Exam 3: Clinical Drug Interactions Dr. Wynd

administration, blood stream, intravenous, intra-arterial, perfusion, chelation, flora, p-glycoprotein

*Absorption* Process by which a drug moves from the site of _________(1) to the _______ _______(2) All routes of _________(1) have an absorption phase, except for _________(3) and _____-________(4) routes Factors that can affect absorption and bioavailability of a drug: -Altered Blood _________(5) -Adsorption -Gastrointestinal pH -_________(6)/ binding -Food -Gastrointestinal motility -Alterations in gastrointestinal ________(7) -____-________(8)

kaolin-pectin, activated charcoal, 1, 4

*Adsorption* Certain substances such as ______-_______(1), _______ _______(2), have large surface areas that adsorb the drug resulting in limited absorption -May be prevented by administering medications ____(3) hour prior or ____(4) hours after the administration of an adsorptive substance -Adsorption is the mechanism of action for the clinical use of ______ ______(2) -If feasible, the use of alternate routes of administration may be necessary

intestinal flora, oral contraceptive, 7, aminosalicylates, coagulation, warfarin, sulfamethoxazole/trimethoprim

*Alterations in normal _______ _______*(1) Antibiotics can decrease the normal _______ _______(1) necessary for the breakdown of _____ ______(2)(OC) estrogen conjugated leading to decreased enterohepatic recirculation. Patient should be advised that the effectiveness of the OC may be diminished and a second non-hormonal contraceptive is necessary for the length of antibiotic use and for ___(3) days after discontinuation of the antibiotic to allow the normal _______ _______(1) to restore itself Antibiotics may decrease normal _______ _______ (1) necessary for the cleaving of _________(4) such as olsalazine, balsalazide, to produce the active drug Antibiotics may decrease normal _______ _______(1) necessary for the metabolism of ___________(5) factors affecting anticoagulants -_________(6) and ________/________(7)(SMX/TMP, Bactrim) are two commonly prescribed medications with this interaction -especially risky in patients who are at risk of falling- elderly.. leads to increase bleeding, bruising, intracranial bleeding, death

bioavailability, opiates, anticholinergics, griseofulvin

*Altered GI motility* Slowing of GI motility can increase _____________(1) Medications include _________(2) and __________(3) *Accelerated GI motility may decrease ___________(1)* Studies show a direct correlation between _______(4) absorption and GI residence time

H2 receptor blockers, proton pump inhibitors, antacids, ketoconazole, itraconazole, atazanavir, dapsone

*Altered GI pH* Reduces GIT acidity -______ ________ __________(1), ________ ________ ________(PPI)(2), ___________(3) Require acid medium in the GIT -_________(4), ___________(5), ________(6) (PPI contraindicated)-antiretroviral, ___________(7): antibacterial medication which is not commonly used We must acknowledge DDI with drugs that change pH.

beta blockers, corticosteroids, diarrhea

*Drug-Disease* Diabetes ____ _______ (1):May mask the signs and symptoms of hypoglycemia, Alter insulin utilization in the body _________ (2) (e.g., prednisone): Increased hyperglycemia GI Disorders Drugs that may cause _________(3) can lead to dehydration, an increase in INR, and decreased drug absorption. ________(3) is an issue with warfarin because of excessive losses of vitamin K Antibiotics (e.g. amoxicillin/clavulanic acid, azithromycin, clindamycin) Neuropsychiatric Antidepressants: sertraline, bupropion Antiepileptics, valproic acid, tiagabine Antipsychotics; ziprasidone Other: donepezil, zolpidem Hyperlipidemic Simvastatin, atorvastatin, gemfibrozil Antiretrovirals Zidovudine, stavudine Antihypertensives Enalapril, metoprolol, propranolol, spironolactone Acid suppressors Omeprazole, pantoprazole

asthma, bronchoconstriction, leukotriene

*Drug-Disease* ________: Beta blockers, can precipitate _____________(2) due to the blockage of the beta 2 receptors of pulmonary smooth muscle NSAIDs/aspirin Inhibit cyclooxygenase and as a result increases __________ (3) production Chronic Obstructive Pulmonary Disease (COPD) Induction of respiratory depression Non-selective beta blockers (e.g., propranolol) Long-acting benzodiazepines (e.g., chlordiazepoxide, diazepam)

hypertension, hypotension

*Drug-Disease* ___________(1): Can be worsened by various medications -Anticholinergics (e.g., diphenhydramine) -Corticosteroids -Cyclosporine -Erythropoietin -Estrogens -Migraine medications such as 5-HT1 agonists (e.g., sumatriptan) -Nasal decongestants (e.g., pseudoephedrine, phenylephrine) ___________(2): Can further reduce blood pressure Antihypertensives (e.g., beta blockers, ACEI) Antipsychotics (e.g., olanzapine, ziprasidone) Levodopa/carbidopa Opiates

nonsteroidal anti-inflammatory drugs, bleeding, nephortoxicity, digoxin, lithium, aminoglycosides, methotrexate, fluid retension

