Description
Q1. Explain the cause of this patient’s difficulty in maintaining her balance?
Q2. Diazepam experiences a significant first-pass effect. What is the first-pass effect, and how can first-pass metabolism be circumvented?
Diazepam is an example of benzodiazepine. Benzodiazepine, one of the major groups of the sedative-hypnotics, is considered as first choice drug for anxiety and insomnia (Rosenthal and Burchum, 2021). Benzodiazepines are generally well-tolerated with rare severe side effects. However, like with most drugs, there are still adverse reactions. Benzodiazepine, when used to help with sleep can cause drowsiness, confusion, lightheadedness, instability and incoordination, and difficulty concentrating (Parrish, 2021). With the case of the 70 year old woman, she is experiencing the side effect of valium. These side effects can cause problems for anyone but can be more dangerous for the elderly population. Thus, nurse practitioners should take extreme caution when prescribing this drug to the elderly. Long term use for benzodiazepines is not usually indicated however, it may be allowed for intermittent use (Parrish, 2021). The American Geriatrics Association does not recommend the use of benzodiazepines as first choice treatment for insomnia and agitation in older adults. (Robertson et al, 2023).
Diazepam First Pass Effect
Orally taken drugs are absorbed from the gastrointestinal tract and are carried directly to the liver for metabolism. This is referred to as the first pass effect. In the case of diazepam, the liver can metabolize it by demethylation and hydroxylation into a pharmacologically active metabolite known as N-desmethyldiazepam (Khalid et al, 2021). To circumvent the first pass effect in the liver, parenteral administration of medications should be chosen over the oral route. Diazepam can be administered via intravenous, intramuscular, intranasal or rectal routes. (Khalid et al, 2021).
Q3. What is likely causing the signs of confusion?
Diphenhydramine, a first generation anti-histamine, acts as an inverse agonist at the H1 receptor. This results in the reversal of the effects of histamine on capillaries, reducing allergic reaction symptoms (Sicarri and Zabbo, 2023). Diphenhydramine can cross the blood brain barrier and antagonize the H1 CNS receptors leading to drowsiness (Bolser, 2008). The AGS Beers category of medications to avoid for older adults include first generation antihistamines like diphenhydramine, since these often cause sedation and cognitive impairment (AGS 2015). Older adults will also experience significantly slower diphenhydramine clearance from the body that can lead to confusion, which in turn can worsen delirium and increase the risk for falls (Zhou et al, 2018).
Q4. How is warfarin metabolized? Does warfarin cross the placental barrier?
Warfarin, a vitamin K antagonist is an oral anticoagulant, that is often used in prevention of thromboembolic complications associated with conditions like atrial fibrillation, or cardiac valve replacement. Warfarin is a racemic mixture of 50% R-warfarin and 50% S-warfarin (Dasgupta and Wahed, 2021). Warfarin is metabolized by the cytochrome P450 system by CYP 2C9, 1A2, and 3A4. (Crader et al, 2023). R-warfarin is metabolized by CYP 1A2 to 6- and 8-hydroxywarfarin, by CYP 3A4 to 10-hydroxywarfarin, and by carbonyl reductase to diastereoisomeric alcohols, while S-warfarin is metabolized by CYP 2C9 to 7-hydroxywarfarin (Hemmings and Egan, 2013). Warfarin can cross the placental barrier, which can have teratogenic effects on the fetus if taken during early stages of pregnancy (Nadeem et al, 2021). It can also lead to an increased risk of spontaneous abortions and stillbirth, and serious bleeding at the time of delivery (Crader, 2023).
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?
Pediatric patients have different responses to drugs compared to adults. Neonates and infants do not have fully developed organ systems that are responsible for regulating drug levels, thus, they are at high risk for prolonged or intense drug effects (Rosenthal and Burchum, 2021). Hepatic metabolism of drugs by the neonates is low with both Phase I and II metabolic processes immature at birth, which may lead to increased risk of drug toxicity in neonates and infants (Lu and Rosenbaum, 2014). Neonates have a distinct hepatic drug metabolism activity compared to adults because of the differences in P450 expression during development (Piekos et al, 2017). The liver’s ability to metabolize drugs increases rapidly 1 month after birth and can potentially reach adult levels after several months (Rosenthal and Burchum, 2021). At 1 year, children will have similar pharmacokinetic parameters as that of adults since the liver has completely matured by that age (Rosenthal and Burchum, 2021).
