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

In the name of God, the Most Gracious, the Most Merciful. Welcome, young people, to the first videos of the CNS chapter. God willing, we will dedicate this video and the next 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, I want to know if someone asks you what types of analgesics you have studied or know, tell them we have 1, 2, 3, 4. The 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 Autacoid 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. It's a family called analgesic antipyretics, which are drugs that relieve pain only, but have no anti-inflammatory effect. This is the family of paracetamol, the Panadol you take for headaches. This Panadol and its relatives. The fourth class of analgesics are drugs used for other conditions. These drugs 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 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 neuropathic pain, no one knows. And they said if duloxetine is not effective, the next one comes, called pregabalin. Pregabalin is from the 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. Half of their face becomes severely painful. 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, as I told you, it was found to relieve pain. So, I have class number four, these are drugs for other conditions. If you want to add more, why not mention sumatriptan? Sumatriptan was the one that relieved the pain of migraine, if you remember from our discussion of the autonomic nervous system. In general, in the end, I want to tell you that if someone asks you in the oral exam and asks you first, "Classify the types of analgesics you have studied in the third year," tell them they will not go beyond the four on the board. We, God willing, will focus our discussion in this video and the next on 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 opioid peptides. You must know the difference between these three terms. First, the word opiates refers to natural morphines. By the way, the opioid family we are talking about today is called the opium family in Arabic, meaning drugs that belong to the family called the opium family in Arabic. 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, which is the hashish family. It has no relation whatsoever to the family of hallucinogenic pills and LSD and others. Agreed? So, we will focus our discussion on the opioid family, meaning this video and the next will be about the opioid family, which is the opium family. Where does the origin of opium come from? This family. 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. Farmers who grow this plant illegally will come and make incisions in the fruit you see here, 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. This exudate you saw, if you take it naturally and separate it by chromatography, will yield natural morphines without any chemical modification. We call them opiates. So, if someone asks you about opiates, tell them they are natural morphines. If you take the exudate you saw and make many chemical modifications, many types of drugs will come out, which are synthetic and semi-synthetic. We call them opioids, meaning something similar to opiates. By convention, we use the word opioid, and it was supposed that the word opioid refers to semi-synthetic substances. However, by convention, this word is used for all types of morphines, whether natural or semi-synthetic. So, when you say opioids, it includes all types of morphines you might see. Opioid peptides, the third term, you studied in physiology that we have natural morphines inside our bodies that God created for us. We have in the brain, it produces something called endorphins and enkephalins, which you studied before. Yes, these endorphins and enkephalins are called opioid peptides because they are natural substances inside the body. So, you have now learned three terms. 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 a legal term more than a medical term. Legal means judicial, meaning legal. The word narcotic itself comes from the word narcosis. Narcosis, you know the word narcosis from which the word narcolepsy also comes, meaning sleep, drowsiness, and so on. So, the word narcotic means drugs in general. In legal books, in English and American legal books, drugs in general are referred to 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 positive aspect of them. In general, it is preferable to use the term opioid analgesics in medical books and to exclude the word narcotic completely. Let the lawyers and legislators and others deal with it. Let's move on to our topic. In this video, we will talk in detail about morphine. 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, I want to do something called classification. This classification I am explaining is a classic one found in books, dating back a long time, 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 classification, as I told you, is a classic one. There are opioids, as I told you, natural ones. They divide opioids into semi-synthetic and synthetic substances. First, who are the natural substances? Chemists divide natural substances into two families. So, 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, many compounds will come out. All these compounds I will mention are called natural opiates or opiates. They are actually divided into two families based on chemistry: a family called phenanthrene derivatives, meaning chemically they contain a phenanthrene ring, and another family called benzyl isoquinolines. This exudate yields 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 smaller brother, codeine. And the third brother, whom no one hears about at all and is not used in medicine at all, is thebaine. Thebaine was named thebaine after the city of Thebes, Thebes, which is the city of Luxor. The city of Luxor had a historical name called Waset. I don't know why they named thebaine after the city of Luxor. What is the connection? You don't understand, but it's 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 begin with and make modifications to it to manufacture the substances they want to produce. So, phenanthrene derivatives are morphine, codeine, and thebaine. As for the benzyl isoquinolines, there are three others: one 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 just 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 with a phenanthrene ring have clear CNS effects. Meaning, they go to the CNS and cause the effects we will mention. One, they cause addiction. Two, they have a spasmogenic effect, meaning if they affect smooth muscles, they cause spasms. Reverse these three words for the second family, the benzyl isoquinolines. This family, which includes papaverine, noscapine, and noscapine, these three substances have almost no CNS effect. And if they do, it's very minimal and not clear at all. Number two, they do not cause addiction. Of course, because they do not reach the CNS. The strangest thing is number three. While phenanthrene compounds have spasmogenic action, meaning they cause spasms in smooth muscles, you find these three are the opposite, they are spasmolytic. Hence, chemists and medicinal chemists started