EX2 Lecture 6 - Drug Interactions Flashcards
what are drug interactions
The modification of the effect of one drug by the prior accompanying administration of another drug
what things are at risk in drug interactions
Risking loss of therapeutic effect, toxicity, unexpected adverse effects, or incompatibility
effect can vary from ____
one person to another
what are risk factors of drug interactions?
Polypharmacy,
multiple prescribers,
multiple pharmacies,
genetic make up,
special populations (elderly, critically ill)
drug make up (a small therapeutic index, prodrug)
two or more drugs given together, create what
an alteration in effect
can be beneficial or harmful
carbidopa and levodopa interaction example
Carbidopa inhibits peripheral breakdown of levodopa, which means more levadopa crosses the blood brain barrier, giving additional and lengthened time and ability in the brain
warfarin drug interaction example
Metabolism of warfarin is increased by some antibiotics meaning the INR becomes reduced (blood is thicker, clots easier), and the drug provides inadequate anticoagulation
drug-dietary supplement interaction examples
prescriptions, OTCs, illicit substances
St johns worts and many drugs
cocaine and antihypertensive
what can drug-food or drink interaction cause? what are two examples?
-may cause interaction or prevent appropriate absorption
- doxyycline and milk
- metronidazole and alcohol ( get red in face, feeling very off)
drug-disease interaction examples
-some drugs are helpful in one disease but harmful in others
- some beta blockers and asthma
-NSAIDs and heart failure
what does A rated drug interaction severity mean (category, action, explanation)
category- unknown
action- no known interaction
explanation- no documentation of interaction
what does B rated drug interaction severity mean (category, action, explanation)
category- minor
action- no action needed
explanation- limited clinical side effects, may increase frequency or severity of side effects but generally does not require a major change in therapy
what does C rated drug interaction severity mean (category, action , explanation)
category- moderate
action- monitor therapy
explanation- may result in exacerbation of patients condition and/or require therapy alteration
what does D rated drug interaction severity mean (category, action, explanation)
category- major
action- consider therapy modification
explanation- may be life threatening and/or require medical intervention to minimize or prevent serious adverse effects
what does X rated drug interaction severity mean (category, action, explanation)
category- contraindicated
action- avoid combination
explanation- the drugs are contraindicated for concurrent use
pharmacodynamic drug interaction classification
-involves process or change of drugs
- interactions at receptor level
pharmacokinetic drug interaction classification
-involves motion of drug through body
- interactions drug moving through body
what are additive effects on same receptor (PD drug interaction) and an example drug and effect
- multiple agonists working on similar receptors = excessive effect
-multiple benzodiazepines (ativan, xanax)
-excessive sedation, breathing issues
what are additive effects on different receptors (PD drug interaction) and example drugs and effect
-different agonists work on different receptors with similar adverse effects (causing the same result)
-benzodiazepines and opiods
= excess respiratory depression
PD additive interactions causing increased bleeding risk
- anticoagulants (warfarin, DOACs)
- antiplatelets (clopidogrel, ticagrelor, prasugrel, aspirin)
- NSAIDs, SSRIs, SNRIs
- natural products (garlic, ginko, ginger, ginseng, glucosamine)
- all these have an increased risk of bleeding but excess when taken together
PD additive interactions causing anticholinergic toxicity, and what are the side effects of this
-antihistamines ( diphenhydramine)
- SSRIs, antipsychotics, tricylic antidepressants
- muscle relaxants (baclofen)
- overactive bladder antimuscarinics (oxybutynin)
- may not have side effect symptoms until given more than one of these together
side effects= dry mouth, dry eyes, urinary retention, constipation
