Sotalol Intoxication,Two Patients with Concentration - Effect Relationships

Abstract Two adult patients ingested an overdose of 2.4 g and 8.0 g of sotalol hydrochloride, respectively, i.e. 7-25 times the mean daily dose. Certain signs as bradycardia and hypotension were similar to those described for other beta-blocking agents. In addition to these, however, both patients had severe cardiac tachyarrhythmias and a considerably prolonged QT-interval in their electrocardiogram. The decline of serum sotalol concentrations followed first-order kinetics with the elimination half-life of 13-15 hours. There was a good correlation between the serum sotalol concentration and the prolongation of the QT-interval. Sotalol differs from other beta-blocking agents in its effects on the action potential of the ventricular muscle and Purkinje fibers of the heart. This is likely to explain the different symptoms and findings of sotalol intoxication compared to those seen in connection with other beta-blocking agents.     

Sotalol intoxication, two patients with concentration-effect relationships.

Two adult patients ingested an overdose of 2.4 g and 8.0 g of sotalol hydrochloride, respectively, i.e. 7-25 times the mean daily dose. Certain signs as bradycardia and hypotension were similar to those described for other beta-blocking agents. In addition to these, however, both patients had severe cardiac tachyarrhythmias and a considerably prolonged QT-interval in their electrocardiogram. The decline of serum sotalol concentrations followed first-order kinetics with the elimination half-life of 13-15 hours. There was a good correlation between the serum sotalol concentration and the prolongation of the QT-interval. Sotalol differs from other beta-blocking agents in its effects on the action potential of the ventricular muscle and Purkinje fibers of the heart. This is likely to explain the different symptoms and findings of sotalol intoxication compared to those seen in connection with other beta-blocking agents.     

Single-dose kinetics of oral propranolol, metoprolol, atenolol, and sotalol: relation to lipophilicity

Nine healthy volunteers received single oral doses of the following four beta-adrenergic blocking agents: propranolol (160 mg), metoprolol (100 mg), atenolol (200 mg), and sotalol (320 mg). The kinetics of each drug were determined from multiple serum concentrations measured during 24-48 h after each dose, and in vitro lipid solubility determined using the liquid chromatographic (HPLC) retention index. Oral clearance for the four drugs ranged from 40.2 ml/min/kg for propranolol down to 2.1 for sotalol. Oral clearance was highly correlated (r = 0.99) with in vitro lipid solubility, with propranolol being the most lipophilic drug and sotalol the least. Thus lipophilicity is a physicochemical property of beta-adrenergic blockers that appears to influence their intrinsic clearance after oral dosage.     

Comparison of the activity and plasma levels of oxprenolol,slow release oxprenolol,long acting propranolol and sotalol

Summary Observations were made in 5 healthy subjects who exercised before and 1, 3, 6, 8 and 24 h after the oral administration on separate occasions of 160 mg oxprenolol, 160 mg slow release oxprenolol, 160 mg long acting propranolol and 400 mg sotalol. Blood samples were obtained before and at 1, 2, 3, 6, 8, 10 and 24 h after drug administration and assayed for drug concentration. Although the plasma concentration of oxprenolol after S. R. oxprenolol was significantly less at 1 and 2 h and significantly greater at 24 h than after conventional oxprenolol, there was little difference between the effects of the two drugs on an exercise tachycardia. The plasma level of propranolol and the reduction in an exercise tachycardia after L. A. propranolol increased slowly to reach a peak at 6 h and then declined gradually to 24 h. The maximum plasma concentration and effect after sotalol occurred at 3 h and then declined with an elimination half-life of 12.1 h. At 24 h the percentage reduction in an exercise tachycardia was 8.3±2.5 after oxprenolol, 10.0±2.3 after S. R. oxprenolol, 18.0±3.2 after L. A. propranolol and 14.7±3.4% after sotalol.     

