Drug Interactions Flashcards
1
Q
Body metabolizes drugs, to make them more polar, so that they are water soluble and capable of being eliminated out in the _________
A
urine
2
Q
Drugs need to be water soluble in order to have a high degree of ______
A
renal excretion
3
Q
Many drugs are Lipid-soluble (Non-polar, uncharged) and will need to be converted to a more ___________________________
A
water-soluble (polar, charged) compound in order to concentrate in the renal filtrate (urine)
4
Q
Phase I metabolism:
A
“Refers to the enzyme catalyzed transformation reactions that take place in the intestine and liver.”
-Oxidation reactions
- CYP450 enzymes
CYP3A4, CYP2C9/8, CYP2D6, CYP1A2, etc
5
Q
Phase II metabolism:
A
“Refers to the enzyme catalyzed transformation reactions that take place in the intestine and liver.”
-primarily involves Conjugation reactions, which further increases a compounds water-solubility.
-involves UGT enzymes
-involves- NAT enzymes
-other reaction types: acetylation
*Phase II metabolism only happens to a small percent of drugs.
6
Q
Ultra -rapid Metabolizer:
A
breaks down substrates/drugs ~2x as fast
7
Q
Poor Metabolizer:
A
lacks specific functional enzyme or enzymes
8
Q
CYP450 enzymes vary among individuals by:
A
ethnic race
9
Q
**With most drugs, INDUCERS make/activate _____________ which ______
A
more enzymes
decreases active drug
10
Q
**With Prodrugs, more enzyme due too an inducer will _________
** remember enzyme makes active drug** its opposite with prodrugs
A
make more active drug
11
Q
With most drugs, INHIBITORS ____________ enzymes, which will
A
inactivate
increase active drug
12
Q
**With Prodrugs, less enzyme due to an inhibitor will make _______
A
decrease active drug
13
Q
** remember Prodrugs are inactive, then once it is catalyzed by an enzyme becomes active.
A
14
Q
Prodrugs are used often to _____________
A
extend the dosing interval
15
Q
Valacyclovir is a prodrug to ______
A
acyclovir
16
Q
Vyvanse is a prodrug to ________
A
d-amphetamine
17
Q
Primidone is the Prodrug of ________
A
phenobarbital
18
Q
A
19
Q
Enzyme Inducers decrease the _________
A
concentration of the substrate drugs
20
Q
InDucers = Decreased levels/effects of substrate
” Decrease level of substrate unless the substrate is ______”
unless ______________
A
It is a Prodrug
21
Q
Some big drugs that are Inducers:
remember PS PORCS
A
Phenytoin
Smoking
Phenobarbital & Primidone
Oxcarbazepine
Rifampin/Rifabutin/Rifapentine
Carbamazepine
St. John’s Wort
22
Q
Dilantin, Infatabs, Phenytek
A
phenytoin
23
Q
Sezaby
A
phenobarbital
24
Q
Mysoline
A
primidone
25
Oxtellar XR, Trileptal
oxcarbazepine
26
Rifadin
rifampin
27
Mycobutin
rifabutin
28
Priftin
rifapentine
29
Epitol, Carbatrol, Equetro, Tegretol, Tegretol-XR
carbamazepine
30
Enzyme inhibitors _____________ the concentration of the drugs UNLESS it is a ___________
**remember**
G <3 PACMAN-----------------------(learn brand names)
Increase
Prodrug
Grapefruit
<3
Protease Inhibitors
Azole antifungals - fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole, isavuconazonium
Cyclosporine/Cobicistat/Cimetidine
Macrolides- clarithromycin, erythromycin BUT NOT azithromycin
Amiodarone & dronedarone
Non-DHP CCB- diltiazem, verapamil
31
Lag time for enzyme induction:
-induction most often requires additional enzyme production, which __________
- when an inducer is stopped, it could take _________
-takes time
-2-4 weeks for the induction effects to disappear completely, the excess enzymes will degrade based on their own half-lives.
32
(P-gp) P-Glycoprotein efflux pumps (transporters)
P-gp transports drugs and their metabolites ______________
OATP is another _________
out of the body by pumping them into the gut, where they can be excreted in the stool.
drug transporter.
