clinical drug interactions

what is absorption?

• process by which a drug moves from the site of administration to the bloodstream

• all routes of administration have an absorption phase, excet for IV and intra-arterial routes

what are the factors that affect absorption and bioavailability of a drug?

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what is adsorption?

• the MOA for the clinical use of activated charcoal

• if feasible, the use of alternate routes of administration may be necessary

• interactions may be clinically beneficial in some circumstances

• certain substanes, such as kaolin-pectin, activated charcoal, have large surface areas that adsorb the drug, resulting in limited absorption

• may be prevented by administering medications 1 hr prior to or 4 hrs after the administration of an adsorptive substance

what reduces GI tract acidity?

• H2 receptor blockers, PPO, antacids, potassium-competitive acid blockers (PCABs)
• increase gastric pH

what requires an acid medium in the GI tract?

• ketconazole, itraconazole
• atazanavir (PPI contraindicated), rilpivirine (PCAB contraindicated)
• dapsone
• requies low gastric pH for optimal absorption

what is the formation of insoluble complexes/chelated compounds?

• fluroquinolones + multivalent cations from antacids, multivitamins, and dairy products
• minimize interaction by avoiding multivalent cations 4 hrs before or 8 hrs after fluroquinolone/tetracycline administration
• sucralfate (carafate): cause of interaction

what is sucralfate (carafate)?

• used to treat and prevent duodenal ulcers
• has a high Al content

what is binding to bile acid sequestrants?

• including colesevelam and cholestyramine
• decreases absorption of oral medications including tetracycline, statins, warfarin, loop diuretics, valproic acid, and β-blockers
• may be prevented by administering the drug 1 hr before or 4 hrs after the bile acid sequestrant
• consider the use of colesevalem to minimize inhibition of drug absorption: drug interaction less prone with colesevalem
• if feasible, use alternate routes of administration

what are alterations in normal intestinal flora?

• patient should be advised that the effectiveness of the OC may be diminished, and a second, nonhormonal contraceptive is necessary for the length of antibiotic use and for 7 days after discontinuation of the antibiotic
• warfarin and sulfamethoxazole/trimethoprim: 2 commonly prescribed medications with this interaction
• antibiotics can decrease the normal intestinal flora necessary for the breakdown of oral contraceptive (OC) estrogen conjugated, leading to decreased enterohepatic recirculation

what is the interaction between digoxin and P-glycoprotein (PGP)?

• potentially life-threatening drug interaction
• 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

what are PDP inhibitors?

ritonavir

what are PGP inducers?

rifampin, ritonavir, phenytoin, st. johns wort

what is albumin?

• the most abundant plasma protein
• acts as a carrier for drugs with low water solubility, which includes sulfonamides, nonsteroidal anti-inflammatory drugs (NSAIDs), and chloral hydrate
• only unbound drugs are pharmacologically active
• coadministration of 2 or more highly protein-bound drugs can cause competitive displacement and an increase in one or both drug's free fraction: use caution when using drugs with narrow therapeutic ranges (e.g. warfarin, phenytoin, methotrexate)
• highly protein-bound drugs also include: clonazepam, valproic acid, carbamazepine, sulfonamides, NSAIDs, chloral hydrate

what is phase I metabolism?

• oxidation, hydrolysis, and reduction
• biotransformation: CYP450 isoenzymes, primarily found in the gut and liver, but can be found in the kidneys, brain, and lungs

what are the classifications of induction?

• strong inducers: ≳80% decrease in AUC
• moderate inducers: 50-80% decrease in AUC
• weak inducers: 20-50% decrease in AUC

what is induction?

• refers to an increase in anyzme activity
• decreased drug concentration of substrate
• decreases with age and hepatic disease
• onset is gradual

what is inhibition of metabolism?

• occurs when a second substrate competes with the primary drug for the active site of the anzyme (competitive inhibition)
• increase drug concentration of substrate
• can be competitive or non-compeitive
• onset is rapid and depends on the inhibitor's half-life

what is the classification of inhibition?

• strong inducers: ≳5-fold increase in AUC or >80% decrease in Cl
• moderate inducers: ≳2 but <5-fold increase in AUC or 50-80% decrease in Cl
• weak inducers: ≳1.25 but <2-fold increase in AUC of 20-50% decrease in Cl

what are carbapenems?