*Drug - OTC/Herbal Interactions* _____________ _______-___________ _______(1)(NSAIDs) Increases the risk of _______(2) events, especially when taken with other anticoagulants and alcohol. Increases risk of _________(3), especially in the setting of dehydration, when taken alone or with other nephrotoxins Can decrease renal clearance of _______(4), _________(5), __________(6), and ___________(7) Antagonizes the effects of antihypertensives such as B-blockers, ACEIs, ARBs, diuretics because of their _______ ___________(8) properties

1a2, 2e1, increase, polyaromatic hydrocarbons

*Drug - Smoking Interactions* CYP_____(1) and CYP_____(2), Smoking can lower the concentrations of drugs metabolized by these enzymes. -Drugs include: theophylline, caffeine, haloperidol, propoxyphene, and propranolol Abrupt discontinuation of smoking (especially in newly hospitalized patients) may _______ (3) concentrations of these drugs Induction is due to _____ ______(4), not nicotine Administering a nicotine patch during the hospital stay may prevent withdrawal, but will not prevent this interaction

beta blockers, Non-dihydropyridine, prednisone, rosiglitazone, triptans

*Drug-Disease* Congestive Heart Failure (CHF) _____ ________(1): may masks the signs and symptoms of hypoglycemia -Alter Insulin utilization in the body -Although some CHF patients take ______ _________(1), it is not recommended during exacerbations and should be started low and titrate slow _______-___________(2) calcium channel blockers(e.g., verapamil, diltiazem) -Negative inotropic effects will decrease contractility ___________(3): Can cause fluid overload and aggravate CHF ___________(4) Can cause sodium and water retention, edema _________(5)(e.g., sumatriptan, others) Serious cardiovascular events and can lead to death

hyperthyroidism, burns, cirrhosis, ascites

*Metabolism* __________(1) and __________(2) may increase metabolism and clearance of drugs ________(3) and _______(4) (the accumulation of fluid in the peritoneal cavity) may decrease metabolism and clearance of drugs

bile acid sequestrant, colesevelam, cholestyramine

*Binding to ________ ________ ________(1) s including ___________(2) and __________(3)* Decreases absorption of oral medications including tetracycline, statins, warfarin, loop diuretics, valproic acid, and B-blockers May be prevented by administering the drug 1 hour before or 4 hours after the _____ _______ ________(1) Consider the use of _______ (2) to avoid inhibition of drug absorption If feasible, use alternate routes of administration

drug, OTC, food, alcohol, environment, disease

*Categories of Interactions* Drug-________(1) Drug-________(2)/herbal Drug-_______(3) Drug-________(4) Drug-________(5) Drug-________(6)

orthostatic hypotension, metronidazole, cefotetan, hypoglycemic, GI bleeding

*Drug - Alcohol Interactions* Alcohol use can lead to increases in CNS depression when taken with benzodiazepines, tricyclic antidepressants, opiates, or antihistamines There may be an increase in ______ _______ (1) when co-administered with antihypertensives such as methyldopa and diuretics Disulfram-like reactions can occur in certain drugs such as __________(2) and __________(3) Flushing, vasodilation, respiratory difficulties, nausea, hypotension Caution should be used even with every day alcohol-containing products such as mouthwash Chronic use with some antidiabetic agents can cause an increased risk of ____________(4) events -Sulfonylureas Increased risk of _____ ______(5) with medications such as warfarin aspirin and NSAIDs

mental, seizure, carbapenems, corticosteroids

*Drug - Disease* Altered ________(1) Status Narcotics, benzodiazepines, barbiturates, amphetamines, tricyclic antidepressants, H1H2 antagonist, anti-parkinson agents, phenytoin, carbamazepine, digoxin, corticosteroids ________ (2) disorders Caution with drugs that can cause ________s(2) or decrease ________(2) threshold (e.g., beta lactams, buproprion, tramadol, meperidine, alcohol, amphetamines, flumazenil in benzodiazepine dependent patients) -___________(3) can decrease valproic acid concentration to subtherapeutic concentrations Glaucoma Prolonged use of ____________(4) may induce glaucoma. Use of certain medication (e.g. diazepam, ipratropium, amitriptyline) in existing glaucoma is not recommended

