Local anesthetics

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Introduction0:00–0:40

Local anesthetics are medications used to reversibly block pain sensation in a specific part of the body in order to perform small surgical procedures.
The common suffix for local anesthetics is -caine, like procaine, tetracaine, lidocaine, Michael Caine - no wait, that’s the actor.
Anyway, so there are two classes of local anesthetics - called esters and amides. Both classes inhibit conduction of action potentials across nerve fibers by blocking calcium sodium (Na+) channels - and thus the perception of pain by the brain.

Physiology0:40–2:24

Pain is sensed by receptors called free nerve endings which are the 1st order neurons in the pain pathway. These neurons send their axons to synapse with 2nd order neurons in the spinal cord which carries the sensory information to the brain, and you feel pain.
Free nerve endings can be triggered in several ways; by mechanical stimulation, like getting punched; by thermal stimulation like heat and cold; or by chemical stimulation from molecules like bradykinin and histamine.
These noxious stimuli trigger the opening of cation channels on the membrane called transient receptor potential channels.
This allows Na+ and other positive ions to flow into the cell. The extra positive charge that flows in makes the cell less negative, - which is called depolarization.
This depolarization causes nearby voltage-gated sodium channels to open up as well, setting off this chain reaction that continues down the entire length of the axon.
Now, voltage-gated Na+ channels are unique because they have inactivation gates on the intracellular side. At resting membrane potential, the channel is closed.
When the membrane depolarizes, the channel opens and sodium ions rush into the cell. A few milliseconds later, the inactivation gate closes and blocks Na+ from entering the cell even though the channel is still open.
This ends the depolarization process. Finally, when the cell repolarizes, the inactivation gate opens, the activation gate closes, and the channel enters the closed state again - ready to start another action potential.
Now, local anesthetics are used to inhibit the conduction of action potentials in free nerve endings. These medications are molecules that have an aromatic part, and an amine chain that are linked by either an ester or an amide bond.

Mechanism of Action2:24–4:46

There’s a number of ways to administer local anesthetics; topical anesthesia is applied directly to the skin or mucosa; infiltration where the medication is injected into the tissue; or nerve block - where the medication is injected into the tissue near a major nerve.
These are frequently used for minor procedures like getting your tooth pulled, or getting a polyp removed from inside your nose.
Local anesthetics can also be injected into the epidural space or the subarachnoid space in the spinal cord to numb larger areas.
This is often useful for orthopedic procedures like joint replacement, C-sections, and pain management during child delivery.
Once administered, local anesthetics are rapidly absorbed into the bloodstream. This decreases the effect at the target area and increases the systemic side effects.
To correct this, vasoconstrictors like epinephrine are given to diminish blood flow to the site. Okay, once the anesthetic reach the neurons, they will go inside the cells.
However, if the pH in the surrounding tissue is low, like if there’s hypoxia or an infection, some of the medication will become ionized and won’t be able to cross the cell membrane.
Once inside the cell, the medication binds to voltage-gated Na+ channel on the cytoplasmic surface of the membrane. Local anesthetics are state dependent, meaning they are more likely to affect neurons that are firing more rapidly.
This is because they bind more tightly to inactivated Na+ channels and prolong the inactivated state. This way, the action potential will not be able to travel up the neuron’s axon and we do not register the pain.
local anesthetic have a larger effect on nerves that are small and myelinated, which is good since nerve fiber carrying the pain sensation are usually small.
At larger doses, they can also block conduction of temperature, then touch, then pressure, and finally there’s loss of motor function.
Local anesthetics can be divided into esters and amides based on their molecular structure. Esters are made up of an aromatic part and a basic chain linked by an ester bond.

Ester Anesthetics4:46–6:21

This class of medications includes cocaine, benzocaine, procaine, and tetracaine. Cocaine and benzocaine are surface anesthetics for topical use only since they have serious side effects.
Cocaine is the only local anesthetic that blocks the reuptake of catecholamines, which are neurotransmitters in the sympathetic system in charge of the fight-or-flight response.
This causes catecholamines to build up and leads to vasoconstriction, tachycardia, and arrhythmia. It also blocks the reuptake of dopamine, a neurotransmitter that regulate the reward pathway.
Increase in dopamine causes the euphoric feeling associated with cocaine, and can lead to addiction. Benzocaine can cause methemoglobinemia where the heme in red blood cells get oxidized from the iron-two-plus (Fe2+) state to the iron-three-plus (Fe3+) state and they lose their ability to transport oxygen.
This causes the blood to take on an unhealthy chocolate color and can lead to cyanosis. Procaine has a short duration of action, but its potential to cause side effects, both in the central nervous system and in cardiovascular system, is really high.
Tetracaine has a long duration of action and is commonly used in spinal and corneal anesthesia. Now, amide anesthetics are made up of an aromatic part and a basic chain linked by an amide bond.

