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• A 70-year-old woman is in your office complaining of recently having trouble maintaining her balance after taking diazepam (valium). She occasionally takes diazepam when she feels anxious and has trouble sleeping. She has a 15-year history of taking diazepam.
• Q1. Explain the cause of this patient’s difficulty in maintaining her balance?
• As we age and tend to slow down, so do our body systems. Metabolism of medications slow down significantly which in turn medications stay in the body longer. There was a study done on eight healthy older patients between the ages of 61-78 and seven younger patients between 21-33 where they were given 2.5 mg of diazepam BID for 15 days (Greenblatt et al., 2021). Predose (through) concentrations were measured during the 15 days and also the post-dosage period. Studies found that plasma concentrations of diazepam dosages were 30-35% higher in the elderly patients (Greenblatt et al., 2021). This is very important to understand as healthcare providers to avoid toxicity. 

Q2. Diazepam experiences a significant first-pass effect. What is the first-pass effect, and how can first-pass metabolism be circumvented?

First pass means medication being broken down before the system circulation and target tissues. So when a medication is taken orally, it goes from the small intestines to the liver via the hepatic portal vein where it is broken down and metabolized (Rosenthal & Burchum, 2021)

A 75-year-old woman develops symptoms of a cold and buys an over-the-counter cold medication at the grocery store. The medication contains diphenhydramine, acetaminophen, and phenylephrine. She takes the recommended adult dose but soon after taking the medication, she becomes very confused and disoriented.

Q3. What is likely causing the signs of confusion? 

• Diphenhydramine and phenylephrine are antihistamine and anticholinergic medications. These medications target the central nervous system by passing the blood brain barrier (Rosenthal & Burchum, 2021).  This causes side effects such as confusion, dizziness, hypotension, and sedation because elderly patients have decreased cholinergic neurons or receptors in the brain, decreased liver and renal function, and increased blood-brain permeability (Rosenthal & Burchum, 2021).

A 26-year-old woman who has never been pregnant is seeking preconception care as she is planning to pursue pregnancy in a couple of months. Currently, she has no symptoms to report and on review of body systems, there were no concerns. Her past medical history is significant for a history of rheumatic fever as a child. She subsequently underwent valve replacement with a mechanical heart valve. She is followed by a cardiologist who has already evaluated her cardiac function and she has received clearance from her cardiologist to pursue pregnancy. Records from her cardiologist include a recent cardiac echocardiography report that reveals a normal ejection fraction indicating normal cardiac function.

She has no alterations in her daily activities related to her heart. She has no other signi?cant medical or surgical history. She is a non-smoker, drinks occasionally but has stopped as she is attempting to conceive, and does not use any non-prescription drugs.

Current Medications: Her current medications include only prenatal vitamins, which she has begun in anticipation of pregnancy, and warfarin. She has no known drug allergies.

• Vital Signs: On examination, her pulse is 80 beats per minute, blood pressure is 115/70 mm Hg, respiratory rate is 18 breaths per minute, and she is afebrile.

Measurements: Weight = 152 pounds, Height = 5?5 ?, BMI= 25.29

Q4. How is warfarin metabolized? Does warfarin cross the placental barrier?

Warfarin is highly protein bound and is metabolized in the liver by hepatic enzymes. Warfarin crosses the placenta because it has a low molecular weight (Daughety et al., 2020). This can cause birth defects in the fetus. 

Q5. Explain the hepatic drug metabolism of children 1 year and older. How do they compare with the hepatic drug metabolism of infants and adults?

Children at 1 year old are still developing their metabolism but is much faster than then neonates. Enzyme activity in the liver is still developing and it is able to metabolize medications more efficiently. Newborns have a high gastric pH and slow gastric emptying resulting in poor absorption (Rosenthal & Burchum, 2021). Newborns also have low serum protein levels. In adults, the enzymes in the liver are fully matured to metabolize medications. One has to take into consideration age and underlying comorbidities when prescribing. 

Q6. Explain protein binding in the neonate.

• Protein binding means attachment of medications to proteins in the blood, the most abundant protein is albumin (Lee et al., 2023). In neonates, since they are still developing, they have lower levels of albumin, which can then lead to higher levels of medications that do not bind that are floating around in the bloodstream. By this happening, medications can be stronger in neonates and stay longer in their system (Lee et al., 2023).

References:

Daughety, M. M., Zilberman-Rudenko, J., Shatzel, J. J., McCarty, O. J. T., Raghunathan, V., & DeLoughery, T. G. (2020). Management of Anticoagulation in Pregnant Women With Mechanical Heart Valves. Obstetrical & gynecological survey, 75(3), 190–198. https://doi.org/10.1097/OGX.0000000000000751

Greenblatt, D.J., Harmatz, J.S., Zhang, Q., Chen, Y. and Shader, R.I. (2021), Slow Accumulation and Elimination of Diazepam and Its Active Metabolite With Extended Treatment in the Elderly. The Journal of Clinical Pharmacology, 61: 193-203. https://doi.org/10.1002/jcph.1726

Lee, Z. M., Chang, L. S., Kuo, K. C., Lin, M. C., & Yu, H. R. (2023). Impact of Protein Binding Capacity and Daily Dosage of a Drug on Total Serum Bilirubin Levels in Susceptible Infants. Children (Basel, Switzerland), 10(6), 926. https://doi.org/10.3390/children10060926

Rosenthal, L.D., & Burchum, J. R. (2021). Lehne’s pharmacotherapeutics for Advanced Practice Nurses. (2nd ed.). St. Louis, MO: Elsevier.