Serum creatine phosphokinase levels during treatment with beta-adrenoreceptor blocking agents

We administered four beta-adrenoreceptor blocking agents--pindolol (15 mg/day), propranolol (60 mg/day), carteolol (15 mg/day), and labetalol (150 mg/day)--to essential hypertensive patients, and followed the changes in levels of serum creatine phosphokinase (CPK) and its isoenzymes for 1 year. Blood pressure was reduced almost equally by all drugs, but the changes in serum CPK levels differed. During treatment with pindolol, 20 of 25 patients showed a 20-760% increase in CPK compared with the pretreatment value. Studies on CPK isoenzymes revealed that the elevation was mainly in the skeletal muscle (MM type), while eight of the 25 patients also showed a slight increase in the myocardial type (MB type). Another beta-blocking agent with intrinsic sympathomimetic activity (ISA), carteolol, also increased the CPK levels significantly in 10 of 15 patients. On the other hand, such increases were observed in only four of 27 patients receiving propranolol and three of nine patients receiving labetalol. These results suggest that beta-blocking agents with ISA increase the serum CPK levels more frequently than those without ISA. Therefore, the serum CPK levels should be carefully evaluated in patients receiving beta-blocking agents, especially those with ISA.     

Interaction between sotalol and an antacid preparation

Aims The aim of the study was to investigate the pharmacokinetic interaction between sotalol and antacids, and its pharmacodynamic relevance. Methods In a randomized cross-over design with three treatment groups, six healthy volunteers received orally either 160 mg of sotalol alone (phase 1), or 160 mg sotalol plus 20 ml of a suspension of an antacid (MAH; magnesium hydroxide (1200 mg) and aluminium oxide (1800 mg)) (phase 2) or 160 mg sotalol plus the antacid given 2 h after sotalol administration (phase 3). Heart rate and plasma sotalol concentrations were measured before and 1, 2, 3, 4, 6, 8, 12 and 24 h after sotalol administration. Urinary sotalol excretion was measured for 24 h after sotalol application. Results C_max of sotalol decreased from 1.22±0.22 mg l⁻¹ (phase 1) to 0.89±0.29 mg l⁻¹ (phase 2) and increased again to 1.27±0.18 mg l⁻¹ in phase 3. A similar significant change was noted in AUC (15.6±2.75 mg l⁻¹ , 12.3±3.04 mg h l⁻¹ and 15.0±2.06 mg l⁻¹ ) and in the amount of cumulative urinary excretion (79.2±11.1 mg, 72.1±11.2 mg and 80.6±7.9 mg), respectively. t_max and elimination half-life (t_1/2,z) of sotalol remained unchanged in the presence of MAH. After combined administration with MAH, the area under the heart rate curve of sotalol was reduced between 0 and 4 h when compared across treatments. Conclusions Combined administration of sotalol and MAH decreased the serum sotalol levels. The interaction can be avoided by a two hour interval between application of these drugs.     

Effects of chlorpromazine on the disposition and beta-adrenergic blocking activity of propranolol in the dog

The effects of chlorpromazine (100mg p.o., 2hr before propranolol) on the disposition and beta-adrenergic blocking actions of both intravenous (6 mg) and oral (40 mg) propranolol were studied in the dog. Chlorpromazine pretreatment significantly reduced (69%) the oral clearance of propranolol, resulting in significant increases in propranolol bioavailability (159%), and in the total beta-adrenergic blocking activity (111%) after the oral dose. The increase in the total beta-adrenergic blocking activity of oral propranolol after chlorpromazine pretreatment was mostly due to an increased contribution from the parent compound; the apparent activity from active propranolol metabolites was not affected by chlorpromazine. Chlorpromazine pretreatment had no significant influence on the systemic clearance, elimination half-life, apparent volume of distribution, and plasma binding of propranolol, or on the apparent hepatic blood flow. After intravenous propranolol, chlorpromazine pretreatment had no effect on either the total amount of beta-adrenergic blocking activity or the amount of activity attributable to active metabolites. The decreased oral propranolol clearance by chlorpromazine was seen as a shift to the left in the propranolol dose vs. AUCrelationship, eliminating the apparent nonlinear kinetic behavior of oral propranolol, and reducing the apparent oral threshold dose. Chlorpromazine's major, if not only, effect on propranolol disposition was to reduce the presystemic elimination of propranolol, possibly through inhibition of its metabolism via a pathway other than ring oxidation.This work was supported by a US Public Health Grant No. HL-22718.     

A study of long acting propranolol in the early management of hyperthyroidism.

