Issue 16 Nonacademic Presenting Alumni

Jelena Tica: “Don’t be afraid to dream big and keep trying no matter what!”

In this month’s Presenting alumni section, we are welcoming Jelena Tica, an inspiring molecular biologist, scientist, traveler. Starting October 1st, she will be working for Johnson & Johnson, on clinical trials testing the Janssen Ad26.CoV2.S COVID-19 Vaccine. Besides her exciting career path, we will also look back at Jelena’s experience as S3 project leader and organizer.

Careers in Science Issue 16

Careers in Science: Consulting

Co-author: Ivana Osredek

Hi everyone! We are continuing with our new topic, where we look at various career paths one can take after studying science. Today we are bringing you consulting, a very interesting career focused on problem solving and strategizing. To get a better sense of what consulting is and what it looks like from the inside, we spoke with our EVO alumni and members Matilda Maleš and Matija Žeško.

Issue 16 Understanding Science

Drug interactions 101

Since I started working as a community pharmacist, it has come to my attention that a big part of the general population takes six or more medicines every day, especially the elderly. Although they prepared us for this at university, it still surprised me once I witnessed it in everyday practice. The major problem with polytherapy are drug interactions, which are often neglected, especially in Croatia. The idea of rational pharmacotherapy is just that – to rationalize drug use and consequently assure safer treatments (fewer side effects, minimal risk of sub-dosing or overdosing), less cost to the healthcare system and greater adherence to the therapy; the latter possibly being the most crucial.

Types of interactions

When discussing drug interactions, there are three main types that need to be considered: pharmacokinetic or pharmacodynamic interactions and pharmaceutical incompatibilities. The most common among them are pharmacokinetic interactions, regarding changes in absorption, distribution and elimination of drugs and their metabolites. Pharmacodynamic interactions refer to interactions between two or more active molecules at the place of action – mostly extracellular and intracellular receptors or messenger molecules.

Pharmaceutical incompatibilities are the rarest and include interactions of two or more active molecules given their chemical form – acids, alkali, salt, ions etc. For example, if calcium chloride and sodium carbonate are taken together, the result is precipitation of calcium carbonate and sodium chloride, resulting in the loss of therapeutic effect. Although rare, this interaction is highly dangerous, given that both salts are administered intravenously – calcium chloride for arrhythmias, hypocalcemia and overdosing with both calcium channels blockers and beta blockers (common antihypertensives); while sodium carbonate is used for overdosing on tricyclic antidepressants and for some arrhythmias.

Pharmacodynamic interactions

As previously stated, pharmacodynamic interactions are mostly observed at the enzyme or receptor site. Both receptors and enzymes are polymers, proteins, built of amino acids which have a certain direction in space. Depending on the available side chains of those amino acids, a drug’s active molecules can interact with them and change the shape and function of a given protein. The real beauty lies in the fact that different active molecules can interact with the same receptor or enzyme either at the same or at a different site. Also, active molecules have different binding affinities than the physiological substrates of those enzymes and receptors. The binding affinity of a certain molecule doesn’t only depend on its properties, but also on the environment. One of the most important factors that can change binding affinities is the concentration of the substrate molecule. Even the molecule with the lowest binding affinity for a certain protein will bind to it if its concentration in a given environment is much higher than that of a protein. Similarly, if there are two substrates of the same protein, one with lower binding affinity but much higher concentration, and one with a much higher binding affinity but a much lower concentration, the protein will bind the molecule with higher concentration, regardless of its low binding affinity. This concept enables us to use some molecules as antidotes in case of overdosing or drug poisoning.

Examples from practice

For example, in case of benzodiazepine overdose (the most common anxiolytics used as anxiety, depression and insomnia treatment), administration of flumazenil – a benzodiazepine with a much higher binding affinity – will prevent further binding of other benzodiazepines and prevent overdosing. Benzodiazepines are GABA receptor agonists. GABA receptors bind gamma aminobutyric acid, one of the main inhibitory neurotransmitters of the central nervous system, responsible for mood regulation. One of the most common side effects of benzodiazepines is somnolence (or drowsiness), occurring due to central nervous system inhibition. Inhibition of the central nervous system that is too powerful can lead to cessation of breathing, resulting in death. Although this requires an extremely high concentration of benzodiazepines and occurs just as rarely, the antidote used for such situations is none other than flumazenil – a GABA receptor antagonist.

