Podcasts about CYP2D6

Fluphenazine is a high-potency typical antipsychotic that primarily acts as a dopamine D2 receptor antagonist in the mesolimbic pathway, reducing positive symptoms of schizophrenia. Extrapyramidal symptoms (EPS), such as dystonia, akathisia, and parkinsonism, are common due to potent D2 blockade in the nigrostriatal pathway. Neuroleptic malignant syndrome (NMS), though rare, is a life-threatening adverse effect characterized by rigidity, hyperthermia, altered mental status, and autonomic instability. CYP2D6 inhibitors (e.g., fluoxetine, paroxetine) can increase fluphenazine plasma concentrations, potentially raising the risk of toxicity and side effects. Concomitant use of fluphenazine with CNS depressants (e.g., alcohol, benzodiazepines) can enhance sedation and respiratory depression.

Ever thought about why medications work differently for different people? In this episode of Absolute Gene-ius, we explore the exciting field of pharmacogenomics with Wendy Wang, pharmacogenetic laboratory supervisor at Children's Mercy Hospital in Kansas City. Wendy shares how genetics can influence drug metabolism, offering a glimpse into how precision medicine can revolutionize healthcare by tailoring treatments based on an individual's unique genetic makeup.At the heart of Wendy's research is CYP2D6, a cytochrome P450 enzyme responsible for metabolizing around 20% of all prescribed medications. She explains how her lab uses digital PCR to analyze copy number variations (CNV), offering a reliable and precise method to predict drug metabolism. Wendy dives into the complexities of structural variants, the role of digital PCR in enhancing assay efficiency, and why pharmacogenomics is a critical piece of the precision medicine puzzle. Her use of delightful metaphors—like comparing genetic testing to ladling soup—makes complex science both relatable and engaging.In the Career Corner, Wendy opens up about her winding path to molecular biology, which included studying classical antiquity and nearly pursuing a career in history. She emphasizes the importance of resilience in research, embracing failure as a learning opportunity, and encourages budding scientists to reach out to mentors and explore diverse interests. Plus, hear about her most embarrassing lab mishap (hint: it involves a fire alarm) and the proud moment of publishing her first, first-author paper.Visit the Absolute Gene-ius page to learn more about the guests, the hosts, and the Applied Biosystems QuantStudio Absolute Q Digital PCR System. 

Meclizine is classified as a first-generation antihistamine. I discuss meclizine pharmacology, adverse effects, drug interactions, and much more. Meclizine is included on the Beers list due to its highly anticholinergic activity. Anticholinergic effects include constipation, dry eyes, dry mouth, urinary retention, and confusion. Sedation is an important adverse effect of meclizine. This adverse effect can be increased when used with other sedating medications such as opioids and benzodiazepines. Meclizine is primarily used for vertigo and motion sickness in clinical practice. The usual starting dose ranges between 12.5 to 25 mg. Meclizine is partially broken down by CYP2D6 so medications like bupropion can inhibit the breakdown of meclizine and lead to higher concentrations.

Contributor: Jorge Chalit-Hernandez, OMS3 Educational Pearls: CYP enzymes are responsible for the metabolism of many medications, drugs, and other substances CYP3A4 is responsible for the majority Other common ones include CYP2D6 (antidepressants), CYP2E1 (alcohol), and CYP1A2 (cigarettes) CYP inducers lead to reduced concentrations of a particular medication CYP inhibitors effectively increase concentrations of certain medications in the body Examples of CYP inducers Phenobarbital Rifampin  Cigarettes St. John's Wort Examples of CYP inhibitors -azole antifungals like itraconazole and ketoconazole Bactrim (trimethoprim-sulfamethoxazole) Ritonavir (found in Paxlovid) Grapefruit juice Clinical relevance Drug-drug interactions happen frequently and often go unrecognized or underrecognized in patients with significant polypharmacy A study conducted on patients receiving Bactrim and other antibiotics found increased rates of anticoagulation in patients receiving Bactrim Currently, Paxlovid is prescribed to patients with COVID-19, many of whom have multiple comorbidities and are on multiple medications Paxlovid contains ritonavir, a powerful CYP inhibitor that can increase concentrations of many other medications A complete list of clinically relevant CYP inhibitors can be found on the FDA website: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers  References Glasheen JJ, Fugit RV, Prochazka AV. The risk of overanticoagulation with antibiotic use in outpatients on stable warfarin regimens. J Gen Intern Med. 2005;20(7):653-656. doi:10.1111/j.1525-1497.2005.0136.x Lynch T, Price A. The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects. Am Fam Physician. 2007;76(3):391-396. PAXLOVID™. Drug interactions. PAXLOVIDHCP. Accessed March 16, 2025. https://www.paxlovidhcp.com/drug-interactions Summarized & Edited by Jorge Chalit, OMS3 Donate: https://emergencymedicalminute.org/donate/  

Be sure to tune in to this episode of the Precision Health and PGX Podcast as Dr. Becky Winslow, and Dr. Angela Cassano, PharmFusion Founder and owner, discuss Dr. Cassano's personal pharmacogenomics testing and how the results impacted her breast cancer treatment, the tamoxifen and CYP2D6 pharmacogenomics clinical utility research currently available, whether CYP2D6 testing for patients prior to tamoxifen is National Comprehensive Cancer Network (NCCN) and American Society of Clinical Oncology (ASCO) recommended, and whether insurers in the United States reimburse the testing. This is a must listen for those interested in the clinical pharmacogenomics' current landscape and a pharmacist-patient's perspective about PGx testing.   

Be sure to tune in to this episode of the Precision Health and PGX Podcast as Dr. Becky Winslow, and Dr. Angela Cassano, PharmFusion Founder and owner, discuss Dr. Cassano's personal pharmacogenomics testing and how the results impacted her breast cancer treatment, the tamoxifen and CYP2D6 pharmacogenomics clinical utility research currently available, whether CYP2D6 testing for patients prior to tamoxifen is National Comprehensive Cancer Network (NCCN) and American Society of Clinical Oncology (ASCO) recommended, and whether insurers in the United States reimburse the testing. This is a must listen for those interested in the clinical pharmacogenomics' current landscape and a pharmacist-patient's perspective about PGx testing.   

