Hello guys and welcome back to Councillor TEN. My name is Arnie and on today's episode we're going to finish talking about general pharmacology. Now I was really hoping today would be a really short sweet episode because we've covered the two big topics already which were farm co-downermix and farm co-kinetics. Now I don't think that's going to be the case, there's a lot of little nuance topics that we haven't touched on yet and I'm not doing this on purpose but it seems like my episodes just get longer and longer. And I'm preparing for these episodes I really try to make sure that I'm giving you the most succinct information but also making sure I cover the broad depth of the curriculum as well. In saying that today's episode is going to cover a little bit about pharmaceuticals, a little bit about variability and drug response, a little bit about drug interactions and then finish off talking about adverse drug reactions. As usual I'll review the past SAQs at the end but as you can guess these are a lot of topics to cover in a short amount of time so I'm going to try to do my best to keep it as succinct as possible and with that said let's dive straight into it. The first learning objective I'm going to cover today is from pharmaceuticals which is outline the mechanisms of action and potential adverse effects of buffers, antioxidants, antimicrobials and solubilizing agents added to drugs. Now I think that's a pretty heavy first learning objective and the related concept on Mac 95 actually covers this really well. But for me before you start to unpack this learning objective you have to go back and understand what is pharmaceuticals and the way I break down pharmaceuticals is in two categories. Pharmaceuticals to me includes the packaging of the drug and the preparation of the drug. When we think about packaging what I think about is the serility of the drug, the stability and the ease of delivery. When I think about the preparation of the drug I'm thinking how is this drug presented? Is it presented in an oral form, a parental form or a transdermal form? Within preparation I also think what is the preservatives that are added within this drug to make it safe? And preservatives can be added for multiple reasons. One reason you can add a preservative is to decrease the rate of conversion of the drug and that can either be conversion of the drug from its inactive state to its active state or conversion of the drug from its active state into a more toxic state. Other common reasons while we add preservatives is to sometimes enhance the solubility of the drug that we're delivering and this is a really key part of drug delivery and pharmaceuticals. In terms of how we enhance that drug solubility, some drugs are really poorly water soluble. In which case you can add a salt in them to improve the delivery. An example of this would be drugs like thyopenetone and ketamine. Other drugs may require a solvent or a co-solvent in order to make it stable. An eclacic example of this is Manitol with dandroline and while you might think this is a very small point, this is actually an examinous favorite as an MCQ for both the part 1 and part 2. Other ways preservatives can enhance drug solubility is by making some drugs into an emulsion. An eclacic example of this would be preperfol. Preperfol is an oil and water emulsion which is stabilized by egglesseth and phospholipids and is one example that you should definitely always remember. The other reason to enhance drug solubility can be to adjust the drug's pH. An alterations of the pH can either alter the onset or the offset of a drug. An example of this would be with medazolam which can have differing pHs leading to different effects of the drug. The last reason that you might want to enhance a drug solubility is to maintain its isotonicity. If a drug is isotonic, it generally tends to be less painful on injection. Finally, the other thing preservatives can do is that they can inhibit microbial growth and the common preservative that you should know which is used for this is benzer alkalonium chloride. You commonly see that within majority of the drugs that we use. So preservatives have multiple functions and it's important not to forget that. Similarly when I used to think about preservatives, I used to only think about the antimicrobial function of preservatives but they do all the other things that lead to the drug being safe on delivery. So going back in summarizing how I think about homicidics, I said you can break it down into the packaging of the drug. Again, this incorporates the sterility, the stability and the easy delivery. Then you have the preparation to how is the drug presented, what dose does it come in, what is the function of the preservatives and are these preservatives for antimicrobial reasons? Are they there to reduce the drug's conversion rate or are they there to enhance the solubility of the drug? And enhancing the solubility can be for a variety of reasons. The key thing with any preservative that's added to a drug is that it should ideally be chemically inert, non-toxic and not have any of its own pharmacological effects. That would be an ideal preservative that's added to drugs. The second component of pharmaceuticals I'd like to think about is this concept of drug shelf life. This describes the time the drug maintains 90% of its activity and remains free of contamination. Therefore, the components of shelf life are drug potency and its ability to avoid microbial contamination. Drug potency will always decrease with time. If you leave a drug for long enough without using it, the potency of that drug will decrease as it's stored for longer and longer. And the reason this occurs is that because inevitably the drug will go through some degree of decompensation. There's four main ways that the drug can be decomposed. The most common is via hydrolysis. And while water is a good carrier for medications, it can create free radicals which lead to hydrolysis. The second method is oxidation and this involves the loss of an electron. And you can try to decrease this process by adding a preservative that acts as a reducing agent and a common preservative is metadysulfite. If you've ever heard of this, you might have seen some patients having an allergy to this. It's commonly a preservatives that we use in vasopressor or ionotropic agents. So commonly you'll see people with adrenaline allergy, but it's because of the preservative, not the adrenaline itself. Then the third mechanism for decompensation can be isomerization. And we'll talk about what isomerization and what isomer is mean in our next learning objective. But how isomerization can lead to decompensation can be either conversion of a drug into its geometric or optical isomer. You can also have raceemic degradation, which usually follows first order kinetics and is dependent on temperature, solvent, catalyst and the presence of light. And if you don't know any of these terms, it's okay. We'll cover it in our next learning objective. The final way drugs can go through decompensation is by photochemical decomposition. And that's why you see some drugs in darker bottles and some drugs that don't need to be in dark bottles. Because the UV light itself can cause decompensation of that drug. So that's my way to think about broadly pharmaceuticals. And while I haven't specifically covered the potential adverse effects to buffers, antioxidants and antimicrobials, hopefully are giving you an understanding of how pharmaceuticals works. Moving on to our next learning objective, which I think is very timely given that people are now starting to study for their vivas. And by the time you get to the actual vivas, you would have done so many vivas on this topic that you will be so grateful that it comes up. And this learning objective that I'm talking about is outline and give examples of the clinical importance of isomerism. Isomerism describes molecules with the same atomic formula, but different structural arrangements or 3D configurations and burn that definition in your head. When you think about isomers, there's two different ways to classify them. The two types are one structural, which are identical chemical formula, but different order of atomic bonds. And within structural, you have three different types. The first type is a positional isomer, in which the atoms occupy different positions on an identical carbon skeleton. And a class example for this is N flurain and isofluorane. Then you have a chain isomer, in which the carbon skeleton varies, but the functional groups remain the same. An example for this is butane and isobutane. And then finally you have a functional group structural isomer, in which the functional groups vary. Out of all these, the easiest to remember is the positional isomer and the example of N flurain and isofluorane. Within structural isomers, you also have a special subset group that falls under this category. And that's called tortomerism. I'm a resident.