PD additive interaction causing nephrotoxicity
-amnioglycosides, vancomyocin, amphotericin B
- NSAIDs
- IV loop diuretics
- chemotherapy (cisplatin, methotrexate) cyclosporine, tacrolimus
PD additive interaction causing QT prolongation examples
- antiarrythmitics- amiodarone, sotalol, dofetilide, ibutilide, procainamide, dronedarone
- antimicrobials- azoles, fluorquinoles, macrolides
-antipsychotics- haloperidol, quetiapine, ziprasidone
- antidepressants- SSRIs, SNRIs, TCAs
-methandone, sumatriptan, ondansetron
PD additive interactions of serotonergic agents examples
- mood-altering meds SSRIs, SNRIs, mirtazapine, trazadone, buspirone, TCAs, MAOi, lithium
- linezolid
-tramadol, methadone, meperidine - dextromethorphan
- antiemetics (ondansetron)
- triptans (sumatriptan)
PD additive interaction of hyperkalemia examples
- excess potassium
- ACE inhibitors, ARBs, sacubitril/valsartan
- K- sparing diuretics
- aldosterone antagonists
- sulfamethoxazole/ trimethoprim
- tacrolimus, cyclosporine
what are synergistic effects (PD interaction) and example
-effect of two drugs magnified beyond what would be expected
- aminoglycosides and penicillins
what are antagonist blocking agonist effects (PD interaction) and example
-antagonist blocks and prevents further activation of receptor
-naloxone for opioid overdose
Chelation, complex formation, disruption of PK Absorption with drug interactions
-antacids, multivitamins reduce availability of fluroquinolone, tetracycline
- cholestyramine binds warfarin, sulfamethoxazole in small intestine
change in PH disruption in PK absorption with drug interactions
- increasing pH of stomach (H2 antagonists, PPI, antacids) may decrease absorption of drugs that need acidic environments (itraconazole, ketoconazole)
increased motility time, disruption of PK absorption example
- metoclopramide increases gastric emptying, may reduce digoxin levels
4th way absorption (PK) is affecte din drug interaction without example ( and list the other three as well)
P- glycoprotien efflux pumps
( chelation- complex formation, change in pH, increased motility time)
PK Distribution effects from drug interactions
binding to alpha 1- acid glycoprotein and binding to albumin
binding to albumin example- PK distribution disruption
diclofenac has same affinity for albumin as warfarin
- displacement of warfarin, increasing plasma concentration
how is phase 1 metabolism affected in PK metabolism with drug interaction
-oxidation, reduction, hydrolysis for inactivation
- includes cytochrome P450 enzymes
how is phase 2 metabolism affected in PK metabolism with drug interaction
-glucuronidation, sulfation, methylation for elimination
how is competition for transport in PK elimination affected in drug interaction
-probenecid blocks penicillin renal excretion, increasing therapeutic levels
how is change in urinary pH in PK elimination affected in drug interaction
-bicarbonate alkalizes urine, increases methotrexate excretion
what are cytochrome (CYP) P450 enzymes and how many are identified and primary break down drugs
- hemeoproteins located in liver
- more than 50 identified, 6 primary break down drugs
small polymorphisms lead ______
changes in metabolism
- poor v extensive v ultrametabolizers
drugs can be ____
substrates, inducers, inhibitors
what are CYP inducers
-increase enzyme activity and metabolism
- often reduce amount of active drug available
- full effect may take days to weeks
— require new enzyme production
— washout period may be lengthened
SCRAP GPS’S
S- sulfonylureas
C- carbazaepine (anti seizure)
R- rifampin and rifabutin (antibiotic)
A- alchohol use (chronic)
P- phenoarbital (anti seizure)
G- griseofulvin
P- phenytoin (anti seizure)
S- smoking
S- st johns wort
what are CYP inhibitors
- reduce enzymnatic activity and metabolism
- often increase active drug availability (by inhibiting enzymes breakdown)
- effects noted quickly (prolonged breakdown-x prolonged drug effect- possible side effects quicker)
- can be used therapeutically - ritonavir, cobiccistat
PACMAN’S GM ( grandma -slow- inhibitors)
P- protease inhibitors (cancer)
A- amiodarone
C- cyclosporine, chlorophenol, cimetidine
M- macrolides (not azithromyocin) (antibiotics)
A-azoles (anti fungals)