• inhibit the hydrolytic enzyme responsible for the conversion of VPA glucuronide to the VPA active metabolite
• decreases serum concentrations of VPA

what are some PPI interactions?

• attenuate the effects of clopidogrel via enzyme inhibition
• if PPI therapy is warranted, consider pantoprazole: less CYP2C19 inhibition than esomeprazole/omeprazole
• possible interaction through the shared CYP2C19 pathway

what is azathioprine?

• allopurinol (and febuxostat) interaction: inhibits xanthine oxidase

• xanthine oxidase converts the active metabolite of azathioprine, 6-mercaptopurine, to an inactive metabolite

• accumulation of 6-MP may lead to bone marrow toxicity (potentially fatal)

• reduce dose by 75% when starting allopurinol

• contraindicated in combination with febuxostat

what drugs are CYP1A2 substrates?

clozapine, imipramine, theophylline

what drugs are CYP1A2 inhibitors?

cimetidine, fluvoxamine

what drugs are CYP1A2 inducers?

tobacco

what drugs are CYP2C9 substrates?

penytoin, voriconazole, warfarin

what drugs are CYP2C9 inhibitors?

amiodarone, fluconazole, gemfibrozil, isoniazid, sulfamethoxazole

what drugs are CYP2C9 inducers?

carbamazepine, phenoarbital, phenytoin, rifampin, St. John's Wort

what drugs are CYP2C19 inhibitors?

cimetidine, esomprazole, fluconazole, fluoxetine, fluvoamine, isoniazid, ketoconazole, lansoprazole, omeprazole

what drugs are CYP2C19 inducers?

carbamazepine, phenytoin

what drugs are CYP2C19 substrates?

citalopram, clopidogrel, phenytoin, PPIs

what drugs are CYP2D6 substrates?

• amitriptyline, codeine, dextromethorphan, duloxetine, haloperidol, metoprolol, tramadol
• propafenone, thioridazine

what drugs are CYP2D6 inhibitors?

amiodarone, buproprion, cimetidine, duloxetine, fluxoteine, methadone, paroxetine, quinidine, ritonavir, sertraline

what drugs are CYP2D6 inducers?

none: not an inducible enzyme

what drugs are CYP3A4 substrates?

alprazolam, amiodipine, cyclosporine, everolimus, felodipine, methadone, midazolam, nifedipine, sildenafil, simvastatin, sirolimus, tacrolimus, tamoxifen, trazodone, triazolam, verapamil, vinblastine, vincristine

what drugs are CYP3A4 inhibitors?

amiodarone, cimetidine, clarithromycin, clotrimazole, diltiazem, fluconazole, grapefruit and its juice, itraconazole, ketoconazole, posaconazole, verapamil, voriconazole, viekira pak

what drugs are CYP3A4 inducers?

carbamazepine, caspofungin, phenobarbital, phenytoin, rifabutin, rifampin, st. john's wort

what is acidification?

• with ascorbic acid
• can increase serum phenobarbital
• urinary pH can alter drug elimination

what is alkalization?

• with antacids
• can alter serum concentrations of amphetamines, salicylates, and quinidine
• urinary pH can alter drug elimination

what is competitive inhibition of renal tubular secretion?

penicillin + probenecid = slower clearance of penicillin

• potentially beneficial interaction
  methotrexate + penicillins/probenecid/NSAIDs leads to prolonged and elevated serum concentration of methotrexate
• potentially fatal interaction

what is biliary secretion?

• 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)

what are agonist interactions?

effect of the 2 drugs are additive which results in greater efficacy and/or greater toxicity

what are the types of agonist interactions?

• amiodarone and moxifloxacin: increased risk of arrhythmia (secondary to QTc prolongation)
• vancomycin and aminoglycosides; increases nephrotoxicity
• aminoglycosides and succinylcholine: prolongs recovery time from muscle paralysis
• opioids and benzodiazepines: increases CNS depressive effects
• nitrates and PDE-5 inhibitors: increases risk of hypotension
• amiodarone and moxifloxacin: increases risk of arrhythmia (second to QTc prolongation)

what are antagonist interactions?

the 2 agents have opposing actions, decreasing the effectiveness of one or both agents

what are the types of antagonist interactions?

