Distribution, Metabolism, Drug Interactions, and the Effects of Aging , Obesity,
ID: 3510647 • Letter: D
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 #1
You are counseling a 50 year-old male patient who has been a heavy cigarette smoker on the use of nicotine replacement patches, which he tells you he is picking up to help him stop smoking. The patient’s other medications include clozapine 300 mg for schizophrenia, omeprazole 20 mg for GERD, lisinopril 10 mg for hypertension, atorvastatin 40 mg for hypercholesterolemia, all taken once daily.. The patient has been well-controlled on these medications for approximately two years with no dosage changes. Answer questions 1-5 regarding this case.
1. When the patient stops smoking and starts nicotine replacement, do you expect to see changes in the steady-state concentrations of any of the medications he is taking? If so, which one(s)?
2. For the drugs you listed in #1, what change in the Css would you expect to observe when he stops smoking?
3. What clinical implications would you expect this to change in Css to have?
(Be specific. If you expect a reduction in efficacy, state what symptoms you might look for, and if you expect toxicity, what adverse events will you monitor for?)
4. What is the mechanism of the interaction between smoking and medications such as those you mentioned in #1?
5. Why is the interaction in #4 absent with nicotine replacement products?
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?
Problem #4
Please describe 3 different processes through which a drug can exert pharmacokinetic non-linearity and give an example of a drug (different drug for each type) that exerts this type of non-linearity for each example (e.g., saturablemetabolism and phenytoin)
Absorption-related non-linearity – mechanism and example of a drug
Distribution-related non-linearity – mechanism and example of a drug
Metabolism-related non-linearity – mechanism and example of a drug
Problem #5
Please describe the influence of extremes of age, obesity, and a disease state of your choice on the following processes and give an example of a drug that may be affected by each. If none – state “no effect.”
5a. Influence of extremes of age (neonate vs. elderly)
Absorption –
Example of drug:
Distribution –
Example of drug:
Metabolism –
Example of drug:
Excretion –
Example of drug:
5b. Influence of obesity
Absorption –
Example of drug:
Distribution –
Example of drug:
Metabolism –
Example of drug:
Excretion –
Example of drug:
5c. Disease state of your choice (write in disease state) _________________________
Absorption –
Example of drug:
Distribution –
Example of drug:
Metabolism –
Example of drug:
Excretion –
Example of drug:
Problem #6
Explain the influence of aging on each of the following:
Drug metabolism through CYP3A4 (consider both gut and liver)
Glucuronidation
Sulfation
Acetylation
Explanation / Answer
Answer 1. yes, there will be change in steady concentration of clozapine.
Answer 2. Nicotine effectively reversed clozapine-induced memory impairment. Some studies demonstrate interactions between nicotine and antipsychotic drugs in terms of memory, which may have important impacts on the treatment of schizophrenia.
Answer 3. Clozapine will decrease memory performance to a smaller extent or not at all. In addition to that acute nicotine can reverse cognitive impairments caused by these antipsychotic medications when co-administered with them.
Answer4.
Clozapine, an atypical antipsychotic, binds to the D4 DA receptor subtype 10 times as strongly as it binds to D2 receptors.it shows a high affinity for 5-HT2 sites and a much lower affinity for D2 sites in the cerebral cortex and striatum. Clozapine affect multiple neurotransmitter systems and are not as specific as other DA antagonists, it is still important to understand the memory effects of this antipsychotic medications in their interaction with nicotine. Furthermore, the interaction of nicotine with DA antagonists is one that occurs frequently in certain human populations. Statistics indicate that almost 90% of schizophrenics smoke cigarettes. Thus, these individuals who are taking antipsychotic medications are co-administering nicotine as well. Through this study, we seek to gain a better understanding of the memory effects of these drug interactions.
Answer 5. there is no interaction between atorvastatin and nicotine as its mechanism of action is defferent. Atorvastatin works by blocking an enzyme that is used to make cholesterol in the liver. When that enzyme is blocked, less cholesterol is produced and the amount of cholesterol in the blood decreases.