photosensitivity

*Drug - Environment* ____________(1) Drugs that commonly cause ___________(1) ACEIs, amiodarone, diltiazem, tetracyclines, fluoroquinolones, sulfonamides, furosemide, hydrochlorothiazide, NSAIDs, quinidine, tacrolimus, tretinoin, voriconazole Counsel patients on the need for sun block, protective clothing, and sunglasses

absorption, 1, 2, decrease, increase

*Drug - Food Interactions* Rate of _________(1): most common cause of interactions Rate can be increased or decreased Possible mechanisms include: alterations in stomach pH and effects on the rate of gastric emptying Such effects can be lowered by taking the drug ____(2) hour before or ____(3) hours after a meal Drugs which experience a _________(4) in the rate of __________(1) include: Penicillins, tetracyclines, erythromycin, levodopa, phenytoin, digoxin Drugs which experience an __________(5) in the rate of absorption include: Spironolactone, griseofulvin, and itraconazole

extent, bisphosphates, ketoconazole, posaconazole

*Drug-Food Interactions* _______(1) of absorption Oral ____________(2): treat and prevent osteoporosis -The ________(1) of absorption can decrease by up to 60% by food, coffee, juices, etc. -Should be taken first thing in the morning with a glass of plain water, at least 30 minutes before the 1st meal, beverage, or other medication -Patients should be advised to remain in an upright position for at least 30 minutes and until food has been consumed in order to reduce esophageal irritation ______________(3): Acidic beverages can lead to higher and prolonged serum concentrations _____________(4): Oral suspension (1st dosage form): requires co-administration with a fatty meal (milk fat ice cream or an oral liquid nutritional supplement or acidic beverage in order to be effectively absorbed -Tablets (extended-release): administer with food, displays a more consistent and predictable absorption profile than the oral suspension

chelation, calcium

*Drug-Food Interactions* __________(1) of drugs by multivalent cations found in everyday foods such as ice cream and milk Be wary of __________(2) fortified food products like orange juice and educate patients accordingly as well

sodium

*Drug-Food interactions* Elimination Lithium and _________: Lithium excretion is increased by high ______ diets and decreased by low _______diets

vitamin b6, grapefruit, cranberry

*Drug-Food interactions* Metabolism _________ ______(1) can increase the metabolism of levodopa _______ juice (2)will inhibit CYP450 3A4 isoenzymes, decreasing the metabolism of many drugs which will lead to an increase in serum concentrations of the drugs ________ juice (2) also affects the extent of absorption of various drugs by inhibiting PGP, in the gut wall, and also the organic anion transporting polypeptide (OATP) ________ (3) juice can inhibit any enzyme implicated in the metabolism of warfarin -Chronic use can increase INR when taken with warfarin. There is very limited information regarding this interaction but possibly may be due to the inhibition of CYP2C9

absorption, chelate, sodium bicarbonate, separation

*Drug-OTC/Herbal interactions* Antacids Lowers the acidity of the stomach, which impairs _________(1), affecting certain drug plasma concentrations including iron, varying oral calcium supplements (calcium carbonate requires an acidic environment, while calcium citrate does not) Certain antacids (those containing polyvalent cations) may _____(2) with medications, decreasing concentrations of fluoroquinolones, tetracyclines, levodopa/carbidopa Can avoid this effect with the use of ________ ________(3)(monovalent cation, so chelation does not occur with this!!!) or with the appropriate __________(4) of doses

iron, multivitamins, chelation, proton pump inhibitors. H2, increase, herbals

*Drug-OTC/________(7) interactions* _________(1) supplements or ___________(2) Same issue of ________(3) by di/trivalent cations, which decreases concentrations of fluoroquinolones, tetracyclines, levodopa/carbidopa _______ ________ _________(4) Suppresses the acidic environment of the GI, decreasing bioavailability and absorption of drugs requiring acidic mediums such as itraconazole, ketoconazole, dapsone, atazanavir ________(5)-receptor antagonists Similar concept as PPIs thus decreasing the absorption of drugs dependent on pH Cimetidine inhibition of CYP450 enzymes can _________(6) serum concentrations of various drugs including warfarin, benzodiazepines, phenytoin, propranolol, theophylline, procainamide, erythromycin _________(7)(this is a concentrated representation, there are many, many more 'herbal' products and dietary supplements available, for many of which there is little to no information regarding interaction potential—exercise caution!)