is a type of structural isomer in which the two isomers exist in equilibrium determined by the surrounding pH. An example of this is medazolam. Medazolam has an open ionized ring at a pH of 4, but a closed, unionized ring at a pH of 7.4. And this goes back to pharmaceuticals when we talked about how you can manipulate the preparation of medazolam and the pH of medazolam in the form prior to when it's given to a patient and then what happens to the drug once it's given to a patient. The other example of a tortimer is thio pentone. When you drop thio pentone in water and put it in the ring, it's in a water soluble form. But after intravenous injection, it is converted to an unionized lipid soluble compound. So in summary, tortimerism refers to the change in the drug's compound associated with its surrounding environment and typically its surrounding pH. So that's structural isomers in a nutshell. Then the second type of isomers are stereo isomers. Stereo isomers have the same chemical constituents and structure but a different 3D spatial configuration. And that's why I incorporate that 3D part into my definition of isomers because that covers talking about stereo isomers. Just like there were different subsets of structural isomers, there's also different subsets of stereo isomers. For stereo isomers there's two different subsets. The first subset is the geometric isomer. So this refers to different arrangements of atoms around a double bond. If both constituents are on the same side of the double bond, this is referred to a cis isomer. If they're on opposite sides, this is referred to a trans isomer. For example, you have mivocurium and cis acochurium. The complex thing with mivocurium is that actually contains 3 different geometric isomers. It has a percentage which is trans trans, it has a percentage which is cis trans and then it has a final percentage which is cis cis. Now this can get really confusing but all you have to remember with a geometric isomer is that it's fixed into position or restricted in its motion because of where the double bond sits. And sometimes there's not a double bond but there's a ring structure which cannot be moved in. Depending on this, either the double bond or the ring structure, if they're all on one side or they're on opposite sides, the geometric isomer can be broken down into it. cis geometric isomer or a trans geometric isomer. And if you're getting questioned more than that in a viber, you are doing really well. Then the second type of isomer is the optical isomer and this is the isomer type that everyone loves to talk about and is defined as a compound that has mirror image of each other around a chiral center. A chiral center is a carbon that has four different compounds coming from it. It doesn't always need to be a carbon. It can sometimes also be a quaternary nitrogen which can be a little nitpick question that a viber examiner can ask you. Don't get bogged down in details too much. Just know these definitions and you will be fine. The other important thing with an optical isomer is to know how they were classified. Originally they were classified according to their ability to rotate the plane of polarized light in opposite directions. This was referred to either LIBO or dextro isomers. Now that you've heard of these terms, think about how many drugs you know of that are optical isomers that you didn't even know. LIBO thiroxine, dextrose, all these are optical isomers and they come from this original classification. The other way to classify optical isomers is by using Fisher Convention. This classifies the optical isomer based on its configuration around the carol atom. I don't think it's a type of classification that's used to often. The more common classification nowadays is the Karn in gold pre-log. Unfortunately there's just not a good way to remember that. You can remember the acronym CIP system but I think people would still expect you to know that abbreviation in full. The way this classification system works is that it uses atomic mass to assign a configuration. Is that configuration based on atomic mass going in a clockwise manner or in an ENT clockwise manner? If it's going in a clockwise manner then we say it's an R optical isomer. If it's going in an ENT clockwise manner we say it's an S optical isomer. You might have already come across this classification system just like the Libre and the Dextro. You have drugs like ketamine which have an R and an S. You have drugs like Bipipicane which have an R and an S. And so this system gets used quite often with optical isomers. The last thing to know with optical isomers is just regarding terminology. You have two important terms to know of. The first term is an enantomer and you might hear this quite a lot and enantomer is a molecule that is a mirror image of each other but cannot be superimposed on each other. The classic example that you can do right now is put your right hand over your left hand. They're both mirror images of each other but they cannot be superimposed on each other. The difference with this term and another term called diostereomers is that diostereomers are not mirror images and are also not superimposable. Commonly to make it simple in my head I think of diostereomers as molecules that have greater than one chiral center and therefore they can be spatially arranged in multiple ways and that's why they're not mirror images of each other. While with enantomers I think of those as just having one chiral center and so therefore their mirror images of each other but cannot be superimposed on each other. An example of a diostereomer is atroquium. Atroquium has four chiral centers but it can have 10 different isomers. I think this is when talking about isomers gets really tricky when you get into the nuances between the enantomers and the diostereomers but just keep it simple in your head. Have that broad classification into structural and stereoisomers? Know that there's three different types of structural isomers and that there's tortimerism. Then within stereoisomers there's geometric and optical isomers. Within optical we can further talk about them as being either enantomers or diostereomers. The last thing and the most important question you should ask is why should we give a crap about all of this? And the reason is because different types of isomerisms can have hugely different clinical impacts as a drug. Take N-fluorane and isofluorane. There two structural isomers you would think they'd be having the same effect but both these drugs have a different Mach value therefore they have a difference in potency. When you look at the stereoisomers you can get into a whole host of examples of different type of stereoisomers and different clinical effects. The common one you should know about is differences in lever bippuricane and normal bippuricane. Lever bippuricane is a stereoisomer of bippuricane. It's thought to be having less toxic effects than bippuricane alone. You have esketamine and arketamine. Esketamine is thought to have greater affinity for the NMDA receptor producing more of the anaesthetic and analgesic effect and having less of the emergence phenomenon compared to the ar enantomer. And so therefore you might see some mixtures that only have es in it or some mixtures that have equal components. If a mixture has equal components of its nanomers it's called a Reseemic mixture. If the mixture is only one nanomer it's called an enanipure mixture and this relates back to pharmaceuticals of the drug and the preparation of the drug. So that nicely ties back into pharmaceuticals. I didn't plan it that way but it gives us a good segue to now talk about drug variability. Now within variability in drug responses there's a lot of learning objectives here to cover but I've targeted a few that I really want to touch on today. The first learning objective is define tackyful axis, tolerance, addiction, dependence and idiosyncrasy. Now these are some really important definitions to know of and we'll start with tackyful axis. Tackyful axis is the rapid decrease in response to repeated drug doses over a short period of time. The key here being a short period of time. A classic example you might know of here is a use of remi-fentinal. Typically at doses of greater than 0.2mg per kilo per minute for prolonged durations you will see patients in recovery requiring a lot more analgesia than expected. Another example is metaraminal. After a long duration of infusion you'll notice that you have to increase that.
