Effective treatment of verapamil intoxication with 4-aminopyridine in the cat.

To study the value of 4-aminopyridine as an antidote to verapamil intoxication, we subjected 12 adult cats to verapamil poisoning by administering doses of 4.0-25.0 mg/kg verapamil by intravenous infusion. Six animals were given 4-aminopyridine 2 X 0.5 mg/kg i.v. after the verapamil infusion was stopped and the other six animals (the control group) were not. Verapamil caused profound cardiovascular depression and also partial neuromuscular block, both of which were completely reversed by 4-aminopyridine within 50 min, in spite of extremely high serum verapamil concentrations (ranging between 3,700 and 13,500 ng/ml). The six animals that received 4-aminopyridine survived the verapamil intoxication, whereas four of the six animals in the control group died. The results suggest that 4-aminopyridine may be useful in the treatment of verapamil intoxication.

4-Aminopyridine kinetics.

Nine healthy subjects (7 men; 2 women) received single 20-mg IV injections of 4-aminopyridine (4-AP). Six of the subjects received the same dose in the form of enteric-coated tablets and four the same dose in uncoated tablets; treatments were at least 2 wk apart. Blood, saliva, and urine were assayed for 4-AP using a high-performance liquid chromatography. Kinetic analysis of serum concentrations after intravenous dosing resulted in the best fitting of a triexponential model in five and a biexponential model in four subjects. The apparent volume of distribution (V) was 2.6 +/- 0.9 (mean +/- SD) 1 kg-1, the terminal half-life (t 1/2) 3.6 +/- 0.9 hr, and the total serum clearance 0.61 +/- 0.14 1 hr-1 kg-1. Saliva concentrations were higher than those in serum after 5 min, with a mean correlation coefficient of 0.989 (n = 5). The t 1/2 and V calculated from serum and saliva concentrations were of the same order. The total urinary excretion of unchanged 4-AP was 90.6 +/- 7.8% after intravenous doses and 88.5 +/- 4.8% after oral doses of enteric-coated tablets. The bioavailability of the enteric-coated tablets calculated from the area under the serum concentration curve (95 +/- 29%) did not differ from that calculated from urinary excretion (98 +/- 8%). Protein binding of 4-AP was found to be negligible. Biotransformation is unlikely.

Clinical pharmacokinetics of neuromuscular blocking drugs.

Neuromuscular blocking agents provide muscle relaxation for a great variety of surgical procedures with light planes of general anaesthesia. Besides having a significant impact in the development of anaesthesia and surgery, these agents continue to play an important role as pharmacological tools in the elucidation of the physiological and pharmacological regulation of neuromuscular transmission and the morphofunctional organisation of the neuromuscular junction. In the daily practice of anaesthesia, muscle relaxants are considered to be safe drugs with predictable, straightforward pharmacological actions. However, the use of relaxants constitutes a deliberate encroachment on respiration, one of the most important physiological mechanisms. The pharmacokinetic behaviour of this class of agents is little influenced by age or anaesthetic agents; however, hepatic or renal disease may profoundly alter their excretion pattern, resulting in prolonged duration of neuromuscular blockade. Biotransformation plays an important role in the total elimination of recently introduced compounds. Consequently, knowledge of the disposition pharmacokinetics, excretion and biotransformation of this class of drugs is indispensable for their rational choice for various surgical procedures. In this review, the known pharmacokinetics of standard compounds (introduced before 1980) are briefly summarised and new information generated by the development of vecuronium, rocuronium, pipecuronium (steroidal agents) and atracurium, mivacurium, doxacurium (benzylisoquinolinium esters) is discussed in more detail.

Pharmacokinetics and neuromuscular blocking effects of atracurium besylate and two of its metabolites in patients with normal and impaired renal function.

