CNS Pharmacology (Ar) -01 - Opioid analgesics (Part 1)

Welcome, young people, to the first video of the CNS chapter. God willing, we will dedicate this video and the next one to discussing or explaining the topic of opioid analgesics. It is one of the important topics that is always present in any exam. Before we delve into opioid analgesics, it is important to me first, if someone asks you, what are the types of analgesics you have studied or know? Tell him we have 1, 2, 3, 4. The whole world has only four types of analgesics. The first type we will talk about today, God willing, is opioid analgesics. The second class is the class of non-steroidal anti-inflammatory drugs, which you studied in the Autacoids chapter. This is a separate class. The third class of analgesics, God willing, we will talk about in the CNS chapter as well, but in a separate video. A family called analgesic anti, which are drugs that only relieve pain, but have no anti-inflammatory effect. This is the family of paracetamol, the Panadol that you take for headaches. This Panadol and its siblings. The fourth family of analgesics are drugs used for pain relief. These are drugs that are not originally analgesics, but it was found that they relieve pain in certain conditions, even if the mechanism is not clear. Let me give you examples and remind you. We talked once about diabetes and we talked about something called diabetic complications, and I told you that diabetic patients after a while develop something called diabetic neuropathy. It was found that the pain that occurs is relieved by a drug called duloxetine. Duloxetine is not originally an analgesic; it is an antidepressant. But how duloxetine relieves diabetic neuropathy, no one knows. And they said if duloxetine was not effective, the next one immediately comes, called pregabalin. Pregabalin is from a family of drugs used for epilepsy, and it is not originally an analgesic. A third drug is called carbamazepine. Carbamazepine, God willing, we will explain to you when we talk about epilepsy, and we will tell you that carbamazepine, whose trade name is Tegretol, is a very famous antiepileptic drug. However, it was found to relieve the pain specifically of something called trigeminal neuralgia. What is trigeminal neuralgia? Some people experience irritation of the trigeminal nucleus in the brain. When the trigeminal nucleus is irritated or inflamed, they start complaining of pain in half of their face, meaning half of their face has severe pain. Sometimes it is diagnosed as migraine, but it is not a classic migraine. This condition is called trigeminal neuralgia. In reality, we do not know the exact mechanism, meaning what caused the irritation of the trigeminal nerve. However, it was found that carbamazepine, if taken in high doses in this case, relieves pain. So, is carbamazepine classified as an analgesic? No, it is classified as antiepileptic. However, it was found, as I told you, that it relieves pain. So, I have class number four. These are drugs for pain relief in certain conditions. Do you want to add more? Why not mention sumatriptan? Sumatriptan was the one that relieved the pain of migraine, if you remember from what we said about the autonomic system a long time ago. In general, in the end, I want to tell you that if someone asks you in the oral exam and asks you first, what are the types of analgesics you have studied in the third year? Tell him they will not go beyond the four on the board. We, God willing, will dedicate this video and the next one to the first class, which is opioid analgesics. Before we delve into opioid analgesics, I want to talk about some definitions, some terms. We have a term called opiates, and we have a term called opioids, and we have a third term called opiopeptins. You must know the difference between these three terms. First, the word opiates. Opiates are natural morphines. By the way, the opioid family we are talking about today is called the opium family in Arabic, which are drugs that belong, in Arabic, to the family called the opium family. Why do we say this? God willing, in the fourth year, next year, you will study something called forensic medicine, and they will divide the types of drugs into separate families. You will find that each family has no relation to the next family. For example, the opium family we are talking about today, the opioid family, has no relation whatsoever in mechanism or pharmacological effect to the cannabis family. Cannabis is the hashish family. It has no relation whatsoever to the family of hallucinogenic pills and LSD and others. Agreed? So, we will dedicate the discussion to the family of opioids. This video and the next one will be about the opioid family, which is the opium family. Where does the origin of opium come from? This family comes from the plant you see in front of you, whose scientific name is Papaver somniferum. Papaver somniferum, which you see, its common name is the poppy plant. Of course, this cultivation is prohibited. However, farmers who cultivate this illegally will come and make incisions in the fruit you see, make cuts, and a milky fluid will exude, as you see. This milky fluid or exudate is what all types of morphines we will talk about are derived from. If you take this exudate that you saw naturally and separate it by chromatography, you will get natural morphines without any chemical modification. We call them opiates. So, if someone asks you what opiates are, tell him they are natural morphines. If you take the exudate you saw and make many chemical modifications, you will get many types of drugs that are synthetic and semi-synthetic. We call them opioids, meaning something similar to opiates. It has become customary to use the word opioid, and it was supposed that the word opioid refers to semi-synthetic substances. However, it has become customary for this word to be applied to all types of morphines, whether natural or semi-synthetic. So, when you say opioids, it includes all types of morphines you might see. What about opiopeptins? This third term. You studied in physiology that we have natural morphines inside our bodies. God created us with them. We have them in the brain, which produces something called endorphins and enkephalins, which you studied a long time ago. These endorphins and enkephalins are what we call opiopeptins because they are natural substances inside the body. So, you have taken three terms with us. I want to differentiate for you or draw your attention to something important. Our topic is opioid analgesics. Well, in some books, you will find the word opioid replaced by the word narcotic. They say narcotic analgesics. Both terms are used interchangeably. The word opioid and the word narcotic. However, it is preferable for you as a doctor not to use the word narcotic, because this word is considered more of a legal term than a medical term. Legal means judicial, meaning lawful. The word narcotic itself comes from the word narcosis. Narcosis means something you know the word narcosis from which the word narcolepsy also comes, meaning sleep and drowsiness. So, the word narcotic means drugs in general. In legal books, it refers to drugs in general. English and American legal books refer to drugs in general by the word narcotic. They write it like this in their books, narcotics, meaning drugs that cause impairment of consciousness. But as doctors, we should not use this word, because we are not talking about drugs from the perspective that they will cause loss of consciousness and impairment and so on. No, we will use it from the perspective that they are analgesics. So, we are looking at the good side or the beneficial aspect of them. In general, it is preferable for you to use the term opioid analgesics in medical books and to exclude the word narcotic entirely. Let the lawyers and legislators and others deal with it. Let's get to our topic. In this video, we will talk in detail about morphine. And in the next video, God willing, we will dedicate it to the rest of the opioid family. Before we delve into morphine and this family, it is important for me to do something called classification. Classification of the entire opioid family. This classification that I am explaining is a classic division found in books, very old, and has not been modified. However, what I will tell you is not all types of opioids in the world. There are now many times more than what I will tell you. But this division, as I told you, is a classic thing. There are opioids, as I told you, natural, and they divide opioids into semi-synthetic and synthetic substances. First, who are the natural substances? Chemists divide natural substances into two families. If you bring the plant called Papaver somniferum, whose picture I showed you, and take the exudate that comes out, and separate it chemically using something called chromatography, you will get many compounds. All the compounds I will mention are called natural opiates or opiates. They are actually divided into two families based on chemistry. One family is called phenanthrene ring, called phenanthrene derivatives, meaning chemically they contain a phenanthrene ring. And another family called benzyl isoquinolines. This exudate produces two large families: either the family contains the ring called phenanthrene, or its structure is something called benzyl isoquinoline. Who are the phenanthrenes? Something like morphine, for example. That's one. Two, its younger sibling, codeine. And the third sibling, whom no one hears about at all and is not used in medicine at all, is thebaine. Thebaine was named thebaine in reference to the city of Thebes. Thebes, which is Luxor, had a historical name called Thebes. I don't know why they named thebaine after Luxor. What is the connection? You don't understand. But it is there in the books. Thebaine is not used medically, but it is used in the manufacture of drugs. Any pharmaceutical company that wants to manufacture types of drugs or opioids, most likely thebaine is the starting compound they start with and make modifications to it to manufacture the things they want to produce. So, the phenanthrene derivatives are morphine, codeine, and thebaine. As for the benzyl isoquinolines, there are three others: one is called papaverine. You will hear about papaverine in the GIT chapter. It is used to treat colic. Two, something called noscapine. Three, noscapine. Why did scientists do this? Why didn't they say there are six natural substances and list them one after another? Why did they divide them into three and three? Because it was found that compounds containing the phenanthrene ring have clear CNS effects. That is, they go to the CNS and cause the things we will mention. One, they cause addiction. Three, they have a spasmogenic effect, meaning if they affect smooth muscles, they cause spasms. Reverse these three words