Local anaesthetic sensitivities of cloned HERG channels from human heart: comparison with HERG/MiRP1 and HERG/MiRP1 T8A

Background. Myocardial potassium channels are complexes formedby different subunits. The subunit composition may influencethe cardiotoxic action of local anaesthetics. The effects ofamide local anaesthetics on HERG channels co-expressed withthe putative subunit MiRP1 have not been established. It isalso unclear if the common polymorphism MiRP1_T8A that predisposesindividuals to drug-induced cardiac arrhythmia increases local-anaestheticsensitivity of HERG/MiRP1 channels. This may suggest the presenceof genetic risk factors for local-anaesthetic-induced cardiacarrhythmia. Methods. Whole-cell patch-clamp recordings and site-directedmutagenesis were combined to compare local anaesthetic sensitivitiesof cloned and mutated human potassium channel subunits. Theion channels were activated by a protocol that approximatedventricular action potentials. Results. The amide local anaesthetics bupivacaine, levobupivacaineand ropivacaine inhibited HERG channels at toxicologically relevantconcentrations, with IC₅₀ values of 20 (SEM 2) µM (n=29),10 (1) µM (n=40) and 20 (2) µM (n=49), respectively.Hill coefficients were close to unity. There were no indicationsof qualitative differences in channel inhibition between thethree anaesthetics. The putative subunit MiRP1 did not alterlocal anaesthetic sensitivity of HERG channels. The common singlenucleotide polymorphism producing MiRP1_T8A did not increaselocal anaesthetic sensitivity of HERG/MiRP1 channels. Conclusions. Amide local anaesthetics target HERG and HERG/MiRP1channels with identical potency. The effects on these ion currentsmay significantly contribute to local-anaesthetic-induced cardiacarrhythmia. MiRP1_T8A does not seem to confer an increased riskof severe cardiac side-effects to carriers of this common polymorphism. Br J Anaesth 2004; 92: 93–101     

Kinetic modulation of HERG potassium channels by the volatile anesthetic halothane

BACKGROUND: (human ether-a-gogo related gene) encodes the cardiac rapidly activating delayed rectifier potassium currents (I(kr)), which play an important role in cardiac action potential repolarization. General anesthetics, like halothane, can prolong Q-T interval, suggesting that they act on myocellular repolarization, possibly involving HERG channels. Evidence for direct modulation of HERG channels by halothane is still lacking. To gain insight on HERG channel modulation by halothane the authors recorded macroscopic currents expressed in Xenopus oocytes and conducted non-stationary noise analysis to evaluate single channel parameters modified by the anesthetic. METHODS: Macroscopic currents were recorded in 120 mM K(+) internal-5 mM K(+) external solutions with the cut open oocyte technique. Macropatch recordings for non-stationary noise analysis of HERG tail currents were made in symmetrical 120 mM K(+) solutions. Pulse protocols designed for HERG current recording were elicited from a holding potential of -80 mV. Halothane was delivered via gravity-fed perfusion. RESULTS: Halothane (0.7%, 1.5%, and 3%) decreased macroscopic currents in a concentration-dependent manner (average reduction by 14%, 22%, and 35% in the range of -40 mV to 40 mV) irrespective of potential. HERG currents had slower activation and accelerated deactivation and inactivation. Non-stationary noise analysis revealed that halothane, 1.5%, decreased channel P(o) by 27%, whereas single-channel current amplitudes and number of channels in the patch remained unchanged. CONCLUSIONS: Halothane inhibits HERG currents expressed in oocytes in a concentration-dependent manner. It slowed down activation and accelerated deactivation and inactivation of HERG channels. The authors' results demonstrate that halothane decreased HERG currents by modulating kinetic properties of HERG channels, decreasing their open probability. Partial block of I(kr) currents could contribute to delayed myocellular repolarization and altered cardiac electrophysiology.     

Hypersensitivity to the local anesthetic articaine hydrochloride.

A patient developed skin erythema and wheals within 1 h after local dental anesthesia with articaine hydrochloride. Pretreatment with oral terfenadine or topical betamethasone dipropionate prevented her reaction to articaine. In contrast, neither pretreatment with oral aspirin nor topical capsaicin affected her reaction to articaine. The results of radioallergosorbent tests (RAST) to articaine and a passive transfer test were negative. The reaction was probably caused by a complement-mediated mechanism leading to the degranulation of mast cells. The patient tolerated local anesthesia with lidocaine.     

