Drug-drug-interactions - PReP-TEAM ENG

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Drug-drug-interactions

PReP-TEAM Know Your Team - Know Your Treatment

Drug interactions can have serious consequences, such as adverse events, therapy failure or even hospitalisations. Ineffective and inefficient communication between healthcare providers can play a role in missing these interactions. In this e-learning, you will gain knowledge about interactions so that you can communicate effectively on the topic during the study group. You will learn about: 1. What drug-drug interactions are and why they are important 2. What pharmacokinetic and pharmacodynamic interactions are and how they occur 3. Recognising and managing clinically relevant interactions.

Learning objectives e-learning

Risk factors and points of notice for clinical practice

Consult with our patient

Pharmacydynamic interactions

Pharmacokinetic interactions

What are drug-drug-interactions

Chapters

What are drug-drug-interactions

Drug interactions occur when the action or effect of a drug is altered by another medicine, diet, or other external factors. These interactions can lead to an increased risk of side effects, decreased treatment effectiveness, or even toxicity.

What are drug-drug-interactions

• Tacrolimus
• Simvastatin
• Fluconazol
• Metoprolol
• Naproxen
• Citalopram
• Paracetamol

• Correct! Fluconazol inhibits CYP3A4

• Correct! Citalopram is a CYP3A4 substrate inhibited by fluconazole

• Correct! SSRIs may increase bleeding risks by NSAIDs

• Metoprolol is a CYP2D6 substrate, but with no interactions with these drugs

• Paracetamol is one of the few drugs without significant interactions!

• Correct! Simvastatin is a CYP3A4 substrate inhibited by fluconazole

• Correct! Tacrolimus is a CYP3A4 substrate inhibited by fluconazole

Which of the medicines below do you think could lead to a drug interaction when combined with another medicine in this list?

Drug-drug-interactions in polypharmacy

02

Pharmacokinetic interactions

Pharmacokinetics is what the body does with the medicine. This involves absorption, distribution, metabolism and excretion (ADME) of medicine, including the bioavailability. These processes determine the concentration, duration and intensity of a drug's action.

Pharmacokinetics

The liver is the main organ for metabolism through liver enzymes. In addition, the liver can excrete metabolites through the bile.

Some medicines are excreted through the skin (e.g., sweat), while others are absorbed through the skin (e.g., transdermal patches or topical corticosteroids).

The small intestine is the main site for absorption because of the large surface area and long residence time of the medicine.

The kidneys filter medicine and their metabolites from the blood and remove them through the urine.

The heart plays a crucial role in the distribution of medicine through the body via blood circulation.

Volatile substances and gaseous medicines, such as anesthetics, are excreted through the lungs.

The stomach is involved in absorption, especially for medicine that dissolve well in an acidic environment.

Medicine that are fat-soluble are often stored in adipose tissue, which affects their distribution through the body.

Click on the organs to see how they are involved in ADME

Pharmacokinetics

Click on the bold words!

Medicines can interfere with each other's absorption. For example, erlotinib, which is normally (1) well soluble at low pH. In this case, it is also (2) well absorbed in the blood, as long as the pH remains below 5. (3) Omeprazole increases the pH and thereby (4) reduces the absorption of erlotinib. The AUC decreases by about 46% as a result.

Absorption

More phenytoin is present at the target site

More phenytoin is degraded

Phenytoin is less effective

Less phenytoin is absorbed

Medicines may compete for the same protein binding sites in the blood, leading to an increased free (active) concentration of a drug. Valproic acid, for example, displaces phenytoin from albumin. What could be the consequence of this?

Distribution

Phenytoin in the brain can reach their target receptors for anti-epileptic action. Phenytoin in the liver, on the other hand, is broken down.

Because of its binding to a large protein complex, phenytoin cannot be transported between endothelial cells.

When phenytoin is displaced by albumin valproic acid, more phenytoin can pass to the brain and liver. After all, it's able to fit between endothelial cells.

It looks as if the total amount of phenytoin in the body is reduced, as more is broken down. However, the free fraction of phenytoin is increased, which can reach the target site!

Liver

Blood

Brain

Click on the bold words!

CYP3A4

Medicines are mostly converted to inactive metabolites in the liver. CYP enzymes play a very important role in this. Tacrolimus, for example, is converted by the enzyme CYP3A4. If you add a medicine, an inhibitor that (1) reduces this activity, tacrolimus will be (2) degraded less and remain present to for an extended period of time. If you add a so-called (3) inducer, which enhances the action of CYP3A4, then logically (4) more tacrolimus will be degraded.

Metabolism

Lithium concentration increases one week after start of diuretic

Lithium concentration increases immediately on start of diuretic

Ltihium is excreted more through diuresis

Lithium binds to potassium and is excreted less

Medicines that are mainly cleared renally are, as expected, dependent on renal function. Thus, with reduced eGFR, these medicines will circulate longer in the blood. Some medicines can block transporters in the kidneys, so those receptive to these transporters will be excreted less. What would happen if a patient is on lithium and starts spironolactone?

Excretion

Li+

Na+

Click on the bold words!

"Spironolactone causes diuresis with retention of potassium ions and increased rate of excretion of (1) sodium ions. To compensate for this, more sodium will be resorbed. This (2) compensatory mechanism takes effect about 3-10 days after sodium depletion. Lithium is resorbed by the kidneys in the same way as sodium is resorbed in the (3) proximal tubule. Thus, this compensatory mechanism ultimately causes increased lithium uptake."

Excretion

Pharmacodynamic interactions

03

Pharmacodynamics is the study of what medicines do to the body: how they bind to receptors, enzymes or other targets to exert effects. Pharmacodynamic interactions occur when medicines affect each other's actions on these targets, which can lead to an enhancing or antagonistic effect. These interactions determine the strength, duration and nature of drug effects, including side effects and clinical outcomes.