infusion rate to get the same effect that was previously seen at the start of the infusion. The next definition is tolerance. Tolerance is a phenomenon whereby larger doses are required to produce the same pharmacological effect. And this is common with things like chronic opioid use, where you need a higher opioid dose compared to what you need at the start to have the same effect. The difference between tolerance and tacky fallaxes is that tolerance takes longer to occur, while tacky fallaxes is that short period of time. In terms of mechanism action for both of these two, with tacky fallaxes we don't really know why it occurs, we think some of the theories revolve around a decrease in the neurotransmitters before their recent facises again, or a downregulation of receptors. With tolerance we think this could be either due to a decrease in receptor density, a decrease in receptor affinity, a depletion of intermediate substances, an alteration by the drug itself, an example of being alcohol use leading to changes in metabolism, or physiological adaptation to the drug itself. What's clear with all these different theories is that there's no one theory that's proven, so you just need to know the broad mechanisms that brings about these changes. Then the next definition is dependence. Dependence is a syndrome which is comprised of both physical and psychological dependence. Physical dependence is really characterized by tolerance, and the onset of withdrawal symptoms, oncisation of administration of the drug. In contrast, psychological dependence is characterized by withdrawal symptoms, but also mood changes that are associated with seizing that drug. So these can be things like irritability, stress, or anxiety. When you go from dependence to the next stage, which is addiction, there's a clear delineation here. The key with addiction is that it's a state of compulsive use of a drug associated with physical, psychological, or social harm, despite evidence of that person knowing of that harm. In my mind, the way I think about it as a step-up ladder, you might start with tolerance, then go on to dependence, and then you're at risk of having addiction. So for addiction, you really need in my mind both tolerance and dependence to be present. The final definition in this learning objective is idiosyncrasy, and this describes an individual response to a drug that is infrequently observed, i.e. an allergic reaction, and we'll talk more about this term later on when we talk about adverse drug reactions. So the next learning objective I'm going to talk about kind of comprises three to four learning objectives into one, and this is describe alterations to pharmacokinetics and pharmacodynamics due to physiological changes with particular reference to the elderly and obesity. With reference to cardiac, respiratory, renal, and hepatic disease, with reference to neonates, and added on to this is reference to pregnancy. So for this huge learning objective, you need to have a structure. With this structure for pharmacodynamics, this is the harder one to get a structure for, and the way I think about it is just go through your body systems from top down. With pharmacokinetics, the structure is already there. It's the classic ADME. So we're going to start off by looking at neonates. Within neonates, if you think about pharmacodynamics and start off with CNS, they have an immature blood brain barrier. This means that they can be an increased drug delivery to the brain and an increased risk of CNS toxicity. From the cardiovascular system, they have immature cardiovascular control. Their heart is less compliant and their sympathetic reflexes are also immature. In terms of the respiratory system, there's an increased risk of respiratory depression because the central respiratory system is also immature and therefore there's an increased susceptibility of respiratory failure with both a general anesthetic and sedation. Then other little changes that don't really fit into the other system that I spoke about, but are unique to neonates. The first thing is the use of muscle relaxant drugs. There's increased sensitivity to non-depolarizing muscle relaxants as there's decrease in type 1 fibres. The other thing is that the mac requirements for neonates are different to that of adults. Neonates behave more like their elderly where their mac requirements are low. Children on the other hand have higher mac requirements and then from childhood, the mac requirements decrease to the mac level of 1 for the 40-year-old adult. So neonates just remember they behave more like their elderly having a lower mac requirement. Moving on to the PK changes and again, you can kind of compartmentalize neonates with the changes in the elderly to help you remember this. In terms of absorption, the oral root may be difficult due to compliance. Typically neonates will need an OG or an NG placed in. Associated with this they can have variability in their gastric pH, variability in their intestinal absorption and variability in their gastric emptying time, all of which leads to an unknown bioavailability for certain drugs. In terms of other roots of administration, the IM root is generally very safe and generally very fast because they have an increased cardiac output compared to adults. The same applies for the subcut tissue, they have a thinner layer of skin and a higher cardiac output and in terms of inhalation bioavailability, this occurs faster because they have a higher minute ventilation and this allows a faster washing. Moving on to distribution, the volume of distribution for water soluble drugs is particularly increased because of the increase in extracellular fluid. There's decrease in volume of distribution for fat soluble drugs, there's decrease protein binding of both albumin bound drugs and alpha-1acic lycoprotein drugs leading to an increase in free drugs as well as a neonatal pH is lower compared to the adult pH, so therefore the degree of ionization of the drugs will also be different compared to an adult. We've already touched on the blood brain barrier and how this is immature and this will also affect the distribution of drugs. Then in metabolism, the key thing here is that the liver is immature, so therefore you'll have slower both phase 1 and phase 2 conjugation reactions. Interestingly enough, the non-specific esterases that break down remi-fentinal are in normal quantity in neonates. Finally with elimination, the creatin clearance is decreased by 10% compared to that of an adult, there's less number of nephrons and they need time to mature. Clinically what that means is that drugs will have a longer high-fly and therefore the time interval that you give between drugs needs to be increased to compensate for this. So that's neonates in a very quick nutshell and like I said, neonates in elderly go hand in hand, so let's look at elderly now in terms of the changes that occur in them. Again using that system-based approach in pharmacodynamics, from the CNS perspective, there's increased sensitivity to the toxic effect of drugs. This leads to decrease in physiological reserve and a decrease in margin of safety of the drugs that we give the elderly. With the cardiovascular system, there's age-rated arthroscalarosis that occurs and this can lead to a huge variability in the doses of itatropes and vasopressas that we give the elderly and the response we see with these drugs. From the respiratory system, you can have impaired reflexes as we age, you can have an increased propensity to have things like OSA and all of these mean they can be increased sensitivity to the side effect of drugs like opioids. In terms of other pharmacodynamic changes that don't fit into any one category and the key things to remember with the elderly patients is that one, they can have more risk of polypharmacy errors. Two, they're at increased risk of having poor compliance of drugs, i.e. forgetting to take drugs, and three, any drug you think of giving to an elderly patient, think about decreasing the dose. So if you apply that broadly into all other systems, you could then think about neuro-muscular blocking drugs as another example. Elzeli patients will have decreased skeletal muscle, so they probably need less neuro-muscular blocking drugs compared to the normal healthy adult. Moving on to the pharmacokinetic changes, with absorption, oral absorption can also be hardly variable. They can have reduced gastric emptying, reduced blood flow to the GI tract, all of this leading to again a variability and bioavailability. With the decrease in cardiac output, you also get decreased blood flow to muscle and to the subcut tissue. With distribution, elderly patients usually have a decreased in total body water leading to a decrease in volume of distribution for hydrophilic drug, and increased in total fat leading to an increase in volume of distribution for lipophilic drugs. They have an age-related decrease in the albumin, therefore acidic and natural drugs might be an increased free concentration, and the alpha-1 glycoprotein can either be the same or slightly increase in decrease depending on what text you read. In terms of the blood brain barrier, they can also be increased penetration to this barrier just like the neonates. Then with metabolism and excretion, they kind of go hand in hand. As you can predict both the liver function and the renal function will be compromised.
