Valentovic- Drug Interactions - Leah :) Flashcards
What patients are predisposed to DD interactions? (5)
- multiple meds
- female (OCPs + CYP inducer–> ineffective)
- age extremes
- major organ/metabolic/ endocrine dysfxn
- genetic polymorphisms
3 examples of drugs that effect OCP efficacy?
- Rifampin, St. Johns Wart (CYP inducers–> less effective)
- Abx (alters gut flora)
Define pharmacokinetics + dynamics:
-pharmacokinetics= what body does to drug
-pharmacodynamics= what drug does to body
(Dynamic= D= “D”rug action on body)
Describe the difference between precipitant and object drugs:
- precipitant: effects body
(i. e. alcohol = more NAPQI production) - object drug: drug effected by initial modification
(i. e. acetaminophen)
What are three types of pharmacodynamic interactions?
- additive (alcohol + BDZ = ^^ resp depression)
- antagonistic (BDZ + flumazenil)
- synergistic (aminoglycoside + succinylcholine = ^^ resp depression during surgery)
How do aminoglycosides interact with succinylcholine in surgery?
How do you reverse these effects?
What kind of interaction is this?
This is an example of synergistic pharmacodynamic interaction:
-further increase respiratory depression
(presynaptic acetylcholine synthesis decreased by AGs)
-neostigmine can reverse these effects
-pharmacodynamic interaction
(precipitant = AG; object drug= succinylcholine)
What two types of interactions effect the absorption of a drug? How do we work around this?
-drug-drug
-drug-food
(altered pH, chelation, transport, metabolism)
-should stagger drugs or drugs/ meals
Ex: cholestyramine should be staggered with food
Antacids:
What can they contain?
What drug can they prevent from being absorbed?
- Ca, Mg, Al
- Complex with TCN –> tetracycline excreted in feces
Cholestyramine effects the absorption of what two drugs? Via what mechanism?
-digoxin
-warfarin
(forms complex)
Mycophenolate mofteil:
- MOA
- COMPLEXES with what drugs? (2)
-Immunosuppressant: Inosine monophosphate dehydrogenase (IMPDH) inhibitor
- ferrous sulfate/ iron 2+ containing vitamins and Ca, Mg, Al (antacids)
- NOT influenced by pH; don’t interact w/ bicarb*
How do drugs that decrease GI motility affect absorption? What drugs slow motility? (2)
- slow peak time, but not extent of absorption (bioavailability)
- morphine/ amitryptilline + other tricyclics
How do drugs that increase GI motility affect absorption?
What drug increases GI motility?***
- shorter peak time, but no change in extent of absorption
- metaclopromide
How do H2 antagonists (–idines) and PPis (–prazole) effect ketaconazole/ itraconazole absorption?
- INCREASE stomach pH –> decreased absorption and levels of ketaconazle/ itraconazole
In addition to azoles, what drug also has decreased bioavailability when taken with PPis?
-atazanavir (HIV protease inhibitor)
- ATP dependent transporters known as the “gatekeepers of metabolism” are called___?
- What specifically is their function?
- Where in the intestine are p glycoproteins found?
- P glycoproteins
- transport lipophilic substances out of the brain, liver, etc –> to bile, gut lumen, urine (excrete lipophilic substances)
- Enterocytes of small intestine
What 4 substances are known to inhibit P glycoproteins?
What drugs will be “object” drugs when taking a P glycoprotein inhibitor? What will be the effect?
- ketaconazole
- Erythro, clarithromycin
- Grapefruit juice
(Many CYP3A4 also = P glycoprotein inhibitors; may balance effects…)
-Drugs that are P glycoprotein substrates will be “object” drugs (i.e. cyclosporin) and have ^^^^ absorption
How is the efficacy of:
-OCPs
-digoxin
Changed when taking abx?
- OCP efficacy decreased
- Digoxin efficacy ^^ (^^^ blood levels due to ^^^ enterohepatic circulation when gut bacteria are killed)
Which drugs have drug-drug binding displacement interactions?
What happens to the “object” drug?