33
When a drug blocks/inhibits P-gp, a drug that is a substrate for P-gp will have _____________ absorption (since less of the drug will be pumped into the gut) and the substrate drug level will __________
increased
increase
34
Common Drug classes that are Substrates for P-gp:
-
-
-
-
-
-Anticoagulants: (apixaban, rivaroxaban) edoxaban, dabigatran
-Cardiovascular drugs: (digoxin, diltiazem, verapamil) carvedilol, ranolazine)
- Immunosuppressants: (cyclosporine, tacrolimus), sirolimus
- HIV drugs: (dasabuvir, ombitasvir, paritaprevir, sofosbuvir
- Others: (colchicine) atazanavir, dolutegravir, posaconazole, raltegravir, saxagliptan
35
Common Drug Inhibitors of P-gp
-
-
-
-
-
-
-
- Anti-infectives: (clarithromycin, itraconazole, posaconazole)
- Cardiovascular drugs: (amiodarone, diltiazem, verapamil), carvedilol, dronedarone, conivaptan, quinidine
- HIV drugs: (cobicistat, ritonavir)
- HCV drugs (ledipasvir, paritaprevir)
-Others: (cyclosporine, fibanserin, ticagrelor)
36
Common Inducers of P-gp
-
-
-
-
-
- carbamazepine
- phenobarbital
- phenytoin
- rifampin
- St. John's wart
dexamethasone, tipranavir
37
There is no Such thing with Prodrugs and P-gp pumps.
38
Enterohepatic recycling:
After a drug has been metabolized, it can be transported through the __________ back to the gut.
From the gut, the drug can be reabsorbed again (primarily though the __________, where most drugs are absorbed) and then enter into the _____________ and travel back to the ________.
bile
small intestine
portal vein
liver
39
The recycling of an already metabolized drug is called _________, which increases the duration of action of many drugs.
ex: Zetia
enterohepatic recycling
40
P-gp inhibitor:
amiodarone
41
substrate for the P-gp enzyme
digoxin (Digitek, Digox, Lanoxin)
42
Drugs that interact with each other:
Amiodarone + Warfarin
-these agents can be used together for atrial fibrillation treatment:
amiodarone for rhythm control
warfarin to reduce clot risk
What is the risk?
If using amiodarone 1st and adding warfarin: ____________
If using warfarin 1st and adding amiodarone: ____________
- "Amiodarone inhibits multiple enzymes including CYP2C9, which is the enzyme that metabolizes the more potent warfarin isomer. This decreases warfarin metabolism and causes an increase in INR and increased bleeding risk"
- start warfarin at a lower dose of < or = to 5mg
-decrease warfarin dose by 30-50%, depending on the INR
43
Drugs that interact with each other:
Amiodarone + Digoxin
- these agents can be used together for atrial fibrillation treatment:
amiodarone for rhythm control
digoxin for rate control
What is the risk?
If adding amiodarone 1st and adding digoxin
if using digoxin 1st and adding amiodarone
When taking both amiodarone and digoxin:
-Amiodarone inhibits P-gp
Digoxin is a substrate for P-gp
So, the excretion of digoxin is decreased, which increases the ADR/toxicity risk profile. Amiodarone and digoxin both decrease HR & this increases risk for bradycardia, arrhythmia, fatality.
- start oral digoxin at a low dose, such as 0.125mg daily
- decrease oral digoxin dose 50% (change 0.25mg to 0.125mg daily or if patient taking 0.125mg daily then have them take 0.15mg every other day)
- instruct patient to monitor for symptoms of digoxin toxicity: nausea, vomiting, vision changes; if present contact provider
-Monitor HR; normal 60-100 BPM) can be lower based on patients' history and physical status. Check for other medications that lower HR: beta-blockers, clonidine, diltiazem, verapamil, dexmedetomidine.
- if digoxin is being used for rate control, inform prescribers to consider beta-blockers or non-DHP CCBs instead
44
Drugs that interact with each other:
Digoxin + Loop diuretic
- can be given together for heart failure treatment:
Digoxin for symptom improvement
Loop Diuretic to alleviate symptoms due to fluid overload
What is the risk?
