Oct 1, 2021
Classroom Lecture Neuro/Psych Pharmacology Part 3 of 4
The Classroom Neuro/Psych Lecture Part 3 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 Pharmacology Three. We have three topics in this section: Parkinson's disease agents, Alzheimer's disease agents, and anti-epileptic agents. The first Parkinson's disease agent we'll talk about is levodopa-carbidopa and selegiline. So, how these work is, we have to kind of go back to the Parkinson's disease pathology. In the substantia nigra, we have an accelerator and brake pedal for the motor cortex of the brain. So, dopamine is the accelerator, and GABA, a neurotransmitter, is the brake. So the normal...
Dopaminergic neuron releases dopamine, and then the GABAergic neuron releases GABA. Okay, and when that happens that way, then we get smooth movement, green light, everything's working fine. With the pathology that comes along with Parkinson's disease, we get low dopamine and elevated acetylcholine. If that's the case, then we're going to see that the movement is not smooth, that the body is very jerky, and we're going to see some very specific movements that go along...
...with Parkinson's. So Parkinson's disease presents as postural impairment, it's difficult to maintain a straight posture, tremors, rigidity of the limbs in the body. Just like bradycardia is a slow heartbeat, brady is low. Bradycardia is less than 60 beats per minute. Bradykinesia, just like kinesiology is a kinesiology major, majors in the study of movement. Bradykinesia is a very slow movement. There's feet shuffling, but it's very distinctive, the Parkinson's presentation.
The treatment goal is to restore dopamine levels in the brain. But it's not as simple as just saying, "Okay, we'll just put some dopamine in their brain." The problem is that dopamine does not cross the blood-brain barrier (BBB). As we grow or as we're born, our blood-brain barrier protects us from many different toxic substances, but unfortunately, with many neuro drugs, it actually prevents something that could really help us from getting there. So the solution is to give a dopamine precursor that does cross the blood-brain barrier, and that precursor is called levodopa; it's also known as L-DOPA. All Parkinson's disease patients eventually require levodopa. It crosses the blood-brain barrier, no problem, and it's converted to dopamine in the brain. We have a second problem, though, in that it converts the dopamine in the peripheral tissues before it even gets to the brain by an enzyme called dopa decarboxylase. This is kind of a deal-breaker.
Until we add dopa decarboxylase inhibitor to stop the conversion. That's called carbidopa. So carbidopa is the dopa inhibitor blocking the enzyme. In a little bit of a different way, it's structurally very similar to levodopa. Because of that, it kind of distracts the enzyme to target carbidopa instead of levodopa. So it's over here, and then levodopa makes it to the finish line, makes it to the brain. So what we have is this combination of levodopa-carbidopa (Sinemet). We adjust the dose based on the symptom response, and then over time, patients will report on and off as the response diminishes. On is the medication working, we've got good movement; off the medication is not working, we've got tremors, rigidity, slowness returns. It should not be given to those with psychosis of any kind because what we're doing is we're adding dopamine and this could be a really bad thing if someone has psychosis. It takes months to see full effects and then there could be a hypertensive crisis if given with non-selective...
...MAOIs, so those are the three caveats to watch out for with carbidopa or levodopa. Carbidopa, another drug that we can use, is selegiline and in the brand name you can see Eldepryl and they were going for elderly that many elderly find this Parkinson's disease is something that they have. Monoamine oxidase B, it's a monoamine B inhibitor and the a isomer of the enzyme breaks down norepinephrine, serotonin or 5th and dopamine. The b isomer breaks down dopamine selectively so it slows the breakdown of this dopamine in the brain and it allows for lower doses of levodopa so two different ways of approaching Parkinson's disease. In both cases, we want to make sure we can get more dopamine in the brain. It should not be given alone and levodopa-carbidopa must also be given to be effective in Parkinson's disease.
"Alzheimer's disease agents, so we're just going to talk about two of them: donepezil and memantine. The thing about Alzheimer's disease is you can never really know until after someone has passed if the person had Alzheimer's disease.
You have to actually look at their brain and see, you know, okay, well, this is what we're seeing, and we'll see what the pathology looks like in the next slide. But the exact cause we still don't know. There are some anomalies or things wrong within the hippocampus. The current treatments can slow disease progression, but there's no cure yet. Diagnosis to death can occur in four to eight years or it could be a bit longer; it depends on who you're reading.