So phase one and phase two reactions will occur lots lower. They also might have a poor billary system, so that rid of elimination will also be compromised. With renal function you'd expect the creatinine clearance to be lower, therefore the half life of the drugs to be longer, and this again clinically means that you should space out the interval between dosing of drugs. Now moving on and looking at the changes with obesity, with the pharmacodynamics, the overall main clinical change occurring here is that there's an increase in total body weight, which is comprised less so of an increase in lean body weight, and more so an increase in fat. In terms of the cardiovascular system, there's generally an increase in cardiac output. In terms of the respiratory system, there can be an increased risk in respiratory depression in our say. It can be an increase in the rate of washing of inhalation drugs, due to two things, both an increase in manipulation and a decrease in FRC. This will lead to a rapid rise in the FAFI ratio. The other side note thing to remember with the obese populations is that one of the few drugs that we still calculate based on actual body weight is SUX, and this is because there's an increase in colonist or as activity with obesity, so therefore you have to dose this drug based on actual body weight. With non-depolarizing drugs however, we base that based on lean body mass, and the guidelines that we use for these are your sober guidelines, in which the maximum lean body weight for a male is roughly 100 kilos, and the maximum lean body weight for a female is generally 70 kilos. Then with pharmacokinetic changes, when you look at absorption, the increase in cardiac output can lead to an increase in absorption, both with splentant blood flow, from the intramuscular root, but from the subcut root, you might have an increase in adipose tissue that might weigh off the effects of the increase in cardiac output. With distribution, as expected, you have an increase in volume with distribution for lipophilic drugs, due to the increase in fat, but also you have an increase in volume with distribution of hydrophilic drugs, due to the increase in the extracellular fluid. The key here is though, that the cardiac output is fast, and so therefore you get a rapid redistribution of the drug from the central compartment, and this is why you normally see going back to the sober guidelines, they say that proper-fold dose for induction, you use the lean body weight, but for maintenance, you use the adjusted body weight. In terms of proteins, albumin levels generally say the same, and alpha-1 acid glycoprotein can slightly increase. Looking at metabolism and excretion, with metabolism, the increase in splentant blood flow can actually lead to a faster metabolism through the hepatic system, but only for drugs that are flow-dependent. Remember when we looked at pharmacokinetics, we said that drugs in the liver could either be capacity limited or flow limited, so for drug is flow limited, here obesity will be beneficial. In terms of excretion, that increase in blood flow will carry on to the kidneys, and therefore could theoretically lead to a faster creatinine clearance, and therefore a shorter half-life of drugs. Generally, what we say clinically is you keep the same timeframe or the same interval duration in the obese patient that you do with a healthy adult though. Now moving on and looking at the pregnant patient, here the majority of changes that are occurring because of the changes in hormones associated with pregnancy. From the pharmacodynamic perspective, with the CNS, the increase in progesterone leads to a decrease in mac requirements, both due to the increase in progesterone and increase in beta endorphins. In terms of the cardiovascular system, there's an increased propensity for hypertension, specifically with niraxials, because pregnant patients are essentially in a hyperdynamic state, where they have a higher cardiac output, but a low systemic vascular resistance. Moving to respiratory, you have an increase in miniaturization, which will lead to an increase in both washing and wash out of volatile anesthetics. And then other specific things that you should know about is specifically with local anesthetics. With local anesthetics, we say that there needs to be a 30% dose reduction in pregnancy. Generally due to two reasons, the first reason is an increase in free drug, which relates to the pharmacokinetic changes, but the second reason is said to be due to the increase in sensitivity to local anesthetics as well. The other pharmacodynamic change, which goes without saying, is that drugs can have an implication on the fetal well-being. So therefore, there's different categories of drugs from A to X based on the safety profile in pregnancy. So that'd be an important point that I would put into this question if it was asked in an SQ form. Then in terms of the PK changes, when looking at absorption, this can be very, very valuable throughout the pregnancy journey. Patients can have increased nausea and vomiting early on and sometimes throughout the whole pregnancy. They can have variability of gastric emptying, specifically when they're closer to the end of pregnancy and in labor. This can lead to a variability in gastric absorption and an unknown by availability through that route. You do have an increase in cardiac output, which should be increasing spank-necked blood flow. You know which side wins that battle. In terms of the IAM and sub-cut route, there should be increased absorption again going back to the increase in cardiac output. And with this population, specifically with the absorption, I would put in a little note about New Axial Root, just because that's a commonly used route in this population base. In terms of distribution, as expected, there's an increase in total body water, which leads to an increase in volume of distribution for hydrophilic drugs. There's an increase in fat, which leads to an increase in volume of distribution for lipid soluble drugs. There's an overall decrease in protein bindings, secondary to the dilutional effects of increasing extracellular volume, leading to an increase in free drug percentage. And there's the increase in cardiac output, which again, like the obese patient, leads to a rapid redistribution of that drug from the central compartment. The other unique thing with distribution in this population is that there's a potential for ion trapping within the fetal circulation. So I'd make a special note for this in this population. In terms of metabolism and excretion, the key thing here with metabolism is that there's a decrease in plasma core on this raise level by 30%. And this means you can theoretically decrease your succostose. But in practice, no one decreases their succostose. You just keep the same dose of succs and expect it to maybe last rather than eight minutes, maybe ten minutes or so. In terms of the hepatic function itself, there's kind of contrasting things occurring here. Progesterone is trying to increase metabolism by inducing hepatic enzymes, while estrogen is decreasing metabolism by inhibiting hepatic enzymes. Now be nice to say that the overall effects are offset, but you do have to put those two points in separately because they are having individual effects. In terms of excretion, because there's an increase in cardiac output, you'd expect there to be an increase in creatinine clearance. And with that, what you specifically see in the pregnant population, and this is really important to note clinically, is that their creatinine number can actually be lower than the quoted adult reference range. And so if they have a mild increase in their creatinine, it might not show up as a different color change and whatever form you use if you use Oslab or Oscale, whatever pathology form you use, noting that small change can be clinically significant, especially if you're trying to figure out if the patient has preeclampsia and any end organ function changes. So that's really the main physiological changes covered for those groups being neonates, elderly, obese and pregnant population. Now we'll look at the changes with disease states starting off with cardiac disease. With cardiac disease, the pharmacodynamic changes can be an alteration in agents that have anotropic or vasopressor effect. An increase in pathosquatic disease leads to an increase in sensitivity to BP altering patients and those can be medications that either increase or decrease the BP and then finally there's an increase in propensity of generating arrhythmias with certain medications. Looking at the PK changes, with regards to absorption, overall you can summarise this as a decrease in cardiac output state, which will lead to a lower bioavailability or a lower rate of absorption more specifically with every type of root that you can think of apart from IV. With IV, of course the absorption of the bioavailability is 100%, but the clinical effect might be delayed compared to a healthy adult because of the low cardiac output state. This leads on to the distribution where slower cardiac output can lead to a slow redistribution of the drug. With cardiac disease, you can also get an increase in the extracellular volume. Therefore the volume of distribution for hydrophilic drugs might be increased. And with this increase, you can get an increase in the amount of blood that you have.