1 The effects of propranolol in its long acting formulation, 160 mg long acting (LA) propranolol, were assessed in a double-blind, controlled study of 20 hyperthyroid patients. Further observations with the addition of carbimazole were also made. 2 LA propranolol effectively improved the clinical manifestations of hyperthyroidism. 3 Plasma concentrations of total T4 and rT3 were increased, but total T3 did not fall significantly during LA propranolol treatment. 4 LA propranolol with carbimazole produced a greater reduction in the clinical indices of hyperthyroidism than carbimazole alone. 5 Total serum T4 and rT3 concentrations remained elevated with LA propranolol and carbimazole compared to carbimazole alone. 6 Carbimazole therapy for 2 weeks did not alter the mean plasma propranolol concentration. 7 We concluded that LA propranolol is effective in hyperthyroidism and its effects are similar to those reported by other workers with conventional propranolol. The clinical and biochemical effects of LA propranolol continue during concomitant carbimazole therapy.     

Interactions of beta-adrenoceptor antagonists and thyroid hormones in the control of heart rate in the dog.

Propranolol, sotalol and nadolol have been infused into conscious dogs, and doses at which the three drugs are equipotent as beta-adrenoceptor antagonists determined. In euthyroid dogs, sotalol was more effective at lowering heart-rate than an equivalent dose of propranolol, while an equivalent dose of nadolol was without effect. Hyperthyroidism potentiated the lowering of heart-rate by sotalol, but inhibited that by propranolol. The effect of sotalol on heart-rate was correlated with its prolongation of the Q-T interval of the ECG. That of propranolol was correlated with its prolongation of the P-R interval. Nadolol did not affect P-R interval or Q-T interval except at relatively high dosage. We conclude that the tachycardia of hyperthyroidism is not affected by blockade of beta-adrenoceptors and therefore that it is not mediated by adrenergic mechanisms. The effectiveness of propranolol and sotalol in lowering heart-rate must be due to actions peculiar to those drugs, and not to beta-adrenoceptor antagonism.     

Ethanol-induced inhibition of hepatic uptake of propranolol in perfused rat liver and in man

Summary Studies were conducted to determine the mechanism whereby ethanol alters the hepatic disposition of propranolol. In eight isolated perfused rat livers, ethanol ( =40.1 mmol/l diminished the clearance of dl-propranolol (1.93±0.43 to 1.24±0.22 ml/min/g liver, p<0.05); increased its t_1/2 (12.8±1.5 to 20.7±3.25 min, p<0.01); and decreased the proportion metabolized (68.7±4.7% to 34.3±10.3%, p<0.01). These results suggest that ethanol could substantially increase the oral bioavailability of propranolol in humans. However, in normal human volunteers administered 80 mg of propranolol orally, alone, or preceded and followed by ethanol to maintain breath ethanol concentrations of 800–1000 mg/l, increases in propranolol AUC were smaller than anticipated. Seven subjects had increases in free propranolol AUC_0–8h (32%, range: 12–61%) (p<0.05), while total propranolol AUC_0–8h increased by a mean 22% (range: –4–+49%). Propranolol free fraction varied with time and was higher after ethanol ( =0.090 vs 0.084) (p<0.077). The extent of the propranolol-induced slowing of heart rate was not influenced by ethanol (mean decrease from baseline of 13 bpm at peak propranolol effect vs 9 bpm without ethanol); mean heart rates following propranolol with ethanol were higher at all times (mean of 7.5 bpm) (p<0.001) than after propranolol alone. Ethanol inhibits the hepatic oxidative metabolism of propranolol in vitro; however, any effect on heart rate of higher concentrations of propranolol induced by ethanol in humans is off-set by the cardio-acceleratory effect of ethanol.     

Influence of hyperthyroidism on the kinetics of methimazole,propranolol, metoprolol and atenolol

Summary The kinetic profiles of oral methimazole 40mg, propranolol 80mg, metoprolol 100mg and atenolol 100mg were compared in hyperthyroid patients both during the hyper-and euthyroid states. For methimazole, neither the peak concentration (C_max), the time to reach peak concentration (t_max), the elimination half-life (t_1/2) nor the area under the curve (AUC) value was affected by the hyperthyroid state. For propranolol and metoprolol, which undergo extensive presystemic clearance, the AUC values were lower (p<0.02) when the patients were hyperthyroid than when they had become euthyroid, but the t_1/2's were not significantly altered. For atenolol, there were no significant kinetic differences between the hyperthyroid and euthyroid states. The findings are compatible with the assumption that hyperthyroidism does not affect the kinetics of methimazole or atenolol, but that it may enhance presystemic clearance of propranolol and metoprolol.     