- drugs that are more than 90% protein bound can have drug-drug binding displacement interactions
- one of the two drugs will have a higher free fraction that normal (important when drug normally has a very SMALL free fraction)
***Example of a drug-drug binding displacement interaction
- Warfarin = 99% protein bound
- TMP-SMX displaces warfarin and can ^^ INR to 6 (normal is below 3)
Five drugs known to DECREASE/ INHIBIT
cyp450 activity?
KNOW THESE FOREVER
- ketaconazole (3A4)
- erythromycin (3A4)
- clarithromycin
- grape fruit juice
- cimetidine (ALL CYPs)
(INCREASE availability of drugs that are cyp 450 metabolites, i.e. warfarin)
Four drugs known to INCREASE CYP 450 acitvity?
Which cyps for each drug?
KNOW THESE FOREVER
- St Johns Wart
- Rifampin (3A4, 2C9, 2C19)
- Phenytoin (3A4)
- Carbamazepine (3A4)
(DECREASE availability of drugs that are cyp450 metabolites, i.e. warfarin)
CYP 1A2 is induced by ____/_____ and its substrate is____.
- cigarette smoke, phenobarbital
- theophylline
***You had phenytoin, and that might have been right but I am going off of the chart on slide 19; I might be misreading it or I might have missed this elsewhere in the notes.
How are opioids effected when combined with abs?
Which two antibiotics in particular will affect their metabolism?
Decreased clearance with erythromycin and clarithromycin = ^^ risk of oxycodone OD due to P450 inhibition
Which CYP metabolizes warfarin?
CYP3A4
There are no known inducers/ few inhibitors of CYP2D6, so why is it important?
- 33% drugs metabolized by this cyp
- Many POLYMORPHISMS: AA > whites > asians
How is CYP2D6 implicated in therapy with tamoxifen?
- Slow CYP2D6 metabolizers get less active metabolite formation = drug is not effective
- siX= tamoXifen
Clopidigrel metabolism is dependent on which CYP?
Population this should be considered in?
- 2C19; 2”C”19= “C”lopidigrel
- Less effective in slow metabolizers because drug requires formation of active metabolite
- 20% Asians are SLOW CYP2C19 metabolizers
Two ways renal elimination may be involved with DD interactions:
- altered tubular secretion
- altered tubular reabsorbtion
Give two examples of DD interactions in which the “object drug” has inadequate “renal secretion”.
- increase penicillin t1/2 by giving probenecid (probenecid more tightly binds secretion transporters= penicillin cant be secreted)
- Giving bactrim will ^^ methotrexate by the same mechanism
How does bactrim effect renal reabsorption of electrolytes?
-High dose bactrim (HIV) inhibits Na ATPase and sodium reabsorption at distal tubule–> HYPERkalemia
(Do not mistake for renal failure)
How can NSAIDs/ diuretics effect renal reabsorption of electrolytes and lithium?
Which diuretics are especially implicated?
-NSAIDs and diuretics (esp THIAZIDES) increase Na/Water reabsorption as well as LITHIUM reabsorption
NOTE: Uworld question- Thiazide + Lithium can = acute lithium toxicity (see tremor, ataxia —> coma)
What drug interaction occurs by inhibiting p-glycoprotein at the kidney?
-Quinidine blocks renal p glycoprotein —> ^^^ levels of digoxin
How does urine pH effect renal excretion of drugs?
- nonionized drugs all reabsorbed
- low pH = basic drugs ionized and excreted
- high pH= acidic drugs ionized and excreted
How does acetazolamine effect blood/urine pH and how do these changed effect excretion of quinidine/amphetamines?
- Acidifies blood (^^^ HCO3- excretion in PT)
- Alkalinize urine –> unionized quinidine + amphetamine–> ^^ reabsorption
How does acetazolamide effect levels of aspirin in the blood?
^^ HCO3 excretion–> ACIDIFICATION of blood–> ^^ aspirin toxicity–> ^^ unionized ASA freely crosses BBB
Which macrolides have a greater potential to interact with other drugs and why?
-erythromycin and clarithromycin are more likely than azithromycin to cause DDis because they are CYP inhib’s
Which H2 inhibitor is most likely to cause DDis? Least?
- cimetidine most (inhibits all CYPs)
- ranitidine least
Which statins are most likely to cause DDIs? Least?
- lovastatin and atorvastatin most likely (prodrugs)
- fluva, prava, rosuva least likely (not pro-drugs)