The pharmacokinetics of atracurium, laudanosine and the quaternary alcohol were studied in patients with normal and impaired renal function following intravenous administration of atracurium. Anaesthesia consisted of thiopental, fentanyl, halothane and nitrous oxide in oxygen. Plasma and urine concentrations of the parent compound and its degradation products were measured by high performance liquid chromatography. Renal failure was defined as a creatinine clearance of less than 5 ml/min; it caused no significant differences in the pharmacokinetics of atracurium but did result in a different pharmacokinetic profile of laudanosine, with a 3-fold increase in the mean ( +/- SD) terminal half-life (176 +/- 84 and 516 +/- 262 minutes for patients with normal and impaired renal function, respectively). Moreover, the half-life of the quaternary alcohol increased from 27.1 +/- 8.3 minutes in patients with normal renal function to 42.5 +/- 8.3 minutes in those with impaired renal function (mean +/- SD). Renal elimination of unchanged atracurium accounted for 11% of the administered dose and at least 27% of the total degradation of atracurium occurred via ester hydrolysis. The neuromuscular function was monitored by measuring the twitch tension of the adductor pollicis muscle elicited by stimulation of the ulnar nerve at 0.1 Hz. The total duration of neuromuscular blockade (51.8 +/- 11.5 minutes) and the recovery index (9.6 +/- 2.0 minutes) are shortened in patients with impaired renal function, compared with those with normal renal function (64.1 +/- 7.2 and 16.7 +/- 4.1 minutes, respectively), indicating that sensitivity to the neuromuscular blocking action of atracurium may be altered by renal failure.

Pharmacokinetics of pancuronium in patients undergoing coronary artery surgery with and without low dose dopamine.

Pancuronium is frequently used in coronary artery surgery, but its pharmacokinetics in these patients are still unknown. It is possible that dopamine, administered to prevent renal impairment induced by the surgery, might promote the elimination of pancuronium. Therefore, the pharmacokinetics of a bolus dose of pancuronium were studied in 2 groups of coronary artery surgery patients, with and without dopamine 2 micrograms/kg/min, administered during and after cardiopulmonary bypass. Dopamine in the administered dose did not influence the systemic haemodynamics. The pharmacokinetic variables in both groups did not differ from those found in an earlier study in healthy normothermic patients. Total renal clearance was not influenced by dopamine, due to post-bypass rebound hyperperfusion in the control group. Pancuronium was shown to be subject to considerable tubular reabsorption, and its elimination was found to be increased during hypothermia. Dopamine increases pancuronium elimination by an increase in glomerular filtration rate. The dopamine-induced decrease in tubular solute reabsorption did not enhance the elimination of pancuronium.

A new method for studying the relationship between hepatic uptake of drugs and their pharmacodynamic effects in anaesthetized cats.

1 A new in vivo experimental method is described whereby the liver can be temporarily excluded from the general circulation by means of a portocaval shunt operation. The influence of this manoeuvre upon the effects of pancuronium and Org 6368 was investigated using the tibialis muscle preparation of anaesthetized cats. 2 The procedure also allowed intraportal injections of the drugs to be made so that the effect of first-passage uptake by the liver could be compared with hapatic exclusion in the same animal. 3 Hepatic exclusion greatly increased the duration of action of both drugs. Whereas intraportal injection did not significantly alter the effect of pancuronium on the tibialis muscle, the effect of Org 6368 was greatly diminished when given by this route. 4 The liver appears to tolerate short periods of hepatic exclusion and it is concluded that this technique may become a useful tool for studying the handling of drugs by this organ.

A method for studying the pharmacodynamic profile of neuromuscular blocking agents on vocal cord movements in anaesthetized cats.

1. A new in vivo experimental method is described whereby the neuromuscular blocking effects of muscle relaxants can be investigated on the intrinsic laryngeal muscles of anaesthetized cats. The peripheral tibialis anterior muscle preparation is employed in the same animal to compare the blocking effect on both preparations. 2. The intrinsic laryngeal muscles react with different sensitivities to the neuromuscular blocking agents when compared to the tibialis anterior muscle. 3. The neuromuscular response in both muscle preparations is similar with steroidal agents but appeared to be different after suxamethonium or isoquinoline analogues. 4. It is concluded that this preparation may become a useful tool for studying new muscle relaxants developed to facilitate rapid intubation conditions.