N- non DHP calcium channel blockers
S- sodium valproate (anti seizure)
G- grapefruit juice
M- metronidazole
3A4 (enzyme) substrates
-analgesics ( buprenorphine, tramadol)
- anticoagulants (warfarin)
- antiplatelets (ticagelor)
- antidiabetics (saxigliptin)
- cardiovascular drugs (amiodorine)
- immunosuppressants (tacrolimus)
- statins (atorvastatin)
- HIV drugs (ritonavir)
-PDE-5 inhibitors (sildenafil)
-others (benzos, buspirone)
2C8/9 (enzyme) substrates
amiodarone, pioglitazone, carvedilol, alosetron, celecoxib, diazepam, glyburide, glipizide, glimepiride, phenytoin, warfarin, ramelteon, zolpidem
2C19 (enzyme) substrates
clopidogrel, phenytoin, voriconazole
2D6 (enzyme) substrates
- analgesics ( codeine, oxy)
- antidepressants/ antipsychotics ( doxepin)
- others ( carvedilol, tamoxifen)
key point: many drugs affected by _____ enzymes
CYP450 enzymes
a pt is taking fluconazole (for prophalaxis of AML) and developed MDD for which he was prescribed citalopram 40mg - what will occur with this reaction
fluconazole is a CYP inhibitor so it slows CYP enzyme so you dont get as much of the inactive metabolite fro citalopram - more citalopram available in the body - additive effect of QT prolongation
*prolonged QTc
a patient was in hospital due to STEMI, got two stents placed in cath lab and has sicne started aspirin and ticagrelor (to keep stent open). He also started OTC st johns wort 2 weeks before MI- what could the implications be
st johns wort is a cyp inducer - adds an extra enzyme so breaks drug down faster so there will be increased risk of thrombosis as the stent wont be able to stay as open
to monitor or to take action in drug interactions
important to consider implication of interaction
- if one is way higher priority and for known causes besst to keep that and discontinue others
-some cases not very clear
- consider each interaction and make clinical decision based on best judgement
pt has PMH of hypolipedemia (HDL) being treated with atorvastatin, he recently got a juicer and makes grapefruit juice - what are the possibel implications of this new habit
grapefruit juice is a cyp inhibitor so in is going to make metabolism slower
increased risk of muscle aches (side effect of statins)
increased atorvastatin levels
what percent of drugs are metabolized by non CYP enzymes? what kind of reaction is it?
33% of top 200 drugs
mainly by phase II elimination
two facts about non cyp p450 enzymes
drug interactions less common
isoniazid toxicity can occur through some pathways
3 examples of non cyp p450 enzymes
UDP- glucuronosyl transferase (UGT)
N- acytytransferase (NAT)
Monoamine oxidase (MAO)
where are P-glyxoprotein (PGP) Efflux pumps found and what is their role
found around the body
pump substrates to prevent activity (OAT efflux pumps)
p-glycoprotein efflux pump substrates
- anticoagulants ( apixaban, rivaroxaban, dabigatran)
- antineoplastics ( docetaxel, vincristine)
-immunosupressants (cyclosporin, tacrolimus) - macrolides (clarithromyocin)
-HIV drugs (dolutegravir)
-digoxin
p-glycoprotein efflux pump inducers
-st johns wort
- rifampin
- carbamazepine
- phenytoin
- phenobarbital
p-glycoprotein efflux pump inhibitors
- antibiotics (clarithromyocin, itraconazole, posaconazole)
- HIV drugs (cobicistat, ritonavir)
-cardio drugs ( verapamil, amiodarone, dronedarone, dilitiazem)
-cyclosporine, ticagrelor
67 YOF w PMH of T2DM, HTN, on metformin, lisinopril, verapamil recently developed Afib and was prescribed dabigatran
what is the risk associated with this drug interaction adn are there potential alternatives
dabigatran is an anticoagulant so there is an increased risk of bleeding due to the use of a p-gp inhibitor (veraprimil)
could switch and use different agents
what is a prodrug, what do they use to activate, what do they risk
- utilize CYP enzyme to activate drug
(first pass metabolism)
-can be used to increase bioavailability, avoid drug abuse - risk lack of activity or potential toxicity
what is first pass metabolism in prodrugs
converts mediation to pharmacologically active formulation (must occur to have an effect)
metabolite of codeine
morphine
Metabolite of clopidogrel
active metabolite
metabolite of lisdexamphetamine