for the other family, which is benzyl isoquinoline. This family, which includes these three compounds: papaverine, noscapine, and narceine. These three compounds have almost no CNS effect, and if they do, it is very minimal and not clear at all. Two, they do not cause addiction. Of course, because they do not reach the CNS at all. The strangest thing is number three. While phenanthrene compounds have a spasmogenic action, meaning they cause spasms in smooth muscles, you find these three are the opposite. They are spasmolytic. From this, chemists and medicinal chemists began to use the benzyl isoquinoline family to make ampoules for treating people with abdominal colic, whatever the type of colic, intestinal, renal, or otherwise. Therefore, papaverine is found in ampoules in the market under the same name, papaverine, for the treatment of various types of colic because it is spasmolytic. And remember always that papaverine and morphine both come from the same plant called Papaver somniferum, even from its name, papaverine, derived from the word Papaver somniferum. Okay, hero, we have finished the natural ones. Now for the semi-synthetic ones. If you take any of the substances on the board and make chemical modifications, you will get semi-synthetic substances. I will give you examples of something like heroin. Heroin, which I mentioned to you once when explaining the video about cough, and I told you that heroin was invented by Bayer company in Germany in 1895. The chemist Felix Hoffmann, who invented heroin by chance, did not intend to. He took morphine and acetylated it, and it produced something called acetylmorphine, which is heroin, which we later knew as heroin and its use was banned almost from 1910. It is no longer found anywhere in the world and has become something of the famous drugs that are pursued legally. No company manufactures it at all, and we do not give it to any patient, nor do we use it in medicine. I want to mention by the way that Felix Hoffmann, who invented heroin, apparently invented two drugs in the same year, and both by chance and both by the same chemical reaction. Let me remind you of aspirin. Aspirin, whose scientific name is (in parentheses) acetylsalicylic acid. Remember when I told you the story of aspirin and that Felix Hoffmann took salicylic acid and acetylated it, and it produced the word aspirin. He did the same thing with morphine. He took morphine and acetylated it, and it produced acetylmorphine, which is heroin. Both drugs, heroin and aspirin, were produced in the same year by the same chemist. In general, we will not talk about heroin at all because it is no longer used medically. There is another one called hydromorphone, its use is also very limited. And there are many others. I will reassure you and tell you that although they are many, the one that is most used is nalbuphine. Number two, when we get to it, God willing. So, hero, this diagram on the board or this classification sometimes comes with three marks. Sometimes the examiner asks you for it in the written exam, saying, classify the opioids you know. And again, I repeat that even if you give this classification, it does not mean that these are all the opioids in the world. But the 17 or 16 names on the board are examples of some opioids that you might see in your life. We have divided them into natural, semi-synthetic substances like heroin and hydromorphone, which we do not use, and we have a large category called synthetic drugs. In this video, God willing, we will talk about morphine, considering that morphine is the parent compound that we always call the prototype, the father of the whole family, to which all on the board belong. So, we will dedicate this video to morphine completely. In the next video, God willing, we will take these drugs, each drug taking one or two lines at most, because we will know most of the information from morphine. Let's talk about morphine in detail. Here is morphine. We will put the fixed headings that we are accustomed to talking about so that we do not get lost. We want to talk about two words: chemistry and pharmacokinetics, and we want to talk about its mechanism and the pharmacological effects it will have on my body. And I will not forget to tell you and remind you that the word mechanism with pharmacological effect, both mean opening a parenthesis and saying pharmacodynamics. When someone asks you what pharmacodynamics means, it means mechanism plus the effect that will occur based on that mechanism. Number three, we will talk about the therapeutic uses of morphine. Four, its adverse effects. Five, contraindications. Almost, we have no unusual headings for morphine. They are all headings we are accustomed to for many drugs. Let's talk about chemistry first and pharmacokinetics. Where does morphine come from? Morphine comes from the plant you saw, whose name is Papaver somniferum. It is a natural compound, a natural alkaloid. Anything ending in -ine, if it is natural, is usually called an alkaloid. So, it is a natural alkaloid from Papaver somniferum. Chemically, is it a phenanthrene or a benzyl isoquinoline? No, it contains the ring called the phenanthrene ring, which had CNS effects. What about its pharmacokinetics? 1, 2, 3, 4. Let's talk about bioavailability. If we take oral morphine, only 25% of the dose reaches our body and enters the blood. You will say, what happened to the other 75%? I will tell you it was lost, either during absorption or it underwent what is called first-pass metabolism. Be careful with this number, because this 25% will be a point of comparison between morphine and the other drugs that will come, God willing, in the next video. So, if anyone takes oral morphine, they should expect that only a quarter of the dose will reach their blood. What about its half-life? How long does it stay in my blood? From 4 to 5 hours, then it disappears, its effect ends. Therefore, addicts, people addicted to morphine, you will find them always needing to inject themselves with morphine every approximately five to six hours, because its effect lasts exactly from four to five hours, at most six hours. Morphine undergoes metabolism in the liver by something called conjugation, specifically glucuronide conjugation, so it is converted into glucuronide metabolites. Your book says that morphine is converted into inactive metabolites, right? But not all morphine is converted into inactive metabolites. Some morphine undergoes conjugation and is converted into inactive metabolites with no value, and some of the morphine is converted into active conjugates, although it is a small portion. In the end, I want to tell you that the correct thing to say is that part of morphine is converted into inactive metabolites, and the other part remains active, although it is a small part, and we do not want to go into the names of the metabolites, as they are of no importance to us. Excretion of morphine: 9% of the dose you take is excreted renally. And only 10% of the remaining amount is excreted through the biliary route. So, here is the pharmacokinetics of morphine. We have mentioned it in four points, and it may come in the exam for two marks, giving you half a mark for each step. So, bioavailability is only 25% because part of it is lost in absorption and first-pass metabolism. Half-life is from 4 to 5 hours. Metabolism in the liver into two things: active and inactive metabolites. Excretion by two routes: renal and biliary. Agreed, hero? Pay attention to these things so that when we make a comparison between morphine and the synthetic substances that I explained to you a little while ago, we keep these points in mind. Now, let's talk about the mechanism and pharmacological effects of morphine. Well, the whole family of opioids, whether morphine or others, all this family works on receptors called opioid receptors. It is very important to pay attention to them. Who are the opioid receptors that we know of so far? Three. One is called mu, delta, and the third is called kappa receptors. And of course, the names are Latin, as you see: mu, delta, kappa. Are these all? No, there are other receptors, but we have not studied them well. What we have studied and have reasonable information about are these three. So, we will talk to you about what we know. Mu is divided into mu-1 and mu-2, and recently, in 2003, they discovered mu-kappa. Delta also has delta-1 and delta-2. Kappa has kappa-1 and kappa-2. Is there more? Perhaps, but what we know is on the board. So, what distinguishes these opioid receptors? All of them are G protein-linked receptors. All of them, whether mu, delta, or kappa, are all like that. Is there one, for example? Can we make a table and divide the receptors as we did before in the autonomic system when we said alpha receptors do 1, 2, 3, 4, beta does what? Can we do that? In the past, in some books, we used to write mu receptors and say they do 1, 2, 3, 4, delta does what? We used to do that. However, recently, studies have proven that mu, delta, and kappa share the same effects. So, you cannot make this distinction. You cannot say mu does this and delta does that. No, they all share all the things I will tell you now. I will list for you a set of pharmacological effects that occur if you take morphine. All that I will mention is shared by the three receptors, with variations in what is called relative contribution. For example, when it comes to analgesia, I might tell you that morphine causes analgesia, but you will find that the mu receptor is the most active one responsible for analgesia. When it comes to constipation, I will tell you that these morphines all cause constipation, but the receptor that contributes most to constipation is, for example, the delta receptor, and so on. But this does not mean that delta does not contribute to analgesia, nor that mu does not contribute to constipation. No, they all share what we will mention. So, the table of distinction in receptors is meaningless now. These receptors are found where? The most important place, of course, you imagine that since it is morphine and related substances, it is the CNS. No, my dear, there is no tissue in your body that does not contain mu, delta, and kappa receptors, whether this tissue is the spinal cord, the brain, or peripheral tissue. Your entire body is full of opioid receptors. So, what will clarify the matters is the following heading, called pharmacological effects. What exactly will happen if I take morphine? Let's break down the discussion at the CNS level. We will count together 1, 2, 3, 4, eight things we will count together. What happens at the cardiovascular system level? We will count together two things. What happens at the peripheral tissue level? Here, we will count together four or five things to talk about. CNS, let's start with it. If I take morphine or an opioid, any agonist from the family, what