Reversal by suramin of neuromuscular block produced by pancuronium in the anaesthetized rat.

1. Rats were anaesthetized with sodium pentobarbitone and maximal twitches of a tibialis anterior muscle were evoked by stimulation of the motor nerve. 2. Suramin, injected intravenously in a series of cumulative bolus doses, each 15 mg kg-1, completely reversed a 90% depression of twitches maintained by a continuous intravenous infusion of pancuronium. The cumulated dose necessary to restore twitches to 50% of their control amplitude was 35 mg kg-1. Suramin did not modify a similar degree of block produced by suxamethonium, nor did it affect the amplitude of control maximal twitches, even in cumulative doses up to 150 mg kg-1. 3. The effects of bolus doses of suramin (85 mg kg-1), neostigmine (0.03 mg kg-1) and 4-aminopyridine (1.2 mg kg-1), calculated to restore pancuronium-blocked twitches to 95% of control amplitude, were compared. Suramin produced the most rapid reversal (1.1 +/- 0.5 min), but its duration of action was the shortest (9.4 +/- 1.6 min). Suramin was without effect on heart rate or blood pressure in the doses used. 4. The results showed that suramin reversed neuromuscular block produced by nondepolarizing blocking drug, pancuronium, but was without effect on a block produced by the depolarizing blocking drug, suxamethonium. Its short duration of action suggests that suramin would probably not be of value clinically as a reversal agent. However, it is possible that it might serve as a starter compound for the synthesis and development of a new class of reversal agents for use in anaesthetic practice.

The effects of dantrolene sodium on cardiac and skeletal muscle in rats.

Dantrolene sodium in different concentrations was administered to the spontaneously beating heart placed in a modified Langendorff apparatus. Heart frequency and contractility were recorded. Dantrolene sodium was also administered to the rat diaphragm. Twitch tension after indirect supramaximal stimulation was recorded. Dantrolene sodium produced a long lasting dose-dependent reduction of the contractility of the isolated rat heart up to 75% of control values. It had no effect on the heart frequency. The drug also decreased the force of contraction of the rat skeletal muscle in vitro to the same extent. The diaphragm appeared to be more sensitive to low concentrations of dantrolene sodium than was heart muscle i.e. the dose-response curve on rat diaphragm was flatter. It may be concluded however that higher concentrations of dantrolene sodium may effect the contractility of heart muscle as well and that this may have clinical implications.

Comparison of the pharmacological actions of some new 4-aminopyridine derivatives.

The pharmacological actions of 2,4-diaminopyridine (2,4-DAP) and 3-[(dimethylamino)-carbonyl] amino 4-aminopyridine (LF-14) were examined and compared with those of 4-aminopyridine (4-AP) in anaesthetized rats and on isolated rat and guinea-pig tissues. Both compounds were more potent than 4-AP in reversing the neuromuscular block caused by pancuronium bromide. The ED50S of LF-14, 2,4-DAP and 4-AP were 100 micrograms/kg, 140 micrograms/kg and 450 micrograms/kg, respectively. LF-14 and 2,4-DAP were also more potent in their in vitro actions on the neuroeffector junctions in the ileum and the isolated heart. 2,4-DAP and LF-14 either did not facilitate or only slightly facilitated the recovery time from xylazine/ketamine anaesthesia which was used as a test for their central action; 4-AP significantly reduced the recovery time. We therefore conclude that both 2,4-DAP and LF-14 are stronger peripherally acting compounds with less central action, and that they may be possible replacements for 4-AP as antagonists of non-depolarizing muscle relaxants.

A comparison of the pharmacological actions of 4-aminopyridine and two of its derivatives in the monkey.

