Applied PK: Psychiatry

1. For lithium, therapeutic drug monitoring (TDM) is a standard of care. What are the therapeutic levels for lithium? Give 2 reasons why TDM is important for lithium.
   
   

• Lithium has a narrow therapeutic index which would require TDM as to prevent lithium toxicity from occuring in the patient. 

• Patients' pharmacokinetics can also vary based on renal function, age, and concurrent medications which can alter the concentrations of lithium in the body. 

• Therapeutic level for lithium: 0.6-1.2 mEq/L

  • lithium levels above 1.5 would cause toxicity

  • when the lithium levels are below 0.6, it may not work as a mood stabilizer

2. Complete washout of lithium will take about 5 days after discontinuation. Lithium’s T½ = 24 hours with people with good renal function.

• Have to monitor renal function → CrCl <30 mL/min is unsafe to use
  
  

3. Patient is on lithium carbonate 300 mg 2 capsules PO BID. She took her morning dose of lithium at 7 am and had her lithium levels drawn at 9 am. Lithium levels were reported to be high at 1.8 mEq/L. Patient has no symptoms of lithium toxicity. Explain why.
   The patient takes a morning dose of lithium at 7am, so since her lithium levels were drawn only 2 hours after the administration of lithium carbonate, the lithium levels appeared to be high. Her lithium levels should be taken later in the day to get a more accurate assessment of her lithium levels.

1-2 hours are usually the peak level of lithium (false elevated peak level), so the lithium levels should be drawn 12 hours after the last dose (has to be taken at a trough level)

4. Patient has a steady lithium level of 1.2 mEq/L (labs from 2 weeks ago). He is in the Urgent Care clinic today c/o severe N/V/D. He is observed to be confused and has a coarse hand tremor. He had a dental procedure three days ago and was given ibuprofen 800 mg PO TID PRN pain. What would you recommend for this patient?

• NSAID would increase the level of lithium if taken both at the same time (levels can fluctuate)

• Advise the pt to take tylenol (APAP) or ASA  

• Sulindac is the only one that doesn't have an effect on the renal prostaglandins
  
  

5. Which antidepressant has the longest half-life (7-16 days considering its active metabolite)? Explain why this antidepressant can continue to have potential drug-drug interactions even after its discontinuation for weeks.

• The antidepressant in question is fluoxetine (Prozac) (only 1-3 days). Its active metabolite is norfluoxetine (can last 7-16 days). 

• Because norfluoxetine's half-life is long, it takes a long time for the drug to be cleared from the body.
  
  

6. Which four antidepressants can inhibit CYP2D6 enzymes? Explain the clinical issue for using these antidepressants in patients on tamoxifen for the treatment of breast cancer.
   
   

   1. Fluoxetine (Prozac), Paroxetine (Paxil), Bupropion (Wellbutrin), Duloxetine (Cymbalta)

   2. Using these antidepressants can cause an interaction that can increase breast cancer treatment failure and recurrence.

      1. Tamoxifen needs CYP2D6 enzyme to metabolize into its active form, since it’s a prodrug.

      2. If you take these CYP2D6 inhibitors, it’s going to prevent Tamoxifen from producing its active form.

7. A patient was doing well on fluoxetine 40 mg PO QAM for 3 years. He recently was given tramadol (Ultram®) for pain with inadequate efficacy. What are the potential PK and PD drug interactions in this case?

• Fluoxetine is a CYP2D6 inhibitor. Tramadol (prodrug) is primarily metabolized by CYP2D6 into its active metabolite. This will increase the levels of tramadol in the patient’s system but because it was not properly converted into its active metabolite, there are no analgesic effects. 

• Both fluoxetine and tramadol can increase serotonin in the body, which can put the patient at risk for serotonin syndrome. 

  • Other opioids w/ same potential DDIs with CYP2D6 enzyme (e.g. fluoxetine)

    • Codeine

    • Hydrocodone

    • Hydromorphone

    • Tramadol

    • Tamoxifen

8. Up to 10% of people with European descent are poor CYP2D6 metabolizers. What is the clinical efficacy for a patient on therapeutic doses of fluoxetine and codeine for CYP2D6 poor metabolizers?