β-Adrenoceptor antagonists: studies on behaviour (delayed differentiation) in the monkey (Macaca mulatta)

1 Activity of six β-adrenoceptor antagonists was studied on behavioural activity (delayed differentiation) in the monkey (Macaca mulatta). The drugs, three relatively lipophilic antagonists (propranolol, oxprenolol and metoprolol), and three relatively hydrophilic antagonists (acebutolol, atenolol and sotalol), were given by intraperitoneal injection (5 to 30 mg/kg).

2 With atenolol (25 to 30 mg/kg), total response time was increased, but there was no effect on the number of correct responses. With acebutolol (25 to 30 mg/kg), the number of correct responses was reduced, but there was no effect on total response time. With metoprolol (25 to 30 mg/kg), there was an increase in total response time and a decrease in the number of correct responses, and correct responses were decreased 4 h after injection over the whole dose range (5 to 30 mg/kg).

3 Some animals failed to respond or complete the task with 30 mg/kg oxprenolol, 25 mg/kg sotalol and 20 mg/kg propranolol. With 25 mg/kg oxprenolol, the total response time was increased and the number of correct responses was decreased. With 5-20 mg/kg sotalol, total response time was increased, but there was no effect on the number of correct responses. With 15 mg/kg of (±)-propranolol and its isomers, there were increases in total response time and decreases in correct responses.

4 The studies suggest that lipophilic antagonists, such as propranolol, oxprenolol and metoprolol, are likely to have, at least, effects on the central nervous system, while hydrophilic antagonists may modify the peripheral nervous system. In the dose-ranges studied, propranolol had the greatest, and atenolol and acebutolol had the least effects. Atenolol and acebutolol may prove to be particularly useful in man when disturbances of the nervous system are to be avoided.

     

5-Methoxy-N,N-dimethyltryptamine: Spinal cord and brainstem mediation of excitatory effects on acoustic startle

The effects of different doses (0.03, 0.06, 0.12, 0.25, 1.0, 2.0, 4.0, and 8.0 mg/kg body weight) of 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) were tested on the acoustic startle reflex in rats. Beginning at 0.12 mg/kg, 5-MeODMT increased startle monotonically up to the highest dose used. 5-MeODMT still increased startle in acutely decerebrate rats or when infused directly onto the spinal cord. The excitatory effects of a high systemic dose of 5-MeODMT were completely blocked by cinanserin, cyproheptadine, and propranolol, but not by parachlorophenylalanine, -methyl-p-tyrosine, haloperidol, sotalol, or phenoxybenzamine. The results were discussed in terms of a new theory, which suggests that stimulation of serotonin receptors in the spinal cord enhance startle whereas serotonin receptors in the forebrain inhibit startle.     

Clinical pharmacokinetics and endocrine disorders. Therapeutic implications

Endocrine disorders are common and produce widespread changes in cellular and organ function. Alterations in the sensitivity of patients with thyroid disorders to digoxin, anticoagulants and sedatives have been recognised for many years. Many of the recently documented kinetic alterations in endocrine patients are explicable on the basis of disease-induced changes in hepatic drug metabolism, protein binding and renal function. In hyperthyroidism the rate of absorption of paracetamol, propranolol and oxazepam is increased due to increased gastrointestinal motility. The volume of distribution of propranolol and digoxin is increased and there is decreased binding of both basic and acidic drugs as a consequence of alterations in alpha 1-acid glycoprotein and albumin concentration. The rate of glucuronidation of paracetamol and oxazepam is increased in hyperthyroidism. While oxidative metabolism of antipyrine, propranolol, metoprolol and theophylline is enhanced, the clearance of a number of other agents, including diazepam, warfarin, antithyroid drugs and phenytoin, is unaltered. The systemic clearance of propranolol is enhanced as a consequence of a 50% increase in liver blood flow. The rate of elimination of a number of endogenous substances, including cortisol, thyroid hormones and insulin, also appear to be enhanced. Hyperthyroidism has a variable effect on renal function, with a possible increase in digoxin elimination, but no effect on the clearance of renally excreted beta-blockers, atenolol, sotalol and nadolol. These kinetic changes suggest that individualization and higher than normal dosage of propranolol is necessary to control hyperthyroidism, and in thyrotoxic atrial fibrillation higher doses of digoxin or additional therapy with beta-blockers, or verapamil, may be indicated. The increased sensitivity of thyrotoxic patients to warfarin suggest care with dosage and frequent monitoring of response are warranted. Less information is available concerning hypothyroidism, but there is a general trend for decreased absorption of paracetamol and propranolol. In addition, the volume of distribution of digoxin is reduced, as is renal clearance. Limited studies suggest no alteration in the glucuronidation of oxazepam, but antipyrine clearance appears to be reduced. Steady-state propranolol concentrations are elevated in hypothyroidism and there appears to be a decreased metabolism of thyroid hormones and cortisol. Preliminary information suggests the binding of propranolol is increased. Thus, in the treatment of hypothyroid patients, a lower dosage of propranolol may be required.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effects and plasma levels of propranolol and metoprolol in hyperthyroid patients