Pharmacogenomics plays a critical role in personalised medicine, as some adverse drug reactions are genetically determined. Adverse drugs reactions (ADRs) account for 6.5% of hospital admissions in the UK, and the application of pharmacogenomics to look at an individuals response to drugs can significantly enhance patient outcomes and safety. In this episode, our guests discuss how genomic testing can identify patients who will respond to medications and those who may have adverse reactions. We hear more about Genomics England's collaboration with the Medicines and Healthcare products Regulatory Agency in the Yellow Card Biobank and our guests discuss the challenges of implementing pharmacogenomics into the healthcare system. Our host Vivienne Parry, Head of Public Engagement at Genomics England, is joined by Anita Hanson, Research Matron and the Lead Research Nurse for clinical pharmacology at Liverpool University Hospitals NHS Foundation Trust, and Professor Bill Newman, Professor of translational genomic medicine at the Manchester Center for Genomic Medicine, and Professor Matt Brown, Chief Scientific Officer at Genomics England.   "I think we're moving to a place where, rather than just doing that one test that might be relevant to one drug, we'd be able to do a test which at the same price would generate information that could be relevant at further points in your life if you were requiring different types of medicine. So, that information would then be available in your hospital record, in your GP record, that you could have access to it yourself. And then I think ultimately what we would really love to get to a point is where everybody across the whole population just has that information to hand when it's required, so that they're not waiting for the results of a genetic test, it's immediately within their healthcare record."   To learn more about Jane's lived experience with Stevens-Johnson syndrome, visit The Academy of Medical Sciences' (AMS) YouTube channel. The story, co-produced by Areeba Hanif from AMS, provides an in-depth look at Jane's journey. You can watch the video via this link: https://www.youtube.com/watch?v=v4KJtDZJyaA  Want to learn more about personalised medicine? Listen to our Genomics 101 episode where Professor Matt Brown explains what it is in less than 5 minutes: https://www.genomicsengland.co.uk/podcasts/genomics-101-what-is-personalised-medicine  You can read the transcript below or download it here: https://www.genomicsengland.co.uk/assets/documents/Podcast-transcripts/Can-genomic-testing-prevent-adverse-drug-reactions.docx   Vivienne: Hello and welcome to Behind the Genes.  Bill: What we've seen is that the limited adoption so far in the UK and other countries has focused particularly on severe adverse drug reactions. They've been easier to identify and there's a clear relationship between some drugs and some genetic changes where that information is useful. So, a good example has been the recent adoption of pharmacogenetic testing for a gene called DPYD for patients undergoing cancer treatment, particularly breast and bowel cancer. And if you have an absence of the enzyme that that gene makes, if you're given that treatment, then you can end up on intensive care and die, so it's a really significant side effect. But as you say, the most common side effects aren't necessarily fatal, but they can have a huge impact upon people and on their wellbeing.  Vivienne: My name's Vivienne Parry and I'm head of public engagement at Genomics England, and today we'll be discussing the critical role of pharmacogenomics in personalised medicine, highlighting its impact on how well medicines work, their safety, and on patient care. I'm joined today by Professor Bill Newman, professor of translational genomic medicine at the Manchester Centre for Genomic Medicine, Anita Hanson, research matron, a fabulous title, and lead research nurse for clinical pharmacology at the Liverpool University Hospital's NHS Foundation Trust, and Professor Matt Brown, chief scientific officer for Genomics England. And just remember, if you enjoy today's episode, we'd love your support, so please like, share and rate us on wherever you listen to your podcasts.  So, first question to you, Bill, what is pharmacogenomics?  Bill: Thanks Viv. I think there are lots of different definitions, but how I think of pharmacogenetics is by using genetic information to inform how we prescribe drugs, so that they can be safer and more effective. And we're talking about genetic changes that are passed down through families, so these are changes that are found in lots of individuals. We all carry changes in our genes that are important in how we transform and metabolise medicines, and how our bodies respond to them.  Vivienne: Now, you said pharmacogenetics. Is it one of those medicine things like tomato, tomato, or is there a real difference between pharmacogenetics and pharmacogenomics?  Bill: So, people, as you can imagine, do get quite irate about this sort of thing, and there are lots of people that would contest that there is a really big important difference. I suppose that pharmacogenetics is more when you're looking at single changes in a relatively small number of genes, whereas pharmacogenomics is a broader definition, which can involve looking at the whole genome, lots of genes, and also whether those genes are switched on or switched off, so the expression levels of those genes as well would encompass pharmacogenomics. But ultimately it's using genetic information to make drug prescription safer and more effective.  Vivienne: So, we're going to call it pharmacogenomics and we're talking about everything, that's it, we'll go for it. So Matt, just explain if you would the link between pharmacogenomics and personalised medicine. And I know that you've done a big Genomics 101 episode about personalised medicine, but just very briefly, what's the link between the two?  Matt: So, personalised medicine's about using the right dose of the right drug for the right individual. And so pharmacogenomics helps you with not only ensuring that you give a medication which doesn't cause problems for the person who receives it, so an adverse drug reaction, but also that they're actually getting the right dose. Of course, people's ability to metabolise, activate and respond to drugs genetically is often genetically determined, and so sometimes you need to adjust the dose up or down according to a person's genetic background.  Vivienne: Now, one of the things that we've become very aware of is adverse drug reactions, and I think they account for something like six and a half percent of all hospital admissions in the UK, so it's absolutely huge. Is that genetically determined adverse drug reactions?  Matt: So, the answer to that is we believe so. There's quite a bit of data to show that you can reduce the risk of people needing a hospital admission by screening genetic markers, and a lot of the very severe reactions that lead to people being admitted to hospital are very strongly genetically determined. So for example, there are HLA types that affect the risk of adverse drug reactions to commonly used medications for gout, for epilepsy, some HIV medications and so on, where in many health services around the world, including in England, there are already tests available to help prevent those leading to severe reactions. It's likely though that actually the tests we have available only represent a small fraction of the total preventable adverse drug reactions were we to have a formal pre-emptive pharmacogenomics screening programme.  Vivienne: Now, I should say that not all adverse drug reactions are genetic in origin. I mean, I remember a rather nasty incident on the night when I got my exam results for my finals, and I'd actually had a big bee sting and I'd been prescribed antihistamines, and I went out and I drank rather a lot to celebrate, and oh my goodness me, I was rather ill [laughter]. So, you know, not all adverse drug reactions are genetic in origin. There are other things that interact as well, just to make that clear to people.  Matt: Yes, I think that's more an interaction than an adverse drug reaction. In fact frankly, the most common adverse drug reaction in hospitals is probably through excess amounts of water, and that's not medically determined, that's the prescription.  Vivienne: Let me now come to Anita. So, you talk to patients all the time about pharmacogenomics in your role. You've been very much involved in patient and public involvement groups at the Wolfson Centre for Personalised Medicine in Liverpool. What do patients think about pharmacogenomics? Is it something they welcome?  Anita: I think they do welcome pharmacogenomics, especially so with some of the patients who've experienced some of the more serious, life threatening reactions. And so one of our patients has been doing some work with the Academy of Medical Sciences, and she presented to the Sir Colin Dollery lecture in 2022, and she shared her story of having an adverse drug reaction and the importance of pharmacogenomics, and the impact that pharmacogenomics can have on patient care.  Vivienne: Now, I think that was Stevens-Johnson syndrome. We're going to hear in a moment from somebody who did experience Stevens-Johnson's, but just tell us briefly what that is.  Anita: Stevens-Johnson syndrome is a potentially life threatening reaction that can be caused by a viral infection, but is more commonly caused by a medicine. There are certain groups of medicines that can cause this reaction, such as antibiotics or anticonvulsants, nonsteroidal anti-inflammatories, and also a drug called allopurinol, which is used to treat gout. Patients have really serious side effects to this condition, and they're often left with long-term health complications. The morbidity and mortality is considerable as well, and patients often spend a lot of time in hospital and take a long time to recover.   Vivienne: And let's now hear from Jane Burns for someone with lived experience of that Stevens-Johnson syndrome. When Jane Burns was 19, the medicine she took for her epilepsy was changed.  Jane: I remember waking up and feeling really hot, and I was hallucinating, so I was taken to the Royal Liverpool Hospital emergency department by my parents. When I reached A&E, I had a temperature of 40 degrees Celsius. I was given Piriton and paracetamol, and the dermatologist was contacted. My mum had taken my medication to hospital and explained the changeover process with my epilepsy medication. A decision was made to discontinue the Tegretol and I was kept in for observation. Quite rapidly, the rash was changing. Blisters were forming all over my body, my mouth was sore and my jaw ached. My temperature remained very high. It was at this point that Stevens-Johnson syndrome, or SJS, was diagnosed.  Over the next few days, my condition deteriorated rapidly. The rash became deeper in colour. Some of the blisters had burst, but some got larger. I developed ulcers on my mouth and it was extremely painful. I started to lose my hair and my fingernails. As I had now lost 65 percent of my skin, a diagnosis of toxic epidermal necrolysis, or TEN, was made. Survivors of SJS TEN often suffer with long-term visible physical complications, but it is important to also be aware of the psychological effects, with some patients experiencing post-traumatic stress disorder. It's only as I get older that I realise how extremely lucky I am to have survived. Due to medical and nursing expertise, and the research being conducted at the time, my SJS was diagnosed quickly and the medication stopped. This undoubtedly saved my life.  Vivienne: Now, you've been looking at the development of a passport in collaborating with the AMS and the MHRA. Tell me a bit more about that.  Anita: Yes, we set up a patient group at the Wolfson Centre for Personalised Medicine approximately 12 years ago, and Professor Sir Munir Pirmohamed and I, we wanted to explore a little bit more about what was important to patients, really to complement all the scientific and clinical research activity within pharmacogenomics. And patients recognised that, alongside the pharmacogenomic testing, they recognised healthcare professionals didn't really have an awareness of such serious reactions like Stevens-Johnson syndrome, and so they said they would benefit from having a My SJS Passport, which is a booklet that can summarise all of the important information about their care post-discharge, and this can then be used to coordinate and manage their long-term healthcare problems post-discharge and beyond. And so this was designed by survivors for survivors, and it was then evaluated as part of my PhD, and the findings from the work suggest that the passport is like the patient's voice, and it really does kind of validate their diagnosis and raises awareness of SJS amongst healthcare professionals. So, really excellent findings from the research, and the patients think it's a wonderful benefit to them.  Vivienne: So, it's a bit like a kind of paper version of the bracelet that you sometimes see people wearing that are on steroids, for instance.  Anita: It is like that, and it's wonderful because it's a handheld source of valuable information that they can share with healthcare professionals. And this is particularly important if they're admitted in an emergency and they can't speak for themselves. And so the passport has all that valuable information, so that patients aren't prescribed that drug again, so it prevents them experiencing a serious adverse drug reaction again.   Vivienne: So, Stevens-Johnson, Bill, is a really scary side effect, but what about the day to day benefits of pharmacogenomics for patients?  Bill: So, what we've seen is that the limited adoption so far in the UK and other countries has focused particularly on severe adverse drug reactions. They've been easier to identify and there's a clear relationship between some drugs and some genetic changes where that information is useful. So a good example has been the recent adoption of pharmacogenetic testing for a gene called DPYD for patients undergoing cancer treatment, particularly breast and bowel cancer. And if you have an absence of the enzyme that that gene makes, if you're given that treatment, then you can end up on intensive care and die, so it's a really significant side effect. But as you say, the most common side effects aren't necessarily fatal, but they can have a huge impact upon people and on their wellbeing.   And it's not just in terms of side effects. It's in terms of the effectiveness of the medicine. Because if a person is prescribed a medicine that doesn't or isn't going to work for them then it can take them longer to recover, to get onto the right medicine. That can have all sorts of detrimental effects. And so when we're thinking about introducing pharmacogenetics more broadly rather than just on a single drug or a single gene basis, we're thinking about that for common drugs like antidepressants, painkillers, statins, the drugs that GPs are often prescribing on a regular basis to a whole range of patients.  Vivienne: So, to go back to you, Anita, we're really talking about dose here, aren't we, whether you need twice the dose or half the dose depending on how quickly your body metabolises that particular medicine. How do patients view that?  Anita: Well, the patient in question who presented for the Academy of Medical Sciences, I mean, her take on this was, she thinks pharmacogenetics is wonderful because it will allow doctors and nurses to then prescribe the right drug, but also to adapt the dose accordingly to make sure that they get the best outcome, which provides the maximum benefit while also minimising any potential harm. And so from her perspective, that was one of the real benefits of pharmacogenomics. But she also highlighted about the benefits for future generations, the fear of her son taking the same medicine and experiencing the same reaction. And so I think her concerns were, if we have pharmacogenetic testing for a panel of medicines, as Bill mentioned then, then perhaps this would be fantastic for our children as they grow up, and we can identify and predict and prevent these type of reactions happening to future generations.  Vivienne: And some of these drugs, Bill, are really very common indeed, something like codeine. Just tell us about codeine, ‘cos it's something – whenever I tell this to friends [laughter], they're always completely entranced by the idea that some people don't need nearly as much codeine as others.  Bill: Yeah, so codeine is a drug that's very commonly used as a painkiller. To have its real effect, it needs to be converted in the body to a different drug called morphine, and that is done by an enzyme which is made by a gene called CYP2D6. And we all carry changes in CYP2D6, and the frequency of those variants, whether they make the gene work too much or whether they make it work too little, they vary enormously across the world, so that if you go to parts of Africa, about 30 percent of the population will make more of the CYP2D6, and so they will convert the codeine much more quickly, whereas if you go to the UK, maybe up to ten percent of the white population in the UK just won't be converting codeine to morphine at all, so they won't get any benefit from the drug. So at both ends, you have some people that don't respond and some people that respond a little bit too much so that they need either an alternative drug or they need a different dose.  Vivienne: So, all those people who say, you know, “My headache hasn't been touched by this painkiller,” and we say, “What a wimp you're being,” actually, it's to do with genetics.  Bill: Yeah, absolutely. There's a biological reason why people don't – not for everybody, but for a significant number of people, that's absolutely right, and we can be far more tailored in how we prescribe medication, and get people onto painkillers that work for them much more quickly.  Vivienne: And that's so interesting that it varies by where you come from in the world, because that means we need to give particular attention – and I'm thinking, Anita, to working with patients from different community groups, to make sure that they understand the need for pharmacogenomics.  Anita: I think that's really important, Vivienne, and I think we are now having discussions with the likes of Canada SJS awareness group, and also people have been in touch with me from South Africa because people have requested the passport now to be used in different countries, because they think it's a wonderful tool, and it's about raising awareness of pharmacogenomics and the potential benefits of that, and being able to share the tools that we've got to help patients once they've experienced a serious reaction.  Vivienne: So, pharmacogenomics clearly is important in the prevention of adverse drug reactions, better and more accurate prescribing, reduced medicines wastage. Does this mean that it's also going to save money, Bill, for the NHS?  Bill: Potentially. It should do if it's applied properly, but there's lots of work to make sure that not only are we using the right evidence and using the right types of tests in the laboratory, but we're getting the information to prescribers, so to GPs, to pharmacists, to hospital doctors, in a way that is understandable and meaningful, such that they can then act upon that information. So, the money will only be saved and then can be reused for healthcare if the whole process and the whole pathway works, and that information is used effectively.  Vivienne: So, a lot of research to make sure that all of that is in place, and to demonstrate the potential cost savings.  Bill: Yes. I mean, there are very nice studies that have been done already in parts of the world that have shown that the savings that could be accrued for applying pharmacogenetics across common conditions like depression, like in patients to prevent secondary types of strokes, are enormous. They run into hundreds of millions of pounds or dollars. But there is an initial investment that is required to make sure that we have the testing in place, that we have the digital pathways to move the information in place, and that there's the education and training, so that health professionals know how to use the information. But the potential is absolutely enormous.  Vivienne: Matt, can I turn now to the yellow card. So, people will be very familiar with the yellow card system. So, if you have an adverse reaction, you can send a yellow card in – I mean, literally, it is a yellow card [laughter]. It does exactly what it says on the tin. You send a yellow card to the MHRA, and they note if there's been an adverse effect of a particular medicine. But Genomics England is teaming up with the MHRA to do something more with yellow cards, and we're also doing this with the Yellow Card Biobank. Tell us a bit more.  Matt: So, yellow card's a great scheme that was set up decades ago, initially starting off, as you said, with literally yellow cards, but now actually most submissions actually come online. And it's important to note that submissions can come not just from healthcare providers, but majority of submissions actually come from patients themselves, and that people should feel free, if they feel they've had an adverse drug reaction, to report that themselves rather than necessarily depending on a medical practitioner or the healthcare provider to create that report. So, Genomics England is partnering with the MHRA in building what's called the Yellow Card Biobank, the goal of which is to identify genetic markers for adverse drug reactions earlier than has occurred in the past, so that we can then introduce genetic tests to prevent these adverse drug reactions much sooner than has occurred previously.   So, what we're doing is basically at the moment we're doing a pilot, but the ultimate plan is that in future, patients who report a serious adverse drug reaction through the Yellow Card Biobank will be asked to provide a sample, a blood sample, that we then screen. We do a whole genome sequence on it, and then combine these with patients who've had like adverse drug reactions and identify genetic markers for that adverse drug reaction medication earlier, that can then be introduced into clinical practice earlier. And this should reduce by decades the amount of time between when adverse drug reactions first start occurring with medications and us then being able to translate that into a preventative mechanism.  Vivienne: And will that scheme discover, do you think, new interactions that you didn't know about before? Or do you expect it to turn up what you already know about?  Matt: No, I really think there's a lot of discovery that is yet to happen here. In particular, even for drugs that we know cause adverse drug reactions, mostly they've only been studied in people of European ancestry and often in East Asian ancestry, but in many other ancestries that are really important in the global population and in the UK population, like African ancestry and South Asian ancestries, we have very little data. And even within Africa, which is an area which is genetically diverse as the rest of the world put together, we really don't know what different ethnicities within Africa, actually what their genetic background is with regard to adverse drug reactions.  The other thing I'd say is that there are a lot of new medications which have simply not been studied well enough. And lastly, that at the moment people are focused on adverse drug reactions being due to single genetic variants, when we know from the model of most human diseases that most human diseases are actually caused by combinations of genetic variants interacting with one another, so-called common disease type genetics, and that probably is similarly important with regard to pharmacogenomics as it is to overall human diseases. That is, it's far more common that these are actually due to common variants interacting with one another rather than the rare variants that we've been studying to date.  Vivienne: So, it's a kind of cocktail effect, if you like. You know, you need lots of genes working together and that will produce a reaction that you may not have expected if you'd looked at a single gene alone.  Matt: That's absolutely correct, and there's an increasing amount of evidence to show that that is the case with medications, but it's really very early days for research in that field. And the Yellow Card Biobank will be one of many approaches that will discover these genetic variants in years to come.  Vivienne: Now, Matt's a research scientist. Bill, you're on the frontline in the NHS. How quickly can this sort of finding be translated into care for people in the NHS?  Bill: So, really quickly is the simple answer to that, Viv. If we look at examples from a number of years ago, there's a drug called azathioprine that Matt has used lots in some of his patients. In rheumatology, it's used for patients with inflammatory bowel disease. And the first studies that showed that there was a gene that was relevant to having bad reactions to that drug came out in the 1980s, but it wasn't until well into this century, so probably 30-plus years later that we were routinely using that test in clinical medicine. So, there was an enormous lot of hesitancy about adopting that type of testing, and a bit of uncertainty. If you move forward to work that our colleague Munir Pirmohamed in Liverpool has done with colleagues in Australia like Simon Mallal around HIV medicine, there was this discovery that a drug called abacavir, that if you carried a particular genetic change, that you had a much higher risk of having a really severe reaction to that. The adoption from the initial discovery to routine, worldwide testing happened within four years.   So, already we've seen a significant change in the appetite to move quickly to adopt this type of testing, and I see certainly within the NHS and within other health systems around the world, a real desire to adopt pharmacogenetics into routine clinical practice quickly and at scale, but also as part of a broader package of care, which doesn't just solely focus on genetics, but thinks about all the other parts that are important in how we respond to medication. So, making sure we're not on unusual combinations of drugs, or that we're taking our medicine at the right time and with food or not with food, and all of those other things that are really important. And if you link that to the pharmacogenetics, we're going to have a much safer, more effective medicines world.  Vivienne: I think one of the joys of working at Genomics England is that you see some of this work really going into clinical practice very fast indeed. And I should say actually that the Wolfson Centre for Personalised Medicine, the PPI group that Anita looks after so well, they've been very important in recruiting people to Yellow Card Biobank. And if anyone's listening to this, Matt, and wants to be part of this, how do they get involved? Or is it simply through the yellow card?  Matt: So at the moment, the Yellow Card Biobank is focusing on alopurinol.   Vivienne: So, that's a medicine you take for gout.  Matt: Which I use a lot in my rheumatology clinical practice. And direct acting oral anticoagulants, DOACs, which are used for vascular disease therapies and haemorrhage as a result of that. So, the contact details are available through the MHRA website, but I think more importantly, it's just that people be aware of the yellow card system itself, and that if they do experience adverse drug reactions, that they do actually complete a report form, ‘cos I think still actually a lot of adverse drug reactions go unreported.  Vivienne: I'm forgetting of course that we see Matt all the time in the Genomics England office and we don't think that he has any other home [laughter] than Genomics England, but of course he still sees some patients in rheumatology clinic. So, I want to now look to the future. I mean, I'm, as you both know, a huge enthusiast for pharmacogenomics, ‘cos it's the thing that actually, when you talk to patients or just the general public, they just get it straight away. They can't think why, if you knew about pharmacogenomics, why you wouldn't want to do it. But it's not necessarily an easy thing to do. How can we move in the future, Bill, to a more proactive approach for pharmacogenomics testing? Where would we start?  Bill: Yes, so I think we've built up really good confidence that pharmacogenetics is a good thing to be doing. Currently, we're doing that predominantly at the point when a patient needs a particular medicine. That's the time that you would think about doing a genetic test. And previously, that genetic test would only be relevant for that specific drug. I think we're moving to a place where, rather than just doing that one test that might be relevant to one drug, we'd be able to do a test which at the same price would generate information that could be relevant at further points in your life if you were requiring different types of medicine. So, that information would then be available in your hospital record, in your GP record, that you could have access to it yourself. And then I think ultimately what we would really love to get to a point is where everybody across the whole population just has that information to hand when it's required, so that they're not waiting for the results of a genetic test, it's immediately within their healthcare record. That's what we'd call pre-emptive pharmacogenetic testing, and I think that's the golden land that we want to reach.  Vivienne: So for instance, I might have it on my NHS app, and when I go to a doctor and they prescribe something, I show my app to the GP, or something pops up on the GP's screen, or maybe it's something that pops up on the pharmacist's screen.  Bill: I think that's right. I think that's what we're looking to get to that point. We know that colleagues in the Netherlands have made some great progress at developing pathways around that. There's a lot of public support for that. And pharmacists are very engaged in that. In the UK, the pharmacists, over the last few years, have really taken a very active role to really push forward this area of medicine, and this should be seen as something that is relevant to all people, and all health professionals should be engaged with it.  Vivienne: And on a scale of one to ten, how difficult is it going to be to implement in the NHS?  Bill: So, that's a difficult question. I think the first thing is identifying what the challenges are. So I have not given you a number, I've turned into a politician, not answered the question. So, I think what has happened over the last few years, and some of our work within the NHS Network of Excellence in pharmacogenetics and some of the other programmes of work that have been going on, is a really good, honest look at what it is we need to do to try to achieve pharmacogenetics implementation and routine use. I don't think the challenge is going to be predominantly in the laboratory. I think we've got phenomenal laboratories. I think we've got great people doing great genetic testing. I think the biggest challenges are going to be about how you present the data, and that data is accessible. And then ensuring that health professionals really feel that this is information that isn't getting in the way of their clinical practice, but really making a difference and enhancing it, and of benefit both to the healthcare system but more importantly to the patients.  Vivienne: Now, when I hear you both talk, my mind turns to drug discovery and research, and Matt, I'm quite sure that that's right at the top of your mind. Tell us how pharmacogenomics can help in drug discovery and research.  Matt: So, pharmacogenomics, I think actually just genetic profiling of diseases in itself just to start off with is actually a really good way of identifying new potential therapeutic targets, and also from derisking drug development programmes by highlighting likely adverse drug reactions of medications that are being considered for therapeutic trials, or targets that are being considered for therapeutic development. Pharmacogenomics beyond that is actually largely about – well, it enables drug development programmes by enabling you to target people who are more likely to respond, and avoid people who are more likely to have adverse drug reactions. And so that therapeutic index of the balance between likely efficacy versus likely toxicity, genetics can really play into that and enable medications to be used where otherwise they might have failed.  This is most apparent I think in the cancer world. A classic example there, for example, is the development of a class of medications called EGFR inhibitors, which were developed for lung cancer, and in the initial cancer trials, actually were demonstrated to be ineffective, until people trialled them in East Asia and found that they were effective, and that that turns out to be because the type of cancers that respond to them are those that have mutations in the EGFR gene, and that that's common in East Asians. We now know that, wherever you are in the world, whether you're East Asian or European or whatever, if you have a lung adenocarcinoma with an EGFR mutation, you're very likely to respond to these medications. And so that pharmacogenomic discovery basically rescued a class of medication which is now probably the most widely used medication for lung adenocarcinomas, so a huge beneficial effect. And that example is repeated across multiple different cancer types, cancer medication types, and I'm sure in other fields we'll see that with expansive new medications coming in for molecularly targeted therapies in particular.  Vivienne: So, smaller and more effective trials rather than larger trials that perhaps seem not to work but actually haven't been tailored enough to the patients that are most likely to benefit.  Matt: Yeah, well, particularly now that drug development programmes tend to be very targeted at specific genetic targets, pharmacogenetics is much more likely to play a role in identifying patients who are going to respond to those medications. So, I think many people in the drug development world would like to see that, for any significant drug development programme, there's a proper associated pharmacogenomic programme to come up with molecular markers predicting a response.  Vivienne: We're going to wrap up there. Thank you so much to our guests, Bill Newman, Anita Hanson, Matt Brown, and our patient Jane Burns. Thank you so much for joining us today to discuss pharmacogenomics in personalised medicine, and the benefits, the challenges and the future prospects for integrating pharmacogenomics into healthcare systems. And if you'd like to hear more podcasts like this, please subscribe to Behind the Genes. It's on your favourite podcast app. Thank you so much for listening. I've been your host, Vivienne Parry. This podcast was edited by Bill Griffin at Ventoux Digital and produced by the wonderful Naimah. Bye for now. 