can happen? First, analgesia. I will list what can happen, headings, and then explain. Analgesia, that's one. Two, euphoria, meaning your mood will be good. Three, miosis will occur. Four, nausea and vomiting will occur because it stimulates the chemoreceptor trigger zone in the medulla. Five, vasodilation. Six, inhibition of the cough center. So, if you are coughing, the cough will stop. Seven, inhibition of the respiratory center, because the cough center and the respiratory center are next to each other, so they are inhibited together. Eight, and finally, increased intracranial pressure. Here are eight things to talk about and finish them, and then look at the peripheral things. Let's take them one by one. Analgesia. Analgesia means pain relief. It is known that morphine is one of the most potent pain relievers on earth. But morphine's analgesia is unique, not like non-steroidal analgesics. It is unique in what? First, this analgesia is sensory and emotional. That's the first term you haven't heard before. What does sensory and emotional mean? Sometimes pain is biological, meaning I have a part of my body that hurts. And sometimes part of the pain is emotional, meaning you find the patient is deluded. Part of his fear is that he is deluded that he will die or something will happen to him, and this causes him pain. Or why would you go far? When you give an injection to a small child, the child cries from the sight of the injection, he hasn't even received it yet. This child crying from the sight of the injection is called emotional pain. He has pain and fear now. Morphine relieves pain by its two components. It relieves the sensory component because it actually works on the pain centers, as I will explain to you. And it also relieves the emotional component. So, if the patient is anxious about his pain, the patient's anxiety will go away. But at the same time, it does not cause loss of consciousness. Morphine will not make the patient sleep. It will make him, yes, it can cause impairment of consciousness, but the patient is still able to localize the source of pain or the site of pain. Meaning, a patient with severe pain, when he takes morphine, the pain starts to decrease by, say, 90% or something. But the patient has not lost consciousness, and if you ask him, where was the place that was hurting you? He will point to it because he is still fine. So, morphine's analgesia is dose-dependent, of course, logically. Let's analyze the story. So, why did analgesia occur exactly? Draw with us, if you are good at histology. We used to draw the spinal cord, a cross-section of the spinal cord. We used to draw it like this a long time ago. We used to draw the spinal cord like this, and then we would do something called the gray matter, if you remember. We used to do this, and this gray matter has here, this is called the anterior horn of the gray matter, and this is called the posterior horn. You studied this in your first year of medical school, and they told you a long time ago in histology or anatomy that any nerve that comes and divides into two parts, the sensory division enters from the dorsal horn, and then the motor part comes out like this. So, if there is a mixed sensory and motor nerve, the sensory division enters the dorsal horn. We don't care about the motor part now. As soon as the sensory division enters the dorsal horn of the gray matter, it finds an area here that looks like an inverted crescent, like something like this area. You called this area in physiology the substantia gelatinosa of Rolando, SGR. What is SGR? It is a collection of neurons that receive the signal of sensation, then allow it to pass. So, the sensory impulse comes out in something called the dorsal spinothalamic tract to the higher centers. So, if I have something with visceral pain, if I have something hurting in my body, the sensory pathway will come from the dorsal side, enter the dorsal root, then to the SGR, then exit in the dorsal spinothalamic tract to the higher centers. And it was found that this area, called the dorsal horn, this whole area, especially the region of the SGR, is full of mu, delta, and kappa receptors. It is full, meaning the highest concentration of these three receptors is in the dorsal horn area. So, when morphine acts on it, what happens? They say the pain sensation stops. It cannot continue. Why can't it continue? Because when mu, delta, and kappa act, they prevent the release of something called substance P, which is the transmitter responsible for the transmission of pain sensation. So, the signal stops, it doesn't continue, it doesn't go to the higher centers. As long as you have stopped the pain sensation at the spinal cord level, you will find the books written for you, they say this is called spinal analgesia. The mechanism I explained is called spinal analgesia. If any examiner in the oral exam asks you, what does the term spinal analgesia mean? Tell him it means that morphine has cut off the pain sensation at the spinal cord level. How? By stimulating mu, delta, and kappa, it reduced the release of substance P, so the pain sensation cannot continue, there is no connection anymore, as if you cut the connection with scissors. So, the nerve cannot continue the signal. It will not go to the higher centers, and I will not feel it. So, this is one. Count with me now. This is the first mechanism. I am still talking about analgesia. Second mechanism. Let's go to the higher centers. Go up to the brain. All the places in the brain are full of mu, delta, and kappa. All three are also present in the brain. I told you that opioid receptors fill your body, both central and peripheral. So, when morphine hits mu, delta, or kappa in the higher centers, what happens? They say it starts to activate something called the descending inhibitory control. This descending control is sometimes called the mesolimbic pathway. What is this story? This is something discovered recently. We used to think until recently that morphine's action was like this, on the spinal cord, the story I am telling you, preventing pain sensation from here. But recently, they said no, it also stimulates mu in the cortex and delta. By the way, delta receptors are found more in something called the basal ganglia, which are the thalamus, caudate nucleus, and these areas. When delta, mu, and kappa act in these higher center areas, they start sending descending inhibitory pain control. The signal coming from above to below will meet the pain sensation that was supposed to exit in the spinothalamic tract and cut it off. It's like pouring cold water from the balcony onto what is coming out. So, you have now created two types of analgesia. Once it acts on the spinal cord, cutting off the signal at the spinal cord level. And once the inhibition comes from the higher centers from above. And as long as the inhibition comes from above through descending pain control, we call this supraspinal analgesia. That's number two. Morphine used to give us spinal analgesia and supraspinal analgesia. Three, it's still not stopping there. There are still three and four. Number three, morphine reduces norepinephrine release in the CNS. What is the story of norepinephrine? When you reduce norepinephrine, norepinephrine is responsible for you being awake and alert. When morphine cuts off norepinephrine and reduces it, the patient starts to become less alert. From here comes the explanation of the term that morphine relieves sensory and emotional pain. Emotional means that morphine not only relieves pain sensation but also relieves the reaction to that pain. What does that mean? The patient is no longer focused on his pain. He is no longer alert. He still has pain, yes, he can still say, doctor, this part still hurts me, but it doesn't matter. This "it doesn't matter" is gone. His mind has gone to other things. Why? Because we have reduced his norepinephrine, so he is no longer focused on his pain, so he is no longer anxious. So, if there was an emotional component to the pain due to anxiety, it is gone because of this norepinephrine. Four, number four, there is now talk and many studies saying that morphine acts on peripheral opioid receptors in inflamed tissue. If I have a part of my body that hurts and is inflamed, morphine does not just act centrally, not here, but also on the higher centers. No, it also acts peripherally on that part and reduces the release of pain mediators in the painful area. It's as if morphine has acted. So, analgesia is achieved through four methods or four mechanisms. Once spinal, when it acts on the spinal cord, it does what we said. When it acts on the substantia gelatinosa of Rolando, it reduces substance P, so the pain sensation cannot exit. It goes to the higher centers, it's cut off. So, this is called spinal analgesia. And once it activates mu and delta in the higher centers, sending descending inhibitory pain control pathways from above, which meet the pain sensation and cut it off. This is called supraspinal analgesia. Three, when it reduces norepinephrine and makes the patient less focused on his pain, thus relieving the emotional component. Last, when it acts peripherally and reduces pain mediators from the inflamed tissue. The surprise is that morphine causes these great things and relieves all types of pain, except itching. Itching, sensitivity, and scratching. If any patient has sensitivity and is itching all over his body and you give him morphine, thinking that morphine will relieve the itching, you will make him miserable. It is morphine itself that increases itching. So, it relieves all types of pain in the world, except itching. Why? For two reasons. One, two. First, itching sensation, fundamentally, if you studied physiology, itching has its own special receptors and its own nerve fibers and centers in the brain that are completely different. So, it does not belong to the family of pain sensation. Two, you will know later that morphine causes histamine release, and histamine itself, you know, increases itching when it acts on itching receptors and causes irritation of nerve endings. So, morphine relieves any pain. Itching, sensitivity, and a patient who is itching all over his body for any reason and has allergies, do not give him morphine, because it will increase it. Therefore, in Arabic movies, when the director wants to portray an addict or a drug dealer, he always shows him making a movement with his neck. Look, for example, Nour El Sherif in this movie, you will see the movement he makes with his neck because they always have irritation in the neck area due to histamine release, so they always make that gesture. So, we have finished with analgesia. We have analyzed it all and said that morphine has nothing to do with itching, quite the contrary, it will increase it. Let's move on to euphoria. Euphoria, we have no discussion about it. We don't have much to say about euphoria. Euphoria means that the patient or person feels good because the mu receptors in the higher centers make the person forget his problems and make him not focused on them. He is not unconscious, no. The person who takes opioids, if he has many problems, the problems exist, but he is not focused on them. And he says, I am relaxed, I don't care. And this is what makes people addicted to opioids. In general, euphoria is not a medical use for us. I can understand using morphine as an analgesic, yes, I understand that. But we will never use morphine or opioids for this purpose. Do not come and ask me why morphine is not used to treat depression. No, I have specialized drugs that make a person feel good without causing addiction or all this nonsense. So, euphoria is a pharmacological effect that exists, but we will not benefit from it. We will not use it for anything. Miosis, number three. Miosis. Why does morphine cause miosis? Because morphine acts on the midbrain, the area.