• B-agonists and B-blockers: non-selective B-blockers may counteract respiratory B-agonists since they both target the same receptor
• NSAIDs and diuretics: may cause sodium retention, leading to decreased efficacy of diuretics
• NSAIDs and ACEIs/ARBs: can reduce the antihypertensive effects of ACEIs and ARBs
• cholinergics and anticholinergics: metoclopramide and amitriptyline

what are the OTC/herbal interactions of nonsteroidal anti-inflammatory drugs (NSAIDs)?

• increases the risk of bleeding events, especially when taken with other anticoagulants and alcohol

• increases risk of nephrotoxicity, especially in the setting of dehydration, when taken along with other nephrotoxins

• can decrease renal clearance of digoxin, lithium, aminoglycosides, and methotrexate

• antagonizes the effects of antihypertensives (e.g. β-blockers, ACEIs, ARBs, diuretics)

what is the OTC/herbal interactions of acetaminophen?

• increases the risk of hepatotoxicity
• 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 ATC acetaminophen

what are the OTC/herbal interactions of antacids?

• lowers the acidity of the stomach, which impairs absorption, 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 chelate with medications, decreasing concentrations of fluoroquinolones, tetracyclines, levodopa/carbidopa
• can avoid this effect with the use of sodium bicarbonate or with the appropriate separation of doses

what are the OTC/herbal interactions of iron supplements/multivitamins?

same issue of chelation of di/trivalent cations as antacids, which decreases concentrations of fluoroquinolones, tetracycliens, levodopa/carbidopa

what are the OTC/herbal interactions of PPIs?

suppresses the acidic environment of the GI, decreasing bioavailability and absorption of drugs requiring acidic media, such as itraconazole, ketoconazole, dapsone, atazanavir

what are the OTC/herbal interactions of H2-receptor antagonists?

• similar concept as PPIs, thus decreasing the absorption of drugs dependent on pH
• cimetidine inhibition of CYP450 enzymes can increase serum concentrations of various drugs, including warfarin, benzodiazepines, phenytoin, propranolol, theophylline, procainamide, erythromycin

what are the herb interactions and effects?

• ginseng: reduction of anticoagulant effect
• garlic, ginger, gingko bilobia: increased risk of bleeding
• st john's wort: decreased drug concentration, lethargy and nausea, reduction of anticoagulant effects, decreased drug concentration

what is rate of absorption?

• most common cause of interactions
• can be increased/decreased
• possible mechanisms: alterations in stomach pH and effects on the rate of gastric emptying
• such effects can be lowered by taking the drug 1 hr before or 2 hrs after a meal
• drugs that experience a decrease in the rate of absorption: penicillins, tetracyclines, erythromycin, levodopa, phenytoin, digoxin
• drugs which experience an increase in the rate of absorption: spironolactone, griseofulvin, itraconazole

how can food affect the extent of absorption of oral bisphosphonates?

• e.g. alendronate (fosamax), risedronate (actonel)
• 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 first 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

how can food affect chelation of drugs?

• by multivalent cations found in everyday foods: e.g. ice cream, milk
• be wary of calcium fortified food products like orange juice
• educate patients accordingly

how can vitamin B6 affect metabolism?

can increase the metabolism of levodopa

how can grapefruit juice affect metabolism?

• will inhibit CYP450 3A4 isoenzymes, decreasing the metabolism of many drugs, which will lead to an increase in serum concentrations of the drugs
• also affects the extent of absorption of various drugs by inhibiting PGP, in the gut wall, and also the organic anion transporting polypeptide

how can sodium affect lithium elimination?

increased by high sodium diets and decreased by low sodium diets

how can vitamin K affect warfarin?

• found in green leafy vegetables, soybeans, and green tea
• prevents and/or antagonizes the anticoagulant effect
• dietary consistency, not absent/present of vitamin K: key to maintaining stability in INR

what are the effects of 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 orthostatic hypotension when co-administered with antihypertensives (e.g., methyldopa and diuretics)
• disulfiram-like reactions can occur in certain drugs such as metronidazole and cefotetan
• chronic use with some antidiabetic agents can cause an increased risk of hypoglycemic events: e.g. sulfonylureas
• increased risk of GI bleeding with medications such as warfarin, aspirin, and NSAIDs

what are drug-smoking interactions?