In diesem Podcast spreche ich mit der Präventionsmedizinerin Dr. med. Kira Kubenz.  Die erfahrene Longevity-Expertin arbeitet mit arbeitet mit Prof. Dr. med. Dr. phil. Kriegsmann zusammen mit dem ich letzte Woche über verschiedene Gentests sprechen durfte (den Link zu dem Interview findet ihr unten). Heute gehen wir noch etwas tiefer in die Materie und besprechen, konkret über die verschiedenen Präventionsmöglichkeiten und -tests. Dr. med. Kira Kubenz ist Allgemeinmedizinerin mit Ausbildung in Psychosomatik, Suchtmedizin, Ernährungsmedizin, Naturheilverfahren, Präventionsmedizin und lehrt an der Dresden International University. Über folgende Bereiche der Präventionsmedizin sprechen wir in dieser Folge: Vorbeugen und aufschieben vom Herzinfarktrisiko, Thromboserisiko, Fettstoffwechselstörung, Diabetes, Muskelschwund, Diabetes Typ 2, Adipositas, Osteoporose, Alzheimer Präventive Ernährungspläne auf Grundlage individueller Analysen Nahrungsmittelunverträglichkeiten (Histamine, Gluten,…) und die Möglichkeit sie genetisch zu bestimmen. Unterschied zwischen Genetik und Epigenetik Vitamine und Nährstoffhaushalt Hormone im Bereich der Präventionsmedizin   Pharmakogenetik: Was sind die vier Stoffwechseltypen und wie verstoffwechseln sie Medikamente? (Extensive Metabolizer, Intermediatyp, Pur-Metabolizer, Ultra-Metabolizer) Was ist ein pharmakogenetischer Notfallpass und wofür ist er sinnvoll? Welche genetischen Besonderheiten kann es bei der Einnahme verschiedener Medikamente geben?   Konkret sprechen wir unter anderem über folgende Medikamente: Schmerzmittel (wie Imbuprofen, Tramal, uvm.) Malariaprophylaxe (Malarone) Protonenpumpenhemmer (PPI), Magensäureblocker (Pantoprazole) Blutfettsenker (Rosuvastatin) Tamoxifen, Krebsmedikamente Blutdrucksenker, Betablocker (Sartane, Bisoprolol, Metoprolol) Anti-Depressiva    Weitere Informationen zu Dr. med. Kira Kubenz findest du hier: www.praxiskubenz.de   Weiterführende  Informationen zu CYP2D6, CYP2C9, CYP2C19 Substraten, Inhibitoren und Induktoren finden Sie in der konstant aktualisierten "Drug Interaction Database" der Abteilung für klinische Pharmakologie der Universität Indiana. Diese Datenbank ist abrufbar unter:   https://drug-interactions.medicine.iu.edu/MainTable.aspx   Prof. Dr. med. Dr. phil. Kriegsmann zu den verschiedenen Möglichkeiten der Gentests: https://link.stayoung.de/STY-106 Du interessierst dich für Gesunde Langlebigkeit (Longevity) und möchtest ein Leben lang gesund und fit bleiben, dann folge mir auch auf den sozialen Kanälen bei Instagram, TikTok, Facebook oder Youtube. https://www.instagram.com/nina.ruge.official https://www.tiktok.com/@nina.ruge.official https://www.facebook.com/NinaRugeOffiziell https://www.youtube.com/channel/UCOe2d1hLARB60z2hg039l9g   Disclaimer: Ich bin keine Ärztin und meine Inhalte ersetzen keine medizinische Beratung. Bei gesundheitlichen Fragen wende dich bitte an deinen Arzt/deine Ärztin.   STY-113

Designing a successful PCR assay is all about selecting the right primers to deliver the sensitivity and selectivity for which PCR is known for. But anyone that's designed an assay themselves will know that doing so successfully is a lot harder it sounds. We're joined by two PCR assay design pros for this episode. Kimi Soohoo Ong, and Dr. Rounak Feigelman, both from Thermo Fisher Scientific, shine a light on the many factors that must be considered to design a winning PCR assay. From the level of fragmentation of nucleic acids in the sample, to what other species' genomes that may be present in the sample, to what the sample matrix may contain, to the PCR master mix being used, if multiplexing is required, to what assay controls will be, and more!  These two practiced bioinformaticians cover these challenges and then tell us how their team overcomes challenges to develop winning assays for both qPCR and dPCR applications. Our conversation uncovers the level of skill and artistry that goes into this craft. As always, you get to learn a bit more about our guests' backgrounds and career paths in the Cassie's Career Corner portion of the interview. They share how they both chose a bioinformatics path over wet lab work, while also acknowledging how important the wet lab work is to what they do. They also share some great advice and resources for anyone looking to explore a career in bioinformatics. Visit the Absolute Gene-ius page to learn more about the guests, the hosts, and the Applied Biosystems QuantStudio Absolute Q Digital PCR System. 

On this podcast episode, I discuss darifenacin pharmacology, adverse effects, drug interactions and much more. CYP3A4 and CYP2D6 are important enzymes in relation to darifenacin. I breakdown the importance of these enzymes and how they can impact drug therapy. Darifenacin has anticholinergic activity but affects the central nervous system less than other agents in its class such as oxybutynin and tolterodine. Darifenacin's pharmacology is selective for the Muscarinic-3 (M3) receptor in bladder tissue which helps reduce the risk for CNS adverse effects.

On this podcast episode, I discuss tamoxifen pharmacology, adverse effects, drug interaction, and much more. Tamoxifen is converted to a more active compound in the body by CYP2D6. CYP2D6 inhibitors such as paroxetine, fluoxetine, or bupropion can essentially reduce the effectiveness of tamoxifen. Hot flashes are a common adverse effect of tamoxifen and I discuss a few pharmacologic options to manage this adverse effect.

In this episode Colby reviews his experiences at the MAPS conference in Denver, we review a couple of topics we missed around LSD and MDMA, and introduce psilocybin!   References: Gotvaldova K, et al. "Extensive Collection of Psychotropic Mushrooms with Determination of Their Tryptamine Alkaloids". International Journal of Molecular Sciences. 2023 (22): 14068. Halpern J, Roth BL "Hallucinogens and dissociative agents naturally growing in the United States". Pharmacology & Therapeutics. 2004; 102 (2): 131–8. Huberman A. The science of MDMA and its therapeutic uses: benefits and risks. Huberman Labs (podcast). 12 Jun 2023 Pollan M. How to change your mind: the new science of psychedelics. Penguin Press. 2019 Sumner R, et al. Microdosed LSD: Dose day outcomes from a home-administered randomized controlled trial. 2023. Unpublished (information from poster presentation at MAPS conference) Woolley DW, Campbell NK (1962). "Serotonin-like and antiserotonin properties of psilocybin and psilocin". Science. 3518. 136 (3518): 777–8 Vizeli P, et al. Genetic influence of Cyp2D6 on pharmacokinetics and acute subjective effects of LSD in a pooled analysis. Scientific Reports. 2021(11); 10851.

