Response to Unveiling the First-Pass Effect of Diazepam-Mechanisms and Strategies for Metabolism Circumvention

Responding to Randeep Kaur

Hello Randeep,

This is a great post. Indeed, the advanced age of the patient predisposes them to the side effects of diazepam and other CNS depressants. As Siddiqui et al. (2020) report, with old age, the side effects of CNS depressants become more profound. In the patient case presented, her balancing problems may be due to the CNS depression upon using diazepam. Your discussion on the impact the aging process has and the role it may have played, in this case, is also impeccable. The aging process results in a gradual reduction in physiological processes that may affect the pharmacokinetic and pharmacodynamic properties of some medications. With old age, metabolizing systems capacity begins to decline, further predisposing patients to drug toxicities.

Diazepam experiences a significant first-pass effect. The majority of drug inactivation is due to the first-pass effect occurring in the liver. The first-pass effect results in a considerable reduction in the drugs’ bioavailability and varies with medications. Drugs such as pentazocine, mercaptopurine, and others experience the first-pass effect of clinical significance, often necessitating circumvention measures. The use of alternative routes of administration, such as IV and IM, can help circumvent the first-pass effect.

As evident in your post, diphenhydramine, a first-generation antihistamine, predisposes individuals to sedation and, ultimately, confusion. However, phenylephrine has also been implicated in confusion cases and the older population. This is thought to be due to increased sensitivity towards the medication with aging. The two medications are thus the most likely culprits in the presenting health concern.

Warfarin is primarily metabolized by CYP2C9, as mentioned in your post. It also crosses the placental barriers readily and is FDA category D for all pregnant women due to its potential for teratogenicity (Conradie et al., 2019). Neonates maintain sensitivity towards many medications because of their low metabolizing capacity for xenobiotics. This is because their metabolizing enzymes have yet to develop fully. Over a year, the metabolizing systems are more mature, and the metabolizing capacity is increased, and in adulthood, the metabolizing enzymes are fully developed. The low neonatal protein binding results from low albumin due to high body water proportions.

References

Conradie, M., Henderson, B. D., & Van Wyk, C. (2019). Preventable warfarin-induced birth defects: A missed opportunity? South African Medical Journal, 109(6), 415. https://doi.org/10.7196/samj.2019.v109i6.13294

Siddiqui, T. G., Cheng, S., Gossop, M., Kristoffersen, E. S., Grambaite, R., & Lundqvist, C. (2020). Association between prescribed central nervous system depressant drugs, comorbidity, and cognition among hospitalized older patients: A cross-sectional study. BMJ Open, 10(7). https://doi.org/10.1136/bmjopen-2020-03843

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