Acetaminophen, hepatotoxicity, OTC

*Drug-________(4)/Herbal interactions* ___________(1): Increases the risk of _________(2) FDA recommends a limit on the maximum daily dose (MDD) of 4 grams in adults or 90 mg / kg in children -In July 2009, FDA proposed MDD of 3.25 grams per day -In 2012, FDA suggested a MDD of 3 grams per day (75 mg/kg/d in children) Avoid concurrent use with other hepatotoxic drugs, including amiodarone, diclofenac, erythromycin, isoniazid, indomethacin, methotrexate, tetracycline, valproic acid Educate patients on combination pain medication containing acetaminophen such as the combo product, oxycodone/ acetaminophen, and to avoid additional _______(4) acetaminophen

urinary incontinence, sedatives, diuretics, muscle relaxants, ace inhibitors

*Drug-disease* _____ _________(1) caused/exacerbated by medications _______(2): diazepam, flurazepam, lorazepam __________(3): furosemide, torsemide _____ _______ (4): baclofen, metazalone, methocarbamol ______ _______(5): benazepril, captopril, enalapril, lisinopril Antipsychotics: haloperidol, risperidone Alpha blockers: doxazosin, prazosin, tamsulosin, terazosin Other: theophylline

renal dysfunction, retention

*Drug-disease* ______ ______(1) Medications that can worsen renal function ACEIs, ARBs, aminoglycosides, amphotericin B, calcineurin inhibitors, loop and thiazide diuretics, NSAIDs, radio contrast dyes, vancomycin Drugs that rely heavily on renal excretion that accumulate in patients with ______ ______(1) -Lithium 90-98% renal clearance Extensive list attached in appendix Urinary ________(2) may be exacerbated with co-administration of anticholinergic (antihistamines, diphenhydramine, tricyclic antidepressants)

St. John's Wort, 3A4, digoxin, ssris, warfarin, hiv protease, cyclosporine, tacrolimus

*Drug/Herb Interactions* ____ _____ ____ (1) is a OTC anti-depressant. It is a CYP______ (2) inducer It can decrease ______ (3) drug concentration Cause lethargy and nausea with _________(4) Reduce the anticoagulation effects of ________(5) Decrease drug concentrations of ______ _________(6) inhibitors and immunosuppresants like ___________(7) and _________(8)

Fish oil, birth control, antihypertensive, anticoagulant

*Drug/Herb Interactions* _____ ______/(1)omega 3 is the most commonly used natural product. ____ _____ (2)pills may intefere with the trigylceride lowering effects of ______ ______s(1) _____ _______s(1) may increase the effects of _______________ (3) drugs and may lower blood pressure too much. ____ ____ (1) interacts with __________ (4) and antiplatelet drugs because it may slow clotting which may cause bleeding

d

*Drugs can interact with:* a. other drugs b. herbal/dietary supplements c. alcohol d. all of the above

filtration, reabsorption, secretion, ascorbic acid, phenobarbital, methotrexate

*Elimination* Most common way drugs or their metabolites are eliminated are through the kidneys Other forms include feces, bile, and breast milk Renal clearance is influenced by glomerular ________(1), tubular _________(2), or active tubular ___________(3) -urinary pH can affect how a drug is eliminated Displacement interactions may increase free drug in the vascular compartment and increase the amount available to be filtered Modification of a compound's degree of ionization can affect overall _________(2) The more un-ionized, more lipid-soluble state, the greater the _________(2) Acidification with ______ _______(4) can increase serum ____________(5) Alkalization with antacids can alter serum concentrations of amphetamines, salicylates, and quinidine Competitive inhibition of renal tubular secretion -Penicillin + probenecid = slower clearance of penicillin -___________(6)+ penicillins/probenecid/NSAIDS leads to prolongs and elevated serum concentration of _____________(6)(not viewed as beneficial interaction because ___________(6) is a bone marrow toxicant and can be lethal). *Biliary secretion is also important* Parent compounds or their metabolites excreted via the bile may be reabsorbed into the systemic circulation from the distal ileum (enterohepatic circulation) May delay and prolong absorption and elimination of some drugs (e.g., carbamazepine)

absorption

*FQs and Divalent/Trivalent Cations* Graph: Levofloxacin administered concomitantly with magnesium oxide or Aluminum oxide. Top arrow, where absorption is the highest, middle arrow, concomitant administration causes decreased __________. Fluoroquinolones work best when their concentration is maximized. In the above case, drug is less effective. Medications should either not be given together, or spaced between dosings.