In this episode, we review the science behind genetic differences in humans in the CYP2D6 hepatic enzyme responsible for drug metabolism and how these genetic variants can lead to certain drugs being metabolized far too much or far too little, which can cause drug toxicities or a lack of effectiveness. Key Concepts About 20-25% of drugs on the market are metabolized by CYP2D6. Humans have a huge degree of variability in CYP2D6 metabolism ranging from “ultra” metabolizers to “poor” metabolizers. Drugs that heavily rely on CYP2D6 metabolism are prone to large variability in responses due to these genetic differences. Some drugs rely on metabolic inactivation of CYP2D6 whereas other drugs use the enzyme to become converted to a more active compound. Codeine and tramadol both heavily rely on CYP2D6 activation to a more potent opioid compound. Patients with excessive CYP2D6 activity will have toxicities (from too much of an active metabolite) whereas patients with low CYP2D6 activity will have little therapeutic effect. Numerous antidepressants (paroxetine, nearly all tricyclic antidepressants, and venlafaxine) rely on CYP2D6 metabolism. Differences in CYP2D6 metabolism have been shown to either cause toxicity or a lack of effectiveness with these medications. References Chartrand R, Forte AM, Hoger JD, Kane SP, Kisor DF. Pharmacogenomics and Commonly Prescribed Medications. AdvanCE. October 10, 2022. https://www.advancepharmacist.com/courses/pharmacogenomics-and-commonly-prescribed-medications. Caudle KE, Sangkuhl K, Whirl-Carrillo M, et al. Standardizing CYP2D6 Genotype to Phenotype Translation: Consensus Recommendations from the Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group. Clin Transl Sci. 2020;13(1):116-124. doi:10.1111/cts.12692 Bousman CA, Stevenson JM, Ramsey LB, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A Genotypes and Serotonin Reuptake Inhibitor Antidepressants [published online ahead of print, 2023 Apr 9]. Clin Pharmacol Ther. 2023;10.1002/cpt.2903. doi:10.1002/cpt.2903 Crews KR, Monte AA, Huddart R, et al. Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6, OPRM1, and COMT Genotypes and Select Opioid Therapy. Clin Pharmacol Ther. 2021;110(4):888-896. doi:10.1002/cpt.2149

I discuss dextromethorphan pharmacology, adverse effects, drug interactions, and more on this podcast episode. CYP2D6 metabolizes Dextromethorphan. A commonly used antidepressant is a CYP2D6 inhibitor. I discuss this on the podcast. Dextromethorphan is a commonly used OTC cough suppressant. There is potential for abuse with this medication. In excessive doses, dextromethorphan may cause euphoria, hallucinations, and other CNS effects, but also cause cardiovascular complications.

On this episode, I discuss risperidone pharmacology, adverse effects, monitoring, and common indications. There are numerous drug interactions that I discuss in this podcast episode. CYP2D6 inhibitors may increase drug concentrations. Risperidone increases prolactin more than most 2nd generation antipsychotics. This can lead to sexual adverse effects. QTC prolongation is a concern with all antipsychotics like risperidone. We can monitor EKG to monitor for this risk.

On this podcast episode, I discuss vortioxetine pharmacology, adverse effects, drug interactions, and much more. Because of vortioxetine's long half-life, antidepressant discontinuation syndrome is going to be less prominent compared to ADPs with shorter half-lives. Vortioxetine is metabolized by CYP2D6. Drugs that inhibit this enzyme will likely raise concentrations and place the patient more at risk for adverse effects. I discuss rare vortioxetine adverse effects like hyponatremia and bleeding in this podcast episode.

In this episode, we discuss the evidence, safety, and place in therapy of Auvelity® (dextromethorphan-bupropion), a newly approved antidepressant with a unique mechanism of action and interesting pharmacokinetic considerations. Key Concepts Auvelity® (bupropion-dextromethorphan) was FDA approved in 2022 for major depressive disorder (MDD). The bupropion component inhibits CYP2D6 metabolism and increases serum concentrations of dextromethorphan. The proposed mechanism of benefit in MDD is via dextromethorphan (as an NMDA antagonist) and possibly with bupropion (as a dopamine/norepinephrine reuptake inhibitor). Although the bupropion component in Auvelity® is being used for its drug interaction, the dose is a therapeutic dose and carries several warnings and precautions, including the risk of seizure and hypertension. In short (6-week) clinical trials, Auvelity® improved depression symptoms quickly (within 1-2 weeks), which is faster than many other antidepressants. Auvelity® is associated with dizziness, anxiety, hyperhidrosis, nausea, headache, diarrhea, and dry mouth. As a CYP2D6 inhibitor, the bupropion component of Auvelity® will cause drug interactions with many other medications, including some antidepressants, antipsychotics, and opioid analgesics (among others). References Iosifescu DV, Jones A, O'Gorman C, et al. Efficacy and Safety of AXS-05 (Dextromethorphan-Bupropion) in Patients With Major Depressive Disorder: A Phase 3 Randomized Clinical Trial (GEMINI). J Clin Psychiatry. 2022;83(4):21m14345. Published 2022 May 30. doi:10.4088/JCP.21m14345 Tabuteau H, Jones A, Anderson A, Jacobson M, Iosifescu DV. Effect of AXS-05 (Dextromethorphan-Bupropion) in Major Depressive Disorder: A Randomized Double-Blind Controlled Trial. Am J Psychiatry. 2022;179(7):490-499. doi:10.1176/appi.ajp.21080800 Kotlyar M, Brauer LH, Tracy TS, et al. Inhibition of CYP2D6 activity by bupropion. J Clin Psychopharmacol. 2005;25(3):226-229. doi:10.1097/01.jcp.0000162805.46453.e3

Brexpiprazole (Rexulti) is a second generation antipsychotic. I discuss its pharmacology, adverse effects, drug interactions, and more in this podcast episode. I like to associate brexpiprazole with aripiprazole. They have a lot of overlapping characteristics, particularly in relation to the adverse effect profile. Brexpiprazole tends to have a low incidence of metabolic adverse effects which makes it a nice selection for patients who have diabetes, hypercholesterolemia, or who are overweight. CYP3A4 and CYP2D6 are the two primary enzymes that break down brexpiprazole. I discuss the pharmacogenomic considerations associated with this medication.

Dr. Judith Paice and Dr. Eduardo Bruera discuss the latest evidence-based recommendations from ASCO on the use of opioids in managing cancer-related pain. They review the safe and effective use of opioids, including when clinicians should offer opioids, which opioids should be offered, how opioids should be initiated and titrated, management of opioid-related adverse events, modifying opioid use for patients with specific comorbidities, management of breakthrough pain, and how opioids should be switched. Additionally, they address barriers to care, considerations of health disparities, cost, and patient-clinician communication in achieving optimal pain management. Read the full guideline, “Use of Opioids for Adults with Pain from Cancer or Cancer Treatment: ASCO Guideline” at www.asco.org/supportive-care-guidelines. TRANSCRIPT Brittany Harvey: Hello, and welcome to the ASCO Guidelines Podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today, I'm interviewing Dr. Judith Paice from Northwestern University Feinberg School of Medicine in Chicago, Illinois and Dr. Eduardo Bruera from the University of Texas MD Anderson Cancer Center in Houston, Texas, co-chairs on “Use of Opioids for Adults with Pain from Cancer or Cancer Treatment: ASCO Guideline.” Thank you for being here, Dr. Paice and Dr. Bruera. Dr. Judith Paice: Thank you. Dr. Eduardo Bruera: Thank you for having us. Brittany Harvey:  First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Paice, do you have any relevant disclosures that are directly related to this guideline topic? Dr. Judith Paice: I have no relevant disclosures. Brittany Harvey:  Thank you. And then Dr. Bruera, do you have any relevant disclosures that are directly related to this guideline topic? Dr. Eduardo Bruera: Regrettably, I don't. Brittany Harvey: Great. Then getting into the content of this guideline, to start us off, Dr. Paice, can you provide an overview of the purpose and the scope of this guideline? Dr. Judith Paice: The use of opioids has become so complicated, so controversial, and just so associated with so much stigma that we wanted to provide oncology clinicians some guidance about safe and effective use of opioids. We wanted to help people be aware of the current literature, and so we conducted a systematic review and identified randomized controlled clinical trials and other systematic reviews. And we found that there were 31 systematic reviews in 16 RCTs. We carefully reviewed all of these literature and all of these studies, and our expert panel met via the web and via numerous conference calls and emails, and we came to consensus regarding these recommendations related to the use of opioids for people with cancer. Brittany Harvey: Great. Sounds like there was a lot of effort that went into developing this and to tackle an important topic. So, then Dr. Bruera, I'd like to review the key recommendations of this guideline for our listeners. This guideline addresses seven different clinical questions. So, let's review these questions starting with; in what circumstances should opioids be offered? Dr. Eduardo Bruera: That's a very important point because the reality is that although opioids have been around for more than 300 years in different modalities, they continue to be the mainstay of care of patients with severe pain. So, it's very important to try to figure out in the clinical practice why the patient has a pain syndrome. But in the great majority of patients who have pain that is due to the presence of the primary cancer or metastatic disease. And also, in the vast majority of patients who develop severe complications from treatment such as mucositis from radiation and chemotherapy, an opioid will be needed. And the oncologist and the oncology clinician is in perfect conditions to safely prescribe that opioid so the patient can achieve fast relief of their pain. Brittany Harvey: Great. Thank you for that explanation. So, then the next clinical question that the panel addressed, Dr. Paice, which opioids does the panel recommend clinicians should offer? Dr. Judith Paice:  Yeah, thank you. This is a really important question, one that gets asked all of the time, and yet, the data are insufficient to really suggest that there is one preferred opioid over another. So, a patient with moderate to severe cancer-related pain is a candidate for any of the approved medications either approved by the FDA or because our audience also includes international experts, other regulatory agencies for pain treatment. We did call out a couple agents for which there is some concern or for issues where they are less than desirable in some settings. So, one of those drugs is tramadol. And our rationale for identifying tramadol as a potential agent of concern is that it's a prodrug. It has a threshold, a ceiling unlike most of the other opioids, and that threshold is pretty low for neurotoxicity, which is of particular concern in the person with cancer. And it also, has a significant amount of drug-drug interactions. So, we were concerned about tramadol, even though it is an agent that many, many people are using, in part, because it is a lower schedule on the controlled substance scheduling system, and there's a perception that it is less potent, and it is less potent. The other drug that we call out is codeine. And our rationale for identifying it as an agent that may be of difficulty in certain populations of patients, is that it is also a prodrug and it is metabolized through the cytochrome P450 system, particularly through the isoenzyme CYP2D6. And that's what allows codeine to be metabolized to morphine, which allows it to be analgesic. The challenge is there are some individuals who are poor metabolizers, and so they will not receive an analgesic effect. And then there are others who are ultra-rapid metabolizers, and they may actually experience a greater prevalence of adverse effects. So, for those reasons, we call out tramadol and codeine. Now, we don't call out methadone as an agent that we're concerned about in terms of not being desirable. It is an agent that has a role in cancer pain management. However, we do caution clinicians that it is a complex drug to use. And so, as result, people should obtain some guidance either from their palliative care program, their supportive care program, pain experts, or pharmacists, whomever can assist them in the dosing associated with this really important, but somewhat complicated drug to use. Brittany Harvey: Understood. And I appreciate you reviewing where there's a lack of evidence and where there is evidence in identifying those potential agents of concern or where clinicians need to seek other expertise in this area. So, then following those recommendations, after identifying patients who should be offered opioids, Dr. Bruera, how should opioids be initiated and titrated? Dr. Eduardo Bruera: One possible way to do this is to give the patient an immediate release opioid. That could be a combination of hydrocodone with acetaminophen, a combination of other opioids or a straight strong opioid in a low concentration. And ideally, we suggest that you use it as needed for the first few days and see if the patient needs to take it frequently. And there is a magic number around 30 milligrams of morphine equivalent per day. Once the patient needs to take that opioid on a more frequent basis and gets through that threshold of needing about five, six tablets a day of immediate release opioid, then it might be necessary to start a regular opioid that is to stay on top of the pain. And the way we do that are two ways; if the patient can afford it and insurance covers it, an extended release opioid is a wonderful option, because then, the patient can take the opioid a couple of times a day or put a patch for three days and they're going to be comfortable. But if that is not an option, taking the immediate release opioid around the clock, not anymore as needed. But now, around the clock, will maintain that blood level and allow the patient to have less episodes of breakthrough pain. An important thing to remember is that whether we decide to go with the extended release opioid or immediate release, it's nice to tell the patient that there might be moments in which the pain might break through. And so, giving that extra prescription and advice might help if there are moments in which the patient might break through. Brittany Harvey: Understood. And then the next clinical question that the guideline panel addressed, Dr. Paice, how should opioid-related adverse events be prevented or managed? Dr. Judith Paice: So, Brittany, I'm glad you asked me that question because I am called the pain and the poop nurse in the clinic, and it is so important whenever we can to prevent the adverse effects of opioids, and constipation is one where we can implement some preventive measures, and then treat unfortunately if your measures have not been totally effective. But we wanted to address the gamut of potential adverse effects. So, we included not only constipation, but delirium, endocrinopathies, sedation, nausea, vomiting, itching, and urinary retention. And we've included a table with very specific suggestions about how to prevent in some cases, and how to manage these adverse effects. Again, we wanted to make this document of the most use for all oncology clinicians who might be prescribing opioids for people with cancer. Brittany Harvey: Absolutely. And that's key to maintaining quality of life for patients. So, then Dr. Bruera, what does the panel recommend regarding modifying opioid use in patients with either renal or hepatic impairment? Dr. Eduardo Bruera: That's a great question, Brittany, and I think we have some evidence that some opioids are particularly desirable when the patient has renal dysfunction. One of the ones that comes to mind is methadone because it has almost no major renal elimination, and therefore, that might be a wonderful option. One of the challenges is that changing from one opioid to another sometimes is a little bit more complex than maintaining the opioid that is being used. And so, in absence of a major and fast deterioration, one option is to carefully titrate the dose of the opioid we're using to reduce the risk of accumulation in a given patient. There are some opioids that have traditionally been associated with a little bit more accumulation in cases of renal failure and traditionally, morphine is included, but there are other opioid agonists that also produce metabolites that are massively eliminated by urine that might be a little bit less desirable in patients with renal failure. With regards to liver failure, it's very hard to find a complete consensus about the opioids that are less desirable or potentially more desirable. And we could say that careful titration is important. But the one that was so good for renal failure might be the one you might not want to use for liver failure, and that would be methadone, because a vast majority of its metabolism happens in liver. So, I think cautious individualized titration might be a nice recommendation to our patients. And perhaps, the most important thing is that there might be a little bit of renal failure or liver failure, but it's very, very important that we maintain the opioid therapy, that we don't give up on the opioids. Brittany Harvey: Yes, those are important clinical considerations for individualized patient care. So, then Dr. Paice, Dr. Bruera touched on this a little bit earlier, but what are the recommendations regarding management of breakthrough pain? Dr. Judith Paice: So, breakthrough pain is very common in the person with cancer. We see this when the individual has bony metastases and they place pressure on that limb or joint. And the patient who's normally well-controlled with either a regularly scheduled immediate release agent or a long-acting agent, now experiences what we call breakthrough. And that's probably the most common type of breakthrough pain. There are also other breakthrough pains where the short-acting agent that's given regularly doesn't provide the relief that lasts four hours or six hours. Or similarly, if a long-acting agent is given every 12 hours, we may see that the pain breaks through prior to the next dose. But for that patient who requires breakthrough medication, unfortunately, the literature does not reveal that one agent is superior to another. So, any immediate release opioid that's appropriate for that patient can be used for breakthrough-related pain. Now, a common clinical conundrum is - which dose? What's the correct dose for the breakthrough medication? And again, the literature has a wide range of appropriate doses, and our committee established a range of 5 to 20% of the daily regular oral morphine equivalent daily dose. And our rationale for that was that you really cannot come up with one figure. Every patient is different. So, on average it's somewhere around 10%, but the range is five to 20% of the daily regular morphine equivalency. And so, what you need to do as you're examining the patient and exploring their needs is to look at the patient's frailty, the patient's pain, of course, their function when these breakthrough episodes occur. What about the comorbid kinds of organ dysfunction that Eduardo just spoke about? So, all of those other factors need to be considered when selecting the appropriate opioid for the breakthrough as well as the appropriate starting dose. Brittany Harvey: Definitely, it's important to consider all of those factors that you just mentioned. So, then the last clinical question that the panel addressed, Dr. Bruera, when and how should opioids be switched or rotated? Dr. Eduardo Bruera: Thank you, Brittany. This is a hugely important issue because for many, many years, we believe that since opioids stimulated an opioid Mu receptor, and they all had a similar effect, there will be limited rationale for changing. The answer to increasing pain was what we call opioid dose escalation. Just give more of the same. And we realized that that had serious limitations. And one of them is the development of side effects. And a lot of those side effects are neurotoxic side effects. Patients get unduly sedated, get hyperalgesia, paradoxical increase in pain due to active metabolites and changes in their receptors, and they also get sometimes myoclonus, hallucinations, confusion. And so, there are moments in which the side effects require us to say, okay, this opioid has done a good job for a while, but now, we have to change. And so, changing can be done due to side effects. But also, sometimes, since we're all different and there's a lot of interpersonal variation in response — as some patients may just not be controlled, their pain syndrome might not be controlled well-enough with one type of opioid because we know there are multiple sub-Mu receptors, and they might really benefit from another. So, the two main reasons are the development of toxicity to the opioid that so far was working reasonably well. And the second is failure, inability to control the pain, and in that case, going cautiously respecting the fact that there is limited cross-tolerance so that the dose of one opioid is not always exactly equivalent to the dose of the other opioid that you find in the actual tables that are published around is necessary to understand that that's a general guideline. But the most important thing is to go progressively and monitor your patient frequently when you change from one opioid agonist to another opioid agonist. There is limited understanding in the literature about the exact equianalgesic dosing. And because of that, a new guideline is being produced that addresses opioid rotation and deals exactly with trying to find out consensus from all the different existing tables on how to change what is the dose that is most likely to be appropriate when you move from one opioid, for example, morphine to hydromorphone or to fentanyl, or to oxycodone or vice versa. We dealt with great trepidation to give all our oncology clinicians some kind of a fixed table, but the evidence is unfortunately not there at this point. It is sad because these medications are not that new, but the evidence unfortunately, is not there. And that's why I think what we can tell you is go through your guidelines, use in a very careful monitoring of your patient to see if the dose you're giving is clearly not enough or it's a little bit too much. And you will learn that very rapidly — in a couple of days, you'll learn if you're doing okay or if you're doing too much or not enough. And stay tuned because hopefully, very soon, ASCO, together with MASCC and a couple of other organizations will provide you with a little bit more evidence around this. Brittany Harvey: Definitely, we'll look forward to that future guideline on opioid conversion tables as it is a confusing and complicated area, but it sounds like a lot of these recommendations are about providing individualized care for your patients. So, I want to thank you both for reviewing all of those recommendations that the panel came up with. So, then Dr. Paice, what does this guideline mean for both clinicians and for patients with pain from cancer or their cancer treatment? Dr. Judith Paice: Well, speaking on behalf of the panel, our wish is that this will improve the management of cancer-related pain, that people will feel more comfortable in safe and effective use of these agents, and they'll be used more effectively. There are other barriers that we've addressed, in addition to all of these recommendations. We talk about the care of people who have multiple chronic conditions. We address the disparities that we see in cancer pain management, and we talk about cost as another consideration, as one is developing a treatment plan for patients. We also address the patient-clinician communication that is so essential. This is definitely a team effort, and we guide our clinicians and offer for patients the need to have clear communication, open dialogue throughout the development of a treatment plan, and then throughout the course of treatment while we reassess whether the plan has been effective. Brittany Harvey: Absolutely. And it's really key what you just said about the safe and effective use of opioids for patients. So, then finally, Dr. Bruera, you've both mentioned this throughout our conversation today, where the literature is either inconclusive or evidence is insufficient. So, what are the outstanding questions about the use of opioids for pain from cancer or cancer therapies? Dr. Eduardo Bruera: I think there are questions that relate to the relative lack of specificity of the opioids for the different receptor pathways, and there are very likely considerable differences because they're chemically quite different, but they're considerable differences. But we have not done an awful lot of the head on comparisons that would be so wonderful to do. And I think we need more studies comparing the different existing medications, and more importantly, we need a lot of translational work to get to specific areas. Wouldn't it be fantastic if we were able to stimulate the Mu receptor all along the nociceptive pathway to reduce nociceptive input, but avoid completely the limbic system and avoid those Mu receptors in the area where reward is going to happen, an anti-reward and the possibility of developing non-medical use and eventually, opioid use disorder. That would be, to me, the corollary, the ability to dissociate those receptors along the nociceptive pathway from those receptors in the areas where we would like our opioids to not go, but we cannot avoid it because they're a bit dummy drugs. And so, hopefully, getting smarter opioids would be wonderful. Brittany Harvey: Absolutely. Well, I want to thank you both so much for your work developing this guideline, addressing these important questions for optimal pain management in patients with cancer. And thank you for your time today, Dr. Paice and Dr. Bruera. Dr.  Judith Paice: Thank you. Dr. Eduardo Bruera:Thank you so much. Brittany Harvey:And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast series. To read the full guideline, go to www.asco.org/supportive-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode. Voiceover: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy, should not be construed as an ASCO endorsement.  

