Oct 2, 2021
The Classroom Neuro/Psych Lecture Part 4 of 4, you can complete the quizzes here https://residency.teachable.com/p/mobile
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Auto Generated Transcript:
Okay, welcome to Neuropsych 4. We're going to go over three topics: local anesthetics in a little more detail than when we first talked about axonal conduction versus synaptic transmission, substances of abuse, including alcohol and nicotine.
So, the two different steps to neuron signal transmission are the targets for medications. The axonal conduction, like the local anesthetics, the drugs aren't selective. All axons work basically the same. There are many adverse effects relative to synaptic transmission. Although they can certainly have some, there are very few medications that inhibit this transmission in this way. On the other side, the synaptic transmission drugs, like the selective serotonin reuptake inhibitors that affect serotonin, or the serotonin-norepinephrine reuptake inhibitors that affect serotonin and norepinephrine, they can be really selective, working on different synapses, specific neurotransmitters, and most medications work this way because we want something selective rather than something that is not selective.
Again, the mechanism of action for a local anesthetic is to inhibit sodium channels. It stops the action potential and the neurotransmitter release. Benzocaine is one example. You can use it over the counter to take care of a toothache, and it's an ester type, so it would be more allergenic and a little bit more of a concern if you were going to inject it. Whereas lidocaine, which you can find over the counter as well, like Solarcaine, is an amide-type that causes fewer allergic reactions. This is one we prefer. We'll talk about lidocaine in a very different use - an injectable use - in a minute. But in this case, when everything's topical, there's not really much of a difference. It's just that you wouldn't really want to inject something like benzocaine. There's less of a risk of CNS depression with something like this than an inhaled systemic anesthetic, just as a caveat. Local anesthetics work on the fast-firing neurons, and the sensory neurons are the ones that fire most frequently. It eventually inhibits the motor neurons but on a graph of time to loss sensation, we begin with getting rid of the pain, then cold, then warmth, touch, pressure, then the motor function. A local anesthetic like an epidural, we would inject into the epidural space that surrounds the spinal cord. Lidocaine, bupivacaine, these are often used for this, and the spinal injections go even closer to the spinal cord. You can get severe hypotension - that's "hypo" meaning less tension in blood pressure, so a severe reduction in blood pressure. Headaches can occur, and then the headaches can be resolved by lying down.
So another use for local anesthetics is going to be when we're talking about Lidocaine and you're going to the dentist. The local anesthetic can cause a bit of vasodilation where the vessels open up, and that creates really fast absorption in a short duration of action. When you're going to have a procedure, you don't want a short duration of action. You want the dentist to have all the time they need to work on whatever's going on with your teeth in as long a time as they need. So what they can do is add a vasoconstrictor to counter these effects. It slows absorption, lengthens the duration of action up to 100 percent, and also reduces some risk of toxicities. Epinephrine is commonly added with local anesthetics.
The first substance of abuse we'll look at is alcohol. It's been consumed for thousands and thousands of years. It used to be there's a book that talks about this great kind of water really caused a real problem back in the day in that getting clean drinking water was really tough, and one well was affected by a diaper.
I think it was that it was in someone's basement, and I know this sounds gross, but what happened was the water went through the feces into the well, and then there was this great cholera epidemic. But one of the area businesses had no problem with cholera, and that business was a brewery, and the workers there would drink during their lunch break. It wasn't the beer that you're thinking of now; it was more like food back then. That was a way to keep drinking water safe because the alcohol would kill the bacteria.
Alcohol we're talking about now is one of the most commonly abused substances in the US and the world. Seventy-five percent of US adults consume it regularly; eight percent have an alcohol abuse disorder, and three percent of children or adolescents have an alcohol abuse disorder. So it's very widespread. What happens with alcohol? Well, if we're doing it in moderation, the effects on the body are a discrete decreased risk of ischemic stroke, coronary artery disease, myocardial infarction, and heart failure. You may have heard this: that a couple of drinks is protective for your cardiovascular system. However, it's very tough because alcohol can be addicting. So, the misuse effects on the brain generalize CNS depression, activates the reward pathway, and kind of feeds into it that you want it over and over again.
