffected by the different treatments. An increase (P < 0.01) in heart rate was associated with both UK‐52046 and the combination. 4 Neither UK‐52046 (doses up to 64μgkg−1) nor atenolol (up to 800μgkg−1) had any effect upon ouabain‐induced arrhythmias in 2 groups of 6 anaesthetized dogs. 5 In a study of the early (1a/1b) arrhythmias of acute myocardial ischaemia, the total number of ventricular ectopic beats occurring within 30min of CAL was not reduced by 4μgkg−1 UK‐52046 but fell (P < 0.01 compared with placebo) after 8μgkg−1 [median values with ranges for placebo, 4μgkg−1 and 8μgkg−1 respectively 190 (4–674), 246 (9–1204) and 12 (1–154)]. Both doses of UK‐52046 were associated with significant falls in blood pressure. 6 The arrhythmias produced by programmed electrical stimulation were studied in 2 groups of 6 conscious dogs, 7–30 days after CAL. With placebo, 4/6 dogs remained unchanged and 2 died: UK‐52046 prevented arrhythmias in 2/6, 2 remained unchanged and 2 died (P = 0.29). Compared with placebo, blood pressure fell with doses greater than 4μgkg−1. 7 These results indicate antiarrhythmic effects of UK‐52046 in a number of experimental models and suggest an enhanced role of α‐receptors in the genesis of ischaemia‐related arrhythmias. In several of the models used, UK‐52046 produced haemodynamic changes in keeping with peripheral α‐adrenoceptor antagonism.