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Welcome to Who Wants to be an APNA Millionaire! Drug-Drinks Interactions Drug-Drug Interactions Mary Gutierrez, PharmD, BCPP Clinical Professor of Pharmacy Practice (Psychiatry) Chapman University, School of Pharmacy Your patient drinks 2-3 cups of coffee a day. He was started on a SSRI a week ago. He now complains that he is very jittery and his blood pressure is high. Which of the following SSRIs can increase the concentration of caffeine by 4-5 fold? Citalopram Fluvoxamine Paroxetine Fluoxetine Fluvoxamine strong binding affinity significant 1A2 inhibition decrease metabolism by 80% (increase 4-5 fold) and increase half-life by 500% (from 5.7 hrs to 28.5 hours!) Ki (binding affinity) is 0.2 vs 4.4-16 for fluoxetine, norfluoxetine, paroxetine, sertaline and desmethylsertraline. The smaller the Ki number, the stronger the affinity. Excessive caffeine!! hypnotics for insomnia, antihypertensives for high blood pressure, beta-blockers for tachycardia?! Mary Gutierrez, PharmD, BCPP 1

Which of the following drinks has the highest concentrations of caffeine? One drink can have the same conc of 10 cups of coffee when taking together with fluvoxamine or other CYP1A2 inhibitors (e.g., ciprofloxacin)? A: 5 Hour Energy B: Monster Energy C: Starbucks Doubleshot D: Red Bull Which of the following antipsychotic agents can have increased concentrations and effects with consumption of excessive caffeine intake (>750 mg/day)? A: Clozapine B: Risperdal C: Quetiapine D: Lurasidone Mary Gutierrez, PharmD, BCPP 2

22% psychiatric inpatients vs. 9% of the general population consume > 750 mg caffeine a day. A 19-year-old woman on long-term clozapine therapy developed unexpected clozapine toxicosis. She had been drinking 6 caffeinated cola drinks per day. Stopping the cola intake was followed by a substantial reduction in clozapine concentrations. In a study of 7 patients on clozapine who drank caffeinated beverages, stopping caffeine for 5 days resulted in a 47% reduction in clozapine plasma concentrations. After resuming the caffeine intake, their clozapine concentrations return to the original levels. Patients on clozapine should avoid wide fluctuations in their caffeine intake. Clinicians should consider changes in caffeine intake in patients on clozapine who develop unexpected clozapine toxicosis or lack of clozapine response. (JR Horn and PD Hansten. Caffeine and Clozapine. ww.pharmacytimes.com/publications/issue/2013/july2013/caffeineand-clozapine) Your patient drinks 7-8 cups of coffee a day. He was advised to switched to decaf coffee because of his HTN. Which of the following mood stabilizers can have increased concentrations when your patient stopped drinking caffeinated beverages? A: Lithium B: Carbamazepine C: Valproic acid D: Lamotrigine Elimination of caffeine from the diet of lithiumtreated patients should be done cautiously, especially in patients with high baseline lithium blood levels Less caffeine would allow the use of lower doses of lithium to achieve the same blood since lithium is 100% renal eliminated, and affected by increased or decreased renal clearance Mester R at al. Caffeine Withdrawal Increases Lithium Blood Levels. Bio Psychiatry 1995;37: 348 50. Jefferson JW. Lithium tremor and caffeine intake: two cases of drinking less and shaking more. J Clin Psychiatry 1988; 49:72 3. Mary Gutierrez, PharmD, BCPP 3

Which of the following antidepressants can have a pharmacodynamic interaction (additive effects on blood pressure and heart rate ) with caffeinated drinks or products? A: Citalopram B: Levomilnacipran C: Vortioxetine D: Escitalopram Levomilnacipran is a serotonin and norepinephrine reuptake inhibitor (SNRI) for the treatment of major depressive disorder. This SNRI differs from previously SNRIs in having twice the potency for NE versus 5-HT reuptake inhibition. Common adverse events occurring twice as often as on placebo include tachycardia and palpitations. Similar to other SNRIs, it warrants monitoring of blood pressure and should be used with caution in individuals with pre-existing hypertension. Mago R et al. Levomilnacipran: a newly approved drug for treatment of major depressive disorder. Expert Rev Clin Pharmacol 2014; 7:137-45. Levomilnacipran (Fetzima ) National Drug Monograph 2014. VA Pharmacy Benefits Management Services, Medical Advisory Panel, and VISN Pharmacist Executives. CONGRATULATIONS! You ve Reached the $1,000 Milestone! Mary Gutierrez, PharmD, BCPP 4

Grapefruit juice can increase the concentrations and toxicity risks for which of the following mood stabilizers? A: Lithium B: Carbamazepine C: Valproic acid D: Lamotrigine Lithium 100% renally eliminated, no hepatic metabolism Carbamazepine (Tegretol) metabolized by CYP3A4 Lamotrigine (Lamictal) metabolized by glucuronic acid conjugation, no CYP450 enzyme metabolism Valproic acid (Depakote) metabolized by non CYP3A4 oxidative pathways (mitochondrial beta-oxidation) and glucuronidation. Which of the following neuropsychiatric agents can be increased with concurrent use of valproic acid (Depakote)? A: Diazepam B: Lamotrigine C: Phenytoin D: All of the above Mary Gutierrez, PharmD, BCPP 5

