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I'll start out with the psychosis, which is the shorter bit. Uh Hopefully it won't take too long. Um And this is the rundown of the agenda. Um First off, I will talk about the biological basis of the neurotransmission. Um And then we'll talk about a bit about this dopamine theory and how that might cause psychosis. And the last part is the one that everybody can feel confused about is the antipsychotics, pharmacology. Um So I'll go through that as well. So the first part, I'll come up with the first questions here. Um Could you tell me I'll give you about a couple of seconds or so. Um Just tell me what do you think will be the answer, type it in the chat? One answer for Mario, which is really good. OK. I got something from Freddie as well. And Chris. OK. So I for the, for, for the interest of time, I'll give you the answer is c um So, um with this chapter, um they don't really talk too much about the soft stuff. Um A lot of it is the science stuff in the SBA especially and it's very important because this is the concept, they repeatedly test you on. I remember having this as a questions uh in my final, a couple of years back and it's hyperactivity of E two and it acts on the mesolimbic system. The reason why I think medical schools emphasized so much on it is because when schizophrenia was first, the first treatment for schizophrenia came out is the first generation, the typical antipsychotics and most of them and actually all of them share one thing in common and that is D2 blockade. So that's a key bit of pharmacology. You want to know and with dopamine, it's a little bit more complicated. Um but uh essentially boils down to four pathway. One is the mesolimbic pathway. That's the reward center, that's the stuff that actually cause you to have addiction. Um And then also it's the sensory center. So maybe, you know, having that being too overactive. It's why we have all these hallucinations um happening in the first place. And then the second one is the mesocortical symptoms. So that's the one that is responsible for all the personality problem. All the negative effect of schizophrenia. The third one is the tuberal in inver indibulin um pathway. That's the pathway that affects the uh hypothalamus which uh dump all the uh so hypothalamus that causes antipituitary gland to pump up all these prolactin. And um the way they regulate that pathway was that if dopamine on being secreted, um dopamine, sorry, the the prolactin get inhibited. So you don't secrete so much prolactin. But when the dopamine was being inhibited, the prolactin sort of gone wild. So it pumps out a lot of prolactin in guys. It shows up and ha having mobs man boobs uh G com matia, but in both gender, both male and female, it will cause libido loss. Um So that's one thing that's one of the side effects of antipsychotics and the fourth one is nigrostriatal. Uh I think there's, there's a spelling type over there, but it's uh nico striatal, not striatal. Um and that affects the pathway that affects the Parkinson's disease. So, in effect by blocking dopamine these antipsychotics sort of induce Parkinson's uh in this uh people who are using the drugs. So it's really important to kind of memorize this table. People ask me about D One and D2 that I also kind of listed out to clarify the matters to help you. Remember our study. So this is I think is a very key table if you can memorize and remember what happens in this table. You got at least 50% of the pharmacology in this unit already. The other part is that the, the stuff kind of a revision for a month. So you got serotonin which is uh secreted from uh raf nuclei. So to help you memorize it, one of my colleague came up this little cute little cartoon. Uh you got Rafael from a teenage to ninja turtle and then he's a kind of a dress up in a sir, kind of a night thing. So you got, sir Raton with Rafael, sir. Rafael. The other one is, uh, non adrenaline. Um, that one is mostly made in Locus Coralus and that is, um, the one that in charge of fight or flight response. So if you're stressed in your exams, you, you're freaking out, your body will make a lot of known adrenaline and you know where to blame and you blame your locus celeus um for causing all these uh havoc in you. So those are the two high, you'll be um the glutamate um mostly excitatory, sorry, excitatory. The Gaba is mostly inhibitory and the key bit um to um you know about Gaba is that Gabaa B is the famous receptors that a lot of the sedatives bind to uh not directly. Um They're just binding on the side to help increase the receptors affinity to Gaba. Um These drugs include alcohol, benzodiazepine, vibrate tu, its that's uh something that will be a pop up in your career again and again, acetylcholine, uh it's made in two places. Uh Main one you need to know is basal four bain nuclei, which is helpful in your um and your in your case 22 as well because that's where a lot of Alzheimer conditions is happening. So you lost those cholinergic neurons in the basal for brain brain. You get Alzheimer dementia. So this is the second questions, you find your buddy in the local pub in Newcastle. He was drunk and totally impaired, which neurotransmitter is being potentiated by alcohol to cost your friend sedation. So give you guys a few seconds to answer that. Please type it in and check. Ok, so I guess the group has been getting the, the message quite clearly is Gabaa. So c is the answer? Ok. This is more for your reference mostly. So they