Getting to the Heart of Cannabis Health Risks Cell Press Cannabis has deleterious effects on cardiovascular physiology. Wei et al. (Cell 185, May 12, 2022) confirm that important inflammatory markers increase transiently after a single marijuana joint and prove a mechanistic link between THC induced vascular inflammation, endothelial dysfunction, cellular oxidative stress, and atherosclerosis using cell-based and mouse models of atherosclerosis. They provide a pharmacological model in which THC-mediated activation of CB1 receptor signaling pathways converge on MAP kinase, TNFa, and NF-kB outputs to create a proinflammatory and atherogenic environment in endothelial cells.   That genistein can antagonize the negative effects of THC with minimal central effects is exciting because genistein is a common component of soy and is already a widely consumed dietary product.   Electronic Cigarettes Versus Nicotine Patches for Smoking Cessation in Pregnancy: A Randomized Controlled Trial Nature Medicine Pregnant smokers were randomized to use either nicotine replacement therapy with patches (NRT, n=571) or e-cigarettes (n=569) for smoking cessation. For the primary outcome, validated prolonged quit rates at the end of pregnancy, the results were 4.4% for NRT and 6.8% for e-cigarettes (P=0.08). However, 25 participants in the NRT arm who reported abstinence also used e-cigarettes. When these participants were excluded from data analysis the quit rates were 3.6% for NRT and 6.8% for e-cigarettes (P=0.02). Low birthweight was less common in the e-cigarette arm, 9.6% versus 14.8% for NRT (P=0.01). The authors conclude that “e-cigarettes were markedly more effective than patches” and do not pose more risk.   Daily Cannabis Use, Cannabis Use Disorder, and Any Medical Cannabis Use Among US Adults: Associations Within Racial, Ethnic, and Sexual Minoritized Identities in a Changing Policy Context Preventive Medicine Reports Cannabis use has steadily increased in the United States, with daily and medical use associated with cannabis use disorder (CUD) and the negative consequences more frequent among marginalized groups. In this study, the authors use the National Survey on Drug Use and Health (NSDUH) to examine medical and daily use and CUD across the intersections of racial, ethnic, and sexual minorities. They found that sexual minorities were more likely to have medical and daily use and CUD than their heterosexual counterparts within each racial and ethnic group. However, when examining the intersection of race, ethnicity and sexual identity, there was more heterogeneity across these groups. In addition, they found that in states with medical cannabis laws (MCL) daily cannabis use was higher across all intersectional groups.     Effect of AXS-05 (Dextromethorphan-Bupropion) in Major Depressive Disorder: A Randomized Double-Blind Controlled Trial AJP Psychiatry Altered glutamatergic neurotransmission is implicated in the pathogenesis of major depressive disorder. AXS-05 (dextromethorphan-bupropion) is an oral NMDA receptor antagonist and sigma-1 receptor agonist, which utilizes inhibition of CYP2D6 to increase its bioavailability. This phase 2 trial assessed the efficacy and safety of dextromethorphan-bupropion in the treatment of major depressive disorder. In patients with major depression, dextromethorphan-bupropion (AXS-05) significantly improved depressive symptoms compared with bupropion and was generally well tolerated.  The most common adverse events were dizziness, nausea, dry mouth, decreased appetite, and anxiety. Dextromethorphan-bupropion was not associated with psychotomimetic effects, weight gain, or sexual dysfunction.   Mental Health and Substance Use Among Homeless Adolescents in the US JAMA Network This study evaluated mental health and substance use outcomes among homeless and non-homeless adolescents in 2019. Alcohol, cigarette, marijuana, and binge drinking during the prior 30 days was assessed, along with lifetime use of cocaine, methamphetamine, heroin, ecstasy, and injection drugs or prescription opioid misuse. Results found current substance use ranging from cigarettes to alcohol were higher among homeless adolescents. Lifetime cocaine use was significantly higher among homeless adolescents, as were methamphetamine, heroin, ecstasy, and injection drug use. Homeless adolescents experience worse mental health outcomes, including depression and suicidality, and struggle with more SUDs than their counterparts.   The Importance of Federal Action Supporting Overdose-Prevention Centers NEJM In this prospective piece, the authors discuss the need for new approaches to harm reduction and substance use disorder treatment in the face of substantially increasing overdose deaths, particularly since the start of the COVID-19 pandemic. One such strategy they discuss is overdose-prevention centers, which operate in other countries and are associated with significant reductions in opioid-overdose morbidity and mortality. However, under Section 856 of the Controlled Substances Act, such facilities may be subject to federal legal sanctions. The authors recommend that the Biden administration declare they will not interfere with such public health interventions or declare that section 856 does not apply to legally sanctioned centers. Further, Congress should modify the Controlled Substance Act to exempt overdose-prevention centers.    Complex Persistent Benzodiazepine Dependence—When Benzodiazepine Deprescribing Goes Awry JAMA Psychiatry Benzodiazepines remain popular medications among patients due to rapid symptom relief and reinforcing effects. As clinicians and patients become more aware of potential risks, and clinical guidelines increasingly urge caution in prescribing, guidance for benzodiazepine deprescribing is needed. The authors propose a new clinical concept for patients experiencing significant psychological or functional decline during or after a benzodiazepine taper—complex persistent benzodiazepine dependence (CPBD). CPBD can be described as symptomatic or functional decompensation with or without the development of aberrant medication behaviors in the setting of benzodiazepine deprescribing–in the absence of a benzodiazepine use disorder. Further research is needed to validate this concept.    What is Success in Treatment for Opioid Use Disorder? Perspectives of Physicians and Patients in Primary Care Settings JSAT Opioid abstinence and treatment retention are typically used as measures of success of MOUD treatment. This study sought to identify other important treatment outcomes and patient-centered measures of success. Qualitative, structured interviews were conducted with physicians (n=14)  and patients (n=18) in 2 family medicine residency programs. The physicians (7 faculty and 7 residents) were experienced buprenorphine prescribers. Both patients and physicians identified 5 themes: staying sober, and improvement in physical health, mental health, relationships, and role functioning. Patients, but not physicians, identified 2 additional themes: tapering off buprenorphine, and decreased stigma and shame. The authors conclude that “clinicians and researchers need to consider a broader scope of success indicators.”  