Q6. Explain protein binding in the neonate.
Protein binding is very important in the pharmacokinetics and distribution of a drug since only the unbound drug is pharmacologically active. In neonates and infants, there is limited binding of drugs to albumin and other plasma proteins because of relatively low levels of serum albumin and the presence of other endogenous compounds that compete with the drugs for available binding sites (Rosenthal and Burchum, 2021). Because of this, the volume of distribution, Vd increases with decreased protein binding, resulting in a higher free fraction of available drug that can cause exaggerated therapeutic or adverse effects (Bansal et al, 2023). Unbound form of the drug, however has a higher clearance rate and is excreted more quickly.
References:
American Geriatrics Society 2015 Beers Criteria Update Expert Panel (2015). American Geriatrics Society 2015 Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. Journal of the American Geriatrics Society, 63(11), 2227–2246. https://doi.org/10.1111/jgs.13702
Bansal, N., Momin, S., Bansal, R., Gurram Venkata, S., Ruser, L., Yusuf, K. (2023). Pharmacokinetics of drugs: newborn perspective. Pediatric Medicine. https://dx.doi.org/10.21037/pm-22-11
Bolser D. C. (2008). Older-generation antihistamines and cough due to upper airway cough syndrome (UACS): efficacy and mechanism. Lung, 186 Suppl 1(Suppl 1), S74–S77. https://doi.org/10.1007/s00408-007-9033-y
Crader, M., Johns, T., Arnold, J. (2023). Warfarin Drug Interactions. Stat Pearls. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK441964/
Dasgupta, A., Wahed, A. (2021). Clinical Chemistry, Immunology and Laboratory Quality Control. Elsevier, Inc.
Hemmings, H., Egan, T. (2013). Pharmacology and Physiology for Anesthesia. Elsevier, Inc.
Khalid, S., Rasool, M. F., Imran, I., Majeed, A., Saeed, H., Rehman, A. U., Ashraf, W., Ahmad, T., Bin Jardan, Y. A., & Alqahtani, F. (2021). A Physiologically Based Pharmacokinetic Model for Predicting Diazepam Pharmacokinetics after Intravenous, Oral, Intranasal, and Rectal Applications. Pharmaceutics, 13(9), 1480. https://doi.org/10.3390/pharmaceutics13091480
Lu, H., & Rosenbaum, S. (2014). Developmental pharmacokinetics in pediatric populations. The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG, 19(4), 262–276. https://doi.org/10.5863/1551-6776-19.4.262
Parrish, E. The ongoing conundrum of long‐term benzodiazepine use: What our patients need to know. (2021). Perspectives in Psychiatric Care, 57(3), 979. https://doi-org.usu.idm.oclc.org/10.1111/ppc.12916
Piekos, S., Pope, C., Ferrara, A., & Zhong, X. B. (2017). Impact of Drug Treatment at Neonatal Ages on Variability of Drug Metabolism and Drug-drug Interactions in Adult Life. Current pharmacology reports, 3(1), 1–9. https://doi.org/10.1007/s40495-016-0078-6
Robertson, S., Peacock, E. E., & Scott, R. (2023). Benzodiazepine Use Disorder: Common Questions and Answers. American Family Physician, 108(3), 260. https://usu.idm.oclc.org/login?url=https://www.pro…
Rosenthal, L. D., & Burchum, J. R (2021). Lehne’s pharmacotherapeutics for advanced practice
and physician assistants. Elsevier, Inc.
Zhou, A., Holmes, H. M., Hurria, A., & Wildes, T. M. (2018). An Analysis of the Inclusion of Medications Considered Potentially Inappropriate in Older Adults in Chemotherapy Templates for Hematologic Malignancies: One Recommendation for All?. Drugs & aging, 35(5), 459–465. https://doi.org/10.1007/s40266-018-0538-2