When taking digoxin & a loop diuretic:
Loop diuretics decrease K, Mg, Ca, and Na.
Low K, Mg, or Ca will worsen arrhythmias.
**Digoxin toxicity risk is increased with low K and Mg levels and increased Ca levels.
Caution: Heart Failure & renal impairment often occur together. Digoxin is cleared by P-gp and excreted by the kidneys; renal impairment (which can be exacerbated by loop diuretics) increases digoxin levels and toxicity risk.
- monitor electrolytes and correct if abnormal
- renal impairment: decrease digoxin dose or frequency, or discontinue
45
Drugs that decrease Heart Rate
diltiazem/verapamil or beta blockers for Rate Control; clonidine and beta-blockers to lower blood pressure
what's the risk?
Actions to take;
Additive effects when drugs that decrease HR are used together, including amiodarone, digoxin, beta-blockers, clonidine, diltiazem, verapamil, and dexmedetomidine (Precedex).
Monitor HR: normal 60-100 BPM (can be lower, based on patients' history and physical state)
46
Drugs that interact with each other:
Statins + Strong CYP3A4 inhibitors
What is the risk?
Action to take:
Increased of CYP3A4 substrates: (lovastatin, simvastatin, atorvastatin).
Increased myopathy risk; if severe (with high CPK), can cause rhabdomyolysis with acute renal failure.
(Simvastatin & Lovastatin are Contraindicated with strong CYP3A4 inhibitors) recommend a statin that is not metabolized by CYP3A4 **pitavastatin, pravastatin, rosuvastatin. **
47
What are the STRONG CYP3A4 inhibitors?
*remember* G <3 PACMAN
Grapefruit juice
<3
Protease inhibitors: ritonavir, but many PIs are potent inhibitors.
Azole Antifungals: fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole, isavuconazonium
Cyclosporine & Cobicistat
Macrolides: clarithromycin & erythromycin
Amiodarone & dronedarone
Non-DHP CCBs: diltiazem & verapamil
48
Drugs that interact with each other:
warfarin + CYP2C9 inhibitors & CYP2C9 inducers
What is the risk with CYP2C9 inhibitors?
What is the risk with CYP2C9 inducers?
Action to take:
- increase levels of warfarin (increase INR AND increases bleeding risk) with CYP2C9 inhibitors
- decrease levels of warfarin (decreases INR AND increases clotting risk) with CYP2C9 inducers
- Monitor INR; therapeutic range is 2-3 for most conditions, (2.5-3.5 for some high-risk indications, such as mechanical mitral valve)
Some drugs (amiodarone) require prophylactic warfarin dose adjustment when started.
49
CYP2C9 inhibitors:
remember
** SAM TAG AEIOV ***
SULFAMETHOXAZOLE/trimethoprim,
AMIODARONE
METRONIDAOLE
Tamoxifen
Azole antifungals (etc FLUCONAZOLE, ketoconazole, voriconazole)
Gemfibrozil
Atazanavir
Efavirenz
Isoniazid
Oritavancin
Valproic acid
50
CYP2C9 inducers:
remember
**PS PORrCSa**
Phenytoin
Smoking
Phenobarbital, primidone
Oxcarbazepine
Rifampin, rifabutin, rifapentine, ritonavir
Carbamazepine
St. Johns wart, aprepitant
51
CYP3A4 inducers:
remember
PS PORCS
Phenytoin
Smoking
Phenobarbital, primidone
Oxcarbazepine
Rifampin, rifabutin, rifapentine,
Carbamazepine
St. Johns wart
52
CYP1A2 inducers:
remember
PS PORCS
Phenytoin
Smoking
Phenobarbital, Primidone
OOOoooooo
Rifampin, ritonavir
Carbamazepine
St. Johns Wart
53
which electrolytes when low cause the digoxin level to increase?
what are the normal ranges for these electrolytes?
K & Mg
54
which electrolytes when high, cause the digoxin level to increase?
what is the normal range for these electrolytes?
Ca
55
What are some important medications in each of the classes that are substrates for CYP3A4?