fluorquinolones, tetracylcines, multivalent cations

*Formation of insoluble complexes or chelated compounds* ___________(1)(many common oral antibiotics), including ciprofloxacin, levofloxacin, and moxifloxacin, or ___________(2), including doxycycline and __________(2) + _______ ________(3)(found in medications and foods) such as Ca++, Mg++, and Al++ ions, from antacids multivitamins, and dairy products -Minimize interaction by avoiding multivalent cations 4 hours before or 8 hours after ___________ (1) or ___________(2) administration

concentration, site of action, effect, potentiated, attenuated

*Interaction Mechanisms* Pharmacokinetics: the ________ (1) of the drug in the plasma and at the _______ ____ ________(2) is affected Pharmacodynamics: the ______(3) of the drug on the body is either _______(4) or ________(5)

drug interactions, adverse drug reaction, failure, toxicity

*Introduction and Epidemiology* ________ ________ (1) occur when a substance that is co-administered with a drug causes a desirable or undesirable effect that is different than the normally observed activity of the drug The outcomes can be beneficial, but usually result in an ________ ______ ________(2)(ADR), therapeutic ________(3) , or _________(4) Significant impact of _____ ______ _______(2): -Increased morbidity and mortality -Increased number and duration of hospitalization -Increased physicians visits -Decreased quality of life of patients -Loss of wages and productivity of patients

CYP450, metabolizer, induction

*Metabolism* Genetic heterogeneity, age, enzyme induction, and enzyme inhibition affects _______(1) Genetic polymorphisms can lead to unexpected drug responses -Poor ________(2) -Extensive _________(2) ________ (3) refers to an increase in enzyme activity -Decrease drug concentration of substrate -Decreases with age and hepatic disease -Onset is gradual -Classification (FDA) -Strong inducers: ≥ 80% decrease in AUC -Moderate inducers: 50 - 80% decrease in AUC -Weak inducers: 20 - 50% decrease in AUC

oxidation, hydrolysis, reduction, glucuronidation, sulfation, methylation

*Metabolism* Many drugs undergo biotransformation reactions as soon as they enter the body Phase I (_____(1), ________(2), and _________(3)) Phase II (__________(4), ________(5), and __________(6)) Phase I biotransformation: cytochrome P-450 isoenzymes (CYP450), primarily found in the gut and liver, but can be found in the kidneys, brain, and lungs Categorized by families (1,2, and 3), divided into subfamilies (A - E), and specified number (CYP3A4)

clopidogrel, CYP2C19, H2RA, famotidine, pantoprazole

*Metabolism* Some proton pump inhibitors attenuate the effects of __________(1) (antiplatelet) via enzyme inhibition Possible interaction through the shared _________(2) pathway An _________(3) (e.g., ______(4) or ranitidine) should be considered If PPI therapy is warranted, consider __________(5)(less __________(2) inhibition than esomeprazole or omeprazole

1A2, 2C9, 2D6, 3A4

*Metabolism* The CYP's we primarily look at: ___,______,_____ and _____

Carbapenems

*Metabolism* _______(1) (e.g., imipenem, meropenem, etc.) interaction with valproic acid (decrease in VPA concentrations) _______inhibit the hydrolytic enzyme responsible for the conversion of VPA glucuronide to the VPA active metabolite; therefore decreasing serum concentrations of VPA- therapeutic drug concentrations of valproic acids are decreased (Interaction may increase the possibility of seizure; _______lower the threshold for seizure)

inhibition

*Metabolism* _________ occurs when a second substrate competes with the primary drug for the active site of the enzyme (competitive ________) Increase drug concentration of substrate Can be competitive or non-competitive Onset is rapid and depends on the inhibitor's half-life Classification (FDA) -Strong inhibitors: ≥ 5-fold increase in AUC or > 80% decrease in Cl -Moderate inhibitors: ≥ 2 but < 5-fold increase in AUC or 50 - 80% decrease in Cl -Weak inhibitors: ≥ 1.25 but < 2-fold increase in AUC of 20 - 50% decrease in Cl