So what happens with certain blood alcohol levels? I'm not sure anymore, but I know that some states have even lowered the 0.08 to even a little bit lower than that, but legal intoxication is where you've got a slowed reaction, and the idea is that if you're drinking alcohol, you're more likely to hurt someone else while you're driving a car. As we go up, and we usually hear like 0.08 is the legal limit in most states, but as you go up, you not only impair motor function, but you can go into a coma and you can actually go into respiratory depression and death. So very dangerous in quantities that exceed that moderation.
We can have acute renal effects, so anti-diuretic hormone causes the kidneys to reabsorb water and decreases urinary formation, and alcohol inhibits ADH in the pituitary gland. It acts as a diuretic and increases urine formation. So when someone's drinking alcohol, sure, they're drinking 12 ounces or 24 ounces of liquid, but the alcohol itself is a diuretic and acts as a diuretic. That's why they're urinating. It's not necessarily that they're just drinking all of this water.
What are the chronic issues that are going to happen to the liver? First of all, we get fatty liver swollen because of fat accumulation. This is reversible. Hepatitis or fibrosis, where scar tissue forms, it's possible to recover, but the scar tissue remains. Cirrhosis is where the connective tissue destroys the liver cells or the hepatic cells, and this is irreversible.
There are a couple of different issues that come along with this. First of all, there's Wernicke's encephalopathy, where you have these involuntary eye movements, mental changes, and ataxia. This is an issue of thiamin deficiency. Korsakoff psychosis is a chronic memory disorder, brain lesions formed because of the lack of thiamine. Wernicke's encephalopathy usually goes away with thiamin administration. Korsakoff psychosis occurs in 85 percent of Wernicke patients that survive, and that unfortunately is permanent.
Another issue is pregnancy. So fetal alcohol syndrome, alcohol is teratogenic, it's a leading cause of mental retardation and congenital malformation in the United States. It can cause certain abnormalities, including craniofacial malformations, growth restrictions, neurodevelopmental irregularities, and withdrawal symptoms can be pretty severe as well.
So the days since last drink on the bottom, have it at 2, 4, 6, 8, and then this very long 30 to 90 days. But if you don't treat it, it can cause ultimately death. If you have tachycardia, hypertension, fever, tremor, delirium, agitation, seizures, those things can be deadly. Hallucinations are possible around the second to sixth day. Anxiety, insomnia, tremors, nausea, and anorexia. And you can see that if someone doesn't get alcohol, these are the things that are in the future for them. Why they would just continue to drink, continue to drink, not only for the pleasure of it but to avoid this withdrawal syndrome.
There are three primary medications that you'll see with someone that has a diagnosis of alcoholism. Naltrexone (Vivitrol), it inhibits the mu-opioid receptor and the euphoria. Disulfiram (Antabuse), literally anti-abuse, creates incomplete alcohol breakdown, building up acetaldehyde, and it causes flushing, headache, and severe nausea and vomiting. But the thing with this is that a patient can just say, "Well, I'm not going to take these pills, and then I won't feel this bad effect." And then the last one is acamprosate (Campral). This binds to the same sites as alcohol in the CNS and prevents the uncomfortable feelings from abstinence. So three different ways now that we can attack this alcoholism. But again, it's a very, very, very difficult thing to get away from.
The second substance of abuse we'll talk about is nicotine. And as with alcohol, it's prevalent. It's a substance with the most people addicted to it around the world. It's the greatest cause of premature deaths and preventable illness in the US. And it's delivered via cigarettes, electronic cigarettes, cigars, chewing tobaccos. Many different ways that someone can get nicotine, and it only takes eight seconds for 90 to 98 percent of nicotine to be absorbed by the lungs and bind to receptors in the CNS. If you're watching rather than listening, I'm going to show you an animation that is in real time, that is eight seconds worth. So that's it, and then you could do the "one one thousand, two one thousand, three one thousand," and so forth, and see just how quickly it goes into the lungs and then into the brain.