The neuromuscular, cardiovascular and central nervous system stimulating effects of 4-aminopyridine (4-AP), 2,4-diaminopyridine (2,4-DAP) and LF-14 were investigated in the monkey. All these compounds were shown to reverse the stable neuromuscular blockade produced by the intravenous infusion of pancuronium bromide. The doses producing 50% antagonism (ED50) of the pancuronium-induced neuromuscular block were 0.50, 0.54 and 0.71 mg/kg for LF-14, 2,4-DAP and 4-AP respectively. The compounds had only slight cardiovascular effects. In contrast to 4-AP, LF-14 and 2,4-DAP did not reduce the duration of ketamine/diazepam-induced anesthesia, suggesting minimal if any central nervous system effects of these two compounds.

The effect of some new aminopyridines on mammalian non-myelinated nerve fibres.

We evaluated the action of 2,4-, 3,4-diaminopyridine and 3-[(dimethylamino)carbonyl]amino,4-aminopyridine (LF-14) on non-myelinated fibres of the guinea-pig vagus nerve. The amplitude and duration of the compound action potential were enhanced similarly by all of the aminopyridines. The propagation velocity of the compound action potential and electrogenic sodium pumping were not changed by the aminopyridines. The results show that 2,4-diAP and LF-14 affect non-myelinated nerve fibres of the guinea-pig in the same way as does 3,4-diAP; sodium pumping was not modified by the aminopyridines.

The action of some new aminopyridines on mammalian non-myelinated nerve fibres.

The effects of a recently synthesized series of aminopyridines 2-methyl-4-AP, 2-chloro-4-AP and 2-(N,N-methyl-benzyl)amino-4-AP (2A-7) on voltage-operated sodium and potassium channels and on the sodium pump activity of non-myelinated fibres of the guinea-pig vagus nerve were studied with the sucrose-gap method. The compound action potential evoked by electrical stimulation and the propagation velocity along the nerve were not affected by 2-methyl-4-AP or 2-chloro-4-AP up to a concentration of 10(-3) M. The post-tetanic potential (PTH) evoked by repetitive stimulation of the nerve and reflecting sodium pumping was also not affected by these agents. The amplitude and duration of the compound action potential were enhanced to some extent by 2-methyl-4-AP at the highest concentration used (3 X 10(-3) M); this action was also observed and was more pronounced with 4-aminopyridine (4-AP). The other aminopyridine 2A-7 (3 X 10(-5) - 3 X 10(-4) M) caused suppression of the compound action potential, a diminished propagation velocity and a reduction of the PTH, an action also observed with lidocaine. These results show that 2-methyl-4-AP and 3-chloro-4-AP did not affect the voltage-operated sodium or potassium channels in non-myelinated fibres of the vagus nerve. Only 2-methyl-4-AP had a small 4-AP-like action at high concentrations. The aminopyridine 2A-7 possesses a local anaesthetic action as reflected by the inhibition of voltage-operated sodium channels.

Suramin reverses non-depolarizing neuromuscular blockade in rat diaphragm.

Unexpectedly, it was observed that the P2-purinoceptor antagonist, suramin (10 microM to 1 mM), reversed the muscle paralysis caused by structurally unrelated non-depolarizing relaxants. Suramin competitively reversed the blocking action of pancuronium. Both the pre- and postsynaptic blockade of nicotinic receptors by pancuronium was counteracted, as shown by the action of suramin, using train-of-four stimulation. Suramin did not affect the paralysis caused by the depolarizing relaxant, succinylcholine. The reversal action of suramin was not due to an increase in the acetylcholine concentration in the synaptic cleft, since neither the contraction of preparations partially paralysed by diminished acetylcholine release in the presence of low Ca2+ or high Mg2+ nor acetylcholinesterase activity were affected. Suramin did not affect the reduction in twitch tension caused by adenosine and potentiated the ATP-induced reduction in twitch, indicating that ATP-sensitive receptors are not involved in the reversal action of suramin. Consequently, these results suggest that the action of suramin is due to binding with a site on the acetylcholine receptor also occupied by non-depolarizing relaxants, but different from the site occupied by succinylcholine.