increase in extracellular volume, you can also have a dilutional effects on the proteins that are available leading to an increase in the free percentage of a drug. Now in terms of metabolism excretion, it really depends on how far you take this person with cardiac disease. Because a person with end stage cardiac disease can have both hepatic and renal involvement, so therefore the function of both these systems would be reduced. But just from a general cardiac point of view, the decrease in cardiac output is the key thing here. A decrease in cardiac output to the liver means those drugs that are flow dependent will have a decrease rate of metabolism. A decrease cardiac output to the kidneys means that the crowning clearance of the drug will be lowered and the half life of the drug will be increased. So overall you should increase the duration interval between drug dosing. Moving on to the next disease state which is respiratory, this can really be summarized by a few lines. In terms of pharmacodynamics, there isn't really any major implication unless there's a significant change in minotventilation or FRC which a patient has due to that respiratory disease. In terms of pharmacokinetics, if a person has respiratory disease, drugs that are absorbed through that root might have a decrease in lung surface area, therefore a decrease absorption area. If the person is a chronic CO2 retina or is an acedotic state, that can lead to eye-on-trapping of basic drugs and in terms of metabolism and excretion, there can be decreased excretion of volatile agents, but generally this is not really the case with respiratory disease because when we're washing our drugs, we're generally controlling that from the ventilator itself. Then the last two disease states which are hepatic and renal, we've kind of already touched on this and it's pretty self-explanatory what the effect of these changes will be in terms of the pharmacokinetic effects. What I'm just going to touch on quickly is just the pharmacodynamic effects with these disease states. With the hepatic disease state, the important pharmacodynamic implications you need to be aware of are the presence of potential hepatic and catholopathy which can alter your CNS system that you need to increase sensitivity of CNS affecting drugs. Again, a classic example for this would be opioids and the increase in side effects from using opioids. Then you need to think about the increased risk of coregalopathy with patients with hepatic disease. And then finally, you need to think about increased toxicity specifically of drugs that are mainly metabolised by the liver and really these are majority of the drugs that we give. And the key ones you want to think about are those that are going to be capacity limited because there might not be the same amount of hepatic cells there to break down that drug. A good example for this is just remembering local anesthetics. You should generally decrease your toxic dose or your safe upper limit dose of local anesthetics if a patient has severe liver disease. Then with renal disease, you can also get the phenomenon of uremic and catholopathy. Again, the same principles apply to hepatic and catholopathy and you just be careful with the same drugs as there's an increased sensitivity in the CNS system. The other specific things that you might be aware about in patients with renal disease is specifically looking at their potassium levels if you're going to give them succumbetronium. So check these prior. And the other thing I'd add on to this is that there's the renal disease patient and then there's the renal disease patient who's on dialysis. These are two different patients that have two different pharmacanetic principles. With the renal disease patient that isn't on dialysis, that patient can be in a fluid overload state. While the patient that's on dialysis, depending on when they have dialysis, can be in a fluid deplete state or more closer to a healthy adult state, depending on when they've had their dialysis. If it's been a while, they can behave more like their end-stage renal failure off dialysis, but if it's just after dialysis, you have to be really careful. So just knowing that there's those two different subtypes of the renal disease patient is an important clinical aspect. So that brings us to the end of this huge learning objective and I wasn't lying at the start when I said that this is going to be a long episode. Although this topic seems like you could get through it really quickly, there is a lot of little nuances attached to this topic. There's a few things I'm going to admit talking about in this episode, specifically the mechanisms of drug interaction and pharmacogenetics. I think these two things are really well covered in Mach 95 and really I wouldn't be doing you any favors just reading what Mach 95 says again in this episode. So the last thing I'm going to touch on today before we move on to the SEQs is talking about adverse drug reactions and this is going to be really quick and my simple way to think about adverse drug reactions. The classification for adverse drug reactions comes from the world allergy organisation. It's a simple A, B, C, D, E, F classification and each one of these things describes a type of classification for an adverse drug reaction. Type A is an augmented drug reaction. Therefore, this type of reaction is a dose related reaction. The features of it is that it has a common reaction. It's related to the pharmacogenomics properties of the drug. It's predictable and it has low clinical significance in majority of cases. An example for this would be the high-potension expected with the vasodilatory effects of giving someone proper fall. Then the next type of effect is a type B effect. This is a bizarre effect and this again refers to the term that we mentioned earlier which is an idiosyncratic effect. What this means is that it's a non-dose related effect. So the key difference between type A and type B is that type B is a non-dose related effect. The other features of this type B effect is that it's uncommon. It's not related to the pharmacogenomics of the drugs. It's unpredictable and unlike a type A effect which has a low mortality or a low clinical significance, a type B effect can have a higher mortality and a very high clinical significance. A classic example of this that we've already said is an anaphylactic reaction. Then a type C effect is a chronic effect. This again goes back to a dose related effect which is also time related. It leads to direct organ damage and the feature of this is that it's uncommon and it's usually dose related. A more common example that you might see in clinical practice is the use of exogenous steroids leading to a depression in the HPA axis. Then we have a type D effect which is a delayed effect. This is again time related but it might not be dose related. It's uncommon and usually becomes apparent as time passes by. An example of this will be drugs that have carcinogenic or teratogenic effects. Then you have type E effects which are end-of-use effects. This has the classical feature of occurring when you stop a drug. The classic example again here being opioid misuse or opioid withdrawal but can be any drug withdrawal. Then finally you have the type F adbestrug reaction. This is the unexpected failure of therapy. This is usually a dose related effect and it's often caused by drug interactions. An example of this would be going back to a term we used being tacky for laxas and remi-fensinal after high dose use for a long period of time. Another example could be the use of sigamidx leading to the interaction and the ineffective use of the oral contraceptive pill. So that brings us to the end of all the learning objectives I want to cover today. There's a lot of learning objectives that I still haven't gone through yet but hopefully I've given you an overview now of the general pharmacology principles that encompass pharmaceuticals, variability in drug responses and adbestrug reactions. With that, let's look at some of the past SAQs that have been asked on this topic in the last few years. The first SAQ is from 2023 first sitting and this had a really poor pass rate of 25% and still currently does not have a model answer. The question was, briefly outlined how body tissue composition is progressively altered by morbid obesity? Define each of the following terms, total body weight, ideal body weight, adjusted body weight and lean body mass and then briefly comment on the suitability of each of the above terms when used as a scalar for estimating an induction dose of preper fall in a morbidly abyss patient. Now you can see why this question has been asked because in terms of clinical relevance, obesity is becoming more and more prevalent and therefore you need to accurately dose these drugs to avoid both underdosing and overdosing. In terms of the examiner report, it wasn't very helpful in terms of what they expected because it kind of just outlines what the question asked already. So the expected domains included the body composition changes in morbid obesity, talking about both the relative and absolute changes in lean adipose mass, the definitions of the terms but precise formulas were not needed and then a suitable dosing estimate. What I do think is really good from this examiner report are the references that are provided
