Knud Landmark

Antihypertensive and metabolic effects of long-term therapy with nifedipine slow-release tablets.

Sixteen nonhospitalized men. average age 41.3 years with essential hypertension (WHO I-II) were given nifedipine slow-release tablets of 20 mg twice daily for 48 weeks. Both supine and standing blood pressure values were significantly reduced, but heart rate was not significantly changed by the drug. A significant decrease in serum sodium and potassium was found. A slight increase in serum magnesium throughout the study became statistically significant at 48 weeks (p < 0.05). It is suggested that a possible diuretic activity, and the increase in magnesium, may add to the direct nifedipine-induced blood pressure reduction. Serum creatinine increased significantly after 24 and 48 weeks of nifedipine administration; serum urea, cholesterol, triglycerides. uric acid, and blood glucose remained essentially unchanged. Most of the patients had low plasma renin activity (PRA) in the control period, and nifedipine significantly increased PRA. Body weight was kept constant. Side effects were few and of no clinical significance. The slow-release preparation of nifedipine seems to be a potent and effective drug in treating essential hypertension of a mild to moderate degree.

The action of promazine and thioridazine in isolated rat atria. 1. Effects on automaticity, mechanical performance, refractoriness and excitability

Abstract The contractile force of spontaneously beating rat atria was recorded isometrically. Promazine (5 × 10−6 M to 5 × 10−5 M) and thioridazine (5 × 10−6 M to 10−4 M) produced a dose and time dependent decrease in the rate of contractions and work index; atrial arrest was observed in some experiments with the highest drug concentrations. Promazine and thioridazine increased the threshold current required to drive the atria and prolonged the effective refractory period since the maximum following frequency (m.f.f.) at which the atria could respond to stimulation was reduced. The drugs increased the threshold for experimentally induced atrial fibrillation. Promazine was in every respect the more potent compound. It is concluded that the changes in automaticity, refractoriness, conduction velocity and excitability caused by promazine and thioridazine can explain the anti-arrhythmic property of these phenothiazine derivatives.

Effects of N-acetylprocainamide as compared with procainamide in isolated rat atria

The actions of procainamide and its major metabolite N-acetylprocainamide were tested and compared on isolated rat atria. While procainamide exerted a negative chronotropic and iontropic effect, N-acetylprocainamide had the opposite effect. It is suggested that a N-acetylprocainamide-induced increase in myocardial work can counteract the negative inotropic action of procainamide and thus to some extent explain the variable results with the latter compound on myocardial performance reported from in vivo experiments. Procainamide increased the refractory period and reduced the excitability of isolated rat atria. N-acetylprocainamide, on the other hand, caused negligible effects on these parameters.

Pharmacokinetics of disopyramide in patients with imminent to moderate cardiac failure

SummaryThe parmacokinetics of disopyramide (DP) in 10 patients with imminent to moderate cardiac failure has been studied and compared with the results in normal volunteers. The biological half life of rapid distribution (T1/2 α) and of elimination (T1/2 β) were increased (11.1±4.4 min and 9.7±4.2 h, respectively). Total body clearance (Clt) was decreased (0.467±0.215 ml · min−1 · kg−1), and the volume of distribution (Vd) was slightly reduced (0.610±0.1361 · kg−1), probably due to the lower cardiac index. After oral administration, the time to peak serum concentration was increased (139±89 min), and the mean peak serum concentration (2.4±0.8% dose · 1−1) was also higher than reported in normal subjects. Comparison of the areas under the concentration versus time curves after intravenous and oral administration (AUC i. v. and AUC oral) showed that DP was almost completely absorbed, its bioavailability being 97.5±15.0%.

The action of promazine and thioridazine in isolated rat atria. 3. Effects of varying concentrations of calcium and different frequencies and strengths of stimulation on contractile force and excitability.