dexamphetamine
metabolite of fosphenytoin
phenytoin
metabolite of enalapril
enalaprilat
metabolite of valacyclovir
acyclovir
metabolite of cortisone
cortisol
metabolite of prednisone
predisolone
metabolite of primidone
phenobarbital
metabolite of tramadol
active metabolite
metabolite of levadopa
dopamine
metabolite of diazepam
oxazepam
how is codeine converted to morphine
how does it affect UM and PM
converted via CYP2D6
UM- potential toxicity
PM (or patients taking CYP2D6 inhibitor)- lack of pain relief
how is clopidogrel converted to active metabolite
how does it affect PM
what can be used alternatively for PM
converted via CYP2C19
PM- reduced platelet inhibition( bc drug not getting activated); use alternative P2Y12 inhibitor
what are CYP2C19 inhibitors
reduce platelet inhibition; avoid combination with clopidogrel
omeprazole
esomeprazole
narrow therapeutic index drugs
aminoglycosides
vancomyocin
digoxin
warfarin
tacrolimus
mycophenolate
cyclosporine
phenytoin
valproic acid
carbamazepine
theopylline
lithium
levothyroxine
what is one of the most noted medications effected by drug interactions
warfarin
metabolic interactions with warfarin
-substrate of CYP 2C9
- CYP3A4, CYP1A2, CYP2C19 also play a role
vitamin K interactions of warfarin
-prescription meds
- OTC products
- foods
what drugs increase bleeding risk of warfarin
anticoagulants, antiplatelets
NSAIDs
SSRIs
what drugs increase metabolism interference of warfarin
ABCDEF
rifampin
what drugs have a reduced vitamin k production by gut flora when taken with warfarin
antibiotics
what drugs interrupt vitamin K cycle when taken with warfarin
acetaminophen (1.5-2.5 g chronically)
Common drugs that change warfarin metabolism from highest INR to lowest INR
A- amiodarone (highest INR-thinnest blood)
B- bactrim
C- cipro (and other FQ)
D- diflucan (and other azoles)
E- erythromyocin (and other macrolides)
F- flagyl
(all above inhibit warfarin breakdown, prolonging activity)
R- rifampin (only one that decreases INR- inducer- thicker blood)
effects of warfarin and amiodarone interaction (commonly seen)
decrease warfarin brekadown
increase bleeding
increase INR
if already on amiodarone and starting warfarin what shoudl you do to the dose
reduce starting dose of warfarin by 30-50%
if already on warfarin and starting amiodarone what should you do to the dose
reduce warfarin dose by about 50%
amiodarone and digoxin interaction
used to control rate and rhythm in patients with Afib
digoxin is a p-gp substrate and amiodarone is a p-gp inhibitor
gives a risk of digoxin toxicity, reduced HR, electrolyte abnormalities
if on amiodarone, used first, and starting digoxin, what should you do to the dose
start digoxin at a lower dose
if on digoxin, used first, and starting amiodarone what should you do to the dose
decrease digoxin dose by 50%
(so basically always decrease digoxin with amiodarone because amiodarone can prolong activity of digoxin)
what are carbamazepine and lamotrigine and what happens when used together
they are antiepileptics
carbamazepine is an enzyme inducer and lamotrigine is a substrate
used together you risk breakthrough seizures - start at a higher dose
what are lamotrigine and valproic acid and what happens when used together
lamotrigine is a substrate and valproic acid is an enzyme inhibitor
risk lamotrogine toxicity (serious skin reactions) - start at lower dose
(becasue you have extended exposure of lamotrigine due to inhibition of its breakdown)
pde-5 inhibitors (give examples) and nitrates (give examples) side effects when used together
pde-5 inhibitors like sildenafil and tadalafil
nitrates like nitroglycerin and isosorbide
cause excessive vasodilation and severe hypotension
concomitant use is CONTRAINDICATED
even PRN nitrates
when should you check for drug interactions
any new medications
any medications on list that give you red flags
any med on pt list with narrow TI
any new adverse effects that may be additive
clinical impact of drug interactions to consider
are there a lot of potential drug interactions
are they all clinically relevant (is someone drinking 15L of grapefruit juice to cause an interaction)
when do drug interactions require action ( based on clinical judgement)