using the benzyl isoquinoline family to make ampoules for treating people with abdominal colic, regardless of the type of colic, intestinal, renal, or otherwise. Therefore, papaverine is found in ampoules in the market under the same name, papaverine, for treating various types of colic because it is spasmolytic. And always remember that papaverine and morphine both come from the same plant called Papaver somniferum, even from its name, papaverine, derived from the word Papaver somniferum. Well, my friend, we have finished the natural ones. Now for the semi-synthetics. If you take any of the substances on the board and make chemical modifications, you get semi-synthetic substances. I will give you examples like heroin. Heroin, which I mentioned to you once when explaining the video about cough, and I told you that heroin was invented by the German company Bayer in 1895. The chemist named Felix Hoffmann invented heroin by chance. He did not intend to. He took morphine and acetylated it, and produced acetylmorphine, which is heroin. We later knew it as heroin and its use was banned almost from 1910. It is no longer present anywhere in the world and has become one 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, both by chance and both with 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 said that Felix Hoffmann took salicylic acid and acetylated it, and produced aspirin? He did the same thing with morphine. He took morphine and acetylated it, and produced acetylmorphine, which is heroin. Both 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 am just mentioning them. In our book, we do not try to list all the names because semi-synthetic substances are actually very numerous. Now for the synthetics. They divide them into agonists, meaning substances that are exactly like morphine in their effect, and blockers, and mixed agonist-antagonists. One by one, let's explain. Agonists mean that companies want to produce drugs that are exactly like morphine in their efficacy, but they do not want to use morphine itself. They do not want to grow the plant you saw for reasons related to medico-legal aspects and so on. They want to get chemical compounds from scratch and make them exactly like morphine. So, they made something called meperidine. This was in the thirties and forties, and they produced many derivatives from meperidine. So, meperidine has a family called the meperidine family, with many names. They also made something called methadone, exactly like morphine. And they made the new one that you hear about a lot all day and is causing us a crisis in the whole world, the drug called tramadol. Tramadol was released in 1977, and it was also a German company. By the way, most of those who worked on opioids and manufactured them were mostly German companies. So, meperidine and its family, methadone and its family, and tramadol are examples, not an exhaustive list. These are examples of opioids that are similar to morphine in their action. Blockers, they said, what if someone took these drugs and had toxicity? What is the solution then? We must have a drug called an opioid blocker to save them from poisoning by these agonists. So, they made something called naloxone and naltrexone. You notice that they start with "N", while most agonists start with "M", like meperidine, methadone, and morphine, all starting with "M". The blockers start with "N", naloxone, naltrexone. And always pay attention to the letter "X", because the letter "X" means it is a blocker, meaning it wants to indicate that it is a blocker. Mixed agonist-antagonist, or partial agonist. I think this term is now old for you. We have already encountered this term multiple times in the CNS chapter, from the general chapter. The term partial agonist means, they say, a drug that is hesitant. It doesn't know whether to be 100% agonist or 100% blocker. It works halfway. How, my friend? They say a drug might go and stimulate some receptors, so it acts as an agonist, and then it might block others, so it acts as an antagonist. So, they call it a mixed agonist-antagonist, or in another version, a partial agonist. Who are the partial agonists they invented? Something like nalorphine, nalbuphine, pentazocine, and butorphanol, and many others. And I will reassure you and tell you that although they are many, the most widely used one is nalbuphine. Number two, when we reach it, God willing. So, my friend, this diagram on the board, or this classification, sometimes comes with three marks. Sometimes the examiner asks you for it in a written exam, asking you to classify the opioids you know. And again, I repeat, 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 ones, and there are semi-synthetic ones 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. Inshallah, in the next video, we will discuss these drugs. We will take each drug with a line or two 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 standard headings that we are used to discussing so that we do not get lost. We want to talk about two things: 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 remind you that the word mechanism and pharmacological effect both mean the same thing. Open a parenthesis, look, and say pharmacodynamics. When someone asks you, "What is pharmacodynamics?" 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 used 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 phenanthrene, which had CNS effects. Now for its pharmacokinetics, 1, 2, 3, 4. Let's talk about bioavailability. If we take oral morphine, only 25% of the dose reaches our body, to 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 aware of 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, for oral morphine, anyone who takes it should expect that only a quarter of the dose will reach their blood. Now, my friend, what about its half-life? How long does it stay in my blood? From 4 to 5 hours, then it disappears, its effect ends. That's why addicts, people addicted to morphine, will always need to inject themselves with morphine every approximately five to six hours, because its effect is exactly like that, 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. In the end, I want to tell you that the correct statement is that morphine is partly converted into inactive metabolites, and the other part remains active, although it is a small part, and we do not need to go into the names of the metabolites. They are of no use to us. The excretion of morphine is 9% of the dose you take, which 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 covered it in four points, and it can be worth two marks in the exam, giving you half a mark for each step. So, bioavailability is only 25% because some is lost during 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 through two routes: renal and biliary. Agreed, my friend? Pay attention to these things so that when we compare morphine with the synthetic substances I explained to you earlier, we can keep these points in mind. Now for the mechanism and pharmacological effects of morphine. Well, the entire opioid family, whether morphine or others, all of 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 called mu, delta, and