Overview – Local Anesthetics

by Pravin Shukle, MD

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    00:01 Welcome to pharmacology by Lecturio.

    00:04 I'm Dr. PJ Shukle and we're going to talk about local anesthetics and oral analgesics.

    00:10 And I'm going to introduce you to the interesting world of controlling pain.

    00:15 Now, here's the problem with this particular type of patient. We need to get a drug across a lipid membrane and act on the inside of the cell, on the inside surface of a channel, to stop the movement of sodium ions.

    00:32 The problem is that the outside of the cell is water, the membrane is lipid, the inside is water.

    00:41 So, how do we change the properties of the drug to be both lipophilic and hydrophilic? Remember that membrane diffusion in this case is going to be a passive process.

    00:53 Unfortunately, there are no active transportase to bring the drug across the membrane.

    01:01 We want to block the receptor from the inside surface. And we want to block movement of sodium channels across that membrane.

    01:10 The reason why we do that is because blocking sodium channels will reduce membrane depolarization.

    01:18 And reducing membrane depolarization will prevent that nerve from firing and therefore the pain response will not reach your brain.

    01:29 We need the polar form of the drug to turn into a nonpolar drug, and then turn back into a polar drug and then do its job. How do we do that? Well, I'm going to bring back the pKa lecture. Now, you thought you got away with never having to deal with pKa once we finished our original pharmacology lectures, I think it was the second lecture we did.

    01:53 Well, here's where pKa really makes a different. So, lidocaine is a local anesthetic. It has a pKa of 7.7.

    02:03 And if you think back to that original lecture, remember that pKa means that 50% of lidocaine is protonated, and 50% of lidocaine is nonprotonated when the pH is 7.7.

    02:17 Now, inflammed tissue may also have pH changes too. So, the pH can be anywhere from 6.8 during active inflammation to 7.4 under normal conditions.

    02:31 Lidocaine, therefore, is sometimes given with bicarbonate to alkalinize the area and make the drug more lipid soluble.

    02:40 So, by giving bicarbonate with the subcutaneous lidocaine, you can change the pH. Let's say it goes up to 8.7, well now, you have a 1:10 ratio, or 10 % of your drug being water soluble, and 90 % of your drug being lipid soluble.

    03:01 Now, once it's inside the neuron or the cell, the pH is 6.9. So, the molecule now becomes more polar and water soluble.

    03:13 That's how we get the drug across the membrane. Once it's in the nerve, there're other things that will affect how well the drug works. First of all, smaller fibres are usually easily blocked.

    03:24 Larger fibres are less easily blocked. Myelinated fibres are also more easily blocked.

    03:30 Rapid firing nerves are more easily blocked, like pain fibres.

    03:35 And location within the nerve bundle will determine how well that local anesthetic works.

    03:40 Obviously, if the nerve is in the middle of the nerve bundle it's going to be hard to get at it.

    03:45 If it's on the surface of the nerve bundle, it will be easier to get at.

    03:51 There are some external tissue factors as well that will determine how well the drug works.

    03:56 Most block neuromuscular transmission. Central effects can cause euphoria such as cocaine.

    04:04 So, these external tissue factors are going to be very important in determining what kind of drugs we're going to be choosing to control our pain. There're some chemical factors that you have to be aware of.

    04:15 A high potassium concentration within the area will enhance local activity of the drug.

    04:22 High calcium levels on the other hand will inhibit local activity. And pH levels as we already discussed will affect the solubility of the drug. So, those chemical factors are important too.

    04:39 Now, most local anesthetics are very quickly absorbed into the blood.

    04:43 For example, lidocaine quickly goes from tissue into blood. And remember that's not a good thing because now the lidocaine is being carried away from the area you wanted. The other problem is that it's going to give us side effects.

    04:57 So, we don't want that. We want all of the lidocaine to stay in one place. So sometimes, we add epinephrine to our lidocaine mixture. So, you'll often see on the bottle of lidocaine as we're going to inject somebody before we do, say a stitch, is it will have bicarbonate to make the area more alkali and it will have epinephrine to give us vasoconstrictor activity.

    05:19 Now, longer acting agents are going to be less dependent upon the vasoconstrictor, but short acting agents like lidocaine is quite critical.

    05:29 Now, cocaine is actually a potent vasoconstrictor due to its intrinsic sympathomimetic function.

    About the Lecture

    The lecture Overview – Local Anesthetics by Pravin Shukle, MD is from the course CNS - Pharmacology.

    Included Quiz Questions

    1. The medications pass through the membrane in a non-polar form. Once inside, they form the active, polar form.
    2. Active transport pumps the medication into the nerve cells.
    3. They enter the cell through endocytosis at the synaptic cleft.
    4. The medication is converted into a base locally, with the use of a bicarbonate adjuvant. Once modified, the medication is activated in the kidney and returned to locally anesthetize the tissue.
    5. The medication interacts with the extracellular matrix, resulting in a secondary messengers cascade to cause anesthesia.
    1. Distribution of nodes of Ranvier
    2. Size of the nerve fiber
    3. Myelination of the nerve fiber
    4. Type of nerve fiber
    5. Location of the fiber in the nerve bundle
    1. Hypercalcemia
    2. Hyperkalemia
    3. Hypomagnesemia
    4. Small nerve fiber size
    5. The superficial location of fiber within the nerve bundle
    1. Neural tissue
    2. Skeletal muscle
    3. Skin and adipose
    4. Tendons and ligaments
    5. Cardiac muscle

    Author of lecture Overview – Local Anesthetics

     Pravin Shukle, MD

    Pravin Shukle, MD

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    great lectures
    By Kristin S. on 22. January 2018 for Overview – Local Anesthetics

    I've never heard someone explain pKa and drug mechanism so simply before.