Symptoms: A lot of times, we think just about the memory loss in Alzheimer's, and that is certainly one of the things that happen with it, but there's also impaired thinking, cognitive decline, and the inability to perform activities of daily living. So it's extremely hard on the patient, certainly, but it's also extremely hard on the partner or caregiver as well.
The pathology: So we have this neuron, and we're going to have these amyloid plaques, which are a hallmark in the anatomy of Alzheimer's. Decreased acetylcholine levels, these deformed microtubules, and the neurons are just kind of a mess.
So, what can we do with it? Well, two classes of medications we'll talk about are cholinesterase inhibitors and NMDA receptor antagonists. The first thing we'll talk about is how a cholinesterase inhibitor works. Much like Parkinson's, where we can't just give dopamine, we can't just give acetylcholine. So instead of giving acetylcholine with donepezil (brand Aricept), which is for mild to moderate symptoms, it prevents the breakdown of acetylcholine, which is a common neurotransmitter. By preventing the breakdown what we do is allow more acetylcholine to be around. The thing is, if you allow more acetylcholine to be around, you're going to see that we're going to have cholinergic adverse drug reactions. We're going to see maybe nausea, vomiting, diarrhea, some dyspepsia as some of the side effects. As you can see in the graphic, it's only effective for 1 in 12 patients. So not the best prognosis for a medication.
Another drug, memantine or Namenda, is an NMDA receptor antagonist. You can see the brand name Namenda, and it regulates calcium levels in the neurons by binding to these NMDA receptors. So high calcium in the neurons is implicit for Alzheimer's disease. We have decreased learning and memory ability, neuron degradation. Regulated calcium in the neurons increased or normalized learning memorability, increased neuron lifespan. But those are the two Alzheimer's disease medications.
Anti-epileptic agents: We're going to first talk a little bit about epilepsy itself, kind of just a very big view of some of the conditions that someone can have. Epilepsy is a chronic seizure condition. We have hyperexcitability of the neurons in the brain. And 70 percent of the time, it's primary; it's idiopathic. We have no idea what's going on, maybe genetic CNS abnormalities. But we need chronic treatment with medications. So these are for partial focal simple and complex generalized tonic-clonic absence myoclonic febrile or fever seizures and status epilepticus. Secondary or symptomatic seizures are caused by illnesses, and so a temporary anti-epileptic treatment is needed until the underlying cause is corrected.
So these seizures can happen, and it's really about figuring out whether it's the illness that's causing it or if it's something that we're just not sure about. But really, the anti-epileptic treatment for each type is pretty much the same. A term that I want you to know, though, is that the seizure focus, that's where the beginning of the seizure is. So in terms of the anti-epileptic agents, they decrease neuronal activity during the seizure focus, they slow or stop the spread of the seizure from the focus to other areas of the brain. But there are these two terms that we want to make sure we're clear about: a seizure is any type of epileptic event, whereas a convulsion is just an abnormal motor phenomenon. So these are just a little bit different. But let's look at some of the medications that we can use.
So as far as the older medications, carbamazepine is one of them, and it inhibits sodium channels on hyperactive neurons and prevents sodium from entering the neuron, stopping the action potential. But we have serious adverse drug reactions, including bone marrow suppression. Grapefruit juice can increase levels. Divalproex or Depakote works in three ways: it inhibits sodium channels on the hyperactive neurons, just like carbamazepine. It inhibits calcium influx into the neurons and promotes GABA activity and release. But there are some serious adverse drug reactions in hepatic and pancreatic toxicities, teratogenicity, and interactions with phenytoin.
The third of the traditional anti-epileptics we'll talk about is phenytoin or Dilantin. It inhibits sodium channels on the hyperactive neurons, prevents sodium from entering the neuron, stopping the action potential, the same as carbamazepine. But it requires lots of monitoring. Small dose increases can cause toxicities, and small dose decreases can cause therapy failure. So what we want to do is make sure we're monitoring appropriately and keeping phenytoin at the right levels.
And then two of the newer medications, just to give you some examples. There are many newer anti-epileptics. Gabapentin, which is Neurontin, and pregabalin, which is Lyrica. Pregabalin happens to be the metabolite of gabapentin, and both work as adjunct therapy for epilepsies. Common adverse drug reactions include drowsiness, blurry vision, and peripheral edema. But that's really how you want to divide them. The older drugs, which we know quite a bit about, have a lot more history, and the newer drugs may have a little bit fewer adverse drug reactions, but we're not necessarily as confident sometimes with the newer ones in terms of what we know about what seizures they work for.
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