This pharmacodynamic interaction is one of the positive examples that we used in our favor, but that is not always the case. Pharmacodynamic interactions are more often undesirable than useful, and will usually cause loss of therapeutic effect. One such scenario would be the application of ibuprofen along with acetylsalicylic acid, where ibuprofen would act as a reversible inhibitor for the cyclooxygenase enzyme (COX), required by erythrocytes for the creation of thromboxane, one of the proteins responsible for blood coagulation. Since ibuprofen possesses a greater binding affinity for COX, it will occupy the receptors much faster, preventing the acetylsalicylic acid from binding to the receptors. Regardless, ibuprofen is also rather quick to release from said receptors, making its inhibition of thromboxane synthesis too short-lasting to achieve any significant anticoagulation effect. In the meantime, acetylsalicylic acid, which is an irreversible COX inhibitor, will be eliminated from the erythrocytes and will never reach COX. In other words, simultaneous application of acetylsalicylic acid and ibuprofen will negate the anticoagulant effects of acetylsalicylic acid.

Pharmacokinetic interactions

Pharmacokinetic interactions occur at the level of peripheral active substance absorption, its metabolism, distribution through tissue and ultimately its elimination. It comes as no surprise that these interactions are the most common ones, so let’s look at what we know about them.

The absorption of active substances from the periphery is affected by the very nature of the molecule, the alkalinity of the medium in which we want the absorption to take place, the concentration of the active substance where the absorption takes place, its size and chemical composition and, in some cases, the excipients used to help them along. Substance absorption is commonly affected by the presence of food when medication is applied orally, respiration rate when administered through inhalation, tissue blood flow when applied intravenously and intranasally, as well as skin damage in case of transdermal medication.

The simplest example of interaction between two active substances in which absorption is affected would be the precipitation of levothyroxine and iron within an acidic medium. Levothyroxine is a “replacement” thyroid hormone used to treat hypothyroidism on strict instructions: take at least half an hour before a meal, the same as some iron supplements. Any form of food presence will reduce the absorption of levothyroxine and iron leading to the common practice of taking levothyroxine and iron simultaneously, half an hour before breakfast. This interaction significantly reduces the therapeutic effect of both active substances and has a significant clinical effect.

Interactions in terms of distribution are primarily related to bonding with plasma proteins, which in turn depends on the acidic/alkalic nature of the active substance. Like receptors, two molecules may compete over the same bonding point on plasma proteins leading to one excluding the other. The molecule bonded to a plasma protein as such is “inactive”, meaning its active concentration available for therapeutic effect is increased when another molecule pushes it off a plasma protein. This sort of interaction is crucial in medication of narrow therapeutic widths, such as warfarin – a widely used coagulant with a powerful binding to the plasma molecule. This active substance getting pushed off plasma molecules by another active substance will increase its concentration, which in turn increases the risk of internal hemorrhage, which may end up being fatal.

Drug metabolism is also dependent on the chemical type of molecules and area of application, with interaction most commonly occurring when bonding to the CYP450 enzyme. There are over 2000 CYP450 enzymes present in almost every type of tissue, their activity being most significant in the liver, through which most orally administered medicines must go through. Some active substances act as inhibitors to the CYP3A4 enzyme, which plays a vital role in the metabolism of atorvastatin – a drug used to treat elevated blood fats. When azithromycin inhibits the metabolism of atorvastatin, the concentration of atorvastatin increases along with its therapeutic effect, also increasing the chances of causing side effects tied to it. One of the more dangerous side effects in this scenario would be rhabdomyolysis – a serious disease which affects muscles and reduces their mass.

Is there a happy ending?