The midbrain's structure, you know, its nucleus number three, which is the oculomotor nerve nucleus. This nucleus is called the Edinger-Westphal nucleus. Morphine stimulates it. When it stimulates it, miosis occurs through a central mechanism. Therefore, how will the eye appear? Always look at the eyes of addicts. If you draw the eye, look at the eye, you will find severe miosis, bilateral, on both sides. So, what if someone, for example, a sharp opium or sharp morphine user, is arrested? They know how to look. He tells him, "I didn't smoke, by God, sir, by God, I didn't smoke." He says, "His eye is already showing. His eye is open because he has something called pinpoint pupils. Pinpoint pupils, as if the pupil is made into a dot with a pen." Why? Because in reality, when you caused miosis, you didn't work peripherally. You brought it from above, from the nucleus of the Edinger-Westphal nucleus. This nucleus is almost a fixed feature in all addicts. You can tell an opium addict by looking at their eyes. This matter exposes them. Their eyes reveal them. After that, nausea and vomiting, because morphine goes and stimulates an area in the medulla. Let's go down a bit. It stimulates something called the chemoreceptor trigger zone. So, those who drink opium always have no appetite and always want to vomit. Three or five. After that, vagal stimulation. It will go down a bit in the medulla. You find the vagal nucleus. It stimulates it. When it stimulates the vagal nucleus, it causes bradycardia. Not just bradycardia, but all the things of the vagus nerve. You can count other things besides bradycardia. After that, unfortunately, we will go down and cause inhibition. We have now stimulated three areas one after another. It stimulated the Edinger-Westphal nucleus in the midbrain. Just below it, the chemoreceptor trigger zone, it stimulated it. Below them, the vagal nucleus, it stimulated it. That's three things. Then, in the medulla, it will go to the cough center and inhibit it. So, if you are coughing, the cough will stop. And from here, when I was explaining to you in the video about the treatment of cough, I told you that for hundreds of years, most people knew that morphine and this family eliminate cough. And this is what led them to use morphine and this family for about 100 years. They used it for this purpose. And Felix Hoffmann, when he made heroin at Bayer, intended to make a drug that would specifically target the cough center. He modified morphine, believing it would be more selective for the cough center. In general, all opioids are distinguished in this matter of cough. After that, the last thing it will do is inhibit, unfortunately, the respiratory center. Because the respiratory center is next to the cough center, it causes inhibition of the respiratory center. But this requires high doses. The dose that the drug user takes normally will not cause this. But over time, when they increase the dose day after day, because they will develop tolerance, there will come a moment when this dose will be able to affect the respiratory center. Then what will happen? Apnea. Their breathing will stop. And carbon dioxide retention will occur. And happy new year. I have now gone through seven things. Let's pause at number eight for a bit. What was number eight? Morphine increases intracranial tension. Let's pause at the word "increase intracranial tension or pressure" for a moment so that you don't get confused when you study. Because you will read that morphine, when it inhibits the respiratory center, in reality, it causes CO2 retention. Naturally, hypercapnia will occur. And it is known that CO2 causes vasodilation. This is its specialty, by the way. Carbon dioxide, when it increases in your blood, causes vasodilation more than it causes cerebral vasodilation. So, what's the story? Why will you get confused? Because you thought that since morphine causes CO2 retention, and this causes cerebral vasodilation, you expected the pressure inside the brain to decrease. Yes, the confusion will come from here. No, my dear. First, you must know that the word "intracranial pressure" does not mean the pressure inside the blood vessels. The matter is different. The word "intracranial pressure" means the pressure inside the cranium, inside the skull as a whole. So, when you talk about the skull, everything inside the skull, from structures, from blood vessels, that's one. CSF, that's two. Brain tissue, that's three. The pressure of these three together is called intracranial pressure. So, how will this be measured? How will the total pressure inside the skull be measured? It is usually measured from the CSF if you want to measure intracranial pressure. You insert a probe into the lateral ventricle, which was in the brain. We measure the CSF pressure. The CSF pressure represents the total pressure inside the cranium, which is the intracranial pressure. The normal intracranial pressure, which is in parentheses, the CSF pressure measured from the lateral ventricle, should be between 7 and 15 mmHg. And when do you say that the intracranial pressure has increased? If it rises above 25 mmHg. In this case, there is an increase in intracranial pressure, and the patient will start complaining of manifestations, stories that are not relevant now. So, why am I explaining all this? To explain to you that when morphine increases CO2, it causes cerebral vasodilation. So, vasodilation means that the amount of blood has increased and the blood vessels have widened. So, where will the volume of this expansion come from? Because the word "blood vessel widening" means that I have increased the volume and blood flow. So, at whose expense will this volume come? Because the skull is bone and cannot expand. So, vasodilation will come at the expense of the blood vessels and all the blood sinuses. They will start to press on the brain tissue. And when the brain tissue is pressed, it will press on the CSF pathways. So, when you want to measure the CSF pressure in this case, you will find that the pressure has increased. This is what is meant by "it raises intracranial pressure." Please pay attention to this word so you don't make a mistake in the exam. You might say, "Doctor, how does morphine cause cerebral vasodilation, and how do you say it raises intracranial pressure?" I have explained it to you. You will respond with one word: "Sir, what is meant by intracranial pressure is the overall pressure inside the cranium, which is the result of the numbers represented by blood volume, the amount of blood flowing in the brain, plus the CSF pressure, plus the pressure inside the brain tissue. These three together are called intracranial pressure. And how is it measured? What represents it? It is the CSF pressure, as I explained to you." In this way, we have finished the central effects of morphine, five things that will happen. Let's move on to the peripheral effects. Let's go to the cardiovascular system. Morphine causes two things: it lowers blood pressure, causing hypotension, and it causes bradycardia. So, why hypotension? As a result of vagal stimulation. You know that the vagus is parasympathetic, so blood pressure decreases. It also causes histamine release, and histamine is known to cause vasodilation. Bradycardia? It comes from the vagus. You know from the autonomic nervous system that if a person's blood pressure is low, they should have reflex tachycardia. This is logical. However, reflex tachycardia will not occur here. It will never happen because the patient has vagal stimulation, and the vagus nerve is known to cause bradycardia. So, blood pressure will decrease, yes, but it is impossible to have reflex tachycardia as long as the vagus is working. When you are in the hospital in the emergency room and a patient comes in with hypotension, and you put your hand on their pulse and find bradycardia, it is likely that this narrows down the causes to a few simple things. The patient might have taken drugs. All drugs, opioids, cause this. They cause, or rather, most of them, not all, cause vagal stimulation and bradycardia. So, you find the patient's blood pressure and pulse are less than 60. That's one. The patient might have taken a beta-blocker. Beta-blockers also lower blood pressure and cause bradycardia. After the cardiovascular system, let's move on to the smooth muscle. On the smooth muscle, morphine, number one, causes constipation. We explained this in the GI tract when we were explaining the diarrhea part. I told you that the entire opioid family, when it stimulates the mu and delta receptors in the enteric nervous system, causes two things. I am repeating this. First, when it stimulates the mu receptor, it increases something called non-propulsive segmental movements. So, the intestine starts to move, but in place, non-propulsive. So, food or fecal content does not move from one place to another. Second, when it stimulates the delta receptor, you are increasing water absorption. So, the food content dries up. As long as the food content dries up, diarrhea will not occur. Constipation will occur. Therefore, remember or go back to the GI tract. We told you that we use opioids to treat diarrhea. But we have made opioids that do not cross the blood-brain barrier. And if your memory is strong, you will remember their names. One was called loperamide, and the other was called diphenoxylate. I told you that they are derivatives of meperidine or opioid derivatives that do not cross the blood-brain barrier. They work peripherally only on mu and delta and cause constipation. When I need to cause constipation in a patient. Number two, they go to the smooth muscle in the bronchi and cause bronchoconstriction. Bronchoconstriction, in fact, has three causes, not just one. Therefore, if you make a mistake and give morphine to a patient with bronchial asthma, you will