The clinical effect would be higher than normal. Codeine (prodrug) cannot be converted to morphine.     

8. Celexa (citalopram) max daily dose has been reduced from 60 mg/day to 40 mg/day to decrease the risk of dose-dependent QT prolongation. The max dose is 20 mg/day for patients with hepatic impairment, > 60 yo, and those who are CYP2C19 poor metabolizers. Which OTC H2RA and PPI medications are associated with the highest risk of increasing the concentrations of Celexa (citalopram)? Do these OTC GERD medications have the same effect on Lexapro (escitalopram)?
   The OTC H2RA would be cimetidine (Tagamet) and the PPIs would be omeprazole (Prilosec) and esomeprazole (Nexium) (a bit 🤏) . → will increase both celexa and lexapro so you do not want to take them together

• Yes these medications would have the same effect on escitalopram (Lexapro) (these CYP2C19 inhibitors will increase Lexapro) as it is also metabolized by CYP2C19. 

• Celexa + lexapro 🙅
  
  

9. A patient on metoprolol 100 mg PO daily had good control of her BP and HR for 2 years. She complained of dizziness with low BP and HR since she started a SSRI antidepressant. List the 2 SSRIs that are potent CYP2D6 inhibitors. Explain the MOA for this DDI.

• Metoprolol is metabolized by CYP2D6

  • Diphenhydramine: CYP2D6 inhibitor (Avoid taking both at the same time)

• fluoxetine and paroxetine are potent CYP2D6 inhibitors and drug toxicities may occur as they can increase the levels of metoprolol in the patient leading to excessive pharmacological effects of metoprolol including the patient’s complaints of dizziness and low BP and HR

  • → This potential interaction could also increase the risk of breast-cancer treatment failure and recurrence
    
    
    

10. A patient on Cymbalta 60 mg/day is complaining of reemerging symptoms of depression and anxiety. He is not taking any OTC or other prescription medications. What needs to be ruled out for this patient? 

• Smoking must be ruled out because it reduces the effect of Cymbalta as smoking induces CYP1A2.

  • 60 mg Cymbalta = 30 mg Cymbalta (smoker): Max dose 120 mg

• increase the dose of cymbalta if they smoke
  
  
  

11. Name the psychiatric medications that are affected by smoking. Explain MOA of the smoke-drug interactions.

Duloxetine(Cymbalta) , clozapine(Clozaril), and olanzapine(Zyprexa). Smoking induces CYP1A2 which is used to metabolize these drugs. Since the enzyme is induced the drugs are metabolized faster resulting in lower bioavailability. 

• The concentration of these drugs would decrease

• Clozapine → you need to get a blood test every week 

• If you take away the inducer (smoking cessation), the concentrations in the body would be too high 

• Caffeine is 1A2 substrate (acts same as smoking)
  
  
  

12. AG is a 23-year-old male stabilized on Risperdal (risperidone) 2 mg PO BID with no ADRs. He was switched from Lexapro (escitalopram) 20 mg/day to Prozac (fluoxetine) 20 mg/day a month ago. He was admitted to the ED with a severe dystonic reaction. What is the DDI mechanism and what would you recommend for management of the dystonic reaction?
    
    

• The mechanism of the DDI is that fluoxetine (Prozac) is a CYP2D6 inhibitor which would inhibit the metabolism of risperidone (Risperdal) into its active metabolite 9-hydroxyrisperidone (Paliperidone). The increased concentration of risperidone (Risperdal) can lead to an increase in the dopamine receptor blockade causing dystonia. 

• To manage the dystonic reaction I would recommend tapering the fluoxetine (Prozac) and changing it to another antidepressant such as sertraline (Zoloft). Immediately use an anticholinergic agent such as diphenhydramine to block the excess dopamine activity. 

