Neostigmine kinetics and metabolism were studied after intracellular administration to 8 patients with myasthenia gravis. The plasma neostigmine level declined monoexponentially from 21 +/- 2 to 9 +/- 1 ng/ml between 30 and 120 min. The data were interpreted in terms of a 1-compartment model. Estimates of plasma half-life (t1/2) ranged from 51.1 to 90.5 min; apparent volume of distribution varied from 32.0 to 60.6 1; and total body clearance from 434 to 549 ml/min. Approximately 80% of the drug was eliminated in urine within 24 hr either as unchanged neostigmine or its metabolites. Approximately 50% of the dose was eliminated as the unchanged drug, 15% as 3-hydroxyphenyltrimethylammonium, and 15% as other unidentified metabolites. The neostigmine t1/2, based on the urinary excretion of the unchanged drug, ranged from 90.2 to 118.7 min. It was concluded that neostigmine was eliminated by renal and extrarenal mechanisms.

Half-Life↗

PubMed1980

Differential effects of myoneural blocking drugs on neuromuscular transmission.

The relationship between the depression in the amplitude of the compound muscle action potential and neuromuscular decrement (fade) was studied during the induction of non-depolarizing blockade, using a train of four supramaximal stimuli. Neuromuscular decrement (%) was defined as: [1 - (amplitude of fourth muscle action potential)/(amplitude of first muscle action potential)] x 100. When the amplitude of the first action potential was reduced by 50%, mean neuromuscular decrement increased in the order pancuronium < alcuronium < tubocurarine < frazadinium < gallamine. Similarly, the slope of the regression line relating the decrease in the amplitude of the action potential to decrement was least with pancuronium and greatest with gallamine. These results may reflect different affinities or intrinsic activities of the five drugs for prejunctional and postjunctional receptors. Thus, pancuronium may have a greater affinity for postsynaptic receptors, while tubocurarine and gallamine affect selectively the motor nerve terminal. It was confirmed that fazadinium had a more rapid onset on action than any of the other myoneural blocking drugs studied.

Action Potentials↗

PubMed1980

Plasma concentration and metabolism of phenoperidine in man.

The plasma concentrations of phenoperidine were measured in five patients during general anaesthesia. The concentration of the drug decreased rapidly between 2 and 40 min and then declined more slowly. Detectable concentrations of phenoperidine were present in plasma for at least 3 h. In the five patients, the distribution half-life of the drug ranged from 3.19 to 14.23 min and the elimination half-life from 47.31 to 162.30 min. Unchanged phenoperidine and two identified metabolites (pethidine and norpethidine) were present in urine.

Adjuvants, Anesthesia↗

PubMed1979

Pharmacokinetics and pharmacological effects of neostigmine in man.

1 The pharmacokinetics of neostigmine was studied in six patients during the reversal of neuromuscular block induced by tubocurarine chloride. The effect of the drug on neuromuscular function was simultaneously assessed by electromyography. 2 Neostigmine was rapidly eliminated from plasma after intravenous administration. The decline in the plasma concentration of the drug was invariably resolved into two exponential components. The fast disposition (distribution) half-life of the drug was invariably less than 1 min; the slow disposition (elimination) half-life ranged from 15.4--31.7 min. 3 Neostigmine usually increased the amplitude of the compound muscle action potential and diminished electromyographic decrement within 2 min of intravenous injection. The pharmacological effect of neostigmine was usually maximal between 7 and 15 min. There was an inverse relationship between the plasma concentration of the drug and the facilitation of neuromuscular transmission. 4 Red cell acetylcholinesterase activity was almost completely inhibited within 2--3 min of intravenous injection of neostigmine. Enzyme activity recovered to approximately 28% of control values by 30 min and to 55% by 60 min.

Acetylcholinesterase↗

PubMed1979

The relationship between the pharmacokinetics, cholinesterase inhibition and facilitation of twitch tension of the quaternary ammonium anticholinesterase drugs, neostigmine, pyridostigmine, edrophonium and 3-hydroxyphenyltrimethylammonium.

1 The relationship between the concentration of drug in plasma, the inhibition of erythrocyte acetylcholinesterase and the facilitation of neuromuscular transmission has been studied in the rat after the administration of neostigmine, pyridostigmine, edrophonium and 3-hydroxyphenyltrimethyl-ammonium (3-OH PTMA). 2 After the administration of neostigmine or pyridostigmine, acetylcholinesterase activity recovered only slowly due to the covalent nature of the inhibition. In contrast, recovery from the reversible inhibition caused by edrophonium or 3-OH PTMA was rapid and showed a direct relationship to the plasma concentration of these drugs. 3 There was a statistically significant linear correlation between the logarithm of the plasma concentration of the drugs and the increase in the tibialis twitch tension. 4 The relationship between the inhibition of acetylcholinesterase and the facilitation of neuromuscular transmission was complex. When the enzyme was less than 85% inhibited no facilitation occurred. Between 85% and 98% inhibition, facilitation was linearly related to enzyme inhibition. Above 98% inhibition, facilitation was unrelated to inhibition of the enzyme.

Acetylcholinesterase↗

PubMed1978

Clearance of neostigmine from the circulation during the antagonism of neuromuscular block.

The plasma concentration of neostigmine was measured in five patients during the antagonism of neuromuscular block. The concentration of the drug decreased rapidly between 2 and 5 min after administration, and then more slowly. Detectable concentrations of neostigmine were present in plasma after 60 min. In the five patients the distribution half-life of neostigmine was less than 1 min; the elimination half-life ranged from 15.4 to 30.1 min.