azathioprine, allopurinol, febuxostat, xanthine, 6-MP

*Metabolism* __________ (1) (immunosuppressive) - _________(2)(and __________(3))(treat and prevent gout) interaction _________(4) oxidase converts the active metabolite of __________(1) , 6-mercaptopurine (___-____(5)) (chemotherapeutic, has bone marrow suppressive effects), to an inactive metabolite __________(2) (and ___________(3)) inhibit _________(4)oxidase Accumulation of ____-______(5) may lead to bone marrow toxicity (which is potentially fatal) -Reduce dose of __________(1) by 75% when starting ________(2) -__________ (1)contraindicated in combination with __________(3)

agonist, aminoglycosides, nephrotoxicity, depressive, hypotension

*PD interactions* Serum drug concentration is not affected, but the effect the drug has on the body is either potentiated or diminished _________(1) Interactions: effect of the two drugs are additive which results in greater efficacy and /or greater toxicity ______________(2) and cell wall active agents (for example, B-lactams and vancomycin): increases antimicrobial activity Vancomycin and ____________(2): increases ____________(3) -the two above bullet points are frequently used together even though there is a risk. _____________(2) and succinylcholine: prolongs recovery from muscle paralysis Opioids and benzodiazepines: increases CNS ___________(4) effects Nitrates and PDE-5 inhibitors (viagra, cialis): increases risk of ___________(5), potentially life threatening (fatal drop in blood pressure)

antagonist, NSAIDs, antihypertensive, metoclopramide, amitryptiline

*PD interactions* __________(1) Interactions: the two agents have opposing actions, decreasing the effectiveness of one or both agents B-agonists and B-blockers: non-selective B-blockers may counteract respiratory B-agonists since they both target the same receptor ________(2) and diuretics: _________(2) may cause sodium retention leading to decreased efficacy of diuretics _______(2) and ACEIs/ARBs: _________(2) can reduce the _____________(3) effects of ACEIs and ARBs Cholinergics and anticholinergics: ___________(4)(nausea) and __________(5) (antidepressant) -results in _________(1) interaction

polypharmacy, adjustments, forms, chronic, social, genetic

*Patient Risk Factors* ___________(1) -3 - 5% risk in patients taking 2 - 4 medications -20% risk in patients taking 10 medications or more Age -There are physiological differences between normal aged adults, the pediatric population and geriatric population that often requires dose __________(2) or different dosage ________(3) -CYP450 enzymes undergo changes throughout life -1A2 has negligible activity in newborns, peaks in adulthood and wanes in the elderly -_________(4) health conditions -Hypoproteinemia -Pregnancy and Lactation -Obesity or malnutrition -_______(5) factors -Financial situation -Smoking, alcohol and/or illicit drugs -___________(6) polymorphisms -Race -Poor/extensive metabolizers

food, extent

*Presence or absence of _________*(1) Usually affects the rate of absorption but may also affect the ________(2) of absorption for some drugs Drug administration with _______ (1) may help absorption but some medications may need to be taken on an empty stomach. If _______(1) does blunt PK of drug, sometimes it is better to take with some ________(1) than if patient takes medicine and then vomits, then drug is lost.

cyp, protease inhibitors, dosage forms, red flag

*Prevention of Interactions* Drug Selection Monitor for any _________(1) interactions especially 3A4 Closely monitor ART (antiretroviral therapy (for HIV and HCV)), particularly _______ _______ (2) Use caution when switching _______ ________(3) because this may precipitate interactions IV to PO moxifloxacin switch Exercise caution when using "______ ______ "(4) drugs

communication, ask, aware, educate

*Prevention of Interactions* Effective _________(1) with the patient ________(2) about the use of prescription medications, OTC, herbals, supplements, vitamins, and any other substances that are being used Be _________(3) of other physicians and pharmacies the patient is utilizing and emphasize the importance of reducing multiple physicians or pharmacies patient visits __________(4) your patients about the medications including proper administration and side effects ____(2) about any unexpected side effects that the patient may be experiencing

specific, co-morbidities, pharmacodynamic, monitoring

*Prevention of Interactions* Patient _______(1) Prescribing Ask about smoking, alcohol use, diet, pregnancy and lactation Consider ____-_______(2) that may alter the drug's activity Consider ___________(3) interactions between drugs used for similar therapeutic effects Avoid polypharmacy as much as possible Always weight the benefits vs. the risk of the medications Patient _________(4) -Check serum concentrations for drugs with narrow therapeutic window -Maintain up-to-date list of medications that are being used and monitor for any therapeutic duplications

drug interactions, adverse events, monitoring

*Red Flag Drugs* These medications and classes are commonly associated with: Significant ______ ________(1) and _____ ________(2) that may result in morbidity and mortality Require close _________(3) due to narrow therapeutic windows

leucorvorin, mesna

*Red Flag* Cancer Chemotherapeutic Agents May lead to serious and additive toxicities, very important to appropriately dose patients Always check to see if premedication is necessary ________(1) with methotrexate, ________(2) with ifosfamide