Novel ideas of local anaesthetic actions on various ion channels to ameliorate postoperative pain

This review considers the ion channels that underlie transduction of nociceptive energies in the periphery, that are involved in impulse initiation and propagation in peripheral sensory neurones, and that participate in pre- and post-synaptic actions in the spinal cord dorsal horn, in light of their susceptibility to local anaesthetics. Although there are results from experiments on isolated cells and tissues ex vivo that support the hypothesized actions, their extrapolation to actions in vivo and the consequences for peri- and postoperative pain control are largely speculative.     

Review of local anaesthetic agents

The currently available local anaesthetic agents are capable of providing high quality nerve blockade in a wide variety of clinical circumstances. Our understanding of the mechanisms and consequences of toxicity is increasing rapidly. Knowledge of the chemistry of local anaesthetics has enabled clinicians to exploit the increased safety of single isomer agents. However, the extent, if any, of this improvement in toxicity has yet to be proven. Established toxicity may be very difficult to treat and no specific reversing therapy is yet available. Until this occurs it is essential that practitioners of regional anaesthesia maintain their knowledge base and skill in techniques of administration of local anaesthetic, are able to recognise impending disaster, and constantly update their skills in resuscitation.     

Developments in local anaesthetic drugs

Br J Anaesth 2001; 87: 27–35     

Operative arthroscopy under local anaesthetic

Forty-six patients requiring arthroscopic surgery following diagnostic arthroscopy under local anaesthetic infiltration had this tried under the same anaesthetic (four patients had to be converted to a general anaesthetic to complete the procedure). Local infiltration provides good anaesthesia for arthroscopic surgery, except in those with an acutely locked knee or a painful collateral ligament.     

Clinical pharmacology and the use of articaine for local and regional anaesthesia

Quicker onset and shorter elimination time favours (+/-) articaine as a short-acting local anaesthetic for regional anaesthesia in day-case settings, e.g. arthroscopy (shoulder, knee), hand and foot surgery, and dentistry, because patients treated with articaine will be 'drug free' more quickly than those who receive other local anaesthetics. Articaine diffuses better through soft tissue and bone than other local anaesthetics. The concentration of articaine in the alveolus of a tooth in the upper jaw after extraction was about 100 times higher than that in systemic circulation. Articaine is metabolised via hydrolysis into articainic acid, 75% of which in turn is excreted as such and 25% in the glucuronidated form by the kidneys. The half-lives of elimination (t1/2alpha and t1/2beta) of articaine are 0.6 and 2.5 hours, whereas the apparent half-life of the metabolite articainic acid is 2.5 hours. Intrinsic half-lives of articainic acid are: t1/2alpha 12 minutes, and t1/2beta 64 minutes (1 hour). In dentistry, articaine is the drug of choice in the vast majority of literature. In other regional anaesthesia techniques (intravenous regional anaesthesia, epidural, spinal and plexus blocks) there are not enough data to prove that (+/-) articaine is safer and more effective than the short-acting local anaesthetics lidocaine, (+/-) prilocaine or (+/-) mepivacaine.     

The effect of age on pharmacokinetics of the local anesthetic drug articaine

BACKGROUND AND OBJECTIVES: With increasing age, there are physiologic changes that could affect pharmacokinetics of drugs. More elderly patients are undergoing routine dental procedures for which local anesthesia could be required. The goal of the present study was to evaluate the effect of age on pharmacokinetics of the local anesthetic agent articaine. METHODS: The submucosal infiltration anesthesia from two different dosages of 4% articaine without epinephrine was compared in healthy elderly and young volunteers. High performance liquid chromatography has been used to determine concentrations of articaine in serum. Basic pharmacokinetic parameters were calculated according to standard procedures using a two-exponent equation. RESULTS: The clearance and volume of distribution (Vdss) of articaine after infiltration anesthesia were significantly lower in elderly volunteers compared with young volunteers. The area under the serum concentration-time curve and maximum drug concentration (Cmax) values did not differ significantly with age; however, both parameters tended to be higher in elderly volunteers. No changes in terminal half-life and time to reach maximum serum concentration (t(max)) were observed. The Cmax and tmax values of the metabolite articainic acid were similar in young and elderly volunteers. CONCLUSIONS The results show that the metabolism of articaine is age-independent in healthy male volunteers. The smaller Vdss in the elderly results in a trend to higher serum levels after a given dose of articaine. No change of dosage of articaine in elderly patients should be necessary.     

Postoperative treatment of myocardial ischaemia by thoracic extradural local anaesthetic

This case report describes an episode of postoperative myocardial ischaemia after total oesophagectomy that was successfully treated by extradural administration of local anaesthetic. Extension of sympathetic blockade in this manner resolved the myocardial ischaemia and haemodynamic disturbances experienced by the patient.