Amide Anesthetics6:21–7:26

When someone is allergic to the ester anesthetics, we can use the amides, or vice versa. This class of local anesthetics includes lidocaine, mepivacaine, and bupivacaine, among others.
And they are metabolized at different rates by cytochrome P450 enzymes in the liver. Lidocaine is the most frequently used amide local anesthetic.
It has an intermediate duration of action and can be used in almost any situation, from topical to spinal anesthesia. Mepivacaine also has an intermediate duration of action, but it’s toxic for newborns, so it’s contraindicated for pregnant women.
Bupivacaine has a long duration of action and its main application is in epidural anesthesia during labor. This medication is very cardiotoxic and can cause severe myocardial depression if the medication is accidentally administered into a blood vessel.

Side Effects7:26–8:18

Both amide and ester local anesthetics have similar side effects. If these medications get into the bloodstream, they can cause inhibition of the central nervous system.
First they decrease the activity of inhibitory neurons which leads to restlessness, anxiety, and even seizures . At larger doses they can decrease the activity of all neurons and lead to depression of the CNS as well as respiratory depression - which can lead to death.
In the cardiovascular system, local anesthetics - in general - have a similar effect as in neurons, they decrease the rate of action potentials on myocytes of the heart - which can cause bradycardia and decreased cardiac output.
In addition, local anesthetics generally cause vasodilatation, which can cause further hypotension. Now, let’s make a simple and fun mnemonic that’ll help you efficiently memorize these pharmacology facts!

Memory Palace8:18–11:06

Let’s use a salt mine to represent the voltage gated sodium channels that these medications bind to. There’s a miner taking a nap in front of the mine because the local anesthetics bind to channels in the inactive state.
He can’t get into the mine because someone spilled acid by the entrance. This represents acidosis preventing entry of the drug into the cell.
Since small, myelinated nerves are affected first, we can make the miner skinny and give him a blanket. Near the entrance of the mine are two large statues.
An Easter Island head represents the esters and a golden statue of King Midas, who turned everything he touched to gold, represents the amides.
On the top of the Easter Island head, are the esters reserved for topical use only. There’s Benjamin Franklin to represent benzocaine.
He’s drinking a giant can of cola to represent cocaine, because Coca-cola used have cocaine as an ingredient, that’s true!.
Benjamin has a melting chocolate bar on his pants to represent methemoglobinemia, which turns your blood a chocolate color.
There’s a cat on the cola to represent increased catecholamine, and the cat is eating a big chunk of cookie dough to represent increased dopamine.
Now, on one side of the statue is a stack of tetris blocks for tetracaine. They are stacked high to represent its long duration.
At the bottom of the stack is a pudgy porcupine for procaine. Its too fat to climb up so it has a short duration.
Now let’s look at the statue of king Midas. In one hand, his holding a map to his treasure which represents mepivacaine.
His other hand is holding a garbage can lid as a shield for lidocaine. He’s holding them at a medium height to represent their medium duration.
Now there’s a lot of skulls drawn on the treasure map, so that adventure is probably not safe for infants or pregnant women.
Behind the statue is an extremely tall man playing a bugle for bupivacaine. His height represent long duration and he’s playing a sad, depressing song that causes severe cardiac depression.
For the serious side effects of local anesthetics, let’s put the mine owner between the two statues. He came to congratulate the miners on doing a great job, but when he saw the napping miner, he got so worked up he had a seizure.
He dropped his heart shaped cake, representing cardiac depression, and the balloons he brought gets deflated for pulmonary depression.
All right, as a quick recap… Local anesthetics are medications used to block pain sensation in a specific part of the body in order to perform small surgical procedures and spinal anesthesia.

Review11:06–11:36

They do this by blocking voltage-gated Na+ channels during their inactive state. There are two classes; esters - which include cocaine, benzocaine, procaine, and tetracaine - and amides - which include lidocaine, mepivacaine, and bupivacaine.

Mind Map11:36–11:46

But wait, there's more: Here's a mind map with all of the mnemonics from the video. Go ahead and pause the video so you can test yourself to see what you remember.
Stay tuned for the answers at the end.