• smoking causes the induction of CYP1A2 and CYP2E1, which can lower concentrations of drugs metabolized by these enzymes
• drugs include: theophylline, caffeine, haloperidol, propoxyphene, and propanolol
• abrupt discontinuation of smoking may increase concentration of these drugs: induction is due to polyaromatic hydrocarbons, not nicotine

what are drug-environment interactions?

• photosensitivity: 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

what are drug-disease interactions?

• altered mental states: narcotics, benzodiazepines, barbiturates, amphetamines, tricyclic antidepressants, H1 & H2 antagonists, anti-Parkinson agents, phenytoin, carbamazepine, digoxin, corticosteroids
• seizure disorders
• glaucoma: prolonged use of corticosteroids may induce glaucoma
• congestive heart failure
• hypertension can be worsened by various medications
• hypotension can further reduce blood pressure
• asthma, COPD
• diabetes: B-blockers may mask the signs and symptoms of hypoglycemia and corticosteroids cause increased hyperglycemia
• GI disorders
• urinary incontinence and retention
• renal dysfunction

what are red flag drugs?

commonly associated with:

• significant drug interactions
• adverse events that may result in morbidity and mortality
• require close monitoring due to narrow therapeutic windows

why are amiodarones red flag drugs?

• 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 and CYP450 system interactions
• serious symptomatic bradycardia has been reported with co-administration of ledipasvir/sofosbuvir

why are antiretrovirals/anti-HCVs red flag drugs?

• causes extensive CVP inhibition/induction effect
• inappropriate combinations of drugs can cause significant toxicity and resistant HIV
• NNRTI: delavirdine, efavirenz, nevirapine
• NRTI: didanosine, stavudine, zidovudine
• protease inhibitors: -navirs

why are azole antifungal agents red flag drugs?

• exhibit antifungal activity through the inhibition of fungal CYP450, but can also inhibit human CYP450, leading to potential interactions
• miconazole has such extensive inhibition that systemic use is not indicated

why are cancer chemotherapeutic/oncologic agents red flag drugs?

• may lead to serious and additive toxicities, very important to appropriately dose patients
• always check to see if premedication is necessary

why are HMG-CoA reductase inhibitors red flag drugs?

• statins
• mostly metabolized by CYP3A4 and CYP2C9, so interactions may occur with other substrates, inhibitors, and inducers: e.g. clarithromycin, erythromycin, grapefruit juice
• rhabdomyolysis: 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 rhabdomyolysis why are amiodarones red flag drugs

why are MAOs red flag drugs?

• coadministration with SSREs can cause serotonin syndrome

• coadministration with sympathomimetics can cause severe hypertension, hyperpyrexia, seizures, arrhythmias, and/or death

MAO-A:

• responsible for the breakdown of tyramine

• to avoid a hypertensive crisis, avoid foods containing high amounts of tyramine, such as various cheeses, chocolate, and aged meats

MAO-B:

• results mostly in breakdown of dopamine and phenylethylamine, but without the requirement of dietary restrictions

• selective inhibition is preferred whenever clinically possible

why are rifamycins red flag drugs?

potent CYP enzyme inducers and can cause interactions

why is st. john's wort a red flag for drugs?

• significant induction of CYP3A4 and some induction of CYP2C9
• may contribute to serotonin syndrome when used in conjunction with other antidepressants that increase serotonin, such as SSRIs
• may contribute to antiretroviral failure

what is drug selection?

• monitor for any CYP interactions, especially 3A4
• closely monitor ART, particularly protease inhibitors
• use caution when switching dosage forms because this may precipitate interactions
• exercise caution when using red flag drugs

what is patient specific prescribing?

• ask about smoking, alcohol use, diet, pregnancy, lactation
• consider comorbidities that may alter the drug's activity
• consider pharmacodynamic interactions between drugs used for similar therapeutic effects
• avoid polypharmacy

what is patient monitoring?

• 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