Pharmacodynamics

Antagonistic

Synergetic

Additive

Pharmacodynamic interactions can have various effects. How would you define these different effects of pharmacodynamic interactions?

eGFR rises

eGFR drops

Vasodilatation by enalapril

Vasoconstriction by ibuprofen

Vasodilatation by enalapril

Vasoconstriction by ibuprofen

Commonly used medicines are ibuprofen and enalapril. However, these may interact. ACE inhibitors lead to vasodilation. NSAIDs, on the other hand, can lead to vasoconstriction via COX-2 inhibition. How does this affect the kidneys? Click on the appropriate buttons for each section.

Example pharmacodynamic interaction

04

Consult with our patient

Mrs. Grun is 78 years old and enjoys spending time with her grandchildren. In recent months, she has had to limit her daily walks due to painful knees caused by severe osteoarthritis. She is now admitted for elective knee surgery. She has multiple chronic conditions, including hypertension, type 2 diabetes, atrial fibrillation and osteoporosis. Her medication regime is complex, and she sometimes finds it difficult to understand all the prescriptions. She has been complaining about fatigue, bruising and mild nausea in recent weeks. At the preoperative interview, she is told that some medication must be temporarily paused, which she finds difficult to understand. ‘Why do I have to stop certain medicines when I already feel so tired?’

Complex case with Mrs. Grun

Ms Grun's medicines may interact with each other. Consider for which ones this could be the case.

Medication: Metoprolol 50 mg: 1 tablet/day Digoxin 0.125 mg: 1 tablet/day Warfarin 5 mg: 1 tablet/day Omeprazol 20 mg: 1 tablet/day Metformin 500 mg: 1 tablet/day Calcium en vitamin D-supplements Ibuprofen 400 mg: 3 tablets/day if necessary Paracetamol 1000 mg: 3 tablets/day

Admission records: Complaints on admission: Fatigue, bruising on arms and legs. Mild nausea. Lab results:

• INR: 4.5 (2.0-3.5)
• Cr.-clearance: 50 ml/min (>60 ml/min)
• Digoxin concentration: 1.8 ng/mL (0.5-2.0 ng/ml)
• Glucose: 6.8 mmol/l (4.5-8 mmol/l)

Grun, L.17-3-1947

Hypercalcaemia due to calcium may increase the risk of digoxin toxicity.

Both drugs slow heart rate, which can lead to bradycardia.

Omeprazole inhibits CYP2C19, which reduces warfarin metabolism. This increases INR and bleeding risk.

Warfarin and ibuprofen increase bleeding risk due to synergistic effects.

Calcium + Digoxine

Digoxin + Metoprolol

Warfarin + Omeprazol

Warfarin + Ibuprofen

These combinations have an interaction. What happens with these combinations?

Medicatie: Metoprolol Digoxin Warfarine Omeprazol Metformine Calcium/vitamin D Ibuprofen Paracetamol

Risk factors and points of notice for clinical practice

05

Interactions are more common in certain groups of patients because of their physiological characteristics, medication use or underlying conditions. Recognising these risk groups is of importance for improving patient safety and optimising treatment plans. Elderly people are often such a risk group.

Risk groups for interactions

• Identify medicines with a high probability of interaction when establishing a treatment plan, either pharmacokinetic or pharmacodynamic.
• Consider the impact of drug interactions on clinical outcomes by using the electronic healthcare system and adjust the regimen if necessary.
• Inform patients clearly about possible interactions and what to do in case of complaints.
• Consider adjusting medication in patients with altered physiological conditions, such as acute illness, dehydration, or fever, as these factors can affect medicine action and interactions.

In summary

We've gone through several aspects of anti-coagulation for the different professions. We will discuss your perceptions of roles and responsibilities in pharmacotherapy and work on a case-simulation in interprofessional groups. For this, do the following: 1) Reflect on these statements and bring you answers to the workgroup.

• How do you represent your health care profession in anticoagulation therapy?What are your responsibilities?
• How do you think other health care professions are involved in this process?
• What skills/competencies do you need to possess to participate in collaborative practice?

2) Download the app Team Up! Find Team Up! in the Google Play Store/App store or scan the QR codes below.

App Store

Google Play Store

You've finished this e-learning!

"Renal insufficiency leads to reduced elimination of medicines excreted through the kidneys. This applies, for example, to lithium, metformin and aminoglycosides. Accumulation can cause toxicity. The liver is responsible for the breakdown of many medicines, including opioids, benzodiazepines and paracetamol. When liver function is impaired, the concentration of these medicines remains elevated in the blood for longer, increasing the risk of side effects. In addition, liver insufficiency leads to reduced production of albumin, an important protein that binds medicines. This can result in increased free drug concentration."

Patients with complex drug regimens have multiple medicines that can logically interact with each other. Especially when medicines compete for the same metabolic pathway in the liver or affect excretion through the kidneys. In addition to these factors, adherence also plays an important role. Patients with complex drug regimens often experience difficulties in following prescriptions correctly. Missing doses or combining medicines at unplanned times can lead to unintended interactions.

Elderly people are often more sensitive to the effects of medicines, a phenomenon known as increased pharmacodynamic sensitivity. This means that side effects such as blood pressure drops caused by antihypertensives or sedation caused by opioids can occur more strongly, even at normal doses. This increases the risk of falls, hospitalisation and other complications.

1. Immediately after taking the medicine.
2. During the steady-state phase of the medicine.
3. After the first dose of the medicine.
4. At any time during treatment.

When should the plasma level of a medicine be measured to determine if there is an interaction?