make them miserable, if not kill them. Bronchoconstriction is caused by three reasons. Let's analyze them. One, it causes vagal stimulation, and the vagus causes bronchoconstriction. Two, it causes histamine release, and histamine is known to be detrimental to the bronchi, causing severe bronchoconstriction. Three, morphine itself, on the mu and delta receptors in the bronchi, causes bronchoconstriction. So, bronchoconstriction comes from multiple pathways. Number three, it affects the urinary bladder, especially in the elderly. It causes something extremely unpleasant. It affects the urinary bladder wall, increases its tone, and causes spasm in the urinary bladder, causing a feeling of urgency. The person feels like they need to go to the bathroom. Then, it also affects the external urethral sphincter. It causes spasm in it as well. That is, it presses on the urinary bladder wall and also causes spasm in the internal urethral sphincter, closing it. So, the patient has a feeling of urgency, wants to go to the bathroom, but has difficulty urinating because you have closed the sphincter. This is a stupid movement. It would have been logical to open the sphincter when you press on the bladder wall. But morphine is annoying, so it presses on the wall and closes the sphincter from the outside. Of course, this will be very annoying and noticeable in the elderly who have enlarged prostates. This will be very pronounced in them. Therefore, I will tell you later not to give morphine to an elderly patient complaining of prostatic enlargement. It will do the same thing in the gallbladder. It will affect the gallbladder wall. That is, the gallbladder, and also cause spasm in the wall, pressing on the gallbladder. Then it will affect the sphincter of the gallbladder, called the sphincter of Oddi. Oddi, by the way, is an Italian name. It will affect the sphincter of Oddi and cause contraction in it. So, it presses on the bladder and closes the sphincter. So, when will this appear and who will it make miserable? It will make miserable the patient who has gallstones. Because someone with gallstones will feel severe colic. You are pressing on the bladder and trapping the flow. It will affect the uterus. If the woman is in labor, the uterus normally contracts in a specific way and opens the cervix. It will do the same thing in the uterus. First, morphine interferes with physiological uterine contractions. The thing that God created during childbirth will not happen. So, childbirth will be prolonged. Not only that, but it will also cause spasm in the cervix. Just as it caused spasm in the sphincter of the gallbladder, and just as it caused spasm, it will also cause it here, or what we call contraction will not happen. So, the result is that if the woman is in labor and takes morphine, instead of giving birth in an hour, she will take two or three hours. So, it will cause prolongation of labor. So, morphine, overall, you feel it is a spasmodic drug. The evidence is here. It causes constipation and intestinal spasm, bronchial spasm, urinary bladder spasm and internal sphincter spasm, and bladder and uterine spasm. The same story. Let's move on to the therapeutic uses of morphine. If you are smart, you will realize from the explanation we have given that we have reviewed the spectrum of morphine's effects, the things morphine does in your body. Pick the things you like and consider them therapeutic uses. The things you don't like from everything I've said, set them aside and consider them adverse effects, so we don't waste much time. The first use or therapeutic use of morphine and the opioid family will be analgesia. And analgesia represents more than 90%, if not more, of the uses of the opioid family. To whom will you give it? Who needs opioids? Who needs morphine? The patient with a headache? No. For mild pain, non-steroidal anti-inflammatory drugs are sufficient. The patient with back pain who comes to the clinic saying, "Doctor, my back hurts a lot and I can't." Well, they can take NSAIDs. But you are talking about severe pain or moderate intensity pain, something that the patient cannot bear, like cancer pain, or pain after major surgery. They can take morphine or any member of the opioid family. So, how is morphine available in the market? What are its forms? We have modified-release morphine tablets. They are called modified-release morphine. The tablet contains 15 mg. That's one type. We have regular morphine tablets. The tablet contains 30 mg. It's not modified-release or anything. The modified-release means the tablet lasts for 12 hours. So, the patient takes one tablet in the morning and one in the evening. But there is regular morphine. The tablet lasts for four to five hours. There is a tablet containing 30 mg. We also have morphine injections or ampoules. The ampoule contains 10 mg. You can give this ampoule if the patient has severe pain. It is best to give it subcutaneously. This is the official route for morphine. But if you are in a hurry and the patient has something like myocardial infarction or acute pulmonary edema, something intensive care, you can divide the ampoule into two. Instead of 10 mg, make it 5 mg and give it intravenously. Please do not give morphine, do not give the whole ampoule intravenously, because morphine causes hypotension, as you have seen. So, if you are in a hurry, it is okay. Morphine can be taken. Divide the ampoule into two and give it intravenously. Some people even say that 5 mg is too much. They say, "No, just 3 mg is enough." 3 or 4 mg intravenously to avoid the hypotension that will occur. There is a fourth way to give morphine. How? For example, if you draw the spinal cord. It ends at something called the cauda equina. Anesthesiologists sometimes, after major surgeries, for a patient who has undergone major surgery and is expected to have severe pain after the operation, instead of giving them morphine orally or by injection, the anesthesiologist inserts a small catheter into the epidural space. They call it an epidural catheter and secure it with plaster. Then they start giving morphine through this catheter. The morphine travels in the epidural space and reaches the central nervous system without causing peripheral manifestations. It doesn't lower blood pressure or anything. And it lasts for 24 hours. The dose you give in the epidural space will last not four hours or 12 hours, but 24 hours. So, this is the fourth method. I just want to draw your attention to something here regarding analgesia. This is often asked in fellowship exams. If you are taking an English fellowship exam, they always ask: If a patient is on morphine for cancer or something, for chronic pain, and you are forced to keep them on morphine, and suddenly they experience what is called breakthrough pain. Breakthrough pain is sudden pain that occurs. This is common in cancer patients. So, they are already on good analgesia, but suddenly during the day, you find them screaming. In this situation, called breakthrough pain, how do you act? They are already on morphine. They are taking morphine in the morning and evening, modified-release tablets of 15 mg. How do you act in this situation? We have a rule and a guideline that we don't disagree on. If this happens, give one-sixth of the morphine dose to the patient to alleviate the breakthrough pain. For example, if your patient was on one tablet in the morning and one in the evening, 15 mg each, then they are taking a total daily dose of 30 mg. If they complain during the day that the pain has increased significantly, what is one-sixth of 30? It's 5 mg. So, I am allowed only 5 mg to give to the patient to alleviate the breakthrough pain. What if my patient is on oral morphine, for example, and the dose was, say, 60 mg per day? This is the total daily dose they are on. They have breakthrough pain during the day and are screaming. So, one-sixth of 60 is 10 mg. So, I will give them 10 mg to alleviate the breakthrough pain. It is forbidden to exceed one-sixth of the total daily dose, otherwise you will get the patient into trouble. This question is often asked in exams. Memorize the number one-sixth. We are done with analgesia. Let's move on to the second use of morphine. It can be used in a condition called acute pulmonary edema. I mentioned it to you once in cardiology. I told you that sometimes a patient already has left-sided heart failure. They have had left-sided heart failure for years. They sleep and wake up suddenly in the early morning with severe shortness of breath, dyspnea, and cannot breathe. They have cyanosis and severe tachypnea. What happened? They say it's because the heart cannot eject blood. So, the blood coming from the lungs accumulates. It cannot be dealt with. So, pulmonary congestion occurs. This happens more at night when they are sleeping. The pulmonary congestion causes pulmonary edema. The patient wakes up in the early morning with shortness of breath, gasping for air, and their life is draining away. I told you that this patient must be hospitalized. They cannot be treated at home. That's one. Second, I told you that they take a morphine injection of 5 mg intravenously. Here, I am in a hurry because this condition is life-threatening. The patient is gasping for air. Imagine what happens to you when a few drops of water accidentally enter your lungs, and the choking you experience. Imagine the patient whose lungs are filled with water. Look at their condition. Of course, they have severe respiratory distress, their life is draining away, they have severe tachypnea, and they are even leaning forward. They cannot even straighten up and talk to you. And I told you that even when you admit the patient to the hospital, they should be in a sitting or semi-sitting position. They must not lie on the trolley, because when they lie on the trolley, the shortness of breath and the water will cause severe dyspnea. So, here I want to tell you that this patient, among the things they will receive, will receive 5 mg of morphine intravenously. Why? Number one, the patient has severe distress, as you can see, and their life is draining away. They have the feeling that they are going to die. As soon as they receive 5 mg intravenously, the distress goes away, and the pain the patient has goes away. I told you it has two components: sensory and emotional. That's one. Second, morphine will also cause vasodilation. Welcome. Vasodilation? How did this happen? Didn't I tell you a while ago that morphine causes histamine release? Didn't we agree that it causes this? Remember when I was explaining histamine, and I told you that histamine dilates or opens the precapillary sphincters? You know that 90% of capillaries in your body are closed to prevent blood from entering the venous side from the arterial side. So, 90% are closed. When you increase histamine release, histamine opens this