Adult↗

PubMed1978

Plasma clearance of neostigmine and pyridostigmine in the dog.

1 The pharmacokinetics of neostigmine and pyridostigmine was studied in conscious dogs by the use of a cross-over design. 2 Both neostigmine and pyridostigmine were cleared from plasma in a biexponential manner. 3 The apparent volume of distribution of pyridostigmine was invariably greater than that of neostigmine, and its fast disposition half-life was approximately three times longer. 4 The whole body clearance and the urinary elimination of pyridostigmine was approximately twice that of neostigmine. 5 The slow disposition half-life of pyridostigmine was approximately three times longer than that of neostigmine, suggesting that the longer duration of action of pyridostigmine is related to the differential clearance of the two quarternary amines from plasma.

Animals↗

PubMed1977

Labetalol in hypertension.

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Antihypertensive Agents↗

PubMed1977

Plasma pyridostigmine levels in patients with myasthenia gravis.

Plasma concentrations of pyridostigmine were measured in 7 patients with myasthenia gravis. Six subjects on oral pyridostigmine bromide were stabilized on widely different doses of the drug (60 to 660 mg/day). Nevertheless, the concentration of the quaternary amine in plasma was maintained within a relatively narrow range (usually between 20 and 60 ng/ml). In 3 myasthenic patients, the area under the plasma concentration-time curve was relatively constant for 4 hr after the same oral dose of pyridostigmine (60 mg). Despite this similarity, there were in general considerable interindividual differences in the bioavailability of pyridostigmine in myasthenic patients. In 1 subject, the bioavailability of the quaternary amine was increased sixfold by doubling the oral dose from 30 mg to 60 mg. After oral administration of pyridostigmine, the half-life of the drug in one subject (4.25 hr) was almost three times as great as after intramuscular administration in a different patient (1.49 hr).

Administration, Oral↗

PubMed1977

Plasma concentration of pyridostigmine and effects in myastenia gravis.

The relation between the plasma concentration of pyridostigmine and its effects was studied in 5 patients with myasthenia gravis. In 4 patients with typical electromyographic decrement in the adductor pollicis, there was a positive correlation between the concentration of pyridostigmine in plasma and the effect on neuromuscular transmission. The plasma concentration of pyridostigmine required to restore transmission to normal (as calculated from the regression line relating plasma concentration to neuromuscular function) varied over a 5-fold range, reflecting the variable severity of the disease. In another myasthenic patient with purely ocular symptoms, there was a significant correlation between the plasma concentration of the drug and the diameter of the palpebral fissure. It is suggested that the routine measurement of the plasma concentration of pyridostigmine may be of value in the management of myasthenia gravis. A method to calculate the optimal daily dose of pyridostigmine in individual myasthenic patients is described.

Blepharoptosis↗

PubMed1977

Plasma concentration and pharmacological effects of pyridostigmine in patients with myasthenia gravis [proceedings].

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Humans↗

PubMed1977

Renal clearance of pyridostigmine in patients with myasthenia gravis.

The urinary clearance of pyridostigmine was studied in six patients with myasthenia gravis. In three patients on pyridostigmine alone, renal clearance ranged from 349 to 481 ml/min, corresponding to a pyridostigmine:creatinine clearance ratio of 2.64 to 3.46. In a patient on bendrofluazide as well as pyridostigmine, a similar clearance ratio was observed. By contrast, the urinary clearance of pyridostigmine and the pyridostigmine:creatinine clearance ratio was reduced in two myasthenic patients concurrently treated with other basic drugs. It is suggested that these results may reflect competition for renal tubular excretion.

Adult↗

PubMed1977

Histochemical characteristics and contractile properties of the spinotrapezius muscle in the rat and the mouse.

In the spinotrapezius muscle of the rat and the mouse approximately equal proportions of A,B and C fibres are present. The spinotrapezius therefore contains a lower proportion of B fibres than are known to be present in soleus, but a higher proportion than in tibialis anterior. These results are consistent with the functional properties of the muscles, for the values for isometric twitch contraction time, the half relaxation time, and the twitch summation frequency of the spinotrapezius are also intermediate between those of soleus and tibialis anterior. The present experiments support the view that the proportion of B fibres to A and C fibres govern the overall functional characteristics of mammalian muscles.

Adenosine Triphosphatases↗

PubMed1976

A quantitative gas-liquid chromatographic method for the determination of neostigmine and pyridostigmine in human plasma.

A sensitive and selective analytical method was used to measure the concentration of neostigmine and pyridostigmine in human plasma. The procedure involved preliminary ion-pair extraction of the drugs into dichloromethane, followed by concentration and anlysis of the ion-pair complex using a gas-liquid chromatographic system fitted with a nitrogen detector. Using the peak area ratio technique, pyridostigmine bromide was used as the internal standard for the quantitation of neostigmine in plasma; neostigmine bromide was the internal marker for the determination of pyridostigmine. The method depends on the thermal dequaternisation of the quaternary amines, and can be used to detect 5 ng/ml in a 3-ml plasma sample. Accurate measurement can be made at levels of 50-1000 ng/ml. This assay procedure has been applied to the separate determination of the plasma concentration of neostigmine and pyridostigmine after single administration of intravenous doses in aneasthetised patients.

Chromatography, Gas↗