• Prozac & paxil inhibit CYP2D6

• Give Benztropine (Cogentin) (anticholinergic) → TO DIMINISH dystonic reactions
  
  

13. A patient on Xanax 1 mg PO BID PRN anxiety and oral contraceptives for 6 months. She started OTC St. John’s wort a month ago for her depression. What are the potential PK DDIs in this case?

• St John’s Wort is a CYP3A4 inducer that can decrease/diminish concentrations of Xanax (Alprazolam). 

  • Benzo that aren’t CYP metabolized (LOT): Lorazepam(Ativan), Oxazepam(Serax), Temazepam(Restoril)

14. Grapefruit juice can increase the concentrations of which benzodiazepines when administered via PO route?

• Grapefruit juice inhibit CYP3A4 enzyme

  • LOT are unaffected by grapefruit juice since they do not go through CYP 3A4 enzyme at all (Lorazepam, Oxazepam, Temazepam)

15. Diazepam and phenobarbital tapering are often used for alcohol use disorder. Patients are tested positive for these drugs in their outpatient urine test days to weeks later. How long can diazepam and its active metabolite (n-desmethyldiazepam) remain in the system after it has been discontinued? What is the half-life of phenobarbital?

• Diazepam has a half life of 1-3 days while n-desmethyldiazepam has a half life of 2-7 days (20-100 hours). Phenobarbital has a half life of 2-5 days. 

• Barbiturates half life = 100 hours → being washed out in 21 days (~ 3 weeks) 

• Diazepam METABOLITE has half life of 20-100 hours
  
  

16. A patient has a new prescription for lamotrigine 25 mg PO daily. She is also picking up a refill for Depakote 500 mg PO BID. Any potential issue in this case?

• Depakote may increase the concentration of lamotrigine. 

• Depakote is a UGT inhibitor (Phase II metabolism = glucuronidation) 

  • If you inhibit UGT by depakote → lamotrigine can increase by 2 times
    
    
    

17. What is the potential DDI between estrogen replacement therapy and lamotrigine (Lamictal)?

• Estrogen replacement therapy may decrease the concentration of lamotrigine. 

• Estrogen is a UGT inducer 

  • so when you use lamotrigine, the levels go WAY down
    
    
    

18. Which SSRI can increase the concentration of caffeine by 4-5-fold? DDI MOA?
    

• Fluvoxamine (Luvox) 

• DDI MOA: inhibition CYP1A2

  • can also inhibit CYP3A4, CYP2C9, and CYP2C19 → NOT 2D6

• Caffeine is a 1A2 substrate so the concentration of caffeine would increase with Fluvoxamine (Luvox) 

19. What is the potential effect of carbamazepine on the PK of oral contraceptives?
    CBZ is an inducer of CYP3A4, and oral contraceptives are metabolized of CYP3A4

• CBZ would induce the metabolism of oral contraceptives, leading to a reduced efficacy of oral contraceptives (subtherapeutic)

20. What is the potential effect of carbamazepine on the PK of acetaminophen?
    
    

CBZ →  INCREASED 2E1 activity →  NAPQI TOXIC METABOLIC

• CBZ can induce most of the enzymes (ex: increase CYP 2E1) → can increase levels of NAPQI (a metabolite that is toxic to the liver) 

21. Low dose quetiapine (Seroquel) 100 mg is often used PRN off-label for insomnia. Would you recommend Seroquel or Seroquel XR?

• For inducing sleep → you want a higher peak (Use Quetiapine IR) 

  • Instead of increasing dose, you change the formulation to get a higher peak which will induce sleep 

• quetiapine XR may not be as effective b/c it doesn’t reach that high of a peak
  
  
  

22. Why are MAOIs contraindicated with all antidepressants? What are the 2 potential DDIs?
    Nardil (phenelzine), Parnate (tranylcypromine), Marplan (isocarboxazid), Emsam (selegiline) are rarely used for depression. 