sluice gate, the precapillary sphincter. So, all the blood on the arterial side enters the venous side. This causes venous pooling. So, the 5 liters of blood in your circulation will be trapped in the venous side, and they will not be apparent, and venous return will decrease. This is one of the causes of low blood pressure, by the way. This action, which histamine causes, this venous pooling, is excellent for a patient with acute pulmonary edema. Why? Because when you take all the blood to the venous side and reduce venous return, the effective plasma volume or effective blood volume in circulation decreases. So, the blood coming from the heart to the lungs decreases. So, pulmonary congestion does not occur. The patient has pulmonary congestion and water in their lungs. When you reduce venous return and cause venous pooling, the right ventricle will not receive much venous return. So, when it ejects blood to the lungs, the amount will be small, and pulmonary congestion will not occur. Number three, the patient with acute pulmonary edema is admitted to the hospital with severe tachypnea. Tachypnea, shortness of breath. Why is there shortness of breath? It is very logical. The patient's lungs are already filled with water. All of this is water. There is no effective gas exchange. This is all considered dead space, water. They are alive and standing on their feet now with the little air in the apical region here. So, they have hypoxia, and hypoxia sends signals to the respiratory center above, increasing the respiratory rate. That's one cause of tachypnea. Is this good? No, it's not good for this patient. Because it causes severe exhaustion. They are completely depleted, their life is draining away. They cannot even complete a sentence when you talk to them because of the severe tachypnea. Morphine, when it goes and calms the respiratory center, didn't you just learn that morphine inhibits the respiratory center? We won't say it causes inhibition. The dose I will give the patient, 5 mg, will not cause inhibition, but it will slightly calm the respiratory center. Instead of firing uncontrollably and the respiratory rate driving the patient crazy, it will calm it down a bit. So, the tachypnea the patient has will decrease due to the hypoxic drive. So, the patient will start to catch their breath, relax, and breathe with you. So, their life will not drain away. So, you have now seen that morphine in acute pulmonary edema has done three excellent things. Let me summarize what I said. First, it is an analgesic, a respectable analgesic, and it will alleviate the stress and pain the patient has, both sensory and emotional. Second, morphine will cause vasodilation because it will open the precapillary sphincters due to histamine release, causing blood pooling on the venous side. So, the effective blood volume in circulation will decrease. So, the blood coming from the heart to the lungs will decrease, and pulmonary congestion will decrease. Third, and finally, the tachypnea that is bothering the patient due to the hypoxic drive will decrease. Because morphine calms, don't say it causes inhibition. Say it just slows down the respiratory rate. Because if you say morphine causes respiratory inhibition, that's not correct. It just slows down the respiratory rate. So, the tachypnea the patient has will decrease, and the exhaustion the patient has will decrease, and they will start to breathe with you. Third use of morphine. In anesthesia. Anesthesiologists sometimes, of course, use many types of general anesthetics. It's not our business now, general anesthesia. But I want to tell you that an anesthesiologist sometimes resorts to morphine as an addition to the anesthesia they give, which is the anesthetic they give. In this case, it is called an anesthetic adjuvant. Adjuvant means a helper. When? In major surgeries, large operations that will take a long time, and the patient is expected to have severe postoperative pain. Then the anesthesiologist uses morphine as an adjuvant, as a helper alongside the anesthetic. Fourth use of morphine. After the three things we mentioned, it will be a recommendation, not a use. We will recommend it to you. We will recommend that you use it, if circumstances force you, as an analgesic for a patient with severe colic. A patient comes to the emergency room. You were on duty in the emergency room, and you found a patient with severe renal colic, which causes terrible pain, or severe intestinal colic. You gave them morphine. Okay, fine. Morphine will alleviate the pain. But I just told you that morphine has an undesirable characteristic: it is spasmodic. So, while it will alleviate the pain sensation centrally through the spinal cord and cortex, etc., peripherally, on the smooth muscle, it is spasmodic. So, complete your kindness. Now, I want to recommend something to you. Complete your kindness and give them an ampoule of atropine with it. Why? Because atropine will prevent vagal stimulation that morphine causes. Because morphine causes vagal stimulation, bradycardia, problems, and spasmogenic effects. Atropine will prevent these disasters caused by the vagus. So, it will reduce the spasmodic effect of morphine. Because atropine is known to be antispasmodic. So, it is preferable to use morphine with atropine if you are treating severe colic. Of course, this sometimes comes up in exams with a grade. They ask: If I am forced to use morphine in treating colic, what is preferable to give with it? I will tell them for these two reasons: because morphine is spasmodic on smooth muscle, while atropine is antispasmodic. And also tell them that morphine causes vagal stimulation, bradycardia, problems, and bronchoconstriction. Atropine will prevent these disasters that morphine causes. Of course, you will find the examiner, if it's an oral exam, will not let you go without asking: "What if it's biliary colic, doctor? Pain in the gallbladder?" I will say, "No, sorry. Here, we stop. Morphine should not be used to treat biliary colic at all. It is contraindicated." Because, as I told you a while ago, if the patient is screaming due to gallstones, morphine will worsen the pain because it will cause spasm of the gallbladder. So, morphine is used for all types of colic except biliary colic. It will worsen biliary colic itself. We have reached adverse effects and contraindications of morphine. And if you are smart and alert, most of the explanation we have given, the bad things, set them aside and consider them adverse effects. They will also be contraindications. Let's start with adverse effects. Let's look at the CNS. What is the most frightening thing about morphine and opioids? Tolerance and physical dependence. The word "physical dependence" is the polite word for addiction. We don't like to say "addiction," so we replace it with "physical dependence." Let's go step by step. What else worries you? I will tell you what worries us is that day after day, the addict or someone who has tried opioids and experienced euphoria will find that yesterday's dose no longer works. Because the receptors, mu, delta, kappa, and others, undergo physiological changes, adaptation. So, the patient will want to take a higher dose of morphine every day. This is the story you studied in general medicine under the title of tolerance. Now, we have a small problem. This is often the reason when you hear that a famous artist, an international celebrity, was a drug addict and you hear that they died suddenly. It will likely be due to the reason I will explain to you. For example, the dose that causes euphoria and makes you feel good might be, say, 10 mg. 10 mg of morphine might make you euphoric and make you feel great. But to cause respiratory inhibition, I told you a while ago that to affect the respiratory center and cause inhibition, you need a high dose. Say, the dose that causes respiratory inhibition was, for example, 100 mg. Let's assume. Ten times. Therefore, a person who is new to opioids, still new to the game, takes 10 mg, feels good, no problem. But tomorrow they will need a higher dose, 20 mg. And after a month, they will need 30 mg. Over time, they will start increasing the dose day after day until one day they will have to take a high dose because they have developed tolerance. It will happen that this high dose is what causes respiratory inhibition. In that case, they take this dose and die. You will say, "Well, shouldn't the respiratory center also adapt? Shouldn't it get used to a higher dose?" No, the respiratory center does not adapt. There is no tolerance to respiratory inhibition. It happens at, say, 100 mg. I'm giving a number. It will continue to happen at 100 mg. You are the one who keeps increasing the dose to get euphoria because you have developed tolerance in the cortex and other areas. One day, you will increase, increase, increase until you reach the dose that causes respiratory inhibition, and the person takes morphine and never wakes up. And this is the scientific reason when you hear, as I told you, that a famous artist, a drug addict, suddenly died at home. They opened the house in the morning and found them dead in bed. They say, "He died of an opioid overdose." This is because they reached the dose that causes respiratory inhibition. Good, hero. That's one piece of information. The second piece of information I want to draw your attention to is dependence or addiction. It occurs with the first dose. No, dependence or addiction occurs with repeated doses of morphine. They say it happens within 24 to 48 hours. Within a day or two, if you take morphine every four hours, that is, its half-life, exactly every four hours, you take a morphine injection for 24 to 48 hours, this person becomes an addict. They can no longer stop taking morphine. After 48 hours, they feel bad. They need to take morphine again, and that's how they enter the path of addiction. There is a second problem still in the CNS. I just told you that morphine causes respiratory center inhibition. That's number two. Still number three. I just told you a while ago that it increases intracranial pressure, and I drew your attention to the word "intracranial pressure." It does not mean the pressure inside the blood vessels, but the overall pressure inside the cranium, inside the skull, called intracranial pressure. And morphine increases this. Outside the CNS, draw a line. At the level of the bronchi, didn't it cause bronchoconstriction and make patients with bronchial asthma miserable? It is absolutely contraindicated, by the way. Any patient with bronchial asthma, never, ever, even think of morphine or opioids. At the cardiovascular system, what did it do? Didn't it cause hypotension with bradycardia? Draw a line. At the level of all smooth muscles, what did it do? Didn't it go to the urinary bladder and cause a feeling of urgency because it pressed on the wall