the third 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 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? Maybe, but what we know is on the board. So, what distinguishes these opioid receptors? They are all G-protein-linked receptors, all of them, whether mu, delta, or kappa, all of them are like this. Is there one, for example? Can we make a table and divide the receptors as we did before in the autonomic nervous system when we said alpha receptors cause 1, 2, 3, 4, beta causes what? Can we do this? In the past, in some books, we used to write mu receptors and say they cause 1, 2, 3, 4, delta causes what? We used to do this. But recently, studies have shown that mu, delta, and kappa all share the same effects. Meaning, you cannot make this distinction. You cannot say mu causes this and delta causes that. No, they all share all the effects 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 say 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 does it mean 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. Where are these receptors located? The most important place, of course, you imagine that since it's morphine and related substances, it's the CNS. No, my friend, no tissue in your body is devoid of 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 situation is the following heading: 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. Then we will see what happens at the cardiovascular system level. We will count together two things. Then at the peripheral tissue level, we will count together four or five things to talk about. Let's start with the CNS. If I take morphine or an opioid, any substance from the family, an agonist, what might happen to us? The first thing is analgesia. I will list what might happen, then we will 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, vagal stimulation. Six, inhibition of the cough center. So, if you are coughing, the cough will stop. Number seven, inhibition of the respiratory center. Because the cough center and the respiratory center are next to each other, they will be inhibited together. Number eight, and finally, an increase in intracranial pressure. Here are eight things to talk about, and then we will 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 distinct, not like non-steroidal ones. It is distinct 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 your pain is emotional. Meaning, you find the patient is deluded. Part of their fear is that they are deluded that they will die or something will happen to them, and this causes them pain. Why go far? When you give an injection to a small child, the child cries from the sight of the injection, they haven't received it yet. This child crying from the sight of the injection is called emotional pain. They have pain and fear. This is emotional. Morphine will relieve pain, it will relieve pain with its two components. It relieves the sensory component because it actually works on pain centers, as I will explain to you. And it also relieves the emotional component. So, if the patient is anxious about their pain, that anxiety will go away. But at the same time, it does not cause loss of consciousness. Morphine will not make the patient sleep. It might 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 they take morphine, the pain starts to decrease by, say, 90% or something, but the patient has not lost consciousness and if you ask them, "Where was the place that was hurting you?" they will point to it because they are 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 a cross-section of the spinal cord like this. We used to draw the spinal cord like this, and then we would make something called the gray matter. If you remember, we used to draw it like 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 medicine, and they told you in histology or anatomy that any nerve that comes divides into two parts. The sensory division enters from the dorsal horn, and then the motor. The motor neurons exit 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 shaped like an inverted crescent, like something like this area. You called this area in physiology Rolando's gelatinous substance, RGS. What is RGS? It is a collection of neurons that receive the signal of sensation, then allow it to pass. So, the sensory impulse exits in the dorsal spinothalamic tract to the higher centers. So, if I have visceral pain, if something is hurting me in my body, the sensation pathway will come from the back, enter the dorsal root, then to RGS, 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 RGS area, 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, what happens when morphine acts on it? They say, "Okay, pain sensation stops. It cannot continue." Why can't it continue? Because mu, delta, and kappa, when they 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 pain sensation at the spinal cord level, you will find 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 spinal analgesia mean?" tell them it means morphine stops pain sensation at the spinal cord level. How? It stimulates mu, delta, and kappa, reducing the release of Substance P, so pain sensation cannot continue. There is no more connection. It's like you cut the connection with scissors, and the nerve cannot continue the signal. It will not go to the higher centers, and I will not feel it. That's one. Count with me now. That's the first mechanism. I am still talking about analgesia. Second mechanism. Let's go to the higher centers. Let's go up to the brain. All areas of the brain are full of mu, delta, and kappa. All three are also present in the brain. I told you that opioid receptors are all over 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 inhibitory control. [Music] This control is sometimes called the mesolimbic pathway. What is this story? This is something newly discovered. Meaning, until recently, we thought that morphine's action was like this, on the spinal cord, the story I am telling you, stopping pain sensation from here. But recently, they said no, it also stimulates mu in the cortex and delta. By the way, delta receptors are more present in something called the basal ganglia, meaning the thalamus and caudate nucleus and these areas. When delta, mu, and kappa act in these higher center areas, they start to send descending inhibitory pain control. This signal coming from above to below will meet the pain sensation that was supposed to exit in the spinothalamic tract and cut it. It's like you are 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 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 cause 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 norepinephrine and reduces it, the patient starts to become less awake. And from here comes the explanation of the term: morphine relieves pain, sensory and emotional. Emotional means that morphine not only relieves pain sensation, but also relieves the reaction to that pain. Meaning, the patient is no longer focused on their pain. They are no longer awake. They have pain, yes, they can still say, "Doctor, this part still hurts," but it doesn't matter. "It doesn't matter" is gone. Their mind has gone to other things. Why? Because we have reduced their norepinephrine, so they are no longer focused on their pain, and therefore they are no longer anxious. So, if there was an emotional component of pain due to anxiety, it has gone because of this norepinephrine. Four, number four, there is now a lot of talk and many studies saying that morphine also 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 and on the higher centers. No, it also acts peripherally on that area and reduces the release of mediators in the painful area. It's as if morphine has acted. So, analgesia is achieved through four ways 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 pain sensation cannot exit. It goes to the higher centers, so it's cut. So, this is called spinal. 