    1. Decreases degradation of monoamines (5HT, DA, NE)

       1. MAOI+SSRI (or any antidepressant) → risk of 5HT syndrome or hypertensive crisis 

• high risk of serotonin syndrome and hypertensive crisis 

• DDI: MAOIs inhibit MAO which can lead to an increase of serotonin levels in the brain. 

• DDI: MAOIs breaks down tyramine which can lead to an increase of BP when combined with antidepressants that increase release or inhibit the reuptake of norepinephrine
  
  
  
  

23. Name 2 antidepressants that have increased absorption when taken with food. Which one should always be taken with food?

    1. Sertraline (Zoloft) → increase absorption by 40%

       1. Has GI distress so also better to take with food

    2. Vilazodone (Viibryd) → increases absorption by 50%

       1. Always take with food!  🥑 🥒 🥕 🥦 🫛 🍅

24. Name 2 antipsychotics that have increased absorption when taken with food.

    1. Ziprasidone (Geodon)

    2. Lurasidone (Latuda) 

25. What is the potential effect on Depakote with higher GI pH from antacid or PPI use?

• Depakote is enteric coated which can be degraded in environments of higher GI pH. High GI pH can be induced through antacid or PPI use.
  
  

26. Abilify’s (aripiprazole) half-life can be doubled from 75 hours to 150 hours for poor metabolizers of CYP2D6. Recommendation is to use ½ of the daily doses. Up to 10% of which ethnic group are CYP2D6 poor metabolizers?

• European descent     🇪🇺

• (not contraindicated, you can still use it)
  
  

27. Which benzodiazepines do not need Phase I metabolism and are better choices for patients with hepatic impairment?

• LOT 

  • Lorazepam (Ativan) 

  • Oxazepam (Serax) 

  • Temazepam (Restoril)
    
    
    

28. Explain why a psychostimulant’s absorption and elimination are reduced when taken concurrently with high doses of vitamin C (> 2,000 mg/day). ⚠ ⏰ 🎉 🚨
    
    

• Dr G: “You NEED to know this” 

• Diminish the effect of the psychostimulant if taken with Vitamin C → acidify the urine and eliminate the psychostimulant faster 

• they should be COMPLETELY separated!!!!!!!!!! 🍊
  
  

29. Explain in PK terms why Vyvanse (lisdexamfetamine) is the least abused (via nasal snorting or IV routes) among the psychostimulants.
    
    

• Vyvanse is a prodrug and needs to undergo GI metabolism in order to gain the active drug d-Amphetamine
  
  

30. A patient is on Saphris (asenapine) 10 mg PO BID and is not doing well on the antipsychotic agent. Explain in PK terms why this route of administration can decrease absorption and efficacy of Saphris.

• PO administration results in less concentration of the drug. It is needed to be administered sublingually (SL) 

31. A 30-year-old Caucasian female was initiated on Paxil 10 mg with intolerable side effects. There are no other medications that she is taking. Explain in PK terms why she is sensitive to this SSRI?
    
    

• poor metabolizer of 2D6 and rapid metabolizer of 2C19⇒ 🇪🇺 european
  
  

32. The same patient was switched to Lexapro and titrated to 30 mg/day (which is above the recommended max dose of 20 mg/day) with no therapeutic effects. Explain, in PK terms, why she is not responding to the higher than usual daily dose of Lexapro. 

    1. 2D6 poor metabolizer for Paxil → metabolize Lexapro fast (2C19) 

    2. 2D6 → pOO(p)R  METABOLIZER

    3. 2C19 → Rap(oop)id metabolizer
       
       
       

33. Your patient on Propranolol LA 60 mg for HTN and tachycardia and Prozac 20 mg/day for depression was switched to Lexapro 10 mg/day. Any potential issue in this case?
    
    

• Fluoxetine (Prozac) is an inhibitor meaning that when therapy is stopped levels of beta-blockers such as propranolol goes down (dose is too low)
  
  

• bupropion (Wellbutrin), paroxetine (Paxil), fluoxetine  (Prozac), duloxetine (Cymbalta) are also inhibitors of CYP2D6