particularly the reference to the BJA article in 2018. So from this, we can kind of make a model answer for this. To start off with my model answer, I would have a quick definition of morbid obesity, being a BMI greater than 40, and this has multi-organ system impacts. In terms of body tissue composition, they've already told you they want you to focus in on the lean and adipose mass, both the absolute and relative changes. So if you think about what happens as a patient becomes from normal weight to obesity to morbid obesity to super obesity, what's occurring with the adipose mass is that there's a linear increase in the adipose tissue. In a normal healthy individual, typically you have 20% adipose mass and 80% lean body mass, and lean body mass is just the Aka fat free mass. What also happens as you go in increasing weight, the lean body mass also increases linearly. However, the rate of linear increase for lean body mass is much lower compared to adipose mass. So therefore, in absolute terms, both of these two things increase, but in relative terms, the proportion of fat mass greatly starts to increase compared to lean body mass. To the point where if a patient is close to morbid obesity/super morbid obesity with a Bm higher than 50, they're reaching nearly a 50/50 distribution of lean and adipose mass. And in that BJA article that is referenced, you can see a great depiction of this on a graph. With this, you get both an increase in cardiac output and an increase in the central compartment. There's a gradual increase in the total body water, the fat mass, the lean body mass, the plasma proteins, and what this means relating it back to drugs is that there's an increase in volume of distribution for both hydrophilic drugs and hydrophobic drugs. The key thing to remember to help you answer part C of this question is that lean body mass is the key thing you want to keep an eye on. Because lean body mass increase is really the main controller of drug clearance and redistribution. So because lean body mass does not increase at the same rate as fat mass, there is not that same level of clearance and redistribution if you were to compare two people, i.e. a BMI 40 compared to a BMI 50. They'll have different degrees of redistribution and different degrees of clearance. And that's really the basis of why this question has been asked and leads us to the second part of this question, which is define each of those following terms. In terms of total body weight, this is self-explanatory. Ideal body weight is the ideal weight based on a patient's height. There's a complex formula for this and it can be adjusted for males and females. But the way I remember it is the height in centimeters minus 100 gives you a rough estimate on what the patient's ideal body weight is. Then you have adjusted body weight and this is kind of like a middle ground between ideal body weight and total body weight. The formula that I have for adjusted body weight is the ideal body weight plus 0.4 times the actual body weight minus the ideal body weight. So it's the difference times 0.4. You add this onto the ideal body weight and you get the adjusted body weight. And that's thought to estimate more accurately what the patient's weight should be to help better guide both induction-dose single drugs and maintain stocing of drugs. Then you have lean body mass which as we said previously is just the fat free mass. So there is a complex formula for this but you just need to know the variables that are involved in this formula. If you do remember the formula, that's really good but the variables are the weight. So that's the total body weight, the height and then sex. There's a different formula for males and there's a different formula for females. And the reason we use lean body weight is that in terms of pharmacokinetics it's probably the best method of dose adjustment for morbidly obese patients or at least the most validated in terms of the number of studies available on it. So what does this then mean for part C which is using each one of these terms to think about what the induction-dose of prepofol should be in a morbidly obese patient. So if we just go step by step if you use total body weight you're probably likely to overdose a patient with an induction dose. If you use ideal body weight you're probably likely to under-dose the patient. If you use lean body mass that's most likely to be the appropriate dose and if you use adjusted body weight that's really a similar profile to the lean body mass. So either the adjusted body weight or the lean body mass should be the weight that you use for the induction dose of prepofol and that's reflected in the widely used sober guidelines. Just one final point to understand with this question and it's a good point that's raised in the examiner report is that just remembering less than 5% of the cardiac output goes to fat. So although in morbidly obese patients there is an increased amount of fat the lean body mass is still the most important factor for determining how much cardiac output is increased proportional to what the weight of the patient is and just remember that when you're thinking about the central compartment and your loading dose equation which is V1 times the desired plasma concentration. Therefore that is the reason why we're using lean body mass or adjusted body weight for dosing of an induction dose of prepofol. So hopefully that helps you make your model answer for this question. The next question we're going to look at is from 2022's second sitting which was using pharmacokinetic and pharmacodynamic principles briefly outlined the mechanisms of drug interactions providing relevant examples. This again had a sub 50% pass rate and in the examiner report as expected the domains that want you to cover in regards to pharmaconetics would be the ADME and with pharmacodynamics it was talking about drugs that might have agonism properties and antagonism properties. You could get extra marks if you correctly drew the isobologram which we haven't discussed in this pod yet. Now in terms of model answer for this question I really like the way that life in the fast lane part one notes approach this topic and that's the way that I would use my model answer for this question. The three overall ways you can have drug interactions go back to our pharmaceuticals pharmacokinetics and pharmacodynamic approach. In this question they've specifically only asked PK and PD principles so we don't really have to worry about the PC principles. So starting off with pharmacodynamic interactions I would break this down to two types of interactions. You can either have a direct interaction or an indirect interaction. What I mean by direct is that drugs act on the same receptor site for an effect. An example here would be niloxone and opioids giving a direct antagonism effect or volatiles and nitrous oxide having an additive effect. When you look at an indirect effect this is when drugs act on different sites for the same effect. Another example using opioids would be opioids and volatiles having indirect synergism while nio-stigmean and non-depolarizing muscle blockers would be having indirect antagonism. So those would be the two statements that I put at the start with pharmacodynamics and then I would represent those statements using an isobologram. Now an isobologram sounds like a complex concept but it's actually quite simple to understand. It's a graph used to study the nature of drug interactions and it describes the combined effects of two different drugs using a line to connect equipotent doses of two drugs that exert a similar effect. So on one axis you have drug A and on the other axis you have drug B. If you draw a line between those drugs those lines can represent whether an effect is being synergistic antagonistic or summative also known as additive. If an effect is synergistic you need decreased doses of both of those drugs to produce the same effect. An example in clinical practice say you're running someone on Tiva you're running them on proper fall and remeventinal. The use of remeventinal with proper fall is synergistic in this sense you require less dose of proper fall to maintain depth of anesthesia while you're running that strong opioid infusion. When you run someone on volatiles and you add in nitrous oxide you will see that the MAC is additive so it's not synergistic but each one of those drugs is equally contributing to the desired effect that you want to get to. Then inhibition or antagonism we've already explained it so that's the first part of my model answer. Moving on to pharmaconetics and this is again going through the ADME model. When you look at drug interactions with the absorption the easiest way to think about this would be what would affect my oral bi availability. These can either be things that will either alter my gastric emptying or my intestinal absorption or alter my gastric or intestinal pH. An example to put here would be opioids. This decreases my gastric emptying