Question

Distribution, Metabolism, Drug Interactions, and the Effects of Aging, Obesity, and Disease

Before beginning this PBL, please review the following references:

https://www.ncbi.nlm.nih.gov/books/NBK100662/

Goodman & Gilman's The Pharmacological Basis of Therapeutics, Chapter 16. Pharmacotherapy of Psychosis and Mania, Jonathan M. Meyer - Available via Access Pharmacy

Goodman & Gilman's The Pharmacological Basis of Therapeutics, Chapter 18. Opioids, Analgesia, and Pain Management, Tony L. Yaksh; Mark S. Wallace - Available via Access Pharmacy

Shargel & Yu: Applied Biopharmaceutics and Pharmacokinetics – 7th Edition – Chapter 23: Application of Pharmacokinetics to Specific Populations: Geriatric, Obese, and Pediatric Patients - Available via Access Pharmacy

Case #2

A 30 year old female patient comes to your retail pharmacy to pick up a prescription for Tylenol #3 (acetaminophen + codeine) for pain control. You enter the prescription into the computer system and the computer’s interaction checker flags an interaction between Tylenol #3 and the patient’s fluoxetine prescription. Answer questions 1-3 regarding this case.

1. Fill in the blanks: Codeine is a prodrug that is metabolized to its active form,____________________,   by the enzyme ____________________________.   

Given this, what is the mechanism responsible for the drug interaction between

fluoxetine and codeine?

2. Is this interaction likely to be of clinical significance? Should you bypass the interaction or call the physician?

3. What would you expect to see if you give codeine to: a) a poor metabolizer for the enzyme mentioned in #1 and b) an ultra-rapid metabolizer of the enzyme mentioned in #1.

Case #3

C.G., A 29 year-old female (yof) patient, presents for inpatient care. You are working as a staff pharmacist in the hospital pharmacy and are asked to verify/fill her prescriptions. Her current medications are for rifampin, nifedipine, amitriptyline, and fluoxetine, valproate sodium, and lamotrigine. Please identify at least three potential biotransformation-related drug interactions in the scenario above and describe the potential mechanism for the interaction. Describe the expected effect (i.e., increased/decreased parent drug concentration, increased/decreased metabolite concentration).

Interaction #1 & effect on plasma concentrations –

Interaction #2 & effect on plasma concentrations –

Interaction #3 & effect on plasma concentrations -

A week later, C.G. is still in the hospital. She is very hypertensive and the physician elects to start IV propranolol 2 mg. Is this an appropriate dose of propranolol for hypertension management when the patient goes home? If not, why not?

In addition to her hypertension, C.G. developed an arrhythmia. The physician ordered lidocaine to be given IV. Initially, this drug produced a therapeutic plasma concentration (Css total of 4 mg/L). This drug has a high extraction ratio and is highly bound to alpha-1-acid glycoprotein. A few days after starting the drug, the total plasma concentration remained the same, but the free drug concentration was found to be increased.

What is a potential explanation for this change in free drug concentration?

Why would total concentration stay the same? What factors would alter the total drug concentration (Css) of lidocaine?

Answer 1

#Case 2 -

1.the prodrug codeine is metabolised to its active form MORPHINE by liver enzyme CYP2D6.

Fluoxetine is a potent inhibitor of CYP2D6 which means it can inhibit the elimination and cause accumulation of medications(in this case codeine metabolised by CYP2D6).Fluoxetine prevents the conversion of codeine to morphine and thereby eliminating the benefits of pain reduction by codeine.

2.Yes definitely the interaction is of clinical significance,as the pain medication would be in effective and also resulting in accumulation of codeine in the patient. A call to the physician would definitely be advised.