- Analgesics:
- Anticoagulants:
- Cardiovascular drugs:
- Immunosuppressants:
- Statins:
- Key HIV drugs:
- PDE-5 inhibitors:
-Others:
- Analgesics:
- Anticoagulants:
- Cardiovascular drugs:
- Immunosuppressants:
- Statins:
- Key HIV drugs:
- PDE-5 inhibitors:
-Others:
56
CYP2C19 inhibitors:
57
Which medications specifically include instructions NOT to take with grapefruit juice?
Amiodarone
Nifedipine
Tacrolimus
Simvastatin
Lovastatin
58
remember, inhibitors of a particular CYP, will increase substrate drug levels which are normally metabolized by that CYP, unless the drug is a Prodrug.
CYP3A4 inhibitors + CYP3A4 substrates (many)
- includes opioids, fentanyl, hydrocodone, oxycodone, methadone, hydrocodone, hydromorphone (major)
- With strong CYP3A4 inhibitors, there is a decrease in metabolism of CYP3A4 substrates, and this will cause an increase in drug levels and an increase in (ADR) Adverse Drug Reactions/toxicity.
- if an opioid is a substrate, sedation will increase, followed by respiratory depression, which can quickly cause fatality.
- Do Not use a CYP3A4 inhibitor with an opioid metabolized by CYP3A4
59
60
Drugs that interact with each other:
Valproate + Lamotrigine
What is the risk?
Action to take.
**Valproate is an inhibitor of Lamotrigine metabolism
- valproate decreases lamotrigine metabolism and this causes lamotrigine concentrations to increase, which causes increased risk of serious skin reactions, including SJS/TEN (can be fatal).
- initiate lamotrigine using starter kit that begins with lower lamotrigine doses. Titrate carefully every 2 weeks.
- Counsel patients to get emergency help if rash develops
61
CYP2D6 inhibitors
duloxetine/fluoxetine/paroxetine/fluvoxamine/amiodarone
62
Nexterone
amiodarone
63
Pacerone
amiodarone
64
Luvox
fluvoxamine
65
Drugs that interact with each other:
MAO inhibitors +
- drugs that increase (Epi) epinephrine, (NE) norepinephrine, (DA) dopamine
OR
- drugs that increase serotonin (5-HT)
What is the risk?
Action to take:
**remember** The MAO enzyme breaks down catecholamines Epi, NE, and DA. When an MAOI is used, it blocks the enzyme from carrying out catabolism of these catecholamines, which causes increased concentrations instead.
When additional drugs are added on that can increase levels in addition to an MAO inhibitor, there is an increased risk for certain adverse drug reactions.
- High Epi, NE, and DA can cause Hypertensive Crisis.
- High serotonin can cause Serotonin Syndrome.
- - Do Not use together. Use a 2-week washout period when switching between drugs with MAO inhibition or serotonergic properties (except with fluoxetine, wait 5 week!!!
66
List of agents that increase Epi, NE, DA:
SNRIs
TCAs
bupropion
levodopa
stimulants including amphetamines.
tyramine rich foods (foods have been aged, pickled, fermented or smoked, including aged cheeses, air dry meats, sauerkraut, some wines and beers)
67
Tyramine is metabolized by the Monoamine oxidase enzyme.
68
Drugs that increase serotonin:
SSRIs
SNRIs
TCAs
mirtazapine
trazodone
fentanyl
methadone
tramadol
buspirone
dextromethorphan (when taken in high doses as a drug od abuse)
lithium
St. John's wort
69
70
71
Drugs that are MAO inhibitors:
which are selective and which are nonselective?
isocarboxazid
phenelzine (Nardil)
tranylcypromine (Parnate)
rasagiline (Azilect)
selegiline (Emsam, Zelapar)
linezolid
methylene blue
72
Calcineurin inhibitors (CNIs)
drugs examples of this class include:
tacrolimus
cyclosporine
73
mTOR kinase inhibitors
drug examples of this class include:
sirolimus
everolimus
74
Drugs that interact with each other:
What is the risk?
75
Digoxin is a narrow therapeutic drug.
0.125mg is equal to how many ng?
125000ng
1mg = 1000000ng
76
1 grain is equal to how many mg?
77
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