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. This is called supraspinal analgesia. Three, when it reduces norepinephrine and makes the patient no longer very focused on their pain, thus relieving the emotional component. The last thing is when it acts peripherally and reduces pain mediators from the inflamed tissue. The surprise is that morphine does all these great things and relieves all types of pain, except itching. Itching, meaning sensitivity, itching, and scratching. If any patient has itching all over their body and you give them morphine, thinking that morphine will relieve the itching, you will make them miserable. Morphine itself increases itching. 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. Second, you will know later that morphine causes histamine release, and histamine itself, you know, increases itching when it acts on itching receptors and irritates nerve endings. So, morphine relieves any pain. Itching and sensitivity, and a patient who is itching all over their body for any reason and has allergies and is suffering from allergies, never, ever give them morphine because it will increase it. That's why in Arabic movies, when the director wants to portray an addict or a drug dealer, they always show him moving his neck like this. Look at Nour El Sherif in this movie, you will see him doing this neck movement because they always have irritation in the neck area due to histamine release, so they are always doing this. So, we have finished with analgesia. We have analyzed it all and said that morphine has nothing to do with itching, quite the opposite, it will increase it. Let's move on to euphoria. Euphoria, we have no special words for it. Euphoria means the patient or person feels good because the mu receptors in the higher centers make the person forget their problems and make them not focused on them. They are not unconscious, no. The person who takes opioids, if they have many problems, the problems are still there, but they are not focused on them. And they say, "I'm high and 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. Don't come and ask me, "Why isn't morphine used to treat depression?" No, I have specialized drugs that make people feel good without causing addiction or all this nonsense. So, euphoria is a pharmacological effect, 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 that its nucleus for the third nerve, which is called the oculomotor nerve, this nucleus is called the Edinger-Westphal nucleus. Morphine stimulates it. When it stimulates, miosis occurs through a central mechanism. Therefore, the eye will appear how? Always, addicts, look in their eyes. If you draw the eye like this, look in the eye, you will find severe bilateral miosis on both sides. So, what is it? One of them, for example, a sharp opium or a sharp morphine, and he is arrested. So, they know. He looks at him and says, "I didn't smoke, by God, sir, by God, I didn't smoke." He says, his eye is already visible. 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 approximately a fixed feature in all addicts. All opium addicts, look in their eyes, you know them. This story exposes him. His eye exposes him.

After that, nausea and vomiting, because morphine goes and stimulates an area in the medulla. We go down a little 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 little 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 many other things besides bradycardia.

After that, unfortunately, we will go down and cause inhibition. We have now stimulated three areas on top of each other. It stimulated the Edinger-Westphal nucleus in the midbrain, above it. Immediately 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 stimulate 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 made them use morphine and this family about 100 years ago. They used it for this purpose. And Felix Hoffmann, when he made heroin at Bayer company, intended to make a drug that would be specialized on the cough center. He took morphine and modified it, 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 inhibition, 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, the usual dose they take, will not cause it. But over time, when they increase the dose day after day, then the third day, because they will develop something called tolerance, there will come a moment when this dose will be able to affect the respiratory center. Then what will happen to him? Apnea. His breath will stop, and he will have CO2 retention. And happy new year. I have now gone through seven things. Let's pause at number eight. 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. Carbon dioxide, when it increases in your blood, causes more vasodilation in the cerebral vessels. So, what's the story? You will get confused because you thought that since morphine causes CO2 retention, and this will cause cerebral vasodilation, you expected the pressure inside the brain to decrease. 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 something called 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 from 7 to 15 mmHg. And when do you say that intracranial pressure has increased? If it rises above 25 mmHg. In this case, there is an increase in intracranial pressure, and the patient begins to complain 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 bone 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. What is meant by "it raises intracranial pressure"? Please pay attention to this word so you don't make a mistake in the exam. Someone 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 pressure of the CSF, plus the pressure inside the brain tissue. These three together are called intracranial pressure. 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, seven things that will happen. Let's move on to the peripheral effects.

On 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 lowers. 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 a person with low blood pressure 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 drop, 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 it narrows the path or limits the causes to a small group of things. Maybe they took drugs. All drugs, opioids, cause this. Most of them, not all of them, cause vagal stimulation and bradycardia. So, you find the patient's blood pressure and pulse are less than 60. That's one. Maybe this patient took a beta-blocker. Beta-blockers also lower blood pressure and cause bradycardia.