while metaclopromide increases my gastric emptying So, therefore. it might be beneficial for intestinal absorption. Sometimes with absorption you can also manipulate drugs to have a beneficial effect. So using local anesthetic we can add in adrenaline to decrease systemic absorption to give a beneficial effect and prolonging the duration of action of that local anesthetic. So the key thing to write here is that sometimes interactions can be beneficial or sometimes they can be harmful. Then looking at drug interactions in distribution the classic example will be drugs that alter or compete for the same plasma protein binding sites. An example of this in neonates that is very important is aspirin which displaces bilirubin from albumin, therefore increasing the bilirubin amount in the systemic circulation. With distribution also you can have drugs that can alter the cardiac output and this will alter the redistribution of drugs both having an effect on the target sites and on the peripheral sites. Then with metabolism there's two main ways that you can have drug interactions. You can either have enzyme induces or enzyme inhibitors. Classic enzyme induces would be drugs like barbituates, phenetone, enzyme inhibitors would be drugs like amyodorone, rapomil, some specific types of antibiotics like siperaphoxacin and then weird and wonderful things like grapefruit juice. Finally with elimination drug interactions can alter the excretion of drugs which can either again be beneficial. Example being provenosid decreasing the excretion of penicillin, therefore leading to a longer half-life or they can be harmful such as endz leading to a decrease in GFR. The other interactions you can also do on purpose is change the pH of the urine, making the urine more alkaline will lead to increased excretion of acidic drugs and the opposite is also true. So while this question sounds tricky initially to answer, we've already discussed all the principles needed for you to develop your own model answer for this question in our general pharmacology series. Now moving on to the next SAQ which was also asked in 2022 but in the first sitting and this was discuss how the responses to opioid medications are altered in the elderly, explain using PK and PD principles. Again this question had a less than 50% pass rate and there are some minor gems in this examiner report. The key thing that they've said and that we all understand is that elderly patients are more sensitive to opioids, hence the reason to ask this question in the first place. But I think the real gem here is that they've said that some excellent examples of answers included using individual drugs, talking about the effects of polypharmacy especially in the elderly, the alterations in pain tolerance and then the cellular changes within the CNS system with aging. So in my model answer I would try to incorporate these higher level points and I would start off my answer with a fluffy statement that the elderly population is increasing and so is the opioid pandemic and hence understanding the PK and PD changes is important both clinically and from a safety perspective. Now you could admit that but I think it just shows the examiner you know why they've asked this question. Then you can go into your PD and PK alterations. With your PD alterations I think it suits nicely to have a system-based approach. Obviously the main changes here are going to be with the CNS in the respiratory system. So with the CNS the key change is that the opioid sensitivity increases as a patient ages and an example of this is that an 80 year old requires half the dose compared to a 40 year old. Additionally with this I would add in that the pain pathways are slower as we get older therefore both the peripheral and central nosyceptors take longer to conduct the pain pathway and this means that the descending pain pathway or the descending analgesic pain pathway is also less efficient. This overall leads to what we see clinically is that the elderly seem to have a higher pain threshold however what is most important is that when they actually experience pain they seem to deal with it much worse because those descending pathways are also slow. This means that elderly patients that are in pain are at higher risk of developing chronic pain and while that's not what's asked for in this question I think it's an important contextual point to put in with this answer. Another important contextual point to put in is that elderly patients may have impairment and this can lead to inadequacy in communicating pain inadequacy in using analgesic modalities and under treatment and within all this the use of analgesics can put them into a state of delirium where they can also develop these issues as a secondary consequence. Then from a respiratory perspective we know that the elderly will have an increased risk of respiratory depression a reduction in their airway reflexes a reduction in their CO2 sensitivity and an increased risk of having all of us say all of these attributes mean that the safety margin for opioids is reduced in the elderly population then the additional point in PD using the examiner report would be to mention that the elderly have increased comorbidities increased risk of polypharmacy errors increased risk of compliance errors all of this means that opioids are high risk drugs in the elderly population and from the perspective of the geriatric giants that kill the elderly things like urinary tension and constipation can all be made worse with opioids then moving on to pharmacokinetic changes again this is all very self-explanatory with the absorption you can have a decrease in gut transit time a decrease in gastric pH thinness skin all of which leads to an unpredictability in the biobailability of drugs in terms of distribution have decrease in total body weight a decrease in lean body mass but an increase in fat therefore hydrophilic drugs may have an increase in concentration and added on to this the elderly generally have a decrease level of proteins leading to an increase in free drug concentration then with metabolism hepatic metabolism is decrease again leading to an increase concentration of potentially active metabolites and there would be a key thing that I would write down here and following on from this elimination is also reduced due to an age related decrease in GFR these two things clinically mean that within the elderly population you generally increase the duration interval between your doses and due to the pharmacodynamic changes you generally decrease the PR and dose of opioids therefore there's a dose reduction and a duration interval increase within the elderly population due to their PK and PD changes to increase the margin of safety within this population the last thing you can do to increase the margin of safety is try to avoid drugs that have active metabolites so you use drugs that have non-active metabolites and as classically YUC patients that are elderly that have a PCA on fentanyl rather than things like oxycodone or morphine then moving on to the next SAQ which was asked in 2021 first sitting which was define the terms tolerance and tachyflaxis 30% discuss the mechanisms by which these can develop giving relevant examples 70% again this had a pass rate of less than 50% and you can start to now see a theme within pass marks for these questions the examiner report for this didn't really add much to what the question already asked and in terms of my model answer we've already gone through the definitions of tolerance and tachyflaxis earlier just briefly summarizing the mechanisms again with tachyflaxis we don't know exactly how it occurs but we think it's probably due to immediate adiplation and an example would be things like effedren which uses all of the noradrenaline stored within the vesicles if you keep using it repeatedly another example will be GTN or remi-fentanyl and with remi-fentanyl it's probably a more complex mechanism rather than just depletion of mediators but that's a good enough mechanism to put in for the other two examples then for the mechanism of tolerance this can be varied they can either be increase in drug clearance receptor down regulation receptor modification secondary messenger upregulation or upregulation of antagonistic mechanisms so there's a wide variety of mechanisms and I would just try to remember one or two examples to go with those different types of mechanisms so easy drugs to remember for examples here will be beta-2 agonist like south butymol, benzodiazepines, alcohol and insulin and remember going back to definition the key thing with the definition is remembering tachyflaxis is short term and tolerance occurs long term then the next SOQ is from 2020 second sitting which was discuss the pharmacanetic implications of severe chronic kidney disease using examples of drugs using anesthesia to illustrate your answer as you guess