According to the American Academy of Family Physicians, there are more than 50 Cytochrome P450 enzymes but there are just 6 of them that metabolize about 90% of the drugs. One of the most significant ones is the CYP2D6. In an article on healio written by Dr. Jai Patel, he talks about CYP2D6 metabolizing many of the SSRIs, SNRIs and TCAs that are the treatment options for depression. The clearance of TCA's for example is 50-67% lowered in CYP2D6 poor metabolizers compared to normal. www.aafp.org/afp/2007/0801/p391.html  Pharmacogenetic testing may improve outcomes for patients with depression (healio.com) Kristine Ashcraft is a molecular biologist by training and is the former CEO and founder of YouScript which was recently acquired by Invitae. She has worked in pharmacogenomics space since 2000 and was recently named one of the 25 leading voices in precision medicine. Kristine has authored multiple publications on both the clinical and economic benefits of PGx testing. She serves on the Steering Committee of STRIPE which is the FDA collaborative community for PGx. She has been interviewed by numerous media including the New York Times, the Wall Street Journal, and NBC Nightly News and has spoken at American Society of Human Genetics, and numerous precision medicine conferences and now speaking at one of the top 20 genomics podcast in the globe, PGx for Pharmacist Podcast. Learn more about your ad choices. Visit megaphone.fm/adchoices

According to the American Academy of Family Physicians, there are more than 50 Cytochrome P450 enzymes but there are just 6 of them that metabolize about 90% of the drugs. One of the most significant ones is the CYP2D6. In an article on healio written by Dr. Jai Patel, he talks about CYP2D6 metabolizing many of the SSRIs, SNRIs and TCAs that are the treatment options for depression. The clearance of TCA's for example is 50-67% lowered in CYP2D6 poor metabolizers compared to normal. www.aafp.org/afp/2007/0801/p391.html  Pharmacogenetic testing may improve outcomes for patients with depression (healio.com) Kristine Ashcraft is a molecular biologist by training and is the former CEO and founder of YouScript which was recently acquired by Invitae. She has worked in pharmacogenomics space since 2000 and was recently named one of the 25 leading voices in precision medicine. Kristine has authored multiple publications on both the clinical and economic benefits of PGx testing. She serves on the Steering Committee of STRIPE which is the FDA collaborative community for PGx. She has been interviewed by numerous media including the New York Times, the Wall Street Journal, and NBC Nightly News and has spoken at American Society of Human Genetics, and numerous precision medicine conferences and now speaking at one of the top 20 genomics podcast in the globe, PGx for Pharmacist Podcast. Learn more about your ad choices. Visit megaphone.fm/adchoices

According to the American Academy of Family Physicians, there are more than 50 Cytochrome P450 enzymes but there are just 6 of them that metabolize about 90% of the drugs. One of the most significant ones is the CYP2D6. In an article on healio written by Dr. Jai Patel, he talks about CYP2D6 metabolizing many of the SSRIs, SNRIs and TCAs that are the treatment options for depression. The clearance of TCA's for example is 50-67% lowered in CYP2D6 poor metabolizers compared to normal. www.aafp.org/afp/2007/0801/p391.html  Pharmacogenetic testing may improve outcomes for patients with depression (healio.com) Kristine Ashcraft is a molecular biologist by training and is the former CEO and founder of YouScript which was recently acquired by Invitae. She has worked in pharmacogenomics space since 2000 and was recently named one of the 25 leading voices in precision medicine. Kristine has authored multiple publications on both the clinical and economic benefits of PGx testing. She serves on the Steering Committee of STRIPE which is the FDA collaborative community for PGx. She has been interviewed by numerous media including the New York Times, the Wall Street Journal, and NBC Nightly News and has spoken at American Society of Human Genetics, and numerous precision medicine conferences and now speaking at one of the top 20 genomics podcast in the globe, PGx for Pharmacist Podcast. Learn more about your ad choices. Visit megaphone.fm/adchoices

On this episode, I discuss duloxetine pharmacology, adverse effects, and common drug interactions. Duloxetine is an SNRI that is used for depression, anxiety, and various pain syndromes like neuropathy and fibromyalgia. Duloxetine can inhibit CYP2D6 which can lead to higher concentrations of clozapine and propranolol and lower activity of tamoxifen. CYP1A2 inhibitors like ciprofloxacin can raise concentrations of duloxetine leading to an increased potential for adverse effects.

On this episode, I discuss oxycodone pharmacology, adverse effect, pharmacokinetics, and drug interactions. Oxycodone is broken down by CYP3A4 and CYP2D6. I discuss this further on the podcast and how interactions may alter concentrations. When a patient stops taking oxycodone after being on it for some time, you must recognize common symptoms of withdrawal. Oxycodone comes as in an extended-release and immediate-release oral formulation.

In this episode, we review the pharmacology, indications, adverse effects, and unique drug characteristics of the most common SSRIs on the market. Key Concepts SSRIs (selective serotonin reuptake inhibitors) are the drug of choice for depression, anxiety, and a variety of other psychiatric indications. Fluoxetine (Prozac) and paroxetine (Paxil) inhibit CYP2D6, a metabolic pathway for several opioid analgesics, tamoxifen, and many other antidepressants. Adverse effects of SSRIs start immediately but the beneficial psychiatric effects take up to 1 to 2 months to occur. Patient counseling about the timing of adverse effects and efficacy are important! SSRIs should not be abruptly discontinued in patients taking the medication chronically. Withdrawal symptoms can include flu-like symptoms, changes in mood or sleep, and (rarely) even electric-like shocks. To discontinue, the SSRI dose should be tapered down over the period of several weeks.

Tiotropium is a long acting muscarinic antagonist (LAMA) that is also known by the brand name Spiriva. It comes as an inhaled aerosol solution as well as an inhaled capsule. The main indications are for the treatment of COPD and Asthma. Tiotropium works through reversible competitive inhibition of acetylcholine at type 3 muscarinic receptors in bronchial smooth muscle which leads to bronchodilation. The medication is poorly absorbed in the GI and hepatically metabolized via the CYP2D6 and CYP3A4 pathways. The time to peak is between 5-7 minutes with the half-life elimination between 25-44 hours. Although the data in pregnancy and lactation is limited, the benefits for use likely outweighs the risk for a patient dealing with uncontrolled asthma. Some common side effects are cough, headache, GERD, rash and UTI. Some serious side effects are paradoxical bronchospasms and angle-closure glaucoma. It is important to note that tiotropium is not intended to be a quick-relief inhaler and should not be used for flare-ups or shortness of breath. It is recommended to clean the inhaler once monthly with water air dried. After usage the patient should rinse the mouth out; not due to the risk of thrush like with an ICS but to help prevent xerostomia and throat irritation. Go to DrugCardsDaily.com for episode show notes which consist of the drug summary, quiz, and link to the drug card for FREE! Please SUBSCRIBE, FOLLOW, and RATE on Spotify, Apple Podcasts, or wherever your favorite place to listen to podcasts are. The main goal is to go over the Top 200 Drugs with the occasional drug of interest. Also, if you'd like to say hello, suggest a drug, or leave some feedback I'd really appreciate hearing from you! Leave a voice message at anchor.fm/drugcardsdaily or find me on twitter @drugcardsdaily --- Send in a voice message: https://anchor.fm/drugcardsdaily/message

Promethazine, also known as Phenergan and Promethegan, is a first generation H1 histamine antagonist. It comes as a solution, suppositories, syrup, and tablets. There are a wide variety of indications for adults and children 2 years of age and older such as for allergic conditions, motion sickness, and sedation. A typical dosing range is between 25-50 mg tid-qid if PO and 6.25-25 mg IM/IV tid-qid. The max dose is 100 mg/day. Promethazine works through strong alpha adrenergic inhibition from blockade of postsynaptic mesolimbic dopaminergic receptors in the brain. It is metabolized via the CYP2D6 and CYP2B6 pathways. The onset of action is around 20 minutes with the duration of action of around 4-6 hours with a max of 12 hours. Common side effects are drowsiness, dizziness, blurred vision, and confusion. Serious side effects are seizures and QT prolongation. There is a Black Box Warning for respiratory depression and gangrene/severe tissue injury. When taken orally, take with food, water, or milk to avoid GI distress. Go to DrugCardsDaily.com for episode show notes which consist of the drug summary, quiz, and link to the drug card for FREE! Please SUBSCRIBE, FOLLOW, and RATE on Spotify, Apple Podcasts, or wherever your favorite place to listen to podcasts are. The main goal is to go over the Top 200 Drugs with the occasional drug of interest. Also, if you'd like to say hello, suggest a drug, or leave some feedback I'd really appreciate hearing from you! Leave a voice message at anchor.fm/drugcardsdaily or find me on twitter @drugcardsdaily --- Send in a voice message: https://anchor.fm/drugcardsdaily/message

The first body system we cover is gastrointestinal and famotidine is one of the H2 blockers we use for conditions like GERD. Find the book here: https://adbl.co/3wAZEmN and TonyPharmD YouTube Channel here: https://www.youtube.com/c/tonypharmd GI: -tidine (not -atadine or -ine) “to dine” Famotidine, (Pepcid), Nizatidine (Axid), Cimetidine (Tagamet) are H-2 receptor antagonists. Ranitidine (Zantac) is off the market. MOA: The stomach's parietal cells secrete stomach acid to lower pH. Histamine-2 will binds the receptors and stimulate them to produce acid. By blocking histamine-2 we can reduce the secreted stomach acid. Indications: Used for GERD and peptic ulcers, conditions of acid secretion disorders such as Zollinger-Ellison syndrome. Pharmacokinetics: The onset of action is a bit faster than PPIs which include omeprazole (Prilosec) and esomeprazole (Nexium), but not near as fast as an antacid which works right away, but the antacid only works for a few hours. Side Effects: Renal (kidney) dose adjustment and can raise serum creatinine as it is a potent inhibitor of tubular creatinine secretion, normally a marker of poor kidney function, though the patient has normal kidney function. Can antagonize testosterone which can lead to sexual dysfunction and gynecomastia (breasts in men). Spironolactone (Aldactone), an aldosterone antagonist, can similarly cause gynecomastia.   B12 deficiency along with proton pump inhibitors, decreased acid leads to malabsorption. Drug Interactions: Since ranitidine (Zantac) was pulled from the market patients might see cimetidine as an OTC alternative, but it does have many drug interactions. Can inhibit the enzymes CYP1A2 (theophylline, asthma), CYP 3A4 (verapamil, CCB), CYP 2C19 (citalopram, SSRI), decrease effects of CYP2D6 (carvedilol, 3rd generation beta blocker) Inhibits enzymes that break the drug down therefore you have more drug which equals toxicity. GMRINCE Neuro/Psych Atypical antipsychotic – aripiprazole (Abilify) Traditional Antiepileptics – carbamazepine (Tegretol), phenytoin (Dilantin) Parkinson's – pramipexole (Mirapex ER) SSRIs – citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac) Cardio Anticoagulant – warfarin (Coumadin) Antihypertensives – carvedilol (Coreg), a beta blocker, verapamil, a non-dihydropyridine calcium channel blocker Antiarrhythmic - amiodarone, risk of QTc prolongation Endocrine Antidiabetics – metformin (Glucophage), a biguanide or glipizide (Glucotrol XL), a sulfonylurea    

Tramadol can be used to treat and manage moderate to severe acute and chronic pain. It is also known as Ultram. An off label use is for Restless Leg Syndrome (RLS). When treating acute or chronic pain initiate 25-50 mg every 4-6 hours as needed with a max dosing range of 50-100 mg every 4-6 hours. The max dose per day is 400 mg. Tramadol acts on the mu-opioid receptor by blocking the ascending pain pathway. It alters the pain response and perception along with blocking reuptake of both serotonin and norepinephrine. Tramadol is extensively metabolized hepatically via the CYP3A4 and CYP2D6 pathway creating the metabolite M1. There is concern in children that are ultra-rapid metabolizers of CYP2D6 and use should be avoided in children. There are numerous black box warnings such as for addiction/abuse/misuse, risk of medication errors, accidental ingestion, and contaminant use w/ benzodiazepines or other CNS depressants. Monitor patients for level of pain relief and EKG and HR in patients with a family history of heart conditions. Go to DrugCardsDaily.com for my episode show notes which will contain a drug summary, quiz, and a link to FREE drug card sheets. SUBSCRIBE on Spotify or Apple Podcasts or search for us on your favorite place to listen to podcasts. I will go over the Top 100-200 Drugs as well as throwing in some recently released drugs that peak my interest. Also, if you'd like to say hello, suggest a drug, or leave any constructive feedback on the show I'd really appreciate it! Leave a voice message at anchor.fm/drugcardsdaily or message us through twitter @drugcardsdaily --- Send in a voice message: https://anchor.fm/drugcardsdaily/message

Tamoxifen is a selective estrogen receptor modulator that comes in both a tablet and solution. The tablet comes in a 10 mg and 20 mg strength and the solution comes in a 10 mg/5 mL concentration. Tamoxifen, also known as the brand name Femara, when used in reducing the risk of Breast Cancer in high risk females the dosing is 20 mg once daily for 5 years. When used in treating Breast Cancer the dosing does vary at 20-40 mg once daily. When 40 mg is needed per day the daily dose is divided into separate doses. When tamoxifen is metabolized via the CYP2D6 and CYP3A4/5 pathways the metabolites are 30-100 times more potent than tamoxifen itself. There is a black box warning for Uterine Malignancies and Thromboembolic Events. The monitoring parameters are bone mineral density, lipid panel, CBC with platelets, ophthalmic exam, and for medication adherence. The medication can be taken with or without food. Go to DrugCardsDaily.com for my episode show notes which will contain a drug summary, quiz, and a link to FREE drug card sheets. SUBSCRIBE on Spotify or Apple Podcasts or search for us on your favorite place to listen to podcasts. I will go over the Top 100-200 Drugs as well as throwing in some recently released drugs that peak my interest. Also, if you'd like to say hello, suggest a drug, or leave any constructive feedback on the show I'd really appreciate it! Leave a voice message at anchor.fm/drugcardsdaily or message us through twitter @drugcardsdaily --- Send in a voice message: https://anchor.fm/drugcardsdaily/message

