Drug Interactions: Things that go BOOM! Who remembers Terfenadine? Once daily non-sedating anti-histamine Amelie Hollier, DNP, FNP-BC, FAANP Advanced Practice Education Associates A strange thing happened ketoconazole erythromycin What is the CYP 450 system? System of enzymes in liver that metabolizes drugs What does the CYP 450 system do? Responsible for metabolism of many drugs (i.e. acetaminophen) Why learn about the CYP 450 system? Learning more about it helps us predict drug interactions! Metabolism of ingested substances (i.e. alcohol) 1
A System of Enzymes? 6 enzymes account for metabolism of nearly ALL clinically important drugs Meet the Enzymes 2 are critically important for drug metabolism If you didn t have enzymes... You couldn t metabolize... Antihistamines (fexofenadine, loratadine) Antibiotics (clarithromycin, erythromycin) You couldn t metabolize... Lipid lowering drugs (simvastatin, atorvastatin) Most CCBs (nifedipine, others) Protease Inhibitors Anti-fungals MANY others! CYP Metabolizes about 50% of all clinically useful medications Most abundant and clinically significant Actually composed of 4 enzymes: 3A3,, 3A5, 3A7 2
Understanding the Names CYP CYP: part of the cytochrome P450 system 3: indicates the family A: indicates the subfamily 4: fourth enzyme in that subfamily Meet the next Enzyme If you didn t have enzymes... You couldn t metabolize... SSRIs (paroxetine, fluoxetine) Pain relievers (codeine) Beta Blockers (metoprolol) Others CYP Metabolizes about 30% of all clinically useful medications Second most abundant Best of the Rest Meet the Enzymes Responsible for conversion of codeine to morphine 3
If you didn t have enzymes... You couldn t metabolize... Proton Pump Inhibitors (omeprazole, rabeprazole) NSAID (indomethacin) Beta Blockers (propanolol) About 10-15% of drugs in current use Clopidogrel & Enzymes Genetic variations in reduce conversion of clopidogrel to its active metabolite Clopidogrel & Enzymes What Effect? Higher risk for cardiovascular events Clopidogrel & Enzymes BLACKBOX WARNING Clopidogrel labeling has a blackbox warning because of this! Clopidogrel & Enzymes FYI Over 50% of Asians have genetic variations that reduce clopidogrel metabolism 4
Clopidogrel & Enzymes Can you test for this? Commercially available tests Usually < $500 Clopidogrel & Enzymes Clinical Options: Double dose of clopidogrel SWITCH to prasugrel (metabolized by and 2B6 enzymes) Change to another agent Best of the Rest Meet the next Enzyme If you didn t have 2C9 enzymes... 2C9 You couldn t metabolize... Sulfonylureas (glimepiride, glipizide) NSAIDs (celecoxib, naproxen, piroxicam) S-warfarin Sildenafil 2C9 Warfarin & 2C9 Enzymes Genetic variations in 2C9 are more sensitive to anticoag effects 2C9 5
Warfarin & 2C9 Enzymes Warfarin labeling NOW gives guidance on how to dose warfarin based on these genotypes Fewer hospitalizations 2C9 Warfarin & 2C9 Enzymes Not cost-effective to check everyone prior to initiating warfarin Cost is several $hundred 2C9 Best of the Rest Meet the next Enzyme If you didn t have enzymes... AM Caff eine You couldn t metabolize... Acetaminophen! R-warfarin Variety of others (Caffeine, tamoxifen, theophylline, verapamil, cyclobenzaprine) Best of the Rest Meet the last Enzyme 6
If you didn t have 2E1 enzymes... 2E1 You couldn t metabolize... Acetaminophen! 2E1 Variety of others: Ethanol, inactivation of toxins, DM, venlafaxine 2E1 CYP 2E1 Metabolizes a small fraction of drugs Significant role in activation and inactivation of toxins Possible use in prevention of hepatic damage with hepatotoxic drugs Actually... There are over 30 isoenzymes in this enzyme system The most important ones identified in human systems are: CYP CYP CYP 2C9 CYP 2E1 CYP CYP Where is it? Located on the endoplasmic reticulum of: Liver Small Intestine Lungs Kidneys Blood vessels??? What does it do? Metabolism and detoxification of ingested substances: Drugs!!! Environmental toxins Dietary substances Steroids Prostaglandins 7