Valproic acid (Depakote) Can increase the concentrations of diazepam, lamotrigine, phenytoin, phenobarbital, warfarin MOA: valproic acid may cause enzyme inhibition of CYP2C9, glucuronidation, and protein binding displacement (increase the unbound drug of concurrently used drug increased pharmacologic actions and side effects) Caution with concurrent use of valproic acid and lamotrigine. Can increase lamotrigine concentrations by 2-fold. NMT 100-200 mg/day with lower initial dose and increments. Your patient is on atorvastatin (Lipitor) and quetiapine (Seroquel). He asked you if he can drink his grapefruit juice in the morning and medications at night to avoid the drug interaction? Your answer is A: Yes B: No C: Maybe D: I don t know Half-life of grapefruit juice is about 12 hours. Wash out period may take 3 days Mary Gutierrez, PharmD, BCPP 6

Which of the following anxiolytic and hypnotic agents have the most significant interactions (increase concentrations by > 9-fold) with grapefruit juice? A: Alprazolam B: Buspirone C: Zolpidem D: Survorexant All are metabolized by CYP3A4 enzymes, but some have more intestinal 3A4 metabolism than others 99% of buspirone (Buspar) metabolism is via intestinal 3A4 metabolism plasma concentrations can be increased by 9.2 fold! Alprazolam (Xanax) has hepatic CYP3A4 metabolism, with significantly less intestinal 3A4 metabolism increase is not significant with GFJ Zolpidem (Ambien) use lower dose or avoid GFJ Suvorexant (Belsomra) dose is recommended at 5 mg, NMT 10 mg is needed. Usual dose is 10-20 mg/night Which of the following antipsychotic agents is metabolized by CYP3A4 and can have interactions with grapefruit juice? A: Risperidone B: Lurasidone C: Asenapine D: Olanzapine Mary Gutierrez, PharmD, BCPP 7

Second generation antipsychotic agents metabolism: Clozapine (Clozaril) 1A2 Olanzapine (Zyprexa) 1A2 Asenapine (Saphris) 1A2 Risperidone (Risperdal) 2D6 Paliperidone (Invega) 2D6 Aripripazole (Abilify) 2D6 and 3A4 Iloperidone (Fanapt) 2D6 and 3A4 Quetiapine (Seroquel) 3A4 Ziprasidone (Geodon) 1/3 via 3A4 Lurasidone (Latuda) 3A4 CONGRATULATIONS! You ve Reached the $32,000 Milestone! Which of the following antipsychotic agents is metabolized by CYP1A2, but has CYP2D6 inhibitory property which can increase paroxetine by 2-fold? A: Clozapine B: Olanzapine C: Asenapine D: All of the above Mary Gutierrez, PharmD, BCPP 8

Clozapine (Clozaril) 1A2 Olanzapine (Zyprexa) 1A2 Asenapine (Saphris) SL 1A2, 2D6 inhibitor -> increase conc of paroxetine and other 2D6 drugs Which of the following drinks can decrease the concentrations of psychostimulants? A: Emergen C B: Red Bull C: Grapefruit juice D: Coffee Most drugs are either weak acids or weak bases. Psychostimulants (e.g., Ritalin, Adderall) are chemically weak bases. Acidifying the urine with vitamin C (ascorbic acid) > 2 gm can increase excretion of the weak bases -> decrease concentrations of the psychostimulants Mary Gutierrez, PharmD, BCPP 9

Which of the following OTC drinks can increase the concentrations of psychostimulants? A: Emergen C B: Nyquil C: Alka Seltzer D:None of the above Alka Seltzer has Sodium Bicarbonate (1916 mg) Psychostimulants (e.g., Ritalin, Adderall) are chemically weak bases. Increased ph of the urine with sodium bicarbonate can decrease the excretion of the weak bases -> increase concentrations of the psychostimulants Alka Seltzer has a formulation with aspirin. Which of the following mood stabilizer is highly protein bound, and aspirin can cause more free unbound concentrations? A: Tegretol B: Depakote C: Trileptal D: Lithium Mary Gutierrez, PharmD, BCPP 10

Aspirin is known to displace a number of drugs from protein binding sites including warfarin (99%) and valproic acid (95% BP) Aspirin itself is not highly protein bound, but it changes the structure of the serum albumin > less binding protein > more unbound drug > increased effects Patients with chronic alcohol use -> CYP450 2E1 enzyme induction -> Increased production of hepatotoxic metabolite NAPQI from acetaminophen. Patients should be advised to use NMT mg/day of acetaminophen.?would this apply to patients on CBZ? A: 1,000 B: 2,000 C: 3,000 D: 4,000 YOU HAVE WON $1 MILLION DOLLARS IN DRUG INTERACTIONS IQ! Mary Gutierrez, PharmD, BCPP 11