After the cardiovascular system, on 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 segmentation, non-propulsive movement. So, the intestine starts to move, but in its place, non-propulsive, so the 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 never occur. Constipation will occur. Therefore, remember or go back to the GI tract. We were telling you that we use opioids to treat diarrhea. But we manufactured 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, which I told you are derivatives of something called 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 reasons, not just one. Therefore, a patient with bronchial asthma, if you make a mistake and give them morphine, you will mess them up, if not kill them. Bronchoconstriction is caused by three reasons. Let's analyze them. One, it caused vagal stimulation, and the vagus causes bronchoconstriction. Two, it caused histamine release, and histamine is known to be a curse on the bronchi, causing severe bronchoconstriction. Three, morphine itself, on the mu and delta receptors in the bronchi, causes bronchoconstriction. So, bronchoconstriction comes from multiple ways. Number three, it affects the urinary bladder, especially in the elderly. It causes something very ridiculous in the world. It affects the urinary bladder wall and increases tone, causing 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 too. So, it presses on the urinary bladder wall and also presses on the internal urethral sphincter and closes it. So, the patient has a feeling of urgency, wants to go to the bathroom, but cannot 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. This will be very annoying and noticeable in the elderly who have enlarged prostates. This will be very prominent in them. Therefore, I will tell you later not to give morphine to an elderly patient complaining of prostate enlargement. The same thing will happen in the gallbladder. It will affect the gallbladder wall, causing 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. So, it presses on the bladder and closes the sphincter. So, when will this appear and who will it mess up? It will mess up a patient with gallstones because someone with gallstones will feel severe colic. You are pressing on the bladder and blocking the flow. It affects the uterus and causes the uterus. If a woman is in labor, the uterus should contract in a specific way and open the cervix. It will do the same thing in the uterus, the same annoyance. Morphine interferes with physiological uterine contractions. What God created during childbirth will not happen. So, childbirth will be prolonged. Not only that, it also causes spasm in the cervix. Just like it caused spasm in the sphincter of the gallbladder and also caused spasm. It will cause it here, or what we call contraction will not happen. So, the result is that if a woman is in labor and takes morphine, instead of giving birth in an hour, she will take two or three hours. So, it causes prolongation of labor. So, morphine, overall, you feel it is a spasmogenic drug. The evidence is here. It caused constipation and spasm in the intestines, and it caused spasm in the bronchi, and it caused spasm in the urinary bladder and internal sphincter, and spasm in the bladder and uterus. The same thing.

Therapeutic Uses of Morphine. If you are a skilled person, you will feel from the explanation we gave that we have reviewed the spectrum of morphine's effects. The things morphine does in your body. Choose the things you like and make them therapeutic uses. The things you don't like in everything I said, put them aside and make them adverse effects, so we don't waste much time. The first use or therapeutic use of morphine and the opioid family will be the word "analgesia." And analgesia represents more than 90%, if not more, of the uses of the opioid family. Who will you give it to? A patient who needs opioids. Who needs morphine? Does a patient with a headache need it? No. For mild pain, non-steroidal anti-inflammatory drugs are enough. For back pain, the one who comes to you and says, "Doctor, my back hurts a lot and I can't stand it." Well, they can take NSAIDs. But you are talking to me about severe pain or moderate intensity pain, something that the patient is suffering from. Cancer pain, for example, or 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, 30 mg, not modified-release or anything. Modified-release means the tablet lasts for 12 hours. So, the patient takes a tablet in the morning and another in the evening. But there is regular morphine, the tablet lasts for four to five hours. There is a 30 mg tablet. 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 saw. So, if you are in a hurry, then 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 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 are drawing the spinal cord. It ends at something called the cauda equina. The anesthesiologist sometimes, after major surgeries, for a patient who had 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 a plaster. Then they start giving morphine through this catheter. The morphine travels in the epidural space and reaches the CNS without causing peripheral manifestations. It doesn't lower blood pressure or cause anything. It lasts for 24 hours. The dose you give in the epidural space will last not four hours or 12, but 24 hours. So, this is the fourth method. I just want to draw your attention to something here regarding analgesia. Sometimes it is asked a lot in fellowship exams. If you are entering an English fellowship exam or something, they always ask. They ask us, if a patient is on morphine, has cancer or anything, has chronic pain, and you are forced to keep them on morphine, and suddenly they develop what is called breakthrough pain. Breakthrough pain is sudden pain that occurs. It happens a lot to cancer patients. So, they are on good analgesia, but suddenly during the day, you find them screaming. In this case, called breakthrough pain, what should you do? They are already on morphine. They are taking morphine in the morning and evening, modified-release tablets, 15 mg in the morning and evening. So, what should you do? We have a rule and a guideline. Let's not disagree. If this happens, give one-sixth of the morphine dose to the patient to relieve the breakthrough pain. For example, if your patient was on a tablet in the morning and evening, 15 mg, then they are taking a total daily dose of 30 mg. If they complain in the middle of the day that the pain has increased, then one-sixth of 30 is 5 mg. So, I am allowed only 5 mg to relieve the breakthrough pain. What if my patient is on oral morphine, for example, and the dose was, say, 60 mg per day? That's the total daily dose. They are on this. They get breakthrough pain during the day and