Block by Local Anesthetics

Sodium channels modified by veratridine are blocked by local anesthetics, but the mechanism seems to differ from that by TTX. The agents dealt with here are local anesthetics in the broadest sense, including antiarrhyth- 

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Weetman (1972) described the preparation of the isolated, innervated urinary bladder in guinea pigs. Contractions of the tissue induced by nerve stimulation could be blocked by local anesthetics and by tetrodotoxin. 

Aakerman SBA, Camougis G, Sandburg RV. Stereoisomerism and differential activity in excitation block by local anesthetics. Eur J Pharmacol 1969 8 337-347. 

Figure 64 J. The rule of three suggests that a minimum of three internodes must be blocked by local anesthetic to reduce salutatory conduction safety to the point that an action potential will no longer be propagated along the nerve fibers. Because of the large internodal distance of thick myelinated A-alpha and A-beta fibers, a relatively large amount of surface must be bathed in local anesthetic solution in order to ensure conduction blockade.

Ragsdale DS, McPhee JC, Scheuer T et al (1994) Molecular determinants of state-dependent block ofNa + channels by local anesthetics. Science 265 1724-1728... 

Starmer C.F. Grant A.O. and Strauss, H.C. Mechanisms of use-dependent block of sodium channels in excitable membranes by local anesthetics. Biophys J 46 5-21, 1984. 

The ion-channel blocking mechanism has been widely tested and found to be important in both pharmacology and physiology. Examples are the block of nerve and cardiac sodium channels by local anesthetics, or block of NMDA receptor channels by Mg2+ and the anesthetic ketamine. The channel-block mechanism was first used quantitatively to describe block of the squid axon K+ current by tetraethylammonium (TEA) ions. The effects of channel blockers on synaptic potentials and synaptic currents were investigated, particularly at the neuromuscular junction, and the development of the single-channel recording technique allowed channel blockages to be observed directly for the first time. 

Peripheral nerve functions are not affected equally by local anesthetics. Loss of sympathetic function usually is followed by loss of temperature sensation sensation to pinprick, touch, and deep pressure and last, motor function. This phenomenon is called differential blockade. Differential blockade is the result of a number of factors, including the size of the nerve, the presence and amount of myelin, and the location of particular fibers within a nerve bundle. For conduction to be effectively blocked, the local anesthetic must exert its effects over the distance between several nodes of Ranvier. Since the smallest nerves (C fibers) have no myelin, they can be most easily blocked thus, sympathetic functions often are blocked soon after a local anesthetic is applied to a particular nerve bundle. Small myelinated nerves have correspondingly short distances between nodes of Ranvier and therefore are often blocked next. These nerves subserve temperature and sharp pain sensation. Larger nerves then become blocked, accounting for the loss of function up to and including motor innervation. 

Raising the concentration of Ca in the medium pathing, a nerve may relieve conduction block produced by local anesthetics. Relief occurs because Ca alters the surface potential on the membrane, and hence the transmembrane electrical field. This, in turn, reduces the degree of inactivation of the Na channels and the affinity of the latter for the local anaesthetic molecule [25, 27]. 

Seizures induced by local anesthetics are usually treated with intravenous anesthetic drugs (eg, thiopental 1-2 mg/kg, propofol 0.5-1 mg/kg, midazolam 0.03-0.06 mg/kg). The muscular manifestations of a seizure can be blocked using a short-acting neuromuscular relaxant drug (eg, succinylcholine, 0.25-0.5 mg/kg IV). It should be emphasized that succinylcholine does not alter the CNS manifestations of local anesthetic-induced seizure activity. Rapid tracheal intubation can prevent pulmonary aspiration of gastric contents and facilitate hyperventilation. 

Smaller A-delta fibers have relatively small internodal distances, and three or more nodes can be more easily blocked (X). Unmyelinated C fibers do not employ salutatory conduction and are particularly vulnerable to local anesthetic blockade. Propagation of action potentials can be prevented by local anesthetic blockade at any point along the course of the nerve fiber. 

Adjunct therapy epidural clonidine as an analgesic adjunct enhances both sensory and motor block caused by local anesthetics (mechanism unclear). It also enhances the effect of other spinal analgesics, including intrathecal opioids. Both quality and duration are enhanced when clonidine is combined with these other neuraxial analgesics... 

Local anesthetics produce anesthesia by blocking nerve impulse conduction in sensory, as well as motor nerve, fibers. Nerve impulses are initiated by membrane depolarization, effected by the opening of a sodium ion channel and an influx of sodium ions. Local anesthetics act by inhibiting the channel s opening they bind to a receptor located in the channel s interior. The degree of blockage on an isolated nerve depends not only on the amount of dmg, but also on the rate of nerve stimulation (153—156). 

Another clinical consideration is the abiUty of local anesthetic agents to effect differential blockade of sensory and motor fibers. In surgical procedures such as obstetrics or postoperative pain rehef, an agent which produces profound sensory block accompanied by minimal motor block is desirable. On the other hand some procedures such as limb surgery require both deep sensory and motor blockade. In clinical practice, bupivacaine ( 22,... 

TTX) and saxitoxin, which block the channel pore from the outer side. The difference in TTX sensitivity among the sodium channels is caused by a single amino acid difference in the P region of repeat I (phenylalanine or tyrosine in TTX-sensitive channels cysteine or serine in TTX-resistant channels). The S6 segments contribute to forming the inner pore of the channel and binding sites for local anesthetics. 

A conduction block is a type of regional anesthesia produced by injection of a local anesthetic drug into or near a nerve trunk. Examples of a conduction block include an epidural block (injection of a local anesthetic into the space surrounding the dura of the spinal cord) a trails sacral (caudal) block (injection of a local anesthetic into the epidural space at the level of the sacrococcygeal notch) and brachial plexus block (injection of a local anesdietic into the brachial plexus). Epidural, especially, and trailssacral blocks are often used in obstetrics. A brachial plexus block may be used for surgery of the arm or hand. 

The answer is local anesthetic properties it can block the initiation or conduction of a nerve impulse. It is biotransformed by plasma esterases to inactive products. In addition, cocaine blocks the reuptake of norepinephrine. This action produces CNS stimulant effects including euphoria, excitement, and restlessness Peripherally, cocaine produces sympathomimetic effects including tachycardia and vasoconstriction. Death from acute overdose can be from respiratory depression or cardiac failure Cocaine is an ester of benzoic acid and is closely related to the structure of atropine. 

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