The effects of promazine and thioridazine on electrically stimulated left rat atria were studied in the presence of varying concentrations of calcium and at different frequencies and strengths of stimulation. An increase of the calcium concentration, [Ca2+]O, in the Ringer solution increased the force of contraction of the preparations. A slight decrease in excitability was found at [Ca2+]O above 4.0 meq/1. Suprathreshold stimulation (50 mA) produced a considerable increase in contractile force when [Ca2+]O was 2.0 meq/1, but on increasing the calcium concentration, this augmentation declined rapidly. On the basis of experiments with an adrenergic β-blocker, practolol, and atropine sulphate, it is concluded that suprathreshold stimulation releases noradrenaline as well as acetylcholine. The decrease in contractile force caused by promazine, 2.5 × 10−5 M, and thioridazine, 2.5 × 10−5 M, was, to a certain extent, antagonized by increasing the concentration of Ca2+. In atria stimulated at suprathreshold values, the results indicate that some sort of competition between Ca2+ and the phenothiazine derivatives may exist, and it is assumed that the drugs interfere with the exchangeability of calcium available for contraction. The decrease in excitability caused by promazine, 2.5 × 10−5 M, seemed to be independent of varying [Ca2+O. An increase in the frequency of contractions increased the threshold for electrical stimulation and reduced the contractile force (‘negative staircase’). Promazine, 2.5 × 10−5 M, enhanced these effects. It is concluded that the degree of the phenothiazine-induced reduction in contractile force of isolated rat atria depends upon the calcium concentration of the Ringer solution and also on the frequency and strength of stimulation.

Prolonged ventricular refractoriness and action potential duration after beta-adrenoreceptor blockade in the dog heart in situ.

Summary We studied the effects of three different β-adrenoreceptor-blocking drugs (atenolol, acebutolol, and propranolol) on the duration of monophasic action potentials and refractoriness of the right ventricular myocardium in closed-chest dogs. Pentobarbital anesthesia, which is known to increase the sympathetic tone, was used. Monophasic action potential recordings were obtained by the suction electrode technique, and refractoriness was measured by means of programmed electrical stimulation. A stepwise decrease in stimulation intervals from 350 to 300, 260, and 230 ms caused a progressive decrease in refractoriness as well as in the duration of the monophasic action potential. Intravenous injections of atenolol 0.5 mg/kg, acebutolol 2.0 mg/kg, and propranolol 0.5 mg/kg after pretreatment with atropine each increased the times for 50 and 90% repolarization of the monophasic action potential at each stimulation interval. The effective and the functional refractory periods paralleled the changes in the action potential duration in all experiments. We conclude that β-adrenoreceptor blockade in the presence of adrenergic receptor stimulation prolongs ventricular refractoriness and action potential duration, and that the presence or absence of cardiac selectivity or slight intrinsic sympathomimetic activity plays no role in this process. These results suggest that if the antiarrhythmic action of β-blocking drugs is due to prolongation of ventricular refractoriness, all types of these drugs may be expected to be equally effective as therapeutic agents.

A new sustained-release tablet formulation of procainamide

SummaryA new sustained-release tablet formulation of procainamide has been tested in 11 patients with chronic ventricular arrhythmias. At 6 h dosing intervals the fluctuations in plasma procainamide concentrations were equal to or less than those found after treatment at the 3 hourly intervals necessary with conventional tablets of Pronestyl®. It was concluded that the sustained release preparation ought to be more convenient for maintenance therapy with procainamide, as it permitted treatment at intervals of 6 h.

Infarct Size Is Reduced and the Frequency of Non-Q-Wave Myocardial Infarctions Is Increased in Patients Using Aspirin at the Onset of Symptoms