are screaming. So, one-sixth of 60 is 10 mg. So, I will give them 10 mg to relieve 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 asked a lot 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 something called acute, an emergency 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 in the morning suddenly with severe shortness of breath, dyspnea, and cannot breathe. They have cyanosis and severe tachypnea. What happened? They say, because the heart cannot eject blood, the blood coming from the lungs is stagnant. It cannot be dealt with. So, lung congestion occurs. This happens more at night when they are sleeping. Lung congestion causes pulmonary edema. The lungs fill with water. The patient wakes up in the morning with shortness of breath, gasping for air, and their life is leaving them. I told you that this patient, when I was explaining cardiology, I told you that this patient must be hospitalized. They should not be treated at home. That's one. Two, I told you that they take a morphine injection, 5 mg intravenously. Here, I am in a hurry because this situation is life-threatening. The patient is gasping for air. Imagine if a few drops of water accidentally go into your lungs, see what happens to you and the choking you experience. Now imagine this patient whose lungs are filled with water. See what they look like. Of course, they have severe respiratory distress, their life is leaving them, they have severe tachypnea, and they are even leaning forward. They cannot even straighten up and talk to you. And that day I told you that even when you admit the patient to the hospital, they should be admitted sitting on a chair, in a sitting or semi-sitting position. It is forbidden to lie them down on the trolley, because when they lie down on the trolley, the shortness of breath and the water will cause severe dyspnea. So, what I want to say here is that this patient, among the things they will receive, will receive 5 mg of morphine intravenously. Why? Number one, the patient has severe stress, as you can see, and their life is leaving them, and they have the illusion that they are going to die. As soon as they receive 5 mg intravenously, the stress goes away, and the pain the patient has goes away. I told you it has two components: sensory and emotional. That's one. Two, morphine also causes vasodilation. Welcome. Vasodilation? How did this happen? Didn't I tell you a little while ago that morphine causes histamine release? Didn't we agree that it causes this? Do you remember when I was explaining histamine and I told you that histamine dilates or opens something called 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, and something called venous pooling occurs. So, the 5 liters of blood you have in circulation will be pooled in the venous side, and they will not appear, and venous return will decrease. This is one of the causes of low blood pressure. This action, that histamine does, 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 blood coming from the heart to the lungs decreases. So, lung congestion does not occur. The patient has lung congestion and water in the lungs. So, 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, it will be a small amount, so lung congestion will not occur. Number three, the patient with acute pulmonary edema comes to the hospital with severe tachypnea. Tachypnea, shortness of breath. Why is the shortness of breath happening? It is very logical. The patient's lungs are already filled with water up to here. All 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 reason for tachypnea. Is this good? No, it is not good for this patient, because it causes severe exhaustion. They are completely depleted. Their life is leaving them. 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 learn with me that morphine inhibits the respiratory center? We will not say that it causes inhibition. The dose I will give this patient, 5 mg, will not cause inhibition, but it will slightly calm the respiratory center. Instead of firing wildly 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 this hypoxic drive. So, the patient will start to catch their breath, relax, and breathe with you. So, their life will not leave them. So, you now have morphine in acute pulmonary edema doing three excellent things. Let me summarize what I said. First, it is an excellent analgesic and will relieve 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 last, the tachypnea that is bothering the patient due to the hypoxic drive they have will decrease, because morphine calms the respiratory center. 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 and talk with you.

Third therapeutic use of morphine. In anesthesia. Sometimes anesthesiologists, of course, use many types of general anesthetics. That's not our job now. But I want to tell you that an anesthesiologist sometimes resorts to morphine as an addition to the anesthesia they give, the anesthetic they give. In this case, it is called an anesthetic adjuvant. Adjuvant means helper. When? In major surgeries, large operations that will be prolonged, and the patient is likely to have severe postoperative pain. So, 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 if you are forced by circumstances, use morphine 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 found a patient with severe renal colic. It causes terrible pain, or severe intestinal colic. You gave them morphine. Okay, sir, fine. Morphine will relieve the pain. But I just told you that morphine has an undesirable characteristic: it is spasmogenic. So, while it will relieve pain sensation through a central mechanism on the spinal cord and cortex and so on, peripherally on smooth muscle, it is spasmogenic. So, complete your favor. I want to recommend something. Complete your favor 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, and so on. Atropine will prevent the disasters caused by the vagus. So, it will reduce the spasmogenic effect because atropine is known to be a spasmolytic. 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 you, if I am forced to use morphine in treating colic, what is it best to give with it? I will tell them for these two reasons: because morphine is spasmogenic on smooth muscle, while atropine is spasmolytic. 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 that the examiner, if it is an oral exam, will not let you go when the topic of colic comes up without asking, "What if it is biliary colic, 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 little while ago, if the patient is screaming due to gallstones, morphine is very dangerous. It will increase the pain because it will cause spasm of the gallbladder. So, morphine is used in all types of colic except biliary colic. It will increase biliary colic itself.

