P.A.

1 - Local Anesthesia
1. How do local anesthetics change the frequency of action potentials propagating along the axons of pain sensing neurons? Local anesthetics decrease the rate of depolarization and repolarization of pain receptors. They work by inhibiting voltage-gated Na+ ion channels causing Na+ to remain outside of the cell, via stabilization of inactivation gate in closed position This greatly decreases the rate of depolarization of the neurons (frequency), which is how degree of pain is coded. 2. Is the relative refractory period altered by local anesthetics? Since Na+ channels are inactivated, the relative refractory period is delayed; this lengthens the entire refractory period. 3. Discuss the clinical efficacy of a modification of lidocaine, drug QX-314, which bears a permanent positive charge. Drug QX-314 should exhibit a low level of clinical efficacy, due to its permanent positive charge. Active local anesthetics must be lipid soluble, in order to enter the neuron. They must become cations once within the cell to be active.
Anesthetics come in two forms: the active form for blocking Na+ channels RNH+ and the lipid soluble inactive form RN. Most Anesthetics are injected in a solution that is buffered so pH is basic and thus will increase the amount of RN available to quickly diffuse through the membrane, where it then binds an H+ and can block the Na+ Channel. Since this drug bears a permanent positive charge it would be an ideal candidate for blocking Na+ voltage gated channels. however this positive charge also inhibits its ability to enter the nerve cell. As an ionic substance (lipiphobic) it is unlikely to bypass the the lipid bilayer of the cell. In conclusion, if the drug cannot be transported or directly injected into the cell it will be ineffective as a clinical anesthetic.

4. Incorrect administration of a local anesthetic will cause your patient to develop symptoms, such as a droopy eyelid or an inability to open and close the jaw correctly. Explain why these undesired symptoms occur after local anesthetic administration. Diffusion or misplaced injection, could hit motor nerve instead of sensory. Decreased AP frequency of cranial nerves. In an attempt to restrict blood flow to the site of injection, manufactures of local anesthetics have added a low concentration of a vasoconstrictor to the solution. Inherently, the amount of the anesthesia being metabolized, due to the restriction of blood flow, will decrease significantly. This allows the anesthesia to act on the nerve cell for a longer period of time. Local

anesthetic such as Bupivicaine -- although slow to absorb in to the nerve cell -- has the ability to strongly bond to cellular proteins, which in turn prolongs its numbing effect. Someone who metabolizes the anesthesia slowly may suffer from prolong numbness. It should be noted, that the rate of resorption is dependent on each individual, and some may be more susceptible to negative side effects, such as paralysis. Variations in internal anatomy can lead to an improperly administered injection. The needle can penetrate a nerve or artery, and cause serious prolonged pain, numbness or paresthesia. The chance of this sort of thing occurring significantly increases in thinner patients -- they lack fat and muscle making the neurovascular bundles larger in respect to the intended injection point. If injected directly into the neurovascular bundle the physician may cause damage due to the expansion of the anesthetic bubble. In doing a anterior superior alveolar nerve black, a dentist may insert the needle too high and actually numb the infraorbital nerve. This could cause the eyelids to droop. Although know permanent damage may be done, there can be a loss in the patients confidence in the doctor. 5a. Explain the confusion. Epinephrine, a sympathomimetic hormone is often administered together with local anesthetics as a potent vasoconstrictor. However, youll find in the literature and in class that epinephrine actually increases blood flow to skeletal muscles (the sympathetic nervous system fight-or-flight response). In order to achieve that, sympathetic hormones dilate various blood vessels. Epinephrine binds alpha 1, GPCR, binds Gq, exchange gdp for gtp, hydrolysis of PIP2 to IP3 and DAG, - released Ca2+ binds target proteins (PKC, calmodulin). Causes Epinephrine is concentration based dilates arteries, constricts veins (due to variability of receptors & receptor density). Epinephrine is a hormone secreted by the adrenal medulla in response to physical or mental stress. It binds to adrenergic receptors throughout the body. The different types of receptors in different tissues will trigger a variety of responses so that the body is better prepared to respond to the stressor. For instance, it will stimulate the heart to beat stronger and faster, as well as increase the metabolic rate and blood glucose concentration, thereby boosting the supply of oxygen and fuel to skeletal muscles. During this fight or flight response, only vital bodily processes occur, and as a byproduct of this, skin arterioles are constricted because that blood could be better utilized in nourishing muscles. So while the use of epinephrine in vasoconstriction may seem to be a contradiction when taken out of context,

it still serves the overall purpose of preparing the body to better deal with a stressful situation. 5b. What receptors does epinephrine act on in order to restrict systemic action of local anesthetic at the place of injection? Describe signaling and cellular responses involved. Affects frequency of AP, pacemaking ability by affecting a nonspecific Na+ channel. Administration of epinephrine along with local anesthetic is usefull clinically for two reasons: First it allows for the prolonged effect of the local anesthetic, second it limits the LAs ability to enter systemic circulation. Epinephrine binds alpha receptors on the vasculature (smooth muscle) surrounding the site of injection, this causes vasoconstriction and thus limits systemic exposure and prolongs the action of the LA as it is now more localized to the site of injection. The cellular mechanism by which this occurs is as follows : binding of epinephrine to its respective alpha receptor causes activation of intracellular G protein Gq, Gq activates phospholipase C, PLC cleaves Phosphatidylinositol 4,5-bisphosphate (PIP2), PIP2 causes an increase in inositol triphosphate (IP3) and diacylglycerol (DAG). The former interacts with calcium channels of endoplasmic and sarcoplasmic reticulum, The intracellular calcium binds with calmodulin, which then binds and activates myosin light-chain kinase. The calcium-calmodulin-myosin lightchain kinase complex phosphorylates myosin on the myosin light chains , initiating contraction and activating the myosin ATPase.