Pharmacokinetics and pharmacodynamics of 2,4-diaminopyridine in the cat.

The pharmacokinetics, antagonistic effects, and cardiovascular effects of 2,4-diaminopyridine (2,4-DAP) were studied in 7 anaesthetized cats. Cats received a pancuronium infusion at a constant rate to cause a 90% block of contraction of the anterior tibialis muscle, stimulated through the sciatic nerve. After steady state was reached, 2,4-DAP (750 micrograms/kg IV) was administered. Plasma, urine, and bile were collected over 8 h and analyzed by means of an HPLC assay. Plasma concentrations decreased biexponentially with half-lives of 9.0 +/- 5.7 min and 140 +/- 36 min, respectively. The volume of the central compartment was 0.85 +/- 0.27 L/kg, and the volume of distribution in the steady state was 3.1 +/- 1.1 L/kg. Total plasma clearance was 18 +/- 5 ml/kg/min. Ninety percent of the administered dose was recovered in the urine and 0.1 percent in the bile in 8 h. The antagonism of the pancuronium-induced steady-state block was 98% +/- 5%, with onset and duration of 3.5 +/- 2 min and 165 +/- 40 min, respectively.

Potentiation of neostigmine and pyridostigmine by 4-aminopyridine in the rat.

The interaction between 4-aminopyridine and neostigmine or pyridostigmine was studied in vivo in the rat sciatic nerve-anterior tibialis preparation using the constant infusion of pancuronium technique. The ED50 (dose of drug which produced a 50% antagonism) of neostigmine, pyridostigmine and 4-aminopyridine were 18, 49 and 440 microgram kg(-1) respectively. The addition of 100 microgram kg(-1) of 4-aminopyridine, which produced no antagonism by itself, decreased the neostigmine ED50 to 7.4 microgram kg(-1). The addition of 200 microgram kg(-1) of 4-aminopyridine, which produced a 30% antagonism by itself, decreased the ED50 of pyridostigmine to 11 microgram kg(-1). We conclude that both neostigmine and pyridostigmine interact with 4-aminopyrine synergistically.

Ataranalgesia. A review.

A review is given of the pharmacodynamic effects of Ketamine and the commonly used Benzodiazepines especially regarding the clinical application of the substances in combination as socalled ataranalgesia. The literature as well as own experimental results show the advantages of ataranalgetic combinations for induction and maintenance of general anesthesia. Special comment is given for new results about the reversal of hypnotic action by means of 4-aminopyridine.

Inhibition of corticosteroidogenesis by etomidate.

The effects of the intravenous anesthetic etomidate have been investigated on ACTH-induced steroidogenesis in vitro, using purified isolated rat adrenal cells. It was found that etomidate almost completely blocked corticosterone production induced by physiological concentrations of ACTH at doses of 200 ng or greater. The mean inhibitory etomidate concentration resulting in 50% inhibition approximated 1.5 X 10(-7)M which is in the range of concentrations measured after clinical doses of etomidate.

Antagonism of the cardiovascular effects of ketamine by diazepam in volunteers.

In healthy volunteers pretreated with atropine (0.5 mg), ketamine given as a bolus i.v. injection (2 mg/kg) followed by an infusion of ketamine (1 mg/kg/hr) for one hour, caused a significant rise in blood pressure and heart rate. This cardiovascular stimulation was rapidly counteracted by diazepam (0.2 mg/kg i.v.) given when the response to ketamine was already maximal.

Effects of the analeptic drug, 4-aminopyridine, upon post-operative respiratory depression in patients. A preliminary study.

The analeptic agent, 4-aminopyridine, was given to patients who had undergone elective ear, nose and throat surgery and showed severe central respiratory depression due to intra-operative fentanyl administration. The respiratory depression due to fentanyl was found to be partially antagonised by 4-aminopyridine. In view of these preliminary findings it is suggested that the drug might find a use in combatting postoperative fentanyl-induced respiratory depression.