Interactions occurring in medication are expected and often predictable. The important thing in terms of preventing and solving side effects is the assessment of their clinical significance, as well as the assessment of individual risks. If we want a safer administration of medication, it is important to secure rational pharmacotherapy for the public, which calls for a tight cooperation of all healthcare experts – and their patients. With that in mind, I would like to take this opportunity and bring this disappointingly common neglect of side effects and drug interactions to your attention, as the only way we can progress in rationalization of pharmacotherapy is – together.

Did you learn something new? Let us know in the comments if you’ve gained a new appreciation for polytherapy, or if you have any questions or examples of your own.

Issue 15 Understanding Science

From Röntgen to Damadian: demystifying radiation and explaining radiology and nuclear medicine

Co-author: Mario Zelić

“Nothing in life is to be feared, it is only to be understood. Now is the time to understand more, so that we may fear less.”

Marie Curie

Radiation is a word that incites fear in a lot of people. Much of that fear originates from a misunderstanding of what it actually is, what it does and what it does not. “Radiation” is a very broad term, generally used to represent any emission of energy by a source of some kind. However, there are many different phenomena that fall under that umbrella, and they come in varying degrees of rarity and of danger. Even those that may be seen as “dangerous” in some respects can be more useful than harmful – which is why medicine has both treatments for those who suffered too much damaging radiation, and treatments utilizing the purposeful irradiation of a patient.

Issue 15 Science Shoutout

How we know what we know

If you have ever sat in a science class, you might be familiar with the classic science-teacher opening to an introductory lesson on a new topic. Quite typically, you are not given an immediate outline of the new concepts, but rather briefed on how and why we came to know them in the first place. If you are to study the classical law of universal gravitation, you first need to know the story of how an apple supposedly decided to study the crown of Isaac Newton’s head. You might think this is somewhat silly. Why turn a physics lecture into a history class? Well, there is a reason for this trend, and it is not to fill time.

Experimental Issue 15

Questioning our past (posts)

Co-author: Mario Borna Mjertan

Greetings, S3 blog reader! We have prepared something special for you – an interactive quiz! The questions are varied, from physics to medicine, so don’t worry if you are not familiar with some terms, and try to answer anyway.

Each question has only one correct answer. When you choose the answer, you will see whether you got it right and get an additional explanation. Beneath each question there is also a link to the text from our blog that deals more with its respective topic. Have fun!

Issue 14 PostDoc Presenting Alumni

Srinath Krishnamurthy: “You may not have the resources to answer a question, but you definitely have the resources to ask the question”

Today, it is my pleasure to present another Presenting Alumni interview, this time with Srinath Krishnamurthy. Srinath was a project leader at the Summer School of Science in 2018, where he held a biochemistry project alongside his wife Sindhuja. He is in his final year as a postdoc in biophysics, working with membrane protein complexes.

Issue 14 Understanding Science

Can we treat Alzheimer’s?

It is likely that most of us, especially if we are hopeless romantics, had heard about the book or movie called „The Notebook“. In this two-hour romantic drama we are led through a wonderful and a bit painful story of a young couple who, against all ods, managed to grow old together. However, „The Notebook“ shows us much more than just a romantic love story – it also shows us the tragic lives of some 50 million people around the world whose memories and families fade away due to dementia.

Issue 14 Understanding Science

Patient tumour avatars improving treatment outcomes

With more than 19 million cases diagnosed per year and around 10 million deaths worldwide, cancer represents a big challenge in health care and an important cause of mortality and morbidity. Some of the most diagnosed cancer types like lung, female breast, and colorectal cancer account for a third of this incidence and mortality rate. So, how come we are still so ineffective in treating cancer? Part of the answer is tremendous tumour heterogeneity: between different types, between two people having the same type, or within one single tumour in one single person. And this biological phenomenon has been challenging scientists for a long time now.

Issue 14 News

The Scientist in Me: Apples, popcorn, memory and fireworks

In the past year or so, the importance of science communication has become clearer than ever, and the need for great science communication ever so stronger. Becaues of this, we’re especially glad that the competition The Scientist in Me was held again this year, although completely online.