Adverse Effects and Contraindications of Morphine. If you are smart and alert, most of the explanation we gave will be the bad things. Put them aside and consider them adverse effects. They will also be contraindications. Let's start with adverse effects first. 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 a 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. Day after day, then the third day, you will find that the addict or someone who has tried to take opioids and experienced euphoria will find that yesterday's dose is no longer effective because the receptors, mu, delta, kappa, and others, undergo physiological changes, adaptation. So, you will find that the patient wants to take a higher dose of morphine every day. This is the story you studied in general medicine under the title "tolerance." We also have a small problem. This is often the reason when you hear that, for example, a famous world-renowned artist 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. Maybe 10 mg of morphine will make you euphoric and elevate your mood. But to cause respiratory inhibition, I told you a little while ago that to affect the respiratory center and cause inhibition, you need a high dose. Say, the dose that causes respiratory center inhibition was, for example, 100 mg. Let's assume, 10 times. That's why a person who is starting opioids, still new to it, takes 10 mg, their mood is good, no problem. But tomorrow they will need to take 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, then the third 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 this case, they take this dose and die immediately. 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. It does not develop tolerance to respiratory inhibition. It happens at, say, 100 mg. I am giving a number. It will continue to happen at 100 mg. You are the one increasing the dose to get euphoria because you have developed tolerance in the cortex and elsewhere. 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 explanation when you hear, as I told you, that there was a famous artist who was a drug addict and suddenly they were found dead in their home. They opened the house in the morning and found them dead in bed. They say, "He died from an opioid overdose." It will be because he reached the dose that causes respiratory inhibition. Good, hero. That's one. The second piece of information I want to draw your attention to is dependence or addiction. It occurs with the first dose. Dependence or addiction occurs if you take repeated doses of morphine. They say it occurs within 24 to 48 hours. Within a day or two, if you take morphine every four hours, exactly every four hours, which is its half-life, you take a morphine injection every four hours for 24 to 48 hours. This person will become an addict. They can no longer stop taking morphine. After 48 hours, they will feel bad. They need to take morphine again, and they have entered the path of addiction.

There is another defect still in the CNS. I just told you that morphine causes respiratory center inhibition. That's number two. I just said it. Three, morphine. I just told you a little while ago that it raises intracranial pressure, and I drew your attention to the word "intracranial pressure" not meaning the pressure inside the blood vessels, but the overall pressure inside the cranium, inside the skull, called intracranial pressure. And morphine raises this. Outside the CNS, draw a line. At the level of the bronchi, didn't it cause bronchoconstriction and mess up patients with bronchial asthma? It is absolutely contraindicated, by the way. Any patient with bronchial asthma, never, never even think of the word morphine or opioid. On the cardiovascular system, what did it do? Didn't it cause hypotension with bradycardia? Draw a line. On the smooth muscle, 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. Where did it go? What did it do in the gallbladder? Didn't it press on the wall and close the sphincter of Oddi? So, if the patient had gallstones, they would be messed up and suffer severe pain, and it is not unlikely that the gallbladder would rupture. It did this to the uterus. What did it do? Didn't it cause spasm in the uterus 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 caused. All these are disasters that morphine causes. It also caused constipation. Patients who take it, or drug addicts, don't always complain of constipation to the point that they often advise us. They say, if someone will be on morphine because they have chronic pain, say they have cancer, and you are forced to keep them on morphine, they say to expect constipation. This is very common. And they always advise us in the guidelines to prescribe a laxative because it is expected that the morphine they are taking will cause severe constipation. So, you will find in the guidelines two lines that we all memorize. They say, a patient taking morphine for cancer, if they complain of breakthrough pain, what is the dose they should take? I have already taught you. They will take one-sixth of the total daily dose. Two, 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 them a laxative because of the constipation they get.

Contraindications. These are the same contraindications. 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, you expect their intracranial pressure to be high, and morphine raises intracranial tension, then avoid morphine here. In reality, you will find books or sources differ on this. You will find many books say, "No, it's okay. Someone with head trauma can take morphine. Don't worry." Not all patients, not all patients. People who have accidents and have head trauma do not have high intracranial pressure. Not all of them. The majority who have car accidents and go to the emergency room and so on do not have high intracranial pressure. Don't worry about that. Give them morphine normally. But who am I telling you not to give morphine to? A patient with head trauma, and it is proven to you by any means that their intracranial pressure is high. You will say, "How can it be 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. It is not my topic now. I don't want to bother you with it. But I want to tell you that an experienced doctor standing in the emergency room at the accident scene, and a patient with head trauma comes to them, as part of their general assessment, they 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 reason, one of these three, 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 in cardiology, I told you that 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 because we don't want 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 press on the gallbladder and close the sphincter of Oddi, so it might 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'll ask me why? I'll 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 has a pharmacological effect that is rare in a myxedema patient, the effect you see will occur at a rate of 2 to 4 times. It's possible for him to have all the problems in the world. 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'll ask me why? I'll 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 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 they develop toxins that come from the intestine and cause portosystemic encephalopathy, if you remember in 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 put him into a coma. Finally, extremes of age, very young children and the elderly. Morphine is not recommended for them at all because very 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 happen especially with children and the elderly, so please stay away from them. For example, a child who is eight years old comes to the emergency room crying 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 can occur, and all these disasters can 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 undiagnosed abdominal pain. That is, a patient comes to the emergency room crying from abdominal pain, called acute abdomen. Acute abdomen could be acute appendicitis, or it could be anything, my friend, that needs diagnosis. First, get a specialist. You are a young intern, or a junior resident, just starting in the hospital. A patient comes crying from abdominal pain. Send him to someone older than you to look at the situation. Because if you rush and give morphine, the pain will go away, and the older person will come and find nothing to put his hand on the patient's abdomen, and the pain will be gone, and the patient will tell him, "I'm fine now, I can go home." And it happens that this patient has acute appendicitis. You have masked his pain. He will come back to you after five or six hours, or the next day, with a ruptured appendix and peritonitis, and get into a lot of trouble. So, please, when a patient comes to you in the emergency room with acute abdomen and crying 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 could be that he is crying from abdominal pain due to gallstones, and he has acute biliary colic, and morphine in this case will worsen the situation. 