Warfarin

*Red Flag* ________ Some interactions are due to hepatic metabolism by CYP 2C9, 1A2, 3A4, while pharmacodynamics accounts for others Requires close monitoring of INR, frequent dose adjustments, and monitoring for signs of bleeding such as black, tarry stools and bruising. Interacts with many different types of medications

azole, miconazole

*Red Flag* ________ Antifungal Agents These agents exhibit antifungal activity through the inhibition of fungal CYP 450, but can also inhibit human CYP 450 leading to potential interactions. ________ (2) has such extensive inhibition that systemic use is not indicated. Fluconazole, itraconazole, ketoconazole, voriconazole, posaconazole, isavuconazonium p-gp inhibitor, CYP3A4 inhibitor, CYP2C9 inhibitor, CYP2C19 inhibitor...

HMG-CoA reductase inhibitors, Rhabdomyolysis, creatinine, pravastatin

*Red Flag* ________-______ ______ ______(1) (i.e., "statins") Atorvastatin, fluvastatin, lovastatin, rosuvastatin, simvastatin, others Mostly metabolized by CYP 3A4 and 2C9 so interactions may occur with other substrates, inhibitors, and inducers such as: Clarithromycin, diltiazem, erythromycin, grapefruit juice, itraconazole, verapamil _____________(2) is potential side effect of statin therapy, but the risk is increased with increased concentrations Use caution when using other drugs that also have the potential side effect of ____________(2) (e.g., gemfibrozil, fenofibrate, niacin). __________(3) phosphokinase should be monitored if any symptoms of muscle pain or weakness arise. A therapeutic alternative may be _________(4), which undergoes very minimal metabolism via CYP450

Amiodarone

*Red Flag* _________ Due to the extended half life of about 58 days, drug interactions may occur even after the patient has discontinued the medication. This potentially includes any drugs that can cause QT prolongation, as well as CYP 450 system interactions. Serious symptomatic bradycardia has been reported with co-administration of ledipasvir/sofosbuvir (Harvoni®), the mechanism is unknown. p-gp inhibitor, CYP3A4 inhibitor, CYP2C9 inhibitor, CYP2D6 inhibitor

antiretrovirals

*Red Flag* ___________(1)/ Anti-HCVs In addition to the extensive CYP inhibition/induction effect, inappropriate combinations of drug can cause significant toxicity (e.g., pancreatitis, hepatotoxicity, neuropathy) and resistant HIV NNRTI (non-nucleoside reverse transcriptase inhibitors) Delavirdine Efavirenz nevirapine NRTI (nucleoside/nucleotide reverse transcriptase inhibitors) Didanosine Stavudine Zidovudine Protease inhibitors Amprenavir Atazanavir Darunavir Fosamprenavir Indinavir Lopinavir Nelfinavir Ritonavir Saquinavir Tipranavir

tyramine, hypertensive crisis, dopamine, phenylethylamine, linezolid, SSRIs, TCAs, sympathomimetics

*Red-Flags* Monoamine Oxidase Inhibitors (MAOIs) MAO-A is responsible for the breakdown of __________(1). To avoid a _______ _______(2), avoid foods containing high amounts of ________(1) such as various cheeses, chocolate, and aged meats MAO-B results mostly in the breakdown of ________(3) and __________(4), but without the requirement of dietary restrictions. Selective inhibition is therefore preferred whenever clinically possible. _______(5) (and tedizolid) is a weak MAOI, so ___________(1) rich foods should be avoided when possible Co-administration with _______ (6) such as citalopram, fluoxetine, can cause serotonin syndrome which can be prevented by separating usage by at least 2 weeks Caution should be used when co-administering ________(7), due to serious adverse reactions caused from serotonergic effects such as convulsions, hyperpyrexia, mania Co-administrations with ____________(8) such as amphetamines, phenylephrine, and pseudoephedrine, can cause severe hypertension, hyperpyrexia, seizures, arrhythmias, and/or death

e

*Risk factors for drug interactions include:* a. polypharmacy b. age-related physiologic changes in drug disposition c. social factors d. failure to recognize interaction and/or the significance of the interaction e. all of the above