asked you about the metabolism of um all these neurotransmitters just showing you where they come from. The only thing I want to highlight is um these ones. So tyrosine, you get it from your diet when you eat a lot of proteins and that get converted into dopa and DOPA is actually one of the pro drug in Parkinson's that turn into dopamine within your body. So that's a key bit because it's related to pharmacology. Um And then the other key bit is uh when you eat a lot of proteins, you usually get sleepy and part. And also sometimes people sell sleeping aid in your natural health food store um by selling you stuff like tryptophan or this 15 hydroxy tryptophan five. And these are the things that kind of help you sleep, but they eventually get turned into serotonin, which is um the thing that you run low on when you have depression. Uh and then you got glucose, turn into glutamate, turned into Gaba and this picture is something that it's more like a review from um your a level. The only thing I really want you to know is that in this unit, they talk about some of the recycling mechanisms in the uh so the recycling mechanism is the circle here. So the presynaptic membranes, they have certain transporters that grab some of the neurotransmitter that is not U used in the synapse anymore. And then they also have enzymes that break down the neurotransmitters there to kind of get rid of the signals when they do not need it to help switch them off. And this is a kind of a table, a chart for you to uh kind of a summary table of all the things they mentioned in the sessions. And again, I'm gonna highlight the key bit that's relevant to pharmacology. Um Catechol methyl Trisa CO MT is the things that help breaks down dopamine in the synapse to help switch off the signal. Now, if you go to your case 22 in Parkinson's, one of the main drug class is called CO MT inhibitor. Things like an decap or Topo Toone. Those are the ones that stop these enzymes from working to allow dopamine to last longer. So that's a drug target. Second one is acetylcholinesterase. So when your acetylcholine uh got secreted into synapse, it stayed in for enough time to get the signals. The body has an enzyme called acetylcholinesterase to break it down to turn it off. Now, when your body is running low on acetylcholine, one of the best way to do it is to inhibit this enzyme to give you more, to make more acetylcholine available. That's the mechanism behind the dementia drugs such as Donepezil, such as gamine or samine. Um because these are all acetylcholinesterase inhibitor. Now, enough of the, the biology stuff, now we talk about the psychosis, what really causes it. So, what's the dopamine theory? Well, the dopamine theory is this um they say that in patients with schizophrenia, that's two finding that's quite significant on the brain imaging. Uh Oh sorry, I got abigail talk about the com again, I can, I can do that totally. So comb CO MT is an enzyme that breaks down dopamine. Um So that to switch it off. Now when you have Parkinson's, your body is not making enough dopamine. So you want to hang on as to as much dopamine as possible to help you get those signaling, to help your body moving, right? So the CO MT inhibitor inhibits the CO MT to stop the enzymes from breaking the dopamine so that the dopamine can last longer in the synapse. So things like anti Capone or tolcapone, those two drugs in that drug class. CO NT inhibitors are what's helping you in Parkinson's, if that helps abigail, just give me a message. All right. So let's go back. Temporal lobe hypothesis. If you guys have any questions, just type it in the chat, I'll go back any time. Um So the patient with schizophrenia, they have smaller hippocampus. They have well, which is part of temporal lobe. Basically temporal lobe is uh the hippocampus is medial part of temporal lobe. The second part is is uh increased activity of hippocampus. So how could something get smaller at the same time being more active? Sounds quite paradoxical. What that happening is that in the body, there are two system in the hippocampus. One is the Gaba system which I just explained was always inhibitory. So to try to calm things down and then the glutamate level which is always to excite to, to get things going. Now, people with schizophrenia they think is that they have Gaba, the the neurons that is secreting Gaba, they're getting damage, they're dying off. So what happened that is when the neurons died off, the hippocampus size get smaller. Now with just the Gaba inhibiting other neurons, those glutamate secreting neurons start to fire like as if there's a party going on. So they have increased activity. So that's how you explain the paradoxical finding. You have smaller temporal lobe because the Gaba part, the part that secrete Gaba is dying and then you got increased activity. It's because the part that is secreting glutamate is going uncontrolled. So it's always having this excitation, this stimulatory activity. And what that end result is your body is dumping a whole lot more dopamine than supposingly into the mesolimbic system and that causes the, the excess dopamine is what causes the schizophrenia. OK. This slide is sort of a summary slide to answer the learning outcomes. Um A lot of it is repetition, not gonna read everything out to you. The main thing I want you to kind of know is that steroid, for example, like predniSONE or dexamethasone, if you take too much of it, you get insomnia and also eventually you can also get psychosis as a side