It had a sub 50% pass rate again and the examiner report here I thought was actually quite useful I'll incorporate the examiner report into the model answer and to start off the model answer I would have a definition of what severe chronic kidney diseases in my head It refers to CKD which is either stage 4 or stage 5 or CKD which is led to the person being on dialysis and CKD which is stage 5 has a GFR less than 15 The issue with severe CKD compared to mild or moderate CKD is that it leads to a significant decrease in the margin of safety of drugs and a lower therapeutic index Now remember what I said when I talked about kidney disease There's the kidney disease patient that is in on dialysis and the kidney disease patient that is on dialysis and Those two patients will differ in terms of their PK changes and here I will just write a brief statement to say that as well Then going through it methodically in your ADME structure Talking about absorption the three key things you want to touch on here is that CKD can lead to retention of water Increasing a total body water which can have an implication on oral absorption Making a mucosal areas a demit is therefore increasing the barrier to diffusion and slowing the onset of drugs Specifically those that are oral or that are patches due to those a demit is changes Then you can also have the effect of uremia which can have a PD effect but also PK effect uremia can lead to a decrease in gastric metility and increase in nausea and vomiting all of which can lead to an unpredictable Biobailability through the oral route Now this is more so important for the patient that isn't on dialysis while the patient who is on dialysis This might be a lesser effect Then moving on to distribution Because we already know that the extra cellular volume is going to be increased We know that the volume of distribution of water solubull drugs will also be increased and therefore These type of drugs will lead to increasing loading dose an example would be sucks or Non-depolarizing muscle relaxants the key thing with your non-depolarizing agents is that your lean body mass in your severe CKD patients might be lower so therefore it might actually lead to a lower dose Compared to sucks for which you might need a higher dose or the same predicted dose Then you can have the other effects of alterations and plasma proteins Typically a lower level of albumin which will lead to an increase in free acidic drugs Examples here being benzodiazepines and the last effect with distribution would be the potential alteration of acid-based changes Then in terms of metabolism Eurea can inhibit certain CYPN enzymes and this can lead to an increased duration of action of certain types of drugs and Example in ketamine nightmares is fentanyl Moving on to excretion this is where CKD will be doing majority of its damage The renal clearance of the drug will be decreased therefore the creatinine clearance will be lower leading to an increased half-life of a drug again two different types of patients if the patient is on dialysis Certain drugs can be cleared through dialysis Typically these are drugs that are small and unbound So clinically what that means is that you might keep the same interval dosing as you would for a normal healthy Individual for a patient who's on dialysis while the CKD patient who's not on dialysis You might increase the duration frequency or that interval frequency The important thing here with excretion in terms of safety Regardless of the patients on dialysis or not you want to try to avoid drugs that have active metabolites And that's why usually you'll never see someone who's on morphine with severe CKD and Generally you should not see people on long-acting opioids either for that reason The important thing here that the examiner reports said with that last point which might show a higher level of understanding Is that saying yes try to avoid those drugs? But if you do need to give those drugs for whatever reason say the patient has allergies You can still give those drugs Understanding you might need to be more vigilant with them decreasing their dose and increasing their interval frequency So it's not an absolute contraindication. It's a relative contraindication Now we're on the home stretch with two more SQs to go the second last SQs from 2017 first sitting Which was outlined the genetic variation on the side of chrome P4502d6 enzyme and Discussed the clinical relevance for drugs using the period operative period This was a very topical question in 2017 and I think that's what led to the question being asked in 2017 And a must-do-court people off guard because they had a pass rate of 7 percent Within the examiner report there's a multitude of drugs you could have used as examples These included coding oxycodone, tramadol, methadone, beta blockers, antioedetics and tricyclic antidepressants Understanding not every drug is converted into its active metabolite some are converted into its inactive metabolite and Therefore the implication of ultra rapid metabolizers is in always just increasing the active drug component It can be also converting the drug from its active component to its inactive component I Think ketamine nightmares has a phenomenal model answer for this question And if it was asked again I would be memorizing this model answer which breaks it down into the CYP 2d6 system mainly existing in the liver affecting 25% of clinically used drugs Breaking it down into the activated drugs and the inactivated drugs so the activated drugs or the pro drugs would be Coding, tramadol, oxycodone and Tamoxifen and the inactivated drugs would be the antidepressants, antipsychotics, metoprolol and clonidine The genetics behind 2d6 so really the variants are either going to be normal activity reduced activity or no activity and the phenotypes can either be ultra rapid extensive intermediate or poor In terms of prevalence majority of us are extensive users That's 80 to 90% and I think of that as like the normal baseline population There's more ultra rapid phenotypes in North Africa and there's more poor phenotypes in Asian population specifically the Hong Kong Chinese What this means clinically is that it depends on if a drug is being activated or inactivated So for drugs being activated for an ultra rapid user It will have a faster peak effect faster toxicity while if a drug is being inactivated It will have a lower peak effect if a person is a poor user the exact opposite occurs The real risk clinically is in the ultra rapid users whether drug is being activated or The poor users whether drug is being inactivated in both these situations you have an increased risk of toxicity For the ultra rapid users the increased risk of toxicity is early for the poor users the increased risk of toxicity is late And that's really from my perspective as much as you need to know for this model answer and for your clinical knowledge Then we move on to our last S.A.Q for today Which was classified isomers Briefly write an account of their significance in drugs used in anesthesia This was so important it was asked in the same year twice Initially having a less than 50% pass rate and then subsequently having a 66% pass rate and the examiner report was essentially carbon copied for both the sittings the key thing in the examiner report were examples of drugs you could use and this could be local anesthetics Neomuscular blockers volatile agents Medazolane thio pentone tramadol and metadone and you could relate any of those drugs onto the effects on pharmaceuticals pharmaceutical dynamics or pharmacokinetics And I think I've talked about isomers at nauseam earlier on and I would just simply use that knowledge to make my model answer Remembering the two broad classifications for isomers are either structural and stereo Within structural you have the three different subtypes and then you have tortomerism as well Which is a great one to remember because you have two examples that you can use being medazolane and thio pentone Within stereo isomers you have the two different subtypes being geometric and optical and then within optical You have the enantomers and the diastereisomers We already know examples for each one of these so just going through it quickly a geometric Stereo isomer an example is mvcureum and optical stereo isomer an example can be bbibicane or ketamine and a diastereisomer an Example is atrocureum So that brings me to the end of this mammoth podcast and I appreciate at a certain point your brain just switches off And I'm very sorry that this podcast went over an hour But there was a whole lot to cram in that didn't really fit into pharmacodynamics and pharmacokinetics This does mean that we've completed our general pharmacology topic and this brings us to the end of another
series and we're slowly moving on to hopefully covering the whole curriculum. I don't have a clear cut idea on which topic I'm going to cover next. I'm trying to get a guest in to do a topic of interest next month and then I'll hopefully have a live private demonstration for you guys again. In the mean time, if you have a suggestion on what topic you want me to cover or what series you want me to go through, send me your suggestions at
[email protected] And as always thank you guys for listening, thank you for your awesome feedback, good luck with all your studying and I'll catch you next time on counter-ten. [BLANK_AUDIO]
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