Summary The effects and plasma concentrations of different doses of propranolol and metoprolol were studied in 34 hyperthyroid patients. The initial daily doses were propranolol 160 mg or metoprolol 200 mg. If the resting heart rate remained above 75 beats per min after treatment for 4–7 days, the dose was increased and the patient re-examined after a further 4–7 days. Propranolol (n=17) caused a reduced heart rate, a decrease in serum 3,3,5-triiodothyronine (T3) and an increase in serum 3,3,5-triiodothyronine (reverse T3, rT3). In 10 patients, there was no change in T3 or rT3 until the daily dose of propranolol had been increased to 240 or 320 mg. The plasma level of propranolol was significantly correlated with the decrease in T3 and the increase in rT3. Metoprolol (n=17) caused a reduction in heart rate similar to that following propranolol. However, serum T3 was only slightly reduced even after an increase in dose to 300 or 400 mg, and serum rT3 was not altered. Metoprolol concentrations were not significantly correlated with the fall in T3. It appears that the influence of-blockers on T4 conversion is of little importance for the clinical improvement in hyperthyroid patients, and rather it is a consequence of ₁-adrenergic blockade interfering with the effect of T3. In addition, the findings support the assumption that therapeutic failure with-blockers in hyperthyroidism may be due to suboptimal treatment, and that individualized dosage is necessary.     

Effects of myricetin on the bioavailability of doxorubicin for oral drug delivery in Rats: Possible role of CYP3A4 and P-glycoprotein inhibition by myricetin

The purpose of this study was to investigate the effect of oral myricetin on the bioavailability and pharmacokinetics of orally and intravenously administered doxorubicin (DOX) in rats for oral delivery. The effect of myricetin on the P-glycoprotein (P-gp) and CYP3A4 activity was also evaluated. Myricetin inhibited CYP3A4 enzyme activity with 50% inhibition concentration of 7.8 μM. In addition, myricetin significantly enhanced the cellular accumulation of rhodamine 123 in MCF-7/ADR cells overexpressing P-gp. The pharmacokinetic parameters of DOX were determined in rats after oral (40 mg/kg) or intravenous (10 mg/kg) administration of DOX to rats in the presence and absence of myricetin (0.4, 2 or 10 mg/kg). Compared to the control group, myricetin significantly (p < 0.05, 2 mg/kg; p < 0.01, 10 mg/kg) increased the area under the plasma concentration-time curve (AUC, 51–117% greater) of oral DOX. Myricetin also significantly (p < 0.05, 2 mg/kg; p < 0.01, 10 mg/kg) increased the peak plasma concentration of DOX. Consequently, the absolute bioavailability of DOX was increased by myricetin compared to that in the control group, and the relative bioavailability of oral DOX was increased by 1.51- to 2.17-fold. The intravenous pharmacokinetics of DOX were not affected by the concurrent use of myricetin in contrast to the oral administration of DOX. Accordingly, the enhanced oral bioavailability in the presence of myricetin, while there was no significant change in the intravenous pharmacokinetics of DOX, could be mainly due to the increased intestinal absorption via P-gp inhibition by myricetin rather than to the reduced elimination of DOX. These results suggest that the increase in the oral bioavailability of DOX might be mainly attributed to enhanced absorption in the gastrointestinal tract via the inhibition of P-gp and to reduced first-pass metabolism of DOX due to inhibition of CYP3A in the small intestine and/or in the liver by myricetin.     