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 lead to complications. We have finished 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, which is drug addiction. First, I want you to know what an addict looks like. Look in his eyes, and you will find 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 find even the way he talks to you, he will be disoriented. You suspect him from his appearance and general look. An addict, you should be aware that he 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 at the beginning. Let's assume it reaches six hours. Then 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 go into something called withdrawal syndrome. What is this withdrawal syndrome? First, withdrawal means abstinence symptoms. What are these abstinence symptoms? This addict, after four or five hours pass, 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 dose he missed. 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 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 start to subside gradually until, within five to ten days, all these symptoms that 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. Now, you will ask me why he gets tachycardia, nervousness, insomnia, and aggression. Why this story? Because this addict, for twenty years since he started taking drugs, the mu receptors in his brain have become accustomed to external drugs. That is, he has been taking morphine for twenty years, so the mu receptors and even delta and kappa in the spinal cord. God has created you with 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 from him, 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. That is, for twenty years since he started taking drugs, his brain's norepinephrine has been low, and he is unaware. Now, it has been ten or twelve hours since he took drugs. From another side, norepinephrine will start to rebound. That is, it will start to rise. So, from one side, he no longer has endorphins or enkephalins, which a normal person has, and from another side, norepinephrine will overwhelm the brain because it will start to rise, and rebound has occurred. This is what leads him into withdrawal syndrome. What is the solution? The solution, of course, is that we will not give him drugs. The solution is to advise his family to take him to specialized addiction treatment hospitals. Inside the hospital, you will find specialized doctors who will start to do gradual withdrawal of morphine. Gradual, never sudden. Gradual withdrawal means they will talk to this addict and ask him, "How much morphine do you take?" 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 treating addiction. It is exactly like morphine; it causes euphoria and a good mood and activates mu receptors like morphine. But what is beautiful about 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 an alternative medication to morphine that will do the same job. Try it, my friend. You and I are just trying it. Try this methadone and tell us how it is." As soon as he takes methadone, he will feel euphoria like morphine. He will say, "Okay, I'm fine now." With time, he will believe it. He will believe that I am not lying to him. I told him I would give him a medication like morphine and to try it. So, he tried it, and it was exactly like morphine. He will say, "Okay, I'm fine." So, he will 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 medication called clonidine. If you are smart and skilled, 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 drives him crazy and makes him want this state of agitation? This is the story of norepinephrine rebound. You are giving him clonidine, which is reducing norepinephrine, so the patient will become 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 it. He has stopped. We will tell him the surprise. We will greet him and say, "Look, 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 from you, so you did not notice." And we will do something called rehabilitation programs and so on, 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 addicted, not at all, and has never seen drugs. This is an innocent, good boy who sat with a bad group of friends. Because he is an innocent boy and people are making fun of him, he wants to prove to them that he can drink. So, he drinks what? He takes, for example, 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 center depression. I am afraid for him from this word. So, what happened is acute opioid toxicity. We are specifically worried about respiratory depression. Why? Because, my friend, 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 child will have hypercapnia and enter a coma and go to the intensive care unit. You look at his breathing, and you find it shallow. He will need a ventilator, a breathing machine, because he will die. The respiratory center 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, 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 even the delta receptors, for that matter, because naloxone blocks all opioid receptors. So, you are no longer worried about him. As soon as he takes naloxone, you have blocked the receptors in the respiratory center, and you are no longer worried about him. But we advise you of something important, which is a technical observation. The naloxone ampoule or vial contains 0.4 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 took stays in his blood for four to five hours, which is the half-life. This means that you, as a doctor, are forced to observe 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 starts again because morphine is still in his blood. This will make you 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 your patient and find that his 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 can be 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 an addict patient, if you mistakenly give him naloxone, you are committing a crime against him and yourself. Why, my friend? Because an addict patient lives on these mu receptors. He is currently standing on his feet because of these mu receptors in his brain. If you mistakenly take naloxone from him, you will suddenly block them, and he will enter acute withdrawal syndrome. Do you know what acute withdrawal syndrome means? It means he might commit suicide while standing, or he might kill anyone while standing. That is, this addict. So, if you encounter an examiner in an oral exam who asks you about naloxone, explain it, doctor. Naloxone is given for acute morphine toxicity, but it is forbidden in addicts. It is absolutely contraindicated. Never make this mistake. You will say, "Yes, sir, I give it only for acute cases in patients who are not addicts, whose bodies are clean, who have not taken drugs. They mistakenly took a large amount of drugs, and they had respiratory depression, so I am saving them with naloxone, which is a blocker. Prevent this situation. But if the patient is an addict, then naloxone is absolutely forbidden because it will lead him into acute withdrawal." So, you will find the examiner will press you and say, "What if an addict patient, someone who has been taking drugs for 30 years, comes to us with respiratory center depression? What is the solution?" You say, "You told me it's forbidden. He can't take naloxone, or he will enter acute withdrawal." You say, "The solution for this patient, this addict, is to put him on a ventilator only. Do not come near him with naloxone. Never give him a blocker. He is an addict and has entered respiratory depression. He came to the hospital. Put him on a ventilator only, a breathing machine only. But do not give him a blocker."