Nicotine is actually a mixed agonist-antagonist. If you have a very low dose, it's very activating to the nicotine receptor, and there are cardiovascular, GI, and central nervous system effects. If you have a very high dose, it actually blocks the nicotinic receptor action, and that's acute poisoning. Nicotine is more complex than just something that makes you feel good. Depending on the dose, it can have very different effects. The GI effects begin by activating the nicotinic receptors in the parasympathetic "rest and digest" system. This activation causes increased acid secretion and GI motility and can promote vomiting. So when you see someone has an ulcer and you see that the person's not supposed to smoke, this is why. The second part is it activates nicotinic receptors in the sympathetic system, the "fight-or-flight" response. So norepinephrine and epinephrine are released, and we see this increased heart rate, constricted blood vessels, and increased ventricular contraction force.
So what do we do to stop smoking? What are the options, and there are a lot of them?
So there are five FDA approved OTC dosage forms (over the counter dosage forms) to help stop smoking:
1. Chewing gum
2. Lozenge
3. Inhaler
4. Nasal spray
5. Transdermal patch
For the gum, the gum must be chewed for nicotine release. You chew and park it between the gum and cheeks for 30 minutes, then repeat. Some of the drug reactions are throat and mouth soreness, kind of aching jaw muscles, get hiccups, get belching, a little bit of an uncomfortable situation with those. But I've heard success stories from all five different forms. It really is personal to the person and deciding what is the best way and what would do the best job of replacing not only the nicotine itself but the action of smoking. I used to have a teacher who would hold their chalk as if they had a cigarette in their hand, and you could just see that the first thing that they were going to do after they got out of class was replace that chalk with a cigarette. So there are mental components as well as physical components that go along with the actual activation of nicotine cessation.
So there are two FDA approved medications for smoking cessation. The story behind the first one, which is bupropion SR (Sustained-Release), has another name called Wellbutrin. It first came out as an atypical antidepressant, and what people found was that while they were getting treated for depression, they just really didn't have much of an urge to smoke. The manufacturer said, "That's great, let's change the brand name from Wellbutrin, which was for depression, let's repackage it as something that's going to help someone with smoking," and they called it Zyban to ban smoking. Now, the issue with bupropion, which we'll talk about in a second, is that there can be some risks with seizures. On the other end, there's varenicline, which is branded as Chantix and has great results, but there can certainly be some side effects with that, which I'll talk about in a second. So these are the two choices that we have.
Bupropion sustained-release, brand Zyban, is the only SR formulation approved for smoking cessation. It's again an atypical antidepressant. We're not exactly sure how it works, so it doesn't fit neatly into SSRI or SNRI and things like that. It decreases the urge to smoke as these depressants were taking the medication, and it reduces withdrawal symptoms. The anxiety, the irritability, all those things that people have as they try to stop smoking. Adverse drug reactions that can come along with it include insomnia, which seems counterintuitive, but some agitation as well, dry mouth, and headache. Here's the big caveat, though: it lowers seizure threshold. Don't use it with a history of seizures. What that means is there's a certain threshold that something has to happen in the brain for someone to have a seizure. This drug would make it easier for that seizure to happen in those with a history of seizures.
The other drug is varenicline or Chantix, and this is a partial nicotinic receptor agonist. It prevents withdrawal symptoms and blocks that nicotine reward pathway. It's the most effective medication for smoking cessation. I personally have heard people that have stopped in a few days, and the issue that they had were some of the side effects: nausea, insomnia, very abnormal dreams, very vivid dreams, headache, and skin rash. The adverse drug reaction for nausea is dose-dependent, so maybe almost a third, maybe a little more, two-fifths can experience that nausea, but the more that someone has to take, the more prevalent the nausea would be.
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