In an observational study we wanted to investigate whether ongoing use of aspirin in a cohort of 753 patients with acute myocardial infarction was able to (1) reduce infarct size as assessed by peak creatine kinase and lactate dehydrogenase, (2) increase the number of non-Q-wave myocardial infarctions, and (3) to what extent thrombolytic treatment at admission could modify these outcomes. We used an exposed (aspirin+)/nonexposed (aspirin–) cohort design, adjusting for the effects of confounders (age, previous coronary heart disease, current smoking, and the prior use of β-blockers and long-acting nitrates) as well as for the modifying effect of thrombolytic treatment. Crude and adjusted effects showed that aspirin reduced infarct size only in patients not receiving thrombolytic treatment at admission to hospital (n = 411 patients). In analyzing the occurrence of non-Q-wave versus Q-wave myocardial infarctions, the outcome was dichotomized. Crude odds ratio (OR) for developing a non-Q-wave myocardial infarction in aspirin users was 2.63 (2p < 0.001), in the restricted cohort of patients receiving thrombolytic treatment, OR was 3.46 (2p = 0.002), whereas in those not receiving such treatment, OR was 1.81 (2p = 0.007). Adjusting for the effects of confounders, retained aspirin was an independent predictor of non-Q-wave myocardial infarctions, an effect that was probably increased (from 51 to 128%) in those who received thrombolytic treatment. Thus, aspirin seems to produce a shift to less severe manifestations of myocardial infarction, an effect that was increased in patients given thrombolytic treatment at admission to hospital.

Choice of initial antihypertensive drugs and persistence of drug use--a 4-year follow-up of 78,453 incident users.

PurposeTo investigate patterns of initial drug therapy for the treatment of hypertension and to evaluate treatment persistence and change of treatment during a 4-year period in patients receiving thiazides (TZs) and/or angiotensin II-receptor blockers (ARBs) as first-line treatment.MethodsAll initial users of antihypertensive drugs in 2005 and 2009 registered in the Norwegian Prescription Database were included. Treatment on five index dates at 1-year intervals was recorded. A patient was considered to be under treatment on an index date if a drug had been dispensed within the previous 180 days and to have maintained treatment persistence if he/she was on any antihypertensive treatment on the index date and all previous index dates.ResultsAmong 78,453 new users of antihypertensives in 2005, women started more often with TZs than men (30 vs. 25 %) and less often with ARBs (22 vs. 25 %). In men, the hazard of non-persistence with antihypertensive treatment was significantly lower among initial ARB users than among TZ users (hazard ratio 0.87, 95 % confidence interval 0.81–0.94); in women no significant difference was found. After 4 years, 49 % of the men and 51 % of the women who had started with plain TZs were still using TZs, whereas 65 % of the male ARB users and 60 % of the female ARB users were still using ARBs.ConclusionTZs and ARBs were the most widely used first-line antihypertensives. Among the men enrolled in the study, ARB users had a somewhat better persistence with antihypertensive treatment than TZ users. Among both genders, continuation on ARBs was more common than continuation on TZs.

The action of promazine and thioridazine in isolated rat atria.2. Effects of varying concentrations of potassium and sodium on automaticity, mechanical performance, refractoriness and excitability

Isolated rat atria were suspended in a water-jacketed organ bath. An increase in the potassium concentrations, [K+]o, of the Ringer solution from 1.325 to 10.6 meq/1 had little effect on the spontaneous rate of atrial contractions, whereas the mechanical performance (work index) was depressed when [K+]o was raised above 5.3 meq/l. The threshold for electrical stimulation increased at potassium levels above 5.3 meq/l; the effective refractory period increased at potassium levels above 7.95 meq/l. Promazine, 2.5 × 10−5M, and thioridazine, 5 × 10−5M, reduced the rate and the work index, and these effects wer the threshold values and in effective refractory period caused by the two drugs were enhanced when [K+]o was raised. Replacement of 59.2 mM/l NaCl with equinolar concentrations of choline chloride did not change the spontaneous atrial rate nor the work index. The threshold values and effective refractory period were, however, increased. The decrease in atrial rate and work index caused by thioridazine, 5 × 10−5M, was not influenced by a reduction in [Na+]o. The drug induceded increase in the threshold for electrical stimulation and in the effective refractory period was potentiated in the presence of low [Na+]o. The results show that the effects of the phenothiazine derivatives on the electrical activity of isolated rat atria is accentuated by a decrease in [Na+]o and a rise in [K+]o, and conversely, counteracted by low [K+]o.