and also caused urinary retention, causing a feeling of urgency and difficulty urinating? That's one, especially in people with enlarged prostates. What did it do in the gallbladder? Didn't it press on the wall and close the sphincter of Oddi? So, if this patient had gallstones, they would be miserable and severe pain would occur, and it's not unlikely that the gallbladder would rupture. It did this to the uterus. What did it do? Didn't it cause uterine spasm and prolong normal labor? If a woman in normal labor would take an hour, I told you it might take two or three hours if she took morphine because of the spasm it causes. All these are disasters that morphine causes. It also causes constipation. Patients who take drugs, drug addicts, don't always complain of constipation to the point that, my dear, they often advise us. They say if someone has to be on morphine for chronic pain, for example, if they have cancer and you are forced to keep them on morphine, they say expect constipation. This is very common. And they always advise us in the guidelines to write a laxative for this patient because morphine is expected to cause severe constipation. So, you will find in the guidelines two lines that we all memorize. They say: The patient taking morphine for cancer, if they complain of breakthrough pain, what is the dose they should take? I have already memorized it for you. They will take one-sixth of the total daily dose. Second, what is the good advice you should write for them in the prescription next to the morphine? I will tell them the best thing is to write a laxative for the constipation they get. We come to contraindications. They are the same contraindications. We will reverse them. They will be the same side effects. First, who should not take morphine? Someone with head trauma. Why someone with head trauma? Because increased intracranial pressure is expected. If a patient is expected to have increased intracranial pressure, and morphine increases intracranial tension, then avoid morphine. Now, in reality, you will find books or sources differ on this. You will find many books saying, "No, it's okay. Someone with head trauma can take morphine. Don't worry." Not all patients, not all patients who have accidents and enter the emergency room, etc., have high intracranial pressure. Not all of them. The majority who have car accidents and enter the emergency room, etc., do not have high intracranial pressure. Don't worry about it. Give them morphine normally. But who am I telling you not to give morphine to? The patient with head trauma, and it has been proven to you by any means that their intracranial pressure is high. You will say, "How was it proven? How will I measure intracranial pressure?" That's not our topic now. But I will quickly tell you. A patient who had a car accident or something, and as part of the assessment, when you are doing a general assessment, you look at the fundus of the eye, you look at the retina. Because the retina is the mirror of the brain. It shows you what is in the brain. A patient with increased intracranial pressure due to an accident or otherwise, it appears immediately in the retina, in the blood vessels of the retina. There are criteria that I am not going to discuss now. But I want to tell you that an experienced doctor standing in the emergency room, seeing a patient with head trauma, as part of their general assessment, can quickly determine if.

This patient has increased intracranial tension, and in this situation, morphine is forbidden. Or, this patient has a hematoma, but there is no problem with the pressure, and therefore, he can receive morphine. Agreed, champ? So, this is just the first part to get it out of the way. Two: The patient with bronchial asthma, I told you that it is absolutely contraindicated. Three: The patient with hypovolemia, hypotension, or bradycardia, for any of these three reasons, should not receive morphine. And I will remind you again because I know you forget. I told you once before when we were explaining cardiology that some people get myocardial infarction, and the infarction is called inferior. When the infarction occurs in the inferior wall, it takes the septum with it, and therefore, the bundle is no longer able to conduct well. So, the patient with inferior MI often has bradycardia. Remember from cardiology that I told you this patient should not receive morphine because morphine causes vagal stimulation and will increase bradycardia, and he will receive an alternative medication that I will explain to you in the next video called meperidine. Meperidine does not cause vagal stimulation; it is a pain reliever, but it does not cause vagal stimulation. So, again, the patient with hypovolemia, hypotension, or bradycardia for any reason should not receive morphine, so as not to increase his bradycardia. Four: The elderly man who is 60 or 70 years old and complains of senile prostatic enlargement. Didn't I tell you that morphine can cause urinary retention? It will cause it, and he doesn't need it. Five: The patient with gallstones. I just told you that morphine will put pressure on the gallbladder and close the sphincter of Oddi, so it can cause rupture and lead us into problems. Six: The patient with something called myxedema. Myxedema, or hypothyroidism. This patient should not receive morphine at all. You will ask me why? I will tell you for more than one reason, not just one or two. First, the patient with myxedema has an exaggerated response to morphine. If morphine causes a pharmacological effect in a patient with myxedema, the effect you see will occur at a rate of 2 to 4 times. He might have all the problems in the world. This is one. Second, the patient with myxedema and hypothyroidism does not have bradycardia. Well, I just told you that morphine should not be given in bradycardia. So, this is another reason why we don't give it to these people. Next: The patient with liver failure, any liver problems, chronic liver disease, avoid morphine. You will ask me why? I will tell you. One: Wasn't morphine metabolized in the liver by 75%? My dear, didn't I tell you at the very beginning that when I take oral morphine, only 25% reaches my blood, and 75% is destroyed by the liver in first-pass metabolism? So, the patient with liver disease, he doesn't have metabolism, so the morphine will accumulate in his blood. And already, second: This patient was prone to hepatic coma, if you remember. We were worried about liver patients because toxins are released from the intestine and cause them something called portosystemic encephalopathy, if you remember from GIT. Since this patient's liver cannot metabolize morphine, and second, he is already prone to coma, morphine will officially put him into a coma because it will accumulate in his blood, and morphine itself will officially lead him into a coma. Finally: Extremes of age. Extremes of age, meaning very young children and the elderly. Morphine is not recommended at all for them. Because young children will not tolerate morphine; they will experience all the adverse effects of morphine that you have heard about, including the most important one, respiratory inhibition. This will occur more with children and the elderly, so please stay away from them. For example, a young boy, eight years old, comes to the emergency room screaming from abdominal pain, and you give him morphine. He will not tolerate morphine. An 80-year-old person comes with a twisted leg while walking, and you give him morphine in the emergency room. No, he will not tolerate morphine. Respiratory inhibition may occur, and all these problems may happen to him. Finally, we advise you, champ, since you will be in the emergency room and giving morphine all day to people, do not give morphine to a patient with an undiagnosed abdominal pain. That is, a patient comes to the emergency room screaming from abdominal pain, called acute abdomen. Acute abdomen could be acute appendicitis, it could be anything that needs diagnosis. First, get a specialist. You are a young intern, or a junior resident, just starting in the hospital. A patient comes in screaming from abdominal pain. Send someone older than you to look into the matter. Because if you rush and give morphine, the pain will go away, and the senior doctor will come and find nothing to examine the patient's abdomen. He will find that the pain is gone, and what is present is not serious, and the patient will tell him, "I'm fine now." He will leave. It happens that this patient has acute appendicitis. You have masked his pain. He will come back from you after five or six hours, or the next day, with a ruptured appendix and peritonitis, and get into a big mess. So, please, when a patient comes to you in the emergency room and has acute abdomen and is screaming from abdominal pain, do not give morphine without knowing what the problem is first. Put your hand on him first and see what he has. What if you don't know what he has? Send someone older than you to diagnose and see what the patient has before giving morphine. It might not be appendicitis; it might be that he is screaming from abdominal pain due to gallstones, and he has acute biliary colic, and morphine in this case will worsen the condition. So, the end result is: do not rush to give morphine, or you will mask the pain, and we will not know what the patient has. It could be something serious, and he will get complications. We are done with the topic of morphine. Let me tell you a couple of words about something at the end called morphine toxicity. Morphine toxicity can be chronic or acute. I will tell you a couple of words about chronic and a couple of words about acute toxicity. Chronic morphine toxicity, or in parentheses, opioid toxicity, means addiction. Addiction, meaning drug addict. First, I want you to know what an addict looks like. Look in his eyes, and you will see miosis because I told you that morphine constricts the pupils bilaterally. So, this is the first feature. You will look in his eyes and recognize him. Second, he will have something called emaciation. Emaciation means he doesn't eat well. Third, he will have itching and behavioral changes, meaning his personality has changed. You will notice even the way he talks to you; he will be disoriented. You suspect him from his appearance and general demeanor. An addict is accustomed to injecting himself with morphine every four hours. This is the problem because morphine, I told you, has a half-life of four to five hours. Let's assume it reaches six hours. So, any opioid addict is forced to take a dose, at most, every six hours. What happens if he doesn't have money to buy morphine? He will enter withdrawal syndrome. What is this withdrawal syndrome? First, withdrawal means abstinence symptoms. What are these abstinence symptoms? This addict, after four or five hours, will start