Interaction of aminoglycoside antibiotics and calcium channel blockers at the neuromuscular junctions.

Aminoglycoside antibiotics (mmol.l-1) gentamicin (0.74), streptomycin (1.02), netilmicin (1.24), amikacin (2.23), sisomicin (2.74), dactimicin (2.75), kanamycin (3.43), kanendomycin (3.45), tobramycin (3.53) and dibekacin (4.35) produce a complete neuromuscular blockade at the isolated phrenic nerve-hemidiaphragm preparation of the rat, which is only reversed by calcium chloride. On the other hand, verapamil (2.04 mmol.l-1), a calcium channel blocker, also produces a complete neuromuscular blockade at the above preparation which is reversed by calcium chloride. Aminoglycoside antibiotics are potentially capable of interacting with verapamil and produce a complete neuromuscular blockade at concentrations significantly reduced. The neuromuscular blockade which is produced by the concurrent administration of the aminoglycoside antibiotics and verapamil is obtained with the usual therapeutic blood concentrations of the individual agents. Furthermore, the neuromuscular blockade which is produced during verapamil-aminoglycoside antibiotics interactions is completely reversed after calcium chloride administration. The mechanism by which aminoglycoside antibiotics and verapamil produce neuromuscular blockade must be the same. Both classes of drugs interfere with calcium ions movements through the calcium channels of the membrane of the motor nerve-endings inhibiting acetylcholine release at the synaptic cleft. The interaction of aminoglycoside antibiotics and calcium channel blockers is of clinical significance because when these agents are given concurrently during the perioperative period they may lead to respiratory depression or prolonged apnoea. These respiratory disturbances can be managed by slow intravenous infusion of 50 to 200 mg of calcium gluconate.

Aminoglycoside antibiotics: interaction with trimethaphan at the neuromuscular junctions.

Trimethaphan, a ganglionic blocking agent which is administered by intravenous drip to produce controlled hypotension during surgery, produces a complete neuromuscular blockade at the isolated phrenic nerve-hemidiaphragm preparation of the rat at a concentration of 0.3 mmol X l-1. This blockade is not reversed by neostigmine, a cholinesterase inhibitor, nor by calcium chloride, and this action is attributed to the local anaesthetic activity of the drug. Trimethaphan (1.5 X 10(-2) mmol X l-1) interacts with the following aminoglycoside antibiotics: gentamicin (0.04), streptomycin (0.05), netilmicin (0.06), amikacin (0.11), sisomicin (0.14), kanamycin (0.17), tobramycin (0.18) and dibekacin (0.21 mmol X l-1) to produce a complete neuromuscular blockade. These pharmacodynamic interactions of trimethaphan and aminoglycoside antibiotics occur at significantly reduced concentrations of the interacting drugs which are very close to the ones obtained after administration of therapeutic doses. When trimethaphan or aminoglycoside antibiotics are used alone at the above reduced concentrations they do not exert any neuromuscular blocking activity. The neuromuscular blockade which is obtained after the interaction of trimethaphan with aminoglycoside antibiotics is not reversed by either neostigmine or calcium chloride, although the neuromuscular blockade which is produced by aminoglycoside antibiotics alone is reversed by calcium chloride. It is concluded that the local anaesthetic effect of trimethaphan is the predominant factor of the mechanism of the above interactions. These interactions may produce severe respiratory disturbances (respiratory depression or apnoea) to the patients, during the perioperative period, which can be reversed only with artificial ventilation.

The influence of age on the distribution and activity of histamine receptors in the rat uterus.

In immature rat uterus histamine (10(-6) mol.l-1) potentiates by 25%, the carbachol (2 x 10(-6) mol.l-1) induced uterine contractions. This potentiation is abolished by mepyramine (6 x 10(-9) mol.l-1), an H1-receptor antagonist. Higher concentrations of histamine, up to 10(-4) mol.l-1, did not exert any inhibitory effect on carbachol-induced uterine contractions. In mature rat uterus carbachol-induced contractions are inhibited by histamine by about 25%. This inhibitory effect of histamine is significantly enhanced by mepyramine by about 50%. Inhibitory effects of higher concentrations of histamine, up to 10(-4) mol.l-1, are not enhanced by mepyramine. Cimetidine (4 x 10(-4) mol.l-1), an H2-receptor antagonist, abolished the inhibitory effects of histamine on carbachol-induced uterine contractions. In conclusion, in immature rat uterus there exists only H1 histamine receptors, activation of which exert an excitatory effect. In mature rat uterus there exists both H1 and H2 histamine receptors. The relaxant effect of histamine on mature rat uterus is exerted by activation of H2-receptors which predominate.

Effect of aminoglycoside antibiotics on the contractility of the uterus.

In the present study the inhibitory effect of five aminoglycoside antibiotics on the contractility of rat uterus was investigated. We found that all the antibiotics tested inhibited the contractility of the isolated rat uterus and only quantitative differences existed among them. The inhibitory potency of the aminoglycoside antibiotics appears to be as follows: sisomicin greater than gentamicin greater than tobramycin greater than dibekacin greater than amikacin. Calcium not only has the ability to restore the normal contractility of the uterus but also to exert protective action against the inhibitory effect of aminoglycoside antibiotics on the uterus contractility.