A comparative study of the pharmacokinetics of propranolol and its major metabolites in the rat after oral and vaginal administration

1. The concentrations of propranolol (PPL) and its metabolites were monitored by?h.p.l.c. in serum of rats during the first 6?h after administering single doses (20?mg/kg) of PPL either orally or intravaginally (i.vg).

2. The results showed that PPL was quickly transferred to the systemic circulation from the rat vagina and the serum concentration profile as substantially altered by the route of administration. Serum concentrations of free PPL were significantly higher in i.vg-dosed animals than their oral dosed counterparts.

3. Inter-animal serum conc. variations of PPL and its metabolites in the i.vg-dosed rats were smaller than those of the orally treated females.

4. In comparison with the i.vg-dosed rats, the levels of PPL metabolites (propranolol glycol, naphthoxylactic acid, naphthoxyacetic acid) were greater by the oral route, though these differences were not statistically significant.

5. The serum elimination half-lives (t_1/2)_β of PPL and its metabolites during the β-phase were not significantly different in the two treatment groups.

6. Following i.vg application, both the AUC and the C_max values of PPL were significantly greater than those of orally dosed females, while no statistically significant differences were found in the t_max values.

7. Comparison of the AUC values showed that relative bioavailability of PPL was approx. 36 times greater in i.vg-treated animals than those of the orally dosed rats.     

The haemodynamic effects of sotalol (MJ 1999) and propranolol in man

Summary In a dose of 40 mg, sotalol (MJ 1999) was more potent than 10 mg propranolol in blocking the cardiovascular effects of isoproterenol (5 healthy males, age 22–28 years). In a dose of 10 mg sotalol had weaker blocking properties. In a dose of 10 mg, propranolol under true basal conditions significantly decreased cardiac output (1.7 ± 0.34 1), stroke volume (31 ± 11 ml) and heart work (– 20 ± 7%), and increased the peripheral resistance (+35 ± 6%). Sotalol (10–40 mg i.v.) had no significant actions on cardiac output or any other cardiac function. There were statistically significant differences in the haemodynamic effects of sotalol and propranolol at doses producing a similar adrenergic -receptor blocking effect.This work was supported by grants from the Swedish State Medical Research Council (B69-14x-2546-01) and AB Bofors, Nobel-Pharma.For technical assistance we are indebted to Mrs. Anna-Greta Berggren and to Mrs. Anita Andersson.     

The effect of propranolol on the rise in plasma ammonia during modest exercise

Summary Changes in plasma ammonia in response to exercise with and without pretreatment with propranolol have been studied. A standardised submaximal treadmill exercise test was used to assess the effects of placebo or propranolol 40 mg, 80 mg, or 160 mg twice daily given in random order for 3 days, the last dose being taken 90 min before exercise. After placebo the mean incremental rise in plasma ammonia in response to exercise was 16 µmol·l^–1. The corresponding rise after propranolol 40mg was 56 µmol·l^–1 (p<0.01). All three doses of propranolol produced similar effects on plasma ammonia and exercise heart rates.     

Sublingual and oral isoxsuprine in patients with Raynaud's phenomenon

Summary Plasma propranolol steady-state concentrations (Css) were measured in 24 hyperthyroid and 6 hypothyroid patients before and after correction of the thyroid disorder. Following treatment of hyperthyroidism by surgery, antithyroid drugs or radioiodine, there was a significant rise in the plasma propranolol Css in patients receiving propranolol either 160 mg/day, 240 mg/day, or 480 mg/day. In addition, in five patients the area under the plasma propranolol concentration versus time curve during a dosing interval increased significantly from 405 ng/ml/h when hyperthyroid to 778 ng/ml/h when euthyroid. In the hypothyroid patients given propranolol 160 mg/day concomitantly with 1-thyroxine therapy the plasma propranolol Css fell significantly when euthyroid. There was a small but significant increase in the degree of plasma protein binding of propranolol, following treatment of hyperthyroidism and a significant decrease following correction of hypothyroidism. It is concluded that thyroid disorders markedly influence propranolol handling.