effect. So something that you know, you might want to know about. The other one is that for key risk factors for schizophrenia, the big one of the biggest one, actually, the biggest one is actually genetic, so much higher risk. If you have a positive family history or first degree relative, this slide sort of talks about the positive symptoms versus the negative symptoms. Now you go to the DSM diagnostic criteria that breaks it down by duration. So the time being, so that might be more helpful guess maybe when you're in your third year, when they do the psychiatry unit, but the positive symptoms is more predominant in the description. So they got three things that are very much the core symptoms. One is hallucinations and the hallucination is much more auditory. So the patient don't necessarily see things that that's not there. Um But uh a and if you have visual hallucination, actually, that's much more likely to be uh dementia of Lewy body, that's one of the key symptoms. Whereas schizophrenia, it's more likely to be auditory, like you're hearing things that are well, really not there. Um And the other thing is you have delusion. So you have fixed and firm belief about something that is outside the cultural appropriate norms, maybe you're feeling you're being persecuted. Sometimes you may be feeling you bigger than you are you Grandia. Um And then the other third one is disorganized. Thoughts. So the thoughts process may be disorganized. So sometimes you just can't think you got a mental block. Sometimes you think that other people put thoughts into you like thought insertion. Sometimes you think people take thoughts away from you. So fought deletion or sometimes you think people can hear what you're thinking that's fought broadcast. Um Those are the kind of thing, negative symptoms. On the other hand, it's not as well described in the diagnostic criteria, but some of the other ones that are, there are interesting ones, I've listed them so flat effect, no, no emotion, avolition, no motivation, alogia, um reduction in speech and he Donia. So inability to experience joy or pleasure, something kind of like depression, um social withdrawal. The last one is called catatonia, which is really interesting. You've got a person who's awake and conscious, but that's not really respond to people on the environment. You got things that are negativism, so not doing something or resting, resisting, doing something at all. So this is the first questions. Um, I'm gonna give you guys some time to, uh, answer that, please type it on the chat. Yeah, this one's kind of random. Um, I just put it there. Um, just, it, it's called Night Smooth Thinking. So what happen is if the person have w salad, it won't even resemble anything like a sentence. So, uh, it's just a mumble jumble of words. Um, flight of ideas would be like, you know, lots of ideas, very disorganized. Clank asso association means something that rhymes, you know, it's almost like a rap song but doesn't make sense, you know. Um, and probably speeches elogy, but he's talking. So it's obviously not night smooth thinking is that the sentence seems like there is a structure but the idea jumped from one to the other very quickly. And that's, um, kind of interesting thought, uh patent disorganizations in the person with schizophrenia. This is a bit, I think that troubles most people. So this is the bit I spend a lot of time making pas to make it s simple for you guys to memorize and uh study. So basically you try to rule out any substance induced causes as in any psychiatry problems with managing schizophrenia, um, the medication, it will be mainstay and oftentimes it would be lifelong. Um, you won't stop that and the non-drug measures, um, good thing to know when you have Os because they always ask you about non-drug measures, even though a medic condition seems very drug driven for management is that you want to reduce stress. So that goes back to the kind of vulnerability model that was laid early on. In that diagram, you try to reduce stress because if you can reduce stress, it's far less likely a person have these symptoms at all. The other thing is just do psycho education um educate the patients, maybe that helps them to gain insight into their problems and also um educate the family so they can recognize the early symptoms if the patient has having problem again and another flare up again and they can seek help quickly. The management wise. It's very simple. First line is uh one of the anti atypical antipsychotic second generations. Um pretty much all the antipsychotic except cloZAPine has similar efficacy. So you're picking them just based on the adverse drug effect, uh adverse drug reaction profile. So ad R is adverse drug reaction. The second line is, if the first one didn't work, we'll try another second generation antipsychotics. But also maybe worthwhile checking drug compliance. If the person is not not compliant all the time, maybe you can do a long acting injections. Um And that's the pharmacokinetic bit in the learning outcome that you know, require them to come back to the clinic maybe every 2 to 4 weeks. And so that will help them with the compliance. And the third line is if you fail two or more antipsychotics, you consider cloZAPine. So, cloZAPine is a bit of a drug of last resort. It is the most effective antipsychotic but has a loads of side effects. Um and uh uh some has one very important side effect. You need to uh manage and monitor. I will go over that in the slide here. So the mechanisms, the