Guest host Vicki L. Ellingrod, PharmD, talks with Kristen M. Ward, PharmD, and Amy Pasternak, PharmD, about integrating pharmacogenomic testing into psychiatric practice. Dr. Ellingrod is senior associate dean at the University of Michigan College of Pharmacy, Ann Arbor, and professor of psychiatry in the medical school. She is also section editor of the savvy psychopharmacology department in Current Psychiatry. Dr. Ellingrod has no relevant financial relationships to disclose. Dr. Ward and Dr. Pasternak are clinical assistant professors of pharmacy at the University of Michigan.  Dr. Ward and Dr. Pasternak report no relevant disclosures. Dr. Ward and Dr. Pasternak are team leads in the University of Michigan’s Precision Health Implementation Workgroup. Take-home points Pharmacogenomics is defined as the study of the relationship between genetic variations and how our body responds to medications. Two common reasons for ordering pharmacogenomic testing are that a patient or clinician wants testing completed before starting the trial of a psychotropic medication and that there are concerns about nonresponse or loss of response to medications. Common insurance criteria used to justify such testing include at least one failed medical trial; future use of a medication likely to be affected by genetic variants, such as metabolism through CYP2D6 or CYP2C19; or identification of human leukocyte antigen (HLA) variants before starting carbamazepine or oxcarbazepine. Quality improvement and usability campaigns around pharmacogenomic testing include ensuring that testing results are readily available in the medical record. Results should be searchable. Alerts can be created for prescribers when they order a medication for which a patient has a relevant genetic variant. After ordering testing, clinicians should document the patient’s medication response genotype and phenotype in the medical record so the information can be used for medications other than psychotropics. Summary Pharmacogenomic testing may be ordered for several reasons, including cases in which a patient or clinician wants information before switching to another medication or there are questions about failed medication trials. For approximately 50% of individuals who undergo pharmacogenomic testing, there may not be a change in treatment plans, or the results might not be conclusive enough to affect treatment. However, pharmacogenomic testing is useful in reassuring and improving adherence in patients who experience somatic adverse effects to psychotropic medications and want to know whether those effects are related to their metabolism. Getting insurance companies to cover pharmacogenetic testing can be tricky, and clinicians should be familiar with the criteria requested by insurers before ordering the tests. Many of the genetic-testing companies include a patient-assistance program to cover payment when insurance companies do not. In the medical record, it’s important to document the patient's genotype and phenotype. The patient’s genotype affects their metabolism of medications beyond psychotropics. Pharmacogenomic testing results can prevent serious adverse drug reactions. If testing comments on a patient’s carrier status for specific HLA subtypes implicated in drug metabolism, carbamazepine or other related medications should be added to the patient’s drug allergy list. States requirements about informed consent for genetic testing vary, so any clinicians who order such tests should be informed about their local laws. References Ellingrod VL. Current Psychiatry. 2019 Apr;18(4):29-33. Deardorff OG et al. Current Psychiatry. 2018 Jul;17(7):41-5. Ellingrod VL and Ward KM. Current Psychiatry. 2018 Jan;17(1):43-6. Bishop JR. Current Psychiatry. 2010 Sep;9(9):32-5. Maruf AA et al. Can J Psychiatry. 2020 Aug;65(8):521-30. National Institutes of Health. National Human Genome Research Institute. Genome Statute and Legislative Database. Clinical Pharmacogenetics Implementation Consortium. CPIC guidelines.. Pharmacogenetics Knowledge Base. *  *  * Show notes by Jacqueline Posada, MD, associate producer of the Psychcast; assistant clinical professor in the department of psychiatry and behavioral sciences at George Washington University in Washington; and staff physician at George Washington Medical Faculty Associates, also in Washington. Dr. Posada has no conflicts of interest. For more MDedge Podcasts, go to mdedge.com/podcasts Email the show: podcasts@mdedge.com

Aripiprazole is metabolized by CYP2D6 and CYP3A4. Because of this, drug interactions can happen. I discuss specific examples in this episode. Partial dopamine agonist activity and serotonergic activity make up a significant amount of aripiprazole's pharmacology. Aripiprazole is classified as an antipsychotic and can be used in schizophrenia, bipolar disorder, and depression augmentation. Aripiprazole can cause significant akathesia. I discuss this adverse effect on this episode.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.14.296467v1?rss=1 Authors: Connick, J. P., Reed, J. R., Cawley, G. F., Backes, W. L. Abstract: Heme oxygenase 1 (HO-1) and the cytochromes P450 (P450s) are endoplasmic reticulum-bound enzymes that rely on the same protein, NADPH-cytochrome P450 reductase (POR), to provide the electrons necessary for substrate metabolism. Although the HO-1 and P450 systems are interconnected due to their common electron donor, they generally have been studied separately. As the expression of both HO-1 and P450s are affected by xenobiotic exposure, changes in HO-1 expression can potentially affect P450 function, and conversely, changes in P450 expression can influence HO-1. The goal of this study was to examine interactions between the P450 and HO-1 systems. Using bioluminescence resonance energy transfer (BRET), HO-1 formed HO-1P450 complexes with CYP1A2, CYP1A1, and CYP2D6, but not all P450s. Studies then focused on the HO-1/CYP1A2 interaction. CYP1A2 formed a physical complex with HO-1 that was stable in the presence of POR. As expected, both HO-1 and CYP1A2 formed BRET-detectable complexes with POR. Whereas the PORCYP1A2 complex was readily disrupted by the addition of HO-1, the PORHO-1 complex was not significantly affected by the addition of CYP1A2. Interestingly, enzyme activities did not follow this pattern. Whereas BRET data suggested substantial inhibition of CYP1A2-mediated 7-ethoxyresorufin deethylation in the presence of HO-1, its activity was actually stimulated at subsaturating POR. In contrast, HO-1-mediated heme metabolism was inhibited at subsaturating POR. These results indicate that HO-1 and CYP1A2 form a stable complex and have mutual effects on the catalytic behavior of both proteins that cannot be explained by simple competition for POR. Copy rights belong to original authors. Visit the link for more info

Paroxetine (Paxil) is an SSRI that can be used in the management of depression. I discuss more on paroxetine pharmacology in this episode. Because paroxetine has some modest anticholinergic effects, it does show up on the Beers list as a potentially inappropriate medication. By inhibiting CYP2D6, paroxetine can have numerous drug interactions. Drugs like atomoxetine, aripiprazole, and metoclopramide can all have their concentrations increased. Tamoxifen is activated by CYP2D6 and paroxetine can ultimately reduce the effectiveness of the medication.

Dr. Patrick Finley provides evidence of a clinically significant CYP2D6 drug interaction when combining antidepressants with beta-blockers. Full manuscript available at: https://accpjournals.onlinelibrary.wiley.com/doi/10.1002/phar.2406

On this episode, I discuss codeine pharmacology and practical clinical practice pearls. Codeine is metabolized by CYP2D6 to the active metabolite morphine. I discuss how this can be affected by genetics as well as other medications. Constipation is a problem with codeine and all opioids in general. Education and making a plan with patients to combat this side effect is important. Codeine is less potent than other opioids such as fentanyl, hydromorphone, and hydrocodone.

Nortriptyline is a TCA that can be used for depression and various pain syndromes. I discuss other less common diagnoses in this podcast episode as well. There are a lot of drug interactions with nortriptyline. It is metabolized by CYP2D6, can have additive anticholinergic effects and has been associated with QTc prolongation. Nortriptyline is very anticholinergic and can blunt the effects of dementia medications. Dry mouth, dry eyes, sedation, urinary retention, and constipation are a few of the more common adverse effects of nortriptyline.

Terbinafine can inhibit CYP2D6 which plays an important role in the metabolism of many drugs such as metoprolol, fluoxetine, and clozapine. With terbinafine's ability to inhibit CYP2D6, it can also increase the risk of treatment failure with drugs like tamoxifen. When using anti-fungal drugs like terbinafine, remember that fungal infections can often require more time to treat. Terbinafine has the potential to cause liver impairment. I discuss this further on the podcast.

Two recent publications add to our knowledge concerning the utility of CYP2D6 genotyping and tamoxifen. TARGET-1: https://www.ncbi.nlm.nih.gov/pubmed/31821071 Tamoxifen D/C rates by 2D6 genotype: https://www.ncbi.nlm.nih.gov/pubmed/31800347

Doxepin is under the class of tricyclic antidepressants. It can inhibit the reuptake of serotonin and norepinephrine. In addition to the serotonin and norepinephrine reuptake inhibition mechanism, doxepin also has antihistamine type effects. Because of the anticholinergic activity of doxepin, it is recommended to avoid this medication in the elderly, particularly at high doses. Be aware that anticholinergics like doxepin can reduce the benefit of dementia medications. CYP2D6 is an important enzyme in the metabolism of doxepin and drugs like bupropion that inhibit CYP2D6 can increase the concentrations of doxepin.

Atomoxetine is a norepinephrine reuptake inhibitor that can be used in the management of ADHD. Atomoxetine is a non-controlled substance option for patients seeking this alternative to traditional stimulants. CYP2D6 is an important enzyme in the breakdown of atomoxetine. CYP2D6 inhibition or poor metabolizers via CYP2D6 can lead to higher concentrations of atomoxetine and put our patients at greater risk for adverse effects.

Fluoxetine is an SSRI used in the management of depression, anxiety, OCD, PTSD, and other psychiatric conditions. Fluoxetine has a very long half-life which can impact clinical management. I discuss how this matters in this podcast episode. Fluoxetine inhibits CYP2D6 which can alter the concentrations of many drugs. Prodrugs like codeine and tamoxifen can have their effects reduced because of fluoxetine. I explain this further in the episode. By inhibiting CYP2D6 concentrations of many drugs can be raised by the use of fluoxetine.

Metoprolol is a beta-blocker commonly used in the management of hypertension, heart failure, and atrial fibrillation. There is an extended release dosage form and immediate release dosage form with metoprolol. The advantage of the extended release product is that it doesn't require as frequent dosing. Metoprolol is selective for beta-1 receptors. It is less likely to interact with asthma medications. CYP2D6 plays an important role in breaking down metoprolol. Alterations in this enzyme's activity can alter concentrations of the drug.

Mirabegron is a beta-3 agonist that can help relax bladder smooth muscle and manage symptoms of overactive bladder. Mirabegron inhibits CYP2D6 which can negatively impact the effectiveness of tamoxifen. I discuss this in greater detail in the podcast. Tramadol and codeine effectiveness can be impacted by mirabegron. Be aware of this when using this medication. By inhibiting CYP2D6, mirabegron can increase the concentrations of many psychotropic medications such as fluoxetine, aripiprazole, clozapine, and paroxetine. I discuss this further in this episode of the podcast.

Introduction: The Dutch Pharmacogenetics Working Group (DPWG) indicated a list of actionable genotypes that affect patients’ response to more 50 drugs; these drugs which show variable effects based on patients’ genetic traits were named as pharmacogenetics (PGX) drugs. Preemptive genetic testing before using these drugs may protect certain patients from serious adverse reactions and could help in avoiding treatment failures. The objectives of this study include identifying the rate of PGX drug usage among Dutch population, estimating the level of users who carry the actionable genotypes and determining the main genes involved in drug’s effect variability. Methods: Usage of PGX drugs over 2011–2017 by the insured population (an average of 11.4 million) in outpatient clinics in Netherlands was obtained from the publically available GIP databank. The data of 45 drugs were analyzed and their interactions with selected pharmacogenes were estimated. Frequency of actionable genotypes of 249 Dutch parents was obtained from the public database: Genome of Netherlands (GoNL), to identify the pattern of genetic characteristics of Dutch population. Results: Over a 7 year period, 51.3 million exposures of patients to PGX drugs were reported with an average of 5.3 exposures per each drug user. One quarterof the exposures (12.4 million) are predicted to be experienced by individuals with actionable genotypes (risky exposures). Up to 60% of the risky exposures (around 7.5 million) were related to drugs metabolized by CYP2D6. SLCO1B1, and CYP2C19 were also identified among the top genes affecting response of drugs users (involved in about 22 and 12.4% of the risky exposures, respectively). Cardiovascular medications were the top prescribed PGX drug class (43%), followed by gastroenterology (29%) and psychiatry/neurology medications (15%). Women use more PGX drugs than men (55.8 vs. 44.2%, respectively) with the majority (84%) of users in both sexes are above 45 years. Conclusion: PGX drugs are commonly used in Netherlands. Preemptive panel testing for CYP2D6, SLCO1B1, and CYP2C19 only could be useful to predict 95% of vulnerable patients’ exposures to PGX drugs. Future studies to assess the economic impact of preemptive panel testing on patients of older age are suggested. Alshabeeb MA, Deneer VHM, Khan A, Asselbergs FW. Use of Pharmacogenetic Drugs by the Dutch Population. Front Genet. 2019;10:567. Published 2019 Jul 2. doi:10.3389/fgene.2019.00567. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Sections of the Abstract, Introduction, and Discussion are presented in the Podcast. Link to the full-text article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614185/