So we know the basics. What it is Where it is What it does. 2E1 2C9 Does everyone make the same amount? Genetically determined Genetic Polymorphism Possess the genes to produce these enzymes in usual amounts you re referred to as a: Metabolizer Genetic Polymorphism Possess the genes to produce too few enzymes you re termed a: Poor Metabolizer Enzymes Who doesn t produce enough? Enzymes Can we test for this? 8
Enzymes Who doesn t produce enough? 7% of US pop has a genetic defect in CYP 8% of Caucasians 4% of African Americans < 1% Asians Suppose a patient tells you: codeine never helps my pain. a. A drug seeker b. Poor metabolizer of enzymes Codeine doesn t relieve pain it s active metabolite relieves pain Codeine enzymes Morphine Enzymes Who makes A LOT? Saudia Arabians Ethiopians Genetic Polymorphism Possess the genes to produce these enzymes in GREAT amounts you re termed an: Ultra Rapid Metabolizer Codeine doesn t relieve pain it s active metabolite relieves pain Codeine enzymes enzymes enzymes enzymes Metabolite Pain! 9
Enzymes Who doesn t make enough? 5% of Caucasians 20% of African Americans 20-30% Asians You couldn t metabolize... Proton pump inhibitors (omeprazole, esomeprazole, rabeprazole) NSAID (indomethacin) Beta Blockers (propanolol) Clinical Query A patient with GERD has tried omeprazole for 28 days with poor relief of symptoms. What next? Why Change? MANY drugs have a secondary way to be metabolized! You d try a different PPI! Which PPI could be used? Lansoprazole Alternate ways to metabolize it: (,, 2C9) 2C9 Enzymes Serotonin Syndrome Occurs when central and peripheral serotonin receptors are overstimulated Usually within 6 hours of ingestion of the offending substance 10
Serotonin Syndrome Autonomic changes: diarrhea, fever, flushing, hypo/hypertension, sweating Neuromuscular changes: hyperreflexia, increased muscle tone, restlessness, rigidity, tremor, shivering Central Nervous system: Agitation, confusion, delirium, hallucinations Why Serotonin Overload? Increased serotonin production: Tryptophan Inhibition of serotonin reuptake: DM, SSRIs, St. John s wort, tramadol Inhibition of serotonin metabolism: Linezolid Increased serotonin release: DM, meperidine, ecstasy, mirtazapine Stimulation of serotonin receptors: Buspirone, LSD, metoclopramide, triptans Sometimes the way the enzymes work is altered INHIBITION 2E1 2C9 Inhibition slowssssss down drug metabolism... Drugs that inhibit enzymes because it won t let the enzymes do their work Ketoconazole, itraconazole, fluconazole Cimetidine Clarithromycin, erythromycin Grapefruit juice 11
Inhibition: Slows metabolism Increases absorption of drugs Classic Example Grapefruit juice and calcium channel blockers, some statins, most benzos, and others! Grapefruit is a POTENT inhibitor Example Grapefruit Juice Verapamil Atorvastatin Inactive metabolite Verapamil Inactive metabolite Diltiazem Inhibition Clinical Implications? Increases the risk of toxicity!!! Increases effect of the drug Enzyme Reactions Substrates Most CCBs, statins, benzos Most HIV protease inh Most nonsedating antihistamines Inhibitors Cimetidine Oral antifungals Clarith/Eryth Grapefruit substrate = drug needs enzymes to metabolize it 12
Interaction with Foods Interaction with Foods Grapefruit PLUS CCBs Ca channel blockers Amlodipine 15% Felodipine >300% Nifedipine 35% Nisoldipine 400% Grapefruit juice Ca channel blockers Nifedipine 35% Day 1 2 3 4 60 mg 80 mg 105 mg 140 mg Interaction with Foods Grapefruit juice Ca channel blockers Amlodipine 15% Felodipine >300% Nifedipine 35% Nisoldipine 400% How long does it inhibit metabolism of drugs? 3 days or more! Interaction with Foods Grapefruit juice Cyclosporine levels Estrogen 37% Quinidine cardiac effects Buspirone levels Lovastatin levels What constitutes grapefruit juice? 8 oz of grapefruit juice or one whole grapefruit Tangelos, limes, Seville oranges 13
