Experimental studies on the effects of ototoxic antibiotics on the neuromuscular junction
Streptomycin and dihydrostreptomycin possess a marked therapeutic efficacy against various infectious diseases, but these antibiotics have been known to exert curious damage to the eighth carnial nerve, as first described in man by Hishaw et al. (1948). although the incidence of this neurotoxic manifestation is directly proportional to the size of the dose and to the duration of therapy, there are reports which indicate that a single conventional dose produced vestibular disturbance and auditory impairment. Besides such ototoxic effects, a large number of untoward and toxic manifestations (nausea, vomiting, dizziness, headache, dyspnea and toxic encephalophathy) have been reported after the administration of streptomycin and dihydrostreptomycin.
In the course of the studies of acute toxicity of streptomycin, Molitor et al., (1946 and 1950) found that death occurred by respiratory paralysis in the warm-blooded animals which had received a lethal dose of the antibiotic and ascribed it to the participation of the neuromuscular function. Later, Brazil and Corrado (1957) demonstrated that steptomycin possesses neuromuscular blocking properties which might be responsible for the respiratory arrest of acute streptomycin posioning.
Jindal and Deshpande (1960) also reported that both streptomycin and dihydrostreptomycin produced neuromuscular blockade in different types of nerve-muscle preparation. They found that calcium chloride reversed the neuromuscular block of streptomycin more rapidly and completely than prostigmine.
The present experiment was undertaken to investigate the influence of ototoxic antibiotics other than streptomycin and dihydrostreptomycin on the neuromuscular junction in vivo and to ascertain the relationaship between these neuromuscular activities and their ototoxic effets.
The neuromuscular action of penicillin was also determined in comparison with the nonototoxic antibiotic.
Cats weighing between 2 and 4kg were anesthetized with pentobarbital sodium (30mg/kg) and prepared for sciatic-tibialis anticus muscle preparation. A tracheal cannula was inserted in order to permit artificial respiration and then the animal was placed on a myographic table. The hind limb was set up in a horizontal position and the tendon of the tibialis anticus muscle was attached to a myograph. An arterial cannula was inserted into one of the carotids in order to record the arterial blood pressure through a mercury manometer. All injections were made intravenously into one of the jugular veins, previously cannulated. Nerve stimulation was performed with a square wave pulse of one millisecond duration delivered from an electronic stimulatro. Supramaximal nerve stimuli of one per second were used.
Drugs used were as follows:
10% Streptomycin sulfate solution
10% Dihydrostreptomycin sulfate solntion
10% Kanamycin sulfate solntion
5% Neomycin sulfate sloution
5% Vancomycin hydrochloride solution
10% Calcium chloride solution
0.01% Prostigmine methyl sulfate solution
300,000u/ml Grystal penicillin G solution
Results and Summary
Streptomycin injected in the dose of 50mg per kg of body weight abolished, in 4 out of 9 cats, the contraction of the tibialis anticus muscle indirectly stimulated with shocks delivered at a rate of one per second. This blockade was seen in all animals at the dose of more than 80mg per kg of body weight. The muscle always responded to direct stimulation. The arterial blood pressure fell after the injection of streptomycin around 50 mmHg. Although the recovery of blood pressure was gradual, the neuromuscular block persisted longer than blood pressure.
Calcium chloride rapidly and completely antagonized the neuromuscular block produced by streptomycin. When this occurred, arterial blood pressure in most experiments rose to more than the level prior to the administration of streptomycin. Prostigmine was also able to antagonize the blockade, but in some experiments the antagonistic effect was slow and incomplete.
Dihydorstreptomycin evoked the same neuromuscular blocking action as streptomycin. However, the effect was weaker than streptomycin. In only 5 oout of 17 experiments was complete blockade obtained in a dose of more than 80 mg/kg.
Calcium or prostigmine antagonizes the blockade produced by dihydrostreptomycin.
Eighty mg/kg of kanamycin produced a complete blockade in 6 out of 11 experiments. This blockade occurred rapidly and easily, counteracted by calcium or prostigmine. Suppression of blood pressure was slighter than that obtained by streptomycin.
Complete blockade of neuromuscular junction occurred in a dose of 30mgkg. Calcium is effective even when neomycin has caused a complete block, but prostigmine is effective only when the block is partial. Blood pressure was fell temporarily to around 10 to 40 mmHg.
Contrary to other ototoxic antibiotics, vancomycin did not have a neuromuscular blcking effect, but it resulted in greater muscle contraction. Blood pressure fell, abruptly then rose immediately after administration of vancomycin and gradually returned to the pre-injection level.
6. Caystal penicillin
Penicillin was ineffective in neuromuscular junction of tibialis anticus in a dose of 600,000 u/kg in cats. Even at the dose as high as 90,000 u/kg the neuromuscular blockade by pencillin appeared to slow acting and slight.
Summarizing the effect on the neuromuscular junction of stimulation of tibialis anticus in situ, the present observations show that the neuromuscular blocking action of investigated ototoxic-antibiotics occurs in a decreasing order: neomycin, streptomycin, kanamycin, dihydrostreptomycin, penicillin. Vancomycin which is reported the most harmful ototoxic antibiotic, did not show any blockade in tibialis anticus preparation in cats. In general, calcium was more effective to counteract in neuromuscular blockade caused by the above antlibiotics thabn prostigmine.
It seems likey that the neuromuscular blockade caused by the ototoxic antibiotics was elicited by the similar mechanism as magnesium. However, vancomycin did not follow this pattern.