This JCO Podcast provides observations and commentary on the JCO article “Tamoxifen pharmacogenetics and metabolism: Results from the prospective CYPTAM study” by Sanchez-Spitman et al. My name is Vered Stearns, and I am a Professor of Oncology and Co-Director of the Breast and Ovarian Cancer Program at the Kimmel Cancer Center at Johns Hopkins in Baltimore, Maryland. My oncologic specialty is medical oncology. In the paper that accompanies this podcast, the authors report results of a prospective clinical study designated CYPTAM, which was designed to correlate endoxifen serum concentrations and outcomes of women prescribed adjuvant tamoxifen. The investigators enrolled 667 women with breast cancer who were initiating tamoxifen or who have been on tamoxifen for fewer than 12 months. The investigators obtained blood samples for CYP2D6 genotyping using the Amplichip CYP450 Test, and measured steady state concentrations of endoxifen with a high-performance liquid chromatography-tandem mass spectrometry. Co-primary endpoints included association of recurrence-free survival with endoxifen concentrations and with CYP2D6 genotypes. The patients were censored at the time of tamoxifen-discontinuation in case of a transition to an aromatase inhibitor. Several additional endpoints included disease-free survival, complete relapse-free survival, complete disease-free survival and overall survival. The statistical analysis plan was designed as a gate-keeper analysis for the co-primary objectives. Only if an association was found with a p-value below 0.05, were the remaining objectives considered.   The authors were not able to demonstrate an association between endoxifen concentrations and recurrence-free survival on tamoxifen. They also were not able to demonstrate an association either when exploring endoxifen concentrations in quartiles or when considering other thresholds. Likewise, there was no association between CYP2D6 genotypes and recurrence-free survival.   Almost two decades ago, researchers recognized that the absence or inhibition of the CYP2D6 enzyme is associated with very low concentrations of endoxifen, a potent and abundant anti-estrogen metabolite of tamoxifen. Whether low concentrations of endoxifen predict an inferior survival outcome has not been definitively determined. Multiple retrospective and small prospective studies evaluated CYP2D6 genotypes and survival outcomes and have provided mixed evidence. Clinicians have, therefore, wondered whether CYP2D6 genotype testing or endoxifen monitoring will assist in treatment recommendations. The CYPTAM investigators attempted to prospectively correlate endoxifen serum concentrations and outcomes for women taking tamoxifen.   The CYPTAM study is associated with several limitations, and, therefore, it does not provide a definitive answer to the controversy. For example, women were enrolled in the study either before starting tamoxifen or up to 12 months after initiation of the drug. This strategy could have led to incomplete baseline data and to the exclusion of individuals with early recurrences. In addition, about two-thirds of study participants transitioned to aromatase inhibitors following a short course of tamoxifen. The sequential administration of tamoxifen and aromatase inhibitors is superior to tamoxifen alone. Some of the patients who transitioned to aromatase inhibitors could have suffered a recurrence had they have stayed on tamoxifen alone. Furthermore, the authors did not have information regarding concomitant CYP2D6 inhibitor use. CYP2D6 inhibitors are commonly co-administered with tamoxifen and can contribute to misclassification of the CYP2D6 phenotype.    The challenge moving forward is that single agent adjuvant tamoxifen is rarely used. Most postmenopausal women with hormone receptor-positive breast cancer are recommended an  aromatase inhibitor instead of, or in sequence with, tamoxifen. Premenopausal women with high risk hormone receptor-positive tumors are recommended ovarian suppression with tamoxifen or an aromatase inhibitor. Women prescribed tamoxifen alone are usually at extremely low risk of recurrence, and a prospective study in this group of women will require a large number of participants to demonstrate differences between phenotypes. Given current practice, it may not be feasible to fully determine the role of endoxifen concentrations and CYP2D6 genotypes as predictors of tamoxifen efficacy.   Retrospective analyses that used samples obtained through large prospective studies, such as the Arimidex, Tamoxifen, Alone or in Combination and the Breast International Group 1-98, failed to demonstrate an association between CYP2D6 phenotypes and survival outcomes. Taken together, the data at present are insufficient to recommend CYP2D6 testing or analysis of metabolic profile in women for whom tamoxifen is considered. Indeed, clinical guidelines from the American Society of Clinical Oncology and the National Comprehensive Cancer Network do not recommend CYP2D6 genotyping. Moving forward, prospective studies of altered metabolism due to single nucleotide polymorphism, or administration of inhibitors, should be considered in clinical trials of standard and novel agents as these can lead to differences in drug efficacy and toxicity.   This concludes this JCO Podcast. Thank you for listening.

Dogma often dictates routine care. There are times when we have to attend to paradigm shifts. An easy way to save lives?  Just say no to (these) drugs: Codeine Normally metabolized into codeine-6-glucuronide (50-70%) and norcodeine (10-15%).  Codeine, codeine-6-glucuronide, and norcodeine have low affinity for the μ (mu) receptor. However, the most active metabolite of codeine is morphine with 200x the affinity for the mu receptor as the codeine derivates.  The problem is, people vary in its metabolism from 0-15% of codeine is metabolized to morphine. Ok, codeine is lame at best, unpredictable at worst. True.  Unless you are hiding a genetic time bomb. You're an ultra-rapid metabolizer. Some people have multiple extra copies of the DNA sequence for the CYP2D6 enzyme.  Ultra rapid metabolizers funnel a huge proportion of their codeine into morphine metabolism, resulting in a bolus of morphine, ending in apnea. Promethazine with codeine This combination is no better than placebo -- all of the risks, with no proven benefit.  This combination is notoriously abused -- as purple drank or sizzurp.  The rapper Pimp C died of this. Speaking of cough syrups... The AAP recommends no cough and cold preparations in children under age 6.  They have not been adequately studied in young children, and are not recommended for treating the common cold. What then?  You gotta give me something, doctor! Ok, Honey! In a study in the Archives of Pediatric and Adolescent Medicine, Dr Paul and colleagues published: Effect of honey, dextromethorphan, and no treatment on nocturnal cough and sleep quality for coughing children and their parents.  They compared a buckwheat honey, honey-flavored dextromethorphan (DM) and no treatment 30 min before bed for children with upper respiratory tract infections. Of the three, honey, dextromethorphan, and no treatment – honey scored the best for symptom improvement and cough frequency. Over age 1?  Cough and cold?  Honey.  There is no concern about accidental overdose, parents are doing something with a proven effect, and compliance is pretty much 100% -- and Grandma approves. Dextromethorphan No proven benefit over placebo.  Also widely abused, in pill form ("Skittles") and/or liquid form mixed in alcoholic beverage ("robotripping"). Alternatives to Codeine Details in Audio: Morphine liquid Acetaminophen and Hydrocodone   PEARLS AND PITFALLS IN PEDIATRIC PAIN Allow the child to speak for himself whenever possible. After acknowledging the parent’s input, perhaps try “I want to make sure I understand how the pain is for you. Tell me more.” Engage parents and communicate the plan to them. Elicit their expectations, and give them of preview of what to expect in the ED. Opioids are meant for pain caused by acute tissue injury, for the briefest period of time feasible. Older school-aged children and adolescents are increasingly at risk for opioid dependence and addiction. Give detailed advice on how to manage pain at home. Set expectations. Let them know you understand and will help them through your good advice that will carry them through this difficult time. Patients and families often just need a plan. Map it out clearly. And... Just say no to: codeine, promethazine with codeine, and dextramethorphan. Selected References Dhaliwal G, Hsu D. Tramadol Ultra Rapid Metabolizers at Risk for Respiratory Depression. Pain Physician. 2016; 19(2):E361. European Medicines Agency. Restriction on the use of codeine for pain relief in children—CMDh endorses PRAC recommendation [press release]. June 28, 2013. FDA. Most Young Children With a Cough or Cold Don't Need Medicine. Hartling L et al. How Safe Are Common Analgesics for the Treatment of Acute Pain for Children? A Systematic Review. Pain Res Manag. 2016; 2016: 5346819. Grond S, Sablotzki A. Clinical pharmacology of tramadol. Clin Pharmacokinet. 2004;43(13):879-923. Jin J. Risks of Codeine and Tramadol in Children. JAMA. 2017 Oct 17;318(15):1514. doi: 10.1001/jama.2017.13534. Kelly LE et al. More Codeine Fatalities After Tonsillectomy in North American Children. Pediatrics. 2012; 129(5). Kirchheiner J, Schmidt H, Tzvetkov M, et al. Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication. Pharmacogenomics J. 2007;7(4):257–265 Orliaguet G et al. A Case of Respiratory Depression in a Child With Ultrarapid CYP2D6 Metabolism After Tramadol. Pediatrics. 2015; 135(3). Poonai N. Analgesia for children in acute pain in the post-codeine era. Curr Pediatr Rev. 2017 Aug 28. doi: 10.2174/157339631366617082911563.1.   This post and podcast are dedicated to Bryan Hayes, PharmD for his practical approach to pharmacologic conundrums and to David Juurlink, MD, PhD for his steadfast dedication to patient safety and clinician education.  Check out Bryan's helpful blog and clinical resource, PharmERToxGuy.  Check out David anywhere one utters the word Tra-ma-dol.

Click Here Or On Above Image To Reach Our ExpertsUS. Can Learn From China's Spot-The-Spy ProgramPeople can respond to drugs very differently. A medication that brings relief for some patients might show no benefit at all in others, or even cause harmful side effects.A growing array of genetic tests is designed to help predict how people are likely to respond to many common medications, from antidepressants and antihistamines to pain relievers and blood thinners. The tests, which are controversial, look for tiny variations in genes that determine how fast or slow we metabolize medications.Because of such gene variations, codeine, frequently prescribed to relieve pain, has little effect on as much as 20% of the population, while 2% of people have such a strong reaction that a normal dose can be life-threatening. About 25% of people can't effectively absorb Plavix, a clot-busting drug, putting them at increased risk for a heart attack or stroke. PRO-DTECH II FREQUENCY DETECTOR(Buy/Rent/Layaway)Even everyday drugs such as Advil and Motrin, for pain relief, and Zocor, to lower cholesterol, can have widely varying effects. Testing patients for gene variations could avoid some of the 700,000 serious drug reactions in the U.S. each year, some experts say. Proponents of the tests, which are done with a cheek swab, say they also could help doctors rely less on trial and error in choosing the right drug and the right dosage for individual patients.CELLPHONE DETECTOR (PROFESSIONAL)(Buy/Rent/Layaway)The Food and Drug Administration has included cautionary information for people with certain gene variations on the labels of more than 100 prescription medications. As yet, only about 20% of doctors order such tests, according to a survey by the American Medical Association, and many patients don't know they exist.PRO-DTECH III FREQUENCY DETECTOR(Buy/Rent/Layaway)Some major medical associations, including the American College of Cardiology and the American Psychiatric Association, have been slow to endorse the testing, mainly because there are no large, randomized controlled trials showing the technique significantly improves patient care. And the tests, which range from $500 to $2,000, are only covered by some insurers in some cases.PRO-DTECH III FREQUENCY DETECTOR(Buy/Rent/Layaway)NOT RIGHT FOR EVERYONEMany common medications can affect people differently depending on minor variations in the genes that regulate key enzymes. The variations can make people metabolize certain drugs either more slowly or rapidly than normal. Some examples:DRUGSPain relievers codeine or oxycodone, including Tylenol 3 and PercocetENZYME PATHWAY AT WORKCYP2D6IMPACTA standard dose can have little effect in up to 20% of people, while as many as 2% can have a life-threatening reaction.DRUGSBlood thinner Plavix (clopidogrel) and acid reducers Prilosec (omeprazole) and Prevacid (lansoprazole)ENZYME PATHWAY AT WORKCYP2C19IMPACTUp to 15% of people metabolize these drugs very slowly, resulting in a higher effective dose and greater risk of side effects.DRUGBlood thinner Coumadin (warfarin)ENZYME PATHWAY AT WORKCYP2C9IMPACTPeople with some gene variants have twice the risk of severe bleeding, but other factors are involved and population percentages are unclear.DRUGCholesterol reducer Zocor (simvastatin)ENZYME PATHWAY AT WORKSLCO181IMPACTUp to 40% of people have impaired ability to metabolize this drug, giving them increased risk of muscle pain and other side effects.Source: Clinical Pharmacogenetics Implementation ConsortiumAlan Pocinki, an internist in Rockville, Md., says he orders gene testing for patients who have a history of unexplained symptoms or who haven't gotten relief from drugs in the past. In many cases, he is able to find a better treatment based on their DNA, he says. “It makes a huge difference clinically among people I see every day.”PRO-DTECH III FREQUENCY DETECTOR(Buy/Rent/Layaway)How people's genes affect their response to medic

MDS presents the latest research and findings from the field of Movement Disorders. Abstracts of articles from the Society Journal, Movement Disorders, are taken from the February 2013 (Vol. 28, Issue 2) issue.

Professor Albert Dahan, head of the Anesthesia and Pain Research Unit at Leiden University Medical Centre, talks about why this common and dangerous phenomenon is under-reported in the literature and as a result, why he has taken this unusual investigative approach. Professor Dahan highlights the paper's main findings including the emerging importance of CYP2D6 genetic polymorphisms and future directions for research.

Commentary on a successful study in which genotype-guided tamoxifen dosing increased endoxifen concentrations in women with reduced CYP2D6 metabolism.

Fri, 21 Nov 2008 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/9531/ https://edoc.ub.uni-muenchen.de/9531/1/Schmid_Dagmar.pdf Schmid, Dagmar ddc:610, ddc:600, Medizinische Fa

Thu, 15 May 2003 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/1034/ https://edoc.ub.uni-muenchen.de/1034/1/Heumueller_Wolfgang.pdf Heumüller, Wolfgang