What constitutes grapefruit juice? Seville oranges are bitter and often used to make orange marmalade! Common misconceptions about grapefruit juice Eating grapefruit is OK Separate the drug by a couple of hours What about other citrus fruits? NO PROBLEMS with oranges, tangerines, citrons, lemons Sooooo. Inhibition slowssssss down drug metabolism... Induction: Speeds up metabolism Decreases affect of drugs Induction Cigarette smoke 14
Alterations of Drug Metabolism Induction-What s the implication? Most inducers decrease efficacy of drugs Omeprazole 20 mg daily Cigarette smoke Return of GERD symptoms Alterations of Drug Metabolism Examples of Inducers: CYP: Cigarette smoke, cruciferous vegetables, charbroiled foods, phenytoin, St. John s wort Induction-EtOH Clinical Example 1: Patient is placed on bisoprolol for tachyarrhythmias. Months later, he begins to drink up to two - 6 packs of beer per day. Potential problem: Return of tachyarrhythmias. Reason: Bisoprolol metabolized by. Ethanol is an inducer of. Ethanol inducer Bisoprolol Return of tachyarrhythmias Clinical Example 2: St. John s wort - Inducer Patient is on protease inhibitors. He takes St. John s wort for depression. Potential problem: Increased viral load. Reason: St. John s wort is inducer and causes reduced efficacy of protease inhibitors. 15
St. John s Wort ( inducer) Protease Inhibitors Increased viral load Induction-EtOH Clinical Example 3: Patient is on metoprolol for arrhythmias. He binge drinks on weekends. Potential problem: Arrhythmias Reason: Metoprolol metabolized by. Ethanol is an inducer of. Ethanol inducer Metoprolol Increased arrhythmias Induction-cig smoke Clinical Example 4: Patient is a smoker who takes theophylline. He decides to quit smoking. Potential problem: Theophylline toxicity! Reason: Theophylline metabolized by CYP. Cigarette smoke is an inducer of. Patient is a smoker. Theophylline Theophylline Theophylline Theophylline Theophylline He produces lots of. Theophylline TOXIC!!! Do ALL drugs in the same class have the same effect on the CYP P450 enzymes? 16
CYP Inhibition Macrolide Antibiotics ERYTHROMYCIN clarithromycin azithromycin CYP Inhibition Antifungal agents ketoconazole itraconazole fluconazole miconazole nystatin CYP Inhibition HIV Protease Inhibitors RITONAVIR indinavir ~= saquinavir nelfinavir CYP Inhibition H2 Blockers CIMETIDINE ranitidine *famotidine, nizatidine do not inhibit CYP CYP Inhibition Quinolone antibiotics Ciprofloxacin enoxacin norfloxacin ofloxacin lomefloxacin Levofloxacin CYP Inhibition SSRIs paroxetine fluoxetine sertraline fluvoxamine Citalopram does not inh (inh, ) 17
CYP Inhibition PPIs Omeprazole lansoprazole = rabeprazole Lansoprazole & rabeprazole are metabolized by the CYP 450, but have clinically insignificant interactions CYP Inhibition HMG-CoA Reductase Inhibitors Atorvastatin = lovastatin = simvastatin Fluvastatin met by CYP 2C9 Pravastatin, rosuvastatin Cytochrome P450 Reactions MOST drugs are metabolized in the liver. Anytime a patient presents with an exaggerated response to a drug, suspect CYP drug interaction and investigate!!! Top 10 Drugs to watch out for! 10. Ciprofloxacin 9. Cimetidine 8. Warfarin 7. Erythro/clarithro 6. Ketoconazole Top 10 Drugs to watch out for! 5. Theophylline 4. Paroxetine & Fluoxetine 3. Phenytoin 2. Rifampin 1. Atorvastatin/ Simvastatin Thank you! To contact me or for questions: amelie@apea.com Amelie Hollier, DNP, FNP-BC, FAANP 18