the typical one, the first one, like I said earlier is D2 receptor blockade. It's a very high tendency of causing motor side effects. So, extrapyramidal side effect is called E PS. So movement disorder because of the drugs, um the classic atypical psychotic that is still being used. This classic typical Ayo that is still being used. It's called halopurine. That's why it's highlighted in red is high potency. Sometimes it can cause QT prolongation so it can mess up the heart rhythm. So usually people do a ECG as well before they start the medications. But most of the typical antipsychotic. Now these days are not used for schizophrenia. It's more likely to be used for as a drug to stop people from vomiting because these drugs also block the D2 receptor in the chemo receptor trigger zones. And so that will help people to stop throwing up. Um The famous example is called chlorproMAZINE or prochlorperazine or metoclopramide. These are all famous example of that uh drug class. The downside. Obviously, you can see is with these medications, sometimes you need to watch out for moderate side effects that I'm gonna be talking about. Um the second generation, the atypical antipsychotics. On the other hand, it is less likely to cause uh motor motor side effects. So the extra pyet side effects, the E PS is likely to happen when you take these drugs. Part of the reason as in terms of pharmacology is that these neuro antipsychotics seems to also target a serotonin receptors called five H 22 A. There's a lot of serotonin receptors out there. Um But it just gives you a back of your mind, your mind that um these newer antipsychotics have blockade antagonistic or blockade effect on these serotonin receptors in addition to the D2 receptors. Um in fact, the D2 receptor blockade is not as strong as some of the typical one that I just discussed. So maybe that's why they have lower E PS side effects and also because of the serotonin receptor blockade effect, that might also explain why it can help reduce some of the negative symptoms in some people. But that's more antidotal. It's not exactly proven yet in drug trial, but these drugs do carry side effects and they mostly on the metabolic side. So by blocking the serotonin receptor, it seems to have reduced its anxiety, the the the the your body's ability to tell you that you're full um when you're eating, so you end up eating more and because you eat more, you get weight gain, you get diabetes and you got hyperlipidemia as a result. So this is another exact questions that I'm gonna check with you if you can give me a moment to type it on the chat. Mhm. Ok. So we're getting a quite a different list of answers here. Um What is happening with this person is um he's getting the E he's experiencing what we call the extrapyramidal side effects. So the E PS um this is the that this gentleman is experiencing and that particular extrapyramidal side effect encompass four different symptoms. And this particular one that this person is having is called dystonia, which is acute muscle contraction. And the wor and one of the worst type worst scenario in dystonia in this scenario, in this situation is called oculogyric crisis where the eyes are moving upward and you got really restricted eye, eye movement and you got also got rigidity because the muscles of the neck and the upper extremities are very contracted, very tight, they're very tense. The way to manage this is to give a drug called procyclidine. So I guess Ahmed is uh got the right answer. Um and procycle is basically is an anticholinergic. Uh It's a drug that kind of used to balance out the dopamine blockade from the antipsychotics. The re the reasoning behind it, the pharmacology behind it are something that takes a while to discuss. So I put it at the end of the slide for you to read over as a Fy I because it's not part of the exam, but it's important to recognize what extrapyramidal side effect is because um there are four components to it. And I would highly recommend you memorize these four things. One is, it's called dystonia. So tight muscle contractions in the head and neck regions. And that's the one that happens the fastest, the soonest. So within hours to days, you will have this effect. The second one, it's called a confusion. So that person just feeling very restless. It's just a fancy word for that. It might happen a little later. Um Days, two weeks, the first one is called pseudo Parkinsonian is um so I don't have to kind of remind you. It's a nice easy acronym called trap that you can memorize the symptoms of Parkinson's. Uh it happens weeks to months. The fourth one is the one that is the most horrific scenario. It's called tardive dyskinesia. Why? It is horrific. And it's because um in this scenario, the muscle side effects, the disorders are permanent. So even when, when you stop the drugs, the first free symptoms could go away. But for whatever reason, the fourth one, the tardive dyskinesia is irreversible. So you don't want to get to that stage if you find that person having this repeated hand twitching lip smacking and tongue protrusions or grimacing face that is just kind of repeatedly happening. Uh And you know, it's senseless, it's not, you know, doing anything. Um you might want to raise suspicions that this might be happening and you might have to stop the antipsychotics because once you stop you, if you, if you let it develop, it will stay on, even if you stop the drugs, the metabolic side effects. So II got the picture from uh youtube. I don't