to worry, become restless, and want to take morphine by any means. If he doesn't find morphine, the curve will start to rise. This curve represents tachycardia. He will start to get tachycardia, nervousness, headache, insomnia, and agitation, meaning he will become very aggressive. The curve will start to rise from six hours, which is the time of the missed dose. The curve of his aggression will start to increase, rise, rise, until it reaches its peak within 48 hours. Within 48 hours, he will have reached the peak of his withdrawal syndrome. At this stage, he will not hesitate to kill to get money to buy drugs. This is within 24 to 48 hours. After that, the symptoms will gradually subside, gradually, until within five to ten days, all these symptoms we are describing disappear. This is called withdrawal syndrome, or abstinence symptoms that occur to an addict if he does not take his dose on time. So, you will ask me, why does he get tachycardia, nervousness, insomnia, and aggression? Why this situation? Because this addict has been taking drugs for 20 years. The mu receptors in his brain have become accustomed to external drugs. That is, he has been taking morphine for 20 years, so the mu receptors, and delta and kappa receptors in the spinal cord, are already there. God has created something called endorphins and enkephalins that work on these receptors. But the addict no longer has endorphins or enkephalins because what he takes from outside suppresses them. He lives on the drug he takes from outside. The mu receptors, he lives with them with the drugs he takes from outside. As soon as you cut off the drugs, and he has neither endorphins nor enkephalins, he will start to experience the symptoms I told you about. Second, the external drugs he takes reduce norepinephrine release. So, for 20 years, his brain's norepinephrine has been low, and he hasn't noticed. Now, it's been ten or twelve hours since he took drugs. From another side, norepinephrine will experience a rebound, meaning it will start to rise. So, from one side, he no longer has endorphins or enkephalins, which a normal person has, and from the other side, norepinephrine will overwhelm the brain because it will start to rise, and he will experience a rebound. This is what leads him into withdrawal syndrome. So, what is the solution? The solution, of course, is that we will not give them drugs. The solution is to advise their families to take them to specialized addiction treatment hospitals. Inside the hospital, specialized doctors will start to gradually withdraw the morphine. Gradually, never suddenly. Gradual withdrawal means they will talk to the addict and ask him how much morphine he takes. He will say, for example, "I take 10 mg of morphine four times a day. If I don't take it, I will die." They will say, "Okay, please, we will give you an alternative medication to morphine, exactly like it. Try it and see. We will give you something called methadone." I will explain methadone to you, God willing, in the next video, and I will tell you that it is a very safe alternative for addiction treatment. It is just like morphine; it causes euphoria and a good mood and activates mu receptors like morphine. But the beauty of methadone is that you can gradually withdraw it without the patient noticing. So, we will agree with this addict and tell him, "We will give you a substitute for morphine that will do the same job. Try it, my friend. You and I, the agreement is that you try this methadone, and tell us how it is." As soon as he takes methadone, he will feel euphoria just like morphine. He will say, "Okay, I'm fine now." With time, he will believe that I am not deceiving him. I told him I would give him a drug like morphine and to try it. He tried it, and it was just like morphine. He will then trust me. With time, I will start to gradually withdraw methadone and substitute it with something called benzodiazepines or sedatives. The patient will not notice that I am withdrawing methadone, and at the same time, I am giving him a drug called clonidine. If you are smart and knowledgeable, you will remember that clonidine is from the autonomic nervous system. It stimulates alpha-2 receptors, and when it stimulates alpha-2, it reduces norepinephrine release. Isn't it what's driving him crazy and making him agitated? This is the issue of norepinephrine rebound. You are giving him clonidine, which is reducing norepinephrine, so the patient will be sedated, and he will not notice that you are withdrawing methadone. This process can take months, a year, whatever it takes. The important thing is that after a period, the patient will find himself in the hospital, no longer taking drugs. He has quit. We will tell him the surprise. We will greet him and say, "See, you have won a prize with us. You have been drug-free for a year." He will say, "Impossible! What were you giving me?" He will say, "I don't feel like I have a problem." We will tell him, "We have been giving you sedatives and clonidine for a year, but we have gradually withdrawn the opioids, so you didn't notice." And we will do rehabilitation programs and all that, which is not our story now. But I have told you how addiction treatment is done in general. Let's move on to the second story, which is acute toxicity. Acute toxicity means a person is not an addict, not at all. He doesn't know drugs and has never seen them. This is an innocent, good-natured boy who sat with his bad friends. Because he is innocent and people are making fun of him, he wants to prove to them that he drinks. So, he drinks what? He takes morphine or any opioid, and he has never seen it before. The person who has never seen opioids is sensitive to any dose. If he happens to take a high dose, it will cause respiratory center depression. This boy will be admitted to the hospital with these two words: respiratory. I am worried about him from this word. So, what happened is acute opioid toxicity. We are specifically worried about respiratory depression. Why? Because, my dear, opioids, at a certain dose, stimulate mu receptors, okay? The mu receptors in the cortex will cause euphoria. But when the dose increases, especially in someone who has never seen it before, it will go to the respiratory center and cause inhibition. So, the boy will experience hypercapnia and enter a coma and the intensive care unit. You look at his breathing, and you will find that it is shallow. He will need a ventilator, artificial respiration, because he will die. The respiratory system has been inhibited. If you want to do this boy a favor when he comes to the hospital, the first thing is to put him on a ventilator because, as I told you, second, quickly block the mu receptors that are causing respiratory depression. We give him an opioid blocker called naloxone. Naloxone. Naloxone. The vial contains 0.4 mg. As soon as you give him naloxone, you block the receptors in the respiratory center, the mu receptors, and the delta as well, for good measure. Because naloxone blocks all opioid receptors, you are no longer worried about him. As soon as he takes naloxone, his condition will improve. But I will advise you of something important: the naloxone ampoule or vial contains 4 mg, and its effect lasts for one hour. That is, it continues to block the receptors in the respiratory center and prevent respiratory center depression for one hour. But the morphine that this boy has taken stays in his blood for four to five hours, which is the half-life. What does this mean? It means that you, as a doctor, are obliged to monitor your patient every hour, assess him, because it is assumed that as soon as he takes naloxone, his breathing will improve. But after the effect of naloxone wears off after an hour, he will start to relapse. You will find that respiratory inhibition begins again because the morphine is still in his blood. This will make you have to give him another naloxone after an hour. So, he has taken two, and after another hour, a third naloxone. So, he has taken approximately four vials of naloxone, one every hour. The deciding factor for you is not the dose, not how much you give him. The deciding factor is when you observe that your patient's breathing has returned to normal and he no longer needs to be on a ventilator, and you leave him for an hour, two, or three, and you find that there is no problem. Here, you are sure that he has passed the danger stage. But do not leave your patient. Do not give him one vial of naloxone and be happy about it, because as soon as you give him naloxone, he will improve. So, you will think that you have treated him. No, keep in mind that he will relapse after an hour, after the effect of naloxone wears off. He must be in the intensive care unit under strict observation, as I told you, and every time the effect of naloxone wears off, give him another one. I want to warn you of something important: never give naloxone to an addict. A patient who is a drug addict. I gave naloxone. Notice that I only used naloxone in acute morphine toxicity in whom? In a person who has never taken drugs, whom you are worried about from respiratory center depression. But if you mistakenly give naloxone to an addict, you are committing a crime against him and yourself. Why, my dear? Because an addict lives with these mu receptors. He is currently standing on his feet because of these mu receptors in his brain. If you mistakenly give him naloxone, you will block them suddenly, and he will enter acute withdrawal syndrome. Do you know what acute withdrawal syndrome means? It means he might commit suicide while standing. He might kill anyone while standing. This addict. So, if you are in an oral exam and the examiner asks you, "Explain naloxone. Why do we give naloxone for acute morphine toxicity, but it is forbidden in addicts?" You will say, "Yes, sir. I give it only for acute toxicity in a patient who is not an addict, a naive patient, meaning his body is clean, he doesn't take drugs. He mistakenly took a large amount of drugs and developed respiratory depression, so I am saving him with naloxone, which is a safe blocker to prevent this situation. But if the patient is an addict, then naloxone is absolutely forbidden because it will lead him into acute withdrawal." So, the examiner will press you and say, "What if an addict patient, say, 30 years old, who has been using drugs and developed respiratory center depression, what is the solution?" You say, "You told me it's forbidden. So, he won't take naloxone, or he will enter acute withdrawal." You say, "The solution for this patient, the addict, is to be put on a ventilator only. Do not approach him with naloxone. Never give him a blocker. He is an addict and developed respiratory depression. He came to the hospital. Put him on a ventilator only, artificial respiration only. But it is forbidden to give him a blocker."