P-glycoprotein, propranolol, clindamycin, amitriptyline, loperamide, qunidine, digoxin

*___-___________ (PGP)*(1) A multi-drug transporter (part of a large family of efflux pumps) that transfers drugs across various organ membranes with the use of ATP Located in the liver, intestinal mucosa, kidney, endothelial cells of the blood-brain barrier (BBB), adrenal cortex, and other organs Possibly involved in multi-drug resistance in tumors Usually transports basic/hydrophobic drugs including _________(2), ___________(3), and __________(4) Co-administration of substrates, inhibitors, and/or inducers can result in altered absorption and/or distribution of drugs -_______(5) and ________(6): __________(5) is usually unable to cross the blood brain barrier due to the PGP efflux pump. When administered with _________(6)(an efflux pump inhibitor), ___________(5) can then cross the BBB and cause CNS side effects _________(7): med for cardiac failure/arrhythmia, increase BP: If administered with a PGP pump inhibitor, dose reduction of 50% or more may be required to remain in therapeutic range and close monitoring is recommended. If administered with a PGP pump inducer, dose increase and close monitoring may be necessary if therapeutic efficacy is not reached.

Albumin, sulfonamides, NSAIDs, chloral hydrate, hypoalbuminemia, warfarin, phenytoin, methotrexate

*_________* (1) The most abundant plasma protein, acts as a carrier for drugs with low water solubility which includes _________(2), _________(3), and _____ ________(4) Only unbound (free fraction) drugs are pharmacologically active (protein binding in plasma decrease Vd, tissue binding increase Vd) Causes for ___________(5): -Cirrhosis -Burns -Malabsorption/ malnutrition -Nephritic syndrome -Pregnancy -Critically ill -Sepsis Co-administration of two or more highly protein bound drugs can cause competitive displacement and increase in one or both drug's free fraction Use caution when using drugs with narrow therapeutic ranges such as _______(6), ________(7), _________(8)

distribution, aminoglycosides, vancomycin, penicllins

*_____________*(1) The process by which a drug moves to and from the site of administration, bloodstream, site of action/ elimination/ tissue compartment and storage sites The volume of _________(1) is the volume in which the amount of drug would need to be uniformly distributed to produce the observed blood concentration -Increased volume of _________(1) as seen in ascites and CHF may alter the ___________(1) of water-soluble drugs such as ________(2), _________(3), and ___________(4) Characteristics of drugs commonly involved in interactions: -Highly protein bound (~90%) -Bound to tissues -Small volume of _________(1): affected to a greater extent by changes that change their volume of ________(1) -Narrow therapeutic index: difference between subtherapeutic concentration and toxic dose is small

Pharmacokinetics, absorption, distribution, metabolism, elimination

*_______________*(1) The study of what the body does to the drug The movement of drugs into, through, and out of the body _________(2), ___________(3), ____________(4), and __________(5)

decrease

An organ transplant recipient on a stable immunosuppression with tacrolimus (a CYP3A4 substrate) develops tuberculosis and is started on a rifampin (a potent CYP3A4 inducer) containing regimen. What is the expected change in tacrolimus steady state concentration?

carafate, tums, mylanta

Ciprofloxacin is chelated be which of the following: -carafate, (aluminum), tums (calcium), gaviscon, mylanta (aluminium/magnesium)

increase

Clarithromycin inhibits PGP efflux pump, so concentrations of digoxin can ________.

QT

Drugs reported to prolong ______ interval

end stage renal

Effects of ____ _____ _______ disease on clearance.

Clonazepam, valproic acid, carbamazepine, sulfonamides, NSAIDs, chloral hydrate

Highly protein bound drugs include: __________(1), _______ _______(2) __________(3), __________(anti-seizure drug), __________(4), __________(5), _____ _____(6)

Rifamycins, St. john's wort

_______(1) Potent CYP enzyme inducers and can cause interactions _____ _____ _______ (2) (Hypericum perforatum) Significant induction of CYP 3A4 and some induction of CYP 2C9 May contribute to serotonin syndrome when used in conjunction with other antidepressants that increase serotonin, such as SSRIs May contribute to antiretroviral failure