know if that's the case if you actually can gain pounds uh that way, but um the, you definitely will gain weight when you take second generation antipsychotics. So this is one of the thing you wanna counsel your patient on to be very wa careful watching what they eat um in terms of severity level, um I just put it there um might be more helpful for you when you in your in the clinical settings in third or fourth year. Um but cloZAPine is the one that cause people to gain weight the fastest and the worst one. OLANZapine pretty bad as well. Um And I kind of explained the mechanism behind it. It's because the serotonin receptor blockade causes people to reduce the amount of stie. So now they get more hungry and they eat more than they need and that's why they get weight gain. OK. The fifth questions. Thanks. Sorry. Um Chris, uh the last question is not the last question, acute dystonia. So that's uh extrapyramidal side effects. This question is not testing on extrapyramidal side effects. So there's a difference there. So I think everybody, most people got the right answer. So, neuroleptic malignant syndromes and NN MS are typified by three things. One is hemodynamic instability. So the persons get really heat, you get high fever, you get tight muscle contractions. Um In fact, so tight, it's basically lead pipe rigidity. It's like trying to bend a lead pipe. You're not gonna do it. It's so tight and the heart run really fast. So you got tachycardia, you breathe really fast, you get tachypnea, uh your BP, shoot all the way up. You got hypertension and also you get confused and agitated. That's mental status change. So the triad of hemodynamic instability, everything runs high. You get lead pipe rigidity. And the third one is you got mental status change. Whereas acute dystonia is just basically you got tight muscles and the tight muscles is very much restricted to just the head and the neck area mostly in the upper body. Whereas this one is lead pipe rigidities like your muscles tone are really, really high. It just can't even move. And these ones take days and months to happen, it hadn't happened any time. So there's a difference there. Now other side effects with antipsychotics. Um like I kinda said, you know, hyperprolactinemia. So you get more prolactin than you need. So guys will develop breast uh and for both men and woman, you will lose libido because prolactin suppress sex hormone secretions. Also some dru uh drugs can cause histamine receptor blockers. So kind of like a antihistamine makes you drowsy. And then the third one is you make alpha receptor blockade. So reduce the BP when you try to stand up to postural hypertension acetyl receptor, acetylcholine receptor blockade is kind of like your an antimuscarinic effect. So you get dry mouth, dry eyes, you get constipation, you got urinary retention, your eyes are blurred and you get cognitive decline. And then the last one is prolonged QT interval, the fifth one. And that's just saying that your heart is not beating properly, the rhythm is off. This is the last question for this unit. Um So give it a try any que any uh any try any attempt on the the answer, more answers. Mm Seems like we got a quite a different, we got some varieties there. OK. So this for this question, the answer is d neutropenia. Um Like I said, cloZAPine is a very powerful drug. It works much better than all the antipsychotics, but not everybody's put on it because of the side effects because it could be lethal. Um The big thing you need to know about cloZAPine monitoring and that's definitely gonna be somewhere in your SBA or ASAP because it's so important is that the drug can cause people to, to reduce um the productions of white blood cell, specifically neutrophils. So you got a phenomenon called agranulocytosis, which is a fancy word of not having enough neutrophils. That's the most serious complications. That's why you get regular monitoring of blood tests, specifically the full blood count. Um and if the person is uh changing dose, um increasing dose or just starting on the new drug, you monitor even more frequently. CloZAPine also can interact with cigarette smoking. So cigarette smoking is actually reduce the amount of drugs of cloZAPine in your body. That's because cigarettes have something that will induce the enzyme activity, it will increase the enzyme activity of the one that breaks down cloZAPine. So if you smoke more, then you need a higher level of drug dose to make up for the loss of it. But if you stop smoking, you also need to reduce the drug because now you're likely to get more drug inside your bloodstream because your enzyme is not breaking up as much of it. The second one is obviously metabolic side effects, which we talked about long time. The third one is it will increase the risk of seizure. Um The fourth one, it might affect the heart. It can cause inflammations of the pericardium of the muscles of all the muscles of the heart. The fifth one is the one that is least serious, but the most common is that it can cause people to develop constipation. So if anything to go by, remember if you take giving patients cloZAPine, make sure you check the full blood count regularly. So the white blood cells are not going down. Otherwise they can get serious infection and could die from it. All right. So that's, uh, the end of the psycho uh psychosis chapter. These are some of the things more